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\begin{document}

\title{Prediction of cesarean delivery after induction of labor in twin
pregnant women: a retrospective cohort study}



\author[1]{Seung Hyun Bang}%
\author[1]{Seung Mi Lee}%
\author[2]{Sohee Oh}%
\author[1]{Su Jin  Sung}%
\author[1]{Jeesun Lee}%
\author[3]{Jee Yoon Park}%
\author[1]{Chan-Wook Park}%
\author[1]{Joong Shin Park}%
\author[1]{Jong Kwan Jun}%
\affil[1]{Seoul National University College of Medicine}%
\affil[2]{Seoul National University Seoul Metropolitan Government Boramae Medical Center}%
\affil[3]{Seoul National University Bundang Hospital Department of Obstetrics and Gynecology}%


\vspace{-1em}



  
  \date{June 09, 2024}


\begingroup
\let\center\flushleft
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\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective: The purpose of this study was to develop a predictive model
for cesarean delivery after induction of labor (IOL) in twin pregnancy.
Design: Retrospective cohort study Setting: University hospital.
Population: Twin pregnancy who underwent IOL from 2005 to 2018 Methods:
The study population was randomly divided into the training and test
sets at a ratio of 2:1. Three-fold cross-validation (CV) with 100 times
repetitions was applied to select the best model. Main outcome measure
to develop and validate a prediction model for cesarean delivery after
IOL in twin pregnancies. Results: A total of 1,703 twin pregnancies were
analyzed, including 1,356 women in the development cohort of the SNUH
database and 347 women in the external validation cohort of the SNUBH
database. In the development cohort, the clinical variables that were
different between the successful and failed IOL groups were included in
the logistic regression analysis, and the final prediction model,
composed of five variables (maternal age, maternal height, parity,
cervical effacement, and summated birth weight of both twins), was
selected with an AUROC of 0.742 (95\% confidence interval {[}CI{]},
0.700-0.785) and 0.733 (95\% CI, 0.671-0.794) in the training set and
test set, respectively. A nomogram for predicting the risk of cesarean
delivery after IOL in twin pregnancies was also developed. Conclusion: A
prediction model to provide information and evaluate the risk of
cesarean delivery after IOL in twin pregnancies was developed. Keywords
Twin pregnancy, induction of labor, cesarean section, prediction model%
\end{abstract}%



\sloppy


\textbf{Prediction of cesarean delivery after induction of labor in twin
pregnant women: a retrospective cohort study}

Seung Hyun Bang\textsuperscript{1}, Seung Mi Lee\textsuperscript{1},
Sohee Oh\textsuperscript{2}, SuJin Sung\textsuperscript{1},Jeesun
Lee\textsuperscript{1}, Jee Yoon Park\textsuperscript{1,3},Chan-Wook
Park\textsuperscript{1},Joong Shin Park\textsuperscript{1}, Jong Kwan
Jun\textsuperscript{1}

1 Department of Obstetrics and Gynecology, Seoul National University
College of Medicine, Seoul, Korea

\textsuperscript{2}Department of Biostatistics, Seoul Metropolitan
Government Seoul National University Boramae Medical Center, Seoul,
Korea

\textsuperscript{3}Department of Obstetrics and Gynecology, Seoul
National University College of Medicine, Seoul National University
Bundang Hospital, Seongnam, Korea

SH Bang and SM Lee contributed equally as the first authors of this
study.

This study was presented at the 40th Annual Pregnancy Meeting in Society
for Maternal-Fetal Medicine (7 February 2020) in Texas, United States

\textbf{Conflicts~of~Interest:~} The authors report no conflicts of
interest.

\textbf{Correspondence to} :

Jong Kwan Jun, MD, PhD

Department of Obstetrics and Gynecology, Seoul National University
College of Medicine, Seoul, 110-744, Korea.

Tel: 82-2-2072-3744

Fax: 82-2-762-3599

E-mail: jhs0927@snu.ac.kr

\textbf{Funding}

This work was supported by a grant from the Korea Health Technology R\&D
Project through the Korea Health Industry Development Institute (KHIDI),
funded by the Ministry of Health \& Welfare, Republic of Korea (grant
number: HI19C0213).

