Rare Birth Defects Linked to Prenatal Pain Medication Use

Allison Shelley

March 23, 2012

March 23, 2012 — Prenatal use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with a small-to-moderate increased risk for a wide range of birth defects, report investigators.

"The use of nonsteroidal anti-inflammatory drugs in early pregnancy does not appear to be a major risk factor for birth defects," although there were a few moderate associations between the drugs and specific birth defects, warn the researchers, led by Rohini Hernandez, PhD, from the Center for Birth Defects Research and Prevention at the Massachusetts Department of Public Health in Boston.

Pain relievers that were problematic in some cases included ibuprofen, aspirin, and naproxen. Use of these medications was associated to a greater or lesser degree with the risk for oral clefts, neural tube defects, anophthalmia, microphthalmia, pulmonary valve stenosis, amniotic band syndrome, limb body wall defects, and transverse limb deficiencies.

The work is published in the March issue of the American Journal of Obstetrics and Gynecology.

Data were from the National Birth Defects Prevention Study, a multisite population-based, case-control study of risk factors for birth defects. The work is funded by the Centers for Disease Control and Prevention (CDC).

There were 3173 women receiving NSAIDs and another 1452 who reported taking them as needed. This represents 23% of women taking NSAIDs in the first trimester of pregnancy.

Of the 29 birth defect groups examined, most were not associated with anti-inflammatory use. However, for 9 defect types there was an elevated risk.

Adjusted Odds Ratios of Birth Defects

Birth Defect Aspirin Ibuprofen Naproxen
Anencephaly or craniorachischisis 2.0 (1.0 - 3.9) 1.3 (0.85 - 2.0) 0.84 (0.30 - 2.3)
Spina bifida 1.6 (0.93 - 2.7) 1.6 (1.2 - 2.1) 0.77 (0.35 - 1.7)
Encephalocele 2.1 (0.75 - 6.1) 1.2 (0.58 - 2.5) 2.5 (0.89 - 7.3)
Anophthalmia or microphthalmia 3.0 (1.3 - 7.3) 1.9 (1.1 - 3.3) 2.8 (1.1 - 7.3)
Cleft lip 1.1 (0.72 - 1.7) 1.3 (1.1 - 1.6) 1.7 (1.1 - 2.5)
Cleft palate 1.8 (1.1 - 2.9) 1.3 (0.99 - 1.7) 1.4 (0.84 - 2.5)
Transverse limb deficiency 1.2 (0.58 - 2.5) 1.3 (0.88 - 1.9) 2.0 (1.0 - 3.8)
Amniotic bands or limb body wall 2.5 (1.1 - 5.6) 2.2 (1.4 - 3.5) 1.6 (0.55 - 4.4)
Isolated pulmonary valve stenosis 1.1 (0.47 - 2.6) 1.3 (0.91 - 1.9) 2.4 (1.3 - 4.5)

Values in parentheses are 95% confidence intervals.

The authors suggest that further studies with detailed data on timing, frequency, dose, and indications are necessary.

Asked by Medscape Medical News to comment on the findings, Gideon Koren, MD, director of the Motherisk Program at the Hospital for Sick Children in Toronto, Ontario, Canada, said this is a large case-control study analyzed by "an outstanding" group.

"Clinicians should be careful not to discontinue nonsteroidal anti-inflammatory drugs in women who need them during pregnancy," he emphasized, pointing out the risks appear to be moderate and must be carefully weighed against the benefits of treatment. "These results concur with other studies, and empower women who need these medications in pregnancy to use them," Dr. Koren said.

Similar Results

Another population-based study conducted by the CDC last year and reported by   Medscape Medical News at the time found that opioid use just before conception or early in pregnancy is linked to birth defects, including hypoplastic left heart syndrome.

"It's important to acknowledge that although there is an increased risk for some types of major birth defects from an exposure to opioid analgesics, that absolute risk for any individual woman is relatively modest," lead investigator Cheryl Broussard, PhD, from the CDC's National Center on Birth Defects and Developmental Disabilities, said in a news release when the study was published online in the American Journal of Obstetrics and Gynecology.

Dr. Broussard declined to comment on these new findings but issued a statement to Medscape Medical News.

"Women should be advised to limit their use to medications that are essential. When prescribing and considering potential adverse effects of any medication, remember to include reproductive effects — the potential teratogenic effects of medications and the dose needed for effective treatment are especially important to consider for women who are pregnant or who are planning to become pregnant."

An estimated 50% of US pregnancies are unplanned, so Dr. Broussard's team says it's important to discuss the potential pregnancy risks associated with medication use with all women of reproductive age who require treatment with medications, including over-the-counter medications.

"The product label, which is used in the Physicians' Desk Reference, is not routinely updated after a drug is marketed and may not contain the most recent information," Dr. Broussard noted. Online subscription services, such as the Teratogen Information System and REPROTOX, an information system developed by the Reproductive Toxicology Center for its members, are available for a fee.

Physicians can also call the Organization of Teratology Information Specialists at 1-866-626-6847 to discuss the effects of certain medications in pregnancy.

The National Birth Defects Prevention Study is funded by the CDC. Dr. Hernandez is now an employee of Amgen; however, the work on this study was conducted before she was hired and Amgen does not manufacture any of the drugs examined in the study. The other authors and commentators have disclosed no relevant financial relationships.

Am J Obstet Gynecol. 2012;206:228.e1-8. Abstract

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