Gastrointestinal Agent (Antisecretory)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The animal reproductive data suggest low risk, but the human pregnancy experience is limited. Nevertheless, there is no evidence that histamine H2-receptor antagonists pose a clinically significant risk to the embryo or fetus. A study showing an association between in utero exposure to gastric acid suppressors and childhood allergy and asthma requires confirmation.
FETAL RISK SUMMARY
Famotidine, a reversible competitive inhibitor of histamine H2-receptors (H2 blockers), is more potent than either cimetidine or ranitidine. It is indicated for the treatment of gastric and duodenal ulcers, in the treatment of gastroesophageal reflux disease (GERD), and in the therapy of pathologic hypersecretory conditions, such as Zollinger-Ellison syndrome. The drug undergoes minimal first-pass metabolism. Plasma protein binding is low (15%–20%) and the elimination half-life is 2.5–3.5 hours (1).
Reproduction studies have been conducted in rats and rabbits. No significant evidence of impaired fertility or harm to the fetus at oral doses up to 2000 and 500 mg/kg/day (comparison to the human dose not stated), respectively, or IV doses up to 200 mg/kg/day in both species were observed. Sporadic abortions were observed in rabbits given maternal toxic (decreased food intake) oral doses that were 250 times the usual human dose (1). In published studies in rats and rabbits, using oral doses ≤2000 mg/kg/day and IV doses of 100–200 mg/kg/day, found no evidence of impaired fertility, fetotoxic effects, teratogenicity, or changes in postnatal behavior attributable to famotidine (2,3).
Famotidine is known to cross the term human placenta based on in vitro studies (4). This is consistent with the molecular weight (about 337), low plasma protein binding, and the elimination half-life.
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 33 newborns had been exposed to famotidine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). Two (6.1%) major birth defects were observed (one expected). No anomalies were observed in six defect categories (cardiovascular defects, oral clefts, spina bifida, polydactyly, limb reduction defects, and hypospadias) for which specific data were available. The number of exposures is too small to draw any conclusions.
A 1996 prospective cohort study compared the pregnancy outcomes of 178 women who were exposed during pregnancy to H2 blockers with 178 controls matched for maternal age, smoking, and heavy alcohol consumption (5). All of the women had contacted a teratology information service concerning gestational exposure to H2 blockers (subjects) or nonteratogenic or nonfetotoxic agents (controls). Among subjects (mean daily dose in parentheses), 71% took ranitidine (258 mg), 16% cimetidine (487 mg), 8% famotidine (32 mg), and 5% nizatidine (283 mg). There were no significant differences between the outcomes of subjects and controls in terms of live births, spontaneous abortions (SABs) and elective abortions (EABs), gestational age at birth, delivery method, birth weight, infants small for gestational age, or major malformations. Among subjects, there were 3 birth defects (2.1%) among the 142 exposed to H2 blockers in the 1st trimester: one each of atrial septal defect, ventricular septal defect, and tetralogy of Fallot. There were 5 birth defects (3.0%) among the 165 exposed anytime during pregnancy. For controls, the rates of defects were 3.5% (1st trimester) and 3.1% (anytime). There were also no differences between the groups in neonatal health problems and developmental milestones, but two children (one subject and one control) were diagnosed as developmentally delayed. The investigators concluded that 1st trimester exposure to H2 blockers did not represent a major teratogenic risk (5).
Data from the Swedish Medical Birth Registry were presented in 1998 (6). A total of 553 infants (6 sets of twins) were delivered from 547 women who had used acid-suppressing drugs early in pregnancy. Famotidine was the only acid-suppressing drug exposure in 58 infants. Three other offspring were exposed in utero to famotidine combined either with cimetidine (one infant) or with ranitidine (two infants). The odds ratio (OR) for malformations after H2 blockers was 0.86, 95% confidence interval (CI) 0.33–2.23. Of the 19 infants with birth defects, 9 had been exposed to H2 blockers, 1 of whom had also been exposed to omeprazole. No birth defects were observed in those exposed to famotidine (see Omeprazole for additional details of this study) (6).
