NEWS UPDATE: VOLUME 32 - September 2006

Birth Defects Linked to NSAIDs and SSRIs

Recent reports have linked pregnant women�s use of non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin-reuptake inhibitors (SSRIs) with birth defects and other adverse effects on newborns. Perhaps most alarming is the fact that NSAIDs � some of which are available over the counter � and SSRIs are still commonly taken by pregnant women. 

While previous studies showed inconsistent results about risks associated with taking NSAIDs a nd SSRIs during pregnancy, current results indicate cause for concern: Investigators have shown that babies of women who took NSAIDs during the first trimester had a significantly higher risk of heart defects and other congenital anomalies, and babies born to women taking SSRIs during pregnancy run a higher risk of low birth-weight or of developing respiratory distress.

The more recent findings for NSAIDs, while requiring confirmation with further studies (according to the investigators) have implications for pregnant women who may self-medicate with non-prescription NSAIDs.

NSAIDs are a class of pain-relief drugs that includes over-the counter medications Aleve (naproxen) and Advil (ibuprofen), and prescriptions drugs Celebrex (celecoxib) and Cataflam (diclofenac). SSRIs are a class of antidepressant drugs that includes Prozac (fluoxetine), Zoloft (sertraline) and Paxil (paroxetine).

Read on for a summary of findings by two different teams about the risks of taking NSAIDs or SSRIs during pregnancy

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The limits of safe pharmacotherapy during pregnancy seem to be growing narrower, with recent announcements that drugs from two common drug-classes � non-steroidal anti-inflammatory drugs (NSAIDs) and selective serotonin-reuptake inhibitors (SSRIs) � carry risks to the unborn child and newborn. The findings are significant, because NSAIDs and SSRIs have been deemed relatively safe for use during pregnancy until now.

In recent studies, NSAIDs have been shown to increase the risk of birth defects, particularly the risk of some heart defects, and SSRIs appear to raise the risk of infant low birth-weight and respiratory distress.

NSAIDs in First Trimester Raise Birth-Defects Risk

Women who took NSAIDs during the first trimester of pregnancy had a significantly higher risk of having babies with heart defects and other congenital anomalies, according to a report in August ^1,2.

According to the study�s authors, Benjamin Orfi and colleagues in Canada, the possible risks associated with taking NSAIDS during pregnancy are not highly publicized. They note, "The hazards reported in this study are in accordance with previous findings but need to be replicated in other study populations."

Before the study, strong documentation existed regarding NSAIDs� effects on the fetus in later pregnancy (i.e., NSAIDs are associated with premature closure of the ductus arteriosus and patent ductus arteriosus). However, the risks of NSAID use in early pregnancy were less clearly documented, according to the investigators.

Conduct of Clinical Trial

During the clinical trial, Dr Orfi and colleagues studied 36,387 pregnant women in Quebec province, Canada. Participants who filled prescriptions for NSAIDs early in their pregnancy more then doubled the risk for any congenital defect. Additionally, women who took NSAIDs in the first trimester also more than tripled the risk of congenital abnormalities related to cardiac septal closure � primarily atrial and ventricular septal defects.

Within the study population, 1,056 women filled prescriptions for NSAIDS during the first trimester. Among the infants of these women, the rate of any congenital abnormalities (any abnormality diagnosed within the first 12 months of life) was 8.8%, versus 7% of 35,331 women who took no NSAIDs. Up to ten controls were selected for each case.

To calculate NSAIDs� independent effect on congenital anomalies, Dr Berard and colleagues adjusted for a variety of conditions, including overall health, hypertension, rheumatoid arthritis, hypothyroidism, socioeconomic status and use of other drugs that had potential to cause congenital defects.

The adjusted odds ratio (OR) for any congenital anomaly with NSAID use was 2.2.

The adjusted OR for anomalies related to cardiac septal closure was 3.34.

No significant associations were noted between NSAID use and anomalies of other major organ systems.

NSAID Prescriptions

Among the women who filled NSAID prescriptions, the five most common NSAID drugs (representing 95% of all NSAID prescriptions) were:

• naproxen 35%

• ibuprofen 26%

• rofecoxib 15%

• celecoxib 9%

• diclofenac 9%

Possible Causes of Anomalies

It is possible that birth defects related to NSAIDs may arise from vascular disruptions, Dr Berard reportedly said, based on the relationship between prostaglandins, COX inhibitors and their effects on the vessels and endothelium.

