USE OF DUPILUMAB IN PREGNANCY

Dupilumab is a recombinant human IgG4 monoclonal antibody that decreases mediators of inflammation by inhibiting interleukin-4 and interleukin-13 signalling. Dupilumab is used to treat atopic dermatitis and asthma, and as an add-on therapy in the treatment of severe chronic rhinosinusitis with nasal polyps.

The available human pregnancy exposure and outcome data are highly limited, provided by a small retrospective cohort study, a disproportionality analysis of spontaneous adverse drug reaction reports, and case reports/series, which together describe 95 dupilumab-exposed pregnancies, with 47 exposed in at least the first trimester.

There is no evidence of an association between in utero dupilumab exposure and an increased risk of either miscarriage, congenital malformation, neonatal complications, or neurodevelopmental impairment. However, the available data are highly limited, and therefore further data are required to confirm these findings. Although there are a small number of uncontrolled case reports of dupilumab exposure which describe impaired fetal growth (n=3) and preterm delivery (n=2), an influence of the underlying maternal condition is possible, and causality cannot be attributed to dupilumab exposure. There are no data regarding the risk of intrauterine death.

Uncontrolled maternal asthma is associated with a number of adverse pregnancy outcomes, including fetal loss, preterm birth, and low infant birth weight, as well as adverse maternal events such as preeclampsia. Where clinically indicated, the benefit of continued treatment with dupilumab in pregnancy is likely to outweigh any theoretical risk posed to the fetus. Dupilumab therapy should not be discontinued on account of pregnancy without careful consideration of the risk to both mother and fetus of uncontrolled maternal asthma.

Where moderate-to-severe atopic dermatitis has been assessed as causing significant social or psychological problems (e.g. sleep disturbance), and where clinically indicated, the benefit of continued maternal treatment with dupilumab in pregnancy may outweigh any theoretical risk posed to the fetus.

There is a theoretical concern that immunosuppressant antibodies which actively cross the placenta during pregnancy could result in neonatal/infant immunosuppression and an increased risk of infection. There are currently no data regarding the effect of in utero dupilumab exposure on the neonatal/infant immune system. Guidance from Public Health England (PHE), issued 2017, specified that live vaccines should not be used until the infant is 6 months old following in utero biologic immunosuppressant exposure. This advice means that rotavirus should usually be avoided and the risks/benefits of BCG (if relevant for the infant) should be weighed up at the time.

The European Respiratory Society/Thoracic Society of Australia and New Zealand (ERS/TSANZ) task force and a Dermatology Association of Ontario (DAO) expert panel has classified dupilumab as possibly safe for use during pregnancy (and breastfeeding).

Exposure to dupilumab at any stage in pregnancy would not usually be regarded as medical grounds for termination of pregnancy or any additional fetal monitoring. However, other risk factors which could independently increase the risk of adverse pregnancy outcome may be present in individual cases. Such factors are important to consider when performing case-specific risk assessments.