August 23, 2018 from ObGynNews The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder […]
August 23, 2018 from ObGynNews
The management of bipolar disorder during pregnancy is a critical clinical situation demanding great attention to issues such as reproductive safety of psychiatric medications used by women with bipolar disorder to maintain emotional well-being, compared with the established risk of relapse if patients stopped those medications.
Treatment of bipolar disorder frequently includes mainstay treatment with mood stabilizers such as sodium valproate, lithium, lamotrigine, and second-generation atypical antipsychotics. While we have robust information regarding the reproductive safety of sodium valproate, it is a teratogen with a very high risk for neural tube defects. In contrast, data over the 15 years have been very supportive of the reproductive safety of lamotrigine. The last decade has seen growing use of second-generation antipsychotics, so-called atypical antipsychotics. There has been growing interest in the reproductive safety of these medicines given their use both for acute mania and for prophylaxis of bipolar disorder; they also are used as an adjunct to treat patients with major depression. Atypical antipsychotics are widely used off-label to treat obsessive compulsive disorder, other anxiety disorders, and a spectrum of psychiatric illness.
Until relatively recently, data on the reproductive safety of second-generation atypical antipsychotics has been relatively sparse, with the small number of prospective studies yielding a small total number of patients. Over the same period of time, the National Pregnancy Registry for Atypical Antipsychotics () at Massachusetts General Hospital (MGH) was established, modeled after the North American Antiepileptic Drug Registry as a prospective registry of women with histories of first trimester exposure to atypical antipsychotics.
Over the last several years, the MGH NPRAA has accumulated very rigorous, prospectively ascertained data on outcomes following first trimester exposure to the atypical antipsychotics. Given the high prevalence of the use of this class of medications in reproductive-age women, data on the reproductive safety of atypical antipsychotics has been anxiously awaited and also has been relatively reassuring based on sources such as the NPRAA and also analyses of data from large administrative databases. For example, a recent paper published in JAMA Psychiatry by KF Huybrechts and her colleagues of 1,360,101 pregnant women who were enrolled in the Medicaid Analytic Extractfound an adjusted relative risk of 1.05 for congenital malformations in births for patients exposed to atypical antipsychotics ( ).
Patients most often present with questions not about the reproductive safety of a class of medications, but about the safety of a particular medicine. A recent paper from our own group published in the American Journal of Psychiatry using data from the MGH NPRAA–described outcome of fetal exposure to quetiapine with a total of 152 women exposed to quetiapine and 205 unexposed patients. These patients were prospectively followed and compared with controls not exposed to the atypical antipsychotic but having a history of psychiatric morbidity. There was a 1.29% risk of major malformations in women exposed to quetiapine vs. 1.43% in the unexposed population ().
The positive features of the MGH NPRAA include the careful rigorous assessments of patients over time as well as review of their obstetric, neonatal, and pediatric records up to 6 months, with blinded adjudication of outcome. The limitation of the small sample size remains with findings including relatively wide confidence intervals. With that being said, included in the paper in the discussion section is a pooled analysis of prospective data regarding quetiapine from the world’s literature that supports the findings of even this small prospective study in our registry, namely flat risk or absence of data suggesting that quetiapine is a major teratogen (pooled risk ratio, 1.03; 95% confidence interval, 0.89-1.19).
The delineation of risk for atypical antipsychotics is an extremely important area of research from a clinical point of view because it may help inform choices made by women with bipolar disorder who are well and maintained on these medicines as they wrestle with risk of relapse when agents are discontinued on one hand and reproductive safety concerns on the other.
Although not as widely used as perhaps a decade ago, data on the reproductive safety of lithium only continue to grow and become more refined. Use of lithium, a known teratogen with studies dating back to the 1970s, has an increased risk for cardiovascular malformations with the classic reference being to the small heightened risk of Ebstein’s anomaly (0.05%-0.1%). More recent studies from large administrative databases have been published with new data regarding risk of fetal exposure to lithium.
Two recent studies on lithium help to clarify some lingering questions about lithium use during pregnancy and risk for cardiovascular malformations. In one study published in the New England Journal of Medicine, researchers have demonstrated a small increased risk for cardiac malformations associated with using lithium during the first trimester (). After researchers controlled for potential confounding factors, the adjusted risk ratio for cardiac malformations among infants exposed to lithium was 1.65 (95% CI, 1.02-2.68), compared with nonexposed infants. In a second study published in Lancet Psychiatry ( ), a primary data meta-analysis of pregnant women and their children from six international cohorts in Denmark, Sweden, and Canada, there was no significant difference in major cardiac malformations between the lithium-exposed group, 2.1% (0.5%-3.7%), and the reference group, 1.6% (1.0%-2.1%).
Women with particularly brittle bipolar disorder or with histories of response to lithium may, in consultation with their doctors, consider use of lithium during pregnancy given the almost 50-year history of data accumulation on its reproductive safety, compared with some of the other mood stabilizers for which there is either confirmed teratogenicity (sodium valproate) or still incomplete data. Moreover, given the high risk for postpartum relapse of mood disorder in women who suffer from bipolar disorder, it is important to remember that the most robust data on prophylactic benefit of mood stabilizer during the peripartum period are with lithium.
Reproductive age women with bipolar disorder have for decades been caught between a teratologic rock and a clinical hard place. More recent data that have emerged from rigorously conducted registries and carefully analyzed administrative databases allow for more effective collaboration between patient and doctor as together they make personal decisions that match individual clinical situations with personal wishes.
The task of referring women with PPD for treatment and then getting them well is a huge undertaking, and one where we currently are falling short. I have been heartened across the last decade to see the focus land on the issue of PPD screening, but failing to couple screening with evidence-based treatment is an incomplete victory. So with the next version of the app, we want to include treatment tools and a way to track women over time, looking at whether they were treated and if they got well.
We want clinicians to be aware of our app and to share it with their patients. But even more importantly, we want to reach out directly to women because they will lead the way on this effort.
The stakes for unrecognized and untreated PPD are simply too great for women, children, and their families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications.
July 5, 2017
The following post was first published in OB/GYN News. Please see our OB/GYN News archives here. Publish date: July 3, 2017 Over the last 2 decades, there has been a growing interest in establishing a rich […]
Publish date: July 3, 2017
Over the last 2 decades, there has been a growing interest in establishing a rich evidence base for treatment of psychiatric illness in pregnancy and the postpartum period. It seems as if a week does not go by when we don’t find multiple publications in the scientific literature describing a new finding or confirmation or inconsistency with existing data – whether it is a small prospective cohort study or an elegant analysis of a large administrative database. The goals of these reports center on refining our knowledge of safe treatments for perinatal psychiatric disorders.
Despite these strides, my colleagues and I frequently see a divergence between recommendations in the literature and what is done clinically by those who treat women around reproductive associated psychiatric disturbance – premenstrual dysphoric disorder or psychiatric disorder during pregnancy and the postpartum period. In some cases, scientific evidence has not filtered into day to day practice and some physicians continue to follow practices that, while outdated, make intuitive sense. In other clinical situations, limited evidence is being applied too broadly or data are too sparse to clearly inform practice. Regardless of the reason, we frequently see patients in clinical situations in which we are forced to rethink the clinical rationale for advice they have received or the clinical path taken.
Here is a sample of the clinical scenarios in which we have seen inconsistencies between current practice and the best evidence in perinatal psychiatry or situations in which data are too sparse to inform the clearest clinical path.
1. Discontinuation of antidepressants proximate to conception
Despite multiple studies supporting the high risk for relapse of major depression in women on maintenance antidepressant therapy with a history of recurrent depressive illness, it is still quite common for clinicians to routinely advise women to stop antidepressants while planning a pregnancy or after documentation of a pregnancy, regardless of the severity of the underlying illness. This runs counter to data showing high rates of relapse in women who stop antidepressants proximate to conception, the safety of antidepressants in pregnancy, and the harm to the mother and fetus when depression during pregnancy is untreated.
2. Use of a lower dose of antidepressants during pregnancy
It makes intuitive sense to use the smallest dose of medicine like antidepressant during pregnancy. However, multiple studies show that, at least in nonpregnant patients, the dose that gets patients well is typically the dose that keeps them well. One of the quickest paths to relapse in depression is a reduction in the antidepressant dose after someone has gotten well. This is even more relevant in pregnant patients because pregnancy itself dilutes the plasma level of the antidepressant given the rapidly expanding plasma volume seen in pregnancy. One can debate whether clinicians should empirically increase the dose of antidepressant during pregnancy to sustain plasma level of medication, but lowering the dose of this medication proximate or during pregnancy makes little sense.
3. A switch to sertraline in pregnancy/post partum
Another scenario that my colleagues and I often see is a pregnant patient whose depression was previously well controlled with a particular antidepressant, but whose physician, once she decides to conceive or becomes pregnant, switched her to sertraline.
The idea, which has been around for a long time, is that sertraline is the safest antidepressant for pregnant women because it has robust reproductive safety data and has particularly modest amounts of medication (if detected at all) in the plasma of infants of mothers who breastfeed while using the medicine. While we certainly have more safety data on SSRIs that were manufactured earlier, as compared with antidepressants that became available later, we have now accumulated data that fails to demonstrate a clear signal for teratogenicity across many antidepressants manufactured over the last 2 decades. Identifying an antidepressant for a given patient to which she will respond can be a challenging course for the patient. Achieving euthymia and subsequently switching to sertraline or another medication may only put her at risk for recurrence of depression and its attendant morbidity.
This is another example of switching a patient to a potentially less effective drug in a somewhat misguided effort at finding a treatment that is safer in pregnancy. While the Food and Drug Administration’s drug category label system was a step forward, or at least a well intentioned effort to give women and their clinicians clearer insight into the reproductive safety of a medication, ultimately, the incomplete nature of the information caused the agency to transition to a new system (see the Pregnancy Labeling and Lactation Rule). Switching a woman to a category B medicine with sparse reproductive safety data instead of a category C medicine, which may not be unsafe but has raised some concerns in animal models, is not a better choice. The new labeling system is a step forward.
5. Discontinuation of lithium during pregnancy
Like discontinuation of antidepressants, the discontinuation of lithium during attempts to conceive in a woman whose illness has been well controlled, is associated with a high risk of relapse. In earlier work, it was sometimes recommended that discontinuation of lithium be considered after a long period of wellness. We have learned over time that this can be a risky move. Even women with a remote history of bipolar disorder appear to be at high risk of relapse when a mood stabilizer is stopped. Exquisite response to medicine does not imply less severe illness. Women who have bipolar disorder who have sustained euthymia on lithium should consider maintaining the safest possible regimen before, during, and after pregnancy despite the known small teratogenic risk associated with fetal exposure to this agent.
6. Try supplements or alternative therapies
Out of a desire to avoid any medication with incomplete reproductive safety data, some women and clinicians make the intuitive leap that “alternative treatments” can mitigate relapse in pregnancy, and they stop pharmacological treatments and switch to supplements or alternative therapies, including acupuncture, massage, or light therapy. Unfortunately, data supporting this clinical maneuver are sparse. Frequently, we see women with past histories of severe depression who have stopped antidepressants and who have started supplements as a substitute and who then relapse. Then, they try to restore euthymia with antidepressants and psychotherapy, and the road to restoration of well-being can be long.
Data on efficacy of alternative therapies continues to evolve and is an exciting and important area of research. However, where these treatments are best employed in the algorithm for treating depression in pregnancy, or at other times, has yet to be adequately defined.
7. Stop breastfeeding or defer antidepressant treatment
Many women continue to be counseled to either stop breastfeeding while using antidepressants or to defer treatment with antidepressants if they wish to breastfeed. Not uncommonly, we see women who are suffering from postpartum depression and who are engaged in psychotherapy but who have deferred treatment with antidepressants despite residual depressive symptoms that impair functioning. Clinicians should keep in mind that data supporting evidence of toxicity in newborns of women using antidepressants while breastfeeding are extremely sparse. Unfortunately, some women with postpartum depression are deferring treatment because they were counseled that it is not compatible with their desire to breastfeed.
8. Use of non-benzodiazepine sedative-hypnotics
Insomnia is a common problem in pregnancy, especially when coupled with comorbid anxiety, and, increasingly, it is being treated with non-benzodiazepine sedative-hypnotics. Clinicians should keep in mind that a known small risk may be better than an unknown risk. If a pregnant woman has severe insomnia, she may benefit from a low dose of a benzodiazepine, such as lorazepam or clonazepam, as opposed to a medication such as zolpidem for which reproductive safety data are particularly limited.
9. Pumping and dumping breast milk
Many women are advised to set an alarm to “pump and dump” their breast milk to minimize their baby’s exposure to antidepressants during breastfeeding. Early literature to pump and dump breast milk at peak antidepressant concentration was of great analytic and theoretical interest but has scant clinical application. As an author of many of those early publications, I can say that we never intended for women to sacrifice precious sleep to dump breast milk with the idea that limiting exposure to trace amounts of antidepressants would have beneficial effects over the long term.
10. Failure to bring up contraception use
We continue to see a 50% unplanned pregnancy rate across sociodemographic groups in the United States. This is a critical statistic because it may affect how treatment is managed. Bringing up the topic of reliable contraception prior to pregnancy allows for planned pregnancy and affords us the time to discuss treatment options and the ability to plot a more thoughtful and safe clinical course. However, often, contraception is not discussed.
One of our goals as clinicians is to, first, do no harm and that continues to be a challenge because the data in perinatal psychiatry is still inconsistent in some areas and there are evidence gaps in others. Nevertheless, our task is to take the best available data along with the patient’s wishes and knowledge of her past clinical history and to then translate that into the best care for the individual.
Over the last decade, appreciation of the prevalence of perinatal depression – depression during pregnancy and/or the postpartum period – along with interest and willingness to diagnose and to treat these disorders across primary care, obstetric, and psychiatric clinical settings – has grown.
The passage of the Affordable Care Act in 2010 included the Melanie Blocker Stokes MOTHERS Act, which provides federal funding for programs to enhance awareness of postpartum depression and conduct research into its causes and treatment. At the same time, there has been increasing destigmatization associated with perinatal mood and anxiety disorders across many communities, and enhanced knowledge among clinicians and the public regarding evidence-based treatments, which mitigate suffering from untreated perinatal psychiatric illness.
There also has been a wave of interest around the country in establishing consistent screening for postpartum depression across a range of clinical settings. Approximately 40 states have instituted guidelines and recommendations regarding screening for postpartum depression. These positive developments, in part, follow recommendations from both the U.S. Preventive Services Task Force and the American College of Obstetricians and Gynecologists to move toward routine screening for depression, particularly among vulnerable populations such as pregnant and postpartum women. Both groups coupled their screening recommendations with a call for adequate systems to ensure treatment and follow-up but neither suggested how to implement it (, ).
The importance of identification of perinatal depression cannot be overestimated given the impact of untreated perinatal mood and anxiety disorders on women and families. Unfortunately, data describing the outcomes of these screening initiatives have been profoundly lacking.
There are many unanswered questions. What proportion of women get screened from state to state? What are the obstacles to screening across different sociodemographic populations? If screened, what proportion of women are referred for treatment and receive appropriate treatment? Of those who receive treatment, how many recover emotional well-being? These are all critically relevant questions and one has to wonder if they would be the same from other nonpsychiatric disease states. For example, would one screen for HIV or cervical cancer and not know the number of women who screened positive but failed to go on to receive referral or frank treatment?
This knowledge gap with respect to outcome of screening for perinatal depression was highlighted in one of the few studies that addresses this specific question. Published in 2016, the systematic review describes the so-called “perinatal depression treatment cascade” – the cumulative shortfalls in clinical recognition, initiation of treatment, adequacy of treatment, and treatment response among women with either depression during pregnancy or postpartum depression ().
The investigators included 32 studies where they were able to look specifically at this question of what happens to women who are identified as having either antenatal depression or postpartum depression. In total, six studies examined the rate of treatment of women who had been diagnosed with antenatal depression, resulting in a weighted mean treatment rate of 13.6%. For women identified as having postpartum depression, four studies examined showed a weighted mean treatment rate of 15.8%. What that means is that even if we have a sensitive and specific screening tool and we look only at women who have screened positive, we still have just 14% and 16% of women receiving treatment of any kind.
Drilling down to the issue of treatment adequacy – defined in the review as at least 6 weeks of daily use of antidepressants or at least 6 weeks of psychotherapy – the picture is unfortunately worse. Among the entire population of women with diagnosed antenatal depression, 8.6% received an adequate trial of treatment. Similarly, 6.3% of women with diagnosed postpartum depression received an adequate trial of treatment.
Continuing down the treatment cascade, remission rates also were extremely low. The overall weighted mean remission rate – reflecting the percentage of women who actually ended up getting well – was just 4.8% for women with antenatal depression and 3.2% for women with postpartum depression. These are striking, although perhaps not surprising, data. It suggests, at least in part, the fundamental absence of adequate referral networks and systems for follow-up for those women who suffer from perinatal depression.
It is well established that postpartum depression is the most common complication in modern obstetrics. The data presented in this paper suggest that most women identified with perinatal depressive illness are not getting well. Assuming a prevalence of 10% for antenatal depression and 13% for postpartum depression, there are about 657,000 women with antenatal depression and about 550,000 women with postpartum depression in the United States. If this review is correct, more than 31,000 women with antenatal depression and almost 18,000 women with postpartum depression achieved remission. That leaves more than 600,000 women with undermanaged depression in pregnancy and more than 500,000 women with incompletely treated postpartum depression.
Right now, we don’t even know for sure what obstacles exist to referral and treatment. Surveys of community clinicians suggest that collaborative care in managing reproductive-age women or pregnant and postpartum women has not evolved to the point where we have a clear, user-friendly system for getting patients referred and treated. In Massachusetts, where I practice, we have a state-funded effort () to train colleagues in obstetrics about how to identify and treat perinatal depression; perinatal psychiatrists also are available to consult with community-based clinicians. However, we do not have data to tell us if these efforts and the resources used to support them have yielded improvement in the overall symptom burden associated with perinatal mood disorders.
The bottom line is that even after identification of perinatal depression through screening programs, we still have women suffering in silence. It is so easy to get on the bandwagon regarding screening, but it seems even more challenging to design the systems that will accommodate the volume of women who are being identified. The fact that we do not have parallel efforts focusing on getting these women referred and treated, and a system to monitor improvement, conjures the image of setting off to sail without checking whether the boat is equipped with life preservers.
Publish date: November 1, 2016
Editor’s note: As Ob.Gyn. News celebrates its 50th anniversary, we wanted to know how far the medical community has come in identifying and mitigating drug risks during pregnancy and in the postpartum period. In this article, our four expert columnists share their experiences trying to find and interpret critical pregnancy data, as well as how they weigh the potential risks and benefits for their patients.
The search for information
The biggest advance in the past 50 years is the availability of information, even though limited, relating to the effects of drugs in pregnancy and lactation. In the first few years of this period, it was a daunting task to obtain this information. I can recall spending hours in the hospital’s medical library going through huge volumes of Index Medicus to obtain references that the library could order for me. The appearance of Thomas H. Shepard’s first edition (Catalog of Teratogenic Agents) in 1973 was a step forward and in 1977, O.P. Heinonen and colleagues’ book (Birth Defects and Drugs in Pregnancy) was helpful.
My first edition (Briggs et al., Drugs in Pregnancy and Lactation) came out in 1983 and was followed in 1993 by James L. Schardein’s book (Chemically Induced Birth Defects). In 2001, the first edition of the European book by Christof Schaefer et al. (Drugs During Pregnancy and Lactation) was released.
Although all of the above sources were helpful, any book in an evolving field will not have the newest information. Two important services, TERIS and Reprotox, were started to allow clinicians to contact them for up-to-date data. Nevertheless, the biggest change was the availability of current information from the U.S. National Library of Medicine via Toxnet, PubMed, and LactMed, relating to the effects of drugs in pregnancy and lactation.
The biggest unanswered question is why so many drugs have minimal, if any, human pregnancy and breastfeeding data? In my 11th edition (in press), about 1,443 drugs are reviewed. The majority have little or no human pregnancy data. The situation is even worse for breastfeeding data. In either situation, it places the clinician in a difficult position. How do we inform the patient regarding the potential embryo, fetal, or nursing infant risk? If the maternal benefit from the drug clearly outweighs the unknown risk, then the clinician can explain this to the patient. However, such situations appear to be infrequent and, in breastfeeding, the infant can be bottle fed. In contrast, in most pregnancy cases the comparison of the maternal benefit to the potential embryo/fetal risk is unknown. So what does the clinician do?
My method is to ask three questions. First, are there other drugs with a similar mechanism of action that have some human data? In most cases, the answer to this question is no, but even when there are data, it is typically very limited. Second, does the drug cross the human placenta? The answer is typically based on the molecular weight. Any drug with a molecular weight less than 1,000 daltons probably crosses. In the second half of pregnancy, especially in the third trimester, almost every drug crosses. Third, do the animal pregnancy data predict embryo/fetal risk? It was thought that it could if the dose causing harm was less than or equal to 10 times the human dose based on BSA or AUC and there were no signs of maternal toxicity. However, using data from my 10th edition, I and eight coauthors, all of whom are knowledgeable on the effects of drugs in pregnancy, found that the animal data for 311 drugs raised the possibility of human embryo-fetal harm that current data confirmed in only 75 (24%) of the drugs (Am J Obstet Gynecol. 2015 Dec;213:810-5).
Gerald G. Briggs
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He is coauthor of “Drugs in Pregnancy and Lactation,” and coeditor of “Diseases, Complications, and Drug Therapy in Obstetrics.” He has no relevant financial disclosures.
Learning the lessons of the past
During the last 50 years, two of the most potent known human teratogens, thalidomide and isotretinoin, became available for prescription in the United States. Thanks to the efforts of Frances Kelsey, MD, PhD, at the FDA, the initial application for approval of thalidomide in the United States was denied in the early 1960s. Subsequently, based on evidence from other countries where thalidomide was marketed that the drug can cause a pattern of serious birth defects, a very strict pregnancy prevention program was implemented when the drug was finally approved in the United States in 2006.
This has produced excellent results in terms of limiting the number of exposed pregnancies. In contrast, when isotretinoin was first approved in the United States in 1982, no pregnancy prevention program was in place. By the late 1980s, it was clear that the drug was linked with a pattern of serious birth defects in numerous infants. Successively more stringent pregnancy prevention/restricted distribution programs were implemented over the years, culminating with the current iPledge program. Despite these unprecedented measures, exposed pregnancies continue to occur and remain a challenge in terms of prevention.
Over the last 50 years, we have also seen an important evolution in our ability to conduct pregnancy exposure safety studies. Though we still have limited ability to conduct clinical trials in pregnant women, the need for good quality observational studies has become more widely accepted. The Centers for Disease Control and Prevention’s National Birth Defects Prevention Study (now in its most recent iteration known as BD STEPS) has been one very important source of data on the safety of a wide variety of medications. Using a case-control study design, women who have delivered infants with specific birth defects and comparison women who have delivered non-malformed infants are interviewed about their exposures in pregnancy. These data have been extremely helpful in generating new hypotheses, confirming or refuting findings from other studies, and in testing hypotheses regarding the safety of medications widely used in women of reproductive age. These analyses, for example, have contributed to the large body of literature now available on the safety of antidepressant medications in pregnancy.
At the same time, in the last 30 years, we have seen a tremendous increase in the number of pregnancy registries required or recommended upon approval of a new drug in the United States. These registry studies, while challenging to complete in a timely manner, have steadily improved in terms of rigor, and several disease-based pregnancy exposure studies have been implemented, which have allowed us to better understand the comparative risks or safety of anticonvulsants and antiretroviral drugs, to name a few.
It is important to note that with all these advances in the last 50 years, we still have a huge gap in knowledge about medication safety in pregnancy and lactation. Recent reviews suggest that more than 80% of drugs currently marketed have insufficient or no data available. If we include over-the-counter medications, the knowledge gap grows larger. With the 2014 approval of the long-awaited Pregnancy and Lactation Labeling Rule, clinicians are now beginning to experience the elimination of the old A-B-C-D-X category system for pregnancy safety. In its place, data-driven product labels are required. These are expected to provide the clinician with a clear summary of the relevant studies for a given medication, and to place these in the context of the background risks for the underlying maternal disease being treated, as well as the population risks. However, it is painfully clear that we have a long way to go to generate the needed, high-quality data, to populate those labels.
Dr. Chambers is a professor of pediatrics and director of clinical research at Rady Children’s Hospital, San Diego, and associate director of the Clinical and Translational Research Institute at the University of California, San Diego. She is director of MotherToBaby California, a past president of the Organization of Teratology Information Specialists, and past president of the Teratology Society. She has no relevant financial disclosures.
Moving toward personalized medicine
Nowhere is a lack of actionable data more pronounced than in the impact of mental health drugs in pregnancy.
As Dr. Briggs and Dr. Chambers have outlined, the quality of data regarding the reproductive safety of medications across the therapeutic spectrum has historically been fair at best. The methodology and the rigor has been sparse and to a large extent, in psychiatry, we were only able to look for signals of concern. Prior to the late 1980s and early 1990s, there was little to guide clinicians on the safety of even very commonly used psychiatric medications during pregnancy. The health implications for women of reproductive age are extraordinary and yet that urgency was not matched by the level of investigation until more recently.
The last 25 years, however, has brought a commitment to the systematic study of reproductive safety. From cohort studies, to large analyses of administrative databases and global registries, we’re now able to look at what medications women took during pregnancy and study the specific outcomes. These studies don’t provide complete information, but the dedication to and the identification of reproductive safety as a major public health issue for women is a huge advance.
In psychiatry, we have rapidly improving data informing women about the risk for major congenital malformations. The clinical dilemma of weighing the necessity to stay on a medication to prevent relapse of a psychiatric disorder with the potential risk of malformation in the fetus is a wrenching one for the mother-to-be. Only good information can help patients, together with their physician, make collaborative decisions that make sense for them. Given the same information and the same severity of illness, women will make different decisions, and that’s a good thing. The calculus couples use to make these private decisions is unique to those involved. But they are able to move through the process because they have a platform of high-quality information.
So where do we go in the future? We need to get beyond the question of risk of major malformations and move toward understanding the long-term neurodevelopmental implications of prenatal exposures – whether such exposures confer risk or are even potentially salutary. One needs only look at the vast body of literature regarding fetal exposure to selective serotonin reuptake inhibitors (SSRIs) to observe the realization of this trend. When it comes to SSRIs, a fairly clear picture has emerged that they pose little absolute risk in terms of congenital malformations. What is missing is how SSRIs impact a child’s learning and development at age 3, 5, and 10. There have been a few studies in this area, but not a single, large prospective study that accurately quantifies both exposure to SSRIs and maternal psychiatric illness during pregnancy.
