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\begin{document}

\title{Pregnancy in women with liver cirrhosis is associated with increased
risk for complications: a systematic review and meta-analysis of the
literature}



\author[1]{Laurine van der Slink}%
\author[2]{Irma Scholten}%
\author[1]{Faridi van Etten-Jamaludin}%
\author[1]{Bart Takkenberg}%
\author[1]{Rebecca Painter}%
\affil[1]{Amsterdam UMC Locatie Meibergdreef}%
\affil[2]{Deventer Hospital}%


\vspace{-1em}



  
  \date{May 08, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
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\endgroup





\selectlanguage{english}
\begin{abstract}
Background Pregnancy and liver cirrhosis is a rare but increasing
combination. Liver cirrhosis can raise the chance of maternal and fetal
mortality and morbidity, although the exact risks remain unclear.
Objective To provide a systematic literature review and meta-analysis on
maternal, fetal and obstetric complications among pregnant women with
liver cirrhosis. Search strategy We performed a systematic literature
search in the databases PubMed/MEDLINE and EMBASE (Ovid) from inception
through 25 January 2021. Selection criteria Studies including
pregnancies with liver cirrhosis and controls were eligible. Data
collection and analysis Two reviewers independently evaluated study
eligibility. We used the random-effects model for meta-analysis. Main
results Our search yielded 3118 unique papers. We included 11 studies,
including 2912 pregnancies in women with cirrhosis from 1982-2020. Seven
studies were eligible for inclusion in the meta-analysis. The overall
maternal mortality rate was 0.89\%. Maternal mortality and variceal
hemorrhage decreased comparing recent and older studies. Most cases of
maternal mortality due to variceal hemorrhage (70\%) occurred during
vaginal delivery. Pregnant women with liver cirrhosis had a higher
chance of preterm delivery (OR 6.7 95\% CI 5.1- 9.1), cesarean section
(OR 2.6, 95\% CI 1.7-3.9), preeclampsia (OR 3.8, 95\% CI 2.2-6.5) and
small for gestational age neonates (OR 2.6, 95\% CI 1.6-4.2) compared to
the general obstetric population. Subgroup-analyses could not be
conducted. Conclusions Liver cirrhosis in pregnant women is associated
with serious increases in maternal mortality and obstetric and fetal
complications. Large international prospective studies are needed to
identify risk factors for unfavorable outcome.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Pregnancy is a rare event in women with liver cirrhosis in part due to
decreased natural fertility rates. \textsuperscript{1,2} The prevalence
of cirrhosis in women of reproductive age is 0.045\%.\textsuperscript{3}
The incidence of cirrhosis in pregnancy is reported as approximately 1
per 4500 pregnancies. \textsuperscript{4, 5}Worldwide, the most common
causes of liver cirrhosis in women are viral hepatitis, autoimmune
hepatitis, alcoholic liver disease and non-alcohol related fatty liver
disease. \textsuperscript{1} Although pregnancy and cirrhosis is a rare
combination, it appears to have become more frequent in the last decades
possibly owing to improvements in the treatment of liver cirrhosis,
increased awareness of cirrhosis after the introduction of screening in
high risk populations, and the availability of assisted reproductive
techniques. \textsuperscript{6-8} For clinicians and patients alike,
when deciding on family planning and obstetric management, the effects
of liver cirrhosis on the course of pregnancy and the effects of
pregnancy on underlying cirrhosis are both of importance.

Previous studies have shown that pregnancy in women with cirrhosis is
associated with a high risk of complications, including maternal and
perinatal mortality. \textsuperscript{3,9} However, studies are small
and report on a variety of outcomes. \textsuperscript{5, 10-14} This
makes it difficult to advise both patients with liver cirrhosis and
their clinicians on the course of a planned pregnancy. A systematic
review and meta-analysis of the literature could provide with robust
estimates of the risks involved in pregnancy. Here, we provide a
systematic review reporting on the maternal, fetal and obstetric
complications among pregnant women with liver cirrhosis.

\textbf{Methods}

The protocol of this review was registered in PROSPERO (CRD42018080575)
on 1 December 2017. We followed the Preferred Reporting Items for
Systematic Reviews and Meta-Analysis (PRISMA) statement and the
Meta-analysis of Observational Studies in Epidemiology (MOOSE) group.
None of the authors received specific funding for this review. There was
no patient or public involvement in the development or implementation of
this review.

