Discussion
Our meta-analysis of nine cohort studies suggests that exposure to a neuraminidase inhibitor during pregnancy is not associated with a significantly increased risk of adverse neonatal outcomes. By contrast, we observed a small decrease in the risk of low birth weight or an SGA outcome after exposure to a neuraminidase inhibitor. Further analyses limited to oseltamivir exposure were consistent with the overall results.
Pregnant women have an elevated risk of complications and poorer outcomes than the general population when infected with influenza. A previous meta-analysis[27] demonstrated that maternal influenza exposure is associated with an increased risk of overall congenital malformation, suggesting that preventing influenza in pregnant women may reduce the risk of congenital anomalies. During the 2009 H1N1 pandemic, treating pregnant women with a neuraminidase inhibitor for suspected or confirmed influenza or prophylaxis was recommended by the World Health Organization and the US Centers for Disease Control and Prevention[4]. Therefore, the association between neuraminidase-inhibitor use during pregnancy and developmental disorders in offspring has been a controversial topic for decades. In theory, neuraminidase inhibitors, such as oseltamivir, pass the placental barrier and directly affect embryonic development[8]. However, preclinical animal studies reported no adverse effects of oseltamivir at normal dosages on reproduction parameters in rats or rabbits[12]. Oseltamivir has no direct effects on embryonic or fetal development even at higher dosages in rabbits[12]. Our meta-analysis found no significant increased risk of congenital malformations in children who were exposed to a neuraminidase inhibitor in utero .
An unanticipated finding was that neuraminidase-inhibitor use during pregnancy was associated with a reduced risk of low birth weight or an SGA outcome. This may have occurred for three reasons. First, the protective effect of neuraminidase inhibitors on fetal growth suggests a “healthy user effect.” Pregnant mothers who have been exposed to a neuraminidase inhibitor may be more likely to receive more extensive assessment and prenatal care from their attending physician, which may then reduce the risk of growth restrictions in the neonate. This bias might have affected the true association. Second, this association may be a chance finding. In our analysis of low birth weight, the study by Graner et al.[23] accounted for 75% of the analytical weight, and when this study was excluded from the analysis, no protective effect of neuraminidase inhibitors was detected. Thus, our results pertaining to neuraminidase-inhibitor use and the risk of low birth weight may be limited by sample size, and further investigation is needed to clarify the issue. Third, an epidemiological study[3] demonstrated that fever associated with influenza is linked with adverse neonatal outcomes; thus, the protective effect observed in our findings might have been driven by several of the included studies, which enrolled pregnant mothers infected with influenza without antiviral treatment as their comparisons.
This systematic review with a meta-analysis is the first to provide an overall estimate of the effect of neuraminidase inhibitors on neonatal outcomes. The strength of our meta-analysis lies in the exclusive use of cohort studies, which are less prone to bias in terms of assessing drug exposure during pregnancy. In addition, the level of heterogeneity for the analyses was low, making the pooled results more convincing.
Nonetheless, this study had some major limitations. The most important limitation of our meta-analysis was the residual number of unknown confounders. Further well-designed studies considering more covariates are required to examine the association between neuraminidase-inhibitor use during pregnancy and adverse neonatal outcomes. Second, we only conducted subgroup analysis to evaluate the effect of oseltamivir due to limited studies that evaluated zanamivir. Third, our study focused on neonatal outcomes, and further research is required to clarify the effects on maternal outcomes. Fourth, various definitions for assessing neonatal outcomes were used among the studies. Finally, the number of eligible studies and the sample size of exposed pregnant mothers were small, which might have influenced the accuracy of our results.
In conclusion, our results suggest that in utero exposure to a neuraminidase inhibitor does not appear to increase the risk of adverse neonatal outcomes. This study supports the current guidelines stating that oseltamivir is recommended for influenza treatment during pregnancy.