Doctors prescribing PPIs to pregnant women with reflux can be reassured about their safety.
The use of proton pump inhibitors during early pregnancy is not associated with a substantial increase in the risk of congenital malformations, researchers have found.
That is the reassuring conclusion of results from the large cohort study that included almost 2.7 million pregnancies in South Korea over an eight-year period, recently published in the JAMA Network Open.
The findings have been welcomed by University of Melbourne Clinical Associate Professor Alex Polyakov, who said he would be “comfortable” prescribing PPIs to pregnant women.
“This sort of study is as good as it gets,” the reproductive expert said.
The population-based cohort South Korean study examined data from 2.69 million pregnancies and live-born infants, looking at primary adverse outcomes such as major congenital malformations, congenital heart defects, cleft palate, hydrocephalus and hypospadias.
The researchers identified 40,540 pregnancies that were exposed to PPIs during the first trimester. They found the absolute risk of major congenital malformations was 397 per 10,000 infants in PPI-exposed pregnancies and 323 per 10,000 infants in unexposed pregnancies.
“The use of PPIs during early pregnancy was not associated with a substantial increase in the risk of congenital malformations, although small increased risks were observed for major congenital malformations and congenital heart defects; findings from sibling-controlled analyses revealed that PPIs were unlikely to be major teratogens,” the authors concluded.
“These findings may help guide clinicians and patients in decision-making about PPI use in the first trimester.”
Professor Polyakov, who is also a consultant at Melbourne’s Royal Women’s Hospital, said the sibling analysis the researchers undertook to account for potential confounding from family related factors was particularly interesting. The researchers identified 16,730 women who had more than one child and had used PPIs during one pregnancy but not another.
“That didn’t show any difference and I think that is very, very reassuring,” said Professor Polyakov.
Gastroesophageal reflux disease was common during pregnancy, occurring in up to 80% of the pregnant population, the researchers reported.
“Although mild symptoms can be alleviated by lifestyle modifications, acid-suppressive medications are often required for a substantial number of patients to manage their inadequately controlled symptoms,” they wrote. “Specifically, the use of proton pump inhibitors (PPIs) during pregnancy has increased worldwide.”
Despite this broad use, the available evidence on their safety during pregnancy remained inconsistent, the authors wrote. This was the basis for their study.
“While earlier studies reported no associations between PPI use and major congenital malformations, several studies published within the past decade have found increased risk, particularly for congenital heart defects, cleft palate, hydrocephalus and hypospadias,” they wrote.
“Accordingly, the latest meta-analysis, which included the previous studies, reported that PPI use during pregnancy was associated with a 28% increase in the risk of overall malformations. However, with respect to the quality of evidence, considerable uncertainties remain because previous studies had important methodological limitations, such as small sample size, inadequate adjustment of confounders, recall bias from self-reports, and exposure misclassification bias (e.g., PPIs are available over the counter in many countries).
“Moreover, to our knowledge, no existing studies have accounted for genetic or familial factors in the association between prenatal PPI exposure and congenital malformations. Given this conflicting evidence and the knowledge gaps among previous studies, the decision for clinicians and pregnant women to use PPIs during pregnancy remains in a grey area.”
In Australia, the use of PPIs in pregnancy carries a B3 category according to the TGA’s Prescribing Medicines in Pregnancy Database, which includes “drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans.”
Professor Polyakov said there was little difference between categories B1, B2, and B3, and it was unlikely that the categorisation would change on the basis of this study.
However, he said PPIs were generally considered very safe in pregnancy, and this research confirmed this.
“They have such a robust collection of data so this is very reliable,” he said.
“But it is important to remember that PPIs are not a first line treatment for reflux.”
He said over-the-counter medications like Mylanta and Gaviscon were usually recommended first, “but they have their own risks, anything you give during pregnancy has some risk”.
“If required, it is totally acceptable to take PPIs during pregnancy,” he said.
“The increased risk, if it’s there at all, is very, very small.”
