Methods:
Design and settings : This parallel-arm design randomized
controlled trial was carried out in the inwards and labour room of the
department of Obstetrics and Gynaecology at Women and Children Block of
Jawaharlal Nehru Institute of Postgraduate Medical Education and
Research (JIPMER) from November 2018 till June 2020 after obtaining
approval from the institute ethics committee (JIP/IEC/2018/0145). This
is a tertiary care teaching hospital located in south India.
Eligibility Criteria : Women more than18 years, with previous
single lower segment caesarean delivery at 40 weeks with a singleton
foetus in vertex presentation and eligible for TOLAC were included.
Women with Inter pregnancy interval greater than 18 months, scan
estimated foetal weight less than 3.5 kg, non-recurrent indication for
the previous section, the previous scar restricted to lower segment,
scar thickness more than 3 mm on ultrasonography, and no clinical
evidence of cephalopelvic disproportion was considered eligible for
TOLAC. The previous caesarean carried out for placenta previa,
transverse lie, preterm and late in the second stage of labour, or
clinical evidence of uterocervical infections after the previous
caesarean section was not considered eligible for TOLAC.
Women with complications like Pre-eclampsia, Diabetes mellitus,
oligohydramnios, or Intrauterine growth restriction (IUGR), foetal
malformations, multiple gestations, those not willing for the trial of
labour after caesarean, women requiring induction of labour for any
other maternal or foetal condition before randomization, and women with
poor or non-confirmed dating were excluded.
Primary outcome : successful vaginal birth rates in the two
groups.
Secondary outcome(s): Maternal complications like scar rupture,
postpartum haemorrhage, sepsis, and any mortality. ii) Perinatal
outcomes like birth asphyxia, respiratory morbidities,
hyperbilirubinemia, sepsis, perinatal mortality, etc.
There were no changes in the outcomes after the trial commenced.
Sample size calculation : As it is was a pilot Randomized
controlled trial (RCT), 30 cases each were studied in both the groups
Stopping guidelines : Interim analysis after 50% sample size did
not reveal a significant difference in the primary outcome so the study
was continued.
Randomization details: Block randomization (block size of 6 each)
was done using varying numbers generated via computer using
randomization software. The allocation ratio was 1:1. Allocation
concealment was done by a person unrelated to the study from the
Department of Preventive and Social Medicine through serially numbered
opaque sealed envelopes. The participants were enrolled by the principal
investigator. There was no blinding.
Study procedure : Women with uncomplicated pregnancy with
a previous caesarean section were screened from 39 weeks onwards
clinically and with sonography for eligibility for TOLAC. The period of
gestation was calculated as per the last menstrual period (LMP) or
calculation based on the early available (<14 weeks scan)
dating scan. After obtaining informed written consent, the women
fulfilling the study criteria, and willing for TOLAC were randomized on
the day of completion of 40 weeks to either group. Bishop Score was
reassessed after randomization.
Induction was carried out on the same day (40 weeks) or within 24 hours
of randomization in the induction group (group II). If the Bishop score
was favourable (>6), induction was done using low dose
oxytocin infusion detailed below. If unfavourable (<6),
induction was done by ripening of the cervix with a single application
of 22 French Foley single balloon catheter just above the internal os,
under aseptic precautions. The bulb was inflated to a total of 60ml. The
women were monitored for onset of contractions/ leaking/ bleeding/ any
other complication and the foetus was monitored by intermittent
auscultation and a nonstress test done after 12 hours. If she did not
spontaneously expel then the Foley catheter was deflated and removed
after 24 hours or earlier if she developed spontaneous rupture of
membranes. Bishop’s score was noted again. Induction was started with
low dose oxytocin infusion delivered through a pump starting from
3mIU/min and incremented by 3mIU every half-hourly and titrated to
achieve target contractions or to a maximum of 24mIU/min. The foetal
heart and uterine contractions were monitored with the help of an
electronic tocodynamometer. The woman was monitored for the progress of
labour and symptoms and signs of scar dehiscence. An artificial rupture
of membranes was carried out four hours after achieving the maximum dose
of oxytocin or when the patient started getting three to four
contractions in ten minutes, each lasting for 30 to 40 seconds. After 6
hours of artificial rupture of membranes, if patients failed to achieve
active labour (4cm dilatation with 75-100% effacement), it was
considered as failed induction and terminated by caesarean section. If
active labour was established, then the trial was continued.