I expect that the future will also bring a greater understanding of the impact of untreated mental illness on the risk for obstetrical, neonatal, and longer-term neurodevelopmental outcomes. Most of the safety concerns have centered around the effect of fetal exposure to medications, but we also need to better understand how untreated psychiatric disorders impact the spectrum of relevant outcomes.
Getting back to the dilemma faced by pregnant women who really need medication to sustain emotional well-being, there simply is no perfect answer. No decision is perfect or risk free. What we can hope is that we’ll have personalized approaches that take into account the best available data and the patient’s individual situation and wishes. We’ve already come a long way toward meeting that goal, and I’m optimistic about where we’re going.
Perception of risk
Every year, numerous new medicines are approved by the FDA without data in pregnancy. Animal studies may show a problem that doesn’t appear in humans, or as was the case with thalidomide, the problem may not be apparent in animals and show up later in humans. There are many drugs that are safe in pregnancy, but women are understandably afraid of the potential impact on fetal development.
While my colleagues have presented the advances we’ve made in understanding the actual risks of medications during the prenatal period, it’s also important to focus on the perception of risk and to recognize that the reality and the perception can be vastly different.
I started to look at this area in 1989, just a few years after starting the Motherisk Program. We discovered that women exposed to nonteratogenic drugs were assigning a 25% likelihood of having a malformed child, when the actual risk for those drugs was between 1% and 3% and is unrelated to the drug being taken.
At the same time, we began to ask women, using a visual analog scale, what would be their trend toward continuing or terminating pregnancy? Over several studies, we found that the likelihood of termination was high, and certainly much higher than was supported by the evidence of actual harm to the fetus. Specifically, if a woman received information about the safety of the drug and she still gave more than a 50% probability of terminating the pregnancy when surveyed, there was a good chance that she would terminate the pregnancy.
When you consider that most of the drugs that women are commonly prescribed in pregnancy – from most painkillers to antidepressants – are not known to cause malformations in pregnancy, you begin to see how problematic an inflated perception of risk can become.
But we see different trends in women with serious and chronic health problems, such as lupus or epilepsy. These women are typically under the care of a subspecialist, who in many cases has developed a significant knowledge base and comfort level around prescribing the drugs in this area and is able to communicate more clearly to patients both the risks to the fetus and the consequences of failure to treat their condition.
So clearly, the role of the physician and the ob.gyn. in particular is critical. It’s no secret that physicians face a negative legal climate that encourages defensive medicine and that they are often hesitant to tell women, without reservation, that it is okay to take a drug. But we must all remember that it is very easy to cause a woman not to take a medication in pregnancy and often that’s not what’s best for her health. Many women now postpone the age of starting a family and more have chronic conditions that require treatment. The idea of not treating certain conditions for the length of a pregnancy is not always a viable option. Yet there are quite a few women who would consider termination “just to be on the safe side.” That must be taken very seriously by the medical profession.
Specifically, this was a placebo-controlled, double-blind randomized trial for 21 women who had severe depressive symptoms with a baseline score of at least 26 on the Hamilton Rating Scale for Depression (HAM-D). For some of the women, postpartum depression was not of new onset, but rather was an extension of depression that had manifested no earlier than the third trimester of pregnancy. A total of 10 women received the drug, while 11 received placebo. Both groups received continuous intravenous infusion over a 60-hour period.
Consistent with the earlier report, participants receiving the active agent had a statistically significant reduction in HAM-D scores at 24 hours, compared with women who received the placebo. Seven out of 10 women who received the active drug achieved remission from depression at 60 hours, compared with only 1 of the 11 patients who received placebo. Even though the results derived from an extremely small sample, the signal for efficacy appears promising.
Of particular interest, there appeared to be a duration of benefit at 30 days’ follow-up. The medicine was well tolerated with no discontinuations due to adverse events, which were most commonly dizziness, sedation, or somnolence. The adverse events were about the same in both the drug and placebo groups.
These early results have generated excitement, if not a “buzz,” in the field, given the rapid onset of antidepressant benefit and the apparent duration of the effect. But readers should be mindful that to date, the findings have not been peer reviewed and are available only through a company-issued press release. It is also noteworthy that on clinicaltrials.gov, the projected enrollment was 32, but 21 women enrolled. This may speak to the great difficulty in enrolling the sample and may ultimately reflect on the generalizability of the findings.
One significant challenge with SAGE-547 is the formulation. It’s hardly feasible for severely ill postpartum women to come to the hospital for 60 hours of treatment. The manufacturer will have to produce a reformulated compound that is able to sustain the efficacy signaled in this proof of concept study.
But even more importantly, we will need to see how the drug performs in a larger, rigorous phase IIB or phase III study to know if the signal of promise really translates into a potential viable treatment option for women with severe postpartum depression. When we have results from a randomized controlled trial with a substantially larger number of patients, then we’ll know whether the excitement is justified. It would be a significant advance for the field if this were to be the case.
The field of depression, in general, has been seeking an effective, rapid treatment for some time, and the role of neurosteriods has been spoken about for more than 2 decades. If postpartum women are in fact a subgroup who respond to this class of agents, then that would be an example of truly personalized medicine. But we won’t know that until the manufacturer does an appropriate large trial, which could take 2-4 years.
As more U.S. states, along with other countries around the world, have begun routine screening of women in the perinatal period, it’s become clear that screening itself is easy to do. What has yet to be adequately demonstrated is how screening moves us toward getting women into treatment and ultimately toward getting women well.
New Jersey and Illinois are good examples of states that should be applauded for recognizing early on how important it is to identify women with perinatal depression. But even in these early-adopter states, the actual implementation of referral systems has been lacking.
Here in Massachusetts, we have a state-funded program designed to teach local women’s health providers – including ob.gyns. – about diagnosing perinatal depression. The MCPAP (Massachusetts Child Psychiatry Access Project) for Moms program also offers resources for consultation and referral. The program is fairly new, so it’s still unclear whether ob.gyns. and primary care physicians will accept the role of de facto mental health treaters, as well as whether the women who are identified through screening will go on to recover acutely and, more importantly, over the long term.
These experiences among the states highlight how great a challenge it is to go from screening to positive health outcomes for women.
A lack of evidence isn’t the only problem. A recent editorial in the Lancet raised the concern that the currently available screening tests are not suitable for clinical practice. The suggestion read to some like heresy.
The Edinburgh Postnatal Depression Scale, which is the most commonly used screening instrument, has a positive predictive value of detecting major depressive disorder of 47%-64%, according to the editorial, making it prone to delivering false positives (doi: 10.1016/S0140-673600265-8).
“This situation is potentially dangerous,” the Lancet editorial noted, since results of qualitative studies “suggest that women are extremely concerned about depression screening, about the stigma associated with a diagnosis of depression, and that a positive result might lead to an automatic social service referral, and potentially removal of their baby.”
A recent article, published in the New York Times, raises an additional concern about what a depression diagnosis could mean for insurability. The article highlights the experience of a woman whose diagnosis of postpartum depression is creating difficulties for her in getting life insurance. The point is underscored that it is perfectly legal for life and disability insurers to charge more to patients with a diagnosis of mental illness or to deny coverage outright.
NO GOING BACK
The whole issue of perinatal depression screening has opened a Pandora’s box, and that is a good thing. The conversation is long overdue in America. It is time for greater national awareness and focus on a disease that is as prevalent as perinatal depression and as disabling for women and their families.
The focus up to this point has been on perinatal depression screening, but we’re about to see a shift toward building the community infrastructure that will be critical for managing patients, including those women who have previously been marginalized and have had very poor access to care.
Widespread screening and treatment will also require a level of cooperation between advocacy groups and providers who are multidisciplinary in their approach, taking advantage of both pharmacologic and nonpharmacologic approaches. A model of crossdisciplinary collaboration will include, for example, providers from psychiatrists to therapists to doulas to social workers to clinicians who focus on mother-infant interaction. It is a long list and models for such collaboration are somewhat lacking.
One good example of a pilot effort for such a collaboration is the Massachusetts Postpartum Depression Commission, which includes a full spectrum of participants from doulas, social workers, and perinatal psychiatrists to lay people. The partnerships and the networking that’s going on across disciplines is absolutely new and is going to be essential if we’re going to manage an issue as large as the treatment of perinatal depression.
The enhanced awareness of the need to screen for, identify, and treat postpartum depression will also lead to better tools with greater specificity, perhaps using new technologies for better identification and treatment, everything from telemedicine to smartphone applications.
There will certainly be growing pains as we gather evidence, refine our screening instruments, and build referral systems, but I don’t see this as a reason not to identify illness in this vulnerable population. Rather, it is a charge to the field that there is work to be done.
But women and their partners are worried about more than the risk of malformations. They also are concerned about how fetal exposure to SSRIs will impact long-term neurobehavioral sequelae. It turns out that is a much more challenging question, and the data available to inform our answers still are relatively sparse.
There have been several reports in the literature that suggest there are modest effects on motor function in children whose mothers used SSRIs during pregnancy, but these reports have not been particularly systematic and have excluded some relevant variables, such as the presence or absence of a psychiatric disorder during pregnancy.
In what is considered a seminal examination of this topic performed more than a decade ago, Dr. Irena Nulman and her colleagues at the Motherisk program in Toronto demonstrated the importance of accounting for postpartum maternal depression and mood. Among a group of children exposed to fluoxetine (Prozac) or tricyclic antidepressants throughout pregnancy, there were no differences in IQ or language development, compared with unexposed children between 15 and 71 months of age. However, children with lower cognitive and language achievement were more likely to have mothers with higher ratings of postpartum mood disturbance (Am J Psychiatry. 2002 Nov;159:1889-95.).
The charge to the field is to tackle this next clinical research frontier: the longer-term effects of fetal exposure to antidepressants and maternal psychiatric illness. Only by factoring in both of these important variables will we be able to get a true model of risk for this very critical issue of longer-term behavioral function.
Recently, researchers attempted to look at this question using data from the Norwegian Mother and Child Cohort study, a large population-based, prospective pregnancy cohort study. Children were assessed at age 3 years and motor development was assessed by maternal reports of fine and gross motor development using items from the Ages and Stages Questionnaire (ASQ). Maternal ASQ scores were compared with data from another Norwegian study in which clinicians assessed motor development using the gross and fine motor Mullen Scales of Early Learning (MSEL).
The strength of the study is that it included a very large number of children – more than 50,000 – although it is noteworthy that only a small percentage of women actually used SSRIs during pregnancy. A total of 381 women reported the use of SSRIs during pregnancy, with about half of the women reporting prolonged use (defined as exposure at two points of observation in the study).
The findings are noteworthy. The study showed that children with prolonged SSRI exposure were more likely to exhibit delays in fine motor development, compared with children with no fetal exposure to SSRIs (odds ratio, 1.42; 95% confidence interval, 1.07-1.87). The association persisted even after adjusting for symptoms of anxiety and depression before and during pregnancy. The severity of maternal depression provided only a partial explanation for the association, and depression after pregnancy appeared to have no impact on the estimated effect of SSRIs during pregnancy (BJOG. 2015 Sep 15. doi: 10.1111/1471-0528.13582).
So how does the clinician translate these findings into practice? While the study indicates that prolonged prenatal exposure to SSRIs was associated with delayed motor development at age 3 years, the association was very weak, and only a few children had clinically significant impairment in motor development. The finding should be reassuring to many women who are faced with this decision.
The researchers should be commended for trying to at least begin to tackle this critical frontier with respect to the risk-benefit decision in using these medicines during pregnancy. The problem is that in the absence of robust data quantifying the exposure to maternal psychiatric illness, the quality of the data still is somewhat limited.
So far the data indicate that there is not a major signal for neurobehavioral dysregulation associated with fetal exposure to SSRIs. That being said, to adequately answer the question for the field it will be important to conduct a single, prospective study where we can accurately quantify exposure to medicine and exposure to maternal psychiatric illness during pregnancy. That type of study will allow us to assess the relative exposures and come up with a much more refined risk estimate. We also will be able to fold in a critical piece – the role of genomics.
Genomics will play a significant role in determining risk because vulnerability to potential disruption in central nervous system development may be a factor in determining the development of the brain in utero. We know, for example, that prenatal stress affects neuromodulation in the brain, and that vulnerability to disruption will be variable from patient to patient. Prospective studies where we not only quantify what medicines women are taking and the severity of psychiatric illness, but also vulnerability to central nervous system disruption, if any, at the level of the genome will be a critical missing piece for future investigators.
Even similar exposure to medicine and psychiatric disorders may have variable effects on the developing brain. If we can identify that variability at the level of the genome, then we will be able to create a refined model of risk that will dictate personalized medicine with respect to reproductive psychopharmacology.
The American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice recently published a revised opinion on screening for perinatal depression, recommending that “clinicians screen patients at least once during the perinatal period for […]
The American College of Obstetricians and Gynecologists (ACOG) Committee on Obstetric Practice recently published a revised opinion on screening for perinatal depression, recommending that “clinicians screen patients at least once during the perinatal period for depression and anxiety symptoms using a standard, validated tool.” The statement adds that “women with current depression or anxiety, a history of perinatal mood disorders, or risk factors for perinatal mood disorders warrant particularly close monitoring, evaluation, and assessment.” A list of validated depression screening tools is included (Obstet. Gynecol. 2015;125:1268-71). In previous iterations, the committee had not recommended formal screening for perinatal depression (referred to as major or minor depressive episodes occurring during pregnancy or during the first 12 months after delivery) and left the utility of screening as an open question to the field.
Noting that screening alone cannot improve clinical outcomes, the ACOG opinion says that it “must be coupled with appropriate follow-up and treatment when indicated,” and – most critically – adds that clinical staff in the practice “should be prepared to initiate medical therapy, refer patients to appropriate health resources when indicated, or both.” The latter recommendation is followed by the statement that “systems should be in place to ensure follow-up for diagnosis and treatment.”
Many states have initiated programs for screening for perinatal depression, which is intuitive given the prevalence of mood and anxiety disorders in women of reproductive age. Unfortunately, to date, there are no data indicating whether screening results in improved outcomes, or what type of treatment women receive as a result of screening; the ACOG opinion notes that definitive evidence on the benefit of screening is “limited.”
In prevalence studies, maternal morbidity associated with untreated perinatal mood and anxiety disorders clearly exceeds the morbidity associated with hemorrhage and pregnancy-induced hypertension, with significant effects on families and children as well. Therefore, even in the absence of an evidence base, there is support for routine screening and for ob.gyns. to initiate treatment and to facilitate referrals to appropriate settings.
In Massachusetts, where I practice, screening is not mandatory but is becoming increasingly popular, and resources to manage those with positive screening results are being developed.
The MCPAP (Massachusetts Child Psychiatry Access Project) for Moms was established to enhance screening for perinatal depression and to provide screening and educational tools, as well as free telephone backup, consultation, and referral service for ob.gyn. practices. MCPAP for Moms is coupled with an extensive community-based perinatal mood and anxiety service network: mental health providers, including social workers; specialized nurses with expertise in perinatal mental health; and support groups for women suffering from perinatal mood and anxiety disorders. The program is new and has promise, although evidence supporting its effectiveness is not yet available.
Some argue that screening and treatment of perinatal depression by nonpsychiatric providers opens up a “Pandora’s box.” But should the box be opened nonetheless?
Obvious problems might include many women with positive screening results not being referred for appropriate treatment or, if referred, receiving incomplete treatment – all very valid concerns. But one could also argue that with a highly prevalent illness that presents during a discrete period of time, the opportunity to screen in the obstetric setting (or in the pediatric setting, a separate topic) is an opportunity to at least help mitigate some of the suffering associated with perinatal depression.
The clinician in the community who will screen these women will need to manage the substantial responsibility of initiating treatment for patients with perinatal depression or referring them for management. The main question following diagnosis of perinatal depression is really not necessarily how “best” to treat a patient with perinatal depression. An evidence base exists supporting efficacy for treatments, including medication and certain psychotherapies. Perhaps the greatest pitfall inherent in an opinion like the one from ACOG relates to the incomplete infrastructure and associated resources in many parts of the country – and in our health care system – needed to accommodate and effectively manage the increasing number of women who will be diagnosed with perinatal mood and anxiety disorders as a consequence of more widespread screening.
Whether community-based OB/GYNs will be comfortable with direct treatment of perinatal psychiatric illness or the extent to which they view this as part of their clinical responsibility remains to be seen. It is possible that they will follow suit, just as primary care physicians became increasingly comfortable prescribing antidepressants in the early 1990s as easy and safe antidepressant treatments became available, particularly for patients with relatively straightforward major depression.
This committee opinion is an incremental advance, compared with previous opinions, and most critically, puts the conversation back on the national scene at an important time, as population health management is becoming an increasingly proximate reality.
The opinion leaves many unanswered questions regarding implementation on a national level, which may be beyond the scope of the committee’s task. But the recommendations, if carried out, will increase the likelihood of mitigating at least some of the substantial suffering associated with a highly prevalent illness.
As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses […]
As reviewed in a previous column, in December 2014, the Food and Drug Administration released the Pregnancy and Lactation Labeling Rule (PLLR), which will go into effect on June 30, 2015. This replaces and addresses the limitations of the system that has been in place for more than 30 years, which ascribed a pregnancy risk category of A,B,C,D, or X to drugs, with the purpose of informing the clinician and patient about the reproductive safety of medications during pregnancy. Though well intentioned, criticisms of this system have been abundant.
The system certainly simplified the interaction between physicians and patients, who presumably would be reassured that the risk of a certain medicine had been quantified by a regulatory body and therefore could be used as a basis for making a decision about whether or not to take a medicine during pregnancy. While the purpose of the labeling system was to provide some overarching guidance about available reproductive safety information of a medicine, it was ultimately used by clinicians and patients either to somehow garner reassurance about a medicine, or to heighten concern about a medicine.
From the outset, the system could not take into account the accruing reproductive safety information regarding compounds across therapeutic categories, and as a result, the risk category could be inadvertently reassuring or even misleading to patients with respect to medicines they might decide to stop or to continue.
With the older labeling system, some medicines are in the same category, despite very different amounts of reproductive safety information available on the drugs. In the 1990s, there were more reproductive safety data available on certain selective serotonin reuptake inhibitors (SSRIs), compared with others, but now the amount of such data available across SSRIs is fairly consistent. Yet SSRI labels have not been updated with the abundance of new reproductive safety information that has become available.
Almost 10 years ago, paroxetine (Paxil) was switched from a category C to D, when first-trimester exposure was linked to an increased risk of birth defects, particularly heart defects. But it was not switched back to category C when data became available that did not support that level of concern. Because of some of its side effects, paroxetine may not be considered by many to be a first-line treatment for major depression, but it certainly would not be absolutely contraindicated during pregnancy as might be presumed by the assignment of a category D label.
Lithium and sodium valproate provide another example of the limitations of the old system, which will be addressed in the new system. While the teratogenicity of both agents has been well described, the absolute risk of malformations with fetal exposure to lithium is approximately 0.05%- 0.1%, but the risk of neural tube defects with sodium valproate is estimated at 8%. Complicating the issue further, in 2013, the FDA announced that sodium valproate had been changed from a category D to X for migraine prevention, but retained the category D classification for other indications.
Placing lithium in category D suggests a relative contraindication and yet discontinuing that medication during pregnancy can put the mother and her baby at risk, given the data supporting the rapid onset of relapse in women who stop mood stabilizers during pregnancy.
For women maintained on lithium for recurrent or brittle bipolar disorder, the drug would certainly not be contraindicated and may afford critical emotional well-being and protection from relapse during pregnancy; the clinical scenario of discontinuation of lithium proximate to or during pregnancy and subsequent relapse of underlying illness is a serious clinical matter frequently demanding urgent intervention.
Still another example of the incomplete informative value of the older system is found in the assignment of atypical antipsychotics into different risk categories. Lurasidone (Latuda), approved in 2010, is in category B, but other atypical antipsychotics are in category C. One might assume that this implies that there are more reproductive safety data available on lurasidone supporting safety, but in fact, reproductive safety data for this molecule are extremely limited, and the absence of adverse event information resulted in a category B. This is a great example of the clinical maxim that incomplete or sparse data is just that; it does not imply safety, it implies that we do not know a lot about the safety of a medication.
If the old system of pregnancy labeling was arbitrary, the PLLR will be more descriptive. Safety information during pregnancy and lactation in the drug label will appear in a section on pregnancy, reformatted to include a risk summary, clinical considerations, and data subsections, as well as a section on lactation, and a section on females and males of reproductive potential.
Ongoing revision of the label as information becomes outdated is a requirement, and manufacturers will be obligated to include information on whether there is a pregnancy registry for the given drug. The goal of the PLLR is thus to provide the patient and clinician with information which addresses both sides of the risk-benefit decision for a given medicine – risks of fetal drug exposure and the risk of untreated illness for the woman and baby, a factor that is not addressed at all with the current system.
Certainly, the new label system will be a charge to industry to establish, support, and encourage enrollment in well-designed pregnancy registries across therapeutic areas to provide ample amounts of good quality data that can then be used by patients along with their physicians to make the most appropriate clinical decisions.
Much of the currently available reproductive safety information on drugs is derived from spontaneous reports, where there has been inconsistent information and variable levels of scrutiny with respect to outcomes assessment, and from small, underpowered cohort studies or large administrative databases. Postmarketing surveillance efforts have been rather modest and have not been a priority for manufacturers in most cases. Hopefully, this will change as pregnancy registries become part of routine postmarketing surveillance.
The new system will not be a panacea, and I expect there will be growing pains, considering the huge challenge of reducing the available data of varying quality into distinct paragraphs. It may also be difficult to synthesize the volume of data and the nuanced differences between certain studies into a paragraph on risk assessment. The task will be simpler for some agents and more challenging for others where the data are less consistent. Questions also remain as to how data will be revised over time.
But despite these challenges, the new system represents a monumental change, and in my mind, will bring a focus to the importance of the issue of quantifying reproductive safety of medications used by women either planning to get pregnant or who are pregnant or breastfeeding, across therapeutic areas. Of particular importance, the new system will hopefully lead to more discussion between physician and patient about what is and is not known about the reproductive safety of a medication, versus a cursory reference to some previously assigned category label.
Our group has shown that when it comes to making decisions about using medication during pregnancy, even when given the same information, women will make different decisions. This is critical since people make personal decisions about the use of these medications in collaboration with their doctors on a case-by-case basis, based on personal preference, available information, and clinical conditions across a spectrum of severity.
As the FDA requirements shift from the arbitrary category label assignment to a more descriptive explanation of risk, based on available data, an important question will be what mechanism will be used by regulators collaborating with industry to update labels with the growing amounts of information on reproductive safety, particularly if there is a commitment from industry to enhance postmarketing surveillance with more pregnancy registries.
Better data can catalyze thoughtful discussions between doctor and patient regarding decisions to use or defer treatment with a given medicine. One might wonder if the new system will open a Pandora’s box. But I believe in this case, opening Pandora’s box would be welcome because it will hopefully lead to a more careful examination of the available information regarding reproductive safety and more informed decisions on the part of patients.
Numerous studies on the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) have been published, particularly over the last decade. With the different methodologies used and often disparate results, the extensive data now available in the medical literature can be overwhelming for clinicians and researchers to sort through. Many of the most recently published studies derive from analyses using large administrative databases, from sources such as Medicare, Medicaid, or large HMO databases. Less common are prospective cohort studies, where patients with or without a history of exposure to SSRIs are followed across pregnancy in real time.
Studies over the past 5-10 years have consistently suggested that the risk of major congenital malformations associated with fetal exposure to SSRIs is nonexistent or modest. A major criticism of this literature has been that much of the data are derived from claims databases, which do not adequately account for the potential confounding effect of major depression – so-called “confounding by indication.”
While the consensus is that fetal exposure to SSRIs is not associated with a significant overall risk for major congenital malformations, questions have lingered about whether antidepressant exposure during pregnancy increases risk for cardiac defects. This had been a particular concern with respect to paroxetine, which in 2006 was changed from a pregnancy category C to D because of a purported increase in risk of heart defects associated with first-trimester exposure to this medication.
This issue was addressed again in a large population cohort study published this past June, using Medicaid data from 2000-2007. The study, in which I participated, involved a collaboration of investigators representing epidemiology, teratology, and reproductive psychiatry (N. Engl. J. Med. 2014;370:2397-2407). The study compared the risk of major cardiac defects in babies with and without exposure to antidepressants during the first trimester, providing a risk estimate unadjusted for depression, and an analysis that adjusted for the potential effect of depression and other potential confounders using propensity score adjustment methodology. (Propensity scores are an analytic tool that makes it possible to match groups with the exception of the variable being scrutinized, to minimize confounding.)
Results indicated that the increased risk identified in the unadjusted analysis is attenuated when factoring in depression: Compared with those not exposed to SSRIs, the unadjusted relative risk of any cardiac defect associated with SSRI exposure was 1.25. But with the fully adjusted analysis, the relative risk approached the null, at 1.06, and is not significant. The results are noteworthy because of the large sample size and the effort to control for relevant confounding factors, relevant to many other previously published studies evaluating risk of fetal SSRI exposure.
One would imagine that the increasing number of studies such as this one would be helpful to clinicians. But it can be very challenging for clinicians and even clinical researchers to navigate the growing literature and to attempt to parse out the methodologic strengths and limitations of the various analyses put forth. What makes interpretation of these growing data even more complicated is that reviews of this topic frequently are selective, and reflect what the author chooses to highlight, with resulting conclusions about safety that may be incomplete. The issue is relevant with respect to the medical literature and even the more general media.
An example is the recent publication of an article in the New York Times about whether antidepressants are safe during pregnancy. The article elicited volley after volley of diverse replies, expressing both outrage at the selective reference of studies associating antidepressants with increased fetal risk, as well as criticism of potential cavalier prescribing and use of antidepressants during pregnancy, with their risks still not absolutely quantified. The New York Times public editor also weighed in with a response, writing in a column that “readers – many of them doctors – wrote to complain that the article was inappropriately alarmist, and that the idea behind it was dangerous for pregnant women suffering from depression.”
As my colleagues and I wrote in a response to the article in a blog, whatever the reason for the brevity, a “cursory presentation of the complexity of decisions made around antidepressant use during pregnancy” can potentially be harmful to patients, and at best “is just incomplete; at its worst, it is irresponsible.”
