Induction in Nulliparous Women at 39 Weeks to Prevent Adverse Outcomes: A Randomized Controlled Trial
Phase: NA
Conditions: Labor and Delivery
Sponsor: The George Washington University Biostatistics Center

Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Grobman WA, Rice MM, Reddy UM, et al. Labor induction versus expectant management in low-
risk nulliparous women. N Engl J Med 2018;379:513-23. DOI: 10.1056/NEJMoa1800566

This supplement contains the following items: 
1. Original protocol
2. Final protocol
3. Summary of changes
Please note that the statistical analysis plan is contained within the study protocol. 

Induction in Nulliparous Women at 39 Weeks to 
Prevent Adverse Outcomes:  A Randomized 
Controlled Trial  
Protocol 
A Randomized Trial of Induction Versus Expectant Management 
(ARRIVE) 
Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD) 
Maternal-Fetal Medicine Units (MFMU) 
 Network  
Prepared by the 
Biostatistical Coordinating Center for the NICHD MFMU Network 
The Biostatistics Center 
George Washington University 
6110 Executive Boulevard, Suite 750 
Rockville, MD 20852 
(301) 881-9260 
October 31, 2013 

Table of Contents 
1 
Introduction ........................................................................................................................................ 1 
1.1 
Study Abstract ............................................................................................................................. 1 
1.2 
Primary Hypothesis ..................................................................................................................... 1 
1.3 
Purpose of the Study Protocol ..................................................................................................... 1 
2 
Background ......................................................................................................................................... 2 
2.1 
Introduction ................................................................................................................................. 2 
2.2 
Complications of Term Pregnancies beyond 39 Weeks of Gestation ......................................... 2 
2.3 
Results from MFMU Network Studies ........................................................................................ 4 
2.4 
Potential Risks and Benefits of Planned Elective Induction of Labor before 41 weeks .............. 5 
2.5 
Rationale for a Randomized Clinical Trial .................................................................................. 7 
3 
Study Design ....................................................................................................................................... 8 
3.1 
Primary Research Question ......................................................................................................... 8 
3.2 
Secondary Research Questions .................................................................................................... 8 
3.3 
Design Summary ......................................................................................................................... 8 
3.4 
Eligibility Criteria ........................................................................................................................ 8 
3.5 
Informed Consent Criteria ......................................................................................................... 10 
3.6 
Randomization Method ............................................................................................................. 10 
4 
Study Procedures.............................................................................................................................. 11 
4.1 
Screening for Eligibility and Consent ....................................................................................... 11 
4.2 
Randomization ........................................................................................................................... 11 
4.3 
Baseline Procedures ................................................................................................................... 12 
4.4 
Study Procedures ....................................................................................................................... 12 
4.5 
Patient Management and Follow-up .......................................................................................... 12 
4.6 
Adverse Event Reporting........................................................................................................... 13 
4.7 
Study Outcome Measures and Ascertainment ........................................................................... 13 
5 
Statistical Considerations ................................................................................................................ 16 
5.1 
Data Relevant to the Primary Outcome ..................................................................................... 16 
5.2 
Sample Size and Power ............................................................................................................. 16 
5.3 
Feasibility .................................................................................................................................. 18 
5.4 
Interim Analysis ........................................................................................................................ 18 
5.5 
Analysis Plan ............................................................................................................................. 18 
6 
Data Collection ................................................................................................................................. 20 
6.1 
Data Collection Forms ............................................................................................................... 20 
6.2 
Web Data Entry System ............................................................................................................ 20 
6.3 
Centralized Data Management System ...................................................................................... 20 
6.4 
Performance Monitoring............................................................................................................ 21 
7 
Study Administration ....................................................................................................................... 22 
7.1 
Organization and Funding ......................................................................................................... 22 
7.2 
Committees ................................................................................................................................ 22 
8 
Study Timetable................................................................................................................................ 24 
8.1 
Training and Certification ......................................................................................................... 24 
8.2 
Recruitment and Data Collection Period ................................................................................... 24 
8.3 
Final Analysis ............................................................................................................................ 25 
Appendix A 
Design Summary ........................................................................................................... 26 
Appendix B 
Sample Informed Consent Form ................................................................................. 27 
Table 1. Maternal Complications in Singleton Gestation by Gestational Week ........................................... 3 
Table 2. Association of Gestational Age with Severe Neonatal Complications ........................................... 4 

Table 3.  Randomized Controlled Trials of Elective Induction of Labor (EIOL) at 39-40 Weeks vs 
Expectant Management (EM) ....................................................................................................................... 6 
Table 4. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP ........................................... 9 
Table 5. Scoring System for the Modified Bishop Score............................................................................ 11 
Table 6. Sample Sizes per Group for Different Primary Outcome Rates, Power and Effect Sizes ............ 17 
Figure 1. Timetable ..................................................................................................................................... 24 

October 31, 2013 
1 Introduction 
1.1 Study Abstract 
Recently, several retrospective studies have shown that certain maternal and perinatal complications 
increase with gestational age after 37-38 completed weeks.  This has called into question whether it is 
appropriate to wait until 41 weeks for induction in uncomplicated pregnancies.  Although it has 
traditionally been held that the disadvantage of labor induction is that it increases the risk of cesarean 
delivery, this conclusion is based on studies with methodological flaws.  In these studies, women who 
were electively induced were compared by gestational week with those who labored spontaneously.  This 
is not the most appropriate comparison group because women who are induced at 39 weeks, for example, 
would not otherwise have immediate spontaneous labor.  Instead, the most fitting comparison group 
should be composed of women who are expectantly managed.  The studies that have used this comparison 
group have largely failed to demonstrate the association between induction and cesarean delivery, as have 
the small trials where women were randomized to labor induction or expectant management.  Thus, 
whether labor induction at 39 weeks of gestation modifies maternal and perinatal outcomes, compared 
with expectant management, remains unknown.  
This protocol describes a randomized trial of 6000 women to assess whether a policy of elective induction 
of labor at 39 weeks of gestation compared with expectant management will improve outcomes.  
1.2 Primary Hypothesis 
Among nulliparous women with singleton uncomplicated term pregnancies, elective induction of labor at 
39 weeks, compared with expectant management, reduces the risk of severe neonatal morbidity and 
perinatal mortality. 
1.3 Purpose of the Study Protocol 
This protocol describes the background, design and organization of the randomized clinical trial and may 
be viewed as a written agreement among the study investigators.  The Data and Safety Monitoring 
Committee (DSMC) and the Network Advisory Board review the protocol.  Before recruitment begins, 
the protocol is approved by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network Steering Committee, and the 
Institutional Review Board (IRB) of each clinical center.  Any changes to the protocol during the study 
period require the approval of the Steering Committee and the IRBs; major changes also require the 
approval of the DSMC. 
A manual of operations supplements the protocol with detailed specifications of the study procedures. 
1 

October 31, 2013 
2 Background 
2.1 Introduction 
Post dates pregnancy, defined as a gestation that persists beyond 294 days or 42 weeks’ gestation, is 
associated with an increased risk of perinatal morbidity and mortality.1  Several studies have shown that 
as pregnancy extends beyond 42 weeks the risk of oligohydramnios, macrosomia, fetal birth injury, 
meconium aspiration syndrome, and stillbirth increase significantly.1  To avoid these risks, common 
practice has been to induce labor once 42 weeks has been reached.  Indeed, because these risks begin to 
increase even before 42 weeks, many investigators have suggested that a policy of induction of labor at 41 
weeks can improve pregnancy outcomes.  In 2006 a Cochrane review was conducted of all trials in which 
women were randomized to induction of labor at 41-42 weeks or expectant management with fetal 
surveillance (including the MFMU Network’s trial).  The investigators found that a policy of induction of 
labor at or beyond 41 completed weeks was associated with fewer (all-cause) perinatal deaths (RR 0.3 
95% CI 0.09, 0.99), with no evidence of a statistically significant difference in the cesarean section rate 
for women in the induction group (RR 0.92 95% CI 0.76, 1.12).2 
The American Congress of Obstetricians and Gynecologists states that both expectant management and 
labor induction at 41 weeks are associated with low complication rates and good perinatal outcomes in 
low-risk post term women but that there appears to be a small advantage to labor induction, regardless of 
parity or method of induction.1  Recently, data have been published showing increased rates of 
complications beyond 39 weeks, suggesting that it may be advantageous to induce uncomplicated 
pregnancies at an earlier gestation than 41 weeks.3-15  
2.2 Complications of Term Pregnancies beyond 39 Weeks of Gestation 
2.2.1 Maternal Complications 
Several studies have demonstrated that certain maternal complications increase in a continuous fashion 
after 37-38 completed weeks.3-8  Investigators have reported that pregnancies that continue beyond 39 
weeks are associated with increased risks of cesarean section, operative vaginal delivery, 3rd and 4th 
degree lacerations, and chorioamnionitis.3-7,9  
Table 1 summarizes the maternal data from the largest and most recent cohort studies that have examined 
adverse outcomes in term pregnancies.  Most of these studies examined maternal complications in 
multivariable models and found that gestational age beyond 39 weeks was predictive of increased risk 
even when controlling for known confounders such as maternal age, ethnicity, education, parity, length of 
labor, induction, and birth weight.   
 
 
2 

October 31, 2013 
Table 1. Maternal Complications in Singleton Gestation by Gestational Week 
Population and Reference 
39 weeks 
40 weeks 
41 weeks 
Adjusted OR (95% CI) 
41 wks vs 39 wks in a 
Multivariable Model 
Primary cesarean delivery (multiparas and nulliparas) 
N=45,673; 1992-20024
14.0% 
15.9%** 
21.2%** 
1.32 (1.17,1.53) 
N=32,828; low risk; 1976-20013 
9.2% 
10.4%** 
14.1%** 
1.44 (1.28, 1.62) 
N=119,254; low risk; 1995-995 
8.8% 
9.0% 
14.0%** 
1.28 (1.20, 1.36) 
N=2,928,722; low risk; from US 
natality data 20037 
12.8% 
14.1%** 
19.8%** 
1.46 (1.44, 1.48) 
Primary cesarean delivery rates by weeks’ gestation in nulliparas only 
N=32,828; low risk; 1976-20013 
11.4% 
14.2%* 
18.9%** 
Not available 
N=119,254; low risk; 1995-995 
14.4% 
14.9% 
21.9%** 
Not available 
N=2,928,722; low risk; from US 
natality data 20037 
21.5% 
23.3%** 
30.1%** 
Not available 
Operative vaginal delivery 
N=45,673; 1992-20024 
15.5% 
17.9%** 
18.5% 
1.14 (1.05, 1.23) 
N=32,828; low risk; 1976-20013 
14.8% 
16.4%** 
17.4%** 
1.22 (1.10, 1.44) 
N=119,254; low risk; 1995-995 
9.4% 
10.9%** 
13.3%** 
1.29 (1.20, 1.36) 
N=2,928,722; low risk; from US 
natality data 20037 
7.6% 
8.1%** 
9.6%** 
1.14 (1.11, 1.16) 
3rd and 4th degree lacerations 
N=32,828; low risk; 1976-20013 
9.4% 
10.8%** 
12.0%** 
1.26 (1.10, 1.44) 
N=119,254; low risk; 1995-995 
4.0% 
4.6%* 
6.7%** 
1.58 (1.44, 1.73) 
Postpartum hemorrhage 
N=32,828; low risk; 1976-20013 
13.4% 
12.8% 
16.0%** 
1.18 (1.06, 2.31) 
N=119,254; low risk; 1995-995 
2.5% 
3.1%** 
4.1%** 
1.21 (1.10, 1.32) 
Febrile morbidity 
N=45,673; 1992-20024 
1.7% 
2.3% 
2.7%** 
1.46 (1.14, 1.87) 
N=32,828; low risk; 1976-20013 
5.2% 
6.0%** 
7.7%** 
1.28 (1.11, 1.49) 
N=119,254; low risk; 1995-995 
2.7% 
3.7%** 
5.1%** 
1.46 (1.14, 1.87) 
N=2,928,722; low risk; from US 
natality data 20037 
1.6% 
2.0%** 
2.7%** 
1.49 (1.45, 1.54) 
Statistical significance compared with rate of outcome in the previous week gestation: * p<.01, ** p<.001 
3 

