Study design

The PULSE study (a physiologic approach to stimulating labor: PULSE a randomized controlled trial of pulsatile vs continuous oxytocin administration) comprised 2 related randomized controlled, parallel group trials undertaken in two United Kingdom inner city university hospitals (Guy’s and St Thomas’ Foundation Trust and St Mary’s Hospital, Manchester) to compare continuous and pulsatile infusion protocols of oxytocin for labor stimulation in women. The study was not blinded as the 2 infusion pumps used for the continuous and pulsatile infusion protocols were visually distinct. The trial was approved by St Thomas’ Hospital Research Ethics Committee (EC03/114) and Central Manchester Research Ethics Committee (03/CM/356), the Medicines and Healthcare products Regulatory Agency (MHRA) (EudraCT number 2004-000946-19 CTA no: 14523/0002/001; protocol N0; RJ103/01/0160) and registered (ISRCTN72773405).

Women undergoing labor induction and augmentation were investigated in separate trials. The decision to undertake 2 related randomized controlled trials for induction and augmentation was based on a likely difference in oxytocin responsiveness. We hypothesized that women requiring augmentation in whom uterine contractility was, by observation, inefficient would respond differently to infused oxytocin than those being induced. The induction group therefore included women requiring oxytocin for stimulation after receiving prostaglandin E ₂ and those women who exhibited prolonged spontaneous rupture of membranes without contractile activity.

Women enrolled to the induction trial were defined as those who required an intervention (eg, vaginal prostaglandin E ₂ agents or artificial rupture of membranes) to artificially initiate uterine contractions and progressive dilatation/effacement of the cervix. This group also included women with spontaneous rupture of the membranes, but without progression to labor. Women enrolled to the augmentation trial were defined as requiring oxytocin because of a failure to maintain adequate uterine contractility after spontaneous onset of labor; this is in accord with the Royal College of Obstetricians and Gynaecologists definition.

Eligibility

Any pregnant woman (over 18 years old who could give informed consent) requiring induction or augmentation of labor was eligible to enter the study. Women were excluded if they were undergoing induction of labor for fetal death in utero, fetal abnormality, breech, or multiple pregnancy. Women with a history of previous cesarean section were also excluded.

Protocol

After providing written informed consent, participants were randomly assigned in a ratio of 1:1 to either the recommended standard oxytocin infusion protocol or to the proposed pulsatile regime ( Table 1 ; starting dose 2 mU/minute or 2 mU/pulse). Within the pulsatile regime, oxytocin (Syntocinon, stock solution: 10 iU/mL; Alliance Pharmaceuticals Ltd, Chippenham, Wiltshire, UK) was administered for 10 seconds every 6 minutes and the dose (mU/pulse) doubled every 30 minutes until uterine contractions were established (3/4 in 10). This regime stems from the observation that physiologic oxytocin may be released in a pulsatile fashion every 4-6 minutes and has been shown to be an effective protocol in previous smaller studies. Labor ward midwives were trained by research midwives at each center to implement the pulsatile infusion protocol using a programmable syringe pump (Perfusor fm pump; B. Braun Medical Ltd, Sheffield, South Yorkshire, UK). The syringe pump was programmed to deliver the range of bolus volumes/delivery rates required and automated syringe size recognition and calculation of delivery rate. Over a 30-minute period this protocol delivered one sixth of the standard continuous dose.

Management of women randomly assigned to continuous infusion followed local guidelines, eg, if satisfactory contractions were not achieved by 1 hour on the maximum infusion rate, then management was discussed with an obstetrician. Similarly, the effectiveness of the pulsatile regimen was reevaluated after 1 hour at maximum infusion rate and if adequate contractions had not been achieved then the concentration/pulse could be doubled further every 30 minutes at the discretion of the obstetric team. Either regimen could be stopped at the discretion of the obstetric team. It was anticipated that this approach would limit clinically directed cross-over from pulsatile to continuous infusion or vice versa.

Randomization procedure

Once the decision to use oxytocin to progress labor had been made on the basis of routine clinical care, women were approached, recruited to the study, and randomly assigned. Randomization was blocked by center, trial (induced or augmentation), and gestation (≥37 weeks or <37 weeks). The concealed randomization sequence provided by the statistician was computer generated, and treatment and unique identification (ID) allocated after entry of baseline information (hospital number, date of birth, gestation, gravida and parity, and reason for receiving oxytocin) and eligibility checks by the recruiting midwife.

Data collection

Data were recorded using a trial-specific collection form and women and neonates were followed-up until discharge. Infusion details (eg, time, rate of infusion, and dose and contraction rate and additional comments) were recorded during labor at the start of every new infusion rate/dose. Data not recorded during labor were collected and entered by a research midwife at each site (pregnancy, labor/delivery, and neonatal details). Information was obtained first from the handheld maternity notes, but when notes were unobtainable, primary and secondary outcome data were obtained from the hospital patient database. Once recruitment was complete, all data were double checked by the research midwives. Further data consistency and missing data checks were performed after input from the study statistician.

Sample size and data analysis

The primary outcome measure in the induction trial was cesarean section rate, with the aim to reliably detect (or demonstrate the absence of) a clinically important difference of 6%, similar to that found by Cummiskey and Dawood, in the cesarean section rate (20% to 14%; odds ratio [OR], 0.651; risk ratio [RR], 0.70) between the 2 administration protocols, requiring a total of 1294 women for 80% power.

The primary outcome in the augmentation trial was operative delivery rate (combined forceps, ventouse, and cesarean section rate) with the aim to reliably detect (or demonstrate the absence of) a clinically important 20% relative risk reduction (27% to 21.6%; OR, 0.745) between the 2 administration protocols, requiring a total of 908 women for 80% power. This calculation was based on data from a study of 94 women comparing pulsatile vs continuous infusions of oxytocin for augmentation. Different primary outcome measures were required as clinically, augmentation is associated with high instrumental delivery rates rather than cesarean section alone.

A blinded interim analysis was undertaken 12 months into the study to consider recruitment and event rates (aggregated by treatment allocation). This analysis found that event rates were much higher than anticipated, whereas recruitment was below target. The data monitoring committee was provided with revised sample size calculations based on current event rates, and plausible and clinically important treatment effects. For the induced arm, the event rates were taken as 24% and 38% (OR, 0.52; RR, 0.63; risk difference, 14%), requiring 484 women for 90% power. For the augmented arm, they were similarly 53% and 69% (OR, 2.0; RR, 1.3; risk difference, 16%), requiring 412 subjects for 90% power. Both these recruitment targets were exceeded comfortably.

The main secondary outcomes for both trials were vaginal delivery not achieved with 24 hours and time from start of induction to delivery. Other secondary measures included pain relief, serious maternal morbidity or death, serious neonatal morbidity or death, uterine hyperstimulation (≥5 contractions in 10 minutes), meconium stained liquor, postpartum hemorrhage, reported (clinician perceived rather than rigorously defined) fetal distress, need for fetal blood sampling, Apgar scores of less than 7 at 5 minutes and neonatal intensive care admission.

Data were analyzed by intention to treat, using Stata version 10.1 (StataCorp LP, College Station, TX). Estimated treatment effects (either mean differences or risk difference and RR) are presented with confidence intervals (CIs). A P value of < .05 was considered significant for all planned analyses of primary and secondary outcomes. As a sensitivity analysis, the powered endpoints were adjusted for parity using the Mantel-Haenszel method.