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

In a Danish population-based cohort study, pregnancy outcomes among 51 women exposed to a PPI were
compared with 13,327 controls without exposure to any prescribed medicine (10). Among those taking PPIs, 38
had only been exposed in the first trimester (35 to omeprazole, three to lansoprazole). Three babies, all exposed
during the first trimester (specific PPI not stated), were born with malformations; one had a ventricular septal
defect, one pyloric stenosis, and the third, a combination of patent ductus arteriosus, atrial septal defect,
hydronephrosis and agenesis of the iris. There were no stillbirths in the exposed group. Compared to the control
group, there was a non-significant increase in the crude relative risk (RR) of low birth weight (1.8 [0.2 to 13.0]) and
malformations (1.6 [0.5 to 5.1]). This relates to a difference in absolute risk of 0.7% for malformations in the
exposed group compared with the control group.
A cohort study of 2,236 pregnancies, which assessed the safety of acid suppression drugs in pregnancy, included
139 babies born to women who had taken omeprazole in the first trimester of pregnancy (11). Five (3.6%) of the
omeprazole-exposed babies were born with malformations, (RR 0.9 [0.3 to 2.2]), including two with cardiac septal
defects.
A study of the outcomes of 944 pregnancies, identified from the Swedish Birth Register, in which the mother had
reported taking omeprazole during pregnancy was published in 2001 (12). 815 women (824 infants) reported
taking omeprazole only during the first trimester, 91 (92 infants) only after the first trimester and 38 (39 infants)
during both the first and later trimesters. There were five stillborn infants following first trimester exposure, none
with known malformations (odds ratio compared to all births recorded in the Register, 1.66 [0.70 to 3.98]). Of the
950 live births, 26 infants (2.7%) were born with malformations of whom 22 (2.3%) were exposed to omeprazole in
the first trimester. 28 malformations were noted in total. There were eight cardiac defects and all but one
(tetralogy of Fallot with an eye malformation) were mild or unspecified. The odds ratio for any cardiovascular
defect was 1.9 [0.8 to 4.4]. The other major malformations were seen mainly in single instances. The odds ratio of
an infant with a birth weight of below 2500g was 0.97 [0.66 to 1.43] for first trimester exposure, and 1.20 [0.49 to
2.91] when taken after the first trimester.
In a multicentre prospective study, 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). Exposure to omeprazole during the first trimester was
reported by 101 women (89%); 15% reported use throughout pregnancy. There was no significant difference in
rate of major malformations among babies with first trimester exposure to omeprazole (5.1%) and non-teratogenic
(3.0%) or disease-paired controls (3.1%). The major defects among the omeprazole-exposed group were
ventricular septal defect, polycystic kidneys, ureteropelvic junction stenosis and patent ductus arteriosus (one
report of each). Major defects among the non-teratogenic group were atrial septal defect with pulmonary stenosis
and development delay (one child each), and among disease-paired controls there was one case of atrial septal
defect and two of ventricular septal defect. Birth weight, gestational age at delivery and number of abortions
(spontaneous and elective) were comparable between groups.
A multicentre prospective controlled study, conducted by the European Network of Teratology Information
Services (ENTIS), followed up 410 pregnancies exposed to PPIs; 295 pregnancies were in women exposed to
omeprazole, with first trimester exposure in 233 (14). The median daily dose of omeprazole was 20mg. There
were 26 elective terminations of pregnancies in women taking omeprazole, two due to prenatal diagnosis of
malformations. In addition there were three stillborn infants (1%) and nine infants (3.6%) born with major
malformations (eight in infants with first trimester exposure). There was no difference in overall rate of
malformations between the omeprazole and the control group (RR 0.95 [0.46 to 1.98]) or the rate when the
comparison was limited to first-trimester exposure only. Omeprazole was associated with a statistically significant
reduction of 60g in median birth weight.
A meta-analysis of seven cohort studies, including the five documented above (10-14), found that in 1,530
exposed pregnancies, administration of PPIs during the first trimester, and specifically omeprazole, does not pose
an important teratogenic risk. For six studies where data for omeprazole could be extracted, there was no
significant difference in the incidence of major malformations (OR 1.17 [0.90 to 1.53]). None of the studies found a
significant association between exposure during the first trimester and risk of major malformation. 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).
The UK Teratology Information Service (UKTIS) has collected prospective outcome data on 75 cases of
omeprazole exposure during pregnancy (16). There were eight elective terminations, eight spontaneous
abortions, one intrauterine death and two babies with neonatal problems. There were 57 healthy babies and two
From the NHS Evidence website www.evidence.nhs.uk