October 31, 2013 
2.2.2 Infant Outcomes 
Studies have also demonstrated that the rates of adverse neonatal outcomes are increased in pregnancies 
that extend beyond 39 weeks.4,6  In a study of singleton deliveries in Scotland between 1985 and 1996, 
Smith showed that the risk of perinatal death (stillbirth or neonatal death) nadirs at 39 weeks.8  In a study 
of deliveries registered in an area of London, the rate of stillbirth increased progressively with advancing 
gestation from 37 to 43 weeks.10  Abnormal neonatal acid-base status has been shown to increase in 
pregnancies delivered beyond 39 weeks.6,11   
In a retrospective cohort study of singleton, cephalic, low-risk neonates delivered at term, Caughey et al. 
concluded that neonatal complications of term pregnancy increase in a continuous, rather than in a 
threshold fashion.  In this cohort the incidence of severe neonatal complications was increased 1.5-2 fold 
in pregnancies delivered at 40-41 weeks compared with those delivered at 39 weeks (Table 2).6  Other 
investigators reported similar trends in neonatal morbidity for pregnancies advancing beyond 39 
weeks.7,11,12  
Table 2. Association of Gestational Age with Severe Neonatal Complications 
 
Gestational week 
Percent with 
complications 
Odds ratio (95% CI) 
39 weeks 
1.84% 
referent 
40 weeks 
2.31% 
1.47 (1.09, 1.98) 
41 weeks 
3.14% 
2.04 (1.50, 2.78) 
42 weeks 
3.82% 
2.37 (1.63, 3.49) 
 
In contrast with maternal outcomes, there is clear evidence that adverse neonatal outcomes are more 
common when elective delivery is undertaken at term but prior to 39 weeks.  Several investigations 
demonstrated an increase in neonatal morbidity for infants delivered at 37-38 weeks, compared with those 
delivered at 39 weeks or beyond.  Specifically, at ages before 39 weeks, the risk of NICU admission, 
RDS, mechanical ventilation, and hypoglycemia are increased, particularly for infants delivered by 
cesarean section.13-15  While the risk of both stillbirth and infant death per 1000 ongoing pregnancies 
increases a modest amount between 37-39 weeks (0.7/1000 to 1.4/1000 respectively), the risk of more 
common adverse events (e.g., RDS, mechanical ventilation) is increased by a factor of 2 to 12.14,15  
Overall, elective delivery prior to 39 weeks is associated with an increase in respiratory and other adverse 
neonatal outcomes.  
2.3 Results from MFMU Network Studies 
Secondary analyses of NICHD MFMU Network data are consistent with the findings above for both 
maternal and neonatal outcomes.  In the MFMU Network trial of fetal pulse oximetry (FOX), a secondary 
analysis of 4086 women found that the risks of a composite maternal outcome (treated uterine atony, 
blood transfusion, or peripartum infection) and cesarean delivery increased with increasing gestational 
age from 39 to 41 or more completed weeks (p value for trend < 0.001).16 
In the Cesarean Registry, a composite outcome of death or adverse neonatal outcome increased from 8% 
to 11.3% as gestational age increased from 39 to 41 weeks in women undergoing elective repeat cesarean 
delivery.14  Also, in the cohort of women in the FOX trial referenced above, risks of a similar composite 
adverse neonatal outcome increased with increasing gestational age after 39 weeks.16 
Based on Caughey et al 2005; severe neonatal complications defined as birth trauma, seizures, intracranial hemorrhage, 
sepsis, meconium aspiration syndrome, respiratory distress syndrome 
4 

October 31, 2013 
In summary, available data lead to the hypothesis that planned delivery at 39 weeks will result in the 
fewest adverse maternal and perinatal outcomes. 
2.4 Potential Risks and Benefits of Planned Elective Induction of Labor before 
41 weeks 
If neonatal risks nadir at approximately 39 weeks, and if the risks of maternal and neonatal complications 
increase monotonically after 39 weeks, the question arises - do the risks of pregnancy prolongation 
beyond 39 weeks outweigh the risks of labor induction?  Whereas planned cesarean delivery in the 
absence of medical or obstetric complications is performed at 39 completed weeks, planned induction of 
labor at 39 weeks has been discouraged due to a potential increase in risk of cesarean delivery.  Indeed, 
several retrospective cohort studies indicate that induction of labor prior to 41 weeks is associated with an 
approximately 2-fold higher risk of cesarean in nulliparous women.17-22  However, these studies have 
several important limitations.  
First, a number of studies compared outcomes in women undergoing both indicated and elective 
inductions with those of spontaneously laboring women.20,23-26  By including women with medical 
indications for induction (e.g., preeclampsia), it is possible that the higher rates of cesarean delivery 
observed in the induction group were due to the pregnancy complications and not the induction per se.  
Other studies have evaluated elective induction of labor separately.17,18,21,22,24,27,28  They consistently 
showed that cesarean delivery is more common in those electively induced.  However, in these studies, 
women who were electively induced were compared with those who were spontaneously laboring.  While 
this is a convenient comparison group it is not the most appropriate one, because women who are induced 
at 39 weeks are not guaranteed the alternative of an immediate spontaneous labor.  In other words, 
women and their providers cannot choose between elective induction and spontaneous labor, but between 
elective induction and expectant management.  Expectant management at 39 weeks may result in a 
proximate spontaneous labor but also may result in circumstances (e.g., preeclampsia, need for labor 
induction at 42 weeks) that increase the risk of cesarean.29  Therefore, the most fitting comparison group 
in an observational study of elective induction would be all women at 39 weeks with ongoing 
pregnancies.   
One group of investigators performed an observational study with just such a nulliparous study 
population.  Osmundson and colleagues compared outcomes of labor between nulliparous women who 
either underwent elective induction or expectant management at or beyond 39 weeks at a single 
center.30,31  Moreover, these investigators ascertained cervical status of all women at 38-39 weeks, in 
order to remove the possibility of selection bias related to this factor.  The findings of this study, in 
contrast with the prior studies that used spontaneously laboring comparison groups, revealed that elective 
induction at 39 weeks or greater, for either women with a favorable or unfavorable cervix, did not 
increase the cesarean delivery rate.  Specifically, for nulliparas with a favorable cervix (modified Bishop 
score ≥5) the cesarean delivery rate was 21% in the electively induced group vs. 20% in the expectantly 
managed group (p = 0.84).  Similarly there was no significant difference in the cesarean rate for women 
with an unfavorable cervix (43% vs. 34%, p =.16).  This study calls into question the long-standing 
dogma that elective induction of labor prior to 41 weeks increases the frequency of cesarean delivery.  
With regard to long-term outcomes of the offspring, there has not been consistent evidence that oxytocin 
use results in neurodevelopmental disorders.32-35  Moreover, as with many studies about labor induction, 
the studies that have assessed associations between intrapartum oxytocin use and neurodevelopmental 
outcomes have had several fundamental methodological flaws.  For example, women are often induced 
for indications which themselves may be associated with adverse neurodevelopmental outcomes; in such 
a case of “confounding by indication”, adequate adjustment for the confounding factors may be difficult if 
not impossible.  There is not evidence that elective induction (i.e., an induction without an underlying 
medical or obstetric induction) specifically is associated with adverse long-term neurodevelopmental 
5 

October 31, 2013 
outcomes.  Moreover, these studies have typically evaluated women undergoing induction versus those 
undergoing spontaneous labor; this comparison is inappropriate and not clinically relevant,36 as 
spontaneous labor is not a choice but an event.  Indeed, many women who are not “induced” at a given 
gestational age will ultimately require induction or oxytocin augmentation at a later gestational age, or 
experience an obstetric complication which itself may be associated with a risk of adverse 
neurodevelopmental outcome, a risk that may have been prevented had the women been induced earlier.  
Thus, the clinically meaningful comparison is labor induction versus expectant management.  Yet, there 
are no data that suggest that elective induction compared with expectant management increases the risk of 
neurodevelopmental disorders or other adverse long-term outcomes. 
Table 3.  Randomized Controlled Trials of Elective Induction of Labor (EIOL) at 39-40 Weeks vs Expectant 
Management (EM) 
Year and 
Reference 
N 
Patient Population 
(% nullips) 
Gestational  
Age at EIOL 
Gestational 
Age for EM  
Outcome: EIOL vs. EM 
(p>0.05 unless noted) 
197537 
228 •
Multiparous or
nulliparous (46%)
39-40 weeks 41 weeks 
Cesarean: 4.5% vs 7.7% 
197838 
230 •
Multiparous or
nulliparous*
39 weeks 
42 weeks 
Cesarean: 4.3% vs 1%  
Operative vaginal delivery: 
 18.5% vs 20.7% 
197939 
112 
•
Multiparous or
nulliparous (45%)** 
•
Favorable cervix
40 weeks 
42 weeks 
Operative vaginal delivery: 
        2.3% vs 4.8% 
198940 
345 
•
Multiparous or
nulliparous (54%)
•
Favorable cervix
40 weeks 
42 weeks 
Nulliparas: 
Cesarean: 1.0% vs 3.4% 
Operative vaginal delivery: 
        3.0% vs 3.4% 
Multiparas: 
Cesarean: 1.2% vs 0%  
Operative vaginal delivery: 
 1.2% vs 0% 
199940 
194 •
Nulliparous†
39 weeks 
42 weeks 
Cesarean: 6.4% vs 5.6%  
Operative vaginal delivery: 
       53.4% vs 33.3% 
(p=.03) 
200541 
226 
•
Multiparous or
nulliparous (45%)
•
Favorable cervix
39-40 
weeks 
42 weeks 
Nulliparas:  
Cesarean: 13.3% vs 10.3% 
Multiparas: 
Cesarean:   2.8% vs 3.8% 
2.4.1 Randomized Trials of Elective Induction at Term versus Expectant Management 
There have been several small randomized clinical trials comparing elective induction of labor at 37-40 
weeks’ gestation with expectant management until 41-42 weeks (Table 3).37-42  None of these studies 
found an increased frequency of cesarean section among induced participants.  However, these trials have 
significant limitations.  First, all were underpowered to detect the magnitude of increase in cesarean rate 
that would be considered clinically relevant. In addition, because two trials only included women with a 
favorable Bishop score, the generalizability of the data to women with an unfavorable score is limited. 
* Excluded women in EIOL group who had spontaneous labor before 39 weeks and women in EM group  if failed to go into
spontaneous labor by 42 weeks 
** Excluded women in either group with spontaneous labor before 40 weeks or who required a cesarean 
†    Excluded women in EIOL group who had spontaneous labor before 39 weeks and women in EM group if induced before 42 
weeks or failed to go into spontaneous labor by 42 weeks 
6 

