Rheumatologists Should Discuss with Patients Use of Immunomodulatory Agents During Pregnancy

The decision to continue or discontinue immunomodulatory medications during pregnancy is a difficult one for both patients and physicians.
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The decision to continue or discontinue immunomodulatory medications during pregnancy is a difficult one for both patients and physicians. On the one hand, when left untreated, rheumatic conditions can cause harm to an unborn child, as well as to the pregnant mother. On the other hand, medications can be harmful to a developing fetus. In a high percentage of women with rheumatic disease, the decision is often to discontinue treatment during pregnancy, according to results from “Patterns and secular trends in use of immunomodulatory agents during pregnancy in women with rheumatic conditions,” which appeared in Arthritis & Rheumatology in May 2016.¹

Additional findings from the study highlighted the popularity of certain medications for rheumatic conditions. Steroids and hydroxychloroquine were the most frequently used agents in the study population over the 12-year study period. Regardless of the treatment or condition, a significant number of women stopped taking their medication during pregnancy.

“The most important finding of our study is the observation that many women on treatment with immunosuppressive agents prior to their pregnancy actually discontinued treatment during pregnancy,” says lead author Rishi J. Desai, MS, PhD, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston. “The rates of discontinuation were different across conditions, but overall there was the same trend.”

There is no simple answer for women who are being treated medically for rheumatic conditions if they become pregnant, but the key is to talk about options before taking action. “We hope that by highlighting this issue, our study will lead to more rheumatologists having conversations with their patients about the importance of continuing treatment during pregnancy,” Dr. Desai says. “I think it’s important to continue treatment in pregnancy, especially when [the disease is] severe enough to require management with medications prior to pregnancy.”

Pregnancy & Rheumatic Disease

The results from Dr. Desai’s study are comparable to results from previous research that showed steroids are the most commonly used immunomodulatory agents among women with RA from the U.S., the Netherlands and Norway, as well as Canadian women with systemic lupus erythematosus (SLE).

Another similarity between the present study and previous research is that the use of potentially teratogenic nonbiologic agents (i.e., methotrexate, mycophenolate mofetil, leflunomide) was found to be extremely low during pregnancy. This finding is “reassuring,” the researchers say. In contrast with the findings from Dr. Desai and his team, previous European research showed that sulfasalazine, not hydroxychloroquine, was the most commonly used nonbiologic agent during pregnancy in cohorts of women with rheumatoid arthritis (RA).

With regard to safety, in 2013, the ACR put out a news release about research showing that medications used to treat RA may affect abortion rates in women. The European League Against Rheumatism considers the use of steroids to be relatively safe during pregnancy.² Additional research suggests that corticosteroids, hydroxychloroquine and azathioprine are safe to use in pregnancy and are not associated with adverse fetal effects.³

One topic that Dr. Desai would like to see investigated further is the effect of uncontrolled disease activity during pregnancy on various maternal and fetal outcomes. Some research suggests that RA may improve during pregnancy, although postpartum flare-ups are likely.⁴ Another study demonstrated “widespread variability in disease response” among 140 pregnant women with RA.⁵ In this study, 16% of women were in complete remission, having no joints with active disease and no therapy, but there was a statistically significant increase in the mean number of inflamed joints in the postpartum period compared with the findings during pregnancy.

An earlier study also showed symptom improvements in pregnant women with RA and psoriatic arthritis (PsA), but researchers noted that it was rare to see improvement in patients with ankylosing spondylitis (AS) during pregnancy.⁶ The study also indicated that fetal outcomes were not adversely affected by AS, PsA or juvenile RA, but postpartum flares in disease activity were seen in 90% of AS pregnancies, 70% of PsA pregnancies and 50% of juvenile RA pregnancies.

A literature review showed an increase in SLE activity during pregnancy, which they noted raises the risk of poor pregnancy outcomes (e.g., stillbirth, preterm birth, low birth weight, preeclamspsia).⁷ Another review that included 37 studies with 1,842 patients and 2,751 pregnancies showed the following maternal complications: lupus flare (25.6%), hypertension (16.3%), nephritis (16.1%), pre-eclampsia (7.6%) and eclampsia (0.8%).⁸ Fetal complications included spontaneous abortion (16.0%), stillbirth (3.6%), neonatal deaths (2.5%) and intrauterine growth retardation (12.7%). Further, the unsuccessful pregnancy rate was 23.4%, and the premature birth rate was 39.4%.

Study Overview

Because a small amount of empirical data exists on the patterns of use for immunomodulatory agents during pregnancy, Dr. Desai and his team designed their study to examine treatment changes at various stages of pregnancy. They included 2,645 pregnant women with SLE, RA, PsA or AS who were being treated with immunomodulatory agents prior to their pregnancies. Additional evaluation was performed to determine secular trends in the use of these agents during pregnancy in the cohort between 2001 and 2012.

