RA Risks in Pregnancy May Run Both Ways

It stands to reason that treating a woman with disease-modifying antirheumatic drugs (DMARDs) for her rheumatoid arthritis (RA) might endanger her pregnancy, given the well-known risks with methotrexate and the fact that DMARDs can cross the placenta. Long-term results are lacking to support that supposition, but many smaller studies do, and new evidence suggests that even methotrexate treatment of the prospective father does not pose a clear risk to the fetus.

That said, a recent study addresses a related question: Poor fetal outcomes more clearly pose an RA risk for the new mother. At the very least, this research raises some interesting questions.

Biologics’ Effects on Babies

Hundreds of pregnancy studies among women with inflammatory arthritis suggest that exposure to biologic DMARDs such as tumor-necrosis alpha (TNF-α) inhibitors at the time of conception or during their first trimester, does not appear to increase the risk for negative pregnancy or fetal outcomes, according to a recent review from the UK published in Rheumatology.¹

Monoclonal antibodies (and, to a lesser extent, recombinant fusion proteins) from new biologics do cross the placenta during the second and third trimesters, enter into fetal circulation and become functional in the fetus, the review notes. The longer-term effects of this in utero exposure to biologics remain unknown.

The UK review concedes that data are extremely limited regarding pregnancy outcomes for women exposed to biologic DMARDs, including anakinra, abatacept and tocilizumab. The limited data that do exist do not suggest adverse pregnancy outcomes when male partners were exposed to anti-TNF therapies or rituximab at the time of conception.

The authors note that most women discontinue biologics during the first trimester. But it's how often that was a rheumatologist's recommendation or the patient's own decision.

Taking the recombinant human interleukin-6 (IL-6) antagonist anakinra is not recommended during pregnancy, but there’s no advice as to when a women should suspend treatment if she hopes to become pregnant. The review cites manufacturers’ cessation guidelines suggesting at least 14 weeks prior to conception for abatacept, and between 3 months (tocilizumab) to 12 months (rituximab) prior to pregnancy for other biologics.

TNF inhibitors are known to increase the risk of infections, and Listeria monoctyogenes infections can cause pregnancy loss and neonatal deaths, so the recommendations include guidance on food safety to avoid Listeria.

Dads Exposed to MTX

The traditional DMARD methotrexate (MTX) is contraindicated for women during pregnancy, since it’s associated with specific fetal malformations.

But there’s uncertainty about the risk of paternal exposure to low-dose MTX.

A prospective observational cohort study from Germany compared pregnancies fathered by men treated with low-dose MTX around the time of conception (n=113) with non-exposed pregnancies (n=412) and found no apparent increased risk of either major birth defects or spontaneous abortion (SAB). Nor did gestational age at delivery or birth weights differ significantly between the groups according to the study, also published in Rheumatology.²

The rate of electively terminated pregnancies was increased in the MTX-exposed patients compared with controls.

The authors say their findings do not support the necessity of a 3-month MTX-free interval for men until conception. In the case of “unavoidable paternal MTX therapy, it seems reasonable not to postpone family planning,” they add.

Microchimerism -- not medication

Perhaps the most provocative question is whether certain adverse pregnancy outcomes increase a woman’s risk of developing RA in the first place.

It’s well-known that autoimmune disease can alter pregnancy and reproductive outcomes. For example, preexisting RA often improves during pregnancy. But researchers at the University of Washington in Seattle suggest that poor pregnancy outcomes, such as having a very low birthweight (VLB) baby or a preterm birth (PTB), may somehow affect maternal risk for future RA.³

They conducted a prospective study of newly-diagnosed RA cases among women who had given birth (n=202) comparing them with age-matched controls (n=1,102) who had received prenatal care in a local healthcare system.

Analyzing 2,488 pregnancy episodes, they found that women who delivered an extremely small baby had a greater risk of developing RA down the line, compared to those with uncomplicated pregnancies.

Specifically, having a VLB (a baby weighing under 2500 grams) or an extremely low birthweight infant (ELBW, 1000 grams or less) were linked to three to five-fold greater risk for developing RA, especially rheumatoid-factor (RF) positive RA.

While prior LBW and ELBW pregnancies were more common among RA cases than among controls, neither outcome from an earlier pregnancy could be correlated with the risk for later disease.

PTB and small for gestational age (SGA) babies were not associated with an increased risk for subsequent RA. In fact, there were greater numbers of SGA babies in the control group.

The authors speculate that that RA and pregnancy complications may share risk factors and possibly pathophysiology. “The complexity of the relationship between RA and reproduction suggests that risk may be conferred during pregnancy,” or “complicated pregnancy itself may confer risk for subsequent RA,” they wrote in Arthritis and Rheumatism in late December.

Recent research indicates that “microchimerism” created by the passage of fetal cells into the mother’s circulation during pregnancy, to persist there for as long as 20 years, increase the risk for autoimmune diseases, including RA.

Interestingly, fetal microchimerism has been associated with adverse pregnancy outcomes such as preeclampsia, preterm delivery, and fetal growth restriction, the authors note. Previous studies have also suggested that severe nausea and vomiting during pregnancy (hyperemesis gravidarum), preeclampsia, and gestational hypertension are associated with subsequent development of RA.

The University of Washington study relied on patient recall, and some data were missing. Still, further research into the intriguing links between adverse pregnancy outcomes and RA may offer new insights into the origins of the disease.

References:

Hyrich KL and  Verstappen SMM. Biologic therapies and pregnancy: the story so far. Rheumatology (2013) doi: 10.1093/rheumatology/ket409 First published online: December 17, 2013.

Weber-Schoendorfer C, Hoeltzenbein M, Wacker E et al. No evidence for an increased risk of adverse pregnancy outcome after paternal low-dose methotrexate: an observational cohort study. Rheumatology (2013) doi: 10.1093/rheumatology/ket390 First published online: December 24, 2013.

Ma KK, Nelson JL, Dugowson CE, Gammill HS. Adverse pregnancy outcomes and risk of subsequent rheumatoid arthritis. Arthritis & Rheumatism. Accepted article, Dec 23, 2013. DOI: 10.1002/art.38247.