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\begin{document}

\title{OUTCOMES OF INDUCTION VERSUS SPONTANEOUS ONSET OF LABOUR WHEN PERFORMED
AT 40 AND 41 GESTATIONAL WEEKS: FINDINGS FROM A PROSPECTIVE INDIVIDUAL
PATIENT DATABASE IN SRI LANKA}



\author[1]{Hemantha Senanayake}%
\author[2]{Ilaria Mariani}%
\author[2]{Emanuelle Pessa Valente}%
\author[2]{Monica Piccoli}%
\author[2]{Benedetta Armocida}%
\author[2]{Caterina Businelli}%
\author[3]{Mohamed  Rishard}%
\author[2]{Benedetta Covi}%
\author[2]{Marzia Lazzerini}%
\affil[1]{University Obstetrics Unit, De Soysa Hospital for Women, Colombo, Sri Lanka}%
\affil[2]{Institute for Maternal and Child Health - IRCCS “Burlo Garofolo” – Trieste }%
\affil[3]{University Obstetrics Unit, De Soysa Hospital for Women}%


\vspace{-1em}



  
  \date{May 28, 2024}


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\selectlanguage{english}
\begin{abstract}
Objectives The World Health Organization (WHO) recommends induction of
labour (IOL) for low risk pregnancy from 41+0 gestational weeks (GW).
Nevertheless, in Sri Lanka IOL at 40 GW is common practice. This study
aimed to compare maternal/newborn outcomes after IOL versus spontaneous
onset of labour (SOL) at 40 GW (IOL40) and 41 GW (IOL41). Design
Observational study. Setting De Soysa Teaching Hospital for Women,
Colombo, the largest maternity hospital in Sri Lanka. Population Low
risk pregnancies at 40 or 41 GW. Methods Data from a routine prospective
individual patient database were analysed. IOL and SOL groups were
compared using logistic regression. Main Outcome Measures Births with
one or more negative maternal/newborn outcome/s; maternal/newborn
complications; caesarean section (CS); operative vaginal delivery.
Results Of 13670 deliveries, 2359 (17.4\%) were singleton and low risk
at 40 or 41 GW. Of these, 456 (19.3\%) women underwent IOL40, 318
(13.5\%) IOL41, and 1585 (67.2\%) SOL. Both IOL40 and IOL41 were
associated with an increased risk of any maternal/newborn negative
outcomes (OR=2.21, 95\%CI=1.75-2.77, p\textless{}0.001 and OR=1.91,
95\%CI=1.47-2.48, p\textless{}0.001 respectively), maternal
complications (OR=2.18, 95\%CI=1.71-2.77, p\textless{}0.001 and OR=2.34,
95\%CI=1.78-3.07, p\textless{}0.001 respectively) and CS (OR=2.75,
95\%CI=2.07-3.65, p\textless{}0.001 and OR=3.01, 95\%CI=2.21-4.12,
p\textless{}0.001 respectively). Results did not change in secondary and
sensitivity analyses. Conclusions Both IOL groups were associated with
higher risk of negative outcomes compared to SOL. These findings, though
potentially explained by selection bias, local IOL protocols and CS
practices, are valuable for the Sri Lankan context, particularly given
contradictory findings from other settings.%
\end{abstract}%



\sloppy


OUTCOMES OF INDUCTION VERSUS SPONTANEOUS ONSET OF LABOUR WHEN PERFORMED
AT 40 AND 41 GESTATIONAL WEEKS: FINDINGS FROM A PROSPECTIVE INDIVIDUAL
PATIENT DATABASE IN SRI LANKA

Short title: Outcomes of induction of labour from a prospective
database, Sri Lanka

Hemantha Senanayake,\textsuperscript{1,2} Ilaria
Mariani,\textsuperscript{3}Emanuelle Pessa Valente,\textsuperscript{3}
Monica Piccoli,\textsuperscript{4} Benedetta
Armocida,\textsuperscript{3}Caterina Businelli,\textsuperscript{4}
Mohamed Rishard,\textsuperscript{1,2} Benedetta Covi,\textsuperscript{3}
Marzia Lazzerini.\textsuperscript{3}

\textsuperscript{1} University Obstetrics Unit, De Soysa Hospital for
Women, Colombo, Sri Lanka

\textsuperscript{2} Faculty of Medicine, Department of Obstetrics \&
Gynaecology, University of Colombo, Colombo, Sri Lanka

\textsuperscript{3} Institute for Maternal and Child Health - IRCCS
``Burlo Garofolo'', WHO Collaborating Centre for Maternal and Child
Health, Trieste, Italy

\textsuperscript{4} Institute for Maternal and Child Health - IRCCS
``Burlo Garofolo'', Department of Obstetrics \& Gynaecology, Trieste,
Italy

