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\begin{document}

\title{Neonatal outcomes after neuraminidase inhibitor use during pregnancy: a
meta-analysis of cohort studies}



\author[1]{Jiangshan Lian}%
\author[1]{Munire  Adilijiang}%
\author[1]{Caihua Chang}%
\author[1]{Hai-yin Jiang}%
\author[1]{Yongping Zhang}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
AIM: Influenza infection poses a severe threat to pregnant mothers, and
antiviral treatment is recommended. However, the safety of
neuraminidase-inhibitor antiviral medications during pregnancy has not
been well described. METHODS: A systematic review and meta-analysis were
performed to evaluate the adverse neonatal outcomes associated with
exposure to neuraminidase inhibitors during pregnancy. The PubMed,
Embase, and Cochrane Library databases were searched to identify
potential studies for inclusion. RESULTS: Nine cohort studies that
estimated adverse neonatal outcomes associated with exposure to
neuraminidase-inhibitor medication during pregnancy were included.
Exposure to a neuraminidase inhibitor during pregnancy was not
associated with an increased risk of congenital malformation (odds ratio
{[}OR{]} 0.9, 95\% confidence interval {[}CI{]} 0.72--1.12, P = 0.341),
low Apgar score (OR 0.96, 95\% CI 0.77--1.2, P = 0.733), or preterm
birth (OR 0.99, 95\% CI 0.89--1.09, P = 0.771) compared with no
exposure. However, exposure to a neuraminidase inhibitor was associated
with a reduced risk of low birth weight (OR 0.79, 95\% CI 0.68--0.92, P
= 0.002) and giving birth to a small-for-gestational-age infant (OR
0.78, 95\% CI 0.69--0.88, P \textless{} 0.001). Further analyses limited
to oseltamivir exposure were consistent with the overall results.
CONCLUSION: Exposure to neuraminidase-inhibitor medication during
pregnancy does not appear to be associated with adverse neonatal
outcomes. We recommend further studies to investigate this association,
which will help clinicians determine whether to prescribe a
neuraminidase inhibitor during pregnancy.%
\end{abstract}%



\sloppy


\textbf{Neonatal outcomes after neuraminidase inhibitor use during
pregnancy: a meta-analysis of cohort studies}

\textbf{Running title: Neuraminidase inhibitors and neonatal outcomes}

Jiangshan Lian\textsuperscript{1,2}, Munire
Adilijiang\textsuperscript{2}, Caihua Chang\textsuperscript{2}, Hai-yin
Jiang\textsuperscript{1}, Yongping Zhang\textsuperscript{2*}

\textsuperscript{1}State Key Laboratory for Diagnosis and Treatment of
Infectious Diseases, National Clinical Research Center for Infectious
Diseases, Collaborative Innovation Center for Diagnosis and Treatment of
Infectious Diseases, Department of Infectious Diseases, The First
Affiliated Hospital, Zhejiang University School of Medicine.

\textsuperscript{2}Department of Infectious Diseases, People's Hospital
of Xinjiang Uygur Autonomous Region

\textbf{Contact information}

*Corresponding author: Yongping Zhang, Department of Infectious Disease,
People's Hospital of Xinjiang Uygur Autonomous Region, Urumqi 830001,
Xinjiang Uygur Autonomous Region, China. E-mail: zhangyongpingxj@126.com

\textbf{Conflicts of Interest}

The authors declare no competing interest.

\textbf{Funding}

None.

\textbf{Authors' contributions}

JSL and YPZ conceived the study and revised the manuscript critically
for important intellectual content. MA made substantial contributions to
its design, acquisition, analysis and interpretation of data. CC and HYJ
participated in the design, acquisition, analysis and interpretation of
data. All authors read and approved the final manuscript.

\textbf{AIM:} Influenza infection poses a severe threat to pregnant
mothers, and antiviral treatment is recommended. However, the safety of
neuraminidase-inhibitor antiviral medications during pregnancy has not
been well described.

\textbf{METHODS:} A systematic review and meta-analysis were performed
to evaluate the adverse neonatal outcomes associated with exposure to
neuraminidase inhibitors during pregnancy. The PubMed, Embase, and
Cochrane Library databases were searched to identify potential studies
for inclusion.

