Are TNF Inhibitors Safe in Pregnancy?

The ethical constraints that prevent inclusion of pregnant women in clinical trials results in a significant knowledge gap in the amount of information available to physicians, who then have to rely on postmarketing data and case studies to understand drug performance in this population. This is a particularly daunting task among pregnant women who suffer from psoriasis, due to limited knowledge on the safety of antiinflammatory agents—tumor necrosis factor (TNF) α inhibitors—in treating these patients.

In a review published in the International Journal of Molecular Sciences, researchers from Denmark evaluate the current landscape of treatments available for pregnant women suffering from inflammatory conditions, and examine guidelines that exist, if any.

Hormonal changes experienced during pregnancy fluctuate the degree of psoriasis and also influence comorbidities including obesity, hypertension, diabetes, and other chronic inflammatory conditions such as rheumatoid arthritis (RA), all of which can have a negative impact on the fetus, the authors write. Disease pathophysiology points to an imbalance in the immune system—specifically, increase in Th17 cells—can disrupt the Th17/regulatory T cell ratio and may impact the status of the pregnancy, and eventually, the outcome.

With the risk that TNFα inhibitors may cross the placental barrier, guidelines developed by the British Association of Dermatologists recommend a case-by-case determination of treating pregnant women with psoriasis or psoriatic arthritis with adalimumab, golimumab, etanercept, or certolizumab pegol, the indicated TNFα inhibitors. According to the European Crohn’s and Colitis Organization, women with inflammatory bowel disease (IBD) should be treated appropriately, to avoid risks to the mother or the fetus, but treatment should be discontinued if possible between gestational weeks 24 and 26.

Managing hypertension in pregnant women.

Below are some of the safety considerations listed in the review:

1. Adverse maternal outcomes. These include preeclampsia, gestational diabetes, hypertension, infections, venous thromboembolism, among others. While the relation between TNFα inhibitors and preeclampsia isn’t understood, research has hinted toward the protective effect of TNFα inhibitors could protect against preeclampsia.
2. Adverse pregnancy outcomes. These include abortion, termination, ectopic pregnancies, intrauterine death, and still birth. Research points to a higher rate of elective termination (17% vs 0.02%) as well as spontaneous abortions (12% vs 1%) among patients with IBD taking TNFα inhibitors, compared with the normal population. However, discontinuing TNFα inhibitors in the first trimester seemed to stimulate spontaneous abortions as against continuing treatment through pregnancy.
3. Adverse neonatal outcomes. An increased risk of congenital malformations and preterm births has been identified in women with chronic inflammatory conditions other than psoriasis, including IBD, who are exposed to TNFα inhibitors. However, contradictory results from a meta-analysis have also been published, that did not observe an increased risk in women with IBD exposed to TNFα inhibitors. A study also found no difference in risk of congenital malformations in women with RA on adalimumab and matched controls and healthy women.
4. Low birth weight and preterm birth. Expression of TNF in the mother and fetus influence birth weight: high levels of TNF can lead to lower weight and can also lead to intrauterine growth retarded, per the review. However, contradictory results from 2 different studies on the influence of TNFα inhibitors keeps the field a bit muddled.
5. Infections. Immunosuppressive effects of TNFα inhibitors can increase the risk of neonatal infections. The CDC recommends avoiding live vaccines in full-terms babies who have been exposed to TNFα inhibitors until they are at least 6 months old.

In their conclusion, the authors point to the wide knowledge gap, particularly around the safety of TNFα inhibitors in pregnancy, and long-term outcomes in children exposed to these agents. Additionally, they also point to the quality of evidence and indicate the need to reduce heterogeneity between studies, curb extrapolation of results (eg, conduct specific studies for psoriasis), narrow confidence intervals for adverse outcomes, and power the trials.

Reference

Johansen CB, Jimenez-Solem E, Haerskjold A, Sand FL, Thomsen SF. The use and safety of TNF inhibitors during pregnancy in women with psoriasis: a review. Int J Mol Sci. 2018;19(5). pii: E1349. doi: 10.3390/ijms19051349.