Review Article: The Management of Heartburn in Pregnancy

J.E. Richter

Disclosures

Aliment Pharmacol Ther. 2005;22(9):749-757. 

In This Article

Medical Treatment of GERD During Pregnancy

The challenge of treatment during pregnancy is the potential teratogenicity of common antireflux medications. Lifestyle modification is the key for treating mild symptoms. Smaller meals, not eating late at night, elevation of the head of the bed and avoiding foods and mediations causing heartburn usually relieve the mild symptoms seen in early pregnancy. Chewing gum stimulates the salivary glands and can help neutralize acid. Abstinence from alcohol and tobacco are encouraged to reduce reflux symptoms and to avoid fetal exposure to these harmful substances.

For more troubling reflux symptoms, the doctor must discuss with the patient the benefits vs. the risk of drug therapy. Informed consent is appropriate. Nearly all medications are not tested in randomized-controlled studies in pregnant women because of ethical and medicolegal concerns. Most recommendations on drug safety arise from case reports and cohort studies by doctors, pharmaceutical companies or the FDA. Voluntary reporting by the manufacturer's suffers from unknown duration of follow-up, absence of appropriate controls and possible reporting bias.[9]

Commonly used medications include antacids, sucralfate, histamine2-receptor antagonists (H2RAs), promotility drugs and proton-pump inhibitors (PPIs). The incidence of major fetal malformations in the general population ranges between 1% and 3%.[10] The FDA divides the safety of drugs during pregnancy into five categories (A, B, C, D and X) based on systemic absorption and reports of congenital defects in animals or humans ( Table 1 ).[11]

The teratogeneic period ranges from day 31 (in a 28-day menstrual cycle) to day 71 from the last menstrual period,[10] essentially the first 10 weeks of gestation. This represents the critical period of organogenesis. Before day 31, exposure to a teratogen usually causes an all-or-none effect; either the fetus dies or survives without anomalies. Fetal cells are totipotential during this time period with respect to organogenesis; therefore, if a few cells die, the remaining cells can replace their function. Drugs that are not urgently required should be withheld until after the teratogeneic period, although drugs can still affect the fetus in later gestation. Drugs used for GERD during pregnancy and their FDA categories are summarized in Table 2 .

Antacids

Antacids are fast and effective at relieving the symptoms of heartburn and are preferred by patients as a result of the immediate symptom relief provided. About 30-50% of women will only require antacids to ease their heartburn of pregnancy. Only limited data exist concerning the effects of antacids on the fetus with no controlled trials of efficacy. Magnesium-, aluminium-, or calcium-containing antacids are not teratogeneic in animal studies,[12] although 15-30% of magnesium and a smaller percentage of aluminium preparations are absorbed after reacting with hydrochloric acid.

One retrospective, case-controlled study in the 1960s[13] reported a significant increase in major and minor congenital malformations in infants exposed to antacids during the third trimester of pregnancy. However, analysis of individual antacids (aluminium hydroxide, sodium bicarbonate, magnesium trisilicate and calcium carbonate) found no association with increased congenital anomalies. A recent European consensus conference recommended calcium/magnesium-based antacids for pregnant women because of their safety profile.[14] These experts found that calcium-based antacids had the added benefit of increasing calcium supplementation to prevent the hypertension and pre-eclampsia associated with pregnancy. In addition, a large, randomized placebo-controlled trial found that magnesium sulphate supplementation reduces the risk of eclampsia by 50% compared with placebo, and may also reduce the risk of maternal death, with no serious short-term side-effects.[15]

Alginates form a strong, non-systemic barrier in the stomach, preventing reflux of acid and food into the oesophagus. They are usually combined with antacids and marketed under the general label of Gaviscon. Recently, a form of Gaviscon with less sodium per dose was studied in an open-label multicentre study in 150 pregnant women over 4 weeks. Overall, the investigator's and women's rating of efficacy was 'very good' or 'good' in 88% and 90% of women, respectively, with most women (57%) reporting symptom relief within 10 min.[16] However, 10 adverse events were reported in 10 fetuses (three episodes of fetal distress) and others report that Gaviscon compounds containing magnesium trisilicate can cause fetal nephrolithiasis, hypotonia, respiratory distress and cardiovascular impairment if used long-term and at high doses.[11]

Antacids containing sodium bicarbonate should be avoided during pregnancy because they cause maternal or fetal metabolic alkalosis and fluid overload. Antacids should be taken at a different time than supplemental iron, because normal gastric acid facilitates the absorption of iron.