Women in the expectant arm of the study remained admitted in the
hospital and were monitored. Non-stress test (NST) was done every 48
hours and a repeat ultrasound for amniotic fluid index and biophysical
profile for foetal surveillance at 40 weeks plus 3 days. It was repeated
at 41 weeks if she had not delivered by then. In case any complications
arose between 40 to 41 weeks, pregnancies were terminated either by
induction of labour or by caesarean as per the case. If they had not
delivered by 41 weeks, induction of labour was carried out in them as
per the protocol followed in the induction group. The neonates and women
were followed up till discharge from the hospital. There were no changes
made in the inclusion criteria or methodology after trial commencement.
Continuous variables were expressed as mean with standard deviation or
median with interquartile range. Categorical were summarized as
frequency and percentage or proportion. The primary outcome variable
(mode of delivery) was expressed as the proportion with a 95%
confidence interval and was analysed using the Chi-square test as the
statistical test. Other baseline characteristics were compared using the
Chi-square test or Fischer’s Exact test if expressed in proportions and
using unpaired student-test or Mann Whitney test is expressed in terms
of mean with standard deviation or median with interquartile range.
Subgroup analysis was attempted for factors associated with successful
VBAC after induction of labour by univariate analysis and logistic
regression analysis.
Results: A total of 1886 women with previous Caesarean section
attending Women and Children Hospital, JIPMER, were screened and 60
women who fulfilled the inclusion criteria and were willing for the
study were randomized. (Figure1) All the 60 recruited patients (30 in
each group) completed the study, and the study was stopped. Two of the
patients in the induction arm went into spontaneous labour after
randomization before induction on the expected date of delivery. One
woman in the expectant arm had a spontaneous version to breech
presentation at 41 weeks and so pre-labour caesarean was performed on
her. These three cases were not excluded from the analysis. So, an
intention to treat analysis was done.
The demographic and pregnancy-related variables are shown in Table1. The
mean age, socio-economic status, parity, previous history of VBAC, the
indication of the previous caesarean, and pre-induction Bishop Score,
etc was comparable in the two groups.
Twenty out of the 30 (66.67%) women in the induction group had a
successful vaginal birth after caesarean section. 53.33% of them had a
normal vaginal delivery and 13.33% had an instrumental vaginal
delivery. The remaining 10 subjects (33.33%) underwent emergency LSCS
for varied indications. The expectant group had a VBAC rate of 33.33%
with only 10 out of the 30 women undergoing successful vaginal delivery
and this difference was significant. (RR 2.0, 95% CI: 1.13-3.52;p=0.016) .
In the expectant group out of the 30 women, thirteen (43.33%) went into
spontaneous labour before 41 weeks, 7 underwent induction before 41
weeks for different complications (one developed gestational
hypertension, five had oligohydramnios and one had reduced fetal
movements), 9 were induced at 41 weeks as per protocol and 1 had a
prelab our cesarean section for the spontaneous conversion of cephalic
to breech presentation.
The mode of delivery details of the expectant group is shown in table 2.
The intrapartum details are shown in Table 3. The proportion of women
with abnormal fetal heart rate patterns and meconium-stained liquor and
the duration of oxytocin infusion was comparable in the two groups. The
birth weight was higher by 270 grams in the expectant group. This was
statistically significant though not clinically significant.
The indication for cesarean section in the two groups is shown in table
4 and the difference in indications was not found to be statistically
significant.