October 31, 2013 
Nevertheless, meta-analysis of these data generated by randomized trials reveals a reduction in the 
frequency of cesarean section with induction (RR 0.89; 95% CI 0.81 to 0.97).2  Although it did not 
address elective induction, the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT), a 
randomized trial comparing induction to expectant management for women with hypertensive disease of 
pregnancy, also demonstrates that labor induction may not increase the risk of cesarean (14% in the 
induction of labor group versus 19% in the expectant management group (RR 0.75; 95% CI 0.55-1.04).43  
2.5 Rationale for a Randomized Clinical Trial 
Given the reported increased risks of adverse events in pregnancies extending beyond 39 weeks it has 
been hypothesized that a policy of planned elective induction at 39 weeks could improve outcomes for the 
infant and the mother.  For multiparous patients, especially those with a favorable cervix, it is perhaps 
easy to justify an elective induction at 39 weeks given the low risk of cesarean section.  However, for 
nulliparous patients the current evidence, derived mainly from retrospective observational studies, does 
not allow a clear recommendation.  Nevertheless, a trend towards an increased rate of elective labor 
induction in pregnancies at 39 weeks has been reported, indicating that practitioners are more commonly 
using elective induction at this gestational age,43 even as others caution against routine elective induction 
prior to 41 weeks given the reported increased risk of cesarean delivery.19,44,45,46  Ultimately, a randomized 
controlled trial is necessary to satisfactorily understand whether elective induction of labor of nulliparas at 
39 weeks improves neonatal and maternal outcomes. 
7 

October 31, 2013 
3 Study Design 
3.1 Primary Research Question 
This randomized trial will address the primary research question: does elective induction of labor in 
nulliparous women at 39 weeks improve perinatal outcome compared with expectant management? 
3.2 Secondary Research Questions 
Secondary research questions this study will address are: 
•
Does elective induction of labor in nulliparous women at 39 weeks reduce the risk of any of the
maternal outcomes listed in Section 4.7.2?
•
Does elective induction of labor in nulliparous women at 39 weeks modify the patient-centered
outcomes listed in section 4.7.2?
•
Does elective induction of labor in nulliparous women at 39 weeks reduce the risk of any of the
fetal and neonatal outcomes listed in section 4.7.3?
•
Does elective induction of labor in nulliparous women at 39 weeks modify the utilization of the
medical resources listed in section 4.7.4?
•
Does the proposed effect of elective induction of labor in nulliparous women at 39 weeks vary
according to any of the subgroups listed in section 5.5?
3.3 Design Summary 
The study is a randomized controlled multi-center clinical trial of 6000 women at 38 weeks 0 days to 38 
weeks 6 days randomized to one of two arms at participating MFMU Network clinical centers. 
•
Elective induction of labor between 39 weeks 0 days and 39 weeks 4 days
•
Expectant management (unless a medical indication arises) until at least 40 weeks 5 days.
3.4 Eligibility Criteria 
3.4.1 Inclusion Criteria 
1.
Nulliparous - no previous pregnancy beyond 20 weeks
2.
Singleton gestation.  Twin gestation reduced to singleton, either spontaneously or therapeutically,
is not eligible unless the reduction occurred before 14 weeks project gestational age (see below).
3.
Gestational age at randomization between 38 weeks 0 days and 38 weeks 6 days inclusive based
on clinical information and evaluation of the earliest ultrasound as described in Gestational Age
Determination in Section 3.4.2 below.
3.4.2 Gestational Age Determination 
Gestational age is determined in the following manner, and is denoted “project gestational age”.  The 
“project EDC”, which is based on the project gestational age, cannot be revised once a determination has 
been made.  If the pregnancy is conceived by in-vitro fertilization, project gestational age is calculated 
from the date of embryo transfer and the embryo age at transfer.  If the pregnancy is conceived 
spontaneously (including ovulation induction and artificial insemination) information from the earliest 
8 

October 31, 2013 
dating ultrasound and the last menstrual period are used to determine project gestational age.  The 
following algorithm is used:   
•
The first day of the last menstrual period (LMP) is determined, and a judgment made as to
whether or not the patient has a “sure” LMP date.
•
If the LMP date is unsure, measurement(s) obtained at the patient’s first dating ultrasound
examination is used to determine the project gestational age. The first dating ultrasound must
have been conducted before 14 weeks 0 days by crown rump length.
•
If the LMP date is sure, project gestational age is determined by a comparison between the
gestational age by LMP and by the earliest dating ultrasound.  The first dating ultrasound must
have been conducted before 21 weeks 0 days by LMP.  If the ultrasound confirms the gestational
age by LMP as in the table below, the LMP-derived gestational age is used to determine the
project gestational age.  Otherwise, project gestational age will be determined based upon the
ultrasound measurement.
Table 4. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP 
Gestational age at first ultrasound by LMP 
Ultrasound agreement with LMP 
Up to 13 weeks 6 days 
± 5 days 
Up to 20 weeks 6 days 
± 10 days 
3.4.3 Exclusion Criteria 
1.
Project gestational age at date of first ultrasound is > 20 weeks 6 days
2.
Plan for induction of labor prior to 40 weeks 5 days
3.
Plan for cesarean delivery or contraindication to labor
4.
Signs of labor (regular painful contractions with cervical change)
5.
Fetal demise or known major fetal anomaly
6.
Heparin or low-molecular weight heparin during the current pregnancy
7.
Placenta previa, accreta, vasa previa
8.
Active vaginal bleeding greater than bloody show
9.
Ruptured membranes
10. Cerclage in current pregnancy
11. Known oligohydramnios, defined as AFI < 5 or MVP < 2
12. Fetal growth restriction, defined as EFW < 10th percentile
13. Known HIV positivity because of modified delivery plan
14. Major maternal medical illness associated with increased risk for adverse pregnancy outcome
(for example, any diabetes mellitus, lupus, any hypertensive disorder, cardiac disease, renal
insufficiency)
15. Refusal of blood products
16. Participation in another interventional study that influences management of labor at delivery or
perinatal morbidity or mortality
17. Delivery planned elsewhere at a non-Network site
9 

October 31, 2013 
3.5 Informed Consent Criteria 
Each center will develop its own consent forms according to the requirements of its own institutional 
review board using the model consent form in Appendix B.  Each center will also develop its own patient 
research authorization documents, as required by the HIPAA Privacy Rule, following the guidelines of its 
own institution.  A copy of the signed consent form will be provided to the patient.   
Women who are not fluent in English will be enrolled by a person fluent in their language.  Both verbal 
and written informed consent and authorization will be obtained in that language; if this is not possible 
the patient will be excluded. 
3.6 Randomization Method 
Randomization for consenting women will occur at 38 weeks 0 days to 38 weeks 6 days of gestation.  
Consenting women will be assigned to induction of labor at 39 weeks 0 days to 39 weeks 4 days or 
expectant management in a 1:1 ratio according to a randomization sequence prepared and maintained 
centrally by the Biostatistical Coordinating Center (BCC).   
The simple urn method will be used to generate the randomization sequences because it provides a high 
probability of balance in treatment assignments, it is unpredictable, and it allows an explicit 
randomization analysis to be conducted with relative ease.47  Randomization will be stratified by clinical 
site to assure balance between the two treatment groups with respect to anticipated differences in the 
clinic populations and possible differences in patient management.
10 

October 31, 2013 
4 Study Procedures 
4.1 Screening for Eligibility and Consent 
All nulliparous women with a singleton gestation between 34 and 38 weeks are potentially eligible for 
screening.  Inclusion/exclusion criteria will be reviewed with the patient’s chart.   
If a patient appears to meet the criteria for the trial, she will be told about the study and asked for written 
informed consent to participate in the trial.  Consent may be obtained anytime from 34 weeks 0 days to 38 
weeks 6 days of gestation. 
Each patient must undergo a digital cervical exam between 72 hours prior to randomization and 24 hours 
after randomization.  The three components of the modified Bishop score must be obtained during this 
exam.  Table 5 provides the scoring system that uses the following three components to derive the 
modified Bishop score: 
•
Cervical dilation
•
Cervical length or effacement
•
Fetal station
Table 5. Scoring System for the Modified Bishop Score 
4.2 Randomization 
Eligibility should be verified again before randomization.  Eligible and consenting patients will be 
randomized by certified research staff using an internet based randomization system maintained by the 
BCC.  Randomization will occur when the patient is from 38 weeks 0 days to 38 weeks 6 days of 
gestation.  The patient will be assigned either to the induction of labor group or the expectant 
management group.  
If the patient has had a digital cervical exam within the past 72 hours, and all components of the modified 
Bishop score are documented (cervical dilation, cervical effacement or cervical length, and fetal station), 
randomization may be done in person or over the telephone.  If the patient has not had a digital cervical 
exam within the past 72 hours, or if components of the modified Bishop score are not documented, she 
must be randomized in person and have a digital cervical exam within that same day. 
Station 
(in relation to the spines) 
-3 cm 
-2 cm 
-1 - 0 cm 
1 - 2 cm 
0 
1 
2 
3 
Dilation 
(of the cervix) 
0 cm 
1-2 cm 
3-4 cm 
>4 cm 
0 
2 
4 
6 
Length 
(of the cervix) 
3 cm 
2 cm 
1 cm 
0 cm 
0 
1 
2 
3 
11 

October 31, 2013 
4.3 Baseline Procedures 
In addition to information collected for eligibility, project gestational age, and project EDC determination, 
the following information will be obtained at randomization from a patient interview followed by a 
review of her chart: 
•
Components of the modified Bishop score: cervical dilation, cervical length or effacement, and
fetal station from digital cervical exam
•
Demographic information: age, race, ethnicity, insurance status
•
Medical history: first clinic weight, current weight, height, chronic disease history
•
Obstetrical history including outcome(s) of any prior pregnancies
•
Social history: marital status, alcohol use, and tobacco use
•
Current pregnancy complications
4.4 Study Procedures 
Women randomized to induction of labor will undergo induction via oxytocin at 39 weeks 0 days to 39 
weeks 4 days.  Those with an unfavorable cervix (modified Bishop score < 5) will first undergo cervical 
ripening (method left to the discretion of the patient’s physician) in conjunction with or followed by 
oxytocin stimulation unless a contraindication arises. 
Women randomized to expectant management will have at least weekly follow-up visits with their 
providers and, unless a medical indication is present, will continue pregnancy until at least 40 weeks 5 
days of gestation.  Antepartum fetal testing will be initiated no later than 41 weeks 6 days according to 
policies at each center. All patients will undergo induction via oxytocin by 42 weeks 2 days.  
4.5 Patient Management and Follow-up 
Patients in the induction of labor group (as well as patients in the expectant management group that 
undergo induction of labor) should be allowed adequate time to labor before considering the induction 
“failed” and proceeding to cesarean section.  An induction will be considered “failed” if at least 12 hours 
have elapsed since both rupture of membranes and use of a uterine stimulant and the patient remains in 
latent labor.  It is expected that the fetal heart rate will be monitored while the patient is being induced 
(including ripening) and during labor and that patients will stay in the hospital until delivery once the 
induction (including ripening) is started.  Mechanical ripening using a Foley catheter without saline 
infusion is permitted without monitoring and may be used in an outpatient setting according to policies at 
each center.   
For patients in the expectant management group, only a valid medical indication should warrant delivery 
before 40 weeks and 5 days.  Otherwise, no attempt will be made to alter or mandate clinical management 
of the subjects.   
Women will be asked about pain experienced during childbirth and asked to complete a questionnaire on 
feelings of control during childbirth.  All women will be contacted at six weeks postpartum to determine 
unanticipated outpatient or inpatient visits for them or their infants since discharge and to complete the 
same questionnaire about feelings of control again.  
12 

