Gastrointestinal Agent (Antisecretory)
PREGNANCY RECOMMENDATION: Compatible
BREASTFEEDING RECOMMENDATION: Limited Human Data—Probably Compatible
PREGNANCY SUMMARY
The absence of teratogenicity or toxicity in animals and the available human pregnancy data suggest that ranitidine is not a major teratogen. Because it has no antiandrogenic activity in animals or nonpregnant humans, ranitidine may be a safer choice than cimetidine for chronic use during pregnancy. The antiandrogenic activity of cimetidine, however, has not been observed or studied following in utero exposure (see Cimetidine). Ranitidine-induced anaphylactoid shock has been reported in four laboring women. A study showing an association between in utero exposure to gastric acid–suppressing drugs and childhood allergy and asthma requires confirmation.
FETAL RISK SUMMARY
Ranitidine is a competitive, reversible inhibitor of histamine H2-receptors (H2 blockers) used in treatment and maintenance of patients with duodenal or gastric ulcers, pathologic hypersecretory conditions such as Zollinger-Ellison syndrome, and gastroesophageal reflux disease (GERD). The drug is partially metabolized to apparently inactive metabolites. Serum protein binding is minimal (average 15%) and the elimination half-life is 2.5–3.0 hours (1).
Reproduction studies with ranitidine in rats and rabbits at doses up to 160 times the human dose have revealed no evidence of impaired fertility or fetal harm (1–3). In contrast to the controversy surrounding cimetidine, ranitidine apparently has no antiandrogenic activity in humans (4) or in animals (5,6) (see also Cimetidine).
Consistent with the molecular weight (about 351), limited metabolism, and elimination half-life, ranitidine crosses the human placenta. At term, mean fetal:maternal ratios after 50 mg IV and 150 mg orally were 0.9 and 0.38, respectively (7–9). An in vitro study also documented transfer in term human placentas (10).
In a surveillance study of Michigan Medicaid recipients involving 229,101 completed pregnancies conducted between 1985 and 1992, 516 newborns had been exposed to ranitidine during the 1st trimester (F. Rosa, personal communication, FDA, 1993). A total of 23 (4.5%) major birth defects were observed (22 expected). Specific data were available for six defect categories, including (observed/expected) 6/5 cardiovascular defects, 1/1 oral clefts, 1/0.5 spina bifida, 1/1 polydactyly, 0/1 limb reduction defects, and 1/1 hypospadias. These data do not support an association between the drug and congenital defects.
Ranitidine has been used alone and in combination with antacids to prevent gastric acid aspiration (Mendelson’s syndrome) before vaginal delivery or cesarean section (7–9,11–14). No effect was observed in the frequency and strength of uterine contractions, in fetal heart rate pattern, or in Apgar scores (7). Neonatal gastric acidity was not affected at 24 hours. No problems in the newborn attributable to ranitidine were reported in these studies.
Ranitidine has been studied for its effectiveness in alleviating the symptoms of heartburn during pregnancy (15–17). A twice-daily dosage regimen of ranitidine was effective for this indication (15–17), including in those cases resistant to antacids alone (17). Ranitidine was also effective in controlling gastric acid secretion in pregnant women with Zollinger-Ellison syndrome (18).
In a 1991 report, 23 women were exposed in the 1st trimester to ranitidine (N = 13), cimetidine (N = 9), or both (N = 1) (19). The pregnancy outcomes were 2 spontaneous abortions (SABs), 2 elective abortions (EABs), 18 normal births, and 1 infant with a large hemangioma of the upper eye lid (removed without incidence). The outcomes suggested that the agents were not teratogenic (19).
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 (20). 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, SABs, 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 (20).
Data from the Swedish Medical Birth Registry were presented in 1998 (21). A total of 553 infants (6 sets of twins) were delivered from 547 women who had used acid-suppressing drugs early in pregnancy. 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 was also exposed to omeprazole. Ranitidine was the only acid-suppressing drug exposure in 156 infants. Twenty other offspring were exposed in utero to ranitidine combined either with famotidine (2 infants) or with omeprazole (18 infants). Seven infants with birth defects were exposed to ranitidine: six where ranitidine was the only acid-suppressing agent used and one exposed to ranitidine combined with omeprazole. The defects were cerebral arteriovenous malformation, unspecified cardiac defect, hydronephrosis, undescended testicle, hypospadias, and unstable hip. Hypospadias was also observed in a newborn exposed to a combination of ranitidine and omeprazole (see Omeprazole for additional details of this study) (21).