Authors' e-mail contacts

HS: senanayakeh@gmail.com

IM: ilaria.mariani@burlo.trieste.it

EPV: emanuelle.pessavalente@burlo.trieste.it

BA: benedetta.armocida@burlo.trieste.it

MP: monica.piccoli@burlo.trieste.it

CB: caterina.businelli@burlo.trieste.it

MR: mrishard@obg.cmb.ac.lk

BC: benedetta.covi@burlo.trieste.it

ML: marzia.lazzerini@burlo.trieste.it

Corresponding author

Ilaria Mariani, MSc

WHO Collaborating Centre for Maternal and Child Health Institute for
Maternal and Child Health~- IRCCS ``Burlo Garofolo'',

Via~dell'Istria 65/1, 34137, Trieste, Italy

Ilaria.mariani@burlo.trieste.it

Tel: +39 040 3785 642

List of abbreviations

AOR= Adjusted odds ratio

APH= Antepartum haemorrhage

BMI= Body mass index

CI= confidence interval

CS= Caesarean section

GW= gestational weeks

IOL= Induction of labour

IUGR= Intrauterine growth restriction at ultrasonography

LMIC= Low and middle-income countries

NICE= National Institute for health and Care Excellence

OT= operating theatre

OVD= operative vaginal delivery

PPH= Postpartum haemorrhage

RCT= randomized clinical trial

SGA= Small for gestational age

SOL= Spontaneous onset of labour

STROBE= STrengthening the Reporting of OBservational studies in
Epidemiology

UK= United Kingdom

US= United States

WHO= World Health Organization

ABSTRACT WORD COUNT=245/250

ABSTRACT

\textbf{Objectives} The World Health Organization (WHO) recommends
induction of labour (IOL) for low risk pregnancy from 41+0 gestational
weeks (GW). Nevertheless, in Sri Lanka IOL at 40 GW is common practice.
This study aimed to compare maternal/newborn outcomes after IOL versus
spontaneous onset of labour (SOL) at 40 GW (IOL40) and 41 GW (IOL41).

\textbf{Design} Observational study.

\textbf{Setting} De Soysa Teaching Hospital for Women, Colombo, the
largest maternity hospital in Sri Lanka.

\textbf{Population} Low risk pregnancies at 40 or 41 GW.

\textbf{Methods} Data from a routine prospective individual patient
database were analysed. IOL and SOL groups were compared using logistic
regression.

\textbf{Main Outcome Measures} Births with one or more negative
maternal/newborn outcome/s; maternal/newborn complications; caesarean
section (CS); operative vaginal delivery.

\textbf{Results} Of 13670 deliveries, 2359 (17.4\%) were singleton and
low risk at 40 or 41 GW. Of these, 456 (19.3\%) women underwent IOL40,
318 (13.5\%) IOL41, and 1585 (67.2\%) SOL. Both IOL40 and IOL41 were
associated with an increased risk of any maternal/newborn negative
outcomes (OR=2.21, 95\%CI=1.75-2.77, p\textless{}0.001 and OR=1.91,
95\%CI=1.47-2.48, p\textless{}0.001 respectively), maternal
complications (OR=2.18, 95\%CI=1.71-2.77, p\textless{}0.001 and OR=2.34,
95\%CI=1.78-3.07, p\textless{}0.001 respectively) and CS (OR=2.75,
95\%CI=2.07-3.65, p\textless{}0.001 and OR=3.01, 95\%CI=2.21-4.12,
p\textless{}0.001 respectively). Results did not change in secondary and
sensitivity analyses.

\textbf{Conclusions} Both IOL groups were associated with higher risk of
negative outcomes compared to SOL. These findings, though potentially
explained by selection bias, local IOL protocols and CS practices, are
valuable for the Sri Lankan context, particularly given contradictory
findings from other settings.

TWEETABLE ABSTRACT WORD COUNT=109/110

Tweetable abstract. Induction of labour in low risk pregnancy at 40/41
GW increases risk of negative birth outcomes in Sri Lanka.

Keywords. Induction of labour; Full term pregnancy; Late term pregnancy;
Pregnancy outcomes; Low risk pregnancies

MAIN TEXT WORD COUNT = 3474/3500

INTRODUCTION WORD COUNT= 785/400

DISCUSSION AND CONCLUSION WORD COUNT =1067/1200

INTRODUCTION

Over the past decades, induction of labour (IOL) rates have continued to
rise, with a reported average incidence of one out of four births at
term (from 37+0 GW) in high-income countries, and very similar rates in
low and middle-income countries (LMIC)\textsuperscript{1}. According to
the World Health Organization (WHO), IOL should be performed only when
there is a clear medical indication and the expected benefits outweigh
its potential harms\textsuperscript{2}. As perinatal risks increase with
gestational age, the current recommendation from WHO, the National
Institute for health and Care Excellence (NICE), and most scientific
societies is to perform IOL in women who are known with certainty to
have reached 41 GW (i.e., from 41+0).\textsuperscript{3-7}

