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Medicines Q&As

Q&A 112.4

Can proton pump inhibitors be used during pregnancy?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals

Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: December 2011

Summary

Most documented exposures to proton pump inhibitors (PPIs) during pregnancy have occurred with
omeprazole. Although there is some suggestion from one or two studies that omeprazole may be associated
with a slightly higher risk of stillbirths or cardiac malformations, these findings may have occurred by chance.
A meta-analysis of seven cohort studies documenting 1,530 exposed pregnancies found that administration
of PPIs during the first trimester of pregnancy, and specifically omeprazole, does not pose an important
teratogenic risk and concludes that PPIs are a reasonable therapeutic option in pregnancy. This finding was
also seen in a cohort study involving 1,800 infants exposed to omeprazole during the first trimester.
Although the US Food and Drug Administration (FDA) classify omeprazole as a higher risk than other PPIs
during pregnancy, this is based on results of animal studies. The UK National Teratology Information Service
(UKTIS) recommends that if a PPI is required during pregnancy, omeprazole should be first choice, as the
majority of available data concern this agent and are reassuring. In addition, the Summary of Product
Characteristics (SmPC) for omeprazole (Losec®) states that there is sufficient evidence of safety to
recommend its use during pregnancy if required.
The SmPCs for other PPIs recommend caution (esomeprazole), suggest use should be avoided
(lansoprazole) or contraindicate use (rabeprazole, pantoprazole). If inadvertent exposure to any PPI does
occur there is no information to suggest that this represents a major risk.

Background
Gastro-oesophageal reflux and heartburn are reported by 45 to 85% of women during pregnancy. The hormonal
effects of oestrogen and progesterone on lower oesophageal sphincter function typically precipitate the heartburn
of pregnancy (1). In mild cases, lifestyle and dietary modifications alone may be sufficient to improve symptoms. If
drug treatment is indicated, first-line therapy includes antacids and alginates. If acid suppression is required, the
H2-receptor antagonist, ranitidine, may be used (2). Although proton pump inhibitors (PPIs) are more effective
than H2-receptor antagonists, there are limited data on their safety during pregnancy.
General information about prescribing in pregnancy can be found here. To put the following into context it is useful
to note that the expected incidence of miscarriage in the UK is 10 to 20% of clinically recognised pregnancies.
The expected incidence of congenital malformations is 2 to 3% of live births (3). Cardiac defects are the most
common malformations observed in the general population (0.5 to 1%), with ventricular septal defect being the
most common cardiac malformation (25 to 30%) (4).

Answer
Omeprazole
Of the five PPIs licensed for use in the UK, most documented exposures during pregnancy have occurred with
omeprazole (5). The SmPC for omeprazole (Losec ) states that analysis of epidemiological studies has revealed
no evidence of adverse events of omeprazole on pregnancy or on the health of the fetus/newborn child, and that
omeprazole may be used in pregnancy (6). Omeprazole has been associated with dose-related embryo and fetal
toxicity in animal studies, and on this basis has been classified by the US FDA as class C (limited safety data
therefore should only be given if the potential benefit justifies the potential risk to the fetus) (7,8). The available
human data to support the safety of omeprazole in pregnancy are described below.
A cohort study of live births between 1996 and 2008 assessed the prevalence of major birth defects after
exposure to PPIs during early pregnancy. 1,800 live-born infants were exposed to omeprazole in the first
trimester. No significant association between exposure to omeprazole during the first trimester and risk of major
birth defects was found (2.9%), adjusted prevalence odds ratio (OR) 1.05 [ 95% CI 0.79 to 1.40]) (9).