Perhaps of even greater concern than the selective discussion of studies was the implication in the article that the decision to take antidepressants during pregnancy is similar to the decision to give up wine, caffeine, and ripened cheese across such an important time. The decision is certainly not that simple. After more than 2 decades and thousands of consults with women contemplating the decision of whether to take an SSRI during pregnancy or not, I remain impressed with the bind faced by patients with major depression who are trying to make this decision with their doctors and partners, applying their own private calculus to the question of whether to use antidepressants during pregnancy.
What is also ironic is that there is common use of other medications during pregnancy for which there are vastly less available reproductive safety data. These medicines would include, for example, sedative hypnotics or antibiotics; so why the enormous concern about SSRIs? One has to wonder whether the scrutiny about SSRIs is not about using the medication but is related to bias regarding the use of a medicine during pregnancy to treat an illness such as depression, where many people, including clinicians, would discount the devastating effect of depression on women’s lives – as well as the evolving data on the impact of untreated psychiatric illness on fetal well-being, and the well-documented association between psychiatric illness during pregnancy and increased risk for postpartum depression.
Ironically, the availability of more data has not made it easier for the clinician but has brought about a need for greater scrutiny; the conversation about this issue is probably good for the field. Ultimately, decisions about what women choose to do will be made on a case-by-case basis, as individuals make the decision with their doctors and partners using available data in the context of their individual clinical situations, factoring in severity of illness as well as their own individual wishes.
Studies using large administrative databases both in the United States and internationally have provided the capacity to look at exposure to psychiatric and other medications during pregnancy in large numbers of women. But many have not adequately addressed the problem of “confounding by indication,” because they compare women taking the antidepressant to untreated women who do not have the underlying disorder for which the medication is used. This is critical because depression may be independently associated with some of the adverse obstetrical and neonatal outcomes that have been ascribed to exposure to antidepressants (Arch. Gen. Psychiatr. 2010;67:1012-24).
But a population-based study published last year using data from the Danish birth, hospital, and psychiatric registries from February 1997 to December 2008 addressed the confounding issue in more than 1 million pregnancies and represents an incremental contribution to the literature on this topic (PLoS One 2013;8:e72095 [doi: 10.1371/journal.pone.0072095]).
Of about 1,005,000 pregnancies, the rate of spontaneous abortion (before 22 weeks’ gestation) was 11%. The risk of spontaneous abortion among pregnancies in women with depression treated with an antidepressant in early pregnancy (22,061 pregnancies) was compared with the risk among pregnancies in women with depression who did not report use of antidepressants (1,843 pregnancies) and in women with no diagnosis of depression and no antidepressant use (981,415). The antidepressants included SSRIs, serotonin-norepinephrine reuptake inhibitors, and tricyclics, and the risk ratios were adjusted for maternal age, education, and other factors.
The risk of spontaneous abortion associated with the use of antidepressants was slightly higher compared with no antidepressant use, with a relative risk of 1.14. However, when the analysis was restricted to women diagnosed with depressive disorder, as documented in the psychiatric registry (which includes information on all admissions to psychiatric hospitals and outpatient treatments in Denmark), the risk associated with antidepressant use dropped to 1.0.
Essentially, after adjustment for the depression diagnosis, the risk moves toward the null, and spontaneous abortion rates are comparable between unexposed and exposed pregnancies. This has never been shown in such a large study, and is a critical finding because this represents an effort in a very large dataset to parse out the relative effects of exposure to the disease versus exposure to the medicine.
When considered in the context of previously available data, where do these results leave the clinician and their patients? Women with depression often ask about the risks of preterm birth and spontaneous abortion associated with antidepressants. This concern is particularly relevant for women with depression undergoing assisted reproductive technology procedures for infertility.
Patients and clinicians can be somewhat reassured by the findings of this study, which indicate that even if there is a risk of increased spontaneous abortion, it is a very small one, and it appears to be even smaller when factoring in the depression diagnosis.
There is no perfect decision with respect to the challenging question of whether to use an antidepressant in women with significant psychological distress, including major affective disorder. Women with the same illness history presented with the same information may make different decisions about psychiatric medication use during pregnancy, and some women may choose not to use an antidepressant.
Finally, this study highlights the importance of factoring in the effect of the underlying illness for which the patient is being treated in clinical studies that examine the fetal effects of exposure to psychiatric medications, as well as for other classes of medications for other nonpsychiatric illnesses. In large datasets, it is challenging to adjust for variables that are relevant to the outcome of interest, and this could explain some of the disparate findings of studies regarding spontaneous abortion and other obstetrical and neonatal outcomes.
When we see large studies with large numbers of patients, while exciting, we need to be more critical in interpreting the results, paying attention to the comparison groups and whether the study adjusts for the variables that can be very relevant to the outcome of interest.
Because of fears of potential adverse effects on infants associated with psychotropic drug use during lactation, many women with a psychiatric disorder who are treated with a range of psychiatric medications are advised not to breastfeed; or if they choose to breastfeed, they are counseled to avoid taking the essential medication that has made them well. This has been a somewhat intuitive, cautious approach. However, in my 25 years of clinical experience taking care of pregnant and postpartum women with a range of psychiatric disorders, one sad scenario I have frequently witnessed is the woman who decides to defer pharmacologic treatment for severe postpartum psychiatric illness after being counseled to defer treatment given a wish to breastfeed. Those women often have been psychiatrically ill for months while breastfeeding after having decided to defer their own treatment because they do not want to expose the baby to even scant amounts of medication secreted into breast milk associated with use of a needed medicine during lactation.
In a recently published clinical report from the American Academy of Pediatrics committee on drugs, authors suggest that advice not to breastfeed or to uniformly avoid medications while nursing because of possible adverse effects in the infant is often not evidence based and may not be necessary in many cases. The committee states that most drugs do not pose a risk to the mother or infant who is nursing, and that “the benefits of breastfeeding outweigh the risks of exposure to most therapeutic agents via human breast milk” (Pediatrics 2013;132:e796-e809).
The report points out that for certain drugs, a careful risk-benefit analysis is needed, especially for drugs that are concentrated in human milk, those with unproven benefits, and those with long half-lives. Importantly, the report notes say that decisions about the use of medications during lactation have to be made on a case-by-case basis. A concrete example would be exercising appropriate vigilance about the use of these medicines in premature infants with immature metabolism.
The report, published on-line in Pediatrics in August 2013, includes a section on antidepressants, anxiolytics, and antipsychotics. As a resource for clinicians, the report highlights LactMed, part of the National Library of Medicine’s toxicology data network (TOXNET), which provides real-time updated scientific information on the excretion of drugs into breast milk.
The report makes the important distinction regarding the range of clinical decisions that get made in the context of different clinical situations. For example, at our center, patients frequently present with questions about whether to use psychiatric medications while breastfeeding when these women have already been taking the medication during pregnancy for treatment of underlying psychiatric disorder. Others make queries about introduction of pharmacologic therapy in the early postpartum period in the context, for example, of new-onset postpartum depression. Specifically, a woman with a history of psychiatric disorder who is treated with antidepressant during pregnancy may continue that medication across the postpartum period to attenuate risk for postpartum depression, particularly if she has a history of recurrent disease, or depressive relapse when medication has been discontinued. That is clinical scenario differs from that of a woman who develops new onset of depression during the postpartum period.
One part of the AAP report addresses use of certain psychiatric medications in the context of available information from the literature regarding extent of excretion of these medications into breast milk. This section states that many antianxiety drugs, antidepressants, and mood stabilizers are excreted in low concentrations into human milk, with the estimated infant doses under 2% of the weight-adjusted maternal dose. However, the authors also cite small series or case reports where infant plasma levels of some drugs were reported to exceed 10% of maternal plasma concentrations. They list 13 such drugs, which include selective serotonin reuptake inhibitors (SSRIs), antipsychotics, anxiolytics, and mood stabilizers. It is important to keep in mind that the number of these cases is small and represent a very small proportion of cases, when the total denominator of reports in the literature of psychotropic drug use during lactation is considered. For example, olanzapine, a second generation antipsychotic is highlighted as an agent of concern based on one case report (J. Psychopharmacol. 2010;24:121-3).
The take-home message for the clinician is that all psychotropics are excreted into breast milk, even if quantification of the agents in breast milk or infant plasma reveals relatively scant concentration (J. Clin. Psychiatry 2003;64:73-80). If mom takes the medicine coincident with lactation, baby is exposed. At our center, we are usually reluctant to discontinue a medication such as an atypical antipsychotic to treat bipolar disorder in the postpartum period even if the mom chooses to breastfeed considering the extent to which women with bipolar disorder are at a high risk for relapse during the puerperium.
Ironically, we probably have more information regarding the excretion of antidepressants and drugs such as lamotrigine, used as a mood stabilizer, into breast milk than most medicines women take during the postpartum period, with data over the past 15 years suggesting that these medications, like other medications, are excreted into breast milk and are present in infant plasma in extremely sparse concentrations. It is noteworthy that cases of frank newborn toxicity directly associated with mothers who breastfeed on psychiatric medications are extremely few and far between, and are anecdotal at best. For some context, the literature on the effects of SSRI use during pregnancy is vast and prevalence of use of these medications during pregnancy and the postpartum period is substantial; that being said, reports of adverse effects reported in the babies of women who breastfeed while taking an SSRI are scant and thus at least somewhat reassuring.
And yet, consistently, I have witnessed that psychiatric medications are highlighted in the literature as particular agents of concern when it comes to lactation, compared with other medicines, for which only sparse data are available. Whether this reflects a bias about the necessity of treating psychiatric disorders during the postpartum period is unknown. Certainly, the long-term implications for the infant of exposure to low concentrations of psychiatric and nonpsychiatric medications in the context of breastfeeding exposure have yet to be clarified.
Whether a woman treated with a psychiatric medication during the post partum should breastfeed is a prime example of a clinical scenario in which there is no perfect decision, and we need to make the best decision possible, taking into account the available data, and the mother’s psychiatric disorder and her wishes. Some women may be extremely committed to breastfeeding and may choose to breastfeed, acknowledging some of the unknowns regarding these medications during lactation, while other women consider some of the ambiguity associated with the long-term effects of exposure while lactating and may choose not to breastfeed.
It is noteworthy that the AAP committee on drugs concluded the benefits of breastfeeding outweigh the risk of exposure to most therapeutic agents via human milk. And those at our center would certainly suggest that this is the case for psychiatric medications, particularly those used to sustain postpartum maternal psychiatric well-being, which is so critical. As is the case with any clinical decision, and certainly with respect to the use of psychiatric medications during pregnancy and lactation, the decision to treat is contingent on a careful risk-benefit analysis, where the risks of exposure to a medicine is weighed against the risk of untreated psychiatric illness. Even with the well-documented benefits of breastfeeding, nothing should trump the treatment of postpartum psychiatric illness, even if the cost is deferring breastfeeding. Treatment cannot be deferred because of the impact of untreated maternal psychiatric illness on maternal morbidity and on the development of children.
Now, the data we have been waiting for, from the registry and other sources, are beginning to emerge, and are providing some reassuring – though still preliminary – information regarding the risk for major congenital malformation risks associated with first trimester exposure to these drugs.
Published in August, a prospective observational cohort study conducted by the Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy in Germany compared the risk for major malformations and other adverse pregnancy outcomes among 561 women exposed to atypical antipsychotics, 284 women exposed to typical antipsychotics, and 1,122 pregnant women treated with medications known not to be harmful during pregnancy (the reference group) from January 1997 to March 2009.
After an effort to adjust for potential confounders, there was not a significant difference between the rates of major malformations, the primary endpoint, between those exposed to atypical antipsychotics (5.1%) or typical antipsychotics (4.2%) in the first trimester. The major malformation rate was higher among those exposed to typical antipsychotics than in the reference group, but the difference was not statistically significant. However, the major malformation rate was about twofold greater among those on atypicals compared to the reference group (odds ratio, 2.17), a significant difference. In the group exposed to atypicals, the most common major malformations were cardiovascular, and of the cardiac malformations, most (8 of 12) were atrial or ventricular septal defects (J. Clin. Psychopharmacol. 2013;33 453-62).
(The rate of symptoms suggesting “poor neonatal adaptation” were also significantly higher in the two antipsychotic-exposed groups.)
As the authors point out, cardiac septal defects are one of the most common congenital malformations, and this difference could be due to a detection bias, because women exposed to a medicine for which there are sparse reproductive safety data – particularly one in a relatively new class of drugs – may be more likely to get prenatal and postnatal diagnostic testing.
In the first presentation of the National Pregnancy Registry for Atypical Antipsychotics at an annual meeting in June, my coinvestigators and I concluded that atypical antipsychotics are unlikely to be major teratogens, like valproic acid. Based on 143 cases of first trimester exposure to atypicals, we described a risk with a very wide confidence interval with its outer bound being 5.5%. These data are considered preliminary at this point, and we plan to publish data based on a larger series with a nonexposed reference group in the next year.
Considering how widely the atypical antipsychotics are used across disease states by sexually active reproductive-age women, what can the clinician conclude based on the currently available reproductive safety data on atypical antipsychotics? Based on the 2005 study, the German study, and our report on the registry data, it is reasonable to conclude that second-generation antipsychotics are not major teratogens. They are not valproate (Depakote) or thalidomide. As I have noted in previous columns, when it comes to using psychiatric medicines, or most other medications for that case during pregnancy, there is no perfect decision and no decision is risk free. Given the importance of treating psychiatric illness during pregnancy and the evolving data that illustrate the adverse impact of untreated psychiatric illness on a wide range of neonatal and obstetrical outcomes – and on increasing the risk for postpartum psychiatric illness – one could consider a risk-benefit decision that places the use of atypical antipsychotics as not contraindicated.
The use of atypical antipsychotics to treat women who suffer from underlying psychiatric illness frequently makes the difference between substantial suffering or takes patients from partial remission to euthymia. In the end, precise quantification of the reproductive safety of atypical antipsychotics may be challenging given the frequency of polytherapy – whether an atypical is used as mood stabilizers for patients with bipolar or as an adjunct to antidepressants in a woman with depression. However, after 2 decades of clinical work and research with the population of women who take psychiatric medications and who are either planning to conceive or who are pregnant, I maintain that little should trump the very significant downside of active psychiatric disorder during pregnancy.
Compared with those early years, we now have a vast amount of data and numerous published studies on the subject, providing us with more information regarding the spectrum of outcomes associated with prenatal exposure to SSRIs. Analyses of those data have become more sophisticated, with the appreciation that any assessment of reproductive safety must take into account both the potential risks of exposure to the medication and the risks of untreated psychiatric illness.
In this column, I will not review the extent to which SSRI exposure increases the risk of major congenital malformations, addressed in previous columns. Based on the literature over the last 10-15 years, it is reasonable to conclude that, if the risk of major congenital malformations following first-trimester exposure to SSRIs is increased, the increase is small (N. Engl. J. Med. 2007;356:2732-3).
The effects of SSRI exposure on other outcomes such as preterm delivery, birth weight, and Apgar scores have been less clear. These outcomes are gaining an increased presence in the literature, and interpretation of the data from either small cohort studies or large administrative databases can be extremely confusing for both biostatistician and clinician alike.
An important study, a meta-analysis of 23 studies published online in February, rigorously evaluated pregnancy and delivery outcomes following prenatal exposure to antidepressants (including SSRIs, tricyclics, and monoamine oxidase [MAO] inhibitors) – mostly SSRIs – factoring in the risk of untreated psychiatric illness on these outcomes. There were no significant associations between prenatal exposure to antidepressant medications and the risk of spontaneous abortion, with no significant differences among exposed vs. nonexposed pregnancies (JAMA Psychiatry 2013 Feb. 27:1-8 [doi:10.1001/jamapsychiatry.2013.684]).
There were, however, significant associations between prenatal antidepressant exposure and gestational age, preterm delivery, lower birth weight, and lower Apgar scores. Antidepressant exposure was significantly associated with a shorter gestation, and preterm delivery was more common among women taking antidepressants, whether or not they were compared with all women not exposed to antidepressants or just depressed women who did not take antidepressants during pregnancy.
Similarly, prenatal antidepressant exposure was significantly associated with lower birth weight (a mean difference of 74 g) when compared with birth weights of babies with no prenatal exposure. But when the comparison was limited to depressed mothers with no exposure to antidepressants, the association was no longer significant.
Antidepressant exposure also was significantly associated with lower Apgar scores at 1 and 5 minutes when compared with all the unexposed mothers and to only the mothers who were depressed but did not take antidepressants. (The study was funded by Canadian government grants, and 4 of the 11 authors disclosed having received honoraria, an unrestricted educational grant, and/or research support from companies that included antidepressant manufacturers).
What do these results mean to the clinician trying to translate these scientific findings into clinical practice? For the clinician, the most critical issue to consider is that, even when there were observed differences in outcomes between exposed and nonexposed pregnancies, those differences were small. Gestational age was less than half a week shorter, and the differences in the mean 1- and 5-minute Apgar scores were less than half a point and the scores were considered excellent.
These results are reassuring because the clinical relevance of the cited differences between the two groups is exceedingly small. Perhaps the most critical finding in this published analysis is that even a statistically significant difference in an outcome only has relevance if the difference informs clinical care. This is not an Olympic downhill ski race, where a hundredth of a second can make a critical difference.
So what is the most appropriate treatment of depression during pregnancy? Navigating the growing literature on relative risks of antidepressant treatment during pregnancy can be particularly burdensome for clinicians. While clearly the amount of data is vast, the quality of these data is highly variable. Randomized controlled clinical trials of antidepressant use during pregnancy are not performed for obvious ethical reasons, and reports of outcomes of fetal exposure to psychiatric medications including antidepressants frequently derive from analyses of data from small cohort studies or from administrative databases, which are limited by serious methodologic difficulties – small numbers of exposed cases, problems ascertaining reliable information regarding actual medication exposure, comorbid substance use, or the presence of active psychiatric disorder across pregnancy. These factors make reliable assessment of risk that much more difficult, and determination of clinical implications of such findings even more challenging. Variable interpretations of the same literature make it even more difficult for clinicians in the community to know how to proceed with the patient presenting for guidance about appropriate use of antidepressants during pregnancy or alternative evidence-based management strategies for perinatal depression.
A recently published article addressing the risks of SSRIs in infertile women, which discusses, among other issues, the risk of SSRIs during pregnancy across outcomes of miscarriage, birth defects, neonatal side effects (so-called neonatal adaptation syndrome), and persistent pulmonary hypertension of the newborn (PPHN), is an example of how published reports and reviews frequently confuse more than they inform. The authors offer the following conclusions: Antidepressants are not effective for most women with depression; a strong signal for teratogenicity is evident for SSRIs; and outcomes such as preterm birth, PPHN, and poor neonatal adaptation are common after prenatal exposure to SSRIs. (The review was published online in October 2012 in Human Reproduction [doi: 10.1093/humrep/des383], and no external funding or conflicts of interest of the authors are noted.) The review, described as “systematic,” appears to be relatively selective with respect to data presented, and as such, many of the conclusions are not uniformly supported by the data in the literature; hence its conclusions should be put in perspective.
As an example, more data support the absence of a strong teratogenic signal with first-trimester exposure to SSRIs than for almost any other medicine taken by pregnant women. This was the main point made in an editorial published in the New England Journal of Medicine in 2007, titled “Teratogenicity of SSRIs – serious concern or much ado about little?” The editorial refers to two studies published in the same issue, and states that the reports “together with other available information, do suggest that any increased risks of these malformations in association with the use of SSRIs are likely to be small in terms of absolute risks” (N. Engl. J. Med. 2007;356:2732-3).
Certainly, over the last decade, efforts have been made to refine the risk-benefit decision regarding antidepressant use during pregnancy by a better understanding of the vast data on the impact of SSRIs on fetal well-being and outcomes such as malformations, as well as the effects of untreated depression on fetal and neonatal well-being. Across the review noted above, the numerous studies citing adverse effects of untreated depression on obstetrical and neonatal well-being are not discussed. Most critical is the omission of a meta-analysis of adverse effects of depression during pregnancy, which identified an increased risk of preterm delivery and low birth weight associated with prenatal depression (Arch. Gen. Psych. 2010;67:1012-24).
Also omitted is what is one the most pivotal studies published to date on the long-term neurobehavioral follow-up of children exposed to antidepressants during pregnancy. This study followed children exposed to fluoxetine (Prozac) or a tricyclic antidepressant for a period of up to 72 months and compared outcomes including IQ, reactivity, temperament, mood, or distractibility to a matched group of nonexposed children; no differences were noted between the groups (N. Engl. J. Med. 1997;336:258-62). Other studies of long-term neurocognitive sequelae of fetal exposure to antidepressants will lay the groundwork for the most critical refinement of guidelines for the use of antidepressants during pregnancy.
The decision to use antidepressants during pregnancy needs to be made with great care and scrutiny, particularly among those who suffer from more mild to moderate depression where nonpharmacologic interventions, such as cognitive behavioral therapy (CBT), are appropriate and may, in some cases, be used as a first-line treatment. However, the greatest concern for those clinicians who manage the care of women who suffer from depression before or during pregnancy centers on extrapolation of the same treatment algorithm used for women with mild depression to those with more refractory disease. Indeed, the clinical scale is weighted toward antidepressant treatment for women with more malignant refractory depression, whose journey to emotional well-being has been long and arduous, and where maintenance antidepressant therapy has been a cornerstone of treatment. Given the small absolute risk associated with SSRI use during pregnancy, our threshold to threaten that well-being should be very high. Relapse or new onset of depression during pregnancy is of great importance because no factor more strongly predicts postpartum depression than depression during pregnancy – and the adverse effects of postpartum depression on long-term development of children and the well-being of the mother and her family are substantial.
The debate over the most appropriate use of SSRIs during pregnancy will invariably continue. Careful reading of the relevant data and appreciating the conclusions made that are justified and, conversely, where the data fail to absolutely inform leaves clinicians in a position to share with patients what we know and what we don’t know. Clinicians then can tailor ultimate decisions based on available information from the scientific literature, patient’s wishes, and individual clinical histories.
Reprinted with permission from Ob. Gyn. News
October 15, 2012
October 2012, ObGyn News, Christina Chambers, PH.D., M.P.H., Lee S. Cohen, M.D., Gideon Koren, M.D., And Gera Despite the fact that prescription medications are commonly used by pregnant women, for most products and for new […]
October 2012, ObGyn News, Christina Chambers, PH.D., M.P.H., Lee S. Cohen, M.D., Gideon Koren, M.D., And Gera
Despite the fact that prescription medications are commonly used by pregnant women, for most products and for new drugs in particular, there is typically little to no human safety information available to aid clinicians and patients in managing risk. As randomized clinical trials are usually not considered ethical to perform in pregnancy, observational epidemiologic studies are often the next best option to address human pregnancy exposure. An increasingly common approach to gathering human safety data is postmarketing pregnancy registries.
These pregnancy registries are initiated many times by agreement between the manufacturer and a regulatory agency as a postmarketing commitment or requirement following shortly after drug approval. Furthermore, because use of a new drug in pregnant women might be relatively rare, a pregnancy registry may be the only feasible method for gathering preliminary safety information as quickly as possible so that potential signals might be detected and clinical decision making can be better informed.
Pregnancy registries vary in design, but all involve collection of data on exposure to the drug of interest in pregnant women, and collection of outcome data for those pregnancies. The primary outcome of interest is typically major congenital anomalies; some registries also collect outcome data on fetal/infant growth, preterm delivery, pregnancy loss, specific neonatal outcomes, and postnatal longer term growth and development. The rates of these outcomes can be compared with general population reference rates, or rates occurring in a specific comparison group that might be more similar to the exposed women, for example, in terms of the underlying maternal condition being treated by the drug.
In addition to early information on a new drug, some of the major advantages of many pregnancy registry designs are the ability to collect information on the exposure and other pregnancy details before the mother knows what the outcome of her pregnancy will be; direct collection of exposure information from the mother herself, so that important factors such as drug and alcohol use, dose, and exact timing of exposure to the drug of interest; information on important other factors such as tobacco, alcohol, and multivitamin use.
The most challenging aspect of pregnancy registries is recruitment, for which registries largely depend on obstetric providers and other specialty physicians. Although low numbers of recruited pregnancies may be caused by limited use of a new drug, clearly most pregnancy registries enroll a very small fraction of all exposed pregnancies that are in existence. A second, related issue is that there may be bias in the self-selection of women who do find out about the registry and agree to participate, thus raising questions about the generalizability of the findings. A third issue is that many registries experience high rates of “lost to follow-up,” in which outcome information is unobtainable from the health care provider or the pregnant woman – in some cases as high as 40%. There is also a concern about bias involved with the timing in gestation when a pregnancy enters a registry, such as the later in gestation a pregnancy is enrolled, the more likely that prenatal diagnosis, pregnancy loss, or other adverse outcomes have already occurred – thus making the enrollment essentially retrospective.
Another concern is that few registries have a concurrently enrolled group of unexposed women for purposes of comparison. Thus, their findings are commonly compared to external reference statistics which may not be the most appropriate. Finally, in some registries, the absence of information on individual dose and specific timing in gestation of exposure may preclude evaluating the biological plausibility of any registry findings. All of these issues can lead to long delays in accumulation of sufficient information to draw meaningful inferences, and potential concerns about interpretation of results.
How can awareness of pregnancy registries and more representative enrollment of exposed women be improved? A variety of methods are used to inform physicians and their patients about existing pregnancy registries for the purpose of encouraging referrals, including the Food and Drug Administration website, information in product labeling and on product websites, direct to provider or direct to consumer advertising, and in commonly used resources for clinicians such as this column and Reprotox, an information system developed by the Reproductive Toxicology Center. However, with the rapidly increasing number of registries, it is challenging for physicians to remain current on which medications are being monitored through a registry, what the criteria for enrollment are, and how a physician or patient can find out more. Pregnancy registry designs that are disease based – such as encompassing all medications used to treat a specific disease in pregnancy – help simplify the referral process by broadening the criteria for enrollment. Particularly for specialty physicians, this can ease the burden of identifying eligible women for enrollment.
How can enrollment be accomplished as early as possible in pregnancy (after exposure, but before the outcome is known), and how can more complete ascertainment of exposure and outcome be improved? An approach that some registries have used to address this is by “direct to consumer” campaigns. Registries such as the Organization of Teratology Information Specialists (OTIS) Autoimmune Diseases in Pregnancy Registry require that the pregnant woman herself enroll in the study, and therefore, the study is marketed directly to those women, although physician referral is encouraged. At least in this case, this has led to low rates of lost to follow-up (less than 5%), recruitment timing that is typically before the seventh or eighth week of gestation, and collection of specific information on dose and timing in gestation of exposure.