\textbf{Search strategy}

A literature search was performed in the databases PubMed/MEDLINE and
EMBASE (Ovid) from inception to 25 January 2021. The search had no
language restrictions. We used medical subject headings as well as title
and abstract terms and word variants of pregnancy and liver cirrhosis.
Appendix S1 presents the complete search strategy.

\textbf{Study selection process}

We selected cohort studies and case control studies with patients who
had liver cirrhosis and were pregnant. Diagnoses of liver cirrhosis were
considered confirmed when based on biopsy findings or based on imaging
combined with laboratory findings. Cohorts or case control studies had
to include a minimum series of five patients with liver cirrhosis.
Results had to contain at least one item of one of the designated
outcome domains (see heading `outcome measurements'). We included
studies in the meta-analysis if they contained a control group. When our
search found papers which analyzed identical patient populations
multiple times, and which reported on identical outcomes, we selected
the most recent or most relevant study, and excluded the other studies
reporting on the same population. Other exclusion criteria were
non-human studies, studies outside pregnancy and case reports, case
series, opinions or reviews.

Two reviewers (LLS and RBT) independently screened the titles and
abstracts of studies retrieved by the database searches. We requested
the full text if a study was potentially relevant and performed
independent screening to assess eligibility in duplo on full text.
Disagreement about including a study were resolved through discussion or
by consulting a third reviewer (RCP).

\textbf{Quality assessment}

We used the Newcastle-Ottawa scale for cohort studies for quality
assessment and estimating the risk of bias. Two reviewers (LLS and IS)
independently assessed the included studies. We did not exclude studies
based on poor quality.

\textbf{Outcome measurements}

The outcomes of interest were divided into three domains, maternal
complications, obstetric complications and fetal outcome or
complications. Maternal complications included maternal mortality,
hepatic decompensation, gastrointestinal bleeding or variceal bleeding.
We defined maternal mortality as maternal death during pregnancy or
within 42 days of termination of pregnancy. \textsuperscript{15} We
defined hepatic decompensation as the presence of jaundice, ascites or
hepatic encephalopathy.

Obstetric complications included caesarean delivery, preterm delivery
(birth \textless{}37 completed weeks gestation), postpartum hemorrhage
(loss of \textgreater{}500 ml blood within 24 hours during or after
delivery), miscarriage (pregnancy loss before 20th week), placental
abruption and hypertensive disorders of pregnancy (including pregnancy
induced hypertension (PIH; systolic blood pressure [?]90 mmHg or diastolic
blood pressure [?]140 mmHg), preeclampsia (hypertension with proteinuria
\textgreater{}300 mg per 24 hours) and the syndrome of hemolysis,
elevated liver enzymes, and low platelet count (HELLP; diagnosed by
laboratory abnormalities)).

Fetal complications included neonatal mortality (death within 28 days
after pregnancy), admission at neonatal intensive care unit,
intrauterine fetal demise (pregnancy loss at or after 20th week of
gestation), congenital malformations and small for gestational age (SGA,
birth weight less than 10th percentile for gestational age). Low birth
weight (birth weight \textless{}2500 g) was used when SGA was not
reported.

\textbf{Data extraction}

Two authors (LLS and IS) independently extracted data from the included
studies using a predefined and structured data extraction form created
for this systematic review. In addition to the outcomes of interest, we
extracted the study characteristics (authors, year and journal of
publication), study design, inclusion and exclusion criteria, number of
patients and number of pregnancies with cirrhosis and if appropriate
number of controls of all included studies. In case of studies missing
data, we contacted first authors, at least two times, in attempt to
request these data.

\textbf{Data analysis}

We performed a meta-analysis, using a random effects model, if at least
three studies reported on the outcome of interest. Odds ratios (OR) and
95\% confident intervals (CI) comparing women with liver cirrhosis to
controls were calculated. A p-value \textless{}0.05 was considered
statistically significant. We used the I\textsuperscript{2} for testing
statistical heterogeneity. \textsuperscript{16} Sensitivity analyses
were performed when the I\textsuperscript{2} test showed evidence of
high heterogeneity, corresponding to
I\textsuperscript{2}\textgreater{}75\%. We performed sensitivity
analyses by removing contributing papers from the analysis that were
thought to be responsible for heterogeneity based on deviating study
design, case definition, study population and etiology of liver
cirrhosis. We used The Cochrane Manager Reviewer (REVMAN 5)
\textsuperscript{17} for the statistical analysis.

