Q&A 112.5
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
Date prepared: April 2014
SummaryMost 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 documenting1,530 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 concernthis 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) orcontraindicate 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).
AnswerOmeprazole
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 prevalenceof 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).
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.
Ameta-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 75cases 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 57healthy babies and two 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). The FDA has classified esomeprazole as a class C risk (limited safety data therefore should only be given if the potential benefit justifies the potential risk to the fetus) (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). UKTIS 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 53live 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 followingtreatment 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).
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 states there are no adequate data from the use of pantoprazole in pregnant women. Studies in animals have shown reproductive toxicity but the potential risk for humans is unknown and pantoprazole should not be used during pregnancy (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 exposureduring pregnancy was unknown in the remaining case; the outcome in this case was a livebirth with neonatal problems which spontaneously resolved and were deemed unrelated topantoprazole 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
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