Repeated implantation failure treatments
Acupuncture, a form of alternative medicine is the stimulation of specific acupuncture points along the skin of the body using thin needles. It is commonly used for pain relief, though it is also used to treat a wide range of conditions. Acupuncture is rarely used alone but rather as an adjunct to other treatment modalities. In Western settings acupuncture is used as a primary intervention for fertility problems. Acupuncture is increasingly used as an adjunct to assisted reproductive technologies and more widely in the complementary health care system.
The Western medical acupuncture approach involves using acupuncture after a medical diagnosis. In traditional acupuncture, the acupuncturist decides which points to treat by observing and questioning the patient to make a diagnosis according to the tradition used.
This method has always been applied to reproductive treatment in China. Western medicine may exert influence on neuroendocrine system, immunological functions and even signal pathway in consideration when discussing the efficacy of acupuncture and these still continue to be studied. The Chinese medicine evaluates the effect of acupuncture from an overall perspective. In Chinese medicine, reproductive function relates not only to reproductive organs, but also to the kidney, the liver, and the heart.
Acupuncture can be used as an adjuvant treatment for unexplained infertility. Although acupuncture did not increase the cumulative pregnancy rate, it decreased the number of control ovarian hyperstimulation (COH) cycles and more patients got pregnant in natural cycles after receiving acupuncture (Tab. 1).
Acupuncture treatment procedures should happen once or twice a week, and will continue for anywhere from a few weeks to a few months. Remember the process may take more time than just twice a week if you are combining it with medical infertility treatments, like IVF. In general, the acupuncture treatment can be completed in 12 appointments. At each appointment, your acupuncturist will most likely take additional time to discuss your current condition and answer any questions that you may have.
Egg donation is the process by which a woman donates eggs for purposes of assisted reproduction or biomedical research. For assisted reproduction purposes, egg donation typically involves IVF technology, with the eggs being fertilized in the laboratory; more rarely, unfertilized eggs may be frozen and stored for later use. Egg donation is a third party reproduction as part of ART.
Egg donor may have several reasons for donate her eggs:
Unrelated donors to the recipients – they do it for altruistic and/or monetary reasons. The European Union limits any financial compensation for donors to at most $1500. In some countries, most notably Spain and Cyprus, this has limited donors to the poorest segments of society. In US, donors are paid regardless of how many egg she produces. In most countries (excluding the US and the UK), the law requires such type of donors to be anonymous.
Egg sharing – the woman decides to provide unused egg from her own IVF for another patient.
Designated donors – couple bring their friend or the donor specifically to help them.
First step is choosing the egg donor by a recipient from the profiles on or clinic databases (or, in countries where donors are required to remain anonymous, they are chosen by the recipient's doctor based on recipient woman's desired trait). This is due to the fact that all of the mentioned examinations are expensive and the agencies/clinics must first confirm that a match is possible or guaranteed before investing in the process.
Each egg donor is first referred to a psychologist who will evaluate if she is mentally prepared to undertake and complete the donation process. These evaluations are necessary to ensure that the donor is fully prepared and capable of completing the donation cycle in safe and success manner. The donor is then required to undergo a thorough medical examination, including a pelvic exam, blood tests to check hormone levels and to test for infectious diseases, Rh factor, blood type, and drugs and an ultrasound to examine her ovaries, uterus and other pelvic organs. A family history of approximately the past three generations is also required, meaning that adoptees are usually not accepted because of the lack of past health knowledge. Genetic testing is also usually done on donors to ensure that they do not carry mutations (e.g., cystic fibrosis) that could harm the resulting children; however, not all clinics automatically perform such testing and thus recipients must clarify with their clinics whether such testing will be done. During the process, which usually takes several months, the donor must abstain from alcohol, sexual intercourse, cigarettes, and drugs, both prescription and non-prescription.
Once the screening is complete and a legal contract signed, the donor will begin the donation cycle, which typically takes between three and six weeks. An egg retrieval procedure comprises both the egg donor's cycle and the recipient's cycle. Birth control pills are administered during the first few weeks of the egg donation process to synchronize the donor's cycle with her recipient's, followed by a series of injections which halt the normal functioning of the donor's ovaries. These injections may be self-administered on a daily basis for a period of one to three weeks. Next, FSH is given to the donor to stimulate egg production and increases the number of mature eggs produced by the ovaries. Throughout the cycle the donor is monitored often by a physician using blood tests and ultrasound exams to determine the donor's reaction to the hormones and the progress of follicle growth.