Sucralfate

Sucralfate, an aluminium salt of a sulphated disaccharide, inhibits pepsin activity and protects against ulcers. It is poorly absorbed from the GI tract, exerting its mucosal protection through a local, rather than systemic action. Each gram of sucralfate contains 207 mg of aluminium.[16] The potential fetal toxicity of sucralfate relates to its aluminium content.

Sucralfate is the only non-absorbable drug that has been studied in a randomized-controlled study during pregnancy. In an Italian study,[17] 42 women were given sucralfate 1 g three times daily and compared with 24 women given information on dietary and lifestyle modifications. Sucralfate-treated patients had a higher frequency of remission of heartburn and regurgitation symptoms at 1 month than controls (90% vs. 43% and 83% vs. 27%, respectively). No maternal or fetal adverse events were reported.

In several animal models, sucralfate did not affect fertility and was not teratogeneic with doses up to 50 times those used in humans.[16] Likewise, human fetal toxicity has not been reported. For example, in a surveillance study of 229 101 pregnancies in Michigan Medicaid patients evaluated between 1985 and 1992, 185 newborn babies were exposed to sucralfate in the first trimester. Five birth defects were observed, whereas eight were expected.[16] Therefore, sucralfate is an FDA category B drug.

Promotility Drugs

Metoclopramide. Metoclopramide, an antidopaminergic drug, improves GER by increasing LES pressure, improving oesophageal acid clearance and promoting gastric emptying. Its major use in pregnancy is for the treatment of nausea and vomiting. Reproductive studies in animals in doses up to 250 times the recommended human dose reveal no evidence of impaired fertility or fetal toxicity.[18] Congenital malformations or fetal toxicity because of metoclopramide have not been reported in humans. In the Michigan Medicaid Surveillance Study,[16] 10 (5.2%) major birth defects were reported in 992 newborns exposed to metoclopramide during the first trimester (eight were expected). Metoclopramide is designated a category B drug during pregnancy.

Cisapride. Cisapride promotes the release of acetylcholine from the myenteric plexus, thereby increasing LES pressure, improving acid clearance and promoting gastric emptying. The drug is toxic to the fetuses of rats and rabbits at doses 112 times the recommended human dose, resulting in lower birth weights and decreased survival.[19]

Human reports suggest cisapride is safe during pregnancy. In a prospective, multicentre study, the outcome of 129 Canadian women who took cisapride during pregnancy between November 1996 and November 1998 were compared with a control group.[20] The mean daily cisapride dose was 25 mg (range: 5-120) and the mean length of exposure was 4.6 weeks (range: 0.14-41). Most women took cisapride during the first trimester (88%), 3% of women took it throughout their pregnancy. Most women were also taking multiple other antireflux medications, including antacids, H2RAs and PPIs. Investigators found no differences in rates of major or minor congenital malformations in the cisapride group compared with the matched controls. In 1998, an observational cohort study described the outcome of 12 pregnancies in women taking cisapride during the first trimester in England.[21] The outcomes included two elective abortions, one lost to follow-up and 10 normal term babies. In two other cases, cisapride was taken during the second or third trimesters and healthy babies were born.

Cisapride is designated a category C drug in pregnancy because of its toxicity in animals. In July 2000, Janssen Pharmaceutical removed cisapride from the market and it now is only available in a limited-access program. High cisapride blood levels, because of other drugs interfering with its metabolism by the cytochrome P-450 3A4 enzyme, caused serious cardiac arrhythmias in more than 400 cases, including 80 fatalities.[22]

Histamine 2-receptor Antagonists


The H2RAs are the most commonly used and safest medications for the pregnant woman with heartburn not responding to lifestyle modification and non-absorbable medication. All four drugs (cimetidine, ranitidine, famotidine and nizatidine) are FDA approved category B drugs for pregnancy.

Cimetidine and Ranitidine. Cimetidine and ranitidine have had considerable use in pregnancy over the last 30 years with an excellent safety profile. Only ranitidine's efficacy has been specifically studied during pregnancy. In a double-blind, placebo-controlled, triple-crossover study, Larson et al.[23] compared ranitidine once or twice daily with placebo in pregnant heartburn subjects not responding to antacids and lifestyle modification. Twenty women at least 20 weeks gestation were studied assessing symptom response and antacid use by daily diaries. In the 18 women completing the 4-week study, only ranitidine 150 mg b.d. reduced symptoms and antacid usage compared with baseline values (P < 0.001) or with placebo (P < 0.001). The average heartburn reduction was 55.6% (95% CI: 34.8-76.5) compared with baseline and 44.2% (95% CI: 15.4-72.9) when compared with placebo. No adverse pregnancy outcomes or drug reactions were noted.

