Gastroesophageal reflux disease – also called heartburn, pyrosis, or reflux esophagitis – is an uncommon complication in women of reproductive age. However, gastroesophageal reflux disease is a common condition in pregnancy with symptoms usually ending shortly after birth (Gastroenterol. Clin. North Am. 2003;32:235-61).
Not surprisingly, the prevalence of heartburn increases as pregnancy progresses. In one study of 607 pregnant women, 22% had heartburn in the 1st trimester, 39% in the 2nd trimester, and 72% in the 3rd trimester (Br. J. Obstet. Gynaecol. 1992;99:731-4).
Gerald G. Briggs
The symptoms of gastroesophageal reflux disease (GERD) are related to relaxation of the lower esophageal sphincter and are most pronounced when lying down. Moreover, intraesophageal pressures are lower and intragastric pressures higher in pregnancy.
Typically, the first over-the-counter (OTC) products that pregnant women turn to for relief of heartburn are antacids, such as aluminum hydroxide or carbonate, calcium carbonate, or magnesium hydroxide or oxide. Although readily available and commonly used to relieve the burning sensation of GERD, antacids are not always effective in providing long-lasting relief. In these cases, patients often turn to OTC histamine2 (H2) antagonists or proton-pump inhibitors (PPIs). Interestingly, women also use these agents to reduce reflux symptoms to lessen nausea and vomiting of pregnancy.
There are four OTC histamine2 antagonists: cimetidine (Tagamet), famotidine (Pepcid), nizatidine (Axid), and ranitidine (Zantac). For the PPIs, six are available, but only the first two agents are OTC: lansoprazole (Prevacid), omeprazole (Prilosec), dexlansoprazole (Dexilant), esomeprazole (Nexium), pantoprazole (Protonix), and rabeprazole (AcipHex).
There is a substantial amount of information regarding the use of H2 blockers and PPIs in pregnancy. Two meta-analyses published in 2009, one on H2 blockers and the other on PPIs, found no increased risk of major defects, spontaneous abortions, or preterm birth (Dig. Dis. Sci. 2009;54:1835-8; Am. J. Gastroenterol. 2009;104:1541-5).
In addition, five reviews on the treatment of GERD in pregnancy have concluded that these agents, with the possible exception of nizatidine, are relatively safe (Drug Saf. 1998;19:325-37; Gastroenterol Clin. North Am. 1998;27:153-67; Curr. Treat. Options Gastroenterol. 2002;5:301-10; Gastroenterol. Clin. North Am. 2003;32:235-61; Aliment Pharmacol. Ther. 2005;22:749-57). Nizatidine was not recommended because in a reproduction study with rabbits, abortions and decreased fetal weight were observed. Importantly, the dose that caused this toxicity was about 80 times the recommended human dose based on body surface area, so the results have no relevance to humans.
Among the H2 blockers, cimetidine has the most reported human pregnancy experience, but there is concern that the drug might cause feminization of male offspring. This concern was based on research from one group that observed the following long-lasting toxic effects in male rats exposed throughout gestation: decreased weights of the testicles, prostate gland, and seminal vesicles; reduced testosterone serum levels; a lack of sexual motivation; and decreased sexual performance (Science 1982;218:493-4; Neurobehav. Toxicol. Teratol. 1984;6:313-8; Gastroenterology 1984;86:675-80). However, research from two other groups using the same methodology failed to confirm this toxicity (Fundam. Appl. Toxicol. 1987;8:188-97; Toxicol. Lett. 1988;44:315-29). In addition, feminization of human males exposed in utero has not been reported.
Severe anaphylactoid reactions have been reported in four women receiving intravenous or oral ranitidine during labor (Br. J. Clin. Pract. 1990;44:78; Anaesthesia 1992;47:360-1; Anaesth. Intensive Care 1993;21:702-3; J. Anesth. 2003;17:199-200). Three of the newborns did well, but the fourth infant had seizures and was still receiving phenobarbital at 8 months of age.
A large 2009 Swedish cohort study evaluated the association between gastric acid suppressors during gestation and a diagnosis in the offspring of allergic disease or a prescription for asthma or allergy medications. The drug types included in the study were H2 antagonists, PPIs, prostaglandins, combinations for eradication of Helicobacter pylori, and drugs for peptic ulcer and GERD. Of 585,716 children, 29,490 (5%) met the diagnosis and 5,645 (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, 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 irrespective of the type of acid-suppressive drug and the time of exposure in pregnancy. The authors proposed three possible mechanisms for their findings: Exposure to increased amounts of allergens could cause sensitization to digestion labile antigens in the fetus, the maternal T helper cell type 2 cytokine pattern could promote an allergy-prone phenotype in the fetus, and maternal allergen-specific IgE could cross the placenta and sensitize fetal immune cells to food and airborne allergens (Clin. Exp. Allergy 2009;39:246-53). It was also possible that a general increase in childhood asthma but not necessarily an increase in allergic asthma had occurred during the 10-year (1995-2004) study period. The study results require confirmation.