Data were obtained from two insurance databases for two time periods: Medicaid (2001–2010) and a private insurance database (2004–2012). Women ages 12–55 were included if their pregnancies were completed and resulted in liveborn infants, if they had a recorded diagnosis of RA, SLE, AS or PsA and had filled at least one outpatient prescription for an immunomodulatory agent three months before the date of their last menstrual period. On the basis of the date on which the prescription was filled, the researchers classified use into one of three trimesters.

The sharp rise seen in the use of biologic agents during pregnancy highlights the need for continuing research evaluating the safety of biologic agents in terms of their effects on various maternal & fetal outcomes.

For the time trend analysis, the researchers aggregated usage data at any time in pregnancy at the class level annually for all nonbiologic disease-modifying agents (except hydroxychloroquine) and for all biologic agents. The researchers thought it was important to separate out hydroxychloroquine for the time trend analysis because “it is actually the preferred agent during pregnancy for rheumatic conditions, and for good reasons,” Dr. Desai says. He cited a large cohort study published in 20069 that showed “taking hydroxychloroquine didn’t result in any significant increases in fetal abnormalities or any risk to the fetus.”

In Dr. Desai’s study, women were split into subgroups by disease: SLE, RA and PsA or AS (but not more than one condition). Results from the analysis indicated the following for each group:

• SLE—Women took steroids (64.1%) and hydroxychloroquine (60.9%) most frequently; 26% stopped filling prescriptions for these agents during pregnancy;
• RA—The most common therapies were steroids (60.4%), hydroxychloroquine (19.5%), etanercept (17.0%), methotrexate (14.9%) and adalimumab (8.1%); 34.5% did not fill a prescription for an immunomodulatory agent during pregnancy; and
• PsA or AS—The most common therapies were steroids (73.0%) and etanercept (16.0%); 61% stopped treatment with immunomodulatory agents during pregnancy.

Steroids and hydroxychloroquine were the most commonly used immunomodulatory agents during pregnancy over the 12-year study period (2001–2012); however, declining trends in the use of steroids were observed over time and there was an increasing trend in the use of biologic agents. The reason for this is likely “a combination of a few things,” Dr. Desai says.

“Steroids are associated with the risk of increased gestational maladies, including gestational diabetes and potentially hypertension, if used in pregnancy. Combined with safety data on other agents (such as hydroxychloroquine) and the availability of other biologic agents that physicians are more comfortable prescribing, it’s expected the use of steroids will decrease even further.”

Regarding the concurrent increase in the use of biologic agents, Dr. Desai added, “With the number of different options available to practicing rheumatologists today compared with 10 years ago, it makes complete sense that it would show an increasing trend.”

Implications

According to Dr. Desai and his team, their results—a decreased use of steroids and nonbiologic agents other than hydroxychloroquine and an increase in the use of biologic agents during pregnancy—may reflect similar trends in the general population.¹⁰ The findings may also suggest that with more research showing the absence of a major fetal adverse event after use of biologic agents in pregnancy, physicians seem to be becoming more comfortable with patients continuing treatment with these agents during pregnancy.¹¹

The sharp rise seen in the use of biologic agents during pregnancy highlights the need for continuing research evaluating the safety of biologic agents in terms of their effects on various maternal and fetal outcomes. Because many women discontinue immunomodulatory treatments during pregnancy, future research should also evaluate the impact of untreated active disease on fetal or maternal health.

“It’s definitely challenging to decide to continue or stop [taking medication during pregnancy], especially since there are no definitive data for fetal safety on most of these agents. This is because the conditions themselves are relatively infrequent in women of reproductive age and treatments are used by even fewer patients during pregnancy, so it’s difficult to design an adequately powered study to draw definitive conclusions regarding safety of these agents,” Dr. Desai says. “It’s a fine balance to keep disease activity in control and [minimize] fetal risk if you keep taking the medication. But at least there should be some clinical discussion around this issue rather than completely stopping out of fear because actually not taking the medication can put the baby into harm’s way even more than to keep taking it.”

To further the conversation about management of pregnant and lactating women with autoimmune disease, the ACR held a Reproductive Health Summit in 2014. The ACR also has an information page on its website regarding pregnancy and rheumatic disease, recommending that women ensure their disease is controlled for three to six months before attempting pregnancy.

Increasing the communication about medications and pregnancy is important, Dr. Desai says. “There was an interesting UK study that showed only about 65% of practicing rheumatologists reported always offering counseling regarding DMARD use during pregnancy,” he says.¹² “This is suboptimal, obviously. Every patient who comes in with these conditions and who is on treatment, they have to be counseled on the risks [of discontinuing treatment] to make sure the decision has a clinical rationale and is not completely driven by fear.”

Kimberly J. Retzlaff is a freelance medical journalist based in Denver.

References

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