A population-based observational cohort study formed by linking data from three Swedish national healthcare registers over a 10-year period (1995–2004) was reported in 2009 (7). The main outcome measures were a diagnosis of allergic disease or a prescription for asthma or allergy medications. The drug types included in the study were gastric acid suppressors, including H2 blockers, prostaglandins, proton pump inhibitors, combinations for eradication of Helicobacter pylori, and drugs for peptic ulcer and gastroesophageal reflux disease. Of 585,716 children, 29,490 (5.0%) met the diagnosis and 5645 (1%) had been exposed to gastric acid suppression therapy in pregnancy. Of these children, 405 (0.07%) were treated for allergic disease. For developing allergy, the OR was 1.43, 98% CI 1.29–1.59, irrespective of the drug, time of exposure during pregnancy, and maternal history of allergy. For developing childhood asthma, but not other allergic diseases, the OR was 1.51, 95% CI 1.35–1.69, irrespective of the type of acid-suppressive drug and the time of exposure in pregnancy. The authors proposed three possible mechanisms for their findings: (i) exposure to increased amounts of allergens could cause sensitization to digestion labile antigens in the fetus; (ii) maternal Th2 cytokine pattern could promote an allergy-prone phenotype in the fetus; and (iii) maternal allergen-specific IgE could cross the placenta and sensitize fetal immune cells to food and airborne allergens. Several limitations of the study that might have affected their findings were identified, including a general increase in childhood asthma but not necessarily an increase in allergic asthma (7). The study requires confirmation.
A 2005 study evaluated the outcomes of 553 pregnancies after exposure to H2 blockers, 501 (91%) in the 1st trimester (8). The data were collected by the European Network of Teratology Information Services (ENTIS). The agents and number of cases were famotidine 75, cimetidine 113, nizatidine 15, ranitidine 335, and roxatidine 15. No increase in the number of major malformations were noted (8).
A 2009 meta-analysis of published studies was conducted to assess the safety of H2 blockers that were used in 2398 pregnancies (9). Compared with 119,892 nonexposed pregnancies, the OR for congenital malformations was 1.14 (95% CI 0.89–1.45), whereas the ORs and 95% CIs for SABs, preterm birth, and small for gestational age were 0.62 (0.36–1.05), 1.17 (0.94–1.147), and 0.28 (0.06–1.22), respectively. The authors concluded that H2 blockers could be used safely in pregnancy (9).
Four reviews on the treatment of GERD have concluded that H2 blockers, with the possible exception of nizatidine, could be used in pregnancy with relative safety (10–13).
A 2010 study from Israel identified 1148 infants exposed in the 1st trimester to H2 blockers (13). No association with congenital malformations was found (OR 1.03, 95% CI 0.80–1.32). Moreover, no association was found with EABs, perinatal mortality, premature delivery, low birth weight, or low Apgar scores (14).
BREASTFEEDING SUMMARY
Famotidine is concentrated in breast milk, but to a lesser degree than either cimetidine or ranitidine (15). Following a single 40-mg dose administered to eight postpartum women who were not breastfeeding, the mean milk:plasma ratios at 2, 6, and 24 hours were 0.41, 1.78, and 1.33, respectively. The mean peak milk concentration, 72 ng/mL, occurred at 6 hours compared with 2 hours for plasma (mean 75 ng/mL). Exposure of the nursing infant to famotidine via milk has not been reported. Although a potential risk may exist for adverse effects, the American Academy of Pediatrics classifies a similar drug (cimetidine) as compatible with breastfeeding. A 1991 reference source suggested that because famotidine and two other H2 blockers, nizatidine and roxatidine, are less concentrated in milk, they might be preferred in the nursing woman in place of cimetidine or ranitidine (16).
References
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