babies with congenital malformations. The frequency of congenital malformations in live born infants (2/61, 3.3%)
was not significantly higher than the background malformation rate for live births (2 to 3%) (5).
There are two further reports worthy of note. 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). She
delivered a second healthy baby after a further pregnancy during which she was given omeprazole 60mg and
cimetidine 150mg, both three times daily (17). The second report notes that follow-up of between two to 12 years
of nine babies after omeprazole-exposure during pregnancy, showed normal development in all children (18).
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. Animal studies
with esomeprazole do not indicate direct or indirect harmful effects with respect to embryonic/fetal
development (19). On this basis the FDA has classified esomeprazole as a class B risk (animal
studies show no risk, but human studies are inadequate or animal studies show some risk not
supported by human studies) (7, 8).
A cohort study of birth defects after early exposure to PPIs, including 668 live-born infants whose mother took
esomeprazole in the first trimester, showed no significant association with risk of major birth defects (3.4%,
adjusted prevalence OR 1.19 [0.77 to 1.84]) (9). The outcome of 13 pregnancies following exposure to
esomeprazole in the first trimester of pregnancy was reported in one observational study. There was one
spontaneous abortion occurring in the second month of pregnancy. There were no cases of congenital
malformations in any of the babies (20). NTIS have outcome data on five pregnancies exposed to esomeprazole.
One woman elected for termination of pregnancy. 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, there is insufficient experience in humans to recommend use during pregnancy and it should therefore be
avoided in pregnancy (22). On this basis the FDA has classified lansoprazole as a class B risk (7, 8).
Reproductive studies in pregnant rats and rabbits, at oral doses of lansoprazole up to 40 times and 16 times
respectively, of the recommended human doses have found no evidence of fetal toxicity (7).
A cohort study included 794 live-born infants exposed to lansoprazole in the first trimester. Analysis showed no
significant association between its use during the first trimester and risk of major birth defects (3.5%, adjusted
prevalence OR 1.13 [0.77 to 1.67]) (9).
The ENTIS study (see under omeprazole) included 62 pregnancies exposed to lansoprazole. 91.7% of the
exposures occurred in the first trimester (14). The median daily dose was 30mg. Two (3.9%) major abnormalities
were observed in the lansoprazole group. There was no difference in the rate of major abnormalities compared to
the control group (RR 1.04 [0.25 to 4.21]). In a further study, based on data from the Swedish Birth Register, one
congenital malformation (atrial septal defect), was observed among 13 infants exposed to lansoprazole during
pregnancy (23). UKTIS have prospective data on the outcome of 58 pregnancies exposed to lansoprazole. Of 53
live born infants, 46 babies were born normal and five babies were born with malformations. The frequency of
congenital malformations in live born infants (5/53, 9.4%) was higher than the background malformation rate for
live births (2 to 3%). However, no specific pattern of malformations was detected (24).
There is one additional case report describing the delivery of a normal baby following treatment with 90mg daily
lansoprazole throughout the pregnancy. A 26 year old female with Zollinger-Ellison syndrome delivered a normal,
healthy baby at 38 weeks (25).
Rabeprazole
The SmPC for rabeprazole (Pariet) states that its use is contraindicated in pregnancy. Reproduction studies in
rats and rabbits have revealed no evidence of harm to the fetus due to rabeprazole, although low fetal-placental
transfer occurs in rats (26). A cohort study included 42 live-born infants exposed to rabeprazole during the first
trimester. There was no significant association between its use during the first trimester and risk of major birth
defects (7.1%, adjusted prevalence OR 2.14 [0.60 to 7.68]). This risk is higher than for other PPIs, however the
number of exposed life births was very small (9).