\textbf{Abstract word count} : 242

\textbf{Text word count} : 2,358

\emph{Abstract}

\textbf{Objective} The purpose of this study was to develop a predictive
model for cesarean delivery after induction of labor (IOL) in twin
pregnancy.

\textbf{Design} Retrospective cohort study

\textbf{Setting} University hospital.

\textbf{Population} Twin pregnancy who underwent IOL from 2005 to 2018

\textbf{Methods} The study population was randomly divided into the
training and test sets at a ratio of 2:1. Three-fold cross-validation
(CV) with 100 times repetitions was applied to select the best model.
Main outcome measure to develop and validate a prediction model for
cesarean delivery after IOL in twin pregnancies.

\textbf{Results} A total of 1,703 twin pregnancies were analyzed,
including 1,356 women in the development cohort of the SNUH database and
347 women in the external validation cohort of the SNUBH database. In
the development cohort, the clinical variables that were different
between the successful and failed IOL groups were included in the
logistic regression analysis, and the final prediction model, composed
of five variables (maternal age, maternal height, parity, cervical
effacement, and summated birth weight of both twins), was selected with
an AUROC of 0.742 (95\% confidence interval {[}CI{]}, 0.700-0.785) and
0.733 (95\% CI, 0.671-0.794) in the training set and test set,
respectively. A nomogram for predicting the risk of cesarean delivery
after IOL in twin pregnancies was also developed.

\textbf{Conclusion} A prediction model to provide information and
evaluate the risk of cesarean delivery after IOL in twin pregnancies was
developed.

\textbf{Keywords} Twin pregnancy, induction of labor, cesarean section,
prediction model

\emph{Introduction}

Recent improvement in assisted reproductive technologies (ART) has led
to an increase in the rate of twin pregnancies.\textsuperscript{1,2}
Compared to singleton pregnancies, twin pregnancies are at a higher risk
for gestational hypertension, preeclampsia,\textsuperscript{3,4}
intrahepatic cholestasis,\textsuperscript{5} and gestational
diabetes.\textsuperscript{6} Moreover, there is a higher risk of
stillbirth with advancing gestational age even in uncomplicated
twins,\textsuperscript{3-8,} and elective delivery at 37-38 weeks of
gestation is generally recommended.\textsuperscript{9,10}

Regarding the mode of delivery, diamniotic twin pregnancies with the
cephalic presentation of the fetus are candidates for vaginal delivery.
Planned vaginal delivery was shown to have a similar risk of neonatal
mortality/morbidity and maternal morbidity compared to planned cesarean
delivery in uncomplicated twin pregnancies.\textsuperscript{11} The
American College of Obstetricians and Gynecologists and the Society for
Maternal-Fetal Medicine recommend that women with twin pregnancies with
either cephalic/cephalic twins or cephalic/non-cephalic twins should
undergo counseling to attempt a vaginal delivery.\textsuperscript{12}

Women with twin pregnancies who plan to give birth through vaginal
delivery without labor pain may undergo labor induction for vaginal
delivery. While several reports have shown that induction can be safely
performed without increased risk\textsuperscript{11,13,14}, others have
reported an increased risk.\textsuperscript{15-19} Therefore, twin
pregnant women should undergo counseling regarding the benefits and
risks of labor induction. The prediction of successful induction is a
clinically important issue. However, there are few studies on the risk
factors for cesarean delivery after IOL in twin pregnancies.

To address this issue, we conducted this study to develop and validate a
prediction model for cesarean delivery after IOL in twin pregnancies.

\emph{Methods}

\textbf{Study design}

(1) Development cohort

In this retrospective cohort study, this group consisted of twin
pregnant women underwent IOL at [?] 36 weeks of gestation at SNUH from
2005 to 2018. Twin pregnant women with the following inclusion criteria
were included: 1) both viable fetuses; 2) the first baby in the cephalic
presentation; 3) no contraindication for IOL (e.g., abnormal
placentation, fetal compromise, fetal congenital anomaly, previous
uterine surgery, or cesarean delivery); and 4) absence of spontaneous
labor, which is defined as regular uterine contractions with cervical
change. Women who gave birth through combined delivery (cesarean
delivery of the second baby followed by vaginal delivery of the first
baby) were excluded.