Multiple drug, disease-based, multiple sponsor registries such as the Antiretroviral Drugs in Pregnancy Registry, the North American Antiepileptic Drugs in Pregnancy Registry (patients call 888-233-2334), and the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388) offer distinct advantages but are not always feasible for a specific product. A national pregnancy registry for all new drugs has been suggested as another solution to many of the challenges facing single product registries and to streamline referral and follow-up. In addition, including pregnant women in selected preapproval studies has several advantages. Finally, creative new technologies for earlier and more complete ascertainment and referral, such as use of electronic medical records, should be fully explored. The need for safety information on new drugs is urgent.
Dr. Chambers is professor of pediatrics and family and preventive medicine at the University of California, San Diego. She is director of the California Teratogen Information Service and Clinical Research Program. Dr. Chambers is a past president of the Organization of Teratology Information Specialists and past president of the Teratology Society. Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, which provides information about pregnancy and mental health. Dr. Koren is professor of pediatrics, pharmacology, pharmacy, and medical genetics at the University of Toronto. He heads the Research Leadership for Better Pharmacotherapy During Pregnancy and Lactation at the Hospital for Sick Children, Toronto, where he is director of the Motherisk program. Mr. Briggs is a pharmacist clinical specialist at the outpatient clinics of Memorial Care Center for Women at Miller Children’s Hospital in Long Beach, Calif.; a clinical professor of pharmacy at the University of California, San Francisco; and an adjunct professor of pharmacy at the University of Southern California, Los Angeles, and Washington State University, Spokane. He also is coauthor of “Drugs in Pregnancy and Lactation.” Dr. Cohen is the principal investigator on the National Pregnancy Registry for Atypical Antipsychotics, which is sponsored by multiple atypical antipsychotic manufacturers.
May 15, 2012
May 2012, ObGyn News, Lee S. Cohen More information is available on the teratogenicity of psychiatric medications than perhaps any other class of medications women use during pregnancy, with the most data available for antidepressants. […]
May 2012, ObGyn News, Lee S. Cohen
More information is available on the teratogenicity of psychiatric medications than perhaps any other class of medications women use during pregnancy, with the most data available for antidepressants. To date, many would argue that no signals for significant teratogenicity across psychiatric medications have been identified – with a few important exceptions such as sodium valproate and lithium carbonate. While data from smaller prospective studies and large administrative databases fail to demonstrate a teratogenic risk of typical antipsychotics, less information is available on the risk associated with newer atypical antipsychotics, such as olanzapine and aripiprazole.
Data also are certainly sparse regarding the potential for long-term neurobehavioral adverse effects of fetal exposure to older and newer antipsychotics, as is the case for most psychiatric medicines. Risk for longer-term neurobehavioral sequelae of fetal exposure to psychiatric medications remains a research frontier, which when mapped, will inform clinical decisions regarding use of these agents during pregnancy.
A prospective study recently published online in the Archives of General Psychiatry has addressed the critical question of long-term neurobehavioral sequelae of fetal exposure to antipsychotic medications. Other than some very preliminary studies dating back several decades, this is one of the first studies to evaluate the longer-term effects of prenatal exposure to antipsychotics.
The study compared neurobehavioral outcomes among 309 mothers with different psychiatric diagnoses and their infants at 6 months post partum: 22 infants had been exposed to antipsychotics, 202 had been exposed to antidepressants, and 85 had not been exposed to any psychotropic medications. Diagnoses among the women in all three groups included depression, bipolar disorder, anxiety disorder, and psychotic disorder. After confounding factors were controlled for, scores on a standardized neuromotor exam looking at parameters of posture, tone, reflexes, and motor skills at 6 months were significantly lower among infants exposed to antipsychotics than in infants in the other two groups (Arch. Gen. Psychiatry 2012 April [doi: 10.1001/archgenpsychiatry.2012.160]).
However, scores also were affected by maternal psychiatric history, including depression, psychosis, or chronicity and severity of maternal psychiatric illness. The authors noted that they could not completely adjust for confounders, and that “disentangling” the effects of medication from the effects of maternal illness remained a challenge. In addition, with a sample of only 12 infants exposed to multiple atypical antipsychotics (aripiprazole, olanzapine, quetiapine, risperidone, or ziprasidone), 9 exposed to the typical antipsychotic haloperidol, and 1 exposed to both haloperidol and ziprasidone, the results are not conclusive and must be interpreted cautiously.
Nonetheless, these investigators should be credited with addressing, even in a preliminary fashion, such an important area with such great clinical implications. Their findings complement the growing amount of existing information on the risk for organ malformations and perinatal sequelae associated with exposure to psychiatric medications during pregnancy.
What then can the clinician take away from this study, and does it inform the care of psychiatrically ill women during pregnancy?
I would argue that even if the authors were able to adjust for the confounders and they identified an even clearer signal suggesting risk, one must consider that this is a population of women who are treated with these medications to stay well during pregnancy and are at an increased risk for postpartum illness if they fail to sustain emotional well-being during pregnancy.
In the literature, depression during pregnancy has been identified as the strongest predictor of postpartum depression, and postpartum affective illness is one of the strongest predictors of long-term cognitive development in the child. This is particularly true for women with bipolar disorder.
Antipsychotic medications are used to treat women with bipolar disorder, psychotic illness, and severe depression, frequently in combination with other psychiatric medications, to sustain emotional well-being during pregnancy. Hence, even if the potential adverse effects of the medicine are equally balanced against the importance of keeping women well, when making a risk-benefit decision, perhaps the scale tilts further because of the extent to which maternal emotional well-being during pregnancy predicts the risk for postpartum psychiatric illness.
The results of the Archives study open the door for future studies that will delineate the long-term effects of prenatal exposure to antipsychotics, and will parse out the effects of other potential confounders like maternal psychiatric illness. Learning more about the effects of fetal exposure to atypical antipsychotics is particularly critical because of the increasing number of psychiatric disorders for which this class of medicine is being used, including bipolar disorder, major depression, and various anxiety disorders.
With growing numbers of women taking atypical antipsychotics, and with half of pregnancies remaining unplanned in this country, we established the National Pregnancy Registry for Atypical Antipsychotics atMassachusetts GeneralHospital,Boston. While registries such as this one will provide information regarding teratogenic potential, subjects who use these medicines during pregnancy also will give birth to a cohort of children who can be studied to more clearly delineate the long-term effects, if any, of in utero exposure to these medicines. But for clinicians today taking care of women with psychiatric disorders requiring this class of compounds, the message is that nothing can trump the importance of maternal euthymia; failure to sustain euthymia is the strongest predictor of postpartum illness and tips the scale from one of equipoise, to one where treatment becomes that much more imperative.
The medical literature consistently supports a small risk, if any, of major congenital malformations associated with first trimester SSRI exposure, compared with the background risk for major congenital malformations. The consensus is that about 25%-30% of babies exposed to an SSRI in late pregnancy experience poor neonatal adaptation, which is typically characterized by transient jitteriness, but the absence of enduring sequelae.
The data on risk for PPHN have been less consistent, creating some confusion among patients and clinicians. An early study published in February 2006 reported a sixfold greater risk of PPHN among newborns whose mothers took an SSRI after 20 weeks’ gestation, compared with newborns whose mothers did not take an SSRI (N. Engl. J. Med. 2006;354:579-87). In response to this striking finding, the Food and Drug Administration issued a public health advisory in July 2006 and SSRI labels were subsequently changed to include information about what the FDA referred to as the “potential risk” for PPHN. Previously, PPHN, a serious and life-threatening condition, had been noted to be associated with increased maternal body mass index, cesarean section, meconium aspiration, and other risk factors (Pediatrics 2007:120;e272-e282).
But since 2006, there have been five other studies with conflicting results, although even the positive studies have not found an increased risk as high as the initial study. A major limitation of these studies is that they have been derived largely from administrative databases, so it is difficult to corroborate exposure to a particular medicine and other possible confounding factors.
After reviewing these studies, the FDA recently issued a drug safety communication stating that “it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN.” In the Dec. 14 statement, the FDA refers to two studies, including the 2006 study, that have found a statistically significant association between SSRI use and PPHN, and three others that found no increase in risk. Because the agency’s review did not find “sufficient evidence to conclude that SSRI use in pregnancy causes PPHN,” the FDA recommended that “health care providers treat depression during pregnancy as clinically appropriate.”
Perhaps creating some confusion, in January – a month after the FDA communication was issued – a study conducted in all five Nordic countries was published online reporting a twofold increased risk of PPHN associated with SSRI exposure in late pregnancy. The study compared the risk of PPHN among infants exposed to SSRIs with unexposed infants in a sample of 1.6 million infants born between 1996 and 2007 in these countries; the increased risk was found across all SSRIs (BMJ 2011;344:d8012 [doi:10.1136/bmj.d8012]).
Although a study of such a large group of women is a welcome addition to the literature, I do not believe these results affect the FDA’s recent conclusions – or how we should approach the management of major depression during pregnancy. Like most of the previous studies, the data presented in the most recent study are from a large administrative database, where documentation of actual ingestion of medication, the existence or severity of the psychiatric diagnosis for which the medication is prescribed, and rigorous confirmation of the outcome – PPHN – is challenging.
The authors noted that while the absolute risk for PPHN among infants exposed to SSRIs was as low as 3 cases per 1,000 infants exposed (risk in unexposed newborns is 1-2 per 1,000), the risk appeared to be doubled and they recommended “caution when treating pregnant women with SSRIs.” They added that it was “essential to plan the treatment and to weigh” the risks of PPHN when treating women in late pregnancy “with those of relapse of depression and neonatal abstinence syndrome if therapy is interrupted.” Clinicians definitely need to weigh these relative risks, but the risks are strikingly different. Even the recent Nordic report supports the very low absolute risk of PPHN with SSRI exposure, compared with risk of relapse of depression during pregnancy noted with antidepressant discontinuation, which is high.
One has to wonder about the wisdom of implying that an antidepressant should be discontinued close to delivery given that the risk of relapse of depression close to term is one of the strongest predictors of postpartum depression, which can have a profound impact on women and their families. As the amount of data on the reproductive safety of SSRIs continues to grow, clinicians are put in a bind as to how to interpret data that has tended to be variable with respect to both results and implications for clinical care. There may be no perfect decision, and no decision is risk free. But suffice it to say, the most recent FDA communication appears to be balanced in its conclusion that some of the earlier concerns regarding extent of elevation of risk have now been modulated or diminished given the data that have emerged over the last 5 years. This modest risk may factor into decisions women make with their doctors about SSRI use during pregnancy; but for many, the accumulated data are now reassuring and may provide some license to use these medications during pregnancy to treat major depression and its attendant morbidity.
Copyright by International Medical News Group, an Elsevier company
Every few months, it seems as if still another study appears in the literature linking fetal exposure to selective serotonin reuptake inhibitors (SSRIs) with an adverse outcome, such as increased risk for a particular congenital malformation or some other ill effect. Despite many studies that have examined a potential association between risk for malformations and prenatal SSRI exposure, a major indication that an agent is a teratogen is consistency of the finding across studies, which has not been the case with SSRIs. On the other hand, studies indicating that babies whose mothers use SSRIs during pregnancy might have symptoms of transient jitteriness for a period following birth (neonatal adaptation syndrome) have been more consistent – and this is generally accepted as a real risk following approximately 20%-25% of deliveries. Other major concerns raised about fetal exposure to SSRIs have not been supported by systematic scientific investigation.
Clinicians may then wonder why we are seeing an increasing number of reports of potential adverse outcomes associated with SSRI treatment during pregnancy. One reason is that technology has afforded us the ability to gather information from large administrative databases (such as Medicaid or large health maintenance organizations) about prescriptions written during pregnancy and a variety of obstetrical and neonatal outcomes data. Conclusions about a teratogenic outcome or adverse perinatal outcome are only as reliable as the quality of the data from which the conclusions are derived and, unfortunately, some of the data from these databases have been profoundly lacking.
In still another study using such data, published online in Archives of General Psychiatry in July, investigators from Kaiser Permanente Northern California reported an association between an increased risk for autism spectrum disorders (ASDs) in children and maternal SSRI use during pregnancy (Arch. Gen. Psychiatry 2011 [doi:10.1001/archgenpsychiatry.2011.73]).
The population-based case-control study used medical records of 298 children diagnosed with an ASD (autism, Asperger’s syndrome, or pervasive developmental disorder not otherwise specified) and 1,507 children without an ASD diagnosis born within the Kaiser Permanente system in northern California between 1995 and 1999. The results suggested a greater risk of an ASD among children exposed to an SSRI in utero, compared with nonexposed children: The mothers of 6.7% of children with ASD (20 children) had been prescribed at least one antidepressant (mostly SSRIs) during the year before the child was born, compared with the mothers of 3.3 % of controls (50 children).
After a purported adjustment for maternal age and other possible confounding factors, maternal use of an SSRI during the year before delivery was associated with a twofold increased risk of an ASD; treatment during the first trimester was associated with almost a fourfold increased risk. Among the children whose mothers had a history of mental health treatment but did not take SSRIs, the risk of ASD was not increased.
This study has received considerable attention from the media and medical bloggers, and it has led to substantial concern among patients and clinicians struggling to understand the results. Most concerning about this type of report is the alarm that is frequently elicited when patients with an incomplete understanding of the relevant data available regarding a compound learn about a new finding that implies risk, even when such a finding derives from an analysis with great limitations.
As an example, after hearing about the study results, we were contacted by a patient treated with a moderate dose of an SSRI for a history of anxiety disorder, including during two pregnancies with healthy outcomes, with a question as to whether she should continue an IVF cycle. She asked whether she should complete the procedure because she was concerned about the study results. We referred her to some of the many articles and blogs that have attempted to qualify the findings, including our own hospital’s blog (see /posts/autism-spectrum-disorders-and-ssris/).
With respect to the SSRI and autism study noted above, we should keep in mind that this was a case-control study with a very small number of SSRI exposures in both the autism and control groups. So not only was the study limited by a small sample, but it also failed to adequately take into account exposure to illness during pregnancy as a variable. Another limitation was the failure to confirm actual ingestion of the medicine by women who were prescribed an antidepressant.
While the investigators point out that an effort was made to adjust for the effects of underlying disease that led to treatment, it is hard to imagine how that was possible given the sparse data available to them. There was no measure of psychiatric disorder during pregnancy – or the severity of psychiatric disorder in the past – a critical issue because of the literature suggesting that exposure to stress and psychiatric disorder during pregnancy may drive adverse neonatal outcomes.
Therefore, while the authors suggest that SSRI exposure may contribute to risk for ASD, they have failed to adequately or accurately quantify one of the strongest, most well-established risk factors for ASD, namely family or personal history of psychiatric disorder. One can hypothesize that women with a more severe underlying psychiatric disorder would be using antidepressants during pregnancy, given the high threshold for using these medicines or any other medicines during pregnancy.
Opportunities to refine our understanding of clinical questions with major public health implications are always welcome. But one does have to wonder about the value of these analyses, when the quality of data in the studies is of questionable reliability.
Clearly, decisions regarding use of any medication, including psychotropics, have to be made on a case-by-case basis. But at least some of these new findings tend to complicate, if not obscure, the most thoughtful clinical path as patients struggle to understand frequently conflicting data in the literature about SSRIs, which are frequently prescribed during pregnancy. Perhaps clinicians then should consider this latest study as a very preliminary report with findings that are far from definitive until we have better prospectively ascertained data regarding the longer-term behavioral sequelae of fetal exposure to SSRIs.<[qm]>n
Over a decade later, there are even fewer data on the risk for organ malformations associated with prenatal exposure to the widely prescribed newer, atypical antipsychotics. This void of information regarding medicines used widely by reproductive-age women prompted the founding of the National Pregnancy Registry for Atypical Antipsychotics, based at Massachusetts General Hospital in Boston (). In the registry, we are enrolling pregnant women aged 18-45 years who are treated with one or more atypical antipsychotics, and prospectively following them for a spectrum of outcomes, including organ malformations and maternal or newborn complications. Those drugs include aripiprazole (Abilify), clozapine (Clozaril), ziprasidone (Geodon), paliperidone (Invega), risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), asenapine (Saphris), and lurasidone (Latuda).
In an ancillary investigation, we also plan to do a prospective study of a subset of newborns exposed in utero to atypical antipsychotics in which we will evaluate these infants for the presence of withdrawal symptoms, such as tremulousness, jitteriness, and potential extrapyramidal symptoms. This pilot investigation follows the drug safety communication from the Food and Drug Administration in February 2011 in which health care providers were notified that the pregnancy section of the medication label for the entire antipsychotic drug class was being changed to reflect the potential risks for extrapyramidal symptoms (EPS) or withdrawal symptoms noted in newborns whose mothers had been treated with these drugs during the third trimester of pregnancy.
The FDA label change is based on 69 cases of neonatal EPS or withdrawal symptoms associated with exposure to both atypical and typical antipsychotics used during pregnancy that were reported to the agency’s Adverse Event Reporting System (AERS) through October 2008. Symptoms included abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty feeding. In some newborns, symptoms subsided within a few hours or days and did not require specific treatment; other newborns required longer hospital stays. Presumably, the frequency of reports reached a threshold that prompted the FDA to change the pregnancy section across the family of compounds, making this information more consistent.
While reports of EPS symptoms associated with fetal exposure to older antipsychotics date back several decades, with periodic case reports describing EPS with increased muscle tone and tremor, data regarding the risk for these symptoms associated with the atypicals have been sparse and typically limited to small case series or adverse event reporting systems.
As the FDA communication notes, one of the problems with these reports is that symptoms observed following in utero exposure have typically not been limited to monotherapy. In fact, most – but not all – of the reported cases were confounded by maternal use of other medications during pregnancy, including benzodiazepines, opiates, or antidepressants, as well as by the presence of obstetric and perinatal complications. Accordingly, the FDA acknowledged the limitations of these reports when the other medications known to be associated with similar withdrawal symptoms – such as benzodiazepines – were coadministered. One has to wonder whether some of the reported cases also were associated with late trimester exposure to selective serotonin reuptake inhibitors (SSRIs).
The FDA communication and label change is an example of another situation where drug safety monitoring provides some data, which at first pass may raise appropriate concern. However, estimating prevalence of the noted adverse events is extremely difficult, if not impossible, to calculate, because the total number of individuals exposed (denominator) is not known. Moreover, severe outcomes in adverse event reporting systems tend to be overreported in any voluntary reporting system.
So what is the clinician to do, particularly given the fact that the newer antipsychotics are being used across disease states – not only for chronic mental illness such as schizophrenia, but for bipolar disorder, obsessive compulsive disorders, anxiety disorders, and as an adjunct treatment for depression? Clinicians will likely see more women who are treated with these drugs during pregnancy and should at least be aware of the potential risk for EPS and some of the other associated symptoms described in the communication, particularly in women treated closer to term.
However, it should be appreciated that for many patients, the use of atypical antipsychotics across pregnancy may be required to sustain psychiatric well-being. In fact, the FDA does not recommend arbitrary discontinuation of these agents, but rather notes that health care professionals “should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy.”
Clearly, given the nature of the psychiatric disorders for which these medicines are being used, the clinician needs to be particularly mindful that abrupt discontinuation of this class of medicines can increase the risk of recurrence of the underlying illness. Perhaps the most prudent clinical approach in this situation is one of careful observation – as opposed to arbitrary discontinuation of a typical or atypical antipsychotic, which is neither suggested nor implied in the FDA’s communication. The FDA communication, which is not a warning, presumably serves to provide extra data for the clinician to factor into risk-benefit decisions.
December 15, 2010
December 2010, ObGyn News, Lee S. Cohen, MD Selective serotonin reuptake inhibitors are currently used in an estimated 5%-7% of pregnant women, and it is now generally accepted that pregnancy is not protective with respect […]
December 2010, ObGyn News, Lee S. Cohen, MD
Selective serotonin reuptake inhibitors are currently used in an estimated 5%-7% of pregnant women, and it is now generally accepted that pregnancy is not protective with respect to new onset or relapse of depression
Multiple studies indicate that if there is an increased risk for major congenital malformations associated with fetal exposure to antidepressants, the risk is particularly small, but other concerns about the safety of SSRI use across pregnancy prevail. Among the most prominent are the increased risk of poor neonatal adaptation associated with late trimester SSRI exposure and persistent pulmonary hypertension of the newborn (PPHN). While more recent results from studies suggest that risk for PPHN following SSRI use during pregnancy is far less than originally estimated, results in the literature consistently indicate that about 25%-30% of infants exposed to SSRIs late in pregnancy manifest symptoms of this transient jitteriness and “poor neonatal adaptation,” with associated symptoms of restlessness, myoclonus, and tachypnea. Critically, these symptoms also have been consistently noted to be transient and not requiring particular intervention.
Whether clinicians might do something that could attenuate risk for poor neonatal adaptation has been a lingering question over the past several years. Some clinicians have been vigilant about the use of SSRIs late in pregnancy and discontinue these drugs in their patients shortly before delivery. In fact, since 2004, the SSRI package inserts have suggested that tapering the drug in the third trimester be considered.
While taper of SSRI proximate to the end of pregnancy might appear to be intuitive, our group and others have questioned the wisdom of discontinuing an antidepressant shortly before delivery, when the risk of depressive relapse increases a woman’s risk for postpartum worsening of mood.
A study published in June provides data that helps refine our understanding of the risks of antidepressant exposure during the latter stage of pregnancy on the health of newborns. Using a large administrative claims database, investigators in British Columbia linked maternal health and prenatal SSRI prescription claims data to more than 119,000 neonatal birth records between 1998 and 2001. To evaluate the impact of discontinuing SSRIs late in pregnancy, they compared infants exposed to SSRIs during the last 14 days of gestation to those exposed earlier in gestation, and controlled for possible confounding factors that could also affect obstetric and neonatal outcomes, such as maternal health characteristics (Acta Psychiatr. Scand. 2010;121:471-9).
Compared with the newborns exposed to SSRIs earlier in gestation, significantly more of the newborns exposed during the last 2 weeks had respiratory problems (36% vs. 30%) and convulsions (0.3% vs. 0%). However, the differences were no longer evident after investigators controlled for the severity of maternal illness in a subgroup of the cases, and the authors concluded that their results “showed that neonatal outcomes did not improve when SSRI medications were stopped before the last 2 weeks of gestation, even when accounting for measures of maternal illness severity.”
This study represents the first effort to parse out the relative contributions of different factors to which women may be exposed on neonatal outcomes (including maternal depression during pregnancy) – and provides information that helps us to refine the risk-benefit decision. The findings of the study imply that women who are taking an SSRI during pregnancy may benefit from continuing with treatment across labor and delivery because exposure at this time does not appear to adversely affect neonatal outcome. This may be particularly true for women with a history of highly recurrent major depression who are at a significant risk for depressive relapse, even shortly after discontinuing antidepressant medication.
The study provides further pause for clinicians to perhaps reconsider tapering or discontinuing antidepressant proximate to delivery because that type of intervention puts a woman at risk for relapse of depression shortly before an “at risk” period such as the postpartum period.
Clearly, there is no perfect decision and no decision is risk free. Some women in collaboration with their physicians may choose to discontinue antidepressant therapy late in pregnancy and to reinstate treatment shortly after delivery. Nonetheless, women with serious histories, those with recurrent disease and evidence of a swift relapse when stopping or even lowering the antidepressant dose, can consider the results of this study to support a decision to continue the medicine across labor and delivery, to sustain euthymia and maternal wellness.
Considering the growing appreciation of what appear to be real effects of exposure to medicine and to the disorder, what we need now are large, prospective studies that provide more reliable data, comparing euthymic women on antidepressants with women who are not depressed and who are not on an antidepressant – a study that has not been conducted to date
In the eight-cohort studies, there were 118 major congenital malformations in 1,565 pregnancies, during which women took valproic acid (a rate of 7.5%). Of those, 14 malformations were found more commonly in valproic acid-exposed offspring: The case-control study used the antiepileptic study database established by European Surveillance of Congenital Anomalies (EUROCAT) of over 3 million live births and about 98,000 major congenital malformations in 14 European countries from 1995 through 2005. Comparing 37,154 cases of any of the 14 malformations with 39,472 controls with other types of major malformations and 11,763 controls with malformations associated with chromosomal abnormalities, first trimester exposure to valproic acid was associated with an increased risk of 6 of the 14 malformations, compared with the two control groups: spina bifida (a 12.7 greater risk), atrial septal defect (2.5), cleft palate (5.2), hypospadias (4.8), polydactyly (2.2), and craniosynostosis (6.8).
Despite the challenges involved when conducting these types of analyses—including inconsistent criteria used to categorize anomalies across studies or registries—the findings reported in this article are highly consistent with findings from previous studies and are, therefore, confirmatory while also refining the risk estimates for major malformations associated with valproic acid other than neural tube defects.
The authors for the EUROCAT Antiepileptic Study Working Group concluded that their results provided further support for the American Academy of Neurology’s recommendation to avoid treatment with valproic acid during pregnancy. Neurologists have certainly been aware of the reproductive risks of valproic acid for many years and typically choose alternative anticonvulsants with comparable efficacy for women of reproductive age.
The situation is somewhat different in psychiatry, however, because valproic acid is a mainstay of therapy for the treatment of bipolar disorder. In previous columns, I have discussed the use of valproic acid, as well as lithium, lamotrigine, and atypical antipsychotics for women of reproductive age with bipolar disorder.
These include a review of the evidence associating in utero exposure throughout pregnancy to valproic acid with neurobehavioral sequelae in children (Ob.Gyn. News, Dec. 15, 2004). I also reviewed the reproductive safety of first trimester exposure to lithium, which is associated with a 0.05% risk (1 in 2,000) of the cardiac malformation Ebstein’s anomaly; and the still sparse reproductive safety data for the newer atypical antipsychotics, such as olanzapine, quetiapine, and risperidone (Ob.Gyn. News, April 15, 2008). First trimester exposure to lamotrigine, another treatment option for bipolar illness, may be associated with a 0.9% risk of oral clefts based on at least one registry but has not been associated with overall increase risk of major congenital malformations. However, lamotrigine monotherapy does not seem to be as effective for the full spectrum of patients clinicians see with bipolar disorder, particularly those with predominantly manic-like symptoms.
In our program, we counsel hundreds of women of reproductive age each year who have bipolar disorder about the reproductive safety of medication options. Given its teratogenicity and behavioral teratogenicity, valproic acid should be considered contraindicated during pregnancy for the treatment of bipolar disorder with only the most rare exceptions, if any.
One option to consider with respect to treatment of bipolar disorder during pregnancy is lithium, where the teratogenic risk is established but is quantified and small (0.05%).
