Gastrointestinal Agent (Antisecretory)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
No reports describing the use of rabeprazole during human pregnancy have been located. A study showing an association between in utero exposure to gastric acid–suppressing drugs and childhood allergy and asthma requires confirmation. Human pregnancy experience with three other proton pump inhibitors (PPIs) (see Lansoprazole, Omeprazole, and Pantoprazole) has not shown a causal relationship with congenital malformations. In some cases, malformations may have been missed because of the design and size of the studies. The carcinogenic and mutagenic data are a potential concern, but the absence of follow-up studies prevents a risk assessment for exposed offspring. As with all drug therapy, avoidance of rabeprazole during pregnancy, especially during the 1st trimester, is the safest course. If rabeprazole is required or if inadvertent exposure does occur early in gestation, the known risk to the embryo–fetus for congenital defects, based on animal data for rabeprazole and the published experience with other PPIs, appears to be low. Long-term follow-up of offspring exposed during gestation is warranted.
FETAL RISK SUMMARY
Rabeprazole is a PPI that blocks gastric acid secretion by a direct inhibitory effect on the gastric parietal cell (1). It is used for the treatment of duodenal ulcer, erosive or ulcerative gastroesophageal reflux disease (GERD), and the long-term treatment of pathologic hypersecretory conditions, such as Zollinger-Ellison syndrome. Rabeprazole is in the same class of PPIs as dexlansoprazole, esomeprazole, lansoprazole, omeprazole, and pantoprazole.
Reproductive studies have been conducted in rats and rabbits with IV doses up to 13 and 8 times, respectively, the recommended human dose based on AUC (1). No evidence was found at these doses of impaired fertility or fetal harm. In male and female rats, rabeprazole caused gastric cell hyperplasia and, in female rats, gastric cell tumors, at all doses tested (1). In addition, positive results with the drug and its inactive metabolite were demonstrated in hamsters and mice with the in vitro Ames mutation assay and in some other mutagenicity tests (1).
It is not known if rabeprazole crosses the human placenta. The molecular weight (about 381 for the sodium salt) is low enough that passage to the fetus should be expected. Another PPI, omeprazole, has a similar molecular weight and chemical structure and it is known to cross the human placenta (see Omeprazole).
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 (2). 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-receptor antagonists, prostaglandins, PPIs, 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 odds ratio (OR) was 1.43, 98% confidence interval (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) maternal Th2 cytokine pattern could promote an allergy-prone phenotype in the fetus; and (c) maternal allergen-specific immunoglobulin E 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 (2). The study requires confirmation.
A meta-analysis of PPIs in pregnancy was reported in 2009 (3). Based on 1530 exposed compared with 133,410 not-exposed pregnancies, the OR for major malformations was 1.12, 95% CI 0.86–1.45. There also was no increased risk for spontaneous abortions (OR 1.29, 95% CI 0.84–1.97) or preterm birth (OR 1.13, 95% CI 0.96–1.33) (3).
In a 2010 study from Denmark, covering the period 1996–2008, there were 840,968 live births among whom 5082 were exposed to PPIs between 4 weeks before conception and the end of the 1st trimester (4). In the exposed group there were 174 (3.4%) major malformations compared with 21,811 (2.6%) not exposed to PPIs (adjusted prevalence odds ratio [aPOR] 1.23, 95 CI 1.05–1.44). When the analysis was limited to exposure in the 1st trimester, there were 118 (3.2%) major malformations among 3651 exposed infants (aPOR 1.10, 95% CI 0.91–1.34). For exposure to rabeprazole in the 1st trimester, there were 3 (7.1%) major birth defects among 42 live births (aPOR 2.14, 95% CI 0.60–7.68; see Esomeprazole, Lansoprazole, Omeprazole, and Pantoprazole for their data). The data showed that exposure to PPIs in the 1st trimester was not associated with a significantly increased risk of major birth defects (4). An accompanying editorial discussed the strengths and weaknesses of the study (5).
In a 2012 publication, the National Birth Defects Prevention study, a multisite population-based case–control study, examined whether nausea/vomiting of pregnancy (NVP) or its treatment were associated with the most common noncardiac defects (nonsyndromic cleft lip with or without cleft palate [CL/P], cleft palate alone [CP], neural tube defects [NTDs], and hypospadias) (6). PPI exposure included esomeprazole, lansoprazole, and omeprazole. There were 4524 cases and 5859 controls. NVP was not associated with cleft palate or NTDs, but modest risk reductions were observed for CL/P and hypospadias. Increased risks were found for PPIs (N = 7) and hypospadias (adjusted OR [aOR] 4.36, 95% CI 1.21–15.81), steroids (N = 10) and hypospadias (aOR 2.87, 95% CI 1.03–7.97), and ondansetron (N = 11) and CP (aOR 2.37, 95% CI 1.18–4.76) (6).
Another 2012 study, using the Danish nationwide registries, evaluated the risk of hypospadias after exposure to PPIs during the 1st trimester and throughout gestation (7). The study period, 1997 through 2009, included all liveborn boys that totaled 430,569 of whom 2926 were exposed to maternal PPI use. Hypospadias was diagnosed in 20 (0.7%) exposed boys, whereas 2683 (0.6%) of the nonexposed had hypospadias (adjusted prevalence ratio [aPR] 1.1, 95% CI 0.7–1.7). For the 5227 boys exposed throughout pregnancy, 32 (0.6%) had hypospadias (PR 1.0, 95% CI 0.7–1.4). When the analysis was restricted to mothers with 2 or more PPI prescriptions, the aPR of overall hypospadias was 1.7, 95% CI 0.9–3.3 and 1.6, 95% CI 0.7–3.9 for omeprazole. The authors concluded that PPIs were not associated with hypospadias (7).
Several reports and reviews describing the use of PPIs during human pregnancy have observed no increased risk of developmental toxicity (see Lansoprazole, Omeprazole, and Pantoprazole).
BREASTFEEDING SUMMARY
No reports describing the use of rabeprazole during human lactation have been located. The molecular weight (about 381 for the sodium salt) suggests that the drug will be excreted into breast milk. Because of the positive carcinogenic tests and the potential for suppression of gastric acid secretion in the nursing infant, the use of rabeprazole during lactation should probably be avoided until clinical data are available.
References
1.Product information. Rapeprazole. Eisai, 2001.
2.Dehlink E, Yen E, Leichtner AM, Hait EJ, Fiebiger E. First evidence of a possible association between gastric acid suppression during pregnancy and childhood asthma: a population-based register study. Clin Exp Allergy 2009;39:246–53.
3.Gill SK, O’Brien L, Einarson TR, Koren G. The safety of proton pump inhibitors (PPIs) in pregnancy: a meta-analysis. Am J Gastroenterol 2009; 104:1541–5.
4.Pasternak B, Hviid A. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects. N Engl J Med 2010;363:2114–23.
5.Mitchell AA. Proton-pump inhibitors and birth defects—some reassurance, but more needed. N Engl J Med 2010;363:2161–3.
6.Anderka M, Mitchell AA, Louik C, Werler MM, Hernandez-Diaz S, Rasmussen SA, and the National Birth Defects Prevention Study. Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects. Birth Defects Res A Clin Mol Teratol 2012;94:22-30.
7.Erichsen R, Mikkelsen E, Pedersen L, Sorensen HT. Maternal use of proton pump inhibitors during early pregnancy and the prevalence of hypospadias in male offspring. Am J Ther 2012 Feb 3; [Epub ahead of print].