Two databases, one from England and the other from Italy, were combined for a study published in 1999 that was designed to assess the incidence of congenital malformations in women who had received a prescription during the 1st trimester for an acid-suppressing drug (ranitidine, cimetidine, and omeprazole) (22). Nonexposed women were selected from the same databases to form a control group. SABs and EABs (except two cases for anomalies that were grouped with stillbirths) were excluded from the analysis. Stillbirths were defined as any pregnancy loss occurring at 28 weeks’ gestation or later. Ranitidine was taken in 322 pregnancies, resulting in 330 live births (29 premature), 2 stillbirths, and 1 neonatal death. Twenty (6.1%) of the newborns had a congenital malformation (shown by system): CNS (spina bifida/hydrocephaly), craniofacial (cleft palate only; asymmetric skull/plagiocephaly; tongue tie), eye (Duane’s eye syndrome), cardiac (septal defect; anomaly of cardiac valve), musculoskeletal (dysplastic hip/dislocation/clicking hip, N = 3; syndactyly; sacral sinus), genital and urinary (undescended testes, N = 2; congenital hydrocele/inguinal hernia, N = 2; ovarian cyst), multiple (pyloric stenosis and talipes equinovarus), and two genetic anomalies (Hallerman-Streiff and Down’s syndromes). In addition, two newborns were small for gestational age and nine had a small head circumference for gestational age. In comparison, the outcomes of 1547 nonexposed pregnancies included 1560 live births (115 premature), 15 stillbirths (includes 2 EABs for anomalies), and 10 neonatal deaths. Sixty-four (4.1%) of the newborns had malformations involving the following: CNS (N = 2), head/face (N = 13), eye (N = 2), heart (N = 7), muscle/skeletal (N = 13), genital/urinary (N = 18), gastrointestinal (N = 2), and those of polyformation (N = 3), or known genetic defects (N = 4). There were 21 newborns that were small for gestational age and 78 had a small head circumference for gestational age. The relative risk of malformation (adjusted for mother’s age and prematurity) associated with ranitidine was 1.5 (95% CI 0.9–2.6), with cimetidine 1.3 (95% CI 0.7–2.6), and with omeprazole 0.9 (95% CI 0.4–2.4) (22).
A population-based observational cohort study formed by linking data from three Swedish national health care registers over a 10-year period (1995–2004) was reported in 2009 (23). 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 GERD. 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: (a) exposure to increased amounts of allergens could cause sensitization to digestion labile antigens in the fetus; (b) the maternal Th2 cytokine pattern could promote an allergy-prone phenotype in the fetus; and (c) maternal allergen-specific immunoglobulin 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 (23). The study requires confirmation.
Severe anaphylactoid reactions were observed in four women who had received IV or oral ranitidine during labor (24–27). Fetal bradycardia was observed in two cases, but the heart rates normalized before birth. The two cases as well as a third newborn had normal Apgar scores and did well (24–26). An emergency cesarean section was required in the fourth case when the mother developed severe systolic hypotension and the fetal heart rate decreased to 70 beats/minute (27). Apgar scores in the newborn were 1 and 4 at 1 and 5 minutes, respectively. The female infant had seizure-like movement in the NICU and was discharged home on day 19 on phenobarbital. At 8 months of age, the baby was still receiving phenobarbital but no seizures or physical or developmental abnormalities were noted (27).
A 2005 study evaluated the outcomes of 553 pregnancies after exposure to H2 blockers, 501 (91%) in the 1st trimester (28). The data were collected by the European Network of Teratology Information Services (ENTIS). The agents and number of cases were ranitidine 335, cimetidine 113, famotidine 75, nizatidine 15, and roxatidine 15. No increase in the number of major malformations were noted (28).
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 (29–32).
A 2009 meta-analysis of published studies was conducted to assess the safety of H2 blockers that were used in 2398 pregnancies (33). 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 (33).
A 2010 study from Israel identified 1148 infants exposed in the 1st trimester to H2 blockers (34). 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 (34).
BREASTFEEDING SUMMARY
Following a single oral dose of 150 mg in six subjects, ranitidine milk concentrations increased with time, producing mean milk:plasma ratios at 2, 4, and 6 hours of 1.9, 2.8, and 6.7, respectively (35).
Markedly different results were observed in 1985 study (36). Ranitidine milk and blood concentrations were determined in a woman breastfeeding her healthy 54-day-old infant. The woman had taken four 150-mg (2.44 mg/kg) doses at 12-hour intervals immediately before sampling. Pooled milk/maternal blood concentrations (ng/mL) (milk:serum ratio) were: predose 993/53 (18.73), 1.5 hours postdose 722/106 (6.81), 5.5 hours postdose 2610/309 (8.44), and 1569/66 (23.77). The data suggested that steady-state conditions had not yet been achieved. No adverse effects in the nursing infant were noted (36).
The effects from long-term exposure to the above concentrations on the nursing infant are not known. Ranitidine decreases gastric acidity, but this effect has not been studied in nursing infants. However, cimetidine, an agent with similar activity, is classified as compatible during breastfeeding by the American Academy of Pediatrics (see Cimetidine).
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