November 30, 2010 — 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.

Clinical Context

Clinical Implications

• 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.

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