Another option might even include a class of medications where the reproductive safety is not yet clearly defined. Although this goes against the maxim “a known is better than an unknown,” medicines such as atypical antipsychotics, which do not seem to be associated with teratogenic risks based on limited experience, may be a better choice than a medicine—namely, valproic acid—where the quantified risk for a variety of malformations is consistently very, very great based on systematically conducted studies. As an example, we might use lithium or lamotrigine or even lamotrigine plus an atypical antipsychotic because the alternative—valproic acid—is so teratogenic.
Considering the declining use of lithium to treat bipolar disorder over the past few years and its known teratogenicity, and the very indicting data regarding valproic acid, we have increasing interest in identifying reproductive safety data of other medicines used to treat the illness, such as atypical antipsychotics. Studies are underway to address these issues, including a recently established national pregnancy registry for atypical antipsychotics (see ). For now, we treat patients with bipolar disorder who plan to get pregnant on a case-by-case basis, realizing that it might be reasonable to use medicines with quantifiable risks or a treatment that does not have a safety signal, compared with drugs with clearly significant risk for both organ dysgenesis and behavioral teratogenicity.
March 2010, ObGyn News, Lee S. Cohen, M.D.
Postpartum depression is a highly prevalent illness, with multiple studies consistently reporting rates of about 7%-10%, which include both minor and major depression. In some countries such as the United Kingdom, screening for postpartum depression is part of standard health care. In the United States, screening is highly variable, although there has been increasing awareness of this illness and the potential value of screening.
Screening for postpartum depression (PPD) has been recommended as part of routine postpartum care by the American College of Obstetricians and Gynecologists (Obstet. Gynecol. 2010;115(pt. 1):394-5). Several states, including New Jersey, have initiated mandated screening programs in a variety of settings to identify women suffering with postpartum depression. In Maine, an interesting pilot project has been launched, supported by the state’s psychiatric association, which entails screening women for postpartum depression by a spectrum of clinicians including obstetricians and primary care physicians, with psychiatric backup by a group of psychiatrists with subspecialty expertise in the management of postpartum depression.
Few would argue about the theoretical value of screening for postpartum depression, particularly when it leads to effective treatment, but very few studies have looked at whether screening is really cost effective. Specifically, it remains unclear whether screening for PPD leads to effective treatment of the illness (remission) and whether over time those treated do better clinically than those who are not identified or treated.
But a study conducted at the University of York (England), took a critical look at the extent to which screening for postpartum depression in a primary care setting was cost effective when a standardized postnatal depression or generic depression screening tool was used. The analysis, using an economic model and a hypothetical population of women seen at 6 weeks post partum in a primary care setting, determined that screening for PPD was not cost effective and therefore, could not be supported by the National Health Service, based on screening criteria established by that organization (BMJ 2009;339:b5203). The authors determined that the main reason screening was not cost effective was the cost of care for women with false-positive screening results. They concluded that the results did not meet the criteria required for formally adopting such a screening program.
The analysis did not factor in the associated costs of untreated postpartum depression, including the effect on the family and the child, despite the extensive literature on the toll of untreated PPD, including the risk for chronic maternal depression, recurrent postpartum depression, and adverse effects on infant and child development associated with untreated puerperal mood disturbance.
This study, although of interest, was conducted in a country with a national health care system that cannot be entirely extrapolated to the United States. But cost effectiveness and other issues surrounding the feasibility and overall value of screening for postpartum depression are still relevant issues that need to be considered in this country, as screening increasingly becomes a part of routine postpartum care and as more of these programs are recommended by professional organizations, if not mandated by given states.
For those of us who treat this illness, the question is not whether we can effectively screen for PPD, because screening is a simple process that can be accomplished with well-validated and readily available instruments. And there are extremely effective modalities for getting patients well, including nonpharmacologic interventions, such as certain psychotherapies, and pharmacologic interventions, such as antidepressants. Therefore, the problem that looms largest with respect to instituting screening programs is not what is the most appropriate screen or how to identify women with the illness. Rather, the most challenging aspect of screening for PPD in the United States centers on what follows identification of illness. How do clinicians ensure that identified patients have access to treatment that restores euthymia?
In the United Kingdom, primary care physicians routinely manage postpartum depression with regional backup from clinicians with expertise in reproductive psychiatry. In the United States, some primary care physicians treat postpartum depression, but others may be reluctant to do so, which highlights the contention that until a system is in place that ensures treatment of the illness following screening, then it may not be advisable to rush to institute such a program.
A critical questions also yet to be addressed is whether early identification of postpartum depression translates into a positive long-term outcome. We need to collect data on what happens after women are diagnosed, whether they get treated, and if so, how they are treated—with psychotherapy or pharmacotherapy. Data are also needed on who provides treatment and what types of treatment appear to be most effective for which types of patients. And when patients do get well, we need to look at data on whether the improvement is sustained. The precise value of screening is impossible to determine until we have these data.
If there ever is a national mandate to screen for postpartum depression, then it is critical to demonstrate that we have a treatment model in place that not only identifies patients who suffer from the illness, but that such a system includes delivery of effective treatment. Lastly, while it currently may not be possible to quantify the benefits of a screening program for PPD, what is clear is that such a program might help to de-stigmatize mental illness and prompt patients to seek treatment from a variety of care providers, including primary care physicians and obstetricians. Perhaps with greater opportunities to receive effective treatment from a variety of clinicians, the morbidity of postpartum mood disturbance could be vastly limited.
Questions about the management of depression during pregnancy continue to elicit discussion in clinical and academic venues. In the last decade, there have been numerous studies and reports evaluating the impact of antidepressant use and maternal depression during pregnancy on fetal and neonatal well-being and on long-term neurobehavioral outcomes.
It is noteworthy that we have more data regarding the effects of prenatal exposure to psychiatric medications than perhaps to any other types of medication women use during pregnancy.
A recent addition to the literature is a joint report from the American Psychiatric Association (APA) and the American College of Obstetricians and Gynecologists (ACOG) on the management of depression during pregnancy. The working group, convened by the APA and ACOG and including a developmental pediatrician, provided a critical review of the available English language literature on fetal and neonatal outcomes associated with exposure to mood disorder and antidepressant treatment during childbearing (Gen. Hosp. Psychiatry 2009;31:403-13; Obstet. Gynecol. 2009;114:703-13).
What’s clear is that although pregnancy was once considered a time of emotional wellbeing, studies over the last decade suggest that pregnancy is not protective with respect to psychiatric disorders such as depression, and that a considerable proportion of women will experience an episode of depression while pregnant. Therefore, it is critical for clinicians to be familiar with the current state of knowledge – and gaps in that knowledge – vis-à-vis the effects of maternal depression and fetal exposure to antidepressants on various reproductive outcomes.
The working group’s copious review suggests that the impact of maternal mood disorder on reproductive outcomes is extremely variable. For example, data on the effects of depression on outcomes such as fetal growth, preterm delivery, and various neonatal effects are highly inconsistent, with some studies suggesting depression during pregnancy is associated with low birth weight or small-for-gestational-age infants and an almost equal number suggesting no such effects.
Similarly, the substantial literature that has emerged over the last decade regarding the impact of antidepressants on birth outcomes has produced variable findings. One would hope that more data would provide the clinician with a more precise quantification of the risks associated with fetal exposure to antidepressants. But the findings in much of the literature have been variable with respect to outcomes, such as the impact of fetal exposure to selective serotonin reuptake inhibitors (SSRIs) on birth weight; some studies have suggested that birth weight is lower with exposure, but others do not show this.
The authors of the joint report highlight the greatest methodological flaw in virtually all of the literature evaluating fetal exposure to antidepressants: the potential confounding factor of maternal mood disorder. We have yet to see a study that compares outcomes among babies born to euthymic women on antidepressants, compared with outcomes among babies born to women who do not have a mood disorder and are not taking these medications during pregnancy.
A concern among both patients and clinicians is the impact of SSRIs on the risk for congenital malformations. The APA/ACOG report, consistent with other reports, states that the cumulative data from prospective studies and administrative databases suggest that the absolute risk of major congenital malformations associated with fetal exposure to SSRIs is inconsistent, and that if there is a risk, it is exceedingly small (OB.GYN. NEWS, June 2009, p. 14).
The most consistent finding across the literature over the last decade regarding fetal exposure to SSRIs is the finding of transient neonatal adaptation symptoms that include irritability, tachypnea, and hypoglycemia among newborns of 15%-30% of women who use SSRIs in the latter part of pregnancy. Few would disagree that this is a syndrome that has been frequently documented in association with SSRI exposure, but the authors of the APA/ACOG report underscore that the syndrome is transient and does not appear to have particular clinical relevance, at least acutely.
Lastly, concerns regarding an increased risk of persistent pulmonary hypertension of the newborn (PPHN) have also been called into question, because of multiple studies with varying results, including one recent study not cited by the working group in which no increase in risk was noted and two earlier studies cited by the working group where a heightened risk for PPHN was described compared with a baseline rate of 0.52/1,000 (OB.GYN. NEWS, March 2009, p. 22).
The working group provides the clinician with several schemata regarding the actual management of perinatal depression, with suggestions that vary based on whether a patient is pregnant already and whether she is being treated with an antidepressant. They suggest that women with milder cases of depression be treated with psychotherapy, with more serious consideration given to continuing pharmacologic treatment of perinatal depression in those with recurrent disease. They recommend that these approaches be considered in the context of a carefully tailored discussion that includes the risks and benefits of deferring treatment versus using the antidepressants.
Reading this report by seasoned investigators in both psychiatry and obstetrics and gynecology, one is left with the following conclusions: When it comes to managing perinatal depression, there are no perfect answers and no decision is risk free. Even with this exhaustive review, we don’t have studies that direct the clinician in an absolute fashion to a particular treatment.
Still, the clinician should be reassured by the numerous studies that have been conducted with antidepressants compared with other medicines that women take during pregnancy. With these data, clinicians can make thoughtful risk-benefit decisions as they collaborate with their patients, matching patient wishes and clinical histories with a given treatment decision that feels appropriate for that particular patient.
June 2009, ObGyn News, Lee S. Cohen, M.D. Studies conducted over the last decade have consistently supported the conclusion that pregnancy is not protective with respect to risk for new onset or recurrence of major […]
June 2009, ObGyn News, Lee S. Cohen, M.D.
Studies conducted over the last decade have consistently supported the conclusion that pregnancy is not protective with respect to risk for new onset or recurrence of major depression. The last decade also has produced numerous studies evaluating the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) with respect to the risk for major malformations, with most data supporting safety or suggesting a small absolute risk of malformations. Therefore, despite some earlier concerns about a possible increased risk for cardiovascular malformations associated with first trimester exposure to paroxetine (Paxil), data suggest that the absolute risk of major congenital malformations associated with first-trimester exposure to SSRIs is small.
There remain, however, residual concerns regarding the risk for preterm labor and neonatal withdrawal syndromes associated with SSRI use during pregnancy, particularly during the latter stages of gestation. The absolute risks for these types of obstetrical and neonatal difficulties remain unclear. With respect to the flip side of the risk-benefit decision, the potential impact of depression alone on the risk for major malformations and other obstetrical and neonatal outcomes, unfortunately, data also are inconclusive. Some studies have used large administrative databases to examine the effects of antidepressants and depression on various obstetric and neonatal outcomes, but these studies have obvious methodologic limitations with respect to being able to confirm either exposure.
Separating out the effects of exposure to depression versus SSRI use during pregnancy is critical because these two factors must be weighed against each other and balanced in one direction or the other when patients and clinicians make decisions about the relative risks and benefits of taking a medication during pregnancy or assuming the risk of an untreated psychiatric disorder.
One recent study represents an important effort to delineate the differential effects of depression and SSRI exposure during pregnancy on obstetric and neonatal outcomes (Am. J. Psychiatry 2009;166:557-66). The prospective, multicenter study evaluated the relative impact of depression and SSRIs on minor physical anomalies, maternal weight gain, infant birthweight, pregnancy duration, and neonatal characteristics in 238 pregnant women who were divided into three groups: those with no SSRI, no depression; those with continuous or partial exposure to an SSRI during pregnancy; and those with major depressive disorder (continuous or partial). As noted previously, while this question has been addressed in previous studies using large administrative databases, this is the first prospective study to do so.
Although limited by small sample sizes in the different groups, the study found no association between partial or continuous exposure to SSRIs and an increased risk in minor anomalies, or between depression and an increased risk of minor anomalies. No major malformations were observed in any group. These results are at variance with the landmark 1996 study reporting an increased risk for minor anomalies associated with first-trimester SSRI exposure (N. Engl. J. Med. 1996;335:10105). In this new study, there was also no association between depression or SSRI exposure and reduced maternal weight gain. Mean infant birth weights were similar in the groups (doi:10.1176/appi.ajp.2008.08081170).
What was particularly noteworthy in this study was that, among women with continuous depression without exposure to an SSRI and those with continuous SSRI exposure, more than 20% of the infants were delivered preterm, compared with 4%-9% of the infants in the other groups. Hence, these results don’t provide compelling data driving the risk-benefit decision with respect to the differential effects of either exposure to SSRI or depression, at least with respect to certain outcomes.
Finally, there were no differences associated with exposure to either continuous SSRI treatment or continuous depression with no SSRI and neonatal adaptation, including respiratory signs (with the exception of 5-minute Apgar scores) or admissions to the neonatal intensive care unit, after adjusting for maternal age, race, and gestational age.
In my view, the data from this study—although advancing the field and representing one more step forward in scientifically delineating the relative risks of antidepressants during therapy—don’t let the clinician off the hook, because the clinician can neither discount the impact of exposure to the medicine or to the disorder. Therefore, patients and their doctors again are left making these individual decisions based on the patient’s wishes, available reproductive safety data, and the severity of the underlying psychiatric disorder.
March 2009, ObGyn News, Lee S. Cohen, MD The risks associated with selective serotonin reuptake inhibitor use in pregnancy have been addressed in previous columns because of the accumulating data suggesting that depression during pregnancy […]
March 2009, ObGyn News, Lee S. Cohen, MD
The risks associated with selective serotonin reuptake inhibitor use in pregnancy have been addressed in previous columns because of the accumulating data suggesting that depression during pregnancy is common and that many pregnant women use SSRIs. A recent study indicated that as many as 8% of pregnant women are treated with SSRIs, so clearly delineating the spectrum of associated risks is of critical clinical importance.
Although an increasing amount of data suggests that the teratogenic risks associated with fetal exposure to SSRIs are small and the potential for problems with neonatal adaptation symptoms are common (about 30%) but typically self-limited, several recent studies have evaluated the risk for persistent pulmonary hypertension of the newborn (PPHN) associated with late trimester exposure to SSRIs.
I have reviewed several studies suggesting a spectrum of risk, dating back to the case-control study using data from a birth defects database, which ascribed about a sixfold increase in risk for PPHN to late trimester exposure to SSRIs (N. Engl. J. Med. 2006;354:579-87). This was followed by a case-control study published last year from the Swedish Medical Birth Register, which found approximately a twofold increased risk of PPHN associated with SSRI exposure late in pregnancy (Pharmacoepidemiol. Drug Saf. 2008;17:801-6).
Recently, another study using an administrative database from four health plans in an ongoing HMO research network study of birth outcomes provided yet another estimate. The investigators retrospectively identified 1,104 full-term infants whose mothers were dispensed an antidepressant in the third trimester and 1,104 full-term infants whose mothers did not receive an antidepressant in the third trimester (Pharmacoepidemiol. Drug Saf. 2009 January 15).
Possible cases of PPHN were identified using different diagnosis and procedure codes and confirmed with reviews of hospital records. There was no difference in risk for PPHN between exposed and unexposed children: The prevalence of PPHN was 2.14 per 1,000 among infants exposed to an SSRI during the third trimester and 2.72 per 1,000 among the infants not exposed to SSRIs. Only a small number of cases of possible PPHN were confirmed-two among SSRI-exposed infants and three among those not exposed-and some cases may have been missed, hence one of the limitations of the study.
The conflicting data are not terribly surprising because these studies are not prospective and they use various databases; each has its own respective limitations. It is noteworthy, however, that in the most recent study, the frequency of PPHN was similar to rates reported in the literature and the general population, suggesting that the methods used were comprehensive and that the results may reflect what we see in the real world. Also noteworthy is that maternal diabetes and asthma, two known risk factors for PPHN, were common in the exposed group, compared with the unexposed group, but other risk factors known to drive PPHN-increased body mass index, alcohol and cigarette smoking, or African American ethnicity-were not ascertained in this study.
Hence, we are faced once again with studies addressing critical questions for patients that have provided different results, which certainly makes it challenging for clinicians to attempt to navigate a thoughtful clinical course for their patients.
When counseling patients, one concern is how these data cumulatively inform the care of patients with histories of recurrent major depression treated with SSRIs during pregnancy. Given the warnings in the SSRI labels regarding PPHN, many patients-in collaboration with their doctors-may elect to discontinue antidepressants just before delivery because of concern over PPHN, an extremely serious outcome. Given the study with the sixfold increased risk, the Swedish registry data indicating a twofold increased risk, and these new data, which suggest the absence of risk, the answer regarding the true risk for PPHN may fall somewhere in the middle, with perhaps some modest increase in risk.
Even if we assume a modest increase in the risk for PPHN in this scenario, the absolute risk is extremely small and it may not justify discontinuing antidepressants close to delivery because this clearly puts patients at risk for depressive relapse and at a very high risk for worsening of mood in the postpartum period, with its attendant morbidity and adverse sequelae for both the mother and child.
Clinicians and patients together will make decisions based on the available information, and those decisions will vary from patient to patient, based on patients’ wishes and individual clinical situations. We make the best clinical decisions possible on a case by case basis, and we welcome more of these analyses from rich datasets so we can continue to refine risk estimates-particularly for rare but serious outcomes such as PPHN.
Over the last several years, the reproductive safety of selective serotonin reuptake inhibitors (SSRIs) has been the focus of continual interest and concern, with data from several studies informing the question of relative risks of fetal exposure to these medicines. Two recent analyses from large birth defects surveillance programs suggest that the risk for major malformations associated with first trimester exposure to SSRIs is extremely small (N. Engl. J. Med. 2007;356:2684-92, 2675-83).
Based on the results of other studies that are particularly consistent, there now appears to be a consensus that late-trimester exposure to SSRIs is associated with an increased risk for symptoms broadly described as “poor neonatal adaptation” including: tremulousness, jitteriness, and myoclonus. These symptoms tend to be transient, and their clinical relevance appears to be limited-because infants born with these symptoms typically do not require any particular clinical intervention.
More recently, an increased risk of a far more serious condition, persistent pulmonary hypertension of the newborn (PPHN), has been associated with exposure to SSRIs late in pregnancy. The first study to describe this association, derived from a case control study using data from a birth defects database, reported that in utero SSRI exposure after 20 weeks’ gestation was associated with an increased risk of PPHN (about sixfold higher), with an absolute risk approaching 1% (N. Engl. J. Med. 2006;354:579-87). When it was published, the study elicited great concern among clinicians and patients; the Food and Drug Administration also suggested inclusion of the finding in the labels of SSRIs.
Factors driving the risk for PPHN have been studied extensively and were the focus of a case-control study of the same birth defects database published last year that found a strong association between PPHN and several common prenatal and perinatal factors, including cesarean delivery, high maternal BMI, being African American or Asian, and being large for gestational age (Pediatrics 2007:120;e272-e82). Though extensive discussion was not given in that article about the relative contributions of these common factors to risk for PPHN, compared with SSRI exposure late in pregnancy, the data suggest that large BMI and cesarean delivery, for example, drive PPHN to a far greater extent that SSRI exposure.
The association between SSRI exposure during pregnancy and PPHN was again addressed recently in a case-control study using data from the Swedish Medical Birth Register of over 800,000 infants born between 1997 and 2005; 506 infants had a discharge diagnosis of PPHN. Across a wide variety of SSRIs to which women had been exposed, the risk of PPHN associated with maternal use of an SSRI among babies born after 34 weeks’ gestation was increased by 2.4, after adjusting for other risk factors (Pharmacoepidemiol. Drug Saf. 2008;17:801-6). This finding was among the women who reported using an SSRI when interviewed early in pregnancy, before the end of the first trimester-a marginally statistically significant increase. These results are consistent with the results of the 2006 study, but suggest a more attenuated risk and might explain why clinicians with patients treated with an SSRI during pregnancy rarely see this condition.
The results may be considered somewhat reassuring because they suggest that even if there is an increased risk, the increase is small. Considering the prevalence of SSRI use during pregnancy-as high as 6%-8%, according to several recent studies-PPHN presumably would be seen more often if the risk were as high as 1%. (On the other hand, it is common to hear about neonatal adaptation symptoms in babies who have been exposed in late pregnancy to SSRIs, where estimates of the prevalence of such symptoms are 25%-30%).
One of the obvious advantages of the Swedish study was that the information about SSRI use was obtained prospectively and did not rely on retrospective recall, as was the case in the 2006 study. But no study is perfect and, in the Swedish study, the investigators were not able to distinguish between early and late exposure. Late exposure was extrapolated by assuming that women on the drug early in pregnancy were also on the drug late in pregnancy. That is not a trivial limitation, because of evidence indicating that is not uncommon for women who are on an antidepressant in early pregnancy to discontinue treatment after either documentation of pregnancy or later in pregnancy.
Therefore, if cases of late exposure were underreported, the estimate that the PPHN risk associated with late-trimester exposure to an SSRI is increased by about 1.5 cases per 1,000 SSRI-exposed infants in the Swedish cohort may be an underestimate. The wish to limit neonatal tremulousness and modulate the risk of PPHN may lead some clinicians and their patients to consider discontinuing an SSRI in late pregnancy. The association between late trimester SSRI exposure and PPHN places the clinician in a bind, because discontinuing an SSRI before labor and delivery clearly puts the woman at risk for relapse prior to delivery and places her at considerable risk for postpartum depression-given that depression during pregnancy is the strongest predictor of postpartum worsening of mood.
As a field, every few months, we see new studies that frequently include analyses of large administrative databases or birth defects surveillance programs where a spectrum of outcomes-ranging from malformations to PPHN-is described following SSRI exposure during pregnancy. It is intuitive that such emerging data might help clinicians make informed decisions with their patients as they weigh these risks on a case by case basis. Under the best of circumstances, new findings and more data inform the pharmacologic treatment of depression during pregnancy.
However, the results of new studies sometimes either refute current associations or suggest greater or lesser associations. That is the case for PPHN in the Swedish study, which can make it more challenging for clinicians to weigh precisely the risks and benefits when managing psychiatric disorders during pregnancy. Ultimately, clinicians and their patients make collaborative decisions, and treatment will be tailored to match the clinical situation using the best available data possible.
July 15, 2008
July 2008, ObGyn News, Lee S. Cohen, MD The Food and Drug Administration has proposed revisions to the longstanding system of pregnancy category labeling for all medications. The current system has classified the reproductive safety […]
July 2008, ObGyn News, Lee S. Cohen, MD
The Food and Drug Administration has proposed revisions to the longstanding system of pregnancy category labeling for all medications. The current system has classified the reproductive safety of medications across five risk categories—A, B, C, D and X—usually based on available data when a drug is approved. The proposed system will eliminate the letter categories and instead will include sections on pregnancy and lactation, each with information summarizing risks, clinical considerations, and available human and animal data.
The implications of the proposed system with respect to psychiatric medications are significant. In previous columns, I have discussed some of the limitations of the category label system for various psychiatric medications. There are examples of medications with a sparse amount of reproductive safety information that does not indicate an adverse effect, which are inbear a a more favorable category label than other medicines for which very extensive reproductive safety are available, but perhaps where animal safety data suggest some cause for concern. There are also examples where evidence of adverse reproductive effects in animals dosed with toxic amounts of a medicine can trump significant amounts of human data supporting reproductive safety.
A dramatic example of the current system’s limitations is lithium, a category D drug because of clear evidence of Ebstein’s anomaly associated with first-trimester exposure. Yet the absolute risk of the cardiac anomaly is only 0.05% following first-trimester exposure. Considering the high rate of relapse of bipolar disorder associated with stopping lithium before or during pregnancy, this may be a risk many patients are willing to take, in collaboration with their psychiatrists.
The current system also does not distinguish between relative amounts of data, and typically lumps a class of medications into one category, instead of considering the drugs as individual molecules. All the selective serotonin reuptake inhibitors are labeled category C, yet the amount of reproductive safety data available for the individual SSRIs is highly variable. Moreover, information in the letter category system has been limited to reproductive safety during the first trimester and does not address some of the potential risks of exposure during the second and third trimesters, and peripartum period.
Part of the problem is that with few exceptions, industry has failed to embrace a global product safety initiative regarding establishing registries for these products in a systematic way shortly after a drug is marketed.
In May, after almost a decade after indicating that the pregnancy and lactation labeling system would be changed, the FDA announced the proposed changes, which address these limitations.
The pregnancy section would include a fetal risk summary, which would describe the risks to the fetus associated with exposure to the medicine based on available data; and clinical considerations, which would include information about the effects of the drug if a woman takes it before she knows she is pregnant and the risks of the disease for the mother and baby. A third section would summarize the available human and animal data that provide the basis of the fetal risk summary. The labor and delivery section in the current drug label would be eliminated, with this information included in the pregnancy section. The section on lactation would include the same sections on risk summary, clinical considerations, and data.
The clinical implications of dropping the letter category system are considerable. These categories have frequently been used to switch patients from one medicine to another somewhat arbitrarily. Even well-intentioned clinicians have switched a patient to a medicine based on the category label, when there are less available reproductive safety data in humans, but perhaps animal data were of some concern. For example, a patient who is exquisitely responsive to a category C drug may have been switched to a category B drug during pregnancy even though there are very sparse data for the drug with the category B rating, but none of it adverse.
Once the new system is in place, this type of arbitrary change in a patient’s medication based on the category label will hopefully cease. Moving from a categorical system of classification to a system that is more inclusive of available reproductive safety information should help clinicians rather than confuse them. Clinicians will be provided with more information in a drug’s label that actually describes results of studies and will be able to see firsthand the type of information that is available and the quality of data, as well as references to studies. As a result, we will be provided with a more global risk assessment across pregnancy, including the peripartum period and lactation.
Some clinicians may miss the category label system because it is simple, despite its flaws. The current plan may make the reproductive safety information less black and white, but that is indeed the current state of the science when it comes to reproductive safety. No decision is perfect and no decision is risk free.
Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, Boston, which provides information about pregnancy and mental health at . He also is a consultant to manufacturers of some psychiatric drugs, including antidepressants.
