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.