From the NHS Evidence website www.evidence.nhs.uk

A multicentre prospective controlled study. none with known malformations (odds ratio compared to all births recorded in the Register. and the third.0]) and malformations (1. The median daily dose of omeprazole was 20mg. the outcomes of 113 women who had taken omeprazole during pregnancy were compared to those of matched controls exposed to non-teratogens and to disease-paired controls who used H2-receptor antagonists for similar indications (13). In addition there were three stillborn infants (1%) and nine infants (3. were born with malformations. A cohort study of 2. including two with cardiac septal defects.5 to 5. does not pose an important teratogenic risk. 1.46 to 1. There were no stillbirths in the exposed group.530 exposed pregnancies.66 to 1. polycystic kidneys.0%) or disease-paired controls (3.66 [0.7%) were born with malformations of whom 22 (2.95 [0.6 [0. atrial septal defect.3%) were exposed to omeprazole in the first trimester. and specifically omeprazole.9 [0. Compared to the control group. Among those taking PPIs. There were five stillborn infants following first trimester exposure.97 [0.236 pregnancies.91] when taken after the first trimester.53]). included 139 babies born to women who had taken omeprazole in the first trimester of pregnancy (11). identified from the Swedish Birth Register. This relates to a difference in absolute risk of 0.In a Danish population-based cohort study. in which the mother had reported taking omeprazole during pregnancy was published in 2001 (12).43] for first trimester exposure. The UK Teratology Information Service (UKTIS) has collected prospective outcome data on 75 cases of omeprazole exposure during pregnancy (16). Major defects among the non-teratogenic group were atrial septal defect with pulmonary stenosis and development delay (one child each).9 [0. There were 57 healthy babies and two From the NHS Evidence website www. There were eight elective terminations.2 to 13. The review concludes that PPIs are not associated with an increased risk for major congenital birth defects and that PPIs can be safely used in pregnancy (15). pregnancy outcomes among 51 women exposed to a PPI were compared with 13.6%) born with major malformations (eight in infants with first trimester exposure). There was no significant difference in rate of major malformations among babies with first trimester exposure to omeprazole (5. and among disease-paired controls there was one case of atrial septal defect and two of ventricular septal defect.49 to 2. A study of the outcomes of 944 pregnancies.1%). 295 pregnancies were in women exposed to omeprazole. Exposure to omeprazole during the first trimester was reported by 101 women (89%). conducted by the European Network of Teratology Information Services (ENTIS). Omeprazole was associated with a statistically significant reduction of 60g in median birth weight. 15% reported use throughout pregnancy. a combination of patent ductus arteriosus.3 to 2. one intrauterine death and two babies with neonatal problems. Five (3. which assessed the safety of acid suppression drugs in pregnancy.nhs.2]). 38 had only been exposed in the first trimester (35 to omeprazole. with first trimester exposure in 233 (14).90 to 1. 815 women (824 infants) reported taking omeprazole only during the first trimester. two due to prenatal diagnosis of malformations. There were eight cardiac defects and all but one (tetralogy of Fallot with an eye malformation) were mild or unspecified. gestational age at delivery and number of abortions (spontaneous and elective) were comparable between groups. 26 infants (2. one pyloric stenosis. including the five documented above (10-14).evidence. The other major malformations were seen mainly in single instances. followed up 410 pregnancies exposed to PPIs. three to lansoprazole). For six studies where data for omeprazole could be extracted. Three babies. ureteropelvic junction stenosis and patent ductus arteriosus (one report of each). 91 (92 infants) only after the first trimester and 38 (39 infants) during both the first and later trimesters. administration of PPIs during the first trimester. and 1.1%) and non-teratogenic (3.4]. there was no significant difference in the incidence of major malformations (OR 1. eight spontaneous abortions. all exposed during the first trimester (specific PPI not stated). The major defects among the omeprazole-exposed group were ventricular septal defect. There were 26 elective terminations of pregnancies in women taking omeprazole. Of the 950 live births. A meta-analysis of seven cohort studies. The odds ratio of an infant with a birth weight of below 2500g was 0.1]).98]) or the rate when the comparison was limited to first-trimester exposure only. Birth weight.98]).17 [0.70 to 3.8 [0.8 to 4.uk . hydronephrosis and agenesis of the iris.327 controls without exposure to any prescribed medicine (10). None of the studies found a significant association between exposure during the first trimester and risk of major malformation. there was a non-significant increase in the crude relative risk (RR) of low birth weight (1. one had a ventricular septal defect.20 [0. 28 malformations were noted in total. (RR 0. The odds ratio for any cardiovascular defect was 1. found that in 1. There was no difference in overall rate of malformations between the omeprazole and the control group (RR 0. In a multicentre prospective study.7% for malformations in the exposed group compared with the control group.6%) of the omeprazole-exposed babies were born with malformations.