To analyze decreases of maternal mortality and variceal hemorrhage we
calculated the odds ratio of the total events that occurred, after
dichotomizing the odds ratios from studies conducted before and after
the median of total study period of all included studies. Also, we made
time sequenced plots to visualize the decreases of maternal mortality
and variceal hemorrhage. We used the median date of inclusion of
individual studies as the value on the X-axis and the incidence rates as
value on the Y-axis.

\textbf{Results}

Our search retrieved 3118 unique publications. After title and abstract
screening, 130 studies were selected for full text eligibility
screening. We included 11 studies (with 2901 pregnancies with liver
cirrhosis) in the systematic review, of which 7 were eligible for the
meta-analysis (Figure 1). The total number of pregnancies with liver
cirrhosis included in the meta-analysis was 2685 as well as 4,283,173
pregnancies without liver cirrhosis (control group). Table 1 describes
the general characteristics of included studies. All retrieved studies
were cohort studies. The etiologies of liver cirrhosis in the included
studies corresponded with the most common etiologies of liver cirrhosis
in women worldwide.

\textbf{Quality assessment}

Six studies were assessed as good quality, four studies as fair quality
and one study as poor quality (Table S1). With one
exception\textsuperscript{22}, all studies scored at least two out of
four stars for selection criteria and two out of three stars for outcome
criteria. Most frequent source of risk of bias included `no control
group' (four studies did not include a control group), `selection of
controls' and `adequacy of follow up', since nine studies were
retrospective cohorts.

\textbf{Maternal complications}

We present only descriptive data on maternal complications since we
could not conduct a meta-analysis for maternal complications, due to a
lack of odds ratios in the published reports on this topic. Maternal
death rate was reported by eight studies and ranged from 0 to 7.8\%. In
total, 25 events of maternal deaths in 2794 pregnancies of women with
cirrhosis (0.89\%) were recorded, compared to 0,010\% in control
pregnancies, which is an 80-fold increase in risk (OR 80.2 95\% CI 27.3
- 235.1; \emph{p} \textless{}0.0001) The total numbers of maternal
deaths in recent studies (range 1982-2002) were lower than in older
studies (range 2004-2016) (OR 2.9 95\% CI 1.2-7.1; \emph{p} = 0.02).
This trend in decreasing maternal mortality over time is illustrated by
the time sequenced plots of the incidences of included studies (Figure
S2). The most common cause of maternal death was variceal hemorrhage
(n=13), the majority of which occurred during vaginal delivery (n=9) and
some occurred during pregnancy (n=2), during cesarean section (n=1) or
in the postpartum period (n=1). Other causes of maternal mortality were
sepsis (n=2), preeclampsia (n=1), hepatic decompensation (n=2), flare of
autoimmune hepatitis (n=1) and unknown (n=6) (figure S3).

Variceal hemorrhage, either resulting in maternal death or not, occurred
113 times in 2858 pregnancies (4,0\%) reported in ten studies. In most
cases the occurrence of variceal hemorrhage during pregnancy was new and
had not occurred preconceptionally. The rate of preconceptional
esophageal varices was mentioned in none of the included studies. In
total 12\% of variceal hemorrhage ended in maternal death (n=13). The
total numbers of variceal hemorrhage in recent studies (range 1982-2002)
were lower than in older studies (range 2004-2016) (OR 2.7 95\% CI
1.7-4.1; \emph{p} \textless{}0.0001), as is illustrated in the time
sequenced plot of incidences of variceal hemorrhage (figure S4). In the
study of Rasheed et all. 47\% of pregnancies were complicated by
variceal hemorrhage. The remaining seven studies found lower percentages
of variceal hemorrhage varying between 0 and 16\%. Screening endoscopy
for esophageal varices during pregnancy was reported in five recent
studies with rates of 3, 17, 28, 35 and 60\%. Accompanying endoscopic
therapy for (non-bleeding) esophageal varices was reported in three
studies with rates 5, 23 and 28\%.

The incidence of decompensated liver cirrhosis varied between 2 and
21\%, with an outlying incidence in the study of Rasheed et al., who
reported 64\%. Ascites prevalence was reported in five studies and
ranged from 3 to 11\%. Hepatic encephalopathy was also reported in five
studies and ranged from 1 to 13\%.