However, especially in the last few years, the debate on optimal timing
for IOL and, specifically, whether IOL around term improves birth
outcomes, has become very lively. The most recent Cochrane review (2018)
including 30 randomized clinical trials (RCTs), seven conducted in
southeast Asia, highlighted that IOL from 37 GW compared to expectant
management is associated with fewer perinatal deaths, neonatal intensive
care unit admissions, babies with low Apgar scores and caesarean
sections (CS), but also with more operative vaginal delivery
(OVD).\textsuperscript{8} Authors concluded that further investigation
is needed into optimal timing of IOL, together with exploration of
women's risk profiles and preferences.\textsuperscript{8}

More recently, other evidence has emerged. In 2019, a meta-analysis of
cohort studies including 15 million pregnancies in high-income countries
reported that stillbirth increases slightly but significantly from 37 GW
onward with a 64\% increase in the risk of stillbirth at 41 GW compared
to 40 GW,\textsuperscript{9} thus suggesting the opportunity of elective
IOL even before the traditional cut-off of 41 GW.

Other relevant RCTs were published in parallel. A single-centre RCT in
the UK among nulliparous women over 35 years old without complications
showed no significant difference in maternal and newborn outcomes
between IOL at 39 GW and expectant management.\textsuperscript{10} More
recently, the ARRIVE trial, a multicentre RCT conducted by Grobman et
al. among 6106 low-risk nulliparous women in the US compared IOL at 39
GW to expectant management and found lower incidence of CS with IOL (RR
0.84; 95\%CI 0.76-0.93) and no significant differences in perinatal
deaths or severe neonatal complications (RR 0.80; 95\%CI
0.64-1.00).\textsuperscript{11} A meta-analysis of cohort
studies\textsuperscript{12} confirmed the results of this
trial.\textsuperscript{11}

Two other RCTs in uncomplicated singleton pregnancies - INDEX, a Dutch
trial enrolling 1801 women,\textsuperscript{13} and SWEPIS, a Swedish
multicentre trial in 14 hospitals including 2760
women\textsuperscript{14} - found that IOL at 41 GW was associated with
fewer adverse perinatal outcomes than expectant management until 42
GW.\textsuperscript{13,14} Notably, the SWEPIS study was stopped early
because of higher perinatal mortality with SOL.\textsuperscript{14}

On the other hand, a national retrospective register-based cohort study
evaluating the effects of changes in routine elective IOL policies in
Denmark (42 GW versus 41+3 and 41+5 GW) found no differences in neonatal
outcomes including stillbirth, despite the number of women with IOL
increasing significantly.\textsuperscript{15} Additionally, a systematic
review reported that IOL at 41 versus 42 GW was associated with an
increased risk of CS (RR 1.11; 95\%CI 1.09-1.14) and adverse maternal
outcomes.\textsuperscript{16}

In conclusion, evidence is still contradictory and the debate is quite
polarized. No clear context-specific evidence exists on women's
preferences on IOL. The ARRIVE trial reported that American women in the
IOL group had a positive perception of increased control over
birth,\textsuperscript{11,17} while other qualitative systematic reviews
concluded that the majority of women feared medical intervention,
preferring a physiological birth promoting their physical and
psychosocial capacities.\textsuperscript{17, 18}

In addition, literature on outcomes of IOL around term versus expectant
management in LMIC is very scarce. According to the WHO Global Survey on
Maternal and Perinatal Health, IOL was performed in Asia in 12.1\% of
deliveries and associated with negative neonatal
outcomes.\textsuperscript{19}According to existing estimates, Sri Lanka
has the highest IOL rate in Asia (about 35.5\% of total
deliveries)\textsuperscript{1,19} with 77.2\% of all IOL being
elective.\textsuperscript{19} Elective IOL at 40 GW is often justified
by local professionals on the basis of supposed earlier foeto-placental
maturation in South Asian populations compared with Caucasian women or
Asian counterparts, and on the fear of increased risk for the
baby.\textsuperscript{20-22}Nevertheless, no study from Sri Lanka has so
far explored outcomes of women with IOL at 40 GW versus 41 GW.

The objective of this study was to assess adverse maternal and neonatal
outcomes in low risk women undergoing IOL at 40 and 41 GW versus women
with a spontaneous onset of labour (SOL) giving birth at the largest
maternity hospital in Sri Lanka. Data for this study were collected over
four years in a prospective individual patient database established in
2015 at the De Soysa Teaching Hospital for Women, Colombo.