91. Esomeprazole The SmPC for esomeprazole (Nexium ) states that clinical data on exposed pregnancies are insufficient to suggest it is safe to use and advises caution when prescribing esomeprazole during pregnancy. UKTIS have prospective data on the outcome of 58 pregnancies exposed to lansoprazole. including 668 live-born infants whose mother took esomeprazole in the first trimester. However. There were no cases of congenital malformations in any of the babies (20). based on data from the Swedish Birth Register.3%) was not significantly higher than the background malformation rate for live births (2 to 3%) (5). Reproduction studies in rats and rabbits have revealed no evidence of harm to the fetus due to rabeprazole. Analysis showed no significant association between its use during the first trimester and risk of major birth defects (3. healthy baby at 38 weeks (25).7% of the exposures occurred in the first trimester (14). There is one additional case report describing the delivery of a normal baby following treatment with 90mg daily lansoprazole throughout the pregnancy. A cohort study of birth defects after early exposure to PPIs. adjusted prevalence OR 1. She delivered a second healthy baby after a further pregnancy during which she was given omeprazole 60mg and cimetidine 150mg. at oral doses of lansoprazole up to 40 times and 16 times respectively.4%. The frequency of congenital malformations in live born infants (5/53. There are two further reports worthy of note.04 [0. was observed among 13 infants exposed to lansoprazole during pregnancy (23). The outcome of 13 pregnancies following exposure to esomeprazole in the first trimester of pregnancy was reported in one observational study. 3.21]).13 [0. The first details a normal pregnancy outcome at 38 weeks gestation in a woman with Zollinger-Ellison syndrome given high-dose omeprazole (60mg twice daily from week 11). On this basis the FDA has classified esomeprazole as a class B risk (animal studies show no risk. This risk is higher than for other PPIs.nhs. 9. both three times daily (17). There was no significant association between its use during the first trimester and risk of major birth defects (7.19 [0. adjusted prevalence OR 1. NTIS have outcome data on five pregnancies exposed to esomeprazole. there is insufficient experience in humans to recommend use during pregnancy and it should therefore be avoided in pregnancy (22).5%.14 [0. The other four cases resulted in normal healthy babies (21). Lansoprazole The SmPC for lansoprazole (Zoton FasTabs®) states that although animal studies do not reveal any teratogenic effects. Rabeprazole The SmPC for rabeprazole (Pariet®) states that its use is contraindicated in pregnancy. On this basis the FDA has classified lansoprazole as a class B risk (7. one congenital malformation (atrial septal defect). The second report notes that follow-up of between two to 12 years of nine babies after omeprazole-exposure during pregnancy. There was one spontaneous abortion occurring in the second month of pregnancy. A cohort study included 42 live-born infants exposed to rabeprazole during the first trimester. One woman elected for termination of pregnancy. The ENTIS study (see under omeprazole) included 62 pregnancies exposed to lansoprazole. no specific pattern of malformations was detected (24). From the NHS Evidence website www. Two (3. but human studies are inadequate or animal studies show some risk not supported by human studies) (7.9%) major abnormalities were observed in the lansoprazole group. Of 53 live born infants.77 to 1.67]) (9). There was no difference in the rate of major abnormalities compared to the control group (RR 1.4%) was higher than the background malformation rate for live births (2 to 3%). showed normal development in all children (18). A 26 year old female with Zollinger-Ellison syndrome delivered a normal.25 to 4. Animal studies with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonic/fetal development (19). of the recommended human doses have found no evidence of fetal toxicity (7).1%.evidence.77 to 1.60 to 7. A cohort study included 794 live-born infants exposed to lansoprazole in the first trimester.uk .84]) (9).babies with congenital malformations. The frequency of congenital malformations in live born infants (2/61. however the number of exposed life births was very small (9). showed no significant association with risk of major birth defects (3. 8).68]). 46 babies were born normal and five babies were born with malformations. although low fetal-placental transfer occurs in rats (26). The median daily dose was 30mg. In a further study. adjusted prevalence OR 2. 8). Reproductive studies in pregnant rats and rabbits.

