Exposure to proton-pump inhibitors (PPIs) during the month before conception, but not during the first trimester, is associated with a significantly increased risk for major birth defects, according to the results of a large cohort study reported in the November 25 issue of the New England Journal of Medicine.
"Symptoms of gastroesophageal reflux are common in pregnancy, but there are limited data on the risk of birth defects associated with exposure to ...PPIs in early pregnancy," write Björn Pasternak, MD, PhD, and Anders Hviid, DrMedSci, from Statens Serum Institut in Copenhagen, Denmark. "We conducted a cohort study to assess the association between exposure to PPIs during pregnancy and the risk of major birth defects among all infants born alive in Denmark between January 1996 and September 2008."
Using nationwide registries, the investigators linked individual-level data on exposure to PPIs on the basis of prescriptions, birth defects, and potential confounders. The standardized classification scheme of the European surveillance of congenital anomalies (EUROCAT) was used to categorize major birth defects diagnosed within the first year of life. Primary analyses determined PPI use from 4 weeks before conception through 12 weeks of gestation and in the first trimester (from 0 through 12 gestational weeks).
PPI exposure between 4 weeks before conception and the end of the first trimester occurred in 5082 of 840,968 live births, including 174 (3.4%) with major birth defects. In the group whose mothers had not been exposed to PPIs during this period, there were 21,811 major birth defects (2.6%; adjusted prevalence odds ratio [OR], 1.23; 95% confidence interval [CI], 1.05 - 1.44).
In analyses of PPI exposure only during the first trimester, 118 (3.2%) of 3651 exposed infants had major birth defects (adjusted prevalence OR, 1.10; 95% CI, 0.91 - 1.34), which was not a significant association. However, women who were exposed to PPIs within 4 weeks before conception were at significantly increased risk of having offspring with major birth defects (adjusted prevalence OR, 1.39; 95% CI, 1.10 - 1.76).
"The risk of birth defects was not significantly increased in secondary analyses of exposure to individual PPIs during the first trimester or in analyses limited to the offspring of women who had filled PPI prescriptions and received enough doses to have a theoretical chance of first-trimester exposure," the study authors write. "In this large cohort, exposure to PPIs during the first trimester of pregnancy was not associated with a significantly increased risk of major birth defects."
Limitations of this study include possible misclassification of the timing of exposure or of identification of birth defects, possible unmeasured confounding or chance findings of the observed association between exposure to PPIs within the month before conception and major birth defects, and limited power to detect associations with individual defects.
In an accompanying editorial, Allen A. Mitchell, MD, from the Slone Epidemiology Center at Boston University in Boston, Massachusetts, cautions that although this study provides some reassurance regarding the safety of PPIs in pregnancy, more data are needed.
"First, the PPIs most commonly represented in the study do not appear to carry major teratogenic risks when they are taken during the first trimester or later in pregnancy," Dr. Mitchell writes. "Second, the modestly increased risk during the period before conception that was observed with PPIs as a group was not seen with omeprazole. Until we have a better understanding of what might explain this latter finding, it may be prudent to consider omeprazole to be the PPI of choice when PPI treatment is clearly needed for women of childbearing potential and particularly for those who are planning to become pregnant."
The Danish Medical Research Council and the Lundbeck Foundation supported this study. Disclosure forms provided by the authors and editorialist are available with the full text of this article at the NEJM Web site .
N Engl J Med. 2010; 363:2114-2123, 2161-2163.
Symptoms of gastroesophageal reflux are common among pregnant women in the first trimester. PPIs are the most efficacious treatment, but omeprazole is classified as a class C drug in pregnancy, and the other PPIs are classified as class B drugs.
This is a nationwide, registry-based cohort study to assess the association between PPI use in the first trimester of pregnancy and the risk for major birth defects.
- The study used data from the Medical Birth Register, the Prescription Drug Register, the National Patient Register, the Central Person Register, and Statistics Denmark.
- A cohort of live-born infants was identified in the Medical Birth Register from 1996 through 2008.
- PPIs were prescription-only drugs during most of the period covered, until omeprazole became available as an over-the counter drug in 2006 and lansoprazole, in 2007.
- The PPIs examined included omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole.
- Cases of birth defects were identified with the use of the National Patient Register.
- The overall predictive value of the register for birth defects was estimated at 88%.
- Major birth defects were defined according to the EUROCAT classification for subgroups of congenital anomalies.
- Minor anomalies were excluded.
- Confounders that were examined included birth year, maternal age, education, smoking status, parity, medical conditions, and use of other medications.
- The cohort of women with exposure during pregnancy was divided into women who had filled PPI prescriptions in the 4-week period before conception and those who had filled prescriptions during the first trimester, defined as the first 12 weeks of gestation.
- Secondary analyses examined birth defects according to organ system (13 groups) and risk by type of PPI (5 types).
- There were 840,968 live births, including 34,925 multiple births.
- Overall, 21,985 cases of major birth defects were diagnosed during the first year of life (2.6%).
- Prevalence of PPI use increased with time, with omeprazole being the most commonly used.
- Exposure peaked between 2005 and 2008 at 2%, and exposure during the first trimester was approximately 0.7%.
- 174 (3.4%) of infants whose mothers were exposed to PPIs at any time between 4 weeks before and 12 weeks after conception had a major birth defect vs 2.6% in the unexposed group.
- The adjusted prevalence OR for risk was 1.23 (95% CI, 1.05 - 1.44).
- 3.2% of infants exposed to PPIs during the first trimester vs 2.6% in the unexposed group had a major birth defect (adjusted prevalence OR, 1.10; 95% CI, 0.91 - 1.34).
- Women exposed to PPIs in the 4 weeks before conception were at significantly increased risk for offspring with major birth defects (adjusted prevalence OR, 1.39; 95% CI, 1.10 - 1.76).
- There was no significant association of any specific PPIs with the risk for birth defects during the first trimester.
- There was no increased risk for major defects for any specific organ system.
- Lansoprazole was the only PPI for which exposure in the 4 weeks before conception was associated with an increased risk for birth defects.
- Subgroup analysis by organ defects showed no significant risk for particular organ defects by exposure.
- The authors concluded that, overall, exposure to PPIs during the first trimester of pregnancy was not associated with an increased risk for major birth defects.
- Use of PPIs in the first trimester of pregnancy is not associated with an increased risk for major birth defects.
- In the first trimester of pregnancy, there is no significant association of the use of any specific PPIs with the risk for birth defects, and there is no increased risk for major defects of any specific organ system.