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\begin{document}

\title{Gestational hypertensive disease and birthweight discordance in twin
pregnancies: a systematic review and meta-analysis}



\author[1]{Yuan Wang}%
\author[2]{Hongying Zeng}%
\author[1]{Jing Liu}%
\author[1]{Feng Zhang}%
\affil[1]{Nantong University}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
Background: For singletons, the relationship between gestational
hypertensive disease (GHD) and fetal growth anomalies has been
established. However, the association between GHD and birthweight
discordance in twin pregnancies is inclusive. Objective: To explore the
association between GHD and birthweight discordance in twin pregnancies.
Search strategy: PubMed, Embase, Web of Science and Cochrane Library
were systematically searched from establishment until July 2021.
Selection criteria: Studies reporting the risk of birthweight
discordance in twin pregnancies complicated by GHD compared with those
not were included. Data collection and analysis: Odds ratios (OR) and
95\% confidence intervals (CI) were extracted. Study heterogeneity was
evaluated by I2 index. Sub-group analyses and stratification were
performed. Risk of bias was assessed with the Newcastle-Ottawa Scale.
Main results: Ten studies (304181 twin pregnancies) were included. GHD
(OR 1.65, 95\% CI 1.41-1.94) was a risk factor for intertwin birthweight
discordance {[}preeclampsia (OR 1.66, 95\% CI 1.32-2.08); chronic
hypertension (OR 1.59, 95\% CI 1.46-1.73){]}. No evident association was
observed between gestational hypertension (GH) and intertwin birthweight
discordance (OR 1.24, 95\% CI 0.96-1.60). After stratification,
birthweight discordance was related to GHD (OR 2.51, 95\% CI 2.01-3.14),
GH (OR 2.08, 95\% CI 1.33-3.25) and preeclampsia (OR 2.74, 95\% CI
2.09-3.61) in dichorionic pregnancies, but no longer associated with GHD
and preeclampsia in monochorionic group. Conclusions: Twin gestations
complicated with GHD, especially in DC pregnancies, were at
significantly higher risk of birthweight discordance. Funding: Science
and Technology Program of Nantong City (MS12020036). Keywords:
gestational hypertensive disease, birthweight discordance, twin
pregnancies, chorionicity, systematic review%
\end{abstract}%



\sloppy


\textbf{Introduction}

During the past decade, the rate of twin pregnancies has remarkably
increased, and this is mainly ascribed to the rise in maternal age and
the improvements in fertility enhancing
treatments.\textsuperscript{1-3}A common adverse outcome for twin
pregnancies is intertwin birthweight discordance, defined as the
birthweight discrepancy divided by the birthweight of larger twin and
multiplied by 100.\textsuperscript{4} Birthweight discordance has been
reported to be related to an increased incidence of fetal intrauterine
death, neonatal neurological morbidities, respiratory distress,
infection, abnormal acid-base status, or necrotizing
enterocolitis.\textsuperscript{4,5}

Though the cause and pathophysiology of rising birthweight discordance
in twin pregnancies are not completely understood and mastered, recent
studies ascribed it to chorionicity,\textsuperscript{6} parental
race,\textsuperscript{7}maternal vitamin D levels,\textsuperscript{8}
total birthweight, maternal age, education, fetal
sex,\textsuperscript{9} weight gain during pregnancy\textsuperscript{10}
and GHD.

Gestational hypertensive disease (GHD), classified into gestational
hypertension (GH), preeclampsia (PE), eclampsia and chronic hypertension
(CH),\textsuperscript{11,12} is one of the most common disorders in
pregnancy and its incidence in twin pregnancies is at least double
greater than in singletons.\textsuperscript{13,14} The risk of PE was
2.3\% in singletons, 8.1\% in dichorionic (DC) twin pregnancies and
6.0\% in monochorionic (MC) twin pregnancies.~GHD is well recognized as
a major risk factor for maternal morbidity, perinatal mortality and
preterm delivery.\textsuperscript{14,15}For singletons, the relationship
between GHD and fetal growth anomalies has been well
established.\textsuperscript{16} However, studies investigating the
association between GHD and birthweight discordance in twin pregnancies
have reported differing results. In spite of the previous negative
findings that the risk of intertwin birthweight discordance was similar
between pregnancies with GHD and normotensive
ones,\textsuperscript{17-19} some other reports have shown that the
degree of intertwin birthweight discordance in twin pregnancies is
directly correlated with the risk of GHD.\textsuperscript{20-26}

It is crucial to clarify the impact of GHD on intertwin birthweight
discordance, as increased risks of perinatal outcomes are associated not
only with GHD itself, but also with intertwin birthweight
discordance.\textsuperscript{4,27-29}Therefore, the aim of this
systematic review was to explore the association between GHD and
birthweight discordance in twin pregnancies.