October 31, 2013 
4.6 Adverse Event Reporting 
Detailed information concerning adverse events will be collected and evaluated throughout the conduct of 
the protocol.  
The NICHD Program Scientist and the BCC will be notified within seventy-two hours of any maternal 
death, perinatal death, or life-threatening maternal event by email/phone/fax, if the event occurred in a 
MFMU Network hospital.  For any maternal death, perinatal death, or life-threatening maternal event 
occurring outside a MFMU Network hospital, the adverse event must be reported to the NICHD and the 
BCC within twenty-four hours of being notified.  These and other adverse events deemed serious, 
unexpected and definitely, possibly or probably related, will be immediately (within twenty-four hours of 
notification) forwarded by the BCC to the DSMC Chair, NIH representative, and any other DSMC 
member who requests notification.  If a death is reported, a copy of the patient’s medical record will be 
made.   
Adverse events which do not qualify under the above definition must be reported to the BCC within 7 
days of being notified.  These adverse events will be collected and sent to the Chair, NIH representative, 
and any other requesting DSMC member on a monthly basis.  The Chair decides whether the adverse 
event reports should be disseminated to the rest of the committee, and whether a follow-up call or meeting 
is required.  NICHD representatives may also request follow-up of specific events.  All adverse events 
will be considered along with other interim safety data in the DSMC deliberations. 
4.7 Study Outcome Measures and Ascertainment 
4.7.1 Primary Outcome 
The primary outcome is a composite of severe neonatal morbidity and perinatal mortality (any one of the 
following): 
•
Antepartum, intrapartum, or neonatal death
•
Intubation, continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) for
ventilation or cardiorespiratory support within first 72 hours
•
Apgar ≤ 3 at 5 minutes
•
Neonatal encephalopathy as defined by Shankaran et al.48
•
Seizures
•
Sepsis.  The diagnosis of sepsis will require the presence of a clinically ill infant in whom
systemic infection is suspected with a positive blood, CSF, or catheterized/suprapubic urine
culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an
unequivocal X-ray confirming infection.
•
Pneumonia confirmed by X-ray or positive blood culture.
•
Meconium aspiration syndrome
•
Birth trauma (bone fractures, brachial plexus palsy, other neurologic injury, retinal hemorrhage
facial nerve injury)
•
Intracranial hemorrhage or subgaleal hemorrhage
•
Hypotension requiring pressor support
13 

October 31, 2013 
4.7.2 Maternal Secondary Outcomes 
1.
Cesarean delivery and indication
2.
Incisional extensions at cesarean section, including J shape or T shape; or cervical traumas
3.
Operative vaginal delivery and indication
4.
Chorioamnionitis, defined as a clinical diagnosis before delivery
5.
Third or fourth degree perineal laceration
6.
Maternal death
7.
Admission to intensive care unit (ICU)
8.
Preeclampsia/gestational hypertension
9.
Postpartum hemorrhage, defined as any of the following:
a.
Transfusion
b.
Non-elective hysterectomy
c.
Use of two or more uterotonics other than oxytocin
d.
Other surgical interventions such as uterine compression sutures, uterine artery
ligation, embolization and hypogastric ligation, balloon tamponade
e.
Curettage
10. Patient-reported outcomes including feelings of control during childbirth, as measured by the
Labour Agentry Scale,49 and two questions regarding pain experienced during childbirth
using a visual analog scale50
11. Interval from randomization to delivery
12. Gestational age at delivery
13. Maternal postpartum infection, defined as any of the following:
•
Clinical diagnosis of endometritis
•
Wound reopened for hematoma, seroma, infection or other reasons
•
Cellulitis requiring antibiotics
•
Pneumonia
•
Pyelonephritis
•
Bacteremia unknown source
•
Septic pelvic thrombosis
14. Maternal venous thromboembolism (deep venous thrombosis or pulmonary embolism)
4.7.3 Fetal and Neonatal Secondary Outcomes 
1.
Birth weight, macrosomia > 4500 g, large for gestational age (LGA) defined as > 90th percentile
weight for gestational age, assessed specifically by sex and race of the infant based on United
States birth certificate data51
2.
Duration of respiratory support including ventilator, CPAP, high-flow nasal cannula (HFNC)
14 

October 31, 2013 
3. Small for gestational age defined as < 5th  and < 10th percentile weight for gestational age, 
assessed specifically by sex and race of the infant based on United States birth certificate data51 
4. Cephalohematoma 
5. Shoulder dystocia 
6. Transfusion of blood products or blood  
7. Hyperbilirubinemia requiring phototherapy or exchange transfusion 
8. Hypoglycemia (glucose < 40 mg%) requiring IV therapy   
9. Admission to neonatal intensive care unit (NICU) or intermediate care unit 
4.7.4 Utilization of Medical Resources  
1. Number of clinic visits post randomization to admission for delivery  
2. ER/urgent care/triage visits post randomization to delivery 
3. Non-stress tests, biophysical profiles (BPPs), modified BPPs, ultrasounds done other than BPP, 
Doppler, contraction stress tests 
4. Epidural use 
5. Intrauterine pressure catheter (IUPC) or fetal scalp electrode placement 
6. Use of induction and ripening agents, maximum dose of oxytocin 
7. Antepartum hospital admission 
8. Number of hours on the labor and delivery unit 
9. Maternal postpartum length of hospital stay 
10. Neonatal length of hospital stay 
11. Length of neonatal intensive care unit or intermediate care stay  
12. Post discharge resource utilization including inpatient and outpatient visits for mother or baby 
 
 
15 

October 31, 2013 
5 Statistical Considerations 
5.1 Data Relevant to the Primary Outcome 
To estimate the rate of the primary outcome in the expectant management group, data from the MFMU 
Network’s APEX study were evaluated.  APEX was an observational study of approximately one-third of 
all deliveries at 25 hospitals in the MFMU Network, collected over a three-year period.  For this analysis 
only nulliparous women with a singleton pregnancy delivered at 39 weeks 0 days to 42 weeks 0 days 
were included; those with diabetes, hypertension before 38 weeks, previa and abruption were excluded, 
yielding a cohort of 24,683 women.  A composite outcome as close as possible to the proposed composite 
primary outcome for this trial was evaluated in these women.  However, APEX only included pregnancies 
with fetal heart tones on admission for delivery and therefore stillbirth would be slightly underestimated.  
In addition, presence of thick meconium was used as a surrogate for meconium aspiration syndrome.  The 
outcome rate in this cohort was 2.3% excluding presence of thick meconium; with thick meconium 
present the outcome rate was 9.3%.  The real primary outcome rate could be expected to be between these 
two estimates.   
Also, among women in the FOX trial, risks of adverse neonatal outcome at term (neonatal composite 
outcome including death, respiratory distress, seizure, sepsis, intubation and ventilator support, 5 minute 
Apgar score of 3 or less or hypoxic ischemic encephalopathy) were 3.7% at 36-38 weeks, 3.5% at 39 
weeks, 3.8% at 40 weeks and 5.0% at ≥ 41 weeks.38   
Therefore the neonatal composite outcome rate for pregnancies expectantly managed beyond 39 weeks 
would be expected to be between 3.5% and 5%.  This is consistent with other literature presented in 
Chapter 1. 
5.2 Sample Size and Power 
5.2.1 Primary Outcome 
Table 6 shows the sample sizes per group (rounded up to the next 10) to detect a 35-40% reduction in the 
primary outcome, with 80% to 90% power, assuming type I error of 5% 2-sided and primary outcome rate 
in the expectant management arm between 3.5% and 5%.  Some women will labor after randomization 
but prior to when their randomized assignment could be implemented (i.e., before 39 weeks).  In addition, 
some women may undergo an elective induction off-protocol before 40 weeks, 5 days without a specific 
indication.  These ‘crossovers’ would therefore behave more like the elective induction group; and it is 
assumed that their primary outcome rate would be the same as that of the elective induction group.  This 
has the effect of reducing the effect size slightly depending on the proportion of crossovers: for example 
with 5% crossovers, the 40% nominal reduction becomes 39%.  
Sample sizes were adjusted to take into account that between 5 and 10% of the women in the expectant 
management group will behave more like the elective induction group.  The actual effect sizes are shown 
in parentheses in the table.  
Data from observational studies suggest that a policy of induction of labor at 39 weeks may result in an 
equivalent reduction in adverse outcome.6, 46  Using a type I error of 5% 2-sided and power of 85%, and 
an estimate that 7.5% of women in the expectant management group will be crossovers, 3000 women in 
each group (total N= 6000) would be needed to detect the actual reduction in primary outcome of 38%.   
If the primary outcome rate is as high as 5%, a sample size of 6000 patients is sufficient to detect a 33-
34% reduction in the primary outcome with at least 85% power, again assuming that 7.5% of women will 
be crossovers.   
16 

October 31, 2013 
Table 6. Sample Sizes per Group for Different Primary Outcome Rates, Power and Effect Sizes 
5.2.2 Cesarean Delivery 
Assuming that the rate of cesarean delivery is 30% in the expectant management group, a sample size of 
6000 women also yields more than 90% power to detect a nominal 15% increase or decrease even after 
adjusting for 7.5% crossovers.    
Reduction in Primary 
Outcome Rate 
(Reduction Adjusted 
for Crossover) 
Power % 
Nominal Primary Outcome Rate in Expectant Management  
Group 
3.5%
4.0%
4.5%
5.0% 
0% Crossover 
35% (35%) 
80 
3030 
2650 
2350 
2120 
85 
3460 
3030 
2690 
2420 
90 
4050 
3540 
3150 
2840 
40% (40%) 
80 
2250 
1970 
1750 
1570 
85 
2570 
2250 
2000 
1800 
90 
3010 
2630 
2340 
2110 
5% Crossover 
35% (33.8%) 
80 
3320 
2900 
2580 
2320 
85 
3790 
3320 
2950 
2660 
90 
4440 
3880 
3450 
3110 
40% (38.8%) 
80 
2460 
2150 
1910 
1720 
85 
2810 
2460 
2190 
1970 
90 
3290 
2880 
2560 
2300 
7.5% Crossover 
35% (33.2%) 
80 
3480 
3040 
2710 
2440 
85 
3980 
3480 
3100 
2790 
90 
4660 
4070 
3620 
3260 
40% (38.1%) 
80 
2580 
2260 
2010 
1810 
85 
2950 
2580 
2290 
2060 
90 
3450 
3020 
2680 
2420 
10% Crossover 
35% (32.6%) 
80 
3650 
3200 
2840 
2560 
85 
4180 
3660 
3250 
2930 
90 
4890 
4280 
3810 
3430 
40% (37.5%) 
80 
2700 
2370 
2100 
1890 
85 
3090 
2710 
2410 
2170 
90 
3620 
3170 
2820 
2530 
17 

October 31, 2013 
5.3 Feasibility 
Given that the sample size estimates are based on a composite of rare outcomes, it is planned that the 
primary outcome rate in the expectant management group be examined in the first 1000 patients.  These 
data would be presented to the DSMC before any comparison by group, and the committee would be 
charged with making a recommendation regarding potential revision of the sample size in addition to 
addressing the feasibility of answering the primary research question. 
5.4 Interim Analysis 
The Data and Safety Monitoring Committee (DSMC) meets in person at least once per year and more 
often if recommended by the committee.  Before each of the annual meetings, a formal detailed report 
will be written by the Biostatistical Coordinating Center (BCC) which presents all baseline variables, 
protocol adherence, side effects, all adverse events reported, as well as center performance in terms of 
recruitment, data quality, loss to follow-up and protocol violations.   
Once sufficient patients have been accrued into the trial, the report will also include a formal interim 
analysis evaluating the primary outcome by treatment group.  For this evaluation, a cohort of patients is 
chosen consisting of all patients randomized before a certain date so that the analysis cohort does not 
depend on gestational age at delivery.   
The main statistical issue relevant to interim analysis is the problem of performing multiple tests of 
significance on accumulating data.  For this trial, the group sequential method of Lan and DeMets will be 
used to characterize the rate at which the type I error is spent.52  This method is flexible with regard to the 
timing of the interim analyses.  Asymmetric stopping boundaries will be used for the Lan-deMets 
procedure.  The upper boundary which describes the stopping rule for benefit will be based on 1-sided 
type I error of .025 and the Lan-deMets generalization of the O’Brien-Fleming boundary.   
The lower boundary will be based on a less stringent stopping rule: 1-sided type 1 error of .05 and the 
Lan-deMets generalization of the Pocock type boundary.   
It is often useful to calculate conditional power given the observed data to date, and conditional on the 
future data showing the originally assumed design effect. If this conditional power is low (under 10 
percent) the DSMC may consider termination for futility if the accrual rate is slow, with confidence that 
the Type II error is not greatly inflated.53  
It is recognized that any decision to terminate the study would not be reached solely on statistical grounds 
but on a number of complex clinical and statistical considerations.  
5.5 Analysis Plan 
All statistical analyses will be based upon the total cohort of patients randomized into the trial.  Although 
data on some patients may be missing, all relevant data available from each patient will be employed in 
the analyses.  Patients will be included in the treatment group to which they were randomly assigned 
regardless of compliance. 
The primary analysis will consist of a simple comparison of binomial proportions.  The relative risk and 
confidence interval will be reported.  The individual components of the composite outcome will also be 
examined.  If the treatment groups are found to differ on a pre-treatment factor known to be a risk factor 
for the outcome, the statistical analysis will adjust for these differences.  An evaluation of treatment by 
center interaction will be included.  An analysis adjusting by center also will be performed to ensure that 
center differences do not change the conclusion.   
If the two groups show a difference in the incidence of the primary outcome, interactions will be 
evaluated and subgroup analyses conducted to determine whether the effect prevails throughout particular 
18 