METHODS

\textbf{Study design}

This is an observational study reported according to the STrengthening
the Reporting of OBservational studies in Epidemiology (STROBE)
statement (\textbf{Table S1} ).\textsuperscript{23}

\textbf{Population and setting}

Data collection, data quality assurance procedures and standard
operating procedures used for the individual patient database are
reported elseswhere.\textsuperscript{24}Briefly, 150 variables (i.e.,
maternal sociodemographic characteristics, risk factors, process
indicators, maternal and neonatal outcomes) were collected for each
birth on two wards of the University Obstetric Unit at De Soysa Teaching
Hospital for Women, using a standardised two-page form, and entered in
real time in an electronic database. De Soysa is the largest referral
hospital for maternity care in Sri Lanka and all deliveries occurring in
these two wards from May 2015 to May 2019 were entered in the database
and considered for inclusion. Overall data quality was routinely
monitored with external independent random review of 5\% of forms and
5\% of entered births to maintain an error rate in data collection below
0.02\%.\textsuperscript{24} Data were also externally monitored for
completeness and internal consistency at roughly 4-month
intervals.\textsuperscript{24}

We included ``low risk women'' with singleton pregnancies and a foetus
in cephalic presentation whose delivery occurred between 40+0 and 41+6
GW. We excluded all cases with any maternal or foetal characteristics
which may have affected outcomes, such as: maternal obesity (Asian
criteria-based body mass index -BMI- more than
27.5\textsuperscript{25}), previous CS, macrosomia at ultrasonography
(defined as estimated birthweight exceeding the
90\textsuperscript{th}centile for gestational age), hypertension
disorders during pregnancy (e.g. pregestational or gestational
hypertension, preeclampsia, eclampsia, HELLP syndrome),
chorioamnionitis, major foetal malformations, intrauterine growth
restriction at ultrasonography (IUGR), small for gestational age (SGA),
pre-gestational diabetes, gestational diabetes with the need of drug
therapy, maternal cardiac disease, maternal hypothyroidism,
polyhydramnios, oligohydramnios, antepartum haemorrhage (APH), major
placenta praevia, placental accretism, severe anaemia (haemoglobin
\textless{}7.0 g/dl) and other foetal and maternal pathological
conditions, i.e. systemic lupus erythematosus, pre-pregnancy deep venous
thrombosis, epilepsy, suspected cephalo pelvic disproportion, recurrent
infection, pancreatitis or glomerulonephritis in pregnancy, chickenpox
disease, chronic disease, signs of potentially impaired foetal wellbeing
(non-reassuring or pathological cardiotocography, reduced foetal
movement, meconium stained amniotic fluid). We also excluded macerated
stillbirth from the IOL40 group, as these births are always induced. All
women with a reported indication for IOL suggesting the presence of
maternal or foetal characteristics described above, such as diabetes,
macrosomia at ultrasound, IUGR/SGA, were excluded from the analysis.

\textbf{Comparison groups and outcomes}

We compared women with IOL at 40 GW (40+0 to 40+6 GW), women with IOL at
41 GW (41+0 to 41+6 GW), and women with SOL in between 40+0 to 41+6 GW.
Artificial separation of membranes alone was not considered induction.

The incidence of births with one or more negative outcome(s) was our
primary outcome. In line with previous
literature,\textsuperscript{2,3,8} we defined negative outcomes as any
birth that included an intervention (i.e. CS, OVD) and/or a maternal or
neonatal complication (i.e., was not completely physiological) (see list
in \textbf{Table S2} ).

\textbf{Data analysis}

Categorical variables were expressed as absolute numbers and compared
among groups with \selectlanguage{greek}χ\selectlanguage{english}\textsuperscript{2} or Fisher exact test as
appropriate.

We evaluated the association between each group and negative outcome(s),
CS, and OVD using multiple logistic regression models adjusting for
baseline characteristics (e.g., age, parity, education, BMI, neonatal
weight). Results of logistic regression are also presented for CS and
OVD since they were evaluated as clinical outcomes related to failed
induction in Sri Lanka.\textsuperscript{26} A one-sided Cochran-Armitage
test for trend was performed to assess the influence of changes of
clinical protocols and staff training practices\textsuperscript{27,
28}over different semesters of the study on CS and OVD.

As secondary analyses we compared IOL at 40 GW to a group composed of
IOL at 41 GW and SOL, in line with analyses by Rydahl and
collegues.\textsuperscript{16} This allowed comparison between IOL group
at 40 GW and spontaneous labour at the same gestational age, and
simultaneously took into account the risks of the ongoing pregnancy
including all births at 41 GW, reducing possible bias.

In addition, we performed a sensitivity analysis including all cases
with reported hypertensive disorders (pregestational hypertension,
preeclampsia, eclampsia, HELLP syndrome), chorioamnionitis,
oligohydramnios, APH, and signs of potentially impaired foetal wellbeing
(non-reassuring or pathological cardiotocography, reduced foetal
movement, meconiumstained amniotic fluid) from 41 GW, considering these
as negative birth outcomes rather than as possible risk factors.

