Study design
This was a pragmatic, parallel group, open-label, superiority randomised control trial of two protocols for labour induction among women with hypertension of pregnancy. All women underwent initial cervical preparation with low dose oral misoprostol; and those who required ongoing induction after membrane rupture were randomised in a 1:1 ratio to LDOM or intravenous oxytocin. The study protocol has been published,10 but brief methods are outlined below.
Participants
Women planning to give birth in three government hospitals in central India were recruited to this trial: Government Medical College, Nagpur and Daga Memorial Women’s Hospital Nagpur, and Mahatma Gandhi Institute of Medical Sciences, Sevagram, Wardha. Women with an indication for induction due to hypertensive disease, irrespective of gestation, and who required cervical preparation for an unfavourable cervix (Bishop’s score ≤ 6) were recruited prior to the start of induction. All consenting women then underwent cervical preparation with LDOM 25mcg 2 hourly. However, only those who subsequently required augmentation following artificial rupture of membranes were randomised. Most did not have prior ultrasound unless growth restriction was suspected clinically prior to the development of hypertension or if the onset was before 34 weeks’ gestation. Those with a previous caesarean section, age <18 years old, known intrauterine fetal death, or multiple pregnancy were excluded.
Randomisation and masking
Potential participants were informed of the study through posters in the antenatal areas and labour ward. Once a clinical decision was made for induction, the woman was provided with an own-language information sheet and a brief slide presentation to view on a tablet. If she was unable to read, a member of the research team read the forms to her in her own language in the presence of family members and/or friends. If she wished to participate, then she signed (or placed a thumb print) on the consent form. If she then required ongoing induction after membrane rupture as part of the induction process, she was randomised to receive misoprostol or oxytocin without the need for additional written consent.
For randomisation, the next consecutive, sequentially numbered opaque envelope containing the allocation was drawn from the trial dispenser by the research assistant and opened. The treatment allocation was generated independently using a computerised pseudo-random number generator, stratified by centre with random block sizes of 4, 6 and 8. Neither participant, researcher nor clinical team were blinded to the allocated treatment.
Procedures
Induction for all women commenced with cervical preparation using 25 mcg oral misoprostol tablets (Cipla Ltd, Goa, India) every 2 hours. Once painful contractions started, labour monitoring commenced with assessments every 30 minutes with a vaginal examination every 4 hours. The next dose of oral misoprostol was omitted when 3 or more moderate or strong contractions occurred every 10 minutes. Artificial rupture of membranes (ARM) was performed as per routine clinical practice when the cervix was 2cm dilated. If spontaneous rupture of membranes occurred before that point, then the cervical preparation doses of misoprostol were stopped. If contractions were inadequate, then LDOM could be restarted as part of the randomised trial.
After membrane rupture, if contractions continued at 3 in 10 or more and there was progressive cervical change (defined as at least 1cm every 2 hrs) then no further LDOM was used, and the participants were not randomised. If, however, the contractions reduced to less than 3 in 10 or if there was no progressive cervical change, then the woman was randomised to either continued LDOM or an oxytocin infusion. This was the point of trial entry. If the cervix was still not favourable for ARM after 24 hours of cervical preparation, then the decision regarding the ongoing management was by the clinical team but was usually a caesarean birth.
The misoprostol 25mcg was given orally every 2 hours in the absence of adequate uterine activity. There was no titration of the misoprostol dose, but the next dose was withheld in the presence of regular uterine activity and only restarted if contractions became inadequate or if there was inadequate cervical change (<1cm every 2 hours). For the oxytocin infusion, 5IU oxytocin (Pfizer Limited, Nani Daman, India) in 500 mL of Ringer’s lactate was given through an electronic infusion pump at a rate of 2 mU/min, and increased every 30 min by 2 mU/min to a maximum of 20mU/min until there were 3-4 contractions every 10 min. If there was any suspicion of fetal distress due to excessive uterine activity, then the oxytocin infusion was stopped, and the participant was put in a left lateral position and continuous electronic fetal heart rate monitoring started.
Maternal and fetal monitoring was conducted on a one-to-one basis by graduate research assistants, specifically trained on fetal monitoring and uterine contraction strength. Intermittent electronic fetal monitoring was done every 30 minutes with continuous electronic fetal monitoring in case of abnormality. Continuous fetal monitoring was also used routinely in high-risk women when available. In case of hyperstimulation, staff were instructed to commence electronic fetal monitoring and, in the event of abnormality, reduce the dose of oxytocin.
Outcomes
Outcomes were based on the Cochrane Collaboration induction of labour generic protocol11 and the induction of labour core outcome set.12 The primary outcome was caesarean birth. Secondary outcomes addressed the success of the induction process, maternal mortality and morbidity, and neonatal morbidity and mortality. Measures of success included the randomisation to birth interval, duration of hospital stay and satisfaction. Data was collected using REDCap (Vanderbilt University, Tennessee, USA). A qualitative study, situational analysis and health economic analysis were also conducted and will be reported separately.
Sample size calculation
In a previous study of labour induction conducted in this population, 157 (52%) women required uterine stimulation after membrane rupture with intravenous oxytocin (standard practice), of whom 49 (31%) had a caesarean birth.12 In a systematic review of LDOM, those whose induction was continued after membrane rupture with LDOM had 42% less caesarean sections than those who changed to oxytocin (15% vs 26%).5 Using this data, it was estimated that a total sample size of 520 women would provide (a) 90% power to detect a reduction in the CS rate from 31% to 18.5% (RR 0.6), or (b) 80% power to detect a reduction in the CS rate from 31% to 20% (RR 0.65) in those women who receive LDOM (superiority; two sided α=0.05). It was proposed to approach and gain consent from 1000 women of whom an estimated 520 would require ongoing induction after cervical preparation. At the point of requiring uterotonics for ongoing induction, consented women would be randomized to either a protocol of continued LDOM (n=260) or the standard oxytocin infusion (n=260).