Once the doctor decides the follicles are mature, the doctor will establish the date and time for the egg retrieval procedure. Approximately 36 hours before retrieval, the donor must administer one last injection of hCG to ensure that her eggs are ready to be harvested. The egg retrieval itself is a minimally invasive surgical procedure lasting 20-30 minutes, performed under sedation (but sometimes without any). A small ultrasound-guided needle is inserted through the vagina to aspirate the follicles in both ovaries, which extracts the eggs. After resting in a recovery room for an hour or two, the donor is released. Most donors resume regular activities by the next day.
Laws by state
The legal status and compensation of egg donation has several models across states with examples:
Totally illegal procedure (Italy, Germany, Austria, Costa Rica, Sunni Muslim countries, Bahrain, Egypt, Hong Kong, Lebanon, Lithuania, Maldives, Norway, Oman, Pakistan, Philippines, Qatar, Saudi Arabia, Syria, Tajikistan, Turkey, Yemen),
Legal, no compensation, anonymous donor (France),
Legal, no compensation, non-anonymous donor (Canada),
Legal, possible compensation, anonymous donor (Spain, Czech Republic, South Africa),
Legal, possible compensation, non-anonymous donor (the UK),
Legal, possible compensation, anonymous or non-anonymous (the US).
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Endometrial scratching
In endometrial scratching, endometrium is gently "scratched" using a thin catheter which causes immunological reaction leading to increase implantation rate in women with unexplained recurrent implantation failure. Inducing injury to the lining of the uterus in the cycle before starting ovarian stimulation for IVF can help improve the chances of achieving pregnancy. The new lining which grows after the procedure is thought to be more receptive to an implanting embryo and so increases the chances.
Although the fertilization rate is relatively high and embryo culture conditions continue to improve, implantation is still the limiting step in the success of in vitro fertilization-embryo transfer. In humans, the uterus becomes receptive during the mid-secretory phase (days 19–24) of the menstrual cycle, which is known as the window of implantation (WOI). It is proposed that approximately 75% of the embryos are lost at the time of implantation resulting in implantation failure. Interactions between endometrium and the embryo as well as endometrial receptivity are considered as two strong factors affecting the outcome of implantation. The endometrial receptivity is proposed to be a period of time in which the endometrium becomes capable of receiving and adhering the human embryo.
Endometrial scratching mechanisms
There are some possible suggested mechanisms by which the endometrial sampling may increase receptivity and improve clinical pregnancy rate. The first one is decidualization of endometrium. Scratching uteruses provokes the rapid growth of the endometrial cells which are similar to the decidual cells of pregnancy. The next mechanism is wound healing process involving a massive secretion of different cytokines and growth factors which are beneficial for embryo implantation. Also, the last mechanism is synchronization of endometrial and embryo development. COH (controlled ovarian hyperstimulation) performed during IVF therapy may negatively affect the embryo implantation. COH cycles resulted in different structural and functional changes compared to the natural cycles.
These observations suggest that mechanical injury of the endometrium may enhance uterine receptivity by provoking the immune system to generate an inflammatory reaction. Alternatively, the local injury could generate a focus for the accumulation of uterine dendritic cells and accompanying increases in innate immune molecules or provide an enhanced angiogenic environment enriched with cytokines and growth factors known to be essential for normal trophoblast invasion.
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ERA test
ERA test (Endometrial Receptivity Array) is a molecular diagnostic test used to assess endometrial status and to determine whether or not the patient's endometrium (uterine lining) had a receptive state (seen from the gene profile) at the time of sampling before embryo transfer.
Principe of ERA
Normally, the optimal endometrial state for embryo transfer is evaluated by ultrasound, but it can only show its thickness and structure. The ERA test requires an endometrial biopsy that should be carried out seven days after luteinizing hormone (LH) surge in natural cycle or after five full days of progesterone exposure of artificial cycle. The test determines the expression (i.e. the information from a gene is used in the synthesis of a functional product, most often proteins) level of 236 genes that are involved in endometrial receptivity at molecular level.
The results from the analysis will determine if the woman was receptive or not at the time of sampling. If she is receptive, this implies that her implantation window (see below) falls on the day of the cycle during which the biopsy was performed and the embryo could therefore be transferred to the uterus during this period.
A non-receptive status may imply a displaced window of implantation. The procedure will be performed once again according to the computational predictor.