\textbf{Meta-analysis on obstetric and fetal outcomes}

Meta-analysis showed a significantly higher chance on preterm delivery
(OR 6.7 95\% CI 5.1- 9.1), cesarean section (OR 2.6, 95\% CI 1.7-3.9),
preeclampsia (OR 3.8, 95\% CI 2.2-6.5) and small for gestational age
neonates (OR 2.6, 95\% CI 1.6-4.2) in pregnant women with liver
cirrhosis compared to pregnant women without liver cirrhosis (Figure 2).
There was high heterogeneity in the analyses of preterm delivery,
cesarean section and small for gestational age. The studies thought to
be responsible for most heterogeneity were the studies of Rasheed et al.
and Flemming et al., based on their study design, patient
characteristics and inclusion criteria (see discussion). Sensitivity
analyses after elimination of these two studies did lower the
I\textsuperscript{2} on the outcomes preterm delivery
(I\textsuperscript{2} before 94\%, after 23\%) and small for gestational
(I\textsuperscript{2} before 71\%, after 0\%). The sensitivity analysis
of cesarean section maintained moderate heterogeneity
(I\textsuperscript{2} before 95\%, after 68\%).

\textbf{Obstetric and fetal complications}

Table 2 shows the most frequently reported obstetric and fetal
complications. Placental abruption was reported in three studies,
respectively Flemming et al., Murthy et al. and Rasheed et al. The
incidence of placental abruption was reported to be respectively 1, 6
and 10\% in these studies. The incidence of congenital malformations was
reported in the study of Hagstr\selectlanguage{ngerman}öm et al. and Salman et al. to be
respectively 2 and 3\%.

\textbf{Discussion}

\textbf{Main results}

Our study demonstrates that women with liver cirrhosis have increased
risks on maternal, fetal and obstetric complications during pregnancy
and delivery compared to healthy pregnant women. The maternal mortality
rate, although lower in recent studies, remained high at 0.89\%, where
in the general obstetric population maternal mortality is exceedingly
rare at 0.010\%. Variceal hemorrhage occurred in 4.0\% of pregnancies
and remained the most common cause of maternal death among women with
liver cirrhosis.

\textbf{Strengths and limitations}

To the best of our knowledge, this is the first systematic review and
meta-analysis on this topic. Previous reviews of the literature studied
considerably fewer pregnancies, were not available in English or were no
systematic reviews \textsuperscript{28-32}. To ensure high quality of
evidence and representativeness of the pregnant population with liver
cirrhosis, we excluded case reports and case series.

Although in individual studies the quality of selection of cohorts and
controls was generally high, selection bias in our study could exist,
since included studies used different inclusion criteria. For example,
some studies\textsuperscript{18, 24} excluded decompensated cirrhosis,
leading to an underestimation of reported outcomes.

Before sensitivity analysis the meta-analysis showed significant
heterogeneity between studies (reasons are mentioned below). The high
heterogeneity of the analysis of cesarean section
(I\textsuperscript{2}68\%) cannot be only attributed to differences in
known patient characteristics, as is demonstrated by the inability of
our sensitivity analyses to lower heterogeneity to an acceptable level.
Overall differences in clinical management differences in cesarean
section rates between countries are more likely to underlie the
heterogeneity. Specifically there may be distinct regional differences
in the management of delivery in liver cirrhosis, where some local
policies may favour cesarean section to prevent variceal hemorrhage
during delivery, while other policies may favor vaginal delivery in
order to avoid perioperative risks involved in abdominal surgery.
\textsuperscript{3, 33}

In our meta-analysis it was not possible to perform subgroup-analyses
based on diagnosis underlying cirrhosis or severity of cirrhosis, due to
the small number of events and missing information in included studies,
which could in future studies further allow individualized counseling
and management.

\textbf{Interpretation}

The maternal mortality rate in women with liver cirrhosis was 0.89\%
which was an 80-fold increased risk compared to pregnant controls
without cirrhosis. The most common cause of maternal mortality was
variceal hemorrhage during vaginal delivery, although there were large
differences in the reported rates of incidence of variceal
hemorrhage.\textsuperscript{34} The risk of maternal death as result of
variceal bleeding may have been overestimated in our review given the
decreases of maternal mortality and variceal hemorrhage in recent
studies. The decrease of variceal hemorrhage is probably the result of
the inclusion in (inter)national clinical guidelines to screen pregnant
women with liver cirrhosis in the second trimester for early detection
of esophageal varices. \textsuperscript{35} In addition, the
availability of treatment options like endoscopic variceal band ligation
have become widely available during the past decades, which were already
used in more recent studies included in this systematic
review.\textsuperscript{4, 18, 20} This treatment is considered safe in
pregnancy \textsuperscript{36, 37} and lowering the risk of (recurrent)
variceal hemorrhage and resulting in lower maternal morbidity and
mortality.

