Gastrointestinal Agent (Antisecretory)
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
There is very limited human pregnancy data for esomeprazole. A study showing an association between in utero exposure to gastric acid suppressing drugs and childhood allergy and asthma requires confirmation. The animal data and human pregnancy experience with other drugs in this class suggest low risk, but the risk of esomeprazole cannot be fully assessed without additional human data. Until such data are available, if a proton pump inhibitor (PPI) is required, the safest course is to use omeprazole or other drugs in this class that have human data, such as lansoprazole or pantoprazole. (See also Omeprazole, Lansoprazole, and Pantoprazole.) Inadvertent exposure in pregnancy, however, does not appear to represent a clinically significant risk to the embryo or fetus.
FETAL RISK SUMMARY
Esomeprazole, a PPI, is the S-isomer of omeprazole, which is a mixture of the S- and R-isomers. It is in the same drug class as dexlansoprazole, lansoprazole, omeprazole, pantoprazole, and rabeprazole. Esomeprazole is indicated for the short-term (4–8 weeks) treatment and maintenance in the healing and symptomatic resolution of gastrointestinal reflux disease. It is also indicated for the reduction in the occurrence of gastric ulcers in patients receiving continuous nonsteroidal anti-inflammatory therapy and, in combination with amoxicillin and clarithromycin, for the treatment of patients with Helicobacter pyloriinfection and duodenal ulcers. Esomeprazole is extensively metabolized in the liver by cytochrome P450 isoenzymes, primarily CYP2C19, but also by CYP3A4. Approximately 3% of whites and 15%–20% of Asians lack CYP2C19 (i.e., “poor metabolizers”). Plasma concentrations in poor metabolizers are about twice those of subjects with unaltered metabolism. In the plasma, esomeprazole is 97% protein bound with an elimination half-life of about 1–1.5 hours (1).
Reproduction studies have been conducted with esomeprazole in rats and rabbits. In these species, oral doses up to about 57 and 35 times, respectively, the human dose of 20 mg/day based on BSA (HD) revealed no evidence of impaired fertility or fetal harm (1).
Studies with omeprazole, a mixture of the S- and R-isomers, found no evidence of teratogenicity in rats and rabbits at doses up to 56 times the HD in both species. However, in rats given doses ranging about 5.6–56 times the HD, dose-related embryo–fetal toxicity and postnatal developmental toxicity were observed (toxicities not specified). In addition, in rabbits given doses ranging about 5.5–56 times the HD, dose-related increases in embryolethality, fetal resorptions, and pregnancy disruptions were noted (1). The no-adverse-effect levels in these studies were not specified.
The carcinogenic potential of esomeprazole was assessed using omeprazole studies. A significant dose-related occurrence of gastric enterochromaffin-like (ECL) cell carcinoid tumors and ECL cell hyperplasia were observed in male and female rats (1). In a mutagenic study with esomeprazole, the in vitro human lymphocyte chromosome aberration test was positive, but three other mutagenesis assays were negative (1).
Consistent with its molecular weight (about 345 for the anhydrous free base), esomeprazole probably crosses the human placenta. Although this has not been specifically studied with esomeprazole, omeprazole has been shown to cross to the fetus at term. (See Omeprazole.)
A meta-analysis of PPIs in pregnancy was reported in 2009 (2). Based on 1530 exposed compared with 133,410 not-exposed pregnancies, the odds ratio (OR) for major malformations was 1.12 and 95% confidence interval (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) (2).
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 (3). 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 H. pylori, and drugs for peptic ulcer and gastro-esophageal reflux disease, such as sucralfate. 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 (3). The study requires confirmation.
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 esomeprazole in the 1st trimester, there were 23 (3.4%) major birth defects among 668 live births (aPOR 1.19, 95% CI 0.77–1.84) (see Lansoprazole, Omeprazole, Pantoprazole, and Rabeprazole 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).
A 2012 case report described the use of esomeprazole (40 mg/day) throughout pregnancy in a woman with an intestinal transplant (6). Other medications used were prednisone (5 mg/day), diphenoxylate-atropine (2 tablets/day), tacrolimus (12 mg/day), ferrous sulfate (650 mg/day), ascorbic acid (1 g/day), prenatal vitamins (1/day), and magnesium supplementation. At 39 3/7 weeks, labor was induced and she had a spontaneous vaginal delivery of a healthy female infant (6).
In a 2012 publication, the National Birth Defects Prevention study, a multi-site 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) (7). 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) (7).
A third 2012 reference, using the Danish nationwide registries, evaluated the risk of hypospadias after exposure to PPIs during the 1st trimester and throughout gestation (8). The study period, 1997–2009, 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 two 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 (8).
Five reviews on the treatment of gastroesophageal reflux disease (GERD) have concluded that PPIs can be used in pregnancy with relative safety (9–13). Because there is either very limited or no human pregnancy data for the three newest agents in this class (dexlansoprazole, esomeprazole, and rabeprazole), other drugs in the class are preferred.
BREASTFEEDING SUMMARY
No reports describing the use of esomeprazole, the S-isomer of omeprazole, during human lactation have been located. The molecular weight (about 345 for the anhydrous free base) is low enough that excretion into breast milk should be expected. The effect of esomeprazole on a nursing infant is unknown. The potential for toxic effects such as those seen in adults (e.g., headache, diarrhea, and abdominal pain) and the suppression of gastric acid secretion are a concern, as is the potential for the gastric tumors that have been observed in animals after long-term use.
Small amounts of omeprazole, a mixture of the S- and R-isomers, are excreted into milk, but the quantity excreted needs further clarification. (See Omeprazole.) If a lactating woman’s condition requires esomeprazole, consideration of the drug’s properties might allow her to nurse without significantly exposing her infant. Esomeprazole is dosed once daily because the inhibition of gastric acid secretion is prolonged. In contrast, the plasma elimination half-life is short (about 1–1.5 hours). Thus, waiting 5–7.5 hours after a dose should eliminate up to 97% of the drug from the plasma. Moreover, the mean peak plasma concentration is reported to occur 1.6 hours after the dose (1), and waiting 5–7.5 hours would avoid the period when the greatest amount of drug is available to enter milk. Emptying both breasts near the end of the waiting period and discarding the milk completes the strategy to limit the infant’s exposure. This strategy was used in one case involving omeprazole but warrants further study.
References
1.Product information. Nexium. AstraZeneca, 2004.
2.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.
3.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.
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.Gomez-Lobo V, Landy HJ, Matsumoto C, Fishbein TM. Pregnancy in an intestinal transplant recipient. Obstet Gynecol 2012;120:497–500.
7.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.
8.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].
9.Broussard CN, Richter JE. Treating gasto-oesophageal reflux disease during pregnancy and lactation. What are the safest therapy options? Drug Saf 1998;19:325–37.
10.Katz PO, Castell DO. Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin N Am 1998;27:153–67.
11.Ramakrishnan A, Katz PO. Pharmacologic management of gastroesophageal reflux disease. Curr Treat Options Gastroenterol 2002;5:301–10.
12.Richter JE. Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin N Am 2003;32:235–61.
13.Richter JE. Review article: the management of heartburn in pregnancy. Aliment Pharmacol Ther 2005;22:749–57.