October 31, 2013 
subgroups of patients.  Indeed, NIH guidelines require investigators to evaluate consistency between the 
genders and across racial subgroups (see Section 5.5.1).  It should be noted, however, that subgroup 
analyses have been greatly abused, particularly when there is no overall treatment difference.54  There is a 
strong temptation to search for a specific subpopulation in which the therapy is nevertheless effective.  
Yusuf et al. concluded “the overall ‘average’ result of a randomized clinical trial is usually a more 
reliable estimate of the treatment effect in the various subgroups examined than are the observed effects 
in individual subgroups.”55  Thus subgroup analyses will be interpreted with care.   
It is generally acknowledged that subgroup analysis that is pre-specified in the protocol has more validity 
than ad-hoc comparisons.  The following factors will be considered for subgroup analysis, if there is a 
significant interaction between the factor of interest and the treatment effect. 
•
Race/ethnicity (see below)
•
Modified Bishop score (< 5 and ≥ 5)
•
Body mass index (obese and non-obese)
Loss to follow-up will be defined as no information regarding stillbirth or neonatal outcome.  There 
should be a low loss to follow-up rate.  It is possible that a woman would deliver at a non-Network 
hospital; however, a record release will be obtained at enrollment to ensure that delivery and neonatal 
information can be obtained.  However, to determine whether the results are robust, a sensitivity analysis 
will be performed including patients lost to follow up with different assumptions regarding their outcome.  
Since many of the secondary endpoints are dichotomous variables like the primary outcome, standard 
statistical methods for rates and proportions will be appropriate.  The Wilcoxon rank sum test will be used 
to compare continuous variables, and survival analysis methodology may be used to compare time-to-
event variables.  
In general, analyses of data will be conducted to address the primary and secondary research questions of 
the trial, and other interrelationships among elements of study data of interest to the investigators and of 
relevance to the objectives of the study. 
5.5.1 Racial/Ethnic Subgroup Analysis 
The racial/ethnic composition of patients of women recruited into the MFMU Network trials varies.  
Assuming for this trial that the composition is 25% African-American and 30% Hispanic, similar to the 
ongoing STAN trial, there is limited power (40-50%) to detect a 50% reduction in the primary outcome in 
the separate subgroups.    
19 

October 31, 2013 
6 Data Collection 
6.1 Data Collection Forms 
Data will be collected on standardized forms on which nearly all responses have been pre-coded.  Each 
form is briefly described below: 
•
AR01   Screening Log.
•
AR02   Eligibility and Randomization Form is completed for all patients eligible and consenting
for the study, and documents the project gestational age and randomization digital cervical exam.
•
AR04   Baseline Form is completed for all randomized patients.  This form includes detailed
demographic and social data, and medical and obstetrical history.
•
AR05   Clinic and Hospital Visit Log documents scheduled and unscheduled clinic, urgent care
and hospital visits, procedures and diagnostic tests, including the antepartum portion of the
delivery admission.
•
AR08   Labor and Delivery Summary Form documents specific pregnancy complications since
randomization, in addition to labor, delivery and postpartum information.
•
AR08A   Labour Agentry Questionnaire
•
AR09   Neonatal Baseline Form records date and time of birth, delivery data and status at
delivery, for each fetus/infant.
•
AR10   Neonatal Outcome Form records outcome data for all infants admitted to the NICU or
special care nursery.
•
AR11   Patient Status Form documents loss to follow up/withdrawal status, last date of contact
for lost to follow-up patients.
•
AR12  Adverse Event Form records serious and non-serious adverse events.
•
AR13  Postpartum Follow-up Form
•
AR13A  Maternal Follow-up Log documents the reasons and diagnoses associated with maternal
clinic, urgent care and hospital visits
•
AR13B  Infant Follow-up Log documents the reasons and diagnoses associated with infant clinic,
urgent care and hospital visits
6.2 Web Data Entry System 
For this protocol, web data entry screens corresponding to the study forms listed above will be developed 
and maintained by the staff of the BCC.  Clinical center staff will enter data into the MySQL database 
located at the BCC through a web data management system (MIDAS).  The data are edited on-line for 
missing, out of range and inconsistent values.  A Users’ Manual documenting this system is provided to 
the centers by the BCC.  
6.3 Centralized Data Management System 
Daily data conversions from the MySQL database create up-to-date SAS datasets.  Data are reviewed 
weekly using edit routines similar to those implemented on-line during data entry, as well as additional 
checks for data consistency within or across forms.  A database of resulting potential data problems is 
20 

October 31, 2013 
generated in MIDAS for initial review by BCC staff, who then evaluate the comments keyed in 
association with edits on missing or unusual values.  Valid edits will be flagged in MIDAS for resolution 
at the clinical centers.   
At regular intervals, specialized data reviews comparing data availability and consistency across forms 
are run by the BCC staff on the entire database or on a specific subset of data.  These reports are also 
submitted to the centers for correction or clarification. 
An audit trail, consisting of all prior versions of each data form as entered in the computer for each 
patient, is maintained so that the succession of corrections can be monitored. 
6.4 Performance Monitoring 
The BCC will present regular reports to the ARRIVE Subcommittee, the Steering Committee, and the 
Data and Safety Monitoring Committee.  These include: 
•
Monthly Recruitment Reports - reports of the number of women screened and enrolled by month
and by clinical center are provided monthly to the ARRIVE Subcommittee and all other members
of the Steering Committee.  Weekly or bi-weekly reports are provided electronically if needed.
•
Quarterly Steering Committee Reports - reports detailing recruitment, baseline patient
characteristics, data quality, incidence of missing data and adherence to study protocol by clinical
center, are provided quarterly to the ARRIVE Subcommittee and all other members of the
Steering Committee.
•
Data and Safety Monitoring Committee Reports - for every meeting of the DSMC, a report is
prepared which includes patient recruitment, baseline patient characteristics, center performance
information with respect to data quality, timeliness of data submission and protocol adherence (in
addition to safety and efficacy data).  The reports also include adverse events, loss to follow-up
and all outcome variables as described previously in this protocol.
21 

October 31, 2013 
7 Study Administration 
7.1 Organization and Funding 
The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD).  The study is conducted by the NICHD Maternal-Fetal Medicine Units (MFMU) 
Network, consisting of fourteen clinical centers, the Biostatistical Coordinating Center (BCC) and the 
NICHD, and is administered under cooperative agreements between each of the centers and the NICHD.  
Each of the funded institutions is represented by a Principal Investigator.  A complete description of the 
organization of the MFMU Network is provided in the MFMU Network Policy Manual.   
7.1.1 Participating Clinical Centers 
The participating Principal Investigators of the clinical centers have agreed to abide by the study protocol, 
to have comparable staff, facilities and equipment and to ensure the proper conduct of the study at each of 
their centers including: recruitment and treatment of patients as specified in the protocol, accurate data 
collection and the transmission of information to the Steering Committee. 
7.1.2 Biostatistical Coordinating Center 
The BCC is responsible for all aspects of biostatistical design, data management, interim and final 
statistical analyses, and preparation of publications based on the study results.  The Principal Investigator 
of the BCC reports to the Steering Committee and the Data and Safety Monitoring Committee. 
7.1.3 NICHD 
In addition to its role as funding agency, the NICHD participates in the activities of the Network, 
including the development of protocols, administration and conduct of the studies and preparation of 
publications. 
7.1.4 Network Advisory Board 
Appointed by the NICHD, the members of the Network Advisory Board consist of a group of experts 
who are not affiliated with research being conducted by the Network and represent the disciplines of 
maternal-fetal medicine, neonatology and biostatistics/epidemiology.  The role of the board includes the 
review and prioritization of proposed studies, in addition to the identification of scientifically and 
clinically important questions and ideas that might be conducted by the Network.  The NICHD Program 
Scientist convenes and attends the meetings. 
7.2 Committees 
7.2.1 Steering Committee 
This committee consists of seventeen members.  The Principal Investigator from each of the fourteen 
clinical centers, the BCC, and the NICHD MFMU Network Program Scientist are all voting members. 
The Chair of the Steering Committee may vote to break a tie.  The Chair, a person independent of the 
participating institutions, is appointed by NICHD.  The Steering Committee has the responsibility for 
identifying topics for Network studies, designing and conducting study protocols and monitoring study 
implementation, recruitment and protocol adherence.  The committee receives recommendations from the 
Data and Safety Monitoring Committee and the Network Advisory Board. 
7.2.2 Protocol Subcommittee 
The subcommittee consists of a chair (who is an investigator from one of the clinical centers), 
investigators from one or more other clinical centers, BCC staff, nurse coordinators, outside consultants 
22 

October 31, 2013 
(if appropriate), and the NICHD Network Program Scientist.  The Protocol Subcommittee is responsible 
for the preparation and conduct of the study, and reporting the progress of the study to the Steering 
Committee. 
7.2.3 Publications Committee 
The Publications Committee is a standing committee of the Steering Committee.  The functions of this 
committee are to develop publication policies and to review all manuscripts and abstracts prior to 
submission.  The goals of this committee are fair and appropriate authorship credit and high quality 
publications. 
7.2.4 Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC), a group of individuals not affiliated with any of the 
participating institutions, was established by the NICHD.  Before the trial can begin, the protocol must be 
approved by the committee.  During the conduct of the study, the committee is charged with monitoring 
the emerging results for efficacy and safety, in addition to center performance and protocol adherence.  
Recommendations by the committee can include protocol modification, early termination for efficacy, or 
for unexpected safety problems.  Recommendations are made to the NICHD and disseminated to the 
Steering Committee. 
23 