The risk of mortality in both pregnant and non-pregnant patients with
cirrhosis depends on etiology, severity and presence of complications,
as well as the presence of comorbid conditions. \textsuperscript{38} The
reported overall 30-day mortality rate after an episode of variceal
bleeding is 15-20\% \textsuperscript{8}, which is similar with the
mortality of 12\% after a variceal bleed in pregnant women in our study.
The one year mortality of non-pregnant patients with compensated liver
cirrhosis is 1.0\% and that of patients with compensated liver cirrhosis
as well as oesofageal varices 3.4\%. These data apply to all cirrhosis
patients, but 67\% of patients with liver cirrhosis are males older than
50 years. \textsuperscript{39} In comparison the maternal mortality
rates (\textless{}1\%) among pregnant cirrhosis patients may be slightly
lower, likely owing to the comparatively young age of pregnant women.
Due to our study design, we were not able to investigate whether
pregnancy is associated with more rapid progression of cirrhosis than
can be expected according to age.

The meta-analysis showed significant heterogeneity, mostly attributed to
two studies (Flemming et al. and Rasheed et al.) as demonstrated by our
sensitivity analysis. The study of Rasheed et al. differs in various
aspects from the other included studies. It is, in contrast to most
other included studies, a prospective cohort study of patients from a
middle-income country, possibly reflecting a lower level of care. This
study included all pregnancies including miscarriages, whereas the other
studies only described deliveries. Moreover, the etiology of liver
cirrhosis, in this study solely viral hepatitis, differs from those in
the other studies which included various causes. The study of Flemming
et al. did not have major differences on study design, study population
or etiology of liver cirrhosis. However, their case definition differed
because their analysis evaluated only primiparous women.



\textbf{Conclusion}

This is the first systematic review and meta-analysis of pregnancy in
women with liver cirrhosis. Liver cirrhosis complicates pregnancies for
both mother and child.

\textbf{Implications for research}

While our systematic review was able to quantify the increased risks of
liver cirrhosis in pregnancy, we were insufficiently powered to
demonstrate whether emerging management options have lowered some, or
all of these risks. Our study was not able to provide evidence on the
patient selection most likely to benefit from such management options.
In particular more data regarding course and treatment of liver
cirrhosis during pregnancy and treatment of specific complications (e.g.
variceal hemorrhage, ascites, jaundice, hepatic encephalopathy) are
needed to improve the knowledge and management of women with these
health issues and identify the women more at risk than others. We
suggest large prospective international studies could provide evidence
for many of these knowledge gaps, and could investigate which diagnostic
and treatment entities contribute to improved perinatal outcomes over
time.

\textbf{Implications for practice}

This systematic review provides evidence-based expectations for
clinicians and pregnant women with cirrhosis and will improve pregnancy
management for pregnant women with liver cirrhosis.

\textbf{Disclosure of interest}

None declared. Completed disclosure of interest forms are available to
view online as supporting information.

\textbf{Contributing to authorship}

The study was conceived by RCP and RBT. FSE performed the literature
search. LLS and RBT carried out selection of eligible studies. LLS and
IS extracted data and carried out the data analysis. RCP supervised the
data analysis. Differences of opinion were resolved by consensus with
RCP. All authors were involved in interpretation of the data and revised
the article critically.

\textbf{Details of ethics approval}

None.

\textbf{Funding} None.

\textbf{Acknowledgments}

None.