\textbf{Material and methods}

\textbf{Protocol, eligibility criteria, information sources and search}

This systematic review was performed and conducted following the
PRISMA\textsuperscript{30} and MOOSE\textsuperscript{31} guidelines,
which were recommended standards for systematic reviews and
meta-analysis. PubMed, Embase, Web of Science and Cochrane Library were
searched systematically for relevant studies from establishment until
July 2021, combining relevant medical subject heading terms, key words
and word variants for ``hypertension'' or ``hypertensive'' or
``preeclampsia'' or ``preeclamptic'' or ``eclampsia'' or ``eclamptic''
and ``birthweight'' and ``discordance'' or ``discordant'' and ``twin
pregnancies'' (Appendix S1). The search and inclusion criteria were
restricted to human data and English language. Additional reports were
manually searched by two authors (YW, HYZ) according to the reference
lists of selected articles and reviews.

\textbf{Study selection, data collection and data items}

All studies (cohort studies and case-control studies) reporting data on
the birthweight discordance affected by GHD in twin pregnancies were
included. This review included all women in both DC and MC twin
pregnancies complicated with gestational hypertension, chronic
hypertension, preeclampsia and eclampsia. We excluded pregnancies with
intrauterine death of one or both twins.

The outcome was the intertwin birthweight discordance, which was
calculated utilizing the following equation: birthweight discordance
(\%) = (larger twin's birthweight - smaller twin's birthweight)/larger
twin's birthweight) \selectlanguage{ngerman}× 100. We performed the review according to one of
the most common cut\selectlanguage{english}-offs of birthweight discordance
(\selectlanguage{english}[?]15\%).\textsuperscript{4}

Furthermore, according to the classification of GHD, we planned to
perform sub-group analyses reporting cases with GH, PE, eclampsia and CH
separately. According to the criteria outlined by
ACOG,\textsuperscript{32,33} concretely, GH was defined as systolic
blood pressure (BP) \selectlanguage{english}[?]140 mmHg or \selectlanguage{english}[?] 90 diastolic mmHg after 20 weeks of
gestation, PE met the same criteria as GH with either proteinuria or
end-organ dysfunction (liver dysfunction, renal dysfunction, central
nervous system disturbances, thrombocytopenia, or pulmonary edema).
Eclampsia was defined as a new onset of seizures in women with PE, who
showed a convulsive episode or other sign of altered consciousness. CH
was diagnosed as a pre-existing hypertensive disease or BP \selectlanguage{english}[?]140 mmHg
systolic or \selectlanguage{english}[?] 90 mmHg diastolic preceding 20 weeks gestation.

In order to ascertain whether the association between GHD and intertwin
birthweight discordance differs according to chorionicity,
stratification by twin chorionicity (DC and MC) was performed. The
assessment of chorionicity was clinically based on the ultrasound
evaluation, including the number of gestational sacs, placenta and
embryos at early pregnancy, \selectlanguage{greek}τ-\selectlanguage{english}sign or \selectlanguage{greek}λ-\selectlanguage{english}sign, the fetal
sex,\textsuperscript{34} and after delivery it was confirmed by
examining the placenta.

Two authors (YW, HYZ) screened all studies independently in view of the
inclusion and exclusion standards. Where there were inconsistencies,
consensus was reached by discussion with another reviewer (FZ). With
full text copies of included studies obtained, the same two reviewers
extracted relevant data in regard to study characteristics and pregnancy
outcomes independently. In case over one study was published based on
the identical cohort with uniform endpoints, the report demonstrating
the most comprehensive information was included.

Quality assessment was performed with the Newcastle-Ottawa Scale (NOS)
adapted for cohort and case-control studies. Each study is evaluated
from three broad aspects: selection of patients, comparability of study
groups and ascertainment outcome of interest. The scores of the NOS
range from 0 to 9. The included studies were interpreted to be of high
risk of bias (for scores [?] 4), medium risk of bias (for scores 5-7), or
low risk of bias (for scores [?] 7).\textsuperscript{35} Articles with low
risk of bias were included in the analysis.