Implantation Window
The implantation (Pic. 1), the process whereby the blastocyst (day 5 embryo) gets fixed to the uterine epithelium and penetrates though it, requires a receptive endometrium and an embryo at the blastocyst stage, as well as an interaction between both. The human endometrium undergoes to a complex series of proliferative and secretory changes in each menstrual cycle and displays only a short period of receptivity, known as the "window of implantation", necessary for the implantation of the blastocyst in the uterus.
Therefore, gene expression in the human endometrium is likely to exhibit neat and distinct changes throughout the various stages of the menstrual cycle in accordance with the oscillations (waves generated by pulsatile release) in estrogen and progesterone serum levels and their tissue receptor levels. Since these ovarian steroid hormones drive these processes eliciting an array of cellular and biochemical responses, mostly through genomic pathways, current thinking suggests that at the onset of receptivity, expression of some genes in given cell types of this tissue, is temporarily turned on or increased while some others are temporarily turned off or decreased.
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During ICSI just one sperm is injected directly into the egg cytoplasm using a micromanipulative apparatus that transforms imperfect hand movements into fine and precise movements of micromanipulation tools.
Intracytoplasmic Sperm Injection (ICSI) is an assisted reproductive technique (ART) initially developed by Dr. Gianpiero D. Palermo in 1993 to treat male infertility. It is most commonly used in conjunction with in vitro fertilization (IVF). Following IVF procedure, the physician places the fertilized egg into the female's uterus for implantation. Sperm are obtained by the same methods as with IVF: either through masturbation, by using a collection condom, or by surgically removing sperm from a testicle through a small incision (MESA, TESE). The females are treated with fertility medications for approximately two weeks prior to oocyte retrieval to stimulate superovulation, where the ovaries produce multiple oocytes rather than the normal one oocyte. The oocytes are retrieved by either laparoscopy, or more commonly, transvaginal oocyte retrieval. In the latter procedure, the physician inserts a thin needle through the cervix, guided by a sonogram and pierces the vaginal wall and then the ovaries to extract several mature ova. Before the embryologist can inject the sperm into the oocyte, the sperm must be prepared by washing and exposing it to various chemicals to slow the sperm movement and prevent it from sticking to the injection plate. Also, the oocytes are treated with hyaluronidase to single out the oocyte ready for fertilization by the presence of the first polar body. Then, one prepared sperm is injected into an oocyte with a thin needle. Often, embryologists try to fertilize several eggs so they can implant more than one into the uterus and increase the chance of at least one successful pregnancy. This also allows them to save extra embryos, using cryopreservation, in case later IVF rounds are needed.
After the embryologist manually fertilizes the oocytes, they are incubated for sixteen to eighteen hours and develop into a pronucleate eggs (successfully fertilized eggs about to divide into an embryo). The egg then grows for one to five days in the laboratory before the physician places it in the female's uterus for implantation.
The chance of fertilization increases dramatically with ICSI compared to simply mixing the oocytes and sperm in a Petri dish and waiting for fertilization to occur unaided (classical IVF procedure). Studies have shown that successful fertilizations occur 50% to 80% of the time. Since the introduction of ICSI, intrauterine insemination (IUI) has decreased in popularity by 80%.
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IMSI is based on a method of high magnification motile sperm organelle morphology examination (MSOME). It requires an inverted light microscope equipped with high power Nomarski optics enhanced with digital imaging. Such examination helps to identify spermatozoa with a normal nucleus and nuclear content. The exact indications of IMSI and usefulness are debatable. Finding normal-looking spermatozoa took a minimum of 60 min, and up to 210 min, depending on the quality of the semen sample. The IMSI procedure improved embryo development and the laboratory and clinical outcomes of sperm microinjection in the same infertile couples with male infertility and poor embryo development over the previous ICSI attempts.
Introduced in 2001, intracytoplasmic morphologically selected sperm injection (IMSI) represents a more sophisticated way of ICSI whereby, prior to injection, the spermatozoon is selected at higher magnification. Doing so, the spermatozoon can be evaluated for fine integrity of its nucleus and the injection of a normal spermatozoon with a vacuole-free head can be assured.
Additional research is needed to unravel the underlying mechanisms responsible for the presence of vacuoles in sperm heads. Vacuoles in human sperm cells appear in various numbers and sizes, both in abnormal-shaped spermatozoa as well as in normal-shaped spermatozoa. Associations with acrosome status, chromatin condensation, DNA fragmentation and sperm aneuploidy have been documented, however, controversy on their nature exists. Spermatozoon shape and large vacuoles are detected and deselected in conventional ICSI as well. However, the detection of subtle small vacuoles depends on the resolving power of the optical system and may impact oocyte fertilization, embryo development and implantation.