\textbf{RESULTS:} Nine cohort studies that estimated adverse neonatal
outcomes associated with exposure to neuraminidase-inhibitor medication
during pregnancy were included. Exposure to a neuraminidase inhibitor
during pregnancy was not associated with an increased risk of congenital
malformation (odds ratio {[}OR{]} 0.9, 95\% confidence interval {[}CI{]}
0.72--1.12, P = 0.341), low Apgar score (OR 0.96, 95\% CI 0.77--1.2, P =
0.733), or preterm birth (OR 0.99, 95\% CI 0.89--1.09, P = 0.771)
compared with no exposure. However, exposure to a neuraminidase
inhibitor was associated with a reduced risk of low birth weight (OR
0.79, 95\% CI 0.68--0.92, P = 0.002) and giving birth to a
small-for-gestational-age infant (OR 0.78, 95\% CI 0.69--0.88, P
\textless{} 0.001). Further analyses limited to oseltamivir exposure
were consistent with the overall results.

\textbf{CONCLUSION:} Exposure to neuraminidase-inhibitor medication
during pregnancy does not appear to be associated with adverse neonatal
outcomes. We recommend further studies to investigate this association,
which will help clinicians determine whether to prescribe a
neuraminidase inhibitor during pregnancy.

\textbf{Keywords:} flu, antiviral, prenatal, maternal.

\textbf{WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT}

Neuraminidase inhibitors are now increasingly used to treat influenza in
pregnant women. It remains controversial whether neuraminidase inhibitor
exposure during pregnancy affects the risk of adverse neonatal outcomes.

\textbf{WHAT THIS STUDY ADDS}

Current evidence does not indicate that neuraminidase inhibitor exposure
during pregnancy is not associated with increased risks of overall
congenital malformations in offspring.

Furthermore analysis did not indicate increased risks of other adverse
neonatal outcomes in offspring exposed to neuraminidase inhibitors.

This study supports the current guidelines stating that oseltamivir is
recommended for influenza treatment during pregnancy.

\textbf{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 \emph{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.

\textbf{Methods}

\textbf{Literature search}

To ensure that the work was of high quality, this study was performed
following the Meta-Analysis of Observational Studies in Epidemiology
(MOOSE) guidelines{[}13{]} (Table S1). English-language publications
were comprehensively searched in the Cochrane Library, PubMed, and
EMBASE databases from the dates of inception until May 2021. The search
terms used were ``pregnancy OR mothers OR pregnant OR gestational OR
prenatal OR perinatal OR gestation'' and ``neuraminidase inhibitors OR
oseltamivir OR zanamivir.'' The reference lists of the retrieved
articles were manually examined to identify studies not found in the
database search.

\textbf{Inclusion criteria}

Studies were initially identified based on their title and abstract and
later included after a full-text evaluation. Observational studies were
included if they met all of the following criteria: used a cohort study
design, explored whether maternal neuraminidase inhibitor use during
pregnancy increased the risk of adverse maternal or neonatal outcomes,
and had sufficient available data to allow the calculation of risk
estimates if adjusted data were not provided. Reviews, letters to the
editor, or conference abstracts; basic studies or those using animal
experiments; case reports or series; studies without a control group;
and studies that included other congenital malformations where it was
not possible to separate the data regarding oral clefts were excluded.

\textbf{Data extraction and quality assessment} Data were independently
extracted by two investigators, and any discrepancies were resolved by
the third author. The extracted information included author names,
publication date, study design, study location, study period, drug
exposure assessment results, outcome measures, statistical analyses
used, and study quality. The most-adjusted effect size estimate was used
when more than one estimate was provided. The risk of bias was estimated
using the Newcastle Ottawa Scale to assess the nonrandomized study
quality{[}14{]}, as recommended by the Cochrane Collaboration. The risk
of bias concerning selection, comparability, and assessment of the
exposure/outcome was estimated according to nine items using a star
allocation scheme. The scale features eight criteria and yields scores
ranging from 0 (high risk of bias) to 9 (low risk of bias). Studies with
scores \textgreater{} 7 were considered high quality. Summary bias risk
assessments were derived for each study.

\textbf{Outcome assessment}

The pregnancy outcomes were analyzed based on the following categories:
overall congenital malformations and heart malformations; and other
neonatal outcomes including low birth weight, low Apgar score, small for
gestational age (SGA), or preterm birth.