One suggested mechanism for the pathogenic cardiovascular effects involves forces within the growing heart tube, coupled with secondary hemodynamic forces produced by blood-flow through cardiovascular structures, affecting cell behavior, heart muscle mass and vessel and chamber size.

"It is conceivable, that disruptions in the normal resistance of intracardiac blood flow by inhibitors of prostaglandin synthesis could result in congenital anomalies such as ventricular septal defects," the authors wrote.

A Matter of Dose?

The researchers noted one important limitation of the study was whether the women who filled the NSAID prescriptions took high enough doses of the drugs to induce the effect. NSAID agents exhibit threshold phenomena, they wrote, and it was therefore not possible to determine whether doses taken were above a critical threshold.

SSRIs During Pregnancy: Risks of Low Birth-Weight & Respiratory Distress

Women with depression during pregnancy also may have cause for concern: a Canadian study³ has found that babies born to women taking SSRIs during pregnancy may have a higher risk of low birth-weight or of developing respiratory distress.

The effect of SSRIs on neonates has been the subject of controversy since their introduction in 1988. Investigators Dr Tim F Oberlander and colleagues wrote, �Soon after the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants in 1988 and their use to manage mood disorders during pregnancy, studies emerged reporting adverse neonatal effects.

�Some early studies suggested that SSRI use was safe, with little or no risk of adverse outcomes, while others reported neurobehavioral disturbances and increased risks of lower birth weight and preterm birth.�

The noted that, while exposure to SSRI had not been linked with major congenital abnormalities, evidence has emerged concerning a group of symptoms often referred to as "poor neonatal adaptation" and which may include respiratory distress, hypoglycemia, temperature instability and irritability.

"[O]ur study was undertaken to distinguish the effects of maternal mental illness � pregnancy-related depression � from its treatment � SSRIs � on neonatal outcomes," Dr Oberlander reportedly told Reuters Health.

Review of Data

Researchers Dr Oberlander and colleagues, at the University of British Columbia, Vancouver, analyzed population health-data for 119,547 babies born during the period 1998-2001. In total, 14% of mothers in this study population had been diagnosed with depression.

Dr Oberlander and colleagues compared the outcomes of babies born to 1,451 mothers with depression who were treated with SSRIs during pregnancy with outcomes of babies born to 14,234 depressed mothers who did not receive SSRIs.

Compared with babies born to untreated mothers, babies of mothers receiving SSRIs had:

• significantly higher incidence of respiratory distress (13.9% versus 7.8%);

• significantly higher incidence of low birth-weight and gestational age, with a significantly greater percentage of babies born before 37 weeks;

• longer hospital stays.

"These findings are contrary to an expectation that treating depressed mothers with SSRIs during pregnancy would be associated with lessening of the adverse neonatal consequences associated with maternal depression," Dr Oberlander reportedly said.

He concluded, �[W]hile our study may add another cautionary note to the use of SSRI medications during pregnancy, the use of antidepressants must be weighed against the risks of untreated or under-treated disease...and thus the decision should be made by an informed patient with her physician on a case-by-case basis."

Click For More Information On�

• Drug Safety During Pregnancy: SafeFetus, Drugs.com 

• Congenital Cardiac Defects (American Heart Association)

• Respiratory Distress Syndrome (American Lung Association)

• Depression: National Institute of Mental Health, Drugs.com Health Encyclopedia 

• Postpartum Depression: Postpartum Support International, Drugs.com Health Encyclopedia

Sources:

1. NSAIDs During First Trimester Linked to Congenital Defects (CME/CE), MedPage Today, August 24, 2006.

2. Risk of congenital anomalies in pregnant users of non-steroidal anti-inflammatory drugs: a nested case-control study. Benjamin Ofori et al. Birth Defects Research Part B: Developmental and Reproductive Toxicology, published online August 23, 2006.

3. Antidepressants during pregnancy may affect baby, Reuters Health, August 25, 2006.

4. Neonatal Outcomes After Prenatal Exposure to Selective Serotonin Reuptake Inhibitor Antidepressants and Maternal Depression Using Population-Based Linked Health Data. Tim F Oberlander, et al. Archives of General Psychiatry, volume 63, pages 898-906, August 2006.