In animal studies, cimetidine has a weak antiandrogenic effect in animals, as evidenced by a reduction of the size of testes, prostate glands and seminal vesicles.[24] Ranitidine has no antiandrogenic activity in animals.[25] Neither H2RA has reports of human sexual defects in infants.

To date, the safety of cimetidine and ranitidine has been assessed in over 2000 pregnancies in database studies not sponsored by the manufacturers. In the surveillance study of 229 101 pregnancies in the Michigan Medicaid recipients between 1985 and 1992,[16] 460 newborns were exposed to cimetidine and 560 newborns were exposed to ranitidine during the first trimester. Twenty (4.3%) major birth defects were observed with cimetidine and 23 (4.5%) with ranitidine, a rate similar (4.3%) to that reported in women taking no medications during their pregnancies. In a 1996 prospective cohort study, 178 women exposed during pregnancy to H2RAs were matched with 178 women with no exposure with similar maternal age, smoking and alcohol history.[26] Among these subjects, 71% took ranitidine, 16% cimetidine, 8% famotidine and 5% nizatidine. The outcomes of both groups were similar in terms of live births, spontaneous or elective abortions, gestational age at delivery, birth weight or major malformation. The latter rate was 2.1% in subjects exposed to H2RAs vs. 3.0% in the non-exposed cohorts.

The Swedish Medical Birth Registry in 1998 reported on 553 babies delivered by 547 women using various acid-suppressing medications in early pregnancy.[27] Seventeen infants had congenital defects (3.1%, 95% CI: 1.8-4.9) compared with the expected rate of 3.9% in the Registry among women not taking any medications. Of the 17 infants, 10 had been exposed to PPIs, six to H2RAs and one to both class of drugs. Two birth defects (5.7%) in 35 infants exposed to cimetidine and six defects (3.8%) in 156 infants exposed to ranitidine were reported. Overall, the odds ratio for malformations after H2RAs was 0.46 (95% CI: 0.17-1.20) in contrast to 0.91 (95% CI: 0.45-1.84) for infants exposed to PPIs, early during pregnancy. Finally, two databases, one from England and another from Italy, were combined in a study published in 1999, which compared the incidence of congenital malformations in infants and women receiving cimetidine, ranitidine or omeprazole during the first trimester of pregnancy with unexposed control women.[28] The relative risk of malformation (adjusted for maternal age and prematurity) were similar among all three drugs: cimetidine (1.3%, 95% CI: 0.7-2.6), ranitidine 1.5 (95% CI: 0.9-2.6) and omeprazole 0.9 (95% CI: 0.4-2.4).

In summary, cimetidine and ranitidine have not been associated with an increased risk of congenital malformations. Ranitidine is the only H2RA with documented efficacy in pregnancy. Some authorities have recommended that cimetidine not be used during pregnancy because of possible feminization as observed in some animals and non-pregnant humans.[29]

Famotidine and Nizatidine. There are much less reported safety data with these latter H2RAs than cimetidine and ranitidine. Animal studies with famotidine revealed no fetal toxicity or teratogenicity.[30] However, pregnant rabbits with the equivalent of 300 times the recommended human dose of nizatidine encountered abortions, low fetal weights and fewer live fetuses.[31] On the contrary, rat studies found no adverse effects on the fetal pups.[32]

In the Michigan Medicaid Surveillance Study,[16] two (6.1%) of 33 fetuses exposed to famotidine during the first trimester of pregnancy developed major birth defects compared with the expected prevalence of one. The small size was too small to draw firm conclusions, however. With nizatidine there is only a single case report of a woman delivering a healthy baby after taking the drug during 14-16 weeks of gestation.[16]

Although few reports are available, famotidine appears safe during pregnancy. Although nizatidine was previously classified as category C, the FDA recently reclassified it as a category B drug. However, the conflicting animal data are troublesome and suggest that other H2RAs may be safer during pregnancy.