\textbf{Data synthesis}

Meta-analyses were performed using STATA version 13 software (Stata
Corp, College Station, TX, USA). Heterogeneity among studies was
assessed using the \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} test and
I\textsuperscript{2}statistic; an I\textsuperscript{2} \textgreater{}
50\% or P \textless{} 0.05 for the Q-statistic indicated significant
heterogeneity{[}15{]}. The DerSimonian and Laird random-effects model
was used when studies were heterogeneous; otherwise, the Mantel-Haenszel
fixed-effects model was used{[}16{]}. When possible, adjusted effect
estimates (odds ratio {[}OR{]}, relative risk, and hazard risk) of
outcome measures from exposure to a neuraminidase inhibitor were
extracted, along with standard errors. Associations between maternal
neuraminidase-inhibitor exposure during pregnancy and adverse neonatal
outcomes were estimated using ORs and corresponding 95\% confidence
intervals (CIs), generated by comparing cases and controls. Publication
bias was evaluated using Begg's test{[}16, 17{]}. A P-value \textless{}
0.05 was considered to indicate significance.

\textbf{Results}

\textbf{Search results}

A total of 865 records without duplicates were identified using our
search strategy with the aforementioned keywords (309 from Pubmed, 643
from Embase, and 8 from the Cochrane Library database). After the titles
and abstracts were screened, 822 citations were selected for full-text
assessment. Finally, nine cohort studies{[}18-26{]} were included in the
analysis. Figure 1 summarizes the number of articles remaining after the
exclusion of non-relevant articles at each stage of the eligibility
assessment.

\textbf{Characteristics of the included studies}

The main characteristics of the included studies are presented in Table
1. The publication years ranged from 2010 to 2021, with the first
members of the offspring cohort delivered in 1997. The sample sizes of
the included studies ranged from 476 to 698,056, and 10,010 pregnant
mothers were exposed to neuraminidase inhibitors during pregnancy; only
one study examined an Eastern population. Overall, two were
hospital-based cohort studies. Based on the methodological quality
assessment scores, most studies were deemed to be of high quality; only
one was categorized as low quality. The score breakdown is shown in
Table S2.

\textbf{Meta-analysis}

\textbf{Overall congenital malformations}

A meta-analysis of seven studies assessing the risk of congenital
malformations concerning neuraminidase-inhibitor exposure during
pregnancy indicated that the combined OR of congenital malformation risk
was 0.9 (95\% CI 0.72--1.12, P = 0.341) (Figure 2). No heterogeneity was
observed among the studies (I\textsuperscript{2} = 0\%, P = 0.852). As
shown in Figure S1, we did not observe any evidence of publication bias
(Begg's test, P = 1; Egger's test, P = 0.63). The sensitivity analyses
revealed no substantial change in the pooled risk estimates upon the
exclusion of any single study from the same database. Six studies
reported the risk of congenital malformations in relation to oseltamivir
exposure during pregnancy; the combined OR was 0.89 (95\% CI 0.69--1.14,
P = 0.361; I\textsuperscript{2} = 0\%) (Figure S2).

We also analyzed the association between neuraminidase-inhibitor
exposure and heart malformations, which was reported by two studies. The
rates of heart malformations (OR 1.11, 95\% CI 0.61--2.03, P = 0.735;
I\textsuperscript{2} = 0\%) (Figure S3) were similar in the two groups.

\textbf{Other neonatal outcomes}

Table 1 presents the results for other neonatal outcomes. Six studies
evaluated the rate of low birth weight, and we found a reduced risk of
low birth weight involving neuraminidase-inhibitor exposure (OR 0.79,
95\% CI 0.68--0.92, P = 0.002; I\textsuperscript{2} = 0\%) (Figure 3A).
Also, oseltamivir exposure during pregnancy was associated with a
reduced risk of low birth weight (OR 0.84, 95\% CI 0.71--0.99, P =
0.039; I\textsuperscript{2} = 0\%) (Figure S4A).