(2) Validation cohort.

In this validation cohort, the study population consisted of twin
pregnant women who underwent IOL at [?] 36 weeks of gestation at SNUBH
from 2005 to 2018. In SNUBH, it is routine practice to perform IOL only
in cases with the cephalic presentation of both fetuses, therefore twin
pregnancies with cephalic (1st baby) / non-cephalic (2nd baby)
presentation are not candidates for IOL.

We collected clinical characteristics including maternal age, maternal
height, maternal weight, pregestational body mass index (BMI, divided by
weight in kilograms (kg) by the square of their height in meters
(m\textsuperscript{2})), parity, gestational age at IOL, gestational age
at delivery, method of conception, cervical examination, chorionicity,
presentation, and birth weight of each twin, and summated birth weight
of both twins. The variables were compared between pregnant women who
had a successful vaginal delivery and those who underwent cesarean
delivery after IOL. This retrospective study was approved by the
Institutional Review Board of SNUH and SNUBH.

\textbf{Induction of labor}

The clinical decision regarding IOL was made at the discretion of the
attending physician. Induction was performed either by transvaginal
prostaglandin (dinoprostone or misoprostol), intravenous oxytocin
infusion, or a combination of both.\textsuperscript{18,20-22} Electronic
monitoring of the fetal heart rate was performed continuously. After the
delivery of the first baby, use of ultrasonography was conducted to
check the presentation and heart rate of the second baby. If the second
baby was in the cephalic presentation, we waited for spontaneous
engagement and vaginal delivery with or without the use of vacuum
extraction. If the second baby had a non-reassuring fetal heart rate or
was not in the cephalic presentation, the obstetrician determined the
best delivery method (vacuum extraction, total breech extraction with or
without internal podalic version, or combined intrapartum cesarean
section). The diagnosis of failure to progress or fetal distress and the
subsequent decision for cesarean delivery was made by the attending
physician.

\textbf{Statistical analysis}

Categorical variables were compared with the chi-square test, and
continuous variables were compared using the Student's t-test. To select
the best prediction model for cesarean delivery in the development
cohort, a three-fold CV with 100 repetitions was applied. CV is a
statistical analysis method used to organize and evaluate study models.
The study population in the development cohort was randomly divided into
a training set and a test set with a ratio of 2:1. In the training set,
the prediction model was developed by logistic regression analysis with
clinical variables that were different between cases with vaginal
delivery and those with cesarean delivery. In logistic regression
analysis, a generalized estimating equation (GEE) was used to account
for the familial correlation between twin pairs within a single mother.
The developed model was evaluated using a test set. The model with the
highest average test area under the receiver operating characteristic
(AUROC) was selected as the best model. To validate the developed
prediction model, AUROC was also calculated in the validation cohort.
The model with the highest average AUROC in the test set was selected as
the final prediction model and was then validated with the external
validation group using the SNUBH database. A P-value of 0.05 was
considered significant and statistical analyses were performed with IBM
SPSS version 25 for Windows.

\emph{Results}

(1) Development cohort

During the study period, a total of 1,356 twin pregnant women who met
the inclusion criteria and delivered at SNUH, were assigned as the
development cohort. The indications for IOL were maternal request
(n=517), prolonged pregnancy (n=484), suspected intrauterine growth
retardation (n=147), rupture of membrane (n=110), preeclampsia (n=60),
gestational diabetes (n=13), suspected large for gestational age fetus
(n=9), chronic hypertension (n=6), oligohydramnios (n=5) and other
reasons for maternal medical condition (n=5).

