Trial Oversight

We conducted this multicenter, randomized, controlled, parallel-group, unmasked trial at 41 hospitals participating in the Maternal–Fetal Medicine Units Network of the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The protocol (available with the full text of this article at NEJM.org) was approved by the institutional review board at each hospital before participant enrollment. Written informed consent was obtained from all participants before randomization. An independent data and safety monitoring committee monitored the trial. The authors vouch for the accuracy and completeness of the data and for the fidelity of the trial to the protocol.

Screening and Recruitment

Low-risk nulliparous women who were at 34 weeks 0 days to 38 weeks 6 days of gestation with a live singleton fetus that was in a vertex presentation, who had no contraindication to vaginal delivery, and who had no cesarean delivery planned were screened for eligibility. Low risk was defined as the absence of any condition considered to be a maternal or fetal indication for delivery before 40 weeks 5 days (e.g., hypertensive disorders of pregnancy or suspected fetal-growth restriction). Reliable information on the length of gestation was also a criterion for enrollment; information was considered to be reliable if the woman was certain of the date of her last menstrual period and that date was consistent with results of ultrasonography performed before 21 weeks 0 days or if the date of the last menstrual period was uncertain but results were available from ultrasonography performed before 14 weeks 0 days. Full eligibility criteria are provided in the Supplementary Appendix, available at NEJM.org.

Randomization and Management Strategy

Women who consented to participate were assessed again between 38 weeks 0 days and 38 weeks 6 days of gestation to ensure that they did not have new indications for delivery that would make them ineligible for the trial. Women who were in labor or had premature rupture of membranes or vaginal bleeding at this time were considered to be ineligible. Women who met the inclusion criteria were randomly assigned in a 1:1 ratio to either labor induction or expectant management. The randomization sequence, prepared by an independent data coordinating center, used the simple urn method, with stratification according to clinical site.13 The cervix was examined before labor, from 72 hours before to 24 hours after randomization, to assess dilation, effacement, and station of the fetus to determine a modified Bishop score (scores range from 0 to 12, with lower scores associated with a higher chance of cesarean delivery) (see the Supplementary Appendix).14

Women in the induction group were assigned to undergo induction of labor at 39 weeks 0 days to 39 weeks 4 days. Women in the expectant-management group were asked to forego elective delivery before 40 weeks 5 days and to have delivery initiated no later than 42 weeks 2 days. A specific induction protocol was not mandated for women who underwent induction in either group. Other protocol guidelines are provided in the Supplementary Appendix.

Trained and certified research staff members abstracted information from medical records, including demographic information, medical history, and outcome data. Participants were followed up with an interview performed by research personnel immediately post partum. During this interview, women were asked to rate their labor pain on a 10-point Likert scale (with higher scores indicating greater pain)15 and to rate their experiences on the Labor Agentry Scale,16 which was designed to assess expectations and experiences of personal control during childbirth (scores range from 29 to 203, with higher scores indicating greater perceived control during childbirth). The score on the Labor Agentry Scale was also assessed in a second interview performed by research personnel 4 to 8 weeks after delivery.

Trial Outcomes

The primary outcome was a composite of perinatal death or severe neonatal complications and consisted of one or more of the following during the antepartum or intrapartum period or during the delivery hospitalization: perinatal death, the need for respiratory support within 72 hours after birth, Apgar score of 3 or less at 5 minutes, hypoxic–ischemic encephalopathy,17 seizure, infection (confirmed sepsis or pneumonia), meconium aspiration syndrome, birth trauma (bone fracture, neurologic injury, or retinal hemorrhage), intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support. The principal prespecified maternal outcome (the main secondary outcome) was cesarean delivery.

Prespecified subgroups for the primary perinatal outcome and for the secondary outcome of cesarean delivery were maternal race or ethnic group as reported by the participant (white, black, Asian, Hispanic, other, unknown, or more than one race), age of 35 years or older versus younger than 35 years, body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more versus less than 30, and a modified Bishop score at the time of randomization of less than 5 versus 5 or higher. In addition, although it was not a baseline variable, the specialty of the admitting provider (obstetrics–gynecology, maternal–fetal medicine, family practice, or midwifery) was prespecified for the subgroup analyses.

Neonatal secondary outcomes included birth weight, duration of respiratory support, cephalohematoma, shoulder dystocia, transfusion of blood products, hyperbilirubinemia requiring phototherapy or exchange transfusion, hypoglycemia requiring intravenous therapy, admission to the neonatal intermediate or intensive care unit, and length of hospitalization. In addition to cesarean delivery, other maternal secondary outcomes included hypertensive disorders of pregnancy (gestational hypertension or preeclampsia), indication for cesarean delivery, operative vaginal delivery, indication for operative vaginal delivery, uterine incisional extensions during cesarean delivery, chorioamnionitis, third-degree or fourth-degree perineal laceration, postpartum hemorrhage, postpartum infection, venous thromboembolism, number of hours in the labor and delivery unit, length of postpartum hospital stay, admission to the intensive care unit, and maternal death. Definitions of secondary outcomes are provided in the Supplementary Appendix.

Records of all infants who met the primary perinatal outcome were reviewed centrally to verify that the primary outcome had occurred. Records of infants in whom the primary outcome did not occur but that suggested (on the basis of a delivery hospitalization of 7 or more days or discharge to a long-term care facility) that clinically significant perinatal complications may have occurred were reviewed centrally as well. Reviewers were unaware of the trial-group assignments.

Statistical Analysis

The expected rate of the primary perinatal outcome in the expectant-management group was estimated to be 3.5%.18 We calculated that enrollment of 6000 women would provide a power of at least 85% to detect a 40% lower rate of the primary outcome in the induction group than in the expectant-management group, at a two-sided type I error rate of 5%. This power analysis incorporated the assumption that for 7.5% of the women, management would not be consistent with the protocol of the assigned strategy.

Analyses were performed according to the intention-to-treat principle. We compared continuous variables using the Wilcoxon signed-rank test and categorical variables using the chi-square and Fisher’s exact tests. A multinomial outcome was compared with the use of multinomial logistic regression. Time variables measured in days were categorized and compared with the Cochran–Armitage trend test. We used a group sequential method to control the type I error with the Lan–DeMets characterization of the O’Brien–Fleming boundary. One interim analysis was performed; in the final analysis of the primary outcome, a two-tailed P value of less than 0.046 was considered to indicate statistical significance. Because the adjustment is minimal, we report the 95% confidence interval for the relative risk. Our statistical analysis plan did not call for adjustment of P values to control for multiple comparisons of the results for the individual components of the primary outcome; therefore, these are reported as point estimates and 95% confidence intervals. For the secondary outcomes, the level of significance was adjusted post hoc for multiple comparisons with the false discovery rate method.19 No method of imputation of missing data was used, although sensitivity analyses were performed in which data from participants who withdrew consent or were lost to follow-up were handled in various ways. To determine whether there was a differential effect of labor induction on the primary perinatal outcome and on the secondary outcome of cesarean delivery within the prespecified subgroups, we performed the Breslow–Day interaction test in which a P value of less than 0.05 was considered to indicate statistical significance. The statistical analysis plan is provided in the protocol, available at NEJM.org.