Risk Factor: D
Class: Anti-infectives/ Tetracyclines
Fetal Risk Summary
Tetracyclines are a class of antibiotics that should be used with extreme caution, if at all, in pregnancy. The following discussion, unless otherwise noted, applies to all members of this class. Problems attributable to the use of the tetracyclines during or around the gestational period can be classified into four areas:
- Adverse effects on fetal teeth and bones
- Maternal liver toxicity
- Congenital defects
- Miscellaneous effectst
Placental transfer of a tetracycline was first demonstrated in 1950 (1). The tetracyclines were considered safe for the mother and fetus and were routinely used for maternal infections during the following decade (2,3,4 and 5). It was not until 1961 that an intense yellow-gold fluorescence was observed in the mineralized structures of a fetal skeleton whose mother had taken tetracycline just before delivery (6). Following this report, a 2-year-old child was described whose erupted deciduous teeth formed normally but were stained a bright yellow because of tetracycline exposure in utero (7). Fluorescence under ultraviolet light and yellow-colored deciduous teeth that eventually changed to yellow-brown were associated with maternal tetracycline ingestion during pregnancy by several other investigators (8,9,10,11,12,13,14,15,16,17,18,19,20,21 and 22). An increase in enamel hypoplasia and caries was initially suspected but later shown not to be related to in utero tetracycline exposure (14,15,22). Newborn growth and development were normal in all of these reports, although tetracycline has been shown to cause inhibition of fibula growth in premature infants (6). The mechanism for the characteristic dental defect produced by tetracycline is related to the potent chelating ability of the drug (13). Tetracycline forms a complex with calcium orthophosphate and becomes incorporated into bones and teeth undergoing calcification. In the latter structure, this complex causes a permanent discoloration, as remodeling and calcium exchange do not occur after calcification is completed. Because the deciduous teeth begin to calcify at around 5 or 6 months in utero, use of tetracycline after this time will result in staining.
The first case linking tetracycline with acute fatty metamorphosis of the liver in a pregnant woman was described in 1963 (23), although two earlier papers reported the disease without associating it with the drug (24,25). This rare but often fatal syndrome usually follows IV dosing of more than 2 g/day. Many of the pregnant patients were being treated for pyelonephritis (24,25,26,27,28,29,30,31,32,33,34,35,36 and 37). Tetracycline-induced hepatotoxicity differs from acute fatty liver of pregnancy in that it is not unique to pregnant women and reversal of the disease does not occur with pregnancy termination (38). The symptoms include jaundice, azotemia, acidosis, and terminal irreversible shock. Pancreatitis and nonoliguric renal failure are often related findings. The fetus may not be affected directly, but as a result of the maternal pathology, stillborns and premature births are common. In an experimental study, increasing doses of tetracycline caused increasing fatty metamorphosis of the liver (39). The possibility that chronic maternal use of tetracycline before conception could result in fatal hepatotoxicity of pregnancy has been raised (36). The authors speculated that tetracycline deposited in the bone of a 21-year-old patient was released during pregnancy, resulting in liver damage.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, a large number of newborns had been exposed to the tetracycline group of antibiotics during the 1st trimester (F. Rosa, personal communication, FDA, 1993). For four tetracyclines (T=tetracycline; D=doxycycline; O=oxytetracycline; M=minocycline), specific data were available for six defect categories, including (observed/expected): T D O M Number of exposures 1004 1795 26 181 Number of major defects 47 78 1 8 Percent 4.7% 4.3% 3.8% 4.4% Number of major defects expected 43 76 1 7 Cardiovascular defects 12/10 20/18 0/0.3 2/2 Oral clefts 1/2 0/3 0/0 1/0.5 Spina bifida 0/0.5 2/1 0/0 0/0 Polydactyly 5/3 7/5 0/0 0/0.5 Limb reduction defects 1/2 0/3 0/0 0/0.5 Hypospadias 1/2 4/4 0/0 0/0.5
These data do not support an association between the drugs and the specific malformations evaluated.
The Collaborative Perinatal Project monitored 50,282 mother-child pairs, 341 of whom had 1st-trimester exposure to tetracycline, 14 to chlortetracycline, 90 to demeclocycline, and 119 to oxytetracycline (40, pp. 297313). For use anytime in pregnancy, 1,336 exposures were recorded for tetracycline, 0 for chlortetracycline, 280 for demeclocycline, and 328 for oxytetracycline (40, p. 435). The findings of this study were as follows:
Tetracycline: Evidence was found to suggest a relationship to minor, but not major, malformations. Three possible associations were found with individual defects, but the statistical significance of these is unknown (40, pp. 472, 485). Independent confirmation is required to determine the actual risk.