\par\null

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\textbf{Table 1.} Characteristics of included studies\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
\textbf{First author} & \textbf{Year of publication} & \textbf{Place} &
\textbf{Study design and origin of data} & \textbf{Study period} &
\textbf{Quality assesement} & \textbf{Number of pregnancies with
cirrhosis} & \textbf{Number of pregnancies without cirrhosis} &
\textbf{Included in meta-analysis}\tabularnewline
\midrule
\endhead
Salman \textsuperscript{18} & 2020 & Cairo, Egypt & Prospective cohort;
Cairo University hospitals & 2013-2018 & Fair & 100 & 100 &
Yes\tabularnewline
Flemming \textsuperscript{19} & 2020 & Kingston, Canada & Retrospective
cohort; Multiple databases housed in the Institute for Clinical
Evaluative Sciences & 2000-2017 & Good & 2098 & 10110 &
Yes\tabularnewline
Hagstr\selectlanguage{ngerman}öm \textsuperscript{20} & 2018 & Stockholm, Sweden & Prospective
cohort; Swedish Medical Birth Register & 1997-2011 & Good & 103 &
1361566 & Yes\tabularnewline
Jena \textsuperscript{21} & 2017 & Bangalore, India & Retrospective
cohort; St. John Medical College & 2010-2015 & Fair & 28 & &
No\tabularnewline
Palatnik \textsuperscript{4} & 2017 & Milwaukee, USA & Retrospective
cohort; Medical College of Winsconsin & 2005-2016 & Good & 31 & 124 &
Yes\tabularnewline
Borss\selectlanguage{ngerman}én \textsuperscript{22} & 2016 & Ume\selectlanguage{ngerman}å, Sweden & Retrospective
cohort; questionnaire & 1999-2010 & Poor & 43 & & No\tabularnewline
Puljic \textsuperscript{23} & 2015 & San Diego, USA & Retrospective
cohort; databases of California Department of Health Services &
2005-2009 & Good & 37 & 2248218 & Yes\tabularnewline
Rasheed \textsuperscript{24} & 2013 & Sohag, Egypt & Prospective cohort;
Sohag University Hospital & 2009-2012 & Good & 129 & 647 &
Yes\tabularnewline
Westbrook \textsuperscript{25} & 2011 & London, UK & Prospective cohort;
King's College Hospital & 1984-2009 & Fair & 62 & & No\tabularnewline
Murthy \textsuperscript{26} & 2009 & Toronto, Canada & Retrospective
cohort; Nationwide Impatient Sample database & 1998-2005 & Fair & 187 &
662408 & Yes\tabularnewline
Britton \textsuperscript{27} & 1982 & Portland, USA & Retrospective
cohort; Maine Medical Center & Unknown & Fair & 83 & & No\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} fetal and obstetric complications\selectlanguage{english}
\begin{longtable}[]{@{}llllllllll@{}}
\toprule
\textbf{Study} & \textbf{\% Cesarean section} & \textbf{\% Preterm
delivery} & \textbf{\% Postpartum hemorrhage} & \textbf{\% Preeclampsia}
& \textbf{\% Neonatal mortality} & \textbf{\% NICU\textsuperscript{*}
admission} & \textbf{\% Small for gestational age} & \textbf{\%
Intrauterine fetal demise} & \textbf{\% Miscarriage}\tabularnewline
\midrule
\endhead
Salman et al. 2020 & 35.0 & 25.0 & & 6.0 & 2.0 & & 7.0 & 5.0
&\tabularnewline
Flemming et al. 2020 & 32.7 & 11.4 & 7.0 & & & & 11.0 & &\tabularnewline
Hagstr\selectlanguage{ngerman}öm et al. 2018 & 35.9 & 18.6 & & 3.9 & 0.9 & & 7.8 & 0.9
&\tabularnewline
Jena et al. 2017 & & 17.9 & 17.9 & 17.9 & 3.6 & 21.4 & 41.7 & 7.2 &
57.1\tabularnewline
Palatnik et al. 2017 & 25.8 & 45.2 & 6.5 & 19.4 & 6.5 & 3.2 & 16.1 & 3.2
&\tabularnewline
Borss\selectlanguage{ngerman}én et al. 2016 & 25.6 & 23.3 & & & & & & & 42.4\tabularnewline
Puljic et al. 2015 & 69.5 & 56.8 & 5.4 & 13.5 & 2.7 & & 16.7 &
&\tabularnewline
Rasheed et al. 2013 & 81.4 & 26.4 & 16.3 & 12.4 & 4.7 & & 35.7 & 0 &
6.2\tabularnewline
Westbrook et al. 2011 & & 63.9 & & & 0 & 16.7 & 22.5 & 6.5 &
19.3\tabularnewline
Murthy et al. 2009 & 50.4 & 38.0 & & & & & & 0.9 &\tabularnewline
Britton et al. 1982 & 13.3 & & & & 3.6 & & & 4.8 & 10.8\tabularnewline
\bottomrule
\end{longtable}

*NICU = neonatal intensive care unit\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\selectlanguage{english}
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