Data were analysed using STATA version 14.0 (Stata Corporation, College
Station TX) and SAS/STAT\selectlanguage{ngerman}® software version 9. All statistical tests were
two-sided and a p-value less than 0.05 was considered statistically
significant.

\textbf{Ethical considerations}

The study was approved by the Ethics Review Committee of the Faculty of
Medicine, University of Colombo. Confidentiality was maintained by
de-identifying all files before database entry. Human subjects were not
directly involved in the study. Informed consent was not requested by
the Ethics Review Committee.

RESULTS

\textbf{Women's characteristics}

A total of 13,670 women delivered in the hospital during the study
period. Of these, 2359 (17.4\%) matched our inclusion criteria of low
risk singleton pregnancy from 40+0 to 41+6 GW with the foetus in
cephalic presentation (\textbf{Figure 1} ). Among the included women SOL
was observed in 1585 women (67.2\%), while among 774 cases of IOL, 456
(58.9\%) were induced from 40+0 to 40+6 GW, and 318 (41.1\%) from 41+0
to 41+6 GW.

Some imbalances among groups were observed (\textbf{Table 1} ). Women
undergoing IOL at 40 GW had a significantly higher level of education
compared to the SOL group (20.0\% vs 13.3\%, p=0.001). Significantly
more women were unmarried and overweight in the IOL at 41 GW group
compared to SOL, and more women were overweight comparing IOL at 41 and
40 weeks (unmarried women: 2.2\% vs 0.9\%, p=0.040; overweight women:
29.9\% vs 23.2\% in IOL at 40 GW vs 23.0 in SOL, p=0.031). IOL group at
41 GW had an increased frequency of newborns with a birth weight between
3500 and 4000 grams (19.2\% vs 12.5\% in IOL at 40 GW vs 14.8\% in SOL,
p=0.035) and above 4000 grams (2.5\% vs 2.4\% in IOL at 40 GW vs 0.8\%
in SOL, p=0.006). Women with SOL were most often multiparous (52.4\% vs
43.0\% in IOL at 40 GW vs 37.7\% in IOL at 41 GW, p\textless{}0.001) and
more frequently assisted at delivery by nurses (56.7\% vs 44.9\% vs
36.5\%, p\textless{}0.001), while mid-level medical staff (either senior
house officers or registrars) was more often involved in IOL groups
(30.7\% vs 30.2\% vs 14.1\%, p\textless{}0.001).

\textbf{Primary outcomes}

The overall incidence of births with one or more negative outcome
(including CS and OVD) is reported in \textbf{Figure 2} . The rate was
significantly lower in the SOL group (27.1\%, p\textless{}0.001),
compared to IOL, without significant difference among IOL at 40 GW and
IOL at 41 GW (47.1\% versus 45.2\%, p= 0.609). As further detailed
in\textbf{Table S3 and S4} , the CS rate was significantly higher among
women undergoing IOL either at 40 GW (25.4\%) or at 41 GW (28.6\%) when
compared with SOL (10.3\%, p\textless{}0.001). OVD rate was
significantly higher in IOL at 40 GW (7.0\%) compared to IOL at 41 GW
(2.8\%, p=0.010) whereas no significant difference was found with SOL.
The proportion of births with complications different from CS and OVD
was not significant among groups (p=0.222).

The trend analysis (\textbf{Figure S1} ) showed an increasing CS rate
over semesters in the group with IOL at 40 GW only (trend test p=0.021),
whereas OVD rate decreased overall (trend test p=0.016) and in IOL at 40
GW (p=0.036).

\textbf{Table S4} details the incidence of maternal and neonatal
complications by type of labour. Maternal complications, as defined
in\textbf{Table S1} , were more frequent in IOL groups (36.2\% and
39.3\% in IOL group at 40 GW and 41 GW respectively vs 19.1\% in SOL,
p\textless{}0.001). Postpartum haemorrhage (PPH) was the most frequent
complication after CS and OVD (2.6\% vs 5.7\% vs 1.9\% respectively,
p=0.001). The incidence of newborn complications was higher in births
with IOL at 40 GW when compared to SOL (22.4\% vs 13.4\%,
p\textless{}0.001), particularly admissions to Special Care Baby Unit
(15.8\% in IOL at 40 GW vs 10.7\% in IOL at 41 GW vs 8.6\% in SOL group,
p\textless{}0.001). Newborn infections, neurological complications and
respiratory distress syndrome were significantly more frequent in the
group with IOL at 40 GW than SOL (respectively, 5.0\% vs 2.2\%, p=0.002;
3.1\% vs 1.3\%, p=0.009; 2.4\% vs 0.9\%, p=0.002). Perinatal deaths and
stillbirth rates were low across all groups (one stillbirth in IOL at 41
GW and less than five perinatal deaths in each group).