Miller RK. lansoprazole. pantoprazole. Drugdex Evaluations – omeprazole.uk . Outcome of pregnancy following maternal treatment with proton pump inhibitors (Abstract). From the NHS Evidence website www. O’Brien L.8%. Cattaruzzi C et al. The timing of exposure during pregnancy was unknown in the remaining case. References 1. 4. Richter JE. data are often confounded due to varying exposure times and in some cases. There were four normal live births and three spontaneous abortions. 96: 63-68. November 2007. Gastroesophageal reflux disease during pregnancy. Loebstein R. Aliment Pharmacol Ther 1999. Kallen BAJ. Losec capsules 10mg. There were 48 live births in the group and one major malformation (14). Pasternak B. 8). Fetal toxicity was observed in animals at doses above 5mg/kg. UKTIS has outcome data on six prospective cases of pantoprazole exposure in pregnancy. The safety of proton pump inhibitors in pregnancy: a multicentre prospective controlled study. Diav-Citrin O. Schaefer C. Accessed via www. Drug Safety 1998.org. Use of omeprazole during pregnancy . 29) The ENTIS study (see under omeprazole) included 53 women who were exposed to pantoprazole. 20mg and 40mg. Pantoprazole The SmPC for pantoprazole (Pantaloc®) states that clinical experience in pregnant women is limited and pantoprazole should only be used when the benefit to the mother is considered greater than the potential risk to the fetus (28). p95-99. Sorensen HT. Richter JE.UKTIS have only four reports of pregnancies exposed to rabeprazole. Ruigomez A. AstraZeneca. there are few data for other PPIs. The median daily dose was 40mg.thomsonhc. The remaining five cases resulted in normal healthy babies (30). Einarson TR.evidence. 14.medicines. 2 nd edition London: Elsevier: 2007. Peters P. Thomas SHL. omeprazole and ranitidine in pregnant women and pregnancy outcomes. As animal studies have shown no risk but data in human pregnancy are limited.85 to 2. Am J Obstet Gynecol 1998. N Engl J Med 2010. 179: 727-30. All four babies were born without malformations (27). Accessed via www. Nielsen GL. 9. Aliment Pharmacol Ther 2005.toxbase. Dr PR McElhatton. Treating gastro-oesophageal reflux disease during pregnancy and lactation.org on 28/12/2011. the outcome in this case was a live birth with neonatal problems which spontaneously resolved and were deemed unrelated to pantoprazole exposure. Gastroenterol Clin N Am 2003. adjusted prevalence OR 1. Broussard CN. Thulstrup AM et al. A cohort study analysed first trimester exposure to pantoprazole in 549 live births. Eur J Obstet Gynecol Reprod Biol 2001. Lalkin A. 5. Use of proton-pump inhibitors in early pregnancy and the risk of birth defects.33 [0. 15. Drugs during pregnancy and lactation. No congenital abnormalities were reported (5. 21: 269-75. Limitations Most human outcome data concern omeprazole. the FDA has classified rabeprazole as a class B risk (7. Personal Communication. Seven were first trimester exposures. Rodriguez LAG. Hedgley CA. Am J Epidemiol 1999.com/home/dispatch on 28/12/2011. Arnon J. 8). 6. There was one spontaneous abortion at six weeks gestation. Summary of Product Characteristics. The outcome of eight pregnancies following exposure to pantoprazole during pregnancy was reported in an observational study. Randomised controlled studies have not been conducted. pregnancies may have been exposed to polytherapy. 104: 1541-45. 7. The safety of proton pump inhibitors (PPIs) in pregnancy: A meta-analysis. 13. The safety of proton pump inhibitors in pregnancy. 8. Addis A et al. Schechtman S et al. 12. Use of cimetidine. 2. 3.no hazard demonstrated in 955 infants exposed during pregnancy. 13: 1085-89. Hviid A. Updated December 2010. UK Teratology Information Service. The FDA has classified pantoprazole as a class B risk (7. No significant increase in major birth defects was found (3. Am J Gastroenterol 2009. 32: 23561.08]) (9).uk/emc on 28/12/2011. Studies available have limitations. Gill SK. 10. The safety of omeprazole during pregnancy: A multicenter prospective controlled study. Accessed via Micromedex Healthcare series http://www. Koren G. Clinical Toxicol 2005.nhs. 19: 325-37. 43(5): 431. esomeprazole. 11. rabeprazole. 150: 476-81. Date of revision of the text 29/3/2011. Head of the National Teratology Information Service. Use of proton pump inhibitors in pregnancy. 363: 2114-23. McElhatton PR.

