Antibiotic (Penicillin)
PREGNANCY RECOMMENDATION: Human Data Suggest Risk in 1st and 3rd Trimesters
BREASTFEEDING RECOMMENDATION: Compatible
PREGNANCY SUMMARY
Penicillins are generally 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 Ampicillin). However, even if the association is causal, the absolute risk is very low. In addition, one study reported an association between amoxicillin–clavulanic acid and necrotizing enterocolitis (NEC) when the antibiotic combination was used near preterm birth. Both of these associations require confirmation.
FETAL RISK SUMMARY
Amoxicillin is an aminopenicillin antibiotic similar to ampicillin. The antibiotic is known to cross the placenta.
Reproduction studies have been conducted in mice and rats at doses up to 10 times the human dose. No effect on fertility or fetal harm was observed at this dose (1).
The Collaborative Perinatal Project monitored 50,282 mother–child pairs, 3546 of whom had 1st trimester exposure to penicillin derivatives (2, pp. 297–313). For use anytime during pregnancy, 7171 exposures were recorded (2, p. 435). In neither group was evidence found to suggest a relationship to large categories of major or minor malformations or to individual defects. Amoxicillin has been used as a single 3-g dose to treat bacteriuria in pregnancy without causing fetal harm (3,4).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 8538 newborns had been exposed to amoxicillin during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 317 (3.7%) major birth defects were observed (363 expected). Specific data were available for six defect categories, including (observed/expected) 76/85 cardiovascular defects, 16/14 oral clefts, 6/7 spina bifida, 17/24 polydactyly, 9/16 limb reduction defects, and 22/22 hypospadias. These data do not support an association between the drug and the defects.
Several reports have described the use of amoxicillin in pregnancy, either for preterm pre-labor rupture of membranes (5,6) or for the treatment of prenatal Chlamydia infection (7–10). The latter reference is of particular interest because of the potential for fetal–newborn harm when amoxicillin–clavulanic acid (ACA) was used. A 2001 randomized study (ORACLE 1) was conducted in patients with preterm, pre-labor rupture of fetal membranes to determine neonatal health benefits of three antibiotic regimens (10). The regimens, compared with a placebo group (N = 1225) were erythromycin (250 mg) (N = 1197), amoxicillin (250 mg)–clavulanic acid (125 mg) (N = 1212), or both (N = 1192) four times daily for 10 days or until delivery. The primary outcome measures were specific outcomes or a composite of neonatal death, chronic lung disease, or major cerebral abnormality. For these neonatal outcomes, the two groups with ACA had no benefit over placebo, whereas erythromycin use resulted in significantly better outcomes (both composite and specific). When any-ACA exposure was compared with no-ACA for outcomes with suspected or proven NEC, the results were 92 (3.8%) and 58 (2.4%) (p = 0.004). The authors thought that a possible mechanism for this outcome was that the ACA combination selected for Clostridium difficile and that abnormal colonization of the neonatal intestinal tract was one possible mechanism for NEC (10).
A population based from Denmark examined the association between amoxicillin use in pregnancy and birth weight, preterm birth, congenital anomalies, perinatal death, and spontaneous abortion (SAB) (11). During the study period (1991–2000), 401 primiparous women obtained a prescription for the antibiotic. The control group consisted of 10,237 primiparous women who did not redeem any prescriptions from 3 months before pregnancy until the end of pregnancy. The mean birth weight of subjects was 57 g (95% confidence interval [CI] 9–105) higher than controls. The odds ratio and 95% CI for the other outcomes were as follows: low birth weight (0.63, 0.26–1.53); preterm birth (0.77, 0.49–1.21); congenital anomalies (1.16, 0.54–2.50); and SAB (0.89, 0.66–1.18) (11).
In a 2004 study, 191 women treated with ACA (subjects) in the 1st trimester were matched with 191 controls exposed to amoxicillin only (12). Maternal age, birth weight, gestational age at birth, and rates of live births and abortions were comparable between the two groups. The rates of major malformations in subjects (3/158, 1.9%) and controls (5/163, 3%) (p = 0.49; relative risk 0.62, 95% CI 0.15–2.55) were within the expected baseline risk for the general population. There were no cases of oral clefts (12).
A retrospective cohort study using data from Tennessee Medicaid included 30,049 infants born in 1985–2000 was published in 2009 (13). Infants with fetal exposures in the 1st trimester to four antibiotics recommended for potential bioterrorism attacks (amoxicillin, ciprofloxacin, azithromycin, and doxycycline) were compared to infants with no fetal exposure to any antibiotic. Erythromycin was included as a positive control. In the 7216 infants exposed to amoxicillin and no other antibiotics, the number of cases, risk ratios, and 95% CI were as follows: any malformation (232, 1.09, 0.55–1.37), cardiac (89, 1.15, 0.79–1.68); musculoskeletal (52, 1.05, 0.66–1.69); genitourinary (52, 1.38, 0.78–2.43); gastrointestinal (26, 0.63, 0.35–1.16); CNS (23, 1.08, 0.50–2.32); and orofacial (15, 1.67, 0.56–5.04). The authors concluded that the four antibiotics should not result in a greater incidence of overall major malformations (see also Azithromycin, Ciprofloxacin, and Doxycycline) (13).