In multivariate analysis (\textbf{Table 2} ) with SOL as reference and
controlling for age, parity, education, BMI and neonatal weight, both
IOL groups were positively associated with higher odds of any negative
birth outcome (AOR=2.21, 95\%CI=1.75-2.77, p\textless{}0.001 for IOL at
40 GW and AOR=1.91, 95\%CI=1.47-2.48,p\textless{}0.001 for IOL at 41
GW), all maternal complications (AOR=2.18, 95\%CI=1.71-2.77,
p\textless{}0.001 for IOL at 40 GW and AOR=2.34, 95\%CI=1.78-3.07,
p\textless{}0.001 for IOL at 41 GW) and CS (AOR=2.75, 95\%CI=2.07-3.65,
p\textless{}0.001 for IOL at 40 GW and AOR=3.01, 95\%CI=2.21-4.12,
p\textless{}0.001 for IOL at 41 GW). IOL at 40 GW was associated with a
higher number of neonatal complications (AOR=1.63, 95\%CI=1.24-2.16,
p\textless{}0.001) and IOL at 41 GW was positively associated with
maternal complications other than CS or OVD (AOR=1.83, 95\%CI=1.19-2.80,
p=0.006).

\par\null

\textbf{Secondary and sensitivity analyses}

IOL at 40 GW was positively associated with increased numbers of
negative birth outcomes (AOR=1.95, 95\%CI=1.56-2.44, p\textless{}0.001),
maternal complications (AOR=1.82, 95\%CI=1.44-2.30, p\textless{}0.001),
CS (AOR=2.09, 95\%CI=1.60-2.74, p\textless{}0.001), and neonatal
complications (AOR=1.58, 95\%CI=1.21-2.06, p\textless{}0.001) when
compared with IOL at 41 GW and SOL combined (\textbf{Table S6} ). No
other significant association was found (\textbf{Table S5 and S6; Figure
S2} ).

We explored a sensitivity analysis including women with risk factors for
IOL (oligohydramnios, APH and impaired foetal wellbeing), resulting in
an additional 4 women eligible for analysis \textbf{Table S7} ). Results
did not differ from the primary analysis (\textbf{Table S8} ).

DISCUSSION

\textbf{Main Findings}

Findings from this study in Sri Lanka suggest that the practice of
elective IOL at 40 GW or induction at 41 GW is associated with a higher
risk of negative maternal and neonatal outcomes, particularly maternal
complications, compared to SOL. Both IOL groups were also associated
with increased odds of CS compared to SOL.

\textbf{Strengths and Limitations}

To our knowledge this is the first published study on the association
between timing of IOL and maternal and newborn outcomes in low-risk
pregnancies in Sri Lanka. It is also the first study from a setting with
limited resources reporting on the use of a prospective
individual-patient database to analyse practices and outcomes of
IOL.\textsuperscript{24} This study contributes to current international
and local debate on the appropriateness of IOL near term. These study
findings are extremely relevant locally both for clinicians, researchers
and policy makers, as IOL at 40 GW is a common practice in Sri Lanka and
has a significant economic impact on the health system and healthcare
resources.

We acknowledge some limitations of this study. As an observational
study, we could only assess associations between IOL and birth outcomes
and not causation. Generalizability of study results may be limited by
the characteristics of the local context and population in this single
centre study. Larger sample sizes are required to detect significant
differences in rare adverse events including stillbirth or maternal or
perinatal death. Although gestational age was mostly determined by
ultrasound examination, for 12\% of the included women gestational age
was estimated by menstrual dating.

Socio-cultural background and women's empowerment may have affected both
requests for induction and the type of care offered by physicians.
Specifically, early induction (IOL at 40 GW) occurred more often in
women with a high level of education. Unmarried women, still subjected
to social stigma in Sri Lanka,\textsuperscript{29} were significantly
more represented in the group undergoing IOL at 41 GW. Thus, numbers of
CS and neonatal complications may have been influenced by socio-economic
status. Other authors have described similar results, where unmarried
women could have limited access to care\textsuperscript{29} while higher
social status or economic condition is related to an increasing
medicalization of birth.\textsuperscript{30,31} However, in our study,
since these imbalances among groups affect results in different
directions, there may be limited risk of bias.

Though results were corrected for confounding, we cannot exclude that
induced women may have differed on characteristics not captured or not
reported in the data collection form (such as unreported small for
gestation foetuses, mild oligohydramnios, etc.). We were not able to
explore specific practices related to IOL (such as safe use of
uterotonics, appropriate maternal-foetal monitoring or CS indications),
therefore we cannot exclude a difference among the groups for these
variables. We had no information on the level of women's participation
in the decision process during labour care, nor specific choices,
inclinations or skills of operators which may have had a substantial
role in the differences observed.\textsuperscript{27, 32-34} Notably,
most of the evidence that we actually rely on may have some of these
biases. Observational studies may not capture these aspects of care,
while RCT, even though controlling these with randomization, may suffer
from study effect.