Of these twin pregnant women, 17.0\% (n=230) underwent cesarean delivery
and 83.0\% (n=1126) underwent vaginal delivery. The reasons for cesarean
delivery were failure to progress (n=81), failed induction (n=64),
maternal condition (such as medical reason or request, n=54), and
non-reassuring fetal status (n=31). Failed induction was defined as
failure to give birth after more than three days of serial induction
without rupture of the membrane.\textsuperscript{23,24}

Table 1 compares the clinical variables according to the final mode of
delivery. The gestational age at labor induction and presentation of the
second twin did not differ between the two groups. However, patients who
underwent cesarean delivery were older, had shorter height, higher
pregestational body mass index, less effaced and dilated cervix, and
heavier birth weight of twins. In addition, patients who underwent
cesarean delivery were more likely to become pregnant after assisted
reproductive techniques and had a higher frequency of nulliparous and
dichorionic twins.

To find the best prediction model for cesarean delivery with these
clinical variables, we conducted a three-fold CV with 100 repetitions.
The study population in the development cohort was randomly divided into
a training set and a test set with a ratio of 2:1, and the prediction
model was developed using logistic regression analysis in the training
set, and the AUROC was calculated in the test set. Table S1 shows the
mean AUROC for each prediction model. Among the possible models, the
prediction model including maternal age, parity, maternal height,
cervical effacement, and total birth weight of twins, had the highest
average AUROC value in the test set and was selected as the best
prediction model {[}AUROC, 0.742 (95\% CI 0.700-0.785) in the training
set and 0.733 (95\% CI, 0.671-0.794) in the test set{]}. Table 2
summarizes the odds ratios of each variable in the best prediction model
in the SNUH development cohort. In addition, a nomogram for predicting
the risk of cesarean delivery after IOL in twin pregnancy (Figure 1) and
a web-based predictive calculator (Figure 2) was developed.

(2) Validation cohort.

In SNUBH, a total of 347 twin pregnant women who met the inclusion
criteria and delivered between 2005 and 2018 were assigned as the
external validation cohort. In this validation cohort, 26.5\% of women
(n=92) underwent cesarean delivery. External validation of the
prediction model for cesarean delivery derived from the SNUH cohort was
performed on this cohort. The AUROC in this cohort was 0.714 (95\% CI,
0.650-0.777), which was similar to that of the development cohort
(Figure 3).

\emph{Discussion}

\textbf{Main findings}

The principal findings of this study were: (1) We developed a prediction
model, composed of five variables (maternal age, maternal height,
parity, cervical effacement, and total birth weight of twins), for
cesarean delivery after IOL in twin pregnant women; (2) In addition, a
nomogram for predicting the risk of cesarean delivery after IOL in twin
pregnancies was developed; and (3) The developed prediction model showed
good performance in both the development and external validation
databases.

To predict the risk of cesarean delivery after IOL in twin pregnancies,
we compared many clinical variables including maternal age, maternal
height, maternal weight, pregestational BMI, parity, gestational age at
IOL, gestational age at delivery, method of conception, cervical
examination, chorionicity, presentation and birth weight of each twin,
and total birth weight of twins. We found some independent risk factors
that increased the risk of cesarean delivery, and the final prediction
model included maternal age, parity, maternal height, cervical
effacement, and total birth weight of twins. Maternal age, maternal
height, and cervical effacement are also known risk factors in singleton
pregnancies.\textsuperscript{25,26} The birth weight-related variable
retained in the final model was the total birth weight of twins.

To our knowledge, this is the first study to develop a prediction model
for cesarean delivery after IOL in twin pregnancies. Several studies
have reported many prediction models after IOL in singleton
pregnancies.\textsuperscript{25,27} The AUROC of the prediction model in
the current study was 0.742 (95\% CI 0.700-0.785) in the training set,
0.733 (95\% CI 0.671-0.794) in the test set, and 0.714 (95\% CI
0.650-0.777) in the validation cohort, which is similar to the reported
AUROC of the prediction models in singleton pregnancies (AUROC 0.787
{[}95\% CI 0.786-0.788{]} in the study by Rossi et
al.\textsuperscript{27}, 0.79 {[}95\% CI, 0.74-0.83{]} in the study by
Levine et al.\textsuperscript{25}).