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

UKTIS have only four reports of pregnancies exposed to rabeprazole. All four babies were born without
malformations (27). As animal studies have shown no risk but data in human pregnancy are limited, the FDA has
classified rabeprazole as a class B risk (7, 8).
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). Fetal toxicity was observed in animals at doses above 5mg/kg. The FDA has classified
pantoprazole as a class B risk (7, 8).
A cohort study analysed first trimester exposure to pantoprazole in 549 live births. No significant increase in major
birth defects was found (3.8%, adjusted prevalence OR 1.33 [0.85 to 2.08]) (9).
The outcome of eight pregnancies following exposure to pantoprazole during pregnancy was reported in an
observational study. Seven were first trimester exposures. There were four normal live births and three
spontaneous abortions. The timing of exposure during pregnancy was unknown in the remaining case; the
outcome in this case was a live birth with neonatal problems which spontaneously resolved and were deemed
unrelated to pantoprazole exposure. No congenital abnormalities were reported (5, 29)
The ENTIS study (see under omeprazole) included 53 women who were exposed to pantoprazole. The median
daily dose was 40mg. There were 48 live births in the group and one major malformation (14). UKTIS has
outcome data on six prospective cases of pantoprazole exposure in pregnancy. There was one spontaneous
abortion at six weeks gestation. The remaining five cases resulted in normal healthy babies (30).

Limitations
Most human outcome data concern omeprazole; there are few data for other PPIs. Randomised controlled studies
have not been conducted. Studies available have limitations; data are often confounded due to varying exposure
times and in some cases, pregnancies may have been exposed to polytherapy.

References
1. Broussard CN, Richter JE. Treating gastro-oesophageal reflux disease during pregnancy and lactation.
Drug Safety 1998; 19: 325-37.
2. Schaefer C, Peters P, Miller RK. Drugs during pregnancy and lactation. 2 nd edition London: Elsevier: 2007.
p95-99.
3. McElhatton PR, Hedgley CA, Thomas SHL. Outcome of pregnancy following maternal treatment with
proton pump inhibitors (Abstract). Clinical Toxicol 2005; 43(5): 431.
4. Personal Communication. Dr PR McElhatton. Head of the National Teratology Information Service.
November 2007.
5. UK Teratology Information Service. Use of proton pump inhibitors in pregnancy. Updated December 2010.
Accessed via www.toxbase.org on 28/12/2011.
6. Summary of Product Characteristics. Losec capsules 10mg, 20mg and 40mg. AstraZeneca. Accessed via
www.medicines.org.uk/emc on 28/12/2011. Date of revision of the text 29/3/2011.
7. Richter JE. Gastroesophageal reflux disease during pregnancy. Gastroenterol Clin N Am 2003; 32: 23561.
8. Drugdex Evaluations omeprazole, esomeprazole, lansoprazole, pantoprazole, rabeprazole. Accessed
via Micromedex Healthcare series http://www.thomsonhc.com/home/dispatch on 28/12/2011.
9. 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.
10. Nielsen GL, Sorensen HT, Thulstrup AM et al. The safety of proton pump inhibitors in pregnancy. Aliment
Pharmacol Ther 1999; 13: 1085-89.
11. Ruigomez A, Rodriguez LAG, Cattaruzzi C et al. Use of cimetidine, omeprazole and ranitidine in pregnant
women and pregnancy outcomes. Am J Epidemiol 1999; 150: 476-81.
12. Kallen BAJ. Use of omeprazole during pregnancy - no hazard demonstrated in 955 infants exposed
during pregnancy. Eur J Obstet Gynecol Reprod Biol 2001; 96: 63-68.
13. Lalkin A, Loebstein R, Addis A et al. The safety of omeprazole during pregnancy: A multicenter
prospective controlled study. Am J Obstet Gynecol 1998; 179: 727-30.
14. Diav-Citrin O, Arnon J, Schechtman S et al. The safety of proton pump inhibitors in pregnancy: a
multicentre prospective controlled study. Aliment Pharmacol Ther 2005; 21: 269-75.
15. Gill SK, OBrien L, Einarson TR, Koren G. The safety of proton pump inhibitors (PPIs) in pregnancy: A
meta-analysis. Am J Gastroenterol 2009; 104: 1541-45.
From the NHS Evidence website www.evidence.nhs.uk