Finally, another limitation related to the database is the absence of
timing for risk factor onset. Hence it was impossible to differentiate
between high-risk pregnancy (with risk factors before 40+0 GW) and low
risk women at 40+0 GW that developed complications due to prolonged
pregnancy (after 40+0 GW). A sensitivity analysis was performed to
assess this limitation and results showed that it did not affect the
overall findings.

\textbf{Interpretation~}

Our findings are partially in line with the most recent Cochrane
systematic review, confirming that there is evidence of higher OVD rate
in IOL at 40 GW vs IOL at 41 GW.\textsuperscript{8} Discrepancies
between our results for CS rates and other studies\textsuperscript{8,
10, 13, 15, 35} could be accounted for by differences in setting, study
design, and different definitions of comparison groups. Our study was
set in Sri Lanka and includes recent data from a maternity hospital
registry, evaluating optimal timing of IOL in routine circumstances in a
LMIC setting at predefined GW. Only 9 of 30RCTs included in the Cochrane
review were conducted in LMIC, while 13 (43\%) studies were published
from 1960s-1980s.\textsuperscript{19} Furthermore, comparison groups in
the Cochrane review are not directly comparable since timing of IOL
differed among included trials as well as group definition, timing, and
monitoring of expectant management.

Moreover, while RCT would be the most appropriate study design to
address the question of optimal timing of IOL, this design has potential
limitations. As shown in the two most recent RCTs comparing IOL at term
versus expectant management\textsuperscript{11, 14}, recruiting women
for such trials is extremely difficult. In both trials a high number of
women declined participation (73\% in the US study and 78\% in the
Swedish study). This could have affected the characteristics of the
sample and the generalizability of findings. Moreover, it highlights the
fact that the views of women on onset of labour can be strong, both in
refusing or requesting induction. This underscores the need for
patient-centered care which takes into account the perspective of
patients,\textsuperscript{36} as well as for more research on women's
preferences and views. Another limitation of RCTs is that the
intervention cannot be masked, thus being open to possible bias due to
differences in treatment/monitoring by allocation group. The
availability of a prospective database capturing characteristics and
outcomes of each delivery provides the opportunity to easily monitor
indicators over time and compare practices and results in a real world
setting.

Overall, findings of this study highlight the need for caution in
generalizing the results of RCT conducted in high income settings to
different clinical settings and populations. More studies should be
conducted to further explore the ideal timing of IOL in LMICs.

CONCLUSIONS

Women with low risk pregnancies who underwent elective induction at 40
GW or induction at 41 GW in Colombo, Sri Lanka had significantly
increased risk of negative birth outcomes (CS, OVD or any complication)
compared to women with spontaneous onset of labour. While more evidence
is needed on a global level to further understand the optimal timing of
IOL in settings with low resources, these findings should be used to
improve monitoring and routine practices in Sri Lanka, as well as in
other LMIC where IOL is frequent practice.

ACKNOWLEDGMENTS

We would like to thank the staff of the Professorial Unit of the De
Soysa Hospital and the Medical Records Officer and his staff for
assisting with this study.

We are thankful to dr. Rebecca Lundin, for the English language review.

DISCLOSURE OF INTERESTS

No competing interests.

FUNDING

The implementation of the database was funded for the first year by a
grant from the GREAT Network, Canadian Institutes of Health Research,
St. Michael's Hospital, Toronto

AUTHOR CONTRIBUTIONS

HS and ML conceived the study and procured funds.

IM analysed data.

HS, IM, EPV, BA, MP, CB, MR, BC, and ML interpreted data and contributed
to the manuscript.

All authors revised and approved the final manuscript.