\textbf{Clinical implications}

For clinical utility, a nomogram for the prediction of cesarean delivery
after induction was constructed according to the final prediction model
(Figure 1). In addition, a web-based calculator was created to estimate
the likelihood of cesarean delivery after IOL in twin pregnancies
(Figure 2, http://snuhtwin.com/). The nomogram and calculator will be
useful when considering counseling for labor induction in twin pregnant
women without contraindications for vaginal delivery. In particular,
this predictive calculator can be used to provide clinical information
for twin pregnant women who are considering IOL.

\textbf{Research implications}

Although we have developed a prediction model and validated the model in
an independent study population, the developed model should be further
evaluated in other institutions with different races/ethnicities to
confirm the results of this current study. Moreover, through a
prospective randomized trial, we may be able to establish new protocols
regarding the usefulness of the developed prediction model. In addition,
the maternal or neonatal outcomes in terms of morbidity/mortality after
IOL in twin pregnancies need to be evaluated.

\textbf{Strengths and limitations}

The strength is that this is the first study to develop a prediction
model for cesarean delivery after IOL in twin pregnancies. Some risk
factors that increased cesarean delivery after IOL have been reported in
previous studies.\textsuperscript{24,28-30} However, we first developed
a prediction model that can estimate the risk of cesarean delivery after
IOL. Another strength of our study is the large sample size. A total of
1,772 twin pregnant women were analyzed. In addition to deriving a
development model for cesarean delivery, we validated the model
internally and externally to interpret the reliability of a model in a
more generalized population.

Nevertheless, the current study has several limitations. Several other
important clinical variables such as Bishop score and cervical length
could not be evaluated as this was a retrospective study, although these
variables might be associated with the risk of cesarean
delivery.\textsuperscript{24,25} In addition, the current study
population included only Asian, mainly Korean women, and investigated
only two tertiary hospitals. Finally, the current study did not evaluate
maternal and neonatal morbidity and mortality, which are beyond the
scope of the current study. Few previous studies have found that such
outcomes were not significantly different between planned cesarean
delivery and vaginal delivery after IOL in twin
pregnancy.\textsuperscript{11,14} Further studies are needed to evaluate
the maternal and neonatal outcomes after IOL in twin pregnancies.

\emph{Conclusion}

A prediction model for cesarean delivery after IOL was created for twin
pregnancies. This model could be used to provide information and
evaluate the risk of cesarean delivery after IOL in twin~pregnant women.

\textbf{Disclosure of interests}

The authors declare no conflicts~of~interest.\textbf{~} Completed
disclosure of interest forms could be viewed online as supporting
information.

\textbf{Contribution to authorship}

All authors were involved in the interpretation of the data. SHB, SML,
JKJ were responsible for the conception and design of this study. SJS,
JL, SO, JYP, CWP, JSP were responsible for data collection, data
management, and analyses. SHB, SML, and JKJ drafted the initial
manuscript, which was reviewed and critically revised by all authors.
All authors approved the final manuscript as submitted.

\textbf{Details of ethics approval}

We follow the ethical standards for human experimentation established in
the Declaration of Helsinki. We have obtained the approval of this study
by The Institutional Review Board. And the patients provided their
written consent for the collection and use of clinical information for
research purposes.

\textbf{Funding}

This work was supported by a grant from the Korea Health Technology R\&D
Project through the Korea Health Industry Development Institute (KHIDI),
funded by the Ministry of Health \& Welfare, Republic of Korea (grant
number: HI19C0213).

\textbf{Acknowledgments}

We are grateful to all the patients (twin pregnant women) for providing
clinical data.

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30. Razavi AS, Chasen ST, Chambers F, Kalish RB. Induction of labor in
twin gestation: can we predict success? \emph{J Perinat Med}
2018;\textbf{46} (7): 771-5.

\textbf{Hosted file}

\verb`3. Twin_Table_Final.docx`  available at \url{https://authorea.com/users/472112/articles/563176-prediction-of-cesarean-delivery-after-induction-of-labor-in-twin-pregnant-women-a-retrospective-cohort-study}

\textbf{Hosted file}

\verb`4. Twin_Figure_Final.docx`  available at \url{https://authorea.com/users/472112/articles/563176-prediction-of-cesarean-delivery-after-induction-of-labor-in-twin-pregnant-women-a-retrospective-cohort-study}

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