We identified five studies reporting low Apgar scores that were eligible
for inclusion. No significant association was detected between
neuraminidase-inhibitor use and a low Apgar score in comparison with
mothers who were not exposed to a neuraminidase inhibitor (OR 0.96, 95\%
CI 0.77--1.2, P = 0.733; I\textsuperscript{2} = 0\%) (Figure 3B). When
our analysis was limited to oseltamivir exposure, we observed no
significant association between oseltamivir exposure and a low Apgar
score (OR 0.96, 95\% CI 0.74--1.25, P = 0.785; I\textsuperscript{2} =
0\%) (Figure S4B).

Four studies reported the risk of an SGA outcome in relation to
neuraminidase-inhibitor exposure during pregnancy; the combined OR of an
SGA outcome was 0.78 (95\% CI 0.69--0.88, P \textless{} 0.001;
I\textsuperscript{2} = 0\%) (Figure 3C). Oseltamivir exposure during
pregnancy was associated with a lower risk of an SGA outcome (OR 0.77,
95\% CI 0.68--0.88, P \textless{} 0.001; I\textsuperscript{2} = 0\%)
(Figure S4C).

We also analyzed the association between neuraminidase-inhibitor
exposure and the preterm birth rate (OR 0.99, 95\% CI 0.89--1.09, P =
0.771; I\textsuperscript{2} = 0\%) (Figure 3D). When our analysis was
limited to oseltamivir exposure, we observed no significant association
between oseltamivir exposure and preterm birth (OR 1.03, 95\% CI
0.93--1.15, P = 0.542; I\textsuperscript{2} = 0\%) (Figure S4D).

\textbf{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 \emph{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 \emph{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.

