Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study.

According to a new publication recently published in the British Medical Journal (BMJ), by Dr. DeKun Li, use of NSAIDs and aspirin during pregnancy increased the risk of miscarriage. However, Dr. Li does caution that these findings need further confirmation in studies designed specifically to examine the apparent association. Dr. Li is a research scientist at Kaiser Permanente’s Division of Research located in Oakland, California.

The study objective was to evaluate whether prenatal use of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with increased risk of miscarriage. The population based cohort study, ascertained prenatal use of NSAIDs, aspirin, and acetaminophen (paracetamol) by in-person interview. The study subjects were sampled from the Kaiser Permanente Medical Care Program, a healthcare delivery system, in the San Francisco area of the United States. Participants included 1055 pregnant women who were recruited and interviewed immediately after their positive pregnancy test. The median gestational age at entry to the study was 40 days.

Pregnancy outcomes up to 20 weeks of gestation were the main outcome measure. The study results indicated that 53 women (5%) reported prenatal NSAID use around conception or during pregnancy. After adjustment for potential confounders, prenatal NSAID use was associated with an 80% increased risk of miscarriage (adjusted hazard ratio 1.8 (95% confidence interval 1.0 to 3.2)). The association was stronger if the initial NSAID use was around the time of conception or if NSAID use lasted more than a week. Prenatal aspirin use was similarly associated with an increased risk of miscarriage. However, prenatal use of acetaminophen (paracetamol), pharmacologically different from NSAIDs and aspirin, was not associated with increased risk of miscarriage regardless of timing and duration of use.

In sum, and as noted above, prenatal use of NSAIDs and aspirin increased the risk of miscarriage. However, these findings need further confirmation in studies designed specifically to examine the apparent association.

Li DK, Liu L, Odouli R. Exposure to non-steroidal anti-inflammatory drugs during pregnancy and risk of miscarriage: population based cohort study. BMJ. 2003 Aug 16;327(7411):368.

Frequently asked Questions regarding NSAID use and Risk of Miscarriage
By DeKun Li

What was the key finding of your study?

--That use of NSAIDs increased risk of miscarriage. The highest risk comes at the time of conception, when the effect is five times higher than later in pregnancy.
----The overall risk is 80%; a woman stands an 80% risk of miscarriage if she uses NSAIDs early in her pregnancy.
--Use of acetaminophen does not increase the risk of miscarriage.

What’s new about this study? Hasn’t the link between NSAID use and infertility been demonstrated before?

This is the first large prospective study in humans of a direct link between the use of these drugs and miscarriage. There was only one previous study, and that showed a tentative link between NSAID use and miscarriage. However, this is the first study to show the importance of timing of use (around the time of conception) and dose-response relationship (use of more than a week). In this study, we followed more than a thousand women from the time of their pregnancy test to the outcome of their pregnancy and found that those who used NSAIDs were 80% more likely than those who did not use NSAIDs to lose a pregnancy.

Why do NSAIDS cause miscarriage?

NSAIDs inhibit production of the body’s prostaglandins, which is why they kill pain. Prostaglandins are also needed to maintain a successful pregnancy, especially during implantation (immediately after conception). Although the process is not completely understood, the underlying reason is that NSAIDs’ effect on prostaglandins also affects a woman’s ability to sustain a successful pregnancy..

Is there a safe dosage level?

We did not directly look at specific dosage levels in this study. However, our data did show that most of the risk was associated with use for more than one week. The use for less than week around the time of conception remained risky. I am beginning a follow up study in which the dose issue will be examined more thoughly.

What’s the difference between NSAIDs and acetaminophen?

NSAIDs and acetaminophen are chemically different, and therefore, they have different pharmacological effects. The most notable difference is the targeted organ systems. Acetaminophen only inhibits the production of prostaglandins in the central nervous system (i.e., brain). However, NSAIDs inhibit the production of prostangladins in all organ systems including the uterus.

Are the new class of NSAIDs (so called Cox-2 inhibitors) such as celecoxib, rofecoxib, valdecoxib safer because they are supposed to have fewer side effects with regard to bleeding?

We did not have women reporting use of those new class of NSAIDs in our study. However, Cox-2 inhibitors are classified by FDA as Pregnancy Category C (generally should be avoided during pregnancy unless benefits outweigh the risk) due to their causing fetal losses and reducing embryo/fetal survival in animal studies. In fact, those animal studies further corroborate our findings on the old class of NSAIDs.

What would you tell a woman who is trying to be pregnant or is already pregnant to do if she has pain for which she’d normally take ibuprofen or aspirin?

She should talk to her doctor about which drugs she can safely use and to see if switching to acetaminophen is a viable alternative choice.

Maureen.McInaney@kp.org