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Sperm donation is the donation by a male (known as a sperm donor) of his sperm (known as donor sperm), principally for the purpose of inseminating a female who is not his sexual partner. Sperm donation is a form of third party reproduction including sperm donation, oocyte donation, embryo donation, surrogacy, or adoption. Number of births per donor sample will depend on the actual ART method used, the age and medical condition of the female bearing the child, and the quality of the embryos produced by fertilization. Donor sperm is more commonly used for artificial insemination (IUI or ICI) than for IVF treatments. This is because IVF treatments are usually required only when there is a problem with the female conceiving, or where there is a "male factor problem" involving the female's partner. Donor sperm is also used for IVF in surrogacy arrangements where an embryo may be created in an IVF procedure using donor sperm and this is then implanted in a surrogate. In a case where IVF treatments are employed using donor sperm, surplus embryos may be donated to other women or couples and used in embryo transfer procedures.
On the other hand, insemination may also be achieved by a donor having sexual intercourse with a female for the sole purpose of initiating conception. This method is known as natural insemination.
The donation
Donor sperm and fertility treatments using donor sperm may be obtained at a sperm bank or fertility clinic. Here, the recipient may select donor sperm on the basis of the donor's characteristics, e.g. looks, personality, academic ability, race, and many other factors. Sperm banks or clinics may be subject to state or professional regulations, including restrictions on donor anonymity and the number of offspring that may be produced, and there may be other legal protections of the rights and responsibilities of both recipient and donor. Some sperm banks, either by choice or regulation, limit the amount of information available to potential recipients; a desire to obtain more information on donors is one reason why recipients may choose to use a known donor and/or private donation.
A sperm donor will usually donate sperm to a sperm bank under a contract, which typically specifies the period during which the donor will be required to produce sperm, which generally ranges from 6–24 months depending on the number of pregnancies which the sperm bank intends to produce from the donor. Donors may or may not be paid for their samples, according to local laws and agreed arrangements. Even in unpaid arrangements, expenses are often reimbursed. Depending on local law and on private arrangements, men may donate anonymously or agree to provide identifying information to their offspring in the future. Private donations facilitated by an agency often use a "directed" donor, when a male directs that his sperm is to be used by a specific person. Non-anonymous donors are also called known donors, open donors or identity disclosure donors.
Donor selection
A sperm donate must generally meet specific requirements regarding age (most often up to 40) and medical history. Potential donors are typically screened for genetic diseases, chromosomal abnormalities and sexually transmitted infections that may be transmitted through sperm. The donor's sperm must also withstand the freezing and thawing process necessary to store and quarantine the sperm. Samples are stored for at least 6 months after which the donor will be re-tested for sexually transmitted infections. This is to ensure no new infections have been acquired or have developed during the period of donation. If the result is negative, the sperm samples can be released from quarantine and used in treatments.
Screening includes:
Taking a medical history of the donor, his children, siblings, parents, and grandparents etc. for three to four generations back. This is often done in conjunction with the patient's family doctor.
HIV risk assessment interview, asking about sexual activity and any past drug use.
Blood tests and urine tests for infectious diseases, such as: HIV-1/2, HTLV-1/2, Hepatitis B and C, Syphilis, Gonorrhea, Chlamydia, Cytomegalovirus (CMV), not all clinics test for this.
Blood and urine tests for blood typing and general health indicators: ABO/Rh typing, CBC, liver panel and urinalysis
Complete physical examination including careful examination of the penis, scrotum and testicles.
Genetic testing for carrier traits, for example: Cystic Fibrosis, Sickle-cell disease, Thalassemia, other hemoglobin-related blood disorders.
Semen analysis for: sperm count, morphology, motility, acrosome activity may also be tested
Preparing the samples
A sperm donor is usually advised not to ejaculate for two to three days before providing the sample, to increase sperm count and to maximize the conception rate. A sperm donor produces and collects sperm by masturbation or during sexual intercourse with the use of a collection condom.