October 31, 2013 
8 Study Timetable 
Figure 1. Timetable 
   July 2013    
 July 2014      
      July 2015                         July 2016         
8.1 Training and Certification 
During the study start-up period, preparation of the final case report forms, manual of operations, and 
randomization sequence, in addition to implementation of the data entry and management system will 
take place.  Training will be held with the nurse coordinators in July and October 2013, with a projected 
study start date of October 2013.  Each participating center must be certified to start the trial before 
recruitment at that center can begin.  The certification requirements are designed to ensure that personnel 
involved in the trial are committed to the study and proficient in study procedures, and that the center has 
satisfied regulatory requirements.  Each center is required to obtain IRB approval for the study before 
they are certified to begin the trial.   
8.2 Recruitment and Data Collection Period 
Approximately 160,000 women deliver at MFMU Network centers annually.  The APEX study database 
was queried to determine what proportion of all deliveries would be eligible for ARRIVE.  A total of 
17,960 pregnancies out of 115,502 or 15.5% satisfied the eligibility criteria.  In addition, a pilot survey 
was conducted at four of the MFMU Network centers.  A total of 204 women were queried to find out 
whether they would consent to this trial if it were presented to them.  A total of 55% responded ‘yes’, 
13% responded ‘maybe’ and 32% responded ‘no’.  Assuming only 20% percent of the 160,000 deliveries 
are available (due to, for example, certain sites or care providers not participating), 15.5% satisfying 
eligibility criteria and a 55% consent rate, this translates to 2700 patients per year.  Assuming no limit on 
the ability to schedule inductions at 39 weeks, the study would easily be completed within 30 months.  
Training/Certification 
Recruitment 
Follow-up 
Data processing 
24 

October 31, 2013 
Allowing an additional six months (i.e., 3 years in total), with only 30 of the 36 sites participating, 
translates to 67 patients per year per hospital (1.3 women per hospital per week) which should be feasible. 
Thus the overall recruitment goal is 167 women per month.     
8.3 Final Analysis 
After a two-month period for completion of data entry for the trial and close-out of the delivery and 
primary outcome, the data set will be locked and available for the primary and other main analyses.  
25 

October 31, 2013 
Appendix A 
Design Summary 
Induction in Nulliparous Women at 39 Weeks to Prevent Adverse Outcomes:  A Randomized Controlled Trial 
OBJECTIVE:  To determine whether elective induction of labor in nulliparous women at 39 weeks improves adverse perinatal/neonatal outcome compared with expectant 
management . 
ORGANIZATION 
SCHEDULED EVALUATIONS / DATA COLLECTION 
Clinical Centers: 
Subcommittee: 
UAB, Ohio State, UTSW, Utah, Brown, Columbia, Case Western, 
UT-Houston, UNC, Northwestern, UTMB-Galveston, Colorado, 
Duke, Stanford 
William Grobman, MD (Chair) 
Randomization: 

Gestational age estimation

Digital cervical exam; Bishop score

Pregnancy, exposure and medical history
Post-randomization: 
Delivery: 
Postpartum: 

Weekly visit with provider (expectant
management group) 

Patient-centered outcomes questionnaire

Delivery and neonatal data

Central chart review for primary outcome

Patient-centered outcomes questionnaire
DESIGN 
Major Eligibility Criteria: 

Singleton gestation

Gestational age  380 to 386  wks

Nulliparous
MANAGEMENT PROTOCOL 
Groups: 

Induction of labor at 39 weeks

Expectant management with induction by 42 weeks, if
undelivered 
Induction Group 

Induction via oxytocin at 390-394 wks.

If unfavorable cervix (modified Bishop score <
5) start with cervical ripening
Random Allocation: 
Standard urn design; 1:1 allocation 
Expectant Mgmt Group 

Continue pregnancy until at least 405 wks
(unless indication for delivery) 

Start antepartum fetal testing no later than 416

All patients induced by 422 wks
Level of Masking: 
Unmasked 
Stratification: 

Clinical site
Sample Size: 

6000
OUTCOME MEASURES 
Assumptions: 

Outcome event=perinatal death /neonatal adverse outcome

Expectant management  event rate = 3.5%

Induction of labor group event rate = 2.28% (38% reduction)

Type 1 error = 5% two sided

Power =85%
Primary: 
Major Secondary: 

Neonatal adverse outcome/fetal death

Cesarean delivery

Maternal adverse outcomes

Gestational age at delivery

Patient centered outcomes

Utilization of medical resources 
Interim Analysis: 

Lan-DeMets group sequential method
TIMETABLE 
Enrollment 
Data Collection 
Closeout 

Oct 2013 to Sep 2016

Oct 2013 to Nov 2016

Dec 2016 to Mar 2017
26 

October 31, 2013 
Appendix B 
Sample Informed Consent Form 
Research Study Title:  A Randomized Trial of Induction Versus Expectant Management (ARRIVE) 
Sponsor:  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 
of the National Institutes of Health (NIH) 
Principal Investigator:  ___________________________Phone  (____)  ___ - ____ 
Introduction 
You are invited to take part in a research study.  This consent form provides the information about the 
risks and benefits of the study.  A member of the research team is available to answer your questions and 
to provide further explanations.  You are free to choose whether or not you will take part in the study.  If 
you agree to take part in the research, you will be asked to sign this consent form.  This process is known 
as informed consent.   
Research Purpose 
You are being invited to participate because you are pregnant, having your first baby, and are planning to 
labor.  The goal of the study is to determine whether coming to the hospital and having your labor started 
with medicine (i.e., labor induction) at 39 weeks of pregnancy can improve the baby’s health at birth 
when compared with waiting for labor to start on its own. 
Many doctors wait until 41 weeks for labor to start on its own.  However, some studies, but not all, have 
shown that being induced at 39 weeks of pregnancy may improve the baby’s outcome.  Some older 
studies have suggested a higher risk of cesarean, but other recent studies have not shown this increased 
risk.  No studies like this one have been done before in the United States.  This study is planning to enroll 
6,000 women across the country.  Half of the women will be induced at about 39 weeks of gestation and 
half will have the existing prenatal care (that is, waiting for start of labor). 
Procedures 
If you consent to the study, when you are within one to two weeks of your due date, you will be 
randomized (like flipping a coin) to one of two groups.  In one group (the “induction of labor” group), 
you will have your labor started through the use of medicine within a few days of reaching 39 weeks of 
pregnancy.  Depending upon how open your cervix is (the cervix is the opening to your uterus or birth 
canal), your doctor will decide the best way to start your labor. In the other group (the “expectant 
management group”) you will continue with your pregnancy until either you begin labor or your care 
provider determines that you need to be delivered or you reach 41-42 weeks of gestation (1-2 weeks after 
your due date).   
Regardless of which group you are in, your care provider will check your cervix (the opening of your 
uterus or birth canal) during a pelvic examination.  This may have already been done as a part of regular 
care within three days of your being randomized in which case it would not have to be repeated.  If you 
receive medication to help open your cervix or start your labor, your baby’s heart rate will be monitored 
all the time you are receiving the medication and when you are in labor.  Once you receive medication to 
help open your cervix or start your labor you should expect to stay in the hospital until delivery.  All other 
care during your pregnancy and during labor will be at the discretion of your care provider.  
After delivery, research staff will review your medical chart for clinical and outcome information such as 
any treatments or medicines given during labor and whether you had a vaginal delivery or cesarean 
section.  They will also review the medical chart of your newborn.  The research team will collect 
information regarding your hospital course and that of your newborn until hospital discharge.  
27 

October 31, 2013 
You will be asked two questions about the pain you experienced during childbirth and asked to fill out 
one questionnaire soon after your baby is born.  The questionnaire will be about how you felt about the 
process of labor and giving birth.  Six weeks after your baby is born, research staff will contact you to 
find out about any unplanned hospital or clinic visits for you or your baby and you will be asked to fill out 
the same questionnaire about the process of labor again.  
Possible Risks 
During labor induction, the same types of complications that can occur during any labor can occur.  At 
present, it is not known whether labor induction at 39 weeks is associated with a greater chance of 
cesarean delivery.  Some older studies have suggested a higher risk of cesarean, but other recent studies 
have not shown this increased risk. 
Benefits 
If you decide to take part in this research study, you and your baby may not directly benefit.  Your 
participation may help doctors determine the best time to plan for delivery in the future. 
Alternative Procedures 
The alternative to this study is not to participate.  Women who do not take part in this study will continue 
with their pregnancies until either they begin labor or their care provider determines there is a reason that 
they need to be delivered before labor begins (i.e., the standard care during pregnancy). 
Costs 
There will be no cost to you to take part in the research study.  The costs of your labor, delivery and care 
after delivery will be billed to you or your insurance company in the usual manner. 
Compensation 
(THIS SECTION WILL BE CENTER SPECIFIC.) You will be paid $XX to compensate you for the time 
and travel associated with the research study. 
Payment for Injury or Harm 
(THIS SECTION WILL BE CENTER SPECIFIC.) This hospital is not able to offer financial 
compensation or absorb the costs of medical treatment in the event of injury resulting from the research.  
In the event of such injury, treatment will be provided but it is not provided free of charge.  Since this is a 
research study, payment for any injury resulting from your participation in this research study may not be 
covered by some health insurance plans. 
Right to Withdraw From the Research Study 
This study is voluntary and it is up to you to decide whether or not you want to participate.  You are free 
to withdraw your consent and stop taking part in this research study at any time without giving a reason.  
Refusal to take part or the decision to withdraw from the study will involve no penalty or loss of benefits 
to which you are otherwise entitled.  Your refusal will not affect your legal rights or quality of health care 
that you will receive at this hospital.  Any significant new information which becomes available during 
your participation in this research, and which may affect your health, safety, or willingness to continue in 
this research study, will be given to you. 
Right of the Investigator to Withdraw 
The researchers of this institution or the National Institutes of Health can withdraw you from this study 
without your approval.  A possible reason for withdrawal could be the early termination of the study by 
the National Institutes of Health. 
Confidentiality 
28 

October 31, 2013 
You have the right to privacy.  All information obtained from this research that can be identified with you 
will remain confidential within the limits of the law.   
The medical information collected on you for this research study will come from your medical record and 
from information you give the nurse, such as your previous pregnancies, height, weight, and whether you 
drink or smoke.  Other information collected about you includes whether you are married, whether you 
have a job, and type of medical insurance.  If we lose track of you, study staff may collect information 
from the internet including social network sites in order to find your contact information. 
The information collected for this research study will be held at the data coordinating center (George 
Washington University Biostatistics Center in Rockville, Maryland) in a database consisting of 
information from all of the participants in this study.  Your information in the database will only be used 
for statistical analysis and may appear in scientific publications but will not identify you.  The 
information at the data coordinating center does not include your name, address, social security number, 
hospital number, date of birth or any other personal identifiers.  Instead the data center will use a unique 
code for each person consisting of a number and the first letter of your first name.  The key to the code 
linking the data to you will be kept here in a locked file.  Only the research study staff employed for this 
study at this hospital will have access to the key to the code.  
The following individuals and/or agencies will be able to look at and copy your research records: 
•
The investigator, study staff and other medical professionals who may be evaluating the study.
•
Authorities from this institution, including the Institutional Review Board (IRB) which is a group
of people who are responsible for making sure the rights of participants in research are respected.
Members or staff of the IRB at this medical center may also contact you about your experience
with this research.  You do not have to answer any questions asked by the representative of the
board.
•
The Office for Human Research Protections (OHRP)
•
The Eunice Kennedy Shriver National Institute of Child Health and Human Development
(NICHD) which sponsors this study, including persons or organizations working with the
sponsors, such as the data coordinating center, the George Washington University Biostatistics
Center in Rockville, Maryland.
A copy of your or your baby’s medical chart may also be sent to research investigators at one of the other 
enrolling centers or the data coordinating center for review.  If your chart is sent, identifying information, 
such as name, address, social security number, or hospital number will be removed.   
The results of this research study will be provided to the sponsor, NICHD, (and/or its representatives).  In 
addition, data from this study will be put in a public data set that will be available to other research 
investigators.  This public data set will not contain any identifying patient data. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this Web site at any time. 
This permission does not end unless you cancel it, even if you leave the study.  You can cancel this 
permission any time except where a healthcare provider has already used or released your health 
information, or relied on your permission to do something.  Even if you cancel this authorization, the 
researchers may still use and disclose protected health information (PHI) they already have obtained 
about you as necessary to maintain the integrity or reliability of the research.  However, no new PHI will 
be collected from you after you revoke your authorization. 
To cancel your authorization, you will need to send a letter to Dr. ________ of the ________ stating that 
you are canceling your authorization.  This letter must be signed and dated and sent to this 
29 