April 2008, ObGyn News, Lee S. Cohen, MD While data regarding the reproductive safety of certain psychotropics such as selective serotonin reuptake inhibitors and anti-epileptic drugs have increased over the last several years, information regarding […]
April 2008, ObGyn News, Lee S. Cohen, MD
While data regarding the reproductive safety of certain psychotropics such as selective serotonin reuptake inhibitors and anti-epileptic drugs have increased over the last several years, information regarding attendant risks of fetal exposure to antipsychotics remains more sparse.
This is particularly true for the newer atypical antipsychotics, which are increasingly being used in women of reproductive age for a range of psychiatric disorders in addition to schizophrenia, including bipolar disorder and depression.
It is therefore critical that clinicians and women have good information upon which to base decisions about continuing treatment during pregnancy. There are several decades’ worth of data from large studies supporting the reproductive safety of the typical antipsychotics such as haloperidol or thiothixene, but the reproductive safety data for the atypical antipsychotics are extremely sparse.
To date, few prospective studies on atypicals in pregnant women have been published. In a study comparing pregnancy outcomes in 151 subjects exposed to different atypicals-60 to olanzapine, 49 to risperidone, 36 to quetiapine, and 6 to clozapine-with nonexposed controls, major malformation rates were not significantly different between the two groups (J. Clin. Psychiatry 2005;66:444-9). However, this is a relatively small sample. (The other two atypicals available are aripiprazole and ziprasidone.)
The other available safety data on atypical antipsychotics in pregnant women are derived mainly from case reports or small case series, which have not identified an increased risk for major malformations.
Most of the prospectively identified cases of exposure are to olanzapine (133), risperidone (over 500), and quetiapine (42), with very few to aripiprazole and clozapine, and possibly none to ziprasidone. In March, some of the first registry data on atypicals were reported at a meeting, from the Australian Pregnancy Registry. Among 38 pregnancies exposed to atypical antipsychotics, there were no major malformations.
The association of the atypicals with weight gain, diabetes, and hypertension raises another potential safety issue when these drugs are used during pregnancy. Weight gain and adiposity in pregnant women have also been associated with an increased risk of neural tube defects, independent of folate status (Am. J. Psychiatry 2002;159:136-7).
As is often the case when considering the use of psychotropics during pregnancy, the specific clinical approach depends on when the patient sees the clinician. For a patient who presents for evaluation before pregnancy on a low dose of an atypical antipsychotic as an adjunct to a mood stabilizer, it may make sense to switch to an antipsychotic for which more reproductive safety data are available, such as perphenazine. This scenario may not always be feasible, however, because many patients
present when they are already pregnant. If they are well maintained, the clinician may be understandably reluctant to make changes.
Because of the absence of indicting data, we have typically maintained patients on atypical antipsychotics if they are already pregnant because of our concerns about clinical destabilization. However, we do recommend close follow-up for safety issues such as weight gain, diabetes, and hypertension during pregnancy, working collaboratively with the obstetrician. Another consideration is that, although there are no robust data clearly distinguishing differences in efficacy, there are patients who appear to derive particular benefit from an atypical antipsychotic.
Based on the limited data available, there does not appear to be a glaring reproductive safety signal for the atypicals. But given the prevalence of use of these medicines in psychiatry, we clearly need more quality data on this drug class, similar to those we have for antidepressants and antiepileptic drugs (AEDs), so that that the atypicals can be safely integrated into the treatment algorithms used during pregnancy to treat women across that spectrum of disease states.
We are establishing an atypical antipsychotic pregnancy registry at Massachusetts General Hospital that will be similar to the North American AED registry. This registry, along with other global AED registries, has produced invaluable data on the reproductive safety of antiepileptics.
Dr. Cohen directs the perinatal psychiatry program at Massachusetts General Hospital, Boston, which provides information about pregnancy and mental health at .He is a consultant to manufacturers of atypical antipsychotics.
October 2007, ObGyn News, Lee S. Cohen MD Over the last 5 years, several studies analyzing the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs), individually and as a group, have been published in […]
October 2007, ObGyn News, Lee S. Cohen MD
Over the last 5 years, several studies analyzing the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs), individually and as a group, have been published in the United States and elsewhere. Earlier studies that failed to show an association between first-trimester exposure to SSRIs and an overall increased risk of major congenital malformations were typically small cohort studies; subsequent meta-analyses of the available cohort studies have also failed to show an increased risk, which has been reassuring.
The cohort study, which prospectively follows both exposed and unexposed people longitudinally, is the gold standard for evaluating the teratogenic potential of drugs. However, such a study is limited by the difficulty in enrolling enough exposed subjects to demonstrate a statistically significant difference between the two groups (which is particularly true for relatively rare outcomes that can easily be missed).
Recently, several large case-control studies have been published that questioned the safety of SSRIs with respect to teratogenic risk. Case-control studies identify cases of an outcome of interest, such as a certain birth defect, and analyze case and control groups of patients to determine if an association exists between various exposures and the outcome.
Such studies have included an analysis of records from a large managed care organization, which found an increased risk of heart defects in the babies of women who were prescribed paroxetine (Paxil) during pregnancy, compared with the babies of women prescribed other antidepressants during pregnancy. Another study, using data from the Swedish Medical Birth Registry, also found an increased risk of cardiac defects among infants with first-trimester exposure to paroxetine.
Two large case-control studies published in June represent the latest efforts to use large multicenter birth defect surveillance programs to refine our understanding of the reproductive safety of SSRIs. Based on their size, these studies might be expected to refine the risk estimate for congenital malformations following fetal exposure to SSRIs, but these investigations produced some divergent results.
The National Birth Defects Prevention Study compared 9,622 infants with birth defects with 4,092 control infants born in the United States from 1997 to 2003 and found no significant association between use of any SSRI from 1 month before to 3 months after conception and congenital heart defects or most other birth defects analyzed.
There was, however, a significantly increased risk for anencephaly (odds ratio 2.4), craniosynostosis (OR 2.5), and omphalocele (OR 2.8) associated with SSRI use in early pregnancy; these are birth defects that have not been associated with in utero exposure to SSRIs in previous studies. The relationship was particularly strong with paroxetine (N. Engl. J. Med. 2007;356:2684-92).
But no associations were identified between maternal SSRI use in early pregnancy and these three anomalies or congenital heart defects overall in the accompanying case-control study of 9,849 infants with birth defects and 5,860 infants with no birth defects enrolled in the Slone Epidemiology Center Birth Defects Study, at Boston University (N. Engl. J. Med. 2007;356:2675-83). However, there was a significant association between the use of sertraline (Zoloft) specifically and both omphalocele (odds ratio 5.7) and septal defects (2.0).There was also a significant association between paroxetine exposure and right-ventricular outflow tract obstruction defects (odds ratio of 3.3). It should be noted that the number of actual exposures in these studies to a specific SSRI was particularly small, fewer than 10 actual reported exposures.
Where do these two important studies leave the patient and the clinician? Despite the divergent findings, both studies suggest that the absolute risk of overall major congenital malformations or even particularly rare malformations is extremely small, as pointed out by the respective authors and the accompanying editorial (N. Engl. J. Med. 2007;356:2732-3). For example, the Slone study authors point out that the estimated prevalence of right-ventricular outflow tract obstruction defects is about 5.5 cases per 10,000 live births, so the risk of this defect would be only 0.2% if an SSRI increased the risk fourfold. It also has been noted that in such studies the search for numerous outcomes associated with potentially numerous exposures may result in a finding by chance.
In addition, clinicians and patients should consider that, while we have not yet absolutely quantified the risk of prenatal exposure of SSRIs (which might not be achievable), a critical finding influencing treatment decisions is that untreated depression during pregnancy dramatically increases risk for postpartum psychiatric relapse. In fact, perhaps nothing trumps the importance of sustaining maternal emotional well-being during pregnancy, even given the small absolute risks that may be associated with an individual SSRI during pregnancy.
January 15, 2007
January 7 , 2007 by LEE COHEN, M.D. The multiple recent reports regarding the reproductive safety of the selective serotonin reuptake inhibitors have raised concerns about a spectrum of potentially adverse outcomes associated with SSRI […]
The multiple recent reports regarding the reproductive safety of the selective serotonin reuptake inhibitors have raised concerns about a spectrum of potentially adverse outcomes associated with SSRI use during pregnancy. But these reports have produced conflicting results and hve been confusing for many patients and clinicians.
To date, no professional medical association has issued formal guidelines regarding treatment with SSRIs during pregnancy. However, in December the American College of Obstetricians and Gynecologists’ Committee on Obstetric Practice published an opinion on this topic that is noteworthy in its clarity and balanced review of the existing data. The opinion artfully underscores the relevant issues for reproductive-age women who suffer from depression and who are being treated with antidepressants (Obstet. Gynecol. 2006;108:1601-3).
The ACOG committee makes clear there is no specific treatment algorithm for this population, recommending that “treatment with all SSRIs or selective norepinephrine reuptake inhibitors or both during pregnancy be individualized” and that decisions about treating depression “should incorporate the clinical expertise of the mental health clinician and obstetrician, and the process should actively engage the patient’s values and perceptions when framing the discussion of the risks and benefits of treatment.”
The committee points out that many studies have not identified an increased risk for major congenital malformations associated with SSRI use during pregnancy. This is noteworthy, since more is known about the teratogenic risk of SSRIs than about most medications prescribed to pregnant women, including, as examples, various anti-infectives, antiemetics, and medicines used to treat gastroesophageal reflux.
The ACOG opinion does refer to the recent unpublished reports from a Swedish registry and a U.S. claims database associating first-trimester exposure to paroxetine with a greater risk of atrial and ventricular septal defects. (This prompted the Food and Drug Administration to change paroxetine’s pregnancy category label from C to D in late 2005.) Interestingly, the committee does not suggest that paroxetine absolutely is contraindicated during pregnancy, but wisely states that paroxetine should be avoided when planning pregnancy, adding that “the benefits of paroxetine therapy may outweigh the potential risk.”
However, the committee does state that “at this time, paroxetine use among pregnant women and women planning pregnancy should be avoided, if possible.”
Also referenced in the opinion are reports of syndromes of perinatal toxicity or poor neonatal adaptation associated with SSRI exposure in late pregnancy – transient neonatal symptoms that include jitteriness, mild respiratory distress, weak cry, and neonatal ICU admissions – findings that I have addressed in previous columns. With respect to persistent pulmonary hypertension of the newborn (PPHN), the more serious outcome, the opinion summarizes the case control study that found a sixfold greater risk in PPHN associated with SSRI use after 20 weeks’ gestation.
The PPHN finding was the topic of another FDA public health advisory in 2006, which, as the ACOG opinion points out, also addressed the risk of depression relapse. That advisory cites our study, which found relapse was fivefold higher among women who had stopped antidepressants during pregnancy than it was among those who continued with treatment.
The opinion then says “the potential risk of SSRI use throughout pregnancy must be considered in the context of the risk of relapse of depression if maintenance treatment is discontinued” and refers to the increased risks of low weight gain and alcohol and substance abuse that are associated with untreated depression.
The ACOG opinion advises that treatment decisions need to be carefully tailored, and “optimally, shared decision making among obstetric and mental health clinicians and women should occur before pregnancy.” But, it concludes, 50% of pregnancies are unplanned; hence, pre conception planning will not always be possible “and decisions regarding treatment with SSRIs will undoubtedly occur during gestation.”
In our clinical experience, we see directly what prompts women to make decisions about SSRI use during pregnancy. These decisions are not necessarily driven by severity or duration of illness, or number of past episodes, but more from their perception of risk and the willingness to accept the risk of depression relapse vs. fetal exposure to medication.
When it comes to prescribing SSRIs during pregnancy, we need to collaborate with patients on a decision in circumstances in which we have imperfect estimates of risk on both sides of the risk-benefit equation. As in any other clinical situation, we tailor treatment based on particular clinical scenarios and patients’ wishes.
July 15, 2006
July 15, 2006 from ObGynNews Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used […]
July 15, 2006 from ObGynNews
Historically, lithium has been a mainstay of treatment for bipolar disorder. However, over the last decade, anticonvulsant drugs such as sodium valproate and lamotrigine (Lamictal) have become more widely used to treat this disorder.
The use of lithium in the first trimester is associated with a 0.05%–0.1% risk for Ebstein’s anomaly, a well-described and frequently serious cardiac malformation. But data from the North American Antiepileptic Drug (NAAED) Pregnancy Registry and other international registries indicate that first-trimester exposure to sodium valproate is associated with an 8%–10% risk of major congenital malformations, notably neural tube defects and cardiac malformations.
As a result, many clinicians have been relieved to have the option of lamotrigine, which is an effective treatment for bipolar disorder and for which there had been extremely reassuring reproductive safety data over the last 5–7 years.
And until recently, several global teratovigilance programs had not found any indication that first-trimester use of this medication was associated with an increased risk for major congenital malformations.
In what is an important development, recent data from the NAAED registry note a prevalence rate of 2.7% for overall major malformations; however, five infants (8.9/1,000) had oral clefts. (See accompanying article.)
The baseline incidence of oral clefts in the general population has been calculated to be between 0.5 and 2.16 per 1,000 births; thus the data from the NAAED registry suggest at least a fourfold increase in the risk of cleft lip and palate or an absolute risk of approximately 0.9%. Interestingly, in five other registries surveyed, the frequency of oral clefts was 2.5 per 1,000 births, far less than reported by the NAAED Registry.
So how is the clinician to understand these new data, which suggest a signal of teratogenic risk, and how do the data inform the clinical care of patients who rely on the medication for control of chronic relapsing illnesses such as epilepsy or bipolar illness?
While stopping medication for the first trimester may appear to be an option for patients with bipolar disorder, unfortunately, a significant proportion of bipolar patients who do so will relapse.
Pregnancy does not appear to protect women with bipolar disorder against relapse if the mood stabilizer they are using is discontinued: In both a retrospective and prospective study, approximately 50% of patients relapsed during the first 6 months of pregnancy following discontinuation of mood stabilizer. It is also noteworthy that women with bipolar disorder are already at a fivefold increased risk for postpartum depression, compared with the general population, a risk that increases further if they relapse during pregnancy.
Therefore, many women with bipolar disorder who want to conceive are caught between a rock and a hard place, because many compounds used to treat bipolar disorder are either known teratogens, or are agents for which the available reproductive safety data are extremely sparse, such as the atypical antipsychotics, i.e., olanzapine (Zyprexa), risperidone (Ripserdal), quetiapine (Seroquel), and aripiprazole (Abilify).
Clinicians need to work collaboratively with patients to make treatment decisions, making every effort to minimize risk of relapse and fetal risk, realizing that some patients may have to assume some risk if they are to sustain affective well-being during pregnancy. For women who are on lamotrigine and are planning to conceive, the patients and prescribing clinician should now discuss the increased risk for oral clefts.
Patients who require treatment with a mood stabilizer, particularly those with recurrent disease, may consider a trial of lithium, which, while a teratogen, is associated with an extremely small risk for a cardiovascular malformation.
Certainly, the risk associated with lamotrigine is dramatically more modest than the risk associated with first-trimester exposure to sodium valproate, and many patients may elect to continue lamotrigine.
When drug choice during pregnancy is considered, proceeding with a drug with known small risks as opposed to one with totally unknown risks is advantageous, particularly if the known risk is a modest one, which is the case with lamotrigine and lithium.
Ultimately, the clinician is left having to make decisions on a case-by-case basis, in collaboration with the patient, realizing that no decision is absolutely risk-free. But decisions can be made that minimize morbidity associated with recurrence of bipolar illness, as well as prenatal exposure to any potentially harmful compound.
When presented with the options, women may make very different decisions. Some women in fact may decide to assume a small risk of oral cleft over a 0.05% risk for a heart malformation because they feel that oral clefts can be repaired more easily, while the morbidity and mortality of Ebstein’s anomaly is high, even though the risk is exceedingly small. That is why these decisions have to be made individually, because such decisions will be made not based on relative risk or even absolute risk but rather on each patient’s perception of risk.
April 15, 2006
April 2006 by LEE S COHEN MD from ObGyn News Until fairly recently, studies and reviews of global teratovigilance data have been relatively reassuring that SSRIs were particularly safe, especially with regard to their teratogenicity. […]
April 2006 by LEE S COHEN MD from ObGyn News
Until fairly recently, studies and reviews of global teratovigilance data have been relatively reassuring that SSRIs were particularly safe, especially with regard to their teratogenicity. In fact, there are more reproductive safety data available for SSRIs than for many medicines women take during pregnancy. However, new reports have raised concerns regarding the teratogenicity of paroxetine, which we have previously discussed (OB.GYN. NEWS, Oct. 15, 2005, p. 9), as well as risk for putative neonatal distress syndromes and, most recently, possible increased rates of persistent pulmonary hypertension of the newborn (PPHN) following late-pregnancy exposure to SSRIs.
What do the new reports describe and how do the findings inform clinical care? One study supports previous reports of a “neonatal abstinence syndrome” with characteristic symptoms of jitteriness, sleep disturbance, dysregulation, tachypnea, and myoclonus in infants whose mothers used antidepressants during pregnancy. In this prospective cohort study of 120 infants, examiners used a systematic scale to assess full-term SSRI-exposed newborns with respect to presence or absence of a wide range of previously reported symptoms.
Of the 60 infants exposed in utero to various SSRIs for a mean of 35.5 weeks, 8 had severe symptoms and 10 had mild symptoms, compared with none of the 60 infants who had not been exposed in utero to these drugs (Arch. Pediatr. Adolesc. Med. 2006;160:173–6). A particularly noteworthy finding is that no infant with symptoms required treatment intervention; symptoms were transient and of little if any clinical significance.
In the second study, investigators using a case-control design described an elevated risk for PPHN, a far more serious syndrome associated with severe respiratory failure, in newborns with in utero exposure to SSRIs late in pregnancy. In this study, which enrolled almost 400 women whose infants had PPHN, matching them to more than 800 control mothers and infants, the use of SSRIs at any point during pregnancy was not associated with PPHN, but there was a significant association between PPHN and in utero exposure to an SSRI after 20 weeks’ gestation (N. Engl. J. Med. 2006;354:579–87).
The study describes a very disturbing and striking finding. But an accompanying editorial points out that the number of cases reported is small (N. Engl. J. Med. 2006;354:636–8). And though not mentioned in the editorial, the vulnerability to reporting bias in such a study is great. One wonders whether women without an adverse outcome may be reluctant to disclose use of an antidepressant during pregnancy, compared with those with an adverse outcome as serious as PPHN. Because the conclusions are based on a small number of PPHN cases, a difference of a small number of cases in either direction can strengthen or attenuate a positive finding.
The authors of the second study suggest that the incidence of PPHN associated with SSRI exposure in late pregnancy approaches 1%. However, given the hundreds of women who have used SSRIs during late pregnancy, it is unlikely that such a dramatic clinical finding would not have been reported, even anecdotally, prior to this particular study—the first of such reports.
These data certainly suggest that pregnancy is not protective with respect to depression and that many women who stop antidepressants will relapse during pregnancy.
While some women will still stop antidepressant therapy during pregnancy, patients should be informed that depression during pregnancy can increase the risk for other neonatal complications and can substantially increase their risk for postpartum depression. Other women will choose to continue antidepressant use during pregnancy, regardless of the findings of some of these more recent studies, given what for some patients will be viewed as a modest risk for the neonatal outcomes described. Regardless of individual choices, which will be extremely variable, it is crucial to present all available information to reproductive-age women on antidepressants who plan to conceive or who are pregnant, so that collaborative decisions can be made based on these data and personal wishes.
January 15, 2006
January 15, 2006 from ObGynNews Multiple studies over the past decade have been supportive of the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs) when used during the first trimester; these studies include one […]
January 15, 2006 from ObGynNews
Multiple studies over the past decade have been supportive of the reproductive safety of the selective serotonin reuptake inhibitors (SSRIs) when used during the first trimester; these studies include one recent metaanalysis and other extensive reviews. Particularly reassuring have been the prospective data on fluoxetine (Prozac) and citalopram (Celexa). As a result, clinicians have been relatively reassured about the absence of teratogenic risk associated with the SSRIs.
New concerns were recently raised about the reproductive safety of paroxetine by a presentation at the Teratology Society annual meeting that reported an increased risk of omphalocele associated with first-trimester exposure. This report was based on preliminary, unpublished data from the National Birth Defects Center, which I reviewed in a recent column (OB.GYN. NEWS, Oct. 15, 2005, p. 9). A weaker association was also found between omphalocele and other SSRIs.
A Food and Drug Administration public health advisory about paroxetine followed in December, describing preliminary results of two other unpublished studies indicating that paroxetine exposure in the first trimester may increase the risk of congenital malformations, particularly cardiac malformations. At the FDA’s request, paroxetine manufacturer GlaxoSmithKline has changed the pregnancy category label for paroxetine from C to D.
It is surprising that the FDA’s recommendation and advisory are based on preliminary analyses from several recent, unpublished, non-peer-reviewed epidemiologic studies, as these are data that should be considered, at least at this point, inconclusive.
Using data from the Swedish National Registry, one study found a 2% rate of cardiac defects among infants exposed during the first trimester to paroxetine vs. 1% among all registry infants. But a previous study using registry data that was based on a slightly smaller number of children exposed to paroxetine did not report this association (J. Clin. Psychopharmacol. 2005;25:59–73).
Another study, using data from a U.S. insurance claims database, found the rate of cardiovascular malformations was 1.5% among infants exposed to paroxetine during the first trimester vs. 1% among infants exposed to other antidepressants. The majority were atrial or ventricular septal defects, which are common congenital malformations.
The modest increases in relative risk of a common anomaly, when derived from a claims database with inherent methodologic limitations, make interpretation of these data problematic. Unfortunately, the language in the FDA advisory, suggesting that “the benefits of continuing paroxetine may outweigh the potential risk to the fetus,” may get lost in the information patients receive.
Although there are not as many published studies on the teratogenic risk of paroxetine as for other SSRIs, it is noteworthy that prospective studies have not identified a higher rate of congenital or cardiac malformations associated with prenatal exposure to paroxetine.
How does the clinician then counsel women of reproductive age who suffer from major depression? And what is the best option for patients who are being treated with paroxetine who want to get pregnant or who have an unplanned pregnancy? Until the issue is clarified with more rigorously obtained and conclusive data, it is reasonable to avoid paroxetine in women who are actively trying to get pregnant or plan to in the future.
For those with major depression who are antidepressant-naive, it may be most prudent to prescribe an SSRI or an SNRI for which there are no unfavorable data to date, such as fluoxetine or citalopram/escitalopram, or an older tricyclic antidepressant such as nortriptyline.
What makes sense for those who have failed to respond to one of those medications previously, as in the all-too-common scenario of nonresponse to multiple SSRIs and response only to paroxetine? In this situation, the use of paroxetine in women who are planning to conceive or who are already pregnant should not be considered absolutely contraindicated.
Until the data are peer-reviewed and published, decisions about use of this medicine in women who are planning a pregnancy or are pregnant will have to be made on a case-by-case basis. But we need to keep in mind that nothing is more critical than sustaining euthymia during pregnancy. Untreated depression in pregnancy is associated with compromised fetal well-being as well as increased risk for postpartum depression.
DR. LEE COHEN directs the perinatal psychiatry program at Massachusetts General Hospital. He is a consultant to manufacturers of several antidepressant drugs, including paroxetine and other SSRIs.
October 15, 2005
October 15, 2005 from ObGynNews By Lee S. Cohen, M.D. Over the past few years, several studies have addressed the reproductive safety of the selective serotonin reuptake inhibitors. Recent studies have focused on the risk […]
October 15, 2005 from ObGynNews By Lee S. Cohen, M.D.
Over the past few years, several studies have addressed the reproductive safety of the selective serotonin reuptake inhibitors. Recent studies have focused on the risk for neonatal discontinuation syndrome or symptoms of perinatal jitteriness associated with maternal use of SSRIs during the latter portions of pregnancy. Estimates of risk of first-trimester exposure to SSRIs derive from data accumulated over the last 15 years, which support the absence of major congential malformations associated with first-trimester exposure. Data on the teratogenicity of SSRIs come from relatively small cohort studies and larger, international teratovigilance programs, and they have cumulatively supported the reproductive safety of fluoxetine (Prozac) and certain other SSRIs. These include a Scandinavian-based registry study of 375 women exposed to citalopram (Celexa) in the first trimester, which failed to indict SSRI as a teratogen. A recent meta-analysis conducted by researchers at the Motherisk Program in Toronto supported the absence of teratogenicity associated with first-trimester exposure to a number of SSRIs.
Another recent report from the Swedish Medical Birth Registry failed to identify higher rates of congenital malformations associated with prenatal exposure to a number of SSRIs, including fluoxetine, citalopram, paroxetine (Paxil), and sertraline (Zoloft). But at the Teratology Society’s annual meeting in June, investigators from the University of British Columbia, Vancouver, reported an increased risk of omphalocele and craniosynostosis associated with first-trimester exposure to SSRIs. Using data from the National Birth Defects Prevention study, they compared data on 5,357 infants with selected major birth defects with 3,366 normal controls and interviewed mothers about exposures during pregnancy and other possible risk factors. Children with chromosomal anomalies or known syndromes were excluded.
They found an association between exposure to any SSRI during the first trimester and omphalocele (odds ratio of 3). Paroxetine accounted for 36% of all SSRI exposures and was associated with an odds ratio of 6.3 for omphalocele. Use of any SSRI during the first trimester was also associated with having an infant with craniosynostosis (odds ratio of 1.8). No association was noted between SSRI use and the other classes of major malformations studied.
This preliminary unpublished report is also described in a letter to physicians from GlaxoSmithKline, which markets paroxetine as Paxil. The letter also includes additional data from an uncontrolled study of SSRI use during pregnancy, which noted a twofold increased risk in overall congenital malformations and cardiovascular malformations (most were ventricular septal defects) in offspring exposed to paroxetine, compared with other SSRIs. These data were derived from an HMO claims database.
Many clinicians who prescribe SSRIs may be confused by the volley of new reports that suggest some potential teratogenic risk associated with this class of compounds. Indeed, previous reports fail to describe such an association. Many more recent findings derive from either retrospective data sets taken from HMO claims data or from case-control studies, which also have certain methodologic limitations, compared with prospective cohort studies.
These recent findings of increased risk with prenatal SSRI exposure are inconsistent with earlier findings. Nevertheless, large case-control studies can uncover an association not previously identified because of the inadequate statistical power of previous cohort studies, which were not large enough to detect an infrequent anomaly.
