A large Danish study concluded there is no evidence that common heartburn drugs known as proton-pump inhibitors (PPIs), available both over the counter and on prescription, significantly increase the risk of birth defects when taken in early pregnancy.

However, an epidemiologist warned that despite the thoroughness of the study and its reassuring findings, more research is needed before we can be confident that PPIs are safe to take while pregnant.

Drs Björn Pasternak and Anders Hviid of the Department of Epidemiology Research, Statens Serum Institut, Copenhagen, wrote about their nationwide cohort study that covered over 840,000 live births in Denmark between January 1996 and September 2008, in a paper published in the New England Journal of Medicine, NEJM on 25 November.

Heartburn, or gastroesophageal reflux, is common in pregnancy, but data on the risk of birth defects from use of the most popular PPIs (omeprazole, lansoprazole, and esomeprazole) in early pregnancy is limited, wrote the researchers in their background information.

For their study, which was funded by the Danish Medical Research Council and the Lundbeck Foundation, Pasternak and Hviid used data from nationwide registries to look for links between individual exposure to PPIs (based on prescriptions) and birth defects. From these registries they also extracted recorded data about some other potential causes of birth defects, so they could adjust for these in their analysis.

They did two types of analysis: use of PPIs from 4 weeks before conception until week 12 of gestation, and from week 0 to week 12 of gestation (the first trimester).

The results showed that:

  • Of the 840,968 live births, 2.6% involved major birth defects.

  • 3.4% (174) of the babies whose mothers had taken PPIs between 4 weeks before conception and the end of the first trimester were diagnosed with a major birth defect, as compared with 2.6% (21,811) of the babies whose mothers had not taken PPIs during this time.

  • In analyses that excluded the 4 weeks before conception, 3.2% (118 out of 3651) of the babies whose mothers took PPIs during the first trimester were diagnosed with major birth defects.

  • The adjusted prevalence odds ratio for this last figure was 1.10 (95% CI, 0.91 to 1.34).

  • Futher secondary analyses also showed no significant increase in risk of birth defects tied to exposure to individual PPIs during the first trimester.

  • This was also the case when the analyses only included babies born to women who “had filled PPI prescriptions and received enough doses to have a theoretical chance of first-trimester exposure”.

The authors concluded that:

“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.”

Dr Allen A. Mitchell, director of Slone Epidemiology Center at Boston University Medical Center in the US, wrote an editorial in the same issue of NEJM. He said in a statement that the findings, together with earlier studies based on smaller numbers, were important and provided “some reassurance” about the safety of taking PPIs in pregnancy.

“However, as the authors acknowledge, these data provide only a broad — and incomplete — overview,” he added, and raised a number of concerns.

One of his concerns is that drugs that cause birth defects, called teratogens, tend to raise the risk of specific birth defects, and not defects overall.

Another concern Mitchell raised was that although drugs in the same class, such as PPIs, have similar pharmacologic effects, they may be quite different in the fetus.

Also, even though the Danish study covered a very large population, Mitchell warned that it was still “too small to consider the risks of specific birth defects in relation to specific PPIs, which is what we need to know”.

For example, among the detailed findings was one showing that taking all but one of the PPIs in the 4 weeks before conception, but not during pregnancy, was linked to an increased risk of birth defects: and this needs to be understood, said Mitchell. (The PPI that did not show this link was omeprazole).

And finally, Mitchell said that although the sources used in the Danish study provided rich data, they did not include information on important variables that might influence links between drugs and birth defects, such as why the mothers might be taking the PPIs in the first place, and also they did not include information about exposure to over-the-counter medication, and whether mothers taking PPIs in this form were taking folic acid around the time of conception. A number of studies have shown that taking folic acid reduces the risk of certain birth defects.

Mitchell urged further studies were needed, and stressed that until they are done, “the current findings, although reassuring, must be considered far from definitive”.

“Use of Proton-Pump Inhibitors in Early Pregnancy and the Risk of Birth Defects.”
Björn Pasternak, and Anders Hviid.
N Engl J Med, 2010; 363: 2114-2123, published online 25 November 2010
DOI:10.1056/NEJMoa1002689

“Proton-Pump Inhibitors and Birth Defects — Some Reassurance, but More Needed.”
Allen A. Mitchell.
N Engl J Med, 2010; 363: 2161-2163, published online 25 November 2010
DOI:10.1056/NEJMe1009631

Additional source: Boston University Medical Center.

Written by: Catharine Paddock, PhD