McVeigh JE.595 patients in England. or Pregnancy-complication#.org on 28/12/2011. 25. 27. North West Medicines Information Centre.uk/emc on 28/12/2011.uk/emc on 28/12/2011. UK Teratology Information Service. Accessed via www. DE) Search limited to ‘human’ ‘adult’ ‘english’. November 2007. Summary of Product Characteristics. Accessed via www. Clinical expert: Dr P McElhatton. Meyer H. Date of revision of the text 27/06/2011.uk/emc on 28/12/2011. Accessed via www..DE. Williams & Wilkins: 2011. Accessed via www. Brunner G. The pharmacovigilance of pantoprazole: the results of postmarketing surveillance on 11. Novartis.evidence. 22. Am J Obstet Gynecol 1995.or Esomeprazole# W.DE or Rabeprazole#.W. 276: 171-73. UK Teratology Information Service. Liverpool. or Pantoprazole#. Wyeth Pharmaceuticals. Date of revision of the text 06/10/2011. Zoton FasTabs.toxbase. Eisai Ltd. Omeprazole for peptic ulcer disease in pregnancy.DE or rabeprazole or esomeprazole or lansoprazole or pantoprazole) Search limited to ‘human’ ‘english’ and ‘adult’ Embase 1974 to date (Pregnancy#. Updated December 2010.org.W. 17.16. 26:121-132. Accessed via www. Drug Safety 2008. Results of a prescription-event monitoring study of 11. Shakir SAW.541 patients in England.org.J or Pregnancy#. 20.W. Use of omeprazole in pregnancy. Freeman RK. Sheiner E. Accessed via www. Holcberg G.uk . Pantoloc. Briggs GG. UK Teratology Information Service. Shakir SAW..org. UK Teratology Information Service. Updated December 2010.org on 28/12/2011.medicines. Wilton LV. Thompson W et al. Updated December 2010. Arch Gynecol Obstet 2007. 9th edition. Successful pregnancy in association with Zollinger-Ellison syndrome. Key C. Wilton LV.org on 28/12/2011.. Use of rabeprazole in pregnancy.MJ) AND (Omeprazole. 18. North West Medicines Information Centre. Use of lansoprazole in pregnancy. Pharmline – [Proton pump inhibitors] and [Abnormalities-drug induced] The UK Teratology Information Service. Date of revision of the text 15/08/2011. Accessed via www. 21.M. Accessed via www.W. Davies M.DE. Liverpool.toxbase. Philadelphia: Lippincott. Quality Assurance Prepared by Simone Henderson. Use of esomeprazole in pregnancy.org on 28/12/2011. 19.medicines. Summary of Product Characteristics. Digestion 1998. UK Teratology Information Service. Zollinger Ellison syndrome treated with lansoprazole during pregnancy. Pharmacy Practice Unit. 70 Pembroke Place. Updated December 2010. Athmann C.uk/emc on 28/12/2011. 26.toxbase.. 24.DE or lansoprazole#. AstraZeneca.. Drugs in Pregnancy and Lactation. pregnancy.medicines.W. Date of check January 2012 Search strategy Medline 1951 to date (Pregnancy-complications#.org on 28/12/2011.org Past enquiries – keyword: Proton pump inhibitors.toxbase. Use of pantoprazole in pregnancy. 29. Harper MA. Accessed via www. Summary of Product Characteristics.W. Date Prepared 28th December 2011 Checked by Joanne McEntee. 59: 651-54. In house databases/resources.nhs.DE) and (proton-pump-inhibitors#. 23. Accessed via www.org. Date of revision of the text 24/11/2010. Pariet. Mayer A. 28. Safety profile of esomeprazole.toxbase. Nexium. Liverpool. L69 3GF. 31: 313-23. 30. 173: 863-64. Yaffe SJ.W.. Christine Proudlove. Drug Safety 2003.DE. From the NHS Evidence website www.toxbase.medicines. Summary of Product Characteristics. or omeprazole#. Head of the National Teratology Information Service. North West Medicines Information Centre.DE. Updated December 2010.