Even if we assume the associations from the new case-control study are true and that they are indeed causal, an odds ratio of 6.4 is associated with an absolute risk for omphalocele of only 0.18%. Absolute risk is of far greater clinical value than relative risk and should be taken into account before patients are arbitrarily counseled to discontinue antidepressants during pregnancy.
However, for women who present when pregnant and still taking SSRIs, including paroxetine, discontinuation should not be arbitrarily pursued. Abrupt discontinuation of antidepressants can threaten maternal affective well-being. That is an unacceptable outcome, which can be stated absolutely.
June 15, 2005 from ObGynNews by Lee S Cohen MD The reproductive safety of the older typical antipsychotics, such as haloperidol, is supported by extensive data that have accumulated over the past 40 years, at […]
June 15, 2005 from ObGynNews by Lee S Cohen MD
The reproductive safety of the older typical antipsychotics, such as haloperidol, is supported by extensive data that have accumulated over the past 40 years, at least with respect to teratogenic risk. Much of the data come from their use in treating nausea, particularly with prochlorperazine (Compazine). While longterm neurobehavioral data have been somewhat sparse, no particular indications of risk have been raised in over four decades of use.
We have far less reproductive safety data on the newer “atypical” class of antipsychotics that have become widely used over the past decade because they lack some of the longterm side effects associated with the typical antipsychotics. These drugs – olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), aripiprazole (Abilify), riprasidone (Geodon), and clozapine (Clozaril) – are approved for schizophrenia; several are approved for acute mania indications as well.
But they are also being used widely across psychiatric disease states, including anxiety, agitation in the elderly, generalized anxiety disorder, and obsessive compulsive disorder), and as adjunctive treatment of depression.
Because reproductive safety data on the atypicals have been sparse, clinicians are again faced with the difficult situation where a relatively new class of medicine is being used frequently in a population of reproductive age women. What data are available have been largely limited to manufacturers’ accumulated case series or spontaneous reports, which have their inherent biases with respect to overreporting of adverse outcomes.
To date, such information has not suggested any “signals” with respect to specific concerns regarding their use during pregnancy but we can make only limited conclusions on such information. Thus, clinicians have been in a bind with respect to use of the atypicals during pregnancy. A study published in April – the first prospective study of the reproductive safety of the atypicals in the literature – provides some reassuring data regarding the risk of malformations, albeit in a relatively small sample of 151 patients. Investigators from the Motherisk Program in Toronto prospectively followed these women who took olanzapine, risperidone, quetiapine, or clozapine during pregnancy. All of the women had taken one of these agents during the first trimester, and 48 were exposed throughout pregnancy. A total of 151 pregnant women who had taken a non-teratogenic drug also were followed.
In the atypical-exposed group, one child was born with a major malformation (0.9%) a rate lower than the 1%-3% background rate in the general population; compared with two (1.5%) babies in the control group – an insignificant difference.
Differences between groups in the rate of spontaneous abortions, stillbirths, or gestational age at birth were not statistically significant. Women taking atypical antipsychotics did have significantly higher rates of low birth weight babies (10% vs. 2%) and therapeutic abortions (10% vs. 1%) (J. Clin. Psychiatry 2005; 66:444-449).
As the authors point out, the sample was relatively small, the study was statistically underpowered, and longterm neurobehavioral outcomes were not evaluated. Still, this is the first prospective study that complements spontaneous reports from the manufacturers.
The authors included the number of spontaneous reports of pregnancy exposures to atypicals, provided by the respective manufacturers, with the exception of the newer atypicals. Among the 242 reports of olanzapine-exposed pregnancies, there was no increase of major malformations or other abnormal outcomes above baseline. Of the 523 clozapine exposed pregnancies reported, there were 22 “unspecified malformations.” Of the 446 quetiapine-exposed pregnancies, 151 outcomes were reported, of which 8 were different congenital anomalies. Eight malformations were reported among the approximately 250 reports of pregnancies and lactation exposed to risperidone, but no pattern of abnormalities was noted.
Obviously, if a patient can do without the medication, then it would be appropriate to discontinue it, but this is frequently not the case and these decisions have to be made on a case-by-case basis weighing the relative risks versus benefits.
For a patient planning a pregnancy who has a severe psychiatric illness and who is maintained on an atypical antipsychotic to sustain functioning, switching to a typical antipsychotic may be prudent. However, we often see women who present when they are already pregnant and on an atypical agent. At this point a switch may not be the wisest decision, if she is at a risk of relapse. For those women, the Motherrisk data are not a guarantee of safety but provide information that is at least moderately reassuring to clinicians. Although this small study is encouraging, given the prevalence of reproductive age women on these agents, it would be ideal if industry performed postmarketing surveillance studies that would rapidly provide the amount of cases we need to reliably estimate reproductive risks. Such studies may soon be mandated by the Food and Drug Administration in this post-Vioxx era with increased emphasis on the safety of marketed drugs.
March 15, 2005
March 15, 2005 from ObGynNews By Lee S. Cohen, M.D. Multiple articles over the past several years have cited perinatal symptoms in newborns whose mothers were taking an antidepressant late in pregnancy, including transient restlessness, […]
March 15, 2005 from ObGynNews By Lee S. Cohen, M.D.
Multiple articles over the past several years have cited perinatal symptoms in newborns whose mothers were taking an antidepressant late in pregnancy, including transient restlessness, jitteriness, tremulousness, and difficulty feeding. There have now been enough reports to suggest certain vulnerable children or subgroups of newborns who were exposed in utero may be at a slightly increased risk for this syndrome.
Last year the Food and Drug Administration required the addition of related information to the labels of selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs).
The results of a recent study of 93 cases worldwide (including 64 associated with paroxetine) from a World Health Organization adverse event reporting database do not represent new findings. The reports include descriptions of nervousness, agitation, abnormal crying, and tremors, which the authors consider a “signal” for perinatal or neonatal toxicity. The study also refers to 11 reports of neonatal convulsions and two grand mal seizures, with no further description of the cases (Lancet 2005;365:482-7).
Although the report of neonatal convulsions is relatively new, the study itself has several notable limitations. It is difficult to interpret these results because they are from a spontaneous adverse event reporting system, where typically adverse outcomes are overreported and do not provide adequate information on when the drug was used, the duration of illness, or whether the woman was depressed during pregnancy. And the absence of a controlled sample makes it difficult to estimate the incidence, which likely is very low, considering the wide use of these medications among reproductive age women. Moreover, depression in the mother has been associated with many of the newborn symptoms reported.
The use of the term “withdrawal” syndrome is a dicey clinical call at best. Based on what we know about the kinetics and placental passage of these medications, certainly what we’re seeing is not acute withdrawal, like we see with heroin or methadone use during pregnancy. The main metabolites of the drugs remain in the baby’s circulation for at least days to weeks, so to see something so early and so transient, even for paroxetine (which has a shorter half-life than the other SSRIs), is not consistent with the pharmacokinetics of the compounds being described.
I don’t disagree with these findings. Acknowledging the probable biases involved with collecting and reporting these cases, the report provides another data set that calls attention to the possibility of some type of perinatal syndrome associated with SSRI exposure later in pregnancy, which may not necessarily be a causal relationship. The authors suggest their findings are more of a “signal” that a problem may exist.
When considered with other case series, this study may indicate the potential risk for some type of perinatal syndrome associated with the use of these medications, particularly around the acute peripartum period.
What is of concern, however, is the impact this report may have on appropriate prescribing of these drugs to pregnant women, and that patients, as well as physicians, will uniformly and arbitrarily avoid these drugs during pregnancy.
The article falls profoundly short in terms of helping the clinician. While the results indicate that more vigilance is necessary during the peripartum period in cases of SSRI use, the data do not imply any particular SSRI should be avoided in women of reproductive age. The authors conclude that the signal is stronger for paroxetine, which they say should either not be used during pregnancy or used at the lowest effective dose. I certainly would not rule out using paroxetine in women of reproductive age on the basis of this report, with the possible exception of a woman with immediate plans to become pregnant or a woman with recurrent disease.
A reduction in the appropriate use of these drugs in depressed pregnant women would be a serious problem because relapse of recurrent depression during pregnancy is exceedingly common, and depression during pregnancy is the strongest predictor of risk for postpartum depression. Reducing the dose or discontinuing the antidepressant around the time of labor and delivery increases the risk of relapse, although some women may tolerate this approach, particularly if the drug is reinstituted immediately post partum.
Physicians should remain vigilant and carefully plan their treatment approach in pregnant patients with depression. The data may, in fact, be a signal that a problem exists. But a signal should be a beacon that guides the clinician. In this case, we have more fog than we have clarification of an already complicated situation.
December 15, 2004
December 2004, ObGyn News, By Lee S. Cohen, M.D. Two of the agents widely used to treat bipolar illness are established teratogens. Lithium is associated with a 0.05% risk of Ebstein’s anomaly, a modest teratogenic […]
December 2004, ObGyn News, By Lee S. Cohen, M.D.
Two of the agents widely used to treat bipolar illness are established teratogens. Lithium is associated with a 0.05% risk of Ebstein’s anomaly, a modest teratogenic effect. Sodium valproate is associated with a risk as high as 8% for major congenital malformations, most notably, neural tube defects and cardiac malformations, according to recent data from the North American Antiepileptic Drug (AED) Pregnancy Registry.
This increased risk for major organ malformations associated with first trimester exposure to these compounds raises concerns about the possible risk of longer term neurobehavioral sequelae associated with prenatal exposure.
Several studies published over the last few years have consistently shown an association between developmental delay and an increased risk for behavioral problems associated with in utero exposure to anticonvulsants, particularly sodium valproate. This growing literature has suggested associations between in utero exposure and higher rates of problems ranging from mild behavioral disruption in school, attention-deficit disorder, and other behavioral problems characterized by hyperactivity, autistic-like behaviors, and problems with learning, speech delay, and gross motor delay.
One study of 52 children exposed to anticonvulsants in utero found that 77% had developmental delay or learning difficulties when followed up at a mean age of 6 ½ years; 80% had been exposed in utero to sodium valproate (J. Med. Genet. 2000;37:489-97).
In another prospective study, children born to women with epilepsy were assessed between ages 4 months and 10 years. The risk of adverse outcomes, including developmental delay, was higher among those exposed to sodium valproate than carbamazepine (Tegretol). Most of the cases were children born to women who received sodium valproate doses that were greater than 1,000 mg/day (Seizure 2002;11:512-8).
These studies were not ideally designed and have inherent methodologic limitations. Eventually, we will have long-term prospective data on children exposed in utero to anticonvulsants. These data will come from the North American AED Registry. Until then, however, the findings of these studies are consistent enough to indicate that in utero exposure to anticonvulsants may have neurotoxic effects; this appears to be the case particularly with sodium valproate monotherapy and polytherapy.
The potential for neurobehavioral sequelae is an issue that has not been adequately factored into the risk-benefit decision for treating women with epilepsy or bipolar disorder during pregnancy. For women with epilepsy, the situation is more difficult, since seizures during pregnancy are associated with particularly bad perinatal outcomes. But for bipolar disorder, we have a spectrum of treatment options.
Often women and their physicians choose to discontinue a psychotropic drug in the first trimester, and they assume that therapy can safely be reintroduced during the second trimester. Still, the data on potential behavioral toxicity, particularly with sodium valproate, should make one pause before reinstituting treatment with sodium valproate during the second and third trimester—and the data should raise the question of whether this is an appropriate medicine to be using at any point during pregnancy in women with bipolar illness.
There is no perfect answer. The goal is to keep women emotionally well during pregnancy and to avoid relapse during pregnancy. Prenatal exposure to a drug is sometimes necessary to sustain well-being of patients. Nevertheless, recent data have indicated that the risk of polycystic ovarian syndrome is increased in women treated with sodium valproate. When this finding is considered with the teratogenicity data for sodium valproate and its possible longer term neurobehavioral sequelae, one has to reconsider the wisdom of using this medication in reproductive-age women, particularly since some of the treatment alternatives for bipolar illness are either less teratogenic or appear to be nonteratogenic.
Reproductive-age women who want to become pregnant or who are already pregnant should consult their physicians about alternative treatment strategies that can be continued throughout pregnancy. Such alternatives are lithium or lamotrigine (Lamictal), both of which may be used with or without one of the older typical antipsychotics, which do not appear to be teratogenic.
Our goal is to avoid exposure to a drug with known teratogenicity with respect to organs, and quite probably, with respect to behavior.
September 15, 2004 from ObGynNews by Lee Cohen, M.D. Physicians and patients may be alarmed by recent changes to the product labels of the selective serotonin reuptake inhibitors and the selective norepinephrine reuptake inhibitor venlafaxine […]
September 15, 2004 from ObGynNews by Lee Cohen, M.D.
Physicians and patients may be alarmed by recent changes to the product labels of the selective serotonin reuptake inhibitors and the selective norepinephrine reuptake inhibitor venlafaxine with respect to their use during pregnancy.
The labels now describe clinical findings in newborns exposed to these drugs late in the third trimester, including respiratory distress, jitteriness, irritability, hypoglycemia, feeding difficulties, cyanosis, hypotonia, hypertonia, hyperreflexia, and constant crying. Complications requiring “prolonged hospitalization, respiratory support and tube feeding” are also mentioned.
Prompting these changes were postmarketing adverse event reports made to the Food and Drug Administration over several years, suggesting a constellation of symptoms associated with third trimester exposure. Because these spontaneous reports were uncontrolled, it is impossible to know with certainty whether they are secondary to the medicine. Some of the symptoms-such as jitteriness, irritability, and feeding difficulties-are consistent with anecdotal reports and case series in the literature, which support at least transient jitteriness and irritability associated with maternal use of these antidepressants, particularly late in the third trimester.
But more serious problems such as prolonged hospitalization and the need for respiratory support are not well supported by any objective data in the medical literature. Listing these in the label may do little but alarm patients and physicians.
One theoretical rationale for mandating the label change derives from the assumption that these symptoms are consistent with discontinuation symptoms now well described in older patients who abruptly stop treatment with these compounds, particularly those that are shorter-acting. While the description of these symptoms as a “neonatal discontinuation syndrome” is an interesting clinical hypothesis, it is untested and not supported by data.
The label also now advises physicians to “carefully consider the potential risks and benefits of treatment” in patients and suggests that clinicians should consider tapering or discontinuing the medicine late in the third trimester before labor and delivery. One has to wonder about the wisdom of suggesting a taper or discontinuation of an antidepressant during this critical time, considering that the risk for relapse among women who discontinue antidepressants during pregnancy is high and that depression during pregnancy is one of the strongest predictors of postpartum depression.
There are no data to suggest that tapering the drug near term attenuates the risk for toxicity in the newborn. In our earlier work, we actually suggested the peripartum taper of antidepressants; the approach was intuitive as it avoided even the potential risk for neonatal toxicity. However, we then observed high relapse rates among women around labor and delivery, prompting us to shift our recommendation to continue antidepressant therapy across the peripartum period.
The labeling changes will likely create alarm about a potential clinical syndrome that has an extremely low incidence and modest clinical significance. Nonetheless, the label change has the potential to affect scores of women for whom depression remains a significant medical problem.
These changes may increase the threshold for using antidepressants during pregnancy not only during the peripartum period but also during other stages of pregnancy-despite data suggesting that depression in pregnancy has an independent adverse effect on fetal well-being and is the strongest predictor of postpartum depression. The text of the label change lacks this context and puts the clinician in the situation of prescribing counter to the new language if the decision is made to treat during at least the third trimester of pregnancy. The label change is an example of blanket, non-evidence-based recommendations that not only fail to thoughtfully inform clinical care, but also may do more harm than good.
Clinicians confused by these changes should weigh the risks and benefits of antidepressant use near delivery. No psychotropic drug is approved for use in pregnancy, so decisions about using these medicines are made on a case-by-case basis. For women who have experienced depression during pregnancy, particularly those who have had residual symptoms of depression, discontinuing antidepressant therapy may lead to significant worsening or relapse of depression. These issues should be discussed with patients in the context of the patient’s individual clinical situation. Only in that context can truly thoughtful treatment decisions be made pending better controlled data.
Having reviewed the report in draft and final form and having testified at the meeting of the expert panel convened to write the report, my greatest concern is what patients and some clinicians may do with the panel’s conclusions. Information in the report, while comprehensive and technically correct in most cases, might easily be misconstrued by women and their families.
The report provides a summary and review of existing data, with a thorough review of the animal and human literature on reproductive safety of fluoxetine. It does not adequately address the clinical context in which fluoxetine or other selective serotonin reuptake inhibitors (SSRIs) are used. While this may not be the aim of the project, failure to address this issue limits the report’s value with respect to its ability to inform clinical care; the absence of a clinical context with which to interpret the report may lead to incorrect conclusions and clinical treatment decisions, putting women at risk for the sequelae of untreated or relapsing depressive illness.
The report criticizes much of the literature regarding reproductive safety of fluoxetine, which is understandable because controlled studies of exposures to any medication during pregnancy are not done for ethical reasons. Conclusions regarding reproductive safety of medications come from various sources, such as case series, postmarketing surveillance registries, and teratovigilance programs. These sources can sometimes provide large enough numbers of drug exposures to allow for useful conclusions regarding reproductive safety.
The panel’s conclusions regarding the risk for major congenital malformations associated with prenatal exposure to fluoxetine are consistent with the literature and suggest an absence of increased risk with first-trimester exposure to the medicine. The report also addresses the risk for “perinatal toxicity,” which typically includes symptoms of jitteriness and autonomic reactivity in the newborn.
Enough literature has accumulated suggesting that third-trimester exposure to SSRIs may be tied to an increased risk of transient symptoms as noted above. Most reports have not associated such exposure with adverse longer-term sequelae. Fluoxetine is the only SSRI for which we have long-term neurobehavioral data, including follow-up of exposed children through ages 4-7 years. No differences in long-term neurobehavioral outcome between exposed and unexposed children were noted.
One of the greatest failures of the NTP report is that an important confounding factor with regard to outcome of SSRI use in pregnancy is neglected: maternal mood. In the recent literature, one can find the same “toxicity,” such as lower Apgar scores or obstetric complications, in children of mothers who have untreated depression during pregnancy. Failure to address this adequately in the report is a significant omission.
Fluoxetine is used to treat a serious illness; it is not a potential environmental toxin, such as those reviewed by other NTP panels. The report does not indicate that decisions about whether to use fluoxetine during pregnancy are clinical choices made by patients in the context of some risk-benefit analysis made collaboratively between the patient, her family, and the physician. My colleagues and I have described high rates of relapse in women with a history of recurrent major depression who discontinue antidepressants in pregnancy. Depression during pregnancy is associated with compromised fetal and neonatal outcomes-risks that are not reflected in the report. Discontinuation of medication near the end of pregnancy appears to increase the risk for postpartum depression.
The panel notes in the report that it recognizes that any risks of fluoxetine need to be weighed against the risks of
untreated disease. But this brief statement embedded in a lengthy document that describes fluoxetine as “a reproductive toxin” is inadequate. One has to wonder how this report will impact what actually goes on as patients make decisions about using these compounds.
Studies that have evaluated the effects of SSRIs on neonatal outcome have suffered from consistent methodologic limitations, the most notable being the failure to blind investigators evaluating the infants with regard to in utero drug exposure and the failure to take into account the potential impact of maternal mood disorder on acute neonatal outcome.
In a study published last month, 34 healthy, full birthweight newborns were evaluated in a prospective trial; 17 mothers took SSRIs during pregnancy and 17 were unexposed. The investigators noted that exposed newborns exhibited significantly more tremors, heightened levels of motor activity and tremulousness, and fewer changes in behavioral state during an hour-long observation period, compared with unexposed newborns (Pediatrics 113:368-75, 2004).
While this is an important study, in which the evaluators were blinded, it is limited by its small sample size. Though both groups were matched for maternal use of cigarettes, alcohol, and marijuana during pregnancy, alcohol use was not insignificant, and four women on SSRIs used marijuana while pregnant.
Most notably, the study failed to include an assessment of maternal mood during pregnancy and did not control for the impact of maternal depression on the outcome variables measured.
The authors acknowledge the negative impact that maternal depression can have on neonatal outcome, though they do not acknowledge adequately how the failure to measure maternal depression in their study could have confounded it greatly. They note that maternal depression, “through its action as a stressor, may have an impact on fetal development through its effect on the hypothalamic-pituitary-adrenal axis, adrenocorticotropic hormones, and b-endorphins,” and that infants of depressed mothers are at risk for physical anomalies and birth complications, delayed habituation of fetal heart rates, higher neonatal cortisol levels, higher levels of indeterminate sleep, and elevated norepinephrine levels.”
They do cite an important study from the Motherisk program in Toronto indicating that postpartum mood is one of the strongest predictors of neurocognitive function in children assessed up to 6 years of age.
The authors suggest that milder forms of tremulousness in the extremities during the neonate’s first week may reflect “CNS depression and/or stress/withdrawal from prenatal drug exposure,” and that these findings “may be a harbinger of the persisting tremors found in SSRI-exposed infants at 6-40 months of age,” as observed in a study last year (J. Pediatr. 142:402-08, 2003). But that study was also limited by a small sample size and the failure to prospectively assess maternal mood during pregnancy.
While data from the latest study are welcome, the recommendation to lower or discontinue antidepressants proximate to delivery is worrisome-not only because of the potential negative impact of depression during pregnancy on neonatal well-being, but because maternal depression also increases the risk for postpartum depression.
DR. LEE COHEN is director of the perinatal psychiatry program at Massachusetts General Hospital, Boston. He is a consultant for and has received research support from manufacturers of several SSRIs.
December 15, 2003
December 1, 2003 from ObGynNews By Lee S. Cohen, M.D. Data on the risk of fetal malformations and adverse peripartum events associated with in utero exposure to antidepressants are reassuring, especially with regard to the […]
December 1, 2003 from ObGynNews By Lee S. Cohen, M.D.
Data on the risk of fetal malformations and adverse peripartum events associated with in utero exposure to antidepressants are reassuring, especially with regard to the tricyclics and some of the selective serotonin reuptake inhibitors. Prospective data on the longer-term neurobehavioral sequelae associated with such exposure are much more limited, however.
In the last several years, some studies have been published in which researchers tracked neurobehavioral
function over a period of months to years in children exposed to SSRIs in utero. While it’s exciting to have some new information in this previously uncharted area, some of the data are inconsistent and have led to confusion among patients and health care providers.
A recent study conducted by investigators at the Motherisk Program at the University of Toronto prospectively evaluated the neurodevelopment of 86 children aged 15-71 months who were exposed to fluoxetine (Prozac) or a tricyclic antidepressant throughout pregnancy.
The study showed no differences in well-established neurobehavioral indices between these children and 36 unexposed children of nondepressed women (Am. J. Psychiatry 159:1889-95, 2002). This study was a follow-up to an earlier study that looked at neurobehavioral function in children exposed to these medications only during the first trimester, and the results were consistent.
Of note, the duration of maternal depression was a significant negative predictor of cognitive function in children; for example, the number of depressive episodes after delivery was negatively associated with language scores. These data support the now well-established finding that an uncontrolled postpartum mood disorder can have adverse effects on the baby’s neurocognitive development.
In a study published in April, Stanford University investigators compared the perinatal and neurobehavioral outcomes of 31 children exposed in utero to fluoxetine, sertraline (Zoloft), fluvoxamine (Luvox), or paroxetine (Paxil), with those of 13 children whose mothers had a major depressive disorder and received psychotherapy but did not take medication during their pregnancies.
When evaluated between ages 6 months and 40 months, the SSRI-exposed children had significantly lower scores on psychomotor indices and on neurobehavioral function (J. Pediatr. 142:402-08, 2003).
On the surface, the results of these two studies are somewhat confusing: Among the possible explanations for the different findings are methodologic limitations of the Stanford study. The Motherisk study was a controlled study in which maternal mood during pregnancy and the postpartum period was assessed prospectively. But the mood of women in the Stanford study was not prospectively assessed; a significant number had already given birth when they were asked to recall what their mood was during pregnancy. As a result, the impact of antidepressant therapy on their mood is unknown. This is a major confounding factor because of the considerable data indicating that maternal mood disorders can adversely affect neurobehavioral function in children.
The results of the Stanford study are interesting, but given these methodologic limitations, it is particularly difficult to draw any conclusions from it or to use the findings to inform clinical care. There certainly is nothing in these findings to suggest that women should avoid taking antidepressants during pregnancy.
The Stanford authors, who acknowledged the difficulty in controlling for certain confounding variables and concluded that it should be viewed as a pilot study, should still be commended for their efforts to perform prospective neurobehavioral assessments and address the potential for behavioral teratogenicity–information that is profoundly lacking in the literature.
Multiple studies have shown the importance of keeping women euthymic during pregnancy, in light of the adverse effects of maternal depression on perinatal outcome and the extent to which maternal depression in pregnancy predicts postpartum depression.
In future studies, it will be important to include prospective assessments of both maternal mood and drug exposure, so the two variables can be teased apart in terms of their relative contribution to both perinatal outcome and long-term neurobehavioral outcome.
treated with the drug for bipolar illness and for epilepsy, which did not demonstrate an increase in major birth defects associated with first-trimester exposure, supporting earlier reports.
The risk of teratogenicity was significantly increased with first-trimester exposure to the combination of lamotrigine and sodium valproate (more commonly used for epilepsy), but not with lamotrigine monotherapy: Among the 302 pregnancies exposed to monotherapy in the first trimester, there were 9 (3%) major birth defects, compared with 7 (10.4%) major birth defects among the 67 cases of firsttrimester exposure to both drugs. There were 5 (3.5%) major birth defects among 148 cases of first-trimester exposure to polytherapy that did not include sodium valproate.
The clinical implications of these long-awaited data on lamotrigine are relatively clear and present an opportunity to navigate the tricky course of maintaining euthymia across pregnancy and minimizing exposure to drugs that might be harmful to the fetus.
For example, sodium valproate can be deferred for a medicine such as lamotrigine in some patients, particularly those who do not respond to or who have not tolerated lithium. Although lamotrigine has not demonstrated efficacy for the treatment of acute mania, the anticonvulsant can be combined with medicines that are helpful in treating this phase of bipolar disorder. Such adjunctive medicines include high-potency typical antipsychotics like haloperidol or trifluoperazine.
Unfortunately, the reproductive safety data available for the newer atypical antipsychotic olanzapine (Zyprexa)–efficacious for both acute mania and for prophylaxis against recurrent mania–are exceedingly sparse. Clinicians are left with the task of trying to minimize exposure to medicines we know very little about, such as olanzapine, and to medicines we know a lot about that appear to be particularly harmful to the fetus, such as sodium valproate.