October 31, 2013 
address:___________________.  If you are unable to write a letter ask one of the research staff to provide 
you with a letter that must be signed, dated, and sent to the above address.  A copy of this revocation will 
be provided to the Study Doctor and his or her research team.  Not signing this form or later canceling 
your permission will not affect your health care treatment outside the study, payment for health care from 
a health plan, or ability to get health plan benefits. 
Your protected health information will be treated confidentially to the extent permitted by applicable laws 
and regulations.  Federal law may allow someone who gets your health information from this study to use 
or release it in some way not discussed in this section and no longer be protected by the HIPAA Privacy 
Rule. 
By signing this form you authorize the Study Doctor and members of the research team to use and share 
with others (disclose) your PHI for the purpose of this study.  If you do not wish to authorize the use or 
disclosure of your PHI, you cannot participate in this study because your PHI is necessary to conduct this 
study. 
Questions  
The researchers are available to answer your questions about this research.  A representative of the 
Institutional Review Board is also available to answer questions about your rights as a participant in 
research or to answer your questions about an injury or other complication resulting from your 
participation in this research study.   
If you have questions or are hurt while taking part in this research study, you should contact 
________________ at (___) ___-____. 
If you have any questions about the informed consent process or any other rights as a research subject, 
please contact __________________, at (____) ___-____.  _______________ .   
Signatures 
By signing below, you indicate that you have read this consent form, the study has been explained to you, 
your questions have been answered, and you agree to take part in this study.  You do not give up any of 
your legal rights by signing this form.  A copy of this consent form will be given to you. 
The investigator or study team may wish to contact you in the future to request permission for additional 
research.  Please initial the appropriate statement to indicate whether or not you give permission for future 
contact. 
YES_____ I give permission to be contacted in the future for research purposes. 
NO_____ I do not give permission to be contacted in the future for research purposes. 
______________________              _______________________  
______________ 
Participant       
          Signature 
         Date 
(Print Name) 
_______________________              ________________________ 
_______________ 
Person Obtaining Consent  
           Signature 
         Date 
(Print Name) 
30 

October 31, 2013 
ASSENT FOR FEMALES UNDER 18 YEARS of AGE (if required by Center IRB): 
I agree __________ 
I do not agree__________ to participate in this study.  
This has been explained to me by ________________________. 
_____________________________    
   _____________________ 
Signature of Minor 
Date 
_____________________________    
_____________________ 
Print Name of Subject        
Age 
Please provide either one or both parental signatures as instructed by your IRB. 
_____________________________    
    _____________________ 
Signature of Mother/Guardian            
  Date 
_____________________________    
  _____________________ 
Signature of Father/Guardian            
Date 
A witness unrelated to the study is necessary if the participant can comprehend but cannot read (i.e., 
blind), or cannot sign (i.e., unable to use hands) the consent form. 
______________________
________________________ 
_______________ 
Witness’ Name              
          Signature 
        Date 
   (Print Name) 
31 

October 31, 2013 
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34 

Induction in Nulliparous Women at 39 Weeks to 
Prevent Adverse Outcomes:  A Randomized 
Controlled Trial  
Protocol 
A Randomized Trial of Induction Versus Expectant Management 
(ARRIVE) 
Eunice Kennedy Shriver  
National Institute of Child Health and Human Development (NICHD) 
Maternal-Fetal Medicine Units (MFMU) 
 Network  
Prepared by the 
Biostatistical Coordinating Center for the NICHD MFMU Network 
The Biostatistics Center 
George Washington University 
6110 Executive Boulevard, Suite 750 
Rockville, MD 20852 
(301) 881-9260 
July 20, 2017 

Table of Contents 
1 
Introduction ........................................................................................................................................ 1 
1.1 
Study Abstract ............................................................................................................................. 1 
1.2 
Primary Hypothesis ..................................................................................................................... 1 
1.3 
Purpose of the Study Protocol ..................................................................................................... 1 
2 
Background ......................................................................................................................................... 2 
2.1 
Introduction ................................................................................................................................. 2 
2.2 
Complications of Term Pregnancies beyond 39 Weeks of Gestation ......................................... 2 
2.3 
Results from MFMU Network Studies ........................................................................................ 4 
2.4 
Potential Risks and Benefits of Planned Elective Induction of Labor before 41 weeks .............. 5 
2.5 
Rationale for a Randomized Clinical Trial .................................................................................. 7 
3 
Study Design ....................................................................................................................................... 8 
3.1 
Primary Research Question ......................................................................................................... 8 
3.2 
Secondary Research Questions .................................................................................................... 8 
3.3 
Design Summary ......................................................................................................................... 8 
3.4 
Eligibility Criteria ........................................................................................................................ 8 
3.5 
Informed Consent Criteria ......................................................................................................... 10 
3.6 
Randomization Method ............................................................................................................. 10 
4 
Study Procedures.............................................................................................................................. 11 
4.1 
Screening for Eligibility and Consent ....................................................................................... 11 
4.2 
Randomization ........................................................................................................................... 11 
4.3 
Baseline Procedures ................................................................................................................... 12 
4.4 
Study Procedures ....................................................................................................................... 12 
4.5 
Patient Management and Follow-up .......................................................................................... 12 
4.6 
Adverse Event Reporting........................................................................................................... 13 
4.7 
Study Outcome Measures and Ascertainment ........................................................................... 13 
5 
Statistical Considerations ................................................................................................................ 16 
5.1 
Data Relevant to the Primary Outcome ..................................................................................... 16 
5.2 
Sample Size and Power ............................................................................................................. 16 
5.3 
Feasibility .................................................................................................................................. 18 
5.4 
Interim Analysis ........................................................................................................................ 18 
5.5 
Analysis Plan ............................................................................................................................. 18 
6 
Data Collection ................................................................................................................................. 20 
6.1 
Data Collection Forms ............................................................................................................... 20 
6.2 
Web Data Entry System ............................................................................................................ 20 
6.3 
Centralized Data Management System ...................................................................................... 20 
6.4 
Performance Monitoring ............................................................................................................ 21 
7 
Study Administration ....................................................................................................................... 22 
7.1 
Organization and Funding ......................................................................................................... 22 
7.2 
Committees ................................................................................................................................ 22 
8 
Study Timetable ............................................................................................................................... 24 
8.1 
Training and Certification ......................................................................................................... 24 
8.2 
Recruitment and Data Collection Period ................................................................................... 24 
8.3 
Final Analysis ............................................................................................................................ 25 
Appendix A 
Design Summary ........................................................................................................... 26 
Appendix B 
Sample Informed Consent Form ................................................................................. 27 
Table 1. Maternal Complications in Singleton Gestation by Gestational Week ........................................... 3 
Table 2. Association of Gestational Age with Severe Neonatal Complications ........................................... 4 

Table 3.  Randomized Controlled Trials of Elective Induction of Labor (EIOL) at 39-40 Weeks vs 
Expectant Management (EM) ....................................................................................................................... 6 
Table 4. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP ........................................... 9 
Table 5. Scoring System for the Modified Bishop Score ............................................................................ 11 
Table 6. Sample Sizes per Group for Different Primary Outcome Rates, Power and Effect Sizes ............ 17 
Figure 1. Timetable ..................................................................................................................................... 24 

July 20, 2017 
1 
1 Introduction 
1.1 Study Abstract 
Recently, several retrospective studies have shown that certain maternal and perinatal complications 
increase with gestational age after 37-38 completed weeks.  This has called into question whether it is 
appropriate to wait until 41 weeks for induction in uncomplicated pregnancies.  Although it has 
traditionally been held that the disadvantage of labor induction is that it increases the risk of cesarean 
delivery, this conclusion is based on studies with methodological flaws.  In these studies, women who 
were electively induced were compared by gestational week with those who labored spontaneously.  This 
is not the most appropriate comparison group because women who are induced at 39 weeks, for example, 
would not otherwise have immediate spontaneous labor.  Instead, the most fitting comparison group 
should be composed of women who are expectantly managed.  The studies that have used this comparison 
group have largely failed to demonstrate the association between induction and cesarean delivery, as have 
the small trials where women were randomized to labor induction or expectant management.  Thus, 
whether labor induction at 39 weeks of gestation modifies maternal and perinatal outcomes, compared 
with expectant management, remains unknown.  
This protocol describes a randomized trial of 6000 women to assess whether a policy of elective induction 
of labor at 39 weeks of gestation compared with expectant management will improve outcomes.  
1.2 Primary Hypothesis 
Among nulliparous women with singleton uncomplicated term pregnancies, elective induction of labor at 
39 weeks, compared with expectant management, reduces the risk of severe neonatal morbidity and 
perinatal mortality. 
1.3 Purpose of the Study Protocol 
This protocol describes the background, design and organization of the randomized clinical trial and may 
be viewed as a written agreement among the study investigators.  The Data and Safety Monitoring 
Committee (DSMC) and the Network Advisory Board review the protocol.  Before recruitment begins, 
the protocol is approved by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network Steering Committee, and the 
Institutional Review Board (IRB) of each clinical center.  Any changes to the protocol during the study 
period require the approval of the Steering Committee and the IRBs; major changes also require the 
approval of the DSMC. 
A manual of operations supplements the protocol with detailed specifications of the study procedures. 
  

July 20, 2017 
2 
2 Background 
2.1 Introduction 
Post dates pregnancy, defined as a gestation that persists beyond 294 days or 42 weeks’ gestation, is 
associated with an increased risk of perinatal morbidity and mortality.1  Several studies have shown that 
as pregnancy extends beyond 42 weeks the risk of oligohydramnios, macrosomia, fetal birth injury, 
meconium aspiration syndrome, and stillbirth increase significantly.1  To avoid these risks, common 
practice has been to induce labor once 42 weeks has been reached.  Indeed, because these risks begin to 
increase even before 42 weeks, many investigators have suggested that a policy of induction of labor at 41 
weeks can improve pregnancy outcomes.  In 2006 a Cochrane review was conducted of all trials in which 
women were randomized to induction of labor at 41-42 weeks or expectant management with fetal 
surveillance (including the MFMU Network’s trial).  The investigators found that a policy of induction of 
labor at or beyond 41 completed weeks was associated with fewer (all-cause) perinatal deaths (RR 0.3 
95% CI 0.09, 0.99), with no evidence of a statistically significant difference in the cesarean section rate 
for women in the induction group (RR 0.92 95% CI 0.76, 1.12).2 
The American Congress of Obstetricians and Gynecologists states that both expectant management and 
labor induction at 41 weeks are associated with low complication rates and good perinatal outcomes in 
low-risk post term women but that there appears to be a small advantage to labor induction, regardless of 
parity or method of induction.1  Recently, data have been published showing increased rates of 
complications beyond 39 weeks, suggesting that it may be advantageous to induce uncomplicated 
pregnancies at an earlier gestation than 41 weeks.3-15  
2.2 Complications of Term Pregnancies beyond 39 Weeks of Gestation 
2.2.1 Maternal Complications 
Several studies have demonstrated that certain maternal complications increase in a continuous fashion 
after 37-38 completed weeks.3-8  Investigators have reported that pregnancies that continue beyond 39 
weeks are associated with increased risks of cesarean section, operative vaginal delivery, 3rd and 4th 
degree lacerations, and chorioamnionitis.3-7,9  
Table 1 summarizes the maternal data from the largest and most recent cohort studies that have examined 
adverse outcomes in term pregnancies.  Most of these studies examined maternal complications in 
multivariable models and found that gestational age beyond 39 weeks was predictive of increased risk 
even when controlling for known confounders such as maternal age, ethnicity, education, parity, length of 
labor, induction, and birth weight.   
 
