Antibiotic (Penicillin)
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st Trimester
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Penicillins are considered low risk at any stage of pregnancy. This assessment may have to be modified for the aminopenicillins (ampicillin and amoxicillin) because there is some evidence that exposure to these two antibiotics during organogenesis is associated with oral clefts (see also Amoxicillin). However, even if the association is causal, the absolute risk is very low. The association requires confirmation.
FETAL RISK SUMMARY
Ampicillin is an aminopenicillin antibiotic (see also Amoxicillin). The drug rapidly crosses the placenta into the fetal circulation and amniotic fluid (1–6). Fetal serum levels can be detected within 30 minutes and equilibrate with maternal serum in 1 hour. Amniotic fluid levels can be detected in 90 minutes, reaching 20% of the maternal serum peak in about 8 hours. The pharmacokinetics of ampicillin during pregnancy have been reported (7,8).
Ampicillin depresses both plasma-bound and urinary-excreted estriol by inhibiting steroid conjugate hydrolysis in the gut (9–13). Urinary estriol was formerly used to assess the condition of the fetoplacental unit, with depressed levels being associated with fetal distress. This assessment is now made by measuring plasma unconjugated estriol, which is not usually affected by ampicillin. An interaction between ampicillin and oral contraceptives resulting in pregnancy has been suspected (14,15). Two studies, however, failed to confirm this interaction and concluded that alternate contraceptive methods were not necessary during ampicillin therapy (16,17).
The use of ampicillin in early pregnancy was associated with a prevalence ratio estimate of 3.3 (90% confidence interval [CI] 1.3–8.1, p = 0.02) for congenital heart disease in a retrospective study (18). A specific defect, transposition of the great arteries, had a risk of 7.7 (90% CI 1.3–38) based on exposure in 2 of the 29 infants with the anomaly. The investigators did note, however, that the results had to be viewed cautiously because the data were subject to recall bias (drug histories were taken by questionnaire or telephone up to a year after presumed exposure) and the study could not distinguish between the fetal effects of the drug versus those of the infectious agent(s) for which the drugs were used. Others have also shared this concern (19). Other reports linking the use of ampicillin with congenital defects have not been located.
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 3546 of whom had 1st trimester exposure to penicillin derivatives (20, pp. 297–313). For use anytime during pregnancy, 7171 exposures were recorded (20, p. 435). In neither group was evidence found to suggest a relationship to large categories of major or minor malformations or to individual defects. Based on these data, it is unlikely that ampicillin is teratogenic.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 10,011 newborns had been exposed to ampicillin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 441 (4.4%) major birth defects were observed (426 expected). Specific data were available for six defect categories, including (observed/expected) 116/100 cardiovascular defects, 13/16 oral clefts, 6/8 spina bifida, 36/29 polydactyly, 9/17 limb reduction defects, and 27/24 hypospadias. These data do not support an association between the drug and the defects.
Ampicillin is often used in the last half of pregnancies in which either the woman or her fetus is at risk for infections because of premature rupture of the membranes or other risk factors (21–23). In one report, a mother with ruptured membranes at 40 weeks’ gestation had an anaphylactic reaction to ampicillin (24). A markedly distressed infant was delivered with severe metabolic acidosis (arterial cord blood pH 6.71). Multifocal clonic seizures and brain edema occurred during the neonatal period, and pronounced neurologic abnormalities were evident at 6 months of age.
A 2001 study from Hungary evaluated the association between ampicillin and birth defects (25). Of 38,151 controls (no defects), 2632 (6.9%) had been treated with ampicillin. In 22,865 cases (with defects), 1643 (7.2%) had been treated with ampicillin. For ampicillin use in the second and third months of gestation, the only significant difference was for cleft palate (odds ratio 4.2, 95% confidence interval 1.4–16.3). However, the authors concluded that the lack of evidence for the association in other studies and in animals suggested that the apparent risk was not real and instead a chance association (25).
BREASTFEEDING SUMMARY
Ampicillin is excreted into breast milk in low concentrations. Milk:plasma ratios have been reported up to 0.2 (26,27). Candidiasis and diarrhea were observed in one infant whose mother was receiving ampicillin (28).
In a 1993 cohort study, diarrhea was reported in 32 (19.3%) nursing infants of 166 breastfeeding mothers who were taking antibiotics (29). For the five women taking ampicillin, diarrhea was observed in one (20%) infant. The diarrhea was considered minor because it did not require medical attention (29).
Although adverse effects are apparently rare, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant (e.g., allergic response or sensitization), and interference with the interpretation of culture results if a fever workup is required.
References
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12.Aldercreutz H, Martin F, Lehtinen T, Tikkanen M, Pulkkinen M. Effect of ampicillin administration on plasma conjugated and unconjugated estrogen and progesterone levels in pregnancy. Am J Obstet Gynecol 1977;128:266–71.
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29.Ito S, Blajchman A, Stephenson M, Eliopoulos C, Koren G. Prospective follow-up of adverse reactions in breast-fed infants exposed to maternal medication. Am J Obstet Gynecol 1993;168:1393–9.