Lamotrigine is the only one of the newer anticonvulsants for which there are enough exposed cases to allow for
some reliable quantification of teratogenic risk. Manufacturers of the other anticonvulsants have not established independent registries. The Antiepileptic Drug Registry at Massachusetts General Hospital is collecting data on a spectrum of newer anticonvulsants, but to date the numbers are too small for any conclusions, except on lamotrigine.
One caveat with respect to use of lamotrigine lies in the very small but quantifiable risk of Stevens-Johnson syndrome associated with lamotrigine therapy. To reduce risk, the manufacturer recommends titrating patients gingerly, by no more than 25 mg weekly.
Still, questions remain about the risks of short-term perinatal toxicity in newborns when antidepressants are used around the time of labor and delivery. These concerns date back 20 years, when case reports suggested that maternal use of tricyclics near term was associated with problems in the newborn such as difficulty feeding, restlessness, or jitteriness.
More recent studies have suggested that peripartum exposure to SSRIs may be associated with poor perinatal outcomes. One study found an association between the use of fluoxetine (Prozac) during the third trimester and a greater risk of neonatal complications (N. Engl. J. Med. 335:1010-15, 1996).
Two more recent studies of perinatal effects associated with third-trimester exposure to antidepressants have generated many questions. The first, conducted by investigators at the Motherisk Program at the University of Toronto, compared 55 newborns exposed to paroxetine (Paxil) late in pregnancy with a control group of newborns exposed to paroxetine early in pregnancy and newborns exposed to nonteratogenic drugs. There was a significantly higher rate of neonatal complications among paroxetine-exposed newborns, resolving in 1-2 weeks. Respiratory distress was the most common adverse effect (Arch. Pediatr. Adolesc. Med. 156:1,129-32, 2002).
The authors posit that the unexpectedly high rate of symptoms in these newborns may be the neonatal equivalent of the discontinuation syndrome commonly seen in adults who develop a variety of somatic symptoms after rapidly stopping paroxetine. While this is an interesting study consistent with some but not all previous reports, it has obvious methodologic limitations: Information was obtained through telephone interviews rather than direct blinded observation, and the well-described effects of maternal mood during pregnancy on neonatal outcome were not considered. Depression during pregnancy has been independently associated with adverse neonatal affects, including low birth weight, small-for gestational-age babies, and increased obstetrical complications.
The second study compared neonatal outcomes following in utero exposure to tricyclics and SSRIs using a large database from a group-model HMO. The malformation rate was not increased among those exposed to antidepressants in utero, but there was an association between third-trimester exposure to SSRIs and lower 5-minute Apgar scores and decreases in mean gestational age and birth weights; these differences were not observed among tricyclic-exposed newborns (Am. J. Psychiatry 159:2055-61, 2002). At ages 6 months and up, there were no significant differences between the groups, despite the differences noted at birth, and exposure to SSRIs or tricyclics was not associated with developmental delays through age 2. As in the previous study, maternal mood during pregnancy was not assessed.
Given the methodologic weaknesses of these studies, one cannot conclude that the use of antidepressants is associated with compromised perinatal outcomes. The findings from these two studies may be a signal of a potential problem. But pending more controlled study, appropriate vigilance of exposed newborns is good clinical care versus arbitrary discontinuation of antidepressants during the peripartum period.
Treatment decisions need to be made in the context of yet to be qualified relative risk (if any) for perinatal sequelae
exposure to antidepressants at term versus the increased risk for adverse neonatal outcomes and postpartum depression associated with pregnancy-associated maternal depression. Accumulated data regarding potential risks of perinatal exposure to antidepressants do not appear to justify lowering the dose of these agents or stopping these medicines around labor and delivery. Doing so may increase risk for depression in the mother and the impact of affective dysregulation on the newborn.
The findings of the two studies are clearly of interest and demand further prospective inquiry. Until results of such studies are available, clinicians should share available information with patients, so together they can make informed decisions regarding the use of antidepressants across pregnancy.
January 1, 2003 from ObGynNews By Lee S. Cohen, M.D. Eating disorders are highly prevalent in the general population, certainly more so in women, appearing to peak during the childbearing years. While we tend not […]
January 1, 2003 from ObGynNews By Lee S. Cohen, M.D.
Eating disorders are highly prevalent in the general population, certainly more so in women, appearing to peak during the childbearing years. While we tend not to see pregnant women with anorexia nervosa because they have secondary reproductive endocrine dysfunction, we do see those who have been successfully treated and are contemplating pregnancy or who are pregnant. Far more often, we see patients with bulimia or other binge-eating disorders on the less severe end of the spectrum.
There is very little information in the literature on the course of these disorders as women try to conceive or in pregnancy–and even less on the treatment of symptomatic women during pregnancy or the postpartum period.
The few data that are available include studies reported in the last several years suggesting that pregnancy is associated with improvements in eating disorders followed by postpartum exacerbation of symptoms. A limitation of these studies was that there were very few women included in the samples with active illness who were on medication.
The two drug classes used most frequently in patients with eating disorders are selective serotonin reuptake inhibitors (SSRIs), most commonly fluoxetine and sertraline, and antianxiety agents, typically lorazepam and clonazepam. In our experience, many women have a recurrence of symptoms of the eating disorder when they stop their medication while trying to conceive or while pregnant-consistent with what we see when women with mood and anxiety disorders stop their medications.
So what is the best way to manage patients? There are two avenues of treatment, group- and individual-based cognitive-behavioral therapy and pharmacologic interventions. We have found that patients who have been on pharmacologic therapy may be able to successfully switch from medication to cognitive-behavioral therapy in conjunction with state-of-the-art nutritional counseling while trying to conceive or during pregnancy.
Patients who do well using this approach are on the less severe ends of the spectrum, for example those who engage in some binge-eating behaviors, followed by some restrictivelike behavior (calorie restriction), or who have intermittent bulimic symptoms when they experience anxiety. Cognitive-behavioral interventions can help these patients justify the need to consume calories and gain weight to sustain a healthy pregnancy.
SSRI doses used to treat eating disorders are frequently higher than those used to treat depression, but the risk of adverse fetal effects, including fetal malformations, is not dose related. Patients who decide to stay on medication therefore should remain on the most effective dose, because reducing the dose increases the risk of relapse.
We frequently prescribe benzodiazepines during pregnancy and post partum in combination with antidepressants to modulate the anxiety symptoms that are frequently associated with eating disorders. A benzodiazepine can often break a cycle of behavior during pregnancy but is particularly effective during the postpartum period. A recent metaanalysis on prenatal exposure to benzodiazepines suggested that if these agents are linked to an increased risk for malformations, that risk is not for overall congenital anomalies, but only for cleft lip or palate. And this risk is less than 0.5% over the normal background risk. The risk of neonatal complications with exposure to benzodiazepines is extremely small.
Postpartum worsening of psychiatric disorders is the rule. In the postpartum period women may demonstrate reemergence of rituals practiced before pregnancy, and comorbid depression and anxiety are common. While prophylaxis with medication is not necessarily indicated, these women should be considered at high risk for postpartum psychiatric disturbance. Women who have been successfully treated with cognitive therapy and nutritional counseling during pregnancy may need to resume or start pharmacologic treatment. For example, it would not be unusual for a patient with mild to moderate symptoms before pregnancy, who managed well during pregnancy with cognitive interventions and nutritional counseling, to experience a reemergence of the eating disorder with major depression post partum. These patients can become ill relatively quickly, so prompt reintroduction of a medication can be extremely important.
The incidence of treatment-emergent side effects in nursing babies whose mothers are taking a benzodiazepine or an SSRI is exceedingly low, and these drugs are not contraindicated during breast-feeding.
Many women make the intuitive leap that some of these widely used complementary or alternative therapies represent a more “natural” and therefore safer alternative to a more standard pharmacologic treatment during pregnancy or while they are trying to conceive. The problem is that we have very little, if any, reproductive safety data on these natural compounds. Many of these products do not contain just the specific herbal compound, but fillers and other components used for compounding, about which we know very little.
Moreover, efficacy data for many of the herbals are limited. For example, there is still an ongoing debate about the efficacy of St. John’s wort for depression. Although there are no data indicating that it’s dangerous, not much is known about the reproductive safety of hypericum, its active ingredient.
While omega-3 fatty acids are not presumed to be teratogenic, the data supporting their efficacy in patients with bipolar disorder have been based primarily on adjunctive use with other mood-stabilizing medications. There are very little data on monotherapy; even the experience with adjunctive therapy was based on an extremely small sample of people.
Based on these uncertainties, an arbitrary switch to an alternative treatment may represent a failed risk-benefit decision, exposing a pregnant woman to both an unknown reproductive safety risk and an increased risk for relapse. A woman therefore will not be in a much better position regarding safety with one of these products than with a drug for which there are only limited reproductive safety data but which is known to be effective.
The growing array of newer antidepressants and anticonvulsants increases the possibility that more women will be successfully treated, although not much is yet known about their reproductive safety. More is known about the older medications, like lithium and divalproex sodium (Depakote), which are known to be teratogenic.
Some antidepressants, including fluoxetine (Prozac) and the tricyclics, are not teratogenic. There are neurobehavioral data following children through age 7 years showing no adverse impact of in utero exposure to these agents, but there is still more to be learned about their long-term neurobehavioral effects.
My biggest concern is the risk of relapse in women who switch to an alternative treatment under the presumption that it will invariably work. What has become increasingly clear, however, is that across psychiatric disorders pregnancy is not protective against relapses or onset of new illness, so more patients are being treated with pharmacologic therapies.
A common scenario we see is a woman who has had multiple episodes of major depression and has been treated with multiple antidepressants. She has been stabilized on a selective serotonin reuptake inhibitor like fluoxetine, for which there is a lot of reproductive safety information, or a medicine like mirtazapine, nefazodone, or bupropion, for which we have very little reproductive safety information. This is the type of patient who is at high risk of relapse if she stops taking medication, and many of these patients do relapse.
An untreated mood disorder during pregnancy is not something to discount. There is a growing literature illustrating the impact of untreated depression during pregnancy, including adverse outcomes on perinatal well-being in terms of Apgar scores, birth weight, and other basic neonatal outcomes. The most dramatic example is with bipolar patients who, without proper treatment, may relapse into severe recurrent mania or depression, placing the fetus and mother at increased risk.
As a clinician and a researcher, I appreciate the efforts to identify safe treatments during pregnancy. Unfortunately, the science to support the belief that natural treatments are safer, held by so many women (and some clinicians) who are concerned about prenatal exposure to any psychiatric medicines, is not substantiated.
While we have pregnancy registries for some psychiatric medications and there are animal data on these medications, we may never have such reproductive safety data on some of the naturally occurring compounds, because to date they remain unregulated.
The atypicals often cause weight gain, and maternal adiposity may increase the risk for neural tube defects. This was noted in a recent study of patients with schizophrenia taking atypical or typical antipsychotics by Dr. Gideon Koren and his associates at the University of Toronto. More than half of the female patients were overweight, and intake of folate was poor. The investigators concluded that women who take atypical antipsychotics are therefore at a greater risk of having a baby with a neural tube defect (Am. J. Psychiatry 159:136-37, 2002).
As obstetricians see more patients in their reproductive years who are on these medications, these issues need to be considered in the context of relative risk. The absence of data does not imply safety, and the arbitrary use of these medications in women of reproductive age is the largest uncontrolled trial in the history of medicine.
The newer treatments may be more effective but may pose greater risks. What we know leaves us to conclude that lithium is the safest treatment for those who need a mood stabilizer.
We advise that if a woman has not responded to lithium but has had an excellent response to a mood stabilizer such as lamotrigine or gabapentin, she would be better off staying on that drug. But patients who have not tried effective mood stabilizers like lithium should consider a trial of lithium before they get pregnant, if possible.
What about the patient who conceives while taking one of those medications that we know nothing about? The clinician has the option to switch the patient to lithium, but this gets tricky because she may not respond. This may be the type of situation where you keep a patient on the drug if she is doing well to avoid a relapse.
Physicians can report pregnancies exposed to any of these drugs to the manufacturers and, in the case of antiepileptics, to the antiepileptic drug pregnancy registry at 888-AED-AED4.
September 1, 2001 from ObGyn News By Lee S. Cohen, M.D.
Over the past decade, adults have been increasingly diagnosed with attention-deficit hyperactivity disorder (ADHD), including many women in their childbearing years. ADHD patients can be successfully treated with medications such as stimulants, the mainstay of treatment, followed by tricyclic antidepressants and bupropion (Wellbutrin). Women who have been stabilized on one of these medications and want to become pregnant often come to see us with questions about whether they should remain on the drug. What we advise these patients depends in part on the severity of their disorder. For women with mild to moderate symptoms that do not interfere dramatically with their life we frequently recommend a switch to a nonpharmacologic intervention even though there’s a fair amount of information on the reproductive safety of one therapeutic option, the tricyclic antidepressants. For these women, the risk of not being treated does not justify fetal exposure to a drug that we do not know much about or even a drug for which we have reassuring reproductive safety data.
The more difficult clinical scenario is with women who unequivocally have severe ADHD that, if left untreated, could dramatically interfere with their functioning and potentially affect the outcome of their pregnancy. Stimulants such as methylphenidate (Ritalin) do not appear to be teratogenic as a class. But there are some data suggesting an association between in utero exposure to psychostimulants and poor fetal or neonatal outcomes, such as small for gestational age or intrauterine growth retardation. These data, however, are not from reports of women with ADHD, but largely from women abusing stimulants such as amphetamines who had other risk factors for poor neonatal or fetal outcomes. This makes it difficult to discern the independent risk associated with fetal exposure to stimulants.
When we see patients with more severe symptoms who have done well on a stimulant, we share these data with them, pointing out that it’s not entirely clear whether exposure is associated with impaired fetal outcome. For women who need treatment in pregnancy, we often recommend a switch to a tricyclic antidepressant because of the robust data supporting the efficacy of these agents for treating ADHD and solid data supporting their reproductive safety. These data include studies showing no increased rate of major congenital malformations with first-trimester exposure. Another study followed exposed children through age 6 and found no differences in long-term neurobehavioral effects between those exposed to tricyclics in utero and those who weren’t.
A switch to a tricyclic antidepressant would also be preferable for a woman on Wellbutrin despite evidence supporting its effectiveness in treating ADHD. Because there are only sparse data on its reproductive safety, we discourage use of this drug during pregnancy. Wellbutrin is a pregnancy category B compound, meaning that it has been categorized as fairly safe in pregnancy. However, this categorization is based on limited information that does not indicate a risk but is insufficient to rule risk out entirely. There are some data suggesting that selective serotonin reuptake inhibitors (SSRIs) are effective for ADHD in some people, but most studies do not show efficacy. For those who have responded to an SSRI, the safest such agents to use during pregnancy are fluoxetine (Prozac) or citalopram (Celexa). Still, the use of a stimulant is not absolutely contraindicated during pregnancy. We occasionally have a treatment-dependent woman with ADHD who did not tolerate or respond to treatment with an antidepressant but was stabilized on a stimulant. We have not observed any problems using stimulants in pregnancy over the past 15 years, but the sample size is small and we have not investigated this question in a controlled fashion.
There are no data on the postpartum course of ADHD, but since worsening of psychiatric disorders during the postpartum period is the rule, we typically reintroduce medications at this time in women who went off them before or during pregnancy. We do not counsel women who have remained on stimulants, tricyclics, or Wellbutrin to defer breast-feeding. The data on stimulant use during breast-feeding are incomplete. At our center we would not consider a stimulant as absolutely contraindicated in women who are breast-feeding, because the amount of the drug secreted into breast milk is small.
Dr. Lee Cohen is a psychiatrist and director of the perinatal psychiatry program at Massachusetts General Hospital,
It is incorrect to assume that all drugs within the same class have equal reproductive safety March 1, 2001 from ObGynNews By Lee S. Cohen, M.D. Clinicians are frequently caught between a teratologic rock and […]
It is incorrect to assume that all drugs within the same class have equal reproductive safety
March 1, 2001 from ObGynNews By Lee S. Cohen, M.D.
Clinicians are frequently caught between a teratologic rock and a clinical hard place when it comes to the use of psychiatric medications during pregnancy. Unfortunately, the Food and Drug Administration’s current classification system, which assigns ratings with respect to the safety of drugs during pregnancy, does not necessarily help and can be misleading.
Recognizing such limitations, the FDA is in the process of revamping the system, but for now it’s incumbent on physicians to go beyond the package insert and refer to the available literature and other resources to get a better picture of the full amount of reproductive safety data available on a certain drug.
The use of certain antidepressants during pregnancy is a striking example of how category labeling does not necessarily help guide clinical care-and how it can make certain compounds with relatively less safety data appear to be “safer” than medicines for which we have far more safety data.
For example, bupropion, marketed as Wellbutrin for depression and Zyban for smoking cessation, has been classified as a category B compound based on anecdotal human data from a very small sample of women and limited animal data, which do not support adverse effects associated with prenatal exposure.
Although the manufacturer has established a bupropion pregnancy registry, the data on this drug are sparse when compared with the amount of safety data on fluoxetine (Prozac) and citalopram (Celexa). Yet both these selective serotonin reuptake inhibitors (SSRIs) are labeled category C, presumably based on adverse effects seen in studies of rats that ingested 10-18 times the maximum human recommended daily doses of these drugs. Under the current system, these types of data justify a C category almost regardless of the amount of human data available.
The category C label does not reflect human data on more than 2,300 cases of first-trimester exposure to fluoxetine or the nearly 400 cases of first-trimester exposure to citalopram; these data do not support an increased risk for major congenital malformations. But we have seen cases of women who are stabilized on citalopram or fluoxetine and then switched during pregnancy to medicines such as bupropion, because clinicians assume a category B drug is “safer” than fluoxetine or citalopram, prompting the clinician to incorrectly assume that the absence of adverse data implies safety.
In this scenario, not only is the patient put at risk of not responding to the new antidepressant and having a relapse, but she is unnecessarily taken off a medicine for which there is a relatively abundant amount of safety data.
Category labeling also fails us when we consider the SSRIs as a class. This is a particularly important issue because it is incorrect to assume that all drugs within the same class have equal reproductive safety. All the available SSRIs are labeled category C, but there’s nowhere near the amount of information on first-trimester exposure to paroxetine (Paxil) and sertraline (Zoloft) as there is for fluoxetine and citalopram.
Lithium is another dramatic example of the complexity of risk assessment of psychiatric medications when considering category label assignment. Other factors come into play when considering whether an agent should be used during pregnancy.
For example, lithium is a category D drug because of clear evidence of an increased risk of a cardiovascular malformation (Ebstein’s anomaly) associated with first-trimester exposure. Many women with bipolar disorder who become pregnant or want to become pregnant are counseled by their physicians to discontinue lithium, even abruptly, solely based on the category D label.
However, the absolute risk of Ebstein’s anomaly is estimated at 0.05%-0.1%. Since the risk of relapse within the first 6 months of lithium discontinuation is so high-over 60%-women with bipolar disease may choose to assume the relatively small absolute risk for teratogenesis associated with first-trimester exposure, regardless of the drug’s category.
These examples underscore the limitations of the category-labeling system and the need to complement this information with other data from the medical literature and elsewhere. By not relying exclusively on the labeling system, physicians and their patients can make more informed decisions when selecting psychiatric drugs.
DR. LEE COHEN is a psychiatrist and director of the perinatal psychiatry program at Massachusetts General Hospital, Boston.
July 15, 2000
More safety data on older antipsychotics make them first choice for use during pregnancy July 1, 2000 from ObGynNews Women typically have been counseled to avoid using psychiatric medications during pregnancy because of known or […]
More safety data on older antipsychotics make them first choice for use during pregnancy
July 1, 2000 from ObGynNews
Women typically have been counseled to avoid using psychiatric medications during pregnancy because of known or unknown risks of prenatal exposure to these medications. But data suggest that pregnancy does not protect women from new onset or relapse of psychiatric disorders. This is particularly true for women who have disorders such as schizophrenia or bipolar illness, which is also now treated with antipsychotics, according to Dr. Lee Cohen, director of the perinatal psychiatry program at Massachusetts General Hospital, Boston. Therefore, women with schizophrenia who stop their antipsychotics are at a great risk for relapse, at which point they frequently pursue behaviors that can be harmful to them and their fetuses, he noted.
The newer atypical antipsychotics are becoming first-line treatment for many people with schizophrenia because they do not have some of the side effects of the older medications and they appear to result in better acute and long-term responses. They are also increasingly being used for a range of other psychiatric disorders, including obsessive-compulsive disorder, posttraumatic stress disorder, anxiety disorders, and depression. But most of the available reproductive safety data come from literature on the typical antipsychotics and are several decades old, he pointed out. These data suggest that there is no increased risk of congenital malformations associated with first-trimester exposure to high-potency antipsychotics like haloperidol (Haldol) or midpotency antipsychotics like perphenazine (Trilafon).
There also appear to be no safety issues when these drugs are used in labor and delivery or postpartum, and there is literature suggesting that these agents are not problematic when used during lactation, said Dr. Cohen, also associate professor of psychiatry, Harvard Medical School, Boston. “Therefore in our clinic, it is our standard approach to continue treatment in patients who are dependent on a typical high-potency antipsychotic, such as haloperidol, fluphenazine hydrochloride (Prolixin, Permitil), or trifluoperazine (Stelazine), or a midpotency antipsychotic,” he said in an interview. “We avoid using low-potency antipsychotics, such as chlorpromazine, because of side effects, such as hypotension, and a suggestion that they might be associated with a slightly increased risk for malformations.”
There are only sparse data on the reproductive safety of the currently available newer compounds, clozapine (Clozaril), risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), and ziprasidone (Geodon). “So we typically suggest that pregnant women who require treatment with antipsychotics and are on an atypical agent should switch to one of the older drugs,” he said. He and his associates also recommend that they not breast-feed while on an atypical agent until better safety data become available.
Some patients do not respond to treatment with typical antipsychotics but respond only to an atypical agent. “We have followed a small number of such patients who have stayed on the atypical drug during pregnancy and so far have not observed any unexpected problems,” Dr. Cohen said. The manufacturer of olanzapine has developed a registry of fewer than 100 women exposed to this drug during pregnancy. To date, there’s been no evidence of an increased risk for congenital malformations or other treatment-emergent difficulties, he said. Typical agents are increasingly being used for psychiatric disorders in women who may be more likely to bear children, such as those with anxiety or mood disorders, compared with those with schizophrenia. As a result, “we may be seeing more women on these drugs becoming pregnant, because they have less of an impact on fertility than the older drugs, which increase prolactin secretion,” he pointed out. With the exception of risperidone, which causes relatively high rates of hyperprolactinemia, ziprasidone, quetiapine, olanzapine, and clozapine are prolactin-sparing compounds.
An option for a woman with bipolar disease who is taking an atypical antipsychotic is to switch her to lithium during pregnancy. “We know that the absolute risk of having a child with Ebstein’s anomaly after first-trimester exposure is about 1 in 1,000 to 1 in 2,000,” Dr. Cohen observed. “And since we basically know nothing about the reproductive safety of atypical antipsychotics, I would rather see a woman who has been on a drug like olanzapine or quetiapine for bipolar disease switched to lithium during pregnancy since it has a known teratogenic potential,” he said.
Originally Printed In: OB.GYN NEWS 2001
May 15, 2000
May 1, 2000 from ObGynNews Even today, many clinicians mistakenly believe that pregnancy is protective against the development or relapse of depression. That misperception persists despite several studies over the past 6 years demonstrating that […]
May 1, 2000 from ObGynNews
Even today, many clinicians mistakenly believe that pregnancy is protective against the development or relapse of depression. That misperception persists despite several studies over the past 6 years demonstrating that women experience episodes of depression and relapse at the same rate during pregnancy as they do when they’re not pregnant.
Likewise, if a woman on antidepressants stops treatment during pregnancy, her risk of recurrence is just as high as it would be if she weren’t pregnant and she discontinued treatment. Still, it’s common for women to be counseled to stop antidepressants before or after they conceive.
The confluence of depression and pregnancy puts clinicians between a rock and a hard place. During pregnancy, the goal is to avoid the use of medications for which we don’t have conclusive safety data and those data concerning antidepressants during pregnancy are more or less complete depending on the medicine. At the same time, treatment cessation in women who are at risk of relapse can have an adverse effect on fetal well-being. Each patient must be managed on a case-by-case basis, weighing the risks and benefits of treatment.
What do we know? There are good data showing that first-trimester exposure to tricyclics such as imipramine (Tofranil) and amitriptyline (Elavil) doesn’t increase the rate of major congenital malformations. But these drugs are not widely used.
Of the selective serotonin reuptake inhibitors (SSRIs), the most data are available on fluoxetine (Prozac). There are about 2,000 cases in the manufacturer’s registry and several prospective studies describing first-trimester exposure to fluoxetine, none of which show an increased rate of major congenital malformations with first-trimester exposure. There are about 300 cases of pregnancy exposure to citalopram (Celexa) and approximately 250 for paroxetine (Paxil), sertraline (Zoloft), or fluvoxamine (Luvox) combined, accumulated from one study. Although these are in the same class as fluoxetine, conclusions that we make must be based on data for that specific medicine, not the class.
Another critical issue: We have very few good data on the risk of long-term neurobehavioral effects associated with prenatal exposure to psychiatric medications. One study of children followed through age 6 found no differences between those exposed to fluoxetine or tricyclics in utero and those not exposed to an antidepressant.
Data suggesting that the rates of perinatal toxicity or low birth weight are higher in babies exposed to fluoxetine in utero are profoundly flawed. We have a study in press that did not find this. Ultimately what we do about maintenance therapy, switching medications, or attempting to discontinue drugs should depend on the patient’s severity of illness and her wishes. Interestingly, women with similar illness histories who are given the same information regarding reproductive safety of these drugs often make very different decisions about how to proceed.
A switch to a safer drug may be appropriate. For example, a woman who is on bupropion (Wellbutrin), for which we have almost no reproductive safety data, would be best served by switching to a drug like fluoxetine or even imipramine. Yet ironically, bupropion is labeled as a category B drug while the SSRIs are labeled as category C drugs, even though there’s next to no information on bupropion’s reproductive safety. That’s why it’s so important for obstetricians to go further than the Physician’s Desk Reference.
We never discontinue antidepressants around the time of labor because depression during pregnancy is one of the strongest predictors of postpartum depression. The potential for withdrawal symptoms in babies born to women on antidepressants is a theoretical concern, but there is nothing more than a rare anecdote suggesting that such symptoms are something about which we need to be concerned.