- Hypospadias (1st trimester only) (5 cases) t
- Inguinal hernia (25 cases) t
- Hypoplasia of limb or part thereof (6 cases)
Chlortetracycline: No evidence was found to suggest a relationship to large categories of major or minor malformations or to individual defects. However, the sample size is extremely small, and safety should not be inferred from these negative results.
Demeclocycline: No evidence was found to suggest a relationship to large categories of major or minor malformations, but the sample size is small (40, pp. 297313). Two possible associations were found with individual defects, but the statistical significance of these is unknown (40, pp. 472, 485). Independent confirmation is required to determine the actual risk.
- Club foot (1st trimester only) (3 cases) t
- Inguinal hernia (8 cases)
Oxytetracycline: Evidence was found to suggest a relationship to large categories of major and minor malformations (40, pp. 297313). One possible association was found with individual defects, but the statistical significance of this is unknown (40, pp. 472, 485). Independent confirmation is required to determine the actual risk.
- Inguinal hernia (14 cases)
In 1962, a woman treated with tetracycline in the 1st trimester for acute bronchitis delivered an infant with congenital defects of both hands (41,42). The mother had a history of minor congenital defects on her side of the family and doubt was cast on the role of the drug in this anomaly (43). A possible association between the use of tetracyclines in pregnancy or during lactation and congenital cataracts has been reported in four patients (44). The effects of other drugs, including several antibiotics, and maternal infection could not be determined, and a causal relationship to the tetracyclines seems remote. An infant with multiple anomalies whose mother had been treated for acne with clomocycline daily during the first 8 weeks of pregnancy has been described (45). Some of the defects, particularly the incomplete fibrous ankylosis and bone changes, made the authors suspect this tetracycline as the likely cause.
Doxycycline has been used for 10 days very early in the 1st trimester for the treatment of Mycoplasma infection in a group of previously infertile women (46). Dosage was based on the patient’s weight, varying from 100300 mg/day. All 43 of the exposed liveborns were normal at 1 year of age. Bubonic plague occurring in a woman at 22 weeks’ gestation was successfully treated with tetracycline and streptomycin (47). Long-term evaluation of the infant was not reported.
A 1997 report examined the question of doxycycline-induced teratogenicity in the large population-based data set of the Hungarian Case-Control Surveillance of Congenital Abnormalities, 19801992 (48). Some mild defects were excluded, including hemangiomas and minor malformations. Moreover, although an extensive retrospective assessment of drug use during pregnancy was performed, a history of tobacco and alcohol exposure was not obtained because the accuracy of these data were believed to have low validity (48). Among the 32,804 pregnant women who had normal infants (controls), 63 (0.19%) had taken doxycycline, whereas 56 (0.30%) of the 18,515 women who delivered infants with congenital anomalies had taken the antibiotic (p=0.01). A case-control pair analysis of exposures during the 2nd and 3rd months of gestation, however, did not show a significant difference among the groups in any of the malformation types.
Under miscellaneous effects, two reports have appeared that, although they do not directly relate to effects on the fetus, do directly affect pregnancy. In 1974, a researcher observed that a 1-week administration of 500 mg/day of chlortetracycline to male subjects was sufficient to produce semen levels of the drug averaging 4.5 g/mL (49). He theorized that tetracycline overdose could modify the fertilizing capacity of human sperm by inhibiting capacitation. Finally, a possible interaction between oral contraceptives and tetracycline resulting in pregnancy has been reported (50). The mechanism for this interaction may involve the interruption of enterohepatic circulation of contraceptive steroids by inhibiting gut bacterial hydrolysis of steroid conjugates, resulting in a lower concentration of circulating steroids.
Breast Feeding Summary
Tetracycline is excreted into breast milk in low concentrations. Milk:plasma ratios vary between 0.25 and 1.5 (4,51,52). Theoretically, dental staining and inhibition of bone growth could occur in breast-fed infants whose mothers were consuming tetracycline. However, this theoretical possibility seems remote, because tetracycline serum levels in infants exposed in such a manner were undetectable (
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