A 2012 study used data from the Slone Epidemiology Center Birth Defects Study (1994–2008) to identify 877 infants with cleft lip with/without cleft palate and 471 with cleft palate alone (14). Controls included 6952 infants without defects, 2.1% of whom were exposed to amoxicillin. The adjusted odds ratio (OR) for cleft lip with/without cleft palate for exposure in the 1st trimester was 2.0 (95% CI 1.0–4.1). For third gestational month exposure, the results were OR 4.3 (95% CI 1.4–13.0). For cleft palate, the results for the two exposure periods were OR 1.0 (95% CI 0.4–2.3) and OR 7.1 (95% CI 1.4–36). No elevated risks were observed for other penicillins or cephalosporins, but the risk for ampicillin could not be evaluated because there were fewer than five exposed subjects. Because the risk for oral clefts among penicillins appeared to be related only to the aminopenicillins (ampicillin and amoxicillin), the authors speculated that the aminobenzyl group has a role in the development of oral clefts. Even so, the background risk for oral clefts is about 1–2 per 1000 and a twofold risk would increase the risk to only 2–4 per 1000 (14).
BREASTFEEDING SUMMARY
Amoxicillin is excreted into breast milk in low concentrations. Following a 1-g oral dose given to six mothers, peak milk levels occurred at 4–5 hours, averaging 0.9 mcg/mL (range 0.68–1.3 mcg/mL) (15). Mean milk:plasma ratios at 1, 2, and 3 hours were 0.014, 0.013, and 0.043, respectively. Although no adverse effects have been observed, three potential problems exist for the nursing infant: modification of bowel flora, direct effects on the infant (e.g., allergy or sensitization), and interference with the interpretation of culture results if a fever workup is required.
In a 1993 cohort study, diarrhea was reported in 32 (19.3%) nursing infants of 166 breastfeeding mothers who were taking antibiotics (16). For the 25 women taking amoxicillin, diarrhea was observed in 3 (12%) infants. The diarrhea was considered minor because it did not require medical attention (16).
The American Academy of Pediatrics classifies amoxicillin as compatible with breastfeeding (17).
References
1.Product information. Amoxil. SmithKline Beecham Pharmaceuticals, 2000.
2.Heinonen OP, Slone D, Shapiro S. Birth Defects and Drugs in Pregnancy. Littleton, MA: Publishing Sciences Group, 1977.
3.Masterton RG, Evans DC, Strike PW. Single-dose amoxycillin in the treatment of bacteriuria in pregnancy and the puerperium—a controlled clinical trial. Br J Obstet Gynaecol 1985;92:498–505.
4.Jakobi P, Neiger R, Merzbach D, Paldi E. Single-dose antimicrobial therapy in the treatment of asymptomatic bacteriuria in pregnancy. Am J Obstet Gynecol 1987;156:1148–52.
5.Almeida L, Schmauch A, Bergstrom S. A randomised study on the impact of peroral amoxicillin in women with prelabour rupture of membranes preterm. Gynecol Obstet Invest 1996;41:82–4.
6.Magwali TL, Chipato T, Majoko F, Rusakaniko S, Mujaji C. Prophylactic augmentin in prelabor preterm rupture of the membranes. Int J Gynecol Obstet 1999;65:261–5.
7.Magat AH, Alger LS, Nagey DA, Hatch V, Lovchik JC. Double-blind randomized study comparing amoxicillin and erythromycin for the treatment of Chlamydia trachomatis in pregnancy. Obstet Gynecol 1993:81:745–9.
8.Alary M, Joly J-M, Mondor M, Boucher M, Fortier A, Pinault J-J, Paris G, Carrier S, Chamberland H, Bernatchez H, Paradis J-F. Randomised comparison of amoxycillin and erythromycin in treatment of genital chlamydia infection in pregnancy. Lancet 1994;344:1461–5.
9.Turrentin MA, Newton ER. Amoxicillin or erythromycin for the treatment of antenatal chlamydial infection: a meta-analysis. Obstet Gynecol 1995;86:1021–5.
10.Kenyon SL, Taylor DJ, Tarnow-Mordi W, for the ORACLE Collaborative Group. Broad-spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. Lancet 2001;357:979–88.
11.Jepsen P, Skriver MV, Floyd A, Lipworth L, Schønheyder HC, Sørensen HT. A population-based study of maternal use of amoxicillin and pregnancy outcome in Denmark. Br J Clin Pharmacol 2003;55:216–21.
12.Berkovitch M, Diav-Citrin O, Greenberg R, Cohen M, Bulkowstein M, Shechtman S, Bortnik O, Arnon J. Ornoy A. First-trimester exposure to amoxycillin/clavulanic acid: a prospective, controlled study. Br J Clin Pharmacol 2004;58:298–302.
13.Cooper WO, Hernandez-Diaz S, Arbogast PG, Dudley JA, Dyer SM, Gideon PS, Hall KS, Kaltenbach LA, Ray WA. Antibiotics potentially used in response to bioterrorism and the risk of major congenital malformations. Paediatr Perinat Epidemiol 2009;23:18–28.
14.Lin KJ, Mitchell AA, Yau W-P, Louik C, Hernandez-Diaz S. Maternal exposure to amoxicillin and the risk of oral clefts. Epidemiology 2012;23:699–705.
15.Kafetzis D, Siafas C, Georgakopoulos P, Papadatos C. Passage of cephalosporins and amoxicillin into the breast milk. Acta Paediatr Scand 1981;70:285–8.
16.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.
17.Committee on Drugs, American Academy of Pediatrics. The transfer of drugs and other chemicals into human milk. Pediatrics 2001;108:776–89.