16. UK Teratology Information Service. Use of omeprazole in pregnancy. Updated December 2010. Accessed
via www.toxbase.org on 28/12/2011.
17. Harper MA, McVeigh JE, Thompson W et al. Successful pregnancy in association with Zollinger-Ellison
syndrome. Am J Obstet Gynecol 1995; 173: 863-64.
18. Brunner G, Meyer H, Athmann C. Omeprazole for peptic ulcer disease in pregnancy. Digestion 1998; 59:
651-54.
19. Summary of Product Characteristics. Nexium. AstraZeneca. Accessed via www.medicines.org.uk/emc on
28/12/2011. Date of revision of the text 06/10/2011.
20. Davies M, Wilton LV, Shakir SAW. Safety profile of esomeprazole. Results of a prescription-event
monitoring study of 11,595 patients in England. Drug Safety 2008; 31: 313-23.
21. UK Teratology Information Service. Use of esomeprazole in pregnancy. Updated December 2010.
Accessed via www.toxbase.org on 28/12/2011.
22. Summary of Product Characteristics. Zoton FasTabs. Wyeth Pharmaceuticals. Accessed via
www.medicines.org.uk/emc on 28/12/2011. Date of revision of the text 27/06/2011.
23. Briggs GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. 9th edition. Philadelphia: Lippincott,
Williams & Wilkins: 2011.
24. UK Teratology Information Service. Use of lansoprazole in pregnancy. Updated December 2010.
Accessed via www.toxbase.org on 28/12/2011.
25. Mayer A, Sheiner E, Holcberg G. Zollinger Ellison syndrome treated with lansoprazole during pregnancy.
Arch Gynecol Obstet 2007; 276: 171-73.
26. Summary of Product Characteristics. Pariet. Eisai Ltd. Accessed via www.medicines.org.uk/emc on
28/12/2011. Date of revision of the text 24/11/2010.
27. UK Teratology Information Service. Use of rabeprazole in pregnancy. Updated December 2010. Accessed
via www.toxbase.org on 28/12/2011.
28. Summary of Product Characteristics. Pantoloc. Novartis. Accessed via www.medicines.org.uk/emc on
28/12/2011. Date of revision of the text 15/08/2011.
29. Wilton LV, Key C, Shakir SAW. The pharmacovigilance of pantoprazole: the results of postmarketing
surveillance on 11,541 patients in England. Drug Safety 2003, 26:121-132.
30. UK Teratology Information Service. Use of pantoprazole in pregnancy. Updated December 2010.
Accessed via www.toxbase.org on 28/12/2011.

Quality Assurance
Prepared by
Simone Henderson, North West Medicines Information Centre, Pharmacy Practice Unit, 70 Pembroke Place,
Liverpool, L69 3GF.
Date Prepared
28th December 2011
Checked by
Joanne McEntee. North West Medicines Information Centre, Liverpool.
Christine Proudlove. North West Medicines Information Centre, Liverpool.
Date of check
January 2012
Search strategy
Medline 1951 to date (Pregnancy-complications#.M.J or Pregnancy#.W..MJ) AND (Omeprazole.W.DE or
rabeprazole or esomeprazole or lansoprazole or pantoprazole) Search limited to human english and adult
Embase 1974 to date (Pregnancy#.W..DE. or Pregnancy-complication#.DE) and (proton-pump-inhibitors#.DE. or
omeprazole#.W..DE or lansoprazole#.W..DE or Rabeprazole#.W..DE. or Pantoprazole#.W..DE.or Esomeprazole#
W. DE) Search limited to human adult english.
Pharmline [Proton pump inhibitors] and [Abnormalities-drug induced]
The UK Teratology Information Service. Accessed via www.toxbase.org
Past enquiries keyword: Proton pump inhibitors, pregnancy.
Clinical expert: Dr P McElhatton. Head of the National Teratology Information Service. November 2007.
In house databases/resources.

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