Proton-Pump Inhibitors

Proton-pump inhibitors are the most effective drug therapy for symptom control and healing of oesophagitis. The PPIs have not been as extensively used in pregnancy as the H2RAs, or is their efficacy proven in pregnancy, and the data about total safety are more limited. Omeprazole is categorized as a class C drug by the FDA because of fetal toxicity. The other PPIs are categorized as class B drugs. However, unlike the non-pregnant heartburn patient, PPIs should only be used during pregnancy in women with well-defined complicated GERD, not responding to lifestyle changes, antacids and H2RAs (Figure 1).

Figure 1.

The pyramid of medical therapy for gastro-oesophageal reflux disease (GERD) in the pregnant woman with heartburn. Unlike the non-pregnant patient, step-up therapy is preferred and proton-pump inhibitors (PPIs) reserved for the women with well-defined complicated GERD not responding to lifestyle changes, antacids or histamine2-receptor antagonists (H2RAs).

Omeprazole. Omeprazole, the first of the PPIs, is classified as a class C drug in pregnancy because at doses similar to those used in humans, omeprazole produced dose-related embryonic and fetal mortality in pregnant rats and rabbits.[33] No teratogenicity was observed.

The FDA has received reports of at least 12 birth defects in pregnant women exposed to omeprazole, including anencephaly and hydroencephaly.[16] However, other case reports[34] and small case series[21,35] have found no infant congenital malformations in mothers taking 20-60 mg omeprazole/day, even in the first trimester of pregnancy.

A recent meta-analysis assessed the risks of congenital fetal malformations in women using PPIs in the first trimester of pregnancy.[36] Five studies met the inclusion criteria, all were cohort studies ascertaining pregnancy outcomes with either registry linkage[27,28,37] or by direct interview with the mother.[36,38] A total of 593 infants were exposed to PPIs, most (534) received omeprazole. The summary relative risk for all major malformations among any PPI exposure was 1.18 (95% CI: 0.72-1.94), a non-significant relative risk (P = 0.7). For the four studies where data for only omeprazole could be extracted (Figure 2), the summary relative risk was 1.05 (95% CI: 0.59-1.85), also indicating a non-significant relative risk for malformations.

Figure 2.

Individual and summary relative risk for studies including all proton-pump inhibitor exposures (from Ref.[36] with permission).

Although the weight of evidence suggests omeprazole is safe in pregnancy, the FDA has not changed its class C rating. With the advent of newer PPIs, especially esomeprazole, omeprazole is currently infrequently prescribed. However, the drug is now over-the-counter at a 20 mg dose and cheaper than prescription PPIs.

Lansoprazole. Animal studies using doses of lansoprazole up to 40 times the recommended human dose have found no evidence of impaired fertility or fetal toxicity.[39]

Human data on the safety of lansoprazole in pregnancy are more limited. In one non-observational cohort study,[21] six pregnant patients taking lansoprazole during the first trimester delivered seven healthy newborns. Lansoprazole was the only acid-suppressing drug exposure in 13 infants reported to the Swedish Medical Birth Registry.[27] Two birth defects were observed; one atrial septal defect and one undescended testes. In a Danish study published in 1999,[37] 38 patients had taken PPIs during the first trimester of pregnancy (35 omeprazole, three lansoprazole). The prevalence of major birth defects, low birth weight and prematurity were no different than in pregnant controls not receiving any medications. In a study published this year,[40] 295 pregnancies exposed to omeprazole, 62 to lansoprazole and 53 to pantoprazole were compared with 868 pregnant controls for the development of congenital abnormalities. As with other studies, the rate of congenital abnormalities did not differ between the exposed and control groups: omeprazole nine of 249 (3.6%), lansoprazole two of 51 (3.9%) and pantoprazole one of 48 (2.1%) vs. controls 30 of 792 (3.8%). No differences were found when exposure was limited to the first trimester.

The lack of teratogenicity in animals is reassuring, accounting for the FDA class C risk category for lansoprazole use during pregnancy. However, the data on safety in human pregnancies are limited and avoidance of this PPI and all PPIs, especially during the first trimester, is the safest course. If lansoprazole is required, or if inadvertent exposure occurs early in gestation, the fetal risk seems to be low.

Newer PPIs

Based on product information from the individual manufacturers, the newer PPIs (rabeprazole, pantoprazole and esomeprazole) have been shown safe in various animal studies. No reports describing the use of these newer PPIs during human pregnancies are available.[16]

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