Immune-suppressing Drugs May Not Harm Fetuses

Taking the drugs in early pregnancy may pose less risk than previously thought.

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Taking medications for autoimmune conditions – including inflammatory types of arthritis, connective tissue disorders and inflammatory bowel disease – during the first trimester of pregnancy does not appear to put a fetus at greatly increased risk of a bad outcome, according to Vanderbilt University researchers. Their 2013 study, published online in Arthritis & Rheumatism recently, is one of the first to describe the effects of immunosuppressive drugs on a developing fetus.

“Autoimmune conditions [such as rheumatoid arthritis and lupus] affect millions of women in the United States, including many women of childbearing age. Yet we have very limited data to guide women and healthcare providers about whether to continue immunosuppressive medications during pregnancy,” explains lead author William Cooper, MD, professor of pediatrics and of health policy at Vanderbilt University School of Medicine in Nashville, Tenn.

Currently, women of childbearing age may be counseled to use one or two types of birth control while on certain medications. Those wishing to have a child are told to stop taking certain drugs and to go through a “wash out” period, so that the medication can flush out of their system before they become pregnant.

But Dr. Cooper points out, “Up to 50 percent of pregnancies are unplanned and women may become pregnant while taking a potentially harmful drug.”

Because clinical trials of medications are rarely, if ever, performed on pregnant women, most of the available information comes from animal studies or case reports. To obtain more definitive data, Dr. Cooper and colleagues conducted an observational study using statistics from three large health plans – Tennessee Medicaid, Kaiser Permanente Northern California and Kaiser Permanente Southern California. Together, the plans cover more than 8 million people each year.

A total of 608 mothers and their infants were included in the study. Although the women were economically, racially and geographically diverse, all had an autoimmune condition, such as RA, lupus or scleroderma, and all had been treated with an immunosuppressive drug before or during pregnancy. Prescribed medications included methotrexate (Rheumatrex, Trexall), hydroxychloroquine (Plaquenil), sulfasalazine (Azulfidine, Sulfazine), azathioprine (Azasan, Imuran), corticosteroids and tumor necrosis factor (TNF) inhibitors (Humira, Enbrel, Remicade and Cimzia).

Of the women studied, 402 took an immunosuppressive medication in the first trimester, when fetuses are thought to be most vulnerable to its effects, and 35 used medication only in the second and third trimesters. The remaining 171 mothers used immunosuppressive drugs before becoming pregnant but not after.

Among the more than 600 pregnancies, there were a total of 68 adverse outcomes. Twenty-five infants had serious birth defects (such as cleft palate or club foot), 33 had life-threatening complications and there were 10 fetal deaths. (The infants were followed through the first three months of life – the period when most neonatal deaths occur and the majority of birth defects are diagnosed.)

Surprisingly, researchers found no statistically significant difference in outcomes for women treated with immunosuppressive drugs in the first trimester compared with those treated before becoming pregnant. (Because some autoimmune diseases can themselves increase the risk of birth abnormalities, healthy women were not used for comparison).

Of particular note were the findings on methotrexate, which the U.S. Food and Drug Administration identifies as a category X medication, meaning it can cause birth defects and fetal death. Yet the Vanderbilt researchers found that of 23 infants exposed to methotrexate in the first trimester, only one developed a birth defect, and it was a type not normally associated with the drug.

Dr. Cooper points out that most reports linking methotrexate with birth defects looked at higher doses, typically used in cancer treatment rather than the lower doses used to treat RA. Still, he stresses that his research doesn’t prove that methotrexate is safe.

One problem is the relatively small size of the study. Small studies often fail to find significant effects that a larger study would have detected. Yet Dr. Cooper believes the findings do provide “a critical piece of information to help guide women and their doctors.”

“Some of the medications in our study are recently approved and haven’t been extensively studied for use in pregnancy, although they are increasingly used and heavily marketed,” he says, referring to TNF inhibitors. “We thought it was important to take a look at them. …As we move forward, it will be important to do larger studies that provide more information.”

For now, he says each case is unique and women with autoimmune conditions should work closely with their health care providers to decide the best course of action to ensure optimal health outcomes for themselves and their babies. 

John M. Davis III, MD, a rheumatologist at Mayo Clinic in Rochester, Minn., adds a similar note of caution.

“Although it’s reassuring that the authors didn’t find evidence of a large increase in adverse fetal outcomes from first trimester exposure to immunosuppressive medications, the study had a low rate of events, which limits the power of this study to detect small but potentially meaningful increases in risk. As the authors acknowledge, further studies of a larger sample size are needed. But in the meantime, this information should be useful to women and their physicians in discussing the risks and benefits of immunosuppressive therapy before and during pregnancy.”

Alana Levine, MD, a rheumatologist with the Barbara Volcker Center for Women and Rheumatic Diseases at Hospital for Special Surgery in New York, is more optimistic, saying, “The results of this study are reassuring, particularly for those women who become inadvertently pregnant while taking these immunosuppressive medications. Now we may be able to allay the fear that early fetal exposure to some of these medications, particularly methotrexate, is as harmful as we currently believe.”

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