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\textbf{Table 1} Characteristics of the included studies\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
Author, year & Location, setting & Study design/ Born period & Drug
exposure measurement & Type of neuraminidase inhibitors & Outcome
assessment & Outcomes & Number of participants & Quality\tabularnewline
Svensson et al, 2011 & Sweden, population-based & Cohort, 2005-2007 &
Swedish Prescribed Drug Register & Oseltamivir or zanamivir & Swedish
Medical Birth Register (ICD-10) & Congenital malformations, low Apgar
score, SGA, low birth weight, preterm birth & 86 (exposed) 860
(no-exposed) & 8\tabularnewline
Xie et al, 2013 & Canada, population-based & Cohort, 2009-2010 & Better
Outcomes Registry and Network (BORN) Ontario & Oseltamivir & Computer
record & SGA, preterm birth, low Apgar score & 1237 (exposed) 5,4118
(no-exposed) & 9\tabularnewline
Greer et al, 2010 & USA, hospital-based & Cohort, 2003-2008 & Medical
records & Oseltamivir & ICD-8 or ICD-10 & Congenital malformations,
stillbirth, low birth weight & 135 (exposed) 82,097 (no-exposed) &
6\tabularnewline
Graner et al, 2017 & Denmark, Norway, Sweden and France,
population-based & Cohort, 2008-2010 & The prescribed drug registers &
Oseltamivir or zanamivir & ICD-10 & Congenital malformations, low Apgar
score, SGA, low birth weight, preterm birth & Scandinavian database
5,502 (exposed) 672,784 (no-exposed) eFeMeris database 3,22 (exposed)
19,448 (no-exposed) & 9\tabularnewline
Ehrenstein et al, 2018 & Denmark, population-based & Cohort, 2002-2013 &
The Danish National Prescription Registry & Oseltamivir & Danish
National Patient Registry & Congenital malformations, SGA, preterm birth
& 1,898 (exposed) 944,278 (no-exposed) & 9\tabularnewline
Chambers et al, 2019 & United States and Canada, population-based &
Cohort, 1997-2013 & Telephone interviews & Oseltamivir & Medical
records, Metropolitan Atlanta Congenital Defects Program coding system &
Congenital malformations, preterm birth, SGA & 112 (exposed) 604
(no-exposed) & 6\tabularnewline
Dunstan et al, 2014 & UK, population-based & Cohort, 2009-2010 & UK
Teratology Information Service & Oseltamivir or zanamivir & UK
Teratology Information Service, EUROCAT classification system &
Congenital malformations, low birth weight, preterm birth, & 207
(exposed) 575 (no-exposed) & 7\tabularnewline
Beau et al, 2014 & France, population-based & Cohort, 2004-2010 & French
prescription database & Oseltamivir & UK Teratology Information Service,
EUROCAT classification system & Congenital malformations, low birth
weight, preterm birth, & 337 (exposed) 674 (no-exposed) &
8\tabularnewline
Abraham et al, 2021 & India, hospital-based & Cohort, 2015-2017 &
Medical records & Oseltamivir & Medical records & SGA, preterm birth,
low Apgar score & 174 (exposed) 302 (no-exposed) & 8\tabularnewline
ICD, international Classification of diseases; SGA, small gestational
age. & ICD, international Classification of diseases; SGA, small
gestational age. & ICD, international Classification of diseases; SGA,
small gestational age. & ICD, international Classification of diseases;
SGA, small gestational age. & ICD, international Classification of
diseases; SGA, small gestational age. & ICD, international
Classification of diseases; SGA, small gestational age. & ICD,
international Classification of diseases; SGA, small gestational age. &
ICD, international Classification of diseases; SGA, small gestational
age. & ICD, international Classification of diseases; SGA, small
gestational age.\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Table 2} Meta-analysis for studies included in the analysis &
\textbf{Table 2} Meta-analysis for studies included in the analysis &
\textbf{Table 2} Meta-analysis for studies included in the analysis &
\textbf{Table 2} Meta-analysis for studies included in the analysis
&\tabularnewline
\midrule
\endhead
Subgroup analysis & Number of studies & Number of estimates & Pooled OR
(95\% CI), I\textsuperscript{2} statistics (\%), P-value for the
heterogeneity Q test & Model used\tabularnewline
Congennital malformations & & & &\tabularnewline
Neuraminidase inhibitor & 7 & 8 & 0.9 (0.72 - 1.12);
I\textsuperscript{2} = 0\%, P = 0.852 & Fixed effects\tabularnewline
Oseltamivir & 6 & 6 & 0.89 (0.69 - 1.14); I\textsuperscript{2} = 0\%, P
= 0.745 & Fixed effects\tabularnewline
Heart malformations & 2 & 2 & 1.11 (0.61 - 2.03); I\textsuperscript{2} =
0\%, P = 0.405 & Fixed effects\tabularnewline
Low birth weight & & & &\tabularnewline
Neuraminidase inhibitor & 6 & 8 & 0.79 (0.68 - 0.92);
I\textsuperscript{2} = 0\%, P = 0.483 & Fixed effects\tabularnewline
Oseltamivir & 5 & 6 & 0.84 (0.71 - 0.99); I\textsuperscript{2} = 16.2\%,
P = 0.309 & Fixed effects\tabularnewline
Low Apgar score & & & &\tabularnewline
Neuraminidase inhibitor & 5 & 6 & 0.96 (0.77 - 1.2);
I\textsuperscript{2} = 0\%, P = 0.643 & Fixed effects\tabularnewline
Oseltamivir & 4 & 5 & 0.96 (0.77 - 1.2); I\textsuperscript{2} = 0\%, P =
0.643 & Fixed effects\tabularnewline
SGA & & & &\tabularnewline
Neuraminidase inhibitor & 4 & 6 & 0.78 (0.69 - 0.88);
I\textsuperscript{2} = 0\%, P = 0.701 & Fixed effects\tabularnewline
Oseltamivir & 4 & 6 & 0.77 (0.68 - 0.88); I\textsuperscript{2} = 0\%, P
= 0.53 & Fixed effects\tabularnewline
Preterm birth & & & &\tabularnewline
Neuraminidase inhibitor & & & 0.99 (0.89 - 1.09); I\textsuperscript{2} =
0\%, P = 0.54 & Fixed effects\tabularnewline
Oseltamivir & 7 & 9 & 1.03 (0.93 - 1.15); I\textsuperscript{2} = 0\%, P
= 0.447 & Fixed effects\tabularnewline
\bottomrule
\end{longtable}

\textbf{Figure 1} Flow chart of the studies considered and finally
selected for review.

\textbf{Figure 2} Neuraminidase inhibitor exposure during pregnancy and
the risk of congenital malformations in the offspring.

\textbf{Figure 3} Neuraminidase inhibitor exposure during pregnancy and
the risk of adverse neonatal outcomes in the offspring (A) low birth
weight (B) low Apgar score (C) SGA (D) preterm birth.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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\end{figure}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

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\end{figure}

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