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TABLE/FIGURE CAPTION LIST

Figure 1. Study sample selection

Table 1. Characteristics of the study population

Figure 2. Births with negative outcomes by type of labour

Table 2. Adjusted odds ratios for negative birth outcomes by type of
labour

Table 1. Characteristics of the study population\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
Population\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
IOL at 40 GW (40+0 to 40+6) N=456 n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
IOL at 41 GW (41+0 to 41+6) N=318 n (\%)\strut
\end{minipage} & \begin{minipage}[b]{0.24\columnwidth}\raggedright\strut
SOL (40+0 to 41+6) N=1585 n (\%)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Maternal Age \textless{} 35 years [?] 35 years\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
401 (87.9) 55 (12.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
290 (91.2) 28 (8.8)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1424 (89.8) 161 (10.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Education None Primary Secondary Higher Missing\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (0.2) 10 (2.2) 353 (77.4) \textsuperscript{1,3} 91 (20.0)
\textsuperscript{1} 1 (0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (0.6) 4 (1.3) 266 (83.6) 46 (14.5) 0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (0.1) 26 (1.6) 1341 (84.6) 211 (13.3) 5 (0.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Working status Working Housewife Missing\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
81 (17.8) 370 (81.1) 5 (1.1)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
48 (15.1) 270 (84.9) 0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
227 (14.3) 1344 (84.8) 14 (0.9)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Marital status Married Unmarried Unmarried living together Missing\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
451 (98.9) 3 (0.7) 1 (0.2) 1 (0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
311 (97.8) 7 (2.2) \textsuperscript{2} 0 0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1570 (98.6) 14 (0.9) 2 (0.1) 6 (0.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Parity 0 [?]1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
260 (57.0) \textsuperscript{1} 196 (43.0) \textsuperscript{1}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
198 (62.3) \textsuperscript{2} 120 (37.7) \textsuperscript{2}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
754 (47.6) 831 (52.4)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Asian criteria-based BMI \textsuperscript{25} Underweight
(\textless{}18.4) Normal (18.5-22.9) Overweight (23-27.4)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
38 (8.3) 312 (68.4) 106 (23.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
33 (10.4) 190 (59.7) \textsuperscript{2, 3} 95 (29.9)
\textsuperscript{2,3}\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
159 (10.0) 1061 (67.0) 365 (23.0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Operator delivering care Nurse Midwife House Officer Mid-level staff *
Consultant Missing\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
200 (43.9) \textsuperscript{1} 110 (24.1) 4 (0.9) 140 (30.7)
\textsuperscript{1} 2 (0.4) 0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
116 (36.5) \textsuperscript{2, 3} 101 (31.8) \textsuperscript{3} 4 (1.3)
96 (30.2) \textsuperscript{2} 1 (0.3) 0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
899 (56.7) 431 (27.2) 24 (1.5) 224 (14.1) 3 (0.2) 4 (0.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Neonatal weight at birth \textless{}2000 2000 to 2499 2500 to 3499 3500
to 4000 \textgreater{}4000 Missing\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0 13 (2.9) 374 (82.0) 57 (12.5) 11 (2.4) \textsuperscript{1} 1
(0.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0 3 (0.9) \textsuperscript{2} 246 (77.4) 61 (19.2) \textsuperscript{2,
3} 8 (2.5) \textsuperscript{2} 0\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0 55 (3.5) 1278 (80.6) 234 (14.8) 13 (0.8) 5 (0.3)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Notes: \textsuperscript{1} Significant p value (p\textless{}0.05) in the
comparison IOL at 40 GW vs SOL; \textsuperscript{2} Significant p value
(p\textless{}0.05) in the comparison IOL at 41 GW vs
SOL;\textsuperscript{3} Significant p value (p\textless{}0.05) in the
comparison IOL at 40 GW vs IOL at 41 GW; * Mid-level staff defined as
Senior House Officer or Registrar.

Abbreviations: BMI= body mass index; GW= gestational weeks; IOL=
induction of labour; SOL= spontaneous onset of labour.

Table 2. Adjusted odds ratios for negative birth outcomes by type of
labour\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\par\null & IOL at 40 GW (40+0 to 40+6) N=456 & IOL at 40 GW
(40+0 to 40+6) N=456 & IOL at 41 GW (41+0 to 41+6) N=318 & IOL at 41 GW
(41+0 to 41+6) N=318 & SOL (40+0 to 41+6) N=1585\tabularnewline
\midrule
\endhead
& Adj OR (95\% CI) & p value & Adj OR (95\% CI) & p value
&\tabularnewline
Any negative outcome & 2.21 (1.75-2.77) & \textbf{\textless{}0.001} &
1.91 (1.47-2.48) & \textbf{\textless{}0.001} & Ref\tabularnewline
All maternal complications & 2.18 (1.71-2.77) &
\textbf{\textless{}0.001} & 2.34 (1.78-3.07) & \textbf{\textless{}0.001}
& Ref\tabularnewline
Caesarean section & 2.75 (2.07-3.65) & \textbf{\textless{}0.001} & 3.01
(2.21-4.12) & \textbf{\textless{}0.001} & Ref\tabularnewline
Operative vaginal delivery & 1.27 (0.82-1.98) & 0.285 & 0.48 (0.24-0.97)
& \textbf{0.041} & Ref\tabularnewline
Other maternal complications & 0.88 (0.55-1.42) & 0.606 & 1.83
(1.19-2.80) & \textbf{0.006} & Ref\tabularnewline
All neonatal complications & 1.63 (1.24-2.14) &
\textbf{\textless{}0.001} & 1.16 (0.83-1.62) & 0.370 &
Ref\tabularnewline
\bottomrule
\end{longtable}

Notes: ORs are adjusted for age, parity, education, BMI and neonatal
weight.

Abbreviations: GW= gestational weeks; IOL= induction of labour; SOL=
spontaneous onset of labour.

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