\textbf{Statistical analyses}

Data analysis was carried out using Review Manager (version 5.3)
software. Heterogeneity between studies was explored using the Higgins
I\textsuperscript{2} statistics. When there was substantial
heterogeneity (I\textsuperscript{2} [?] 50\%), the random effect model was
used to estimate the pooled risk ratio, otherwise the fixed effect model
was used. Subgroup analyses were employed to evaluate the sources of
heterogeneity, and stratification by twin chorionicity (DC and MC) was
performed to exclude the impact of chorionicity on the outcome. The odds
ratio (OR) and 95\% confidence interval (CI) were the summary measures
applied to assess each endpoint. Potential publication biases were
statistically examined by Egger's test and visually by funnel plots
(Figure S2).

\textbf{Results}

\textbf{General characteristics}

A total of 2532 articles were identified, 57 were assessed with respect
to their eligibility for inclusion, and 10
studies\textsuperscript{17-26} were deemed suitable to be included in
this systematic review (Table S1; Figure S1). These 10 studies
(including 304181 twin pregnancies) reported the occurrence of
birthweight discordance in twin pregnancies complicated by GHD compared
with those not. Eight of these included papers were cohort studies,
whereas two were case-control studies\textsuperscript{17,19}. Three of
them were conducted in China\textsuperscript{19,24,26}, two in the
USA\textsuperscript{21,22}, two in the UK\textsuperscript{17,25}, two in
Rome\textsuperscript{18,20} and one in Ireland\textsuperscript{23}.
Among the selected studies, four reported the intertwin birthweight
discordance affected by GH\textsuperscript{17,18,24,26}, three affected
by CH\textsuperscript{17,21,22} and five affected by
PE\textsuperscript{19-21,24,26} in detail. Only three of the included
studies\textsuperscript{24-26} conducted stratification by twin
chorionicity.

Quality assessment of the selected studies performed using NOS is
presented in Table S2. Most of the studies scored well in terms of
selection, comparability and outcome. The main weaknesses of these
studies were their retrospective design, small sample size, lack of
information on the follow-up outcome, different gestational ages at scan
and heterogeneity in the cut-off of birthweight discordance adopted.

\textbf{Synthesis of the results}

\textbf{GHD VS Normotensive}

Ten studies (304181 twin pregnancies) explored the risk of birthweight
discordance ([?]15\%) in twin pregnancies complicated by GHD compared with
Normotensive group. Considering all twin pregnancies, the risk of
birthweight discordance was significantly higher in twin pregnancies
with GHD (OR 1.65, 95\% CI 1.41-1.94; I\textsuperscript{2} =57\%). After
stratified by twin chorionicity, birthweight discordance was associated
with an increased risk for GHD (OR 2.51, 95\% CI 2.01-3.14;
I\textsuperscript{2} =0\%) in DC twin pregnancies. However, no
significant association was observed in MC group (OR 1.14, 95\% CI
0.76-1.72; I\textsuperscript{2} =0\%). (Figure 1)

\textbf{GH VS Normotensive}

Four studies (5216 twin pregnancies) explored the risk of birthweight
discordance ([?]15\%) in twin pregnancies with GH compared to Normotensive
group. In all, no evident association was observed between GH and the
incidence of intertwin birthweight discordance (OR 1.24, 95\% CI
0.96-1.60; I\textsuperscript{2} =0\%). According to the stratified
sampling, GH was a risk factor for birthweight discordance in DC group
(OR 2.08, 95\% CI 1.33-3.25; I\textsuperscript{2} =0\%), but a
protective factor in MC group (OR 0.37, 95\% CI 0.16-0.82;
I\textsuperscript{2} =0\%). (Figure 2)

\textbf{PE VS Normotensive}

Five studies (293612 twin pregnancies) explored the risk of birthweight
discordance ([?]15\%) in twin pregnancies with PE compared to Normotensive
group. It turned out that the risk of birthweight discordance was
significantly higher in twin pregnancies with PE (OR 1.66, 95\% CI
1.32-2.08; I\textsuperscript{2} =64\%). Birthweight discordance was
associated was PE in DC (OR 2.74, 95\% CI 2.09-3.61;
I\textsuperscript{2} =40\%) but not in MC (OR 1.21, 95\% CI 0.68-2.15;
I\textsuperscript{2} =0\%) twin pregnancies based on the stratification
by chorionicity. (Figure 3)

