Maternal and Neonatal Outcomes Associated With Biologic Exposure Before and During Pregnancy in Women With Inflammatory Systemic Diseases

A Systematic Review and Meta-Analysis of Observational Studies

Nicole W. Tsao; Nevena Rebic; Larry D. Lynd; Mary A. De Vera


Rheumatology. 2020;59(8):1808-1817. 

In This Article

Abstract and Introduction


Objective: To determine the association between exposure to biologics in pregnant women with inflammatory systemic diseases and maternal and neonatal outcomes through a meta-analysis of findings from studies identified in a systematic review.

Methods: We conducted a systematic review of Medline, Embase, and Cochrane Database of Systematic Reviews to identify observational studies assessing the perinatal impacts of biologic in women with inflammatory systemic disease. Findings were meta-analysed across included studies with random-effects models. Crude risk estimates and, where possible, adjusted risk estimates were pooled to determine the impact on results when confounding is addressed.

Results: Overall, 24 studies were included in the meta-analysis. Meta-analyses of crude risk estimates resulted in pooled odds ratios (OR) for the association of biologic use during pregnancy and the following respective outcomes: congenital anomalies (1.30, 95% CI: 1.02, 1.67), preterm birth (OR 1.61, 95% CI: 1.37, 1.89), and low birth weight (OR 1.68, 95% CI: 1.21, 2.31). However, in pooled analyses of adjusted risk estimates we observed that the association between biologics use during pregnancy in disease-matched exposed and unexposed pregnant women was no longer statistically significant for congenital anomalies (adjusted OR 1.18, 95% CI: 0.88, 1.57).

Conclusion: Pooled results from studies reporting adjusted risk estimates showed no increased risk of congenital anomalies associated with biologics use, suggesting that increased rates of adverse outcomes may be due to disease activity itself or other confounders.


Chronic inflammatory systemic diseases, including inflammatory arthritides, share commonalities in pathophysiology and epidemiology.[1,2] Their chronic and systemic nature stems mainly from perpetual dysfunction of key pro-inflammatory cytokines, such as TNF, IL-1 and IL-6.[3–6] Further, there is a 'sex gap' in inflammatory diseases,[7] where women are disproportionately affected and with peak incidences during their reproductive years.[8–11] Growing recognition that uncontrolled disease activity prior to conception and disease flares during pregnancy represent the greatest risks to maternal and infant outcomes[12,13] has prompted more evidence to guide treatment decisions that balance the risks of active disease vs the risks of medications.[14]

Biologics, predominantly those targeting TNF, are now increasingly used in this patient population.[15] Correspondingly, adverse effects of biologic use before or during pregnancy are under scrutiny. A 2017 systematic review and meta-analysis by Komaki et al. of 11 studies published before November 2015 assessed the pregnancy outcomes and neonatal complications in individuals exposed to anti-TNF agents.[16] Since then, more evidence has rapidly emerged, necessitating a responsive approach to evidence synthesis, particularly in light of continued need for treatment guidance. Our objectives were to identify observational studies from a systematic review and pool available evidence to assess the impact of biologic use during pregnancy on the risk of adverse maternal and neonatal outcomes in women with inflammatory systemic diseases, with the hypothesis that there was no direct association. We were particularly interested in determining differences possibly attributable to confounding and attempts to address it; as such, we pooled crude results as well as adjusted results separately.