Introduction
Influenza is an acute infectious disease caused by the influenza A, B, and C viruses that threatens pregnant mothers[1]. During seasonal influenza and pandemic influenza outbreaks, pregnant women have increased susceptibility to severe infection and worse clinical outcomes from influenza[2]. Maternal influenza exposure during pregnancy is associated with adverse maternal and neonatal outcomes[3], suggesting that influenza should be prevented and treated in pregnant women.
The neuraminidase-inhibitor antiviral medications oseltamivir and zanamivir have been recommended for preventing and treating influenza among exposed and/or infected pregnant women since the 2009 HIN1 pandemic[4]. Since then, there has been a notable increase in the number of pregnant women treated with neuraminidase inhibitors[5]. However, little is known about the reproductive safety of these drugs. A study using an ex vivo human placental model showed that transplacental transfer of the oseltamivir metabolite is incomplete and its accumulation is minimal[6]. Several cases of adverse outcomes have been reported in mothers exposed to oseltamivir[7, 8]. Some studies without control women suggest that maternal exposure to laninamivir does not increase the rate of adverse pregnancies or fetal outcomes[9, 10]. Previous systematic reviews with small sample sizes have summarized this association and reported that exposure to a neuraminidase inhibitor during pregnancy does not appear to increase the overall risk of congenital malformations[11, 12]. Additional studies have been published since that systematic review, enabling a more detailed analysis of the association between neuraminidase-inhibitor use during pregnancy and congenital malformation risk. Those studies also investigated the effects of neuraminidase inhibitors on other pregnancy outcomes, but the results were inconsistent. Therefore, we conducted a meta-analysis to collect evidence-based, relevant research regarding maternal neuraminidase-inhibitor exposure during pregnancy and neonatal outcomes to provide a scientific basis for recommendations to avoid adverse outcomes.