Exposure to Biological Therapies During Conception and Pregnancy

A Systematic Review

E. Pottinger; R.T. Woolf; L.S. Exton; A.D. Burden; C. Nelson-Piercy; C.H. Smith

Disclosures

The British Journal of Dermatology. 2018;178(1):95-102. 

In This Article

Abstract and Introduction

Abstract

Background Biological therapies are effective treatments for psoriasis and are often prescribed to women of child-bearing age.

Objectives To evaluate the safety of biological therapy in conception and/or pregnancy.

Methods We performed a systematic review of PubMed, MEDLINE, Embase and Cochrane databases for multivariate-adjusted studies of women exposed to biologics relevant to the treatment of psoriasis during conception and/or pregnancy.

Results We identified four population-based cohort studies involving 1300 women exposed to tumour necrosis factor (TNF)-α inhibitors (TNFi) 3 months prior to or during the first 3 months of pregnancy. These studies showed a trend towards drug-specific harm with TNFi exposure in women with different inflammatory diseases, with an increased risk of congenital malformations [three studies; odds ratio (OR) range 1·32–1·64] and preterm birth (one study; OR 1·69, 95% confidence interval 1·10–2·60). This trend did not reach statistical significance in all studies; study heterogeneity, variation across comparator cohorts, inadequate adjustment for important confounding variables such as co-therapy, and an absence of a common constellation of malformations means there is uncertainty about the causal role of TNFi. No studies specifically addressed the effect of TNFi exposure in psoriasis during conception and/or pregnancy, or of interleukin (IL)-17 and IL-12/23 antagonists in any indication.

Conclusions When counselling women these findings must be balanced against the potential impact of untreated severe psoriasis on conception and/or pregnancy and maternal wellbeing; ongoing pharmacovigilance via registries remains essential to address this evidence gap.

Introduction

Biological therapies are effective treatments for psoriasis that specifically block proinflammatory cytokine pathways central to disease immunopathogenesis. Psoriasis often first develops in young adults, of which a significant number may require treatment with a biological agent. Therefore, understanding the potential impact of biologics on conception and pregnancy is important.

All of the biological therapies currently licensed for psoriasis are derivatives of human immunoglobulin G (IgG) and are actively transported across the placenta via neonatal Fc receptors. IgG1 is most efficiently transferred across the placenta, which occurs as early as 13 weeks' gestation but increases significantly after 20 weeks' gestation.[1,2] Adalimumab, etanercept and infliximab all contain a human IgG1 Fc region and have been detected in the serum of neonates exposed in utero during the third trimester, with adalimumab and infliximab detected at up to 11 weeks and 7 months postpartum, respectively.[3,4] It is hypothesized that because fetal exposure to biologics is absent during early embryogenesis the risk of teratogenicity is low, whereas the increasing exposure during the second and third trimesters may adversely affect fetal development, lead to neonatal immunosuppression or increase the risk of neonatal infection.[5]

Regulatory authorities state that there are no adequate studies to evaluate drug safety at conception or during pregnancy and advise against their use. However, in practice these situations are challenging given the clinical need to treat ongoing active disease. Recent national and international guidelines for the treatment of inflammatory bowel disease (IBD) and rheumatic diseases state that tumour necrosis factor (TNF)-α inhibitors (TNFi) should still be considered until 16–30 weeks of pregnancy, and throughout pregnancy where there is clear clinical need.[6–8] These recommendations are in part driven by evidence that the underlying disease state alone is independently associated with adverse pregnancy outcomes, including preterm birth, intrauterine growth retardation and spontaneous miscarriage/stillbirth.[9–14] The impact of psoriasis on pregnancy outcome is less well characterized. Severe psoriasis may be associated with preterm birth and intrauterine growth restriction;[15] however, a recent systematic review found that this was not a consistent finding across all identified studies.[16] Other factors that may adversely confound outcomes should also be considered, including alcohol, smoking, comorbidities and prior exposure to other disease-modifying agents, such as methotrexate.

A number of studies report favourable outcomes in women exposed to biologics and narrative reviews discuss the potential risks and benefits of therapy and emphasize the importance of a case-by-case basis for clinical decision-making.[17] However, clinicians and patients require clear information on the risk of drug-specific harm to make these decisions. To address this need, we performed a systematic review of published population-based studies that report pregnancy outcomes in women exposed to biological therapies relevant to the treatment of psoriasis during conception and/or pregnancy. To identify evidence for drug-specific harm, we critically evaluated study quality and bias with a specific focus on the disease and control populations, time of exposure, and adjustment for potential confounders.

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