\textbf{CH VS Normotensive}

Three studies (269259 twin pregnancies) explored the risk of birthweight
discordance ([?]15\%) in twin pregnancies affected by CH compared with
Normotensive group. Overall, twin pregnancies affected by CH were at a
higher risk of birthweight discordance (OR 1.59, 95\% CI 1.46-1.73;
I\textsuperscript{2} =3\%). (Figure 4)

\textbf{Discussion}

\textbf{Main Findings}

This systematic review demonstrated that birthweight discordance was
associated with GHD in twin pregnancies. The risk of birthweight
discordance increases in parallel to the incidence of GHD. After
stratification, birthweight discordance was related to GHD, GH and PE in
DC pregnancies, but no longer associated with GHD and PE in MC group.

\textbf{Strengths and Limitations}

To the best of our knowledge, few systematic reviews explored the
association between GHD and birthweight discordance in twin pregnancies.
The main strengths are an inclusive and accurate literature search
strategy, multitude of explored outcomes, sub-group analyses performed
according to the classification of GHD and stratified sampling conducted
based on twin chorionicity.

However, some limitations needed to be acknowledged were small number of
selected studies, different inclusion criteria for the included
population, and different approach towards the antenatal management of
twin pregnancies. The reliability of the systematic review was strongly
limited by the small sample size of individual studies. Furthermore, the
findings were subject to the differences in the cut-off of birthweight
discordance adopted by each study. Another major limitation of our
present systematic review was that as only one of the included
studies\textsuperscript{21} reported twin pregnancies with eclampsia,
lack of related data made it a challenge to report the association
between the incidence of eclampsia and the risk of intertwin birthweight
discordance.

In spite of these limitations, this study represents the newest and most
comprehensive published assessment of the association between GHD and
birthweight discordance in twin pregnancies.

\textbf{Interpretation}

GHD, particularly PE and CH, is a significant risk factor for intertwin
birthweight discordance. Though the reason for the existence of this
association remains unclear and may be in connection with the
multifactorial aspect of GHD, there are some possible explanations for
this association. Findings such as retroplacental hematomas, thrombotic
lesions, fibrin deposition and more velamentous cord insertions were
observed in the placentas of discordant twins.\textsuperscript{36,37}

In discordant twins complicated with PE, the placental mass hypothesis
might further explain the histological findings observed in the
placentas. In twin pregnancies, an increased release of some
antiangiogenic molecules may be related to lager placental mass. Soluble
fms-like tyrosine kinase-1 (sFlt-1) turned out to play a crucial part in
the pathogenesis of PE,\textsuperscript{38,39} which possibly causes
placental ischemia/hypoxia, supposing the placentas contract diseases,
the smaller one in the twins might fail to achieve the growth potential
because of the placental vascular dysfunction.\textsuperscript{40,41}

Moreover, the genetic incompatibility and/or increased immunologic
response theory maybe another explanation. Some studies revealed higher
levels of syncytiotrophoblast microparticles and fetal nucleic acids in
the maternal blood in twin pregnancies complicated by
PE.\textsuperscript{42-44} Other studies showed that the interactions
between paternal antigens of leukocytes and maternal natural killer
cell, and cytotoxic T-cell response to those antigens were mechanisms
contributing to the development of PE.\textsuperscript{45} Exposed to
increased levels of placental microparticles or fetal antigens which can
trigger in appropriate immune responses, women will possibly deliver
twins with birthweight discordance.

Additionally, as common umbilical cord abnormalities, velamentous cord
insertions are risk factors for PE.\textsuperscript{46} It was found
that velamentous cord insertion is a crucial indicator of intertwin
birthweight discordance.\textsuperscript{47} It was speculated that the
high incidence of velamentous insertions in twin pregnancies complicated
with PE leads to an increased risk of birthweight discordance.

When it comes to twin pregnancies complicated with CH, Sparks et
al.\textsuperscript{22} pointed out that the chronic hypertension
environment may further impose much more stress on twins with
pre-existing differences regarding growth potential. However, whether
related to potential genetic differences or not, abnormal placentation
itself might lead to the development of fetal growth abnormalities.
Therefore, the mechanism of the correlation between CH and intertwin
birthweight discordance deserves further investigation.

However, GH might play an unknown beneficial role in MC pregnancies
according to the stratified analysis, which was reflected by Ferrazzani
S et al.\textsuperscript{18} that GH could be a paraphysiological
phenomenon in twin pregnancies ensuring a better placental perfusion.
More studies are necessary to explain the pathogenesis of this finding.