Sperm banks and clinics usually "wash" the sperm sample to extract sperm from the rest of the material in the semen. A cryoprotectant semen extender is added if the sperm is to be placed in frozen storage in liquid nitrogen, and the sample is then frozen in a number of vials or straws. One sample will be divided into 1-20 vials or straws depending on the quantity of the ejaculate and whether the sample is washed or unwashed. Following the necessary quarantine period, the samples are thawed and used to inseminate women through artificial insemination or other ART treatments. Unwashed samples are used for ICI treatments, and washed samples are used in IUI and IVF procedures.
Anonymous sperm donation occurs where the child and/or receiving couple will never learn the identity of the donor, and non-anonymous when they will. Non-anonymous sperm donors are, to a substantially higher degree, driven by altruistic motives for their donations.
Even with anonymous donation, some information about the donor may be released to the female/couple at the time of treatment. Limited donor information includes height, weight, eye, skin and hair color. In Sweden, this is all the information a receiver gets. In the US, on the other hand, additional information may be given, such as a comprehensive biography and sound/video samples.
Information made available by a sperm bank will usually include the race, height, weight, blood group, health, and eye color of the donor. Sometimes information about his age, family history and educational achievements will also be given.
Different factors motivate individuals to seek sperm from outside their home state. For example, some jurisdictions do not allow unmarried women to receive donor sperm. Jurisdictional regulatory choices as well as cultural factors that discourage sperm donation have also led to international fertility tourism and sperm markets.
A sperm donor is generally not intended to be the legal or de jure father of a child produced from his sperm. Depending on the jurisdiction and its laws, he may or may not later be eligible to seek parental rights or be held responsible for parental obligations. Generally, a male who provides sperm as a sperm donor gives up all legal and other rights over the biological children produced from his sperm. However, in private arrangements, some degree of co-parenting may be agreed, although the enforceability of those agreements varies by jurisdiction.
Laws prohibits sperm donation in several countries: Algeria, Bahrain, Costa Rica, Egypt, Hong Kong, Jordan, Lebanon, Lithuania, Libya, Maldives, Oman, Pakistan, Philippines, Qatar, Saudi Arabia, Syria, Tajikistan, Tunisia, Turkey, UnitedArab Emirates, and Yemen.
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Standard IVF
In vitro fertilization (IVF) is a process by which an egg is fertilised by sperm outside the body: in vitro . The process involves monitoring and stimulating a woman's ovulatory process, removing an ovum or ova (egg or eggs) from the woman's ovaries and letting sperm fertilise them in a liquid in a laboratory. The fertilised egg (zygote) is cultured for 2–6 days in a growth medium and is then implanted in the same or another woman's uterus, with the intention of establishing a successful pregnancy.
IVF techniques can be used in different types of situations. It is a technique of assisted reproductive technology for treatment of infertility. IVF techniques are also employed in gestational surrogacy, in which case the fertilised egg is implanted into a surrogate's uterus, and the resulting child is genetically unrelated to the surrogate. In some situations, donated eggs or sperms may be used. Some countries ban or otherwise regulate the availability of IVF treatment, giving raise to fertility tourism. Restrictions on availability of IVF include to single females, to lesbians and to surrogacy arrangements. Due to the costs of the procedure, IVF is mostly attempted only after less expensive options have failed.
The first successful birth of a "test tube baby", Louise Brown, occurred in 1978. Louise Brown was born as a result of natural cycle IVF where no stimulation was made. Robert G. Edwards, the physiologist who developed the treatment, was awarded the Nobel Prize in Physiology or Medicine in 2010. With egg donation and IVF, women who are past their reproductive years or menopause can still become pregnant. Adriana Iliescu held the record as the oldest woman to give birth using IVF and donated egg, when she gave birth in 2004 at the age of 66, a record passed in 2006.
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How can Repeated implantation failure affect fertility
Although several medical causes have been established, up to 50% of cases of recurrent pregnancy loss, defined as two or more spontaneous abortions, still remain unexplained after standard gynecological, hormonal, and karyotype investigations. However, it has been postulated that the major single cause of failed pregnancy is an error of embryo implantation, which may be as high as 78% in humans.
Embryo implantation is a complex and progressive process which involves synchronous molecular events in the uterus and the embryo promoting a perfect interaction between them. This phenomenon is characterized by apposition, adhesion and invasion of the endometrium by the blastocyst.
The establishment of consistent junctions between the embryo trophoblast and the endometrium requires the expression of adhesion molecules and elimination of nonadhesive molecules from the apical cell lining of both tissues. In this phase, called pre-implantation period, the embryo plays an important role in the receptive phase of implantation, modulating endometrial molecules and controlling the implantation process.