Ampicillin

 Risk Factor: B
 Class: ANTI-INFECTIVES / Penicillins

Contents of this page:

Fetal Risk Summary
Breast Feeding Summary
References
Questions and Answers

Fetal Risk Summary

Ampicillin is a penicillin antibiotic (see also Penicillin G). The drug rapidly crosses the placenta into the fetal circulation and amniotic fluid (1,2,3,4,5 and 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 (9,10,11,12 and 13). Urinary estriol was formerly used to assess the condition of the fetoplacental unit, 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 intervals [CI] 1.38.1, 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 1.338) 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, 3,546 of whom had 1st trimester exposure to penicillin derivatives (20, pp. 297313). For use anytime during pregnancy, 7,171 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 (21,22 and 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.

Breast Feeding Summary

Ampicillin is excreted into breast milk in low concentrations. Milk:plasma ratios have been reported up to 0.2 (25,26). Candidiasis and diarrhea were observed in one infant whose mother was receiving ampicillin (27). Other reports of this effect have not been located. 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

1. Bray R, Boc R, Johnson W. Transfer of ampicillin into fetus and amniotic fluid from maternal plasma in late pregnancy. Am J Obstet Gynecol 1966;96:93842.
2. MacAulay M, Abou-Sabe M, Charles D. Placental transfer of ampicillin. Am J Obstet Gynecol 1966;96:94350.
3. Biro L, Ivan E, Elek E, Arr M. Data on the tissue concentration of antibiotics in man. Tissue concentrations of semi-synthetic penicillins in the fetus. Int Z Klin Pharmakol Ther Toxikol 1970;4:3214.
4. Elek E, Ivan E, Arr M. Passage of penicillins from mother to foetus in humans. Int J Clin Pharmacol Ther Toxicol 1972;6:2238.
5. Kraybill EN, Chaney NE, McCarthy LR. Transplacental ampicillin: inhibitory concentrations in neonatal serum. Am J Obstet Gynecol 1980;138:7936.
6. Jordheim O, Hagen AG. Study of ampicillin levels in maternal serum, umbilical cord serum and amniotic fluid following administration of pivampicillin. Acta Obstet Gynecol Scand 1980;59:3157.
7. Philipson A. Pharmacokinetics of ampicillin during pregnancy. J Infect Dis 1977;136:3706.
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9. Willman K, Pulkkinen M. Reduced maternal plasma and urinary estriol during ampicillin treatment. Am J Obstet Gynecol 1971;109:8936.
10. Boehn F, DiPietro D, Goss D. The effect of ampicillin administration on urinary estriol and serum estradiol in the normal pregnant patient. Am J Obstet Gynecol 1974;119:98101.
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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;128:26671.
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14. Dossetor J. Drug interactions with oral contraceptives. Br Med J 1975;4:4678.
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16. Friedman CI, Huneke AL, Kim MH, Powell J. The effect of ampicillin on oral contraceptive effectiveness. Obstet Gynecol 1980;55:337.
17. Back DJ, Breckenridge AM, MacIver M, Orme M, Rowe PH, Staiger C, Thomas E, Tjia J. The effects of ampicillin on oral contraceptive steroids in women. Br J Clin Pharmacol 1982;14:438.
18. Rothman KJ, Fyler DC, Goldblatt A, Kreidberg MB. Exogenous hormones and other drug exposures of children with congenital heart disease. Am J Epidemiol 1979;109:4339.
19. Zierler S. Maternal drugs and congenital heart disease. Obstet Gynecol 1985;65:15565.
20. Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA:Publishing Sciences Group, 1977.
21. Boyer KM, Gotoff SP. Prevention of early-onset neonatal group B streptococcal disease with selective intrapartum chemoprophylaxis. N Engl J Med 1986;314:16659.
22. Amon E, Lewis SV, Sibai BM, Villar MA, Arheart KL. Ampicillin prophylaxis in preterm premature rupture of the membranes: a prospective randomized study. Am J Obstet Gynecol 1988;159:53943.
23. Morales WJ, Angel JL, O'Brien WF, Knuppel RA. Use of ampicillin and corticosteroids in premature rupture of membranes: a randomized study. Obstet Gynecol 1989;73:7216.
24. Heim K, Alge A, Marth C. Anaphylactic reaction to ampicillin and severe complication in the fetus. Lancet 1991;337:859.
25. Wilson J, Brown R, Cherek D, Dailey JW, Hilman B, Jobe PC, Manno BR, Manno JE, Redetzki HM, Stewart JJ. Drug excretion in human breast milk: principles, pharmacokinetics and projected consequences. Clin Pharmacol Ther 1980;5:166.
26. Knowles J. Excretion of drugs in milka review. J Pediatr 1965;66:106882.
27. Williams M. Excretion of drugs in milk. Pharm J 1976;217:219.