There was one case of scar dehiscence in the expectant arm, confirmed
intra-operatively. This woman did not go into spontaneous labour during
the expectant management period. She underwent labour induction at 41
weeks as per protocol. She was taken up for an emergency caesarean for
failed induction. However intraoperatively, a 3cm horizontal scar
dehiscence was observed. The same was repaired and the recovery was
uneventful. There were no cases of scar dehiscence in the induction at
40 weeks arm. There was no case of a third or fourth-degree perineal
tear in women who had a spontaneous vaginal or operative vaginal
delivery.
None of the women developed any complications like sepsis or postpartum
haemorrhage. None of them required a blood transfusion or hysterectomy.
There were no stillbirths. None of the babies was born with a low Apgar
score. None of the neonates required admission to an intensive care
unit. There were no morbidity or mortality amongst these sixty
new-borns.
We did subgroup analysis to find the factors associated with successful
VBAC amongst the forty-four women who were induced (16 from group I and
28 from group II). We found that the mean pre-induction Bishop score was
significantly higher in the successful VBAC group (3.86+ 1.12)
compared to the emergency caesarean section group (3.04+ 1.29) (
t=-2.24, p=0.029, 95% CI for mean difference: 0.08 to 1.5) and duration
of oxytocin infusion was significantly shorter in the VBAC group( 5.9
hours+ 3.1) compared to the emergency caesarean group( 8.67+ 4.65hours) ( t=2.26, P=0.028, 95% CI for mean difference:
-5.10 to -0.29). After adjusting for the intervention, Birthweight, scar
thickness, interpregnancy interval, and parity, these two factors
(Pre-induction Bishop score and duration of oxytocin) were not
significantly associated with VBAC (Table5). We excluded Indication from
LSCS from multivariable analysis as the sample size is too small to run
an analysis with too many categories under indications.
The sample size was too small for subgroup analysis to find the factors
associated with spontaneous onset of labour(n=13) in the expectant
group.
Discussion :
Main Findings : In our pilot randomized controlled trial we found
that in the low-risk pregnant woman with a previous caesarean delivery,
induction of labour (IOL) at 40 completed weeks achieves significantly
higher successful vaginal deliveries than expectant management till 41
weeks. We recruited only 30 women in each group and the study was not
powered to analyse maternal or perinatal outcomes. We had strict
inclusion criteria. Though 43% of the women in the expectant group in
our study went into spontaneous labour, only half of these women
successfully delivered vaginally. 23 % of women in the expectant group
developed a maternal or foetal complication. One woman (3.3%) in the
expectant group developed gestational hypertension de novo after 40
weeks.
The landmark ARRIVE trial11, as well as the two
metanalysis12,13 of randomized controlled trials, have
shown a reduction in the adverse perinatal outcome and caesarean
delivery rates in those undergoing IOL at 39 weeks compared to those
managed expectantly. However, all these involved women without a
previous caesarean section. The meta-analysis of cohort study by Grobman
et al 14 also reported similar results. None of the 6
cohort studies analysed by them had included women with a previous
caesarean section.
There are no randomized controlled trials on this subject in women with
previous caesarean delivery. There are only a few cohort studies
comparing IOL with expectant management in women with a previous
caesarean section at term. The first study was a large retrospective
cohort of 16 years.10 It showed lower odds of
caesarean and higher odds of spontaneous vaginal delivery in the IOL
group at various periods of gestation from 39 to 41 weeks. They did not
find a higher rate of rupture in the IOL group. However, heterogeneity
and changing practice over the 16-year study period could have
influenced the results. In another study15 the authors
reported higher VBAC rates (OR1.3) in the IOL group but an increased
rate of rupture in the IOL group. This was a secondary analysis of a
registry from a 4-year multicentre observational
study.16 The original study has not detailed the
induction protocol. Many women had received prostaglandins with or
without oxytocin and information on confounder-like cervical status in
the two groups was not available.