According to the subgroup and stratified analyses, the risk of intertwin
birthweight discordance differed based on chorionicity. DC twins are
mostly fraternal twin pregnancies, either due to two separate placentas
or pre-existing genetic differences between twins in growth
potential.\textsuperscript{40} The potential genetic differences between
the twins might probably interact with hypertensive environments,
leading to discordant uteroplacental blood flow, placental changes, and
growth in DC group. The placental anatomy is unique in MC twin
pregnancies, and the fetal circulations were conjoined in a single
placenta. Among MC twins, birthweight discordance is related to
placental territory discordance between the fetuses, velamentous cord
insertions, and the type and number of vascular
anastomoses.\textsuperscript{48-50}

So as to why birthweight seemed to be less affected by GHD in MC twin
pregnancies. It could be attributed to an earlier gestational age at
delivery and before the occurrence of PE in MC twin
pregnancies,\textsuperscript{51} otherwise the true risk of birthweight
discordance in MC twin pregnancies with PE might actually be higher. In
addition, compared to DC ones, the circulating blood volume is lower in
MC twin pregnancies, which brings about better cardiovascular adaptation
to pregnancy.\textsuperscript{52}

However, the findings of our study should be elucidated carefully due to
small number and sample size of selected studies, more fundamental and
clinical studies are warranted to focus on the effect of GHD on
intertwin birthweight discordance.

\textbf{Conclusion}

We collected evidence suggesting the association between GHD and
birthweight discordance in twin pregnancies. Twin gestations complicated
with GHD, especially CH and PE, were at significantly higher risk of
birthweight discordance. The influence of GHD on intertwin birthweight
discordance differed based on chorionicity. GHD had greater effect on
the risk of birthweight discordance of DC twins. The findings from the
present review suggest that better clinical assessments and evaluations
of prognosis, and increased maternal and fetal monitoring in twin
pregnancies are justified, which can assist in providing better
individualized counseling and optimal pregnancy management for twin
gestations complicated by GHD.

\textbf{Acknowledgements}

None.

\textbf{Disclosure of interests}

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

supporting information.

\textbf{Contribution to authorship}

YW and HYZ contributed to planning the review, screening all titles and
abstracts, reviewing full articles, and performing data extraction. FZ
was a third reviewer in case where there were inconsistencies. YW
performed the data analysis and drafted the initial manuscript. JL
assisted with the study design and data analysis. FZ contributed to
interpreting the data and revising the manuscript. All authors approved
the final version of this manuscript.

\textbf{Details of ethics approval}

Not applicable.

\textbf{Funding}

This work was supported by the Funding of Science and Technology Program
of Nantong City (MS12020036).

\textbf{Conflicts of interest}

None

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\textbf{Figure legends}

\textbf{Figure 1.} Forest plots showing the risk of birthweight
discordance in twin pregnancies with GHD. Stratification by twin
chorionicity (DC and MC) was performed. GHD, gestational hypertensive
disease; DC, dichorionic; MC, monochorionic.

\textbf{Figure 2.} Forest plots showing the risk of birthweight
discordance in twin pregnancies with GH. Stratification by twin
chorionicity (DC and MC) was performed. GH, gestational hypertension;
DC, dichorionic; MC, monochorionic.

\textbf{Figure 3.} Forest plots showing the risk of birthweight
discordance in twin pregnancies with PE. Stratification by twin
chorionicity (DC and MC) was performed. PE, preeclampsia; DC,
dichorionic; MC, monochorionic.

\textbf{Figure 4.} Forest plots showing the risk of birthweight
discordance in twin pregnancies with CH. CH, chronic hypertension.

\textbf{Online Supporting Information}

\textbf{Appendix S1.} Search strategy.

\textbf{Table S1.} General characteristics of the studies included in
the meta-analysis.

\textbf{Table S2.} Risk of bias assessment cohort studies
(Newcastle\selectlanguage{english}-Ottawa Quality Assessment Scale criteria).

\textbf{Figure S1.} Flowchart showing the selection process of the
included studies.

\textbf{Figure S2.} Funnel Plot of the studies included.

\textbf{Hosted file}

\verb`Figure1-4.docx`  available at \url{https://authorea.com/users/734972/articles/711624-gestational-hypertensive-disease-and-birthweight-discordance-in-twin-pregnancies-a-systematic-review-and-meta-analysis}

\selectlanguage{english}
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\end{document}