In yet another secondary analysis study of an obstetric cohort from
Consortium of safe labour, among women with previous caesarean section
who attempted TOLAC, the authors 17 observed higher
rates of failed VBAC in the women induced from 37 to 39 weeks but not at
40 weeks. This cohort included both high and low-risk women, which could
have influenced a quicker decision to terminate labour by emergency
caesarean section.
A 3- year retrospective cohort has been recently
published.18 The authors observed that among women
with previous caesarean section, induction of labour at 39 weeks was
associated with lower intraamniotic infection and improved 5-minute
APGAR score in the IOL arm but at the cost of 70% increase in caesarean
delivery rates. They also observed that 2.2% of the expectant arm women
developed new-onset hypertension after 39 weeks. In this study, the
induction protocol was not detailed and oligohydramnios as an indication
for induction was not excluded. Also, women who did not go into
spontaneous labour in the expectant arm but opted for scheduled
caesarean section instead of IOL were excluded. This could have
influenced the higher caesarean rates in the induction arm.
In our study, we had strict inclusion criteria. We took 3mm as the
cut-off for eligibility for TOLAC though RCOG recommends scar thickness
above 2mm. We took a higher cut-off for the full thickness of scar on
sonography because induction of labour has 2 to 3 times higher risk of
scar rupture and meta-analysis done in 201319 had
shown variable sensitivity for variable cut-offs and that the full
thickness more than 3mm provided the strongest negative predictive value
of occurrence of defect during TOLAC. We used Foley single balloon
catheter for ripening of the cervix which is considered a safe method in
women with previous caesarean section.
Strengths and limitations : The biggest strength of our study is
that it is a randomized controlled trial. The two groups were comparable
for important variables like Bishop score and previous vaginal delivery
that are known to influence VBAC rates. We had a strict induction
protocol for both groups. We excluded any maternal or foetal
complications requiring induction including oligohydramnios at the time
of recruitment at 40 weeks. Since we followed standard induction
protocol and monitoring, the results can be generalized to most tertiary
centres with infrastructure for delivering women with previous caesarean
pregnancy. The limitation of our study is that our study had a small
sample size as it was a pilot study. It was powered for our primary
outcome of successful vaginal delivery rates and was not powered for
adverse maternal and perinatal outcomes. We terminated labour by
emergency caesarean section if the women failed to go into the active
phase of labour within 6-8 hours of artificial rupture of membranes. So,
the trial of labour did not last longer than 24 hours if the women had
not gone into the active phase of labour. We did not give a second
application of Foley if the Bishop score had not improved.
Interpretation : The successful VBAC rate is significantly higher
with the induction of labour at 40 weeks compared to expectant
management till 41 weeks. Expectant management is likely to increase the
risk of a maternal or foetal complication. Even though around one-fourth
of women went into spontaneous labour after 40 weeks, only half of them
delivered vaginally.
Conclusion : We recommend induction of labour at 40 weeks
instead of expectant management till 41 weeks, for women with previous
one lower segment caesarean section, with singleton foetus and
uncomplicated pregnancy, who are eligible for TOLAC. We recommend larger
trials for studying the adverse maternal and perinatal outcomes of this
strategy.
Acknowledgements : None.
Disclosure of Interest : None of the authors has any financial
or other conflicts of interest to declare.
Author contribution : GD Conceived the work. GD and RK planned
it. RK carried out the work. SSK and CP analysed the data. GD wrote the
manuscript. RK, GD, SSK, and CP approved the final manuscript.
Details of Ethics Approval: Ethical clearance was obtained from
the Institute Ethics committee. Reference no : JIP/IEC/2018/0145.
Name of the Ethics Committee : Institutional Ethics Committee
(Human Studies), JIPMER.
Date of approval by the Ethics committee: 6thJuly 2018.
And prospective registration was done with the Clinical Trial Registry
of India (number-CTRI/2018/09/015719),
Funding: This study did not involve any funding from any
agency. The Infrastructure of Obstetrics and Gynaecology department of
JIPMER was used to carry out the study.