 

July 20, 2017 
3 
Table 1. Maternal Complications in Singleton Gestation by Gestational Week 
 
Population and Reference 
39 weeks 
40 weeks 
41 weeks 
Adjusted OR (95% CI) 
41 wks vs 39 wks in a 
Multivariable Model 
Primary cesarean delivery (multiparas and nulliparas) 
 
N=45,673; 1992-20024 
14.0% 
15.9%** 
21.2%** 
1.32 (1.17,1.53) 
N=32,828; low risk; 1976-20013 
9.2% 
10.4%** 
14.1%** 
1.44 (1.28, 1.62) 
N=119,254; low risk; 1995-995 
8.8% 
9.0% 
14.0%** 
1.28 (1.20, 1.36) 
N=2,928,722; low risk; from US 
natality data 20037 
12.8% 
14.1%** 
19.8%** 
1.46 (1.44, 1.48) 
 
 
Primary cesarean delivery rates by weeks’ gestation in nulliparas only 
N=32,828; low risk; 1976-20013 
11.4% 
14.2%* 
18.9%** 
Not available 
N=119,254; low risk; 1995-995 
14.4% 
14.9% 
21.9%** 
Not available 
N=2,928,722; low risk; from US 
natality data 20037 
21.5% 
23.3%** 
30.1%** 
Not available 
 
 
Operative vaginal delivery 
 
N=45,673; 1992-20024 
15.5% 
17.9%** 
18.5% 
1.14 (1.05, 1.23) 
N=32,828; low risk; 1976-20013 
14.8% 
16.4%** 
17.4%** 
1.22 (1.10, 1.44) 
N=119,254; low risk; 1995-995 
9.4% 
10.9%** 
13.3%** 
1.29 (1.20, 1.36) 
N=2,928,722; low risk; from US 
natality data 20037 
7.6% 
8.1%** 
9.6%** 
1.14 (1.11, 1.16) 
 
 
3rd and 4th degree lacerations 
 
N=32,828; low risk; 1976-20013 
9.4% 
10.8%** 
12.0%** 
1.26 (1.10, 1.44) 
N=119,254; low risk; 1995-995 
4.0% 
4.6%* 
6.7%** 
1.58 (1.44, 1.73) 
 
 
Postpartum hemorrhage 
 
N=32,828; low risk; 1976-20013 
13.4% 
12.8% 
16.0%** 
1.18 (1.06, 2.31) 
N=119,254; low risk; 1995-995 
2.5% 
3.1%** 
4.1%** 
1.21 (1.10, 1.32) 
 
 
Febrile morbidity 
 
N=45,673; 1992-20024 
1.7% 
2.3% 
2.7%** 
1.46 (1.14, 1.87) 
N=32,828; low risk; 1976-20013 
5.2% 
6.0%** 
7.7%** 
1.28 (1.11, 1.49) 
N=119,254; low risk; 1995-995 
2.7% 
3.7%** 
5.1%** 
1.46 (1.14, 1.87) 
N=2,928,722; low risk; from US 
natality data 20037 
1.6% 
2.0%** 
2.7%** 
1.49 (1.45, 1.54) 
Statistical significance compared with rate of outcome in the previous week gestation: * p<.01, ** p<.001 
 

July 20, 2017 
4 
2.2.2 Infant Outcomes 
Studies have also demonstrated that the rates of adverse neonatal outcomes are increased in pregnancies 
that extend beyond 39 weeks.4,6  In a study of singleton deliveries in Scotland between 1985 and 1996, 
Smith showed that the risk of perinatal death (stillbirth or neonatal death) nadirs at 39 weeks.8  In a study 
of deliveries registered in an area of London, the rate of stillbirth increased progressively with advancing 
gestation from 37 to 43 weeks.10  Abnormal neonatal acid-base status has been shown to increase in 
pregnancies delivered beyond 39 weeks.6,11   
In a retrospective cohort study of singleton, cephalic, low-risk neonates delivered at term, Caughey et al. 
concluded that neonatal complications of term pregnancy increase in a continuous, rather than in a 
threshold fashion.  In this cohort the incidence of severe neonatal complications was increased 1.5-2 fold 
in pregnancies delivered at 40-41 weeks compared with those delivered at 39 weeks (Table 2).6  Other 
investigators reported similar trends in neonatal morbidity for pregnancies advancing beyond 39 
weeks.7,11,12  
Table 2. Association of Gestational Age with Severe Neonatal Complications 
 
Gestational week 
Percent with 
complications 
Odds ratio (95% CI) 
39 weeks 
1.84% 
referent 
40 weeks 
2.31% 
1.47 (1.09, 1.98) 
41 weeks 
3.14% 
2.04 (1.50, 2.78) 
42 weeks 
3.82% 
2.37 (1.63, 3.49) 
 
In contrast with maternal outcomes, there is clear evidence that adverse neonatal outcomes are more 
common when elective delivery is undertaken at term but prior to 39 weeks.  Several investigations 
demonstrated an increase in neonatal morbidity for infants delivered at 37-38 weeks, compared with those 
delivered at 39 weeks or beyond.  Specifically, at ages before 39 weeks, the risk of NICU admission, 
RDS, mechanical ventilation, and hypoglycemia are increased, particularly for infants delivered by 
cesarean section.13-15  While the risk of both stillbirth and infant death per 1000 ongoing pregnancies 
increases a modest amount between 37-39 weeks (0.7/1000 to 1.4/1000 respectively), the risk of more 
common adverse events (e.g., RDS, mechanical ventilation) is increased by a factor of 2 to 12.14,15  
Overall, elective delivery prior to 39 weeks is associated with an increase in respiratory and other adverse 
neonatal outcomes.  
2.3 Results from MFMU Network Studies 
Secondary analyses of NICHD MFMU Network data are consistent with the findings above for both 
maternal and neonatal outcomes.  In the MFMU Network trial of fetal pulse oximetry (FOX), a secondary 
analysis of 4086 women found that the risks of a composite maternal outcome (treated uterine atony, 
blood transfusion, or peripartum infection) and cesarean delivery increased with increasing gestational 
age from 39 to 41 or more completed weeks (p value for trend < 0.001).16 
In the Cesarean Registry, a composite outcome of death or adverse neonatal outcome increased from 8% 
to 11.3% as gestational age increased from 39 to 41 weeks in women undergoing elective repeat cesarean 
delivery.14  Also, in the cohort of women in the FOX trial referenced above, risks of a similar composite 
adverse neonatal outcome increased with increasing gestational age after 39 weeks.16 
Based on Caughey et al 2005; severe neonatal complications defined as birth trauma, seizures, intracranial hemorrhage, 
sepsis, meconium aspiration syndrome, respiratory distress syndrome 

July 20, 2017 
5 
In summary, available data lead to the hypothesis that planned delivery at 39 weeks will result in the 
fewest adverse maternal and perinatal outcomes. 
2.4 Potential Risks and Benefits of Planned Elective Induction of Labor before 
41 weeks 
If neonatal risks nadir at approximately 39 weeks, and if the risks of maternal and neonatal complications 
increase monotonically after 39 weeks, the question arises - do the risks of pregnancy prolongation 
beyond 39 weeks outweigh the risks of labor induction?  Whereas planned cesarean delivery in the 
absence of medical or obstetric complications is performed at 39 completed weeks, planned induction of 
labor at 39 weeks has been discouraged due to a potential increase in risk of cesarean delivery.  Indeed, 
several retrospective cohort studies indicate that induction of labor prior to 41 weeks is associated with an 
approximately 2-fold higher risk of cesarean in nulliparous women.17-22  However, these studies have 
several important limitations.  
First, a number of studies compared outcomes in women undergoing both indicated and elective 
inductions with those of spontaneously laboring women.20,23-26  By including women with medical 
indications for induction (e.g., preeclampsia), it is possible that the higher rates of cesarean delivery 
observed in the induction group were due to the pregnancy complications and not the induction per se.  
Other studies have evaluated elective induction of labor separately.17,18,21,22,24,27,28  They consistently 
showed that cesarean delivery is more common in those electively induced.  However, in these studies, 
women who were electively induced were compared with those who were spontaneously laboring.  While 
this is a convenient comparison group it is not the most appropriate one, because women who are induced 
at 39 weeks are not guaranteed the alternative of an immediate spontaneous labor.  In other words, 
women and their providers cannot choose between elective induction and spontaneous labor, but between 
elective induction and expectant management.  Expectant management at 39 weeks may result in a 
proximate spontaneous labor but also may result in circumstances (e.g., preeclampsia, need for labor 
induction at 42 weeks) that increase the risk of cesarean.29  Therefore, the most fitting comparison group 
in an observational study of elective induction would be all women at 39 weeks with ongoing 
pregnancies.   
One group of investigators performed an observational study with just such a nulliparous study 
population.  Osmundson and colleagues compared outcomes of labor between nulliparous women who 
either underwent elective induction or expectant management at or beyond 39 weeks at a single 
center.30,31  Moreover, these investigators ascertained cervical status of all women at 38-39 weeks, in 
order to remove the possibility of selection bias related to this factor.  The findings of this study, in 
contrast with the prior studies that used spontaneously laboring comparison groups, revealed that elective 
induction at 39 weeks or greater, for either women with a favorable or unfavorable cervix, did not 
increase the cesarean delivery rate.  Specifically, for nulliparas with a favorable cervix (modified Bishop 
score ≥5) the cesarean delivery rate was 21% in the electively induced group vs. 20% in the expectantly 
managed group (p = 0.84).  Similarly there was no significant difference in the cesarean rate for women 
with an unfavorable cervix (43% vs. 34%, p =.16).  This study calls into question the long-standing 
dogma that elective induction of labor prior to 41 weeks increases the frequency of cesarean delivery.  
With regard to long-term outcomes of the offspring, there has not been consistent evidence that oxytocin 
use results in neurodevelopmental disorders.32-35  Moreover, as with many studies about labor induction, 
the studies that have assessed associations between intrapartum oxytocin use and neurodevelopmental 
outcomes have had several fundamental methodological flaws.  For example, women are often induced 
for indications which themselves may be associated with adverse neurodevelopmental outcomes; in such 
a case of “confounding by indication”, adequate adjustment for the confounding factors may be difficult if 
not impossible.  There is not evidence that elective induction (i.e., an induction without an underlying 
medical or obstetric induction) specifically is associated with adverse long-term neurodevelopmental 

July 20, 2017 
6 
outcomes.  Moreover, these studies have typically evaluated women undergoing induction versus those 
undergoing spontaneous labor; this comparison is inappropriate and not clinically relevant,36 as 
spontaneous labor is not a choice but an event.  Indeed, many women who are not “induced” at a given 
gestational age will ultimately require induction or oxytocin augmentation at a later gestational age, or 
experience an obstetric complication which itself may be associated with a risk of adverse 
neurodevelopmental outcome, a risk that may have been prevented had the women been induced earlier.  
Thus, the clinically meaningful comparison is labor induction versus expectant management.  Yet, there 
are no data that suggest that elective induction compared with expectant management increases the risk of 
neurodevelopmental disorders or other adverse long-term outcomes. 
Table 3.  Randomized Controlled Trials of Elective Induction of Labor (EIOL) at 39-40 Weeks vs Expectant 
Management (EM) 
Year and 
Reference 
N 
Patient Population 
(% nullips) 
Gestational  
Age at EIOL 
Gestational 
Age for EM  
Outcome: EIOL vs. EM 
(p>0.05 unless noted) 
197537 
228 •
Multiparous or
nulliparous (46%)
39-40 weeks 41 weeks 
Cesarean: 4.5% vs 7.7% 
197838 
230 •
Multiparous or
nulliparous*
39 weeks 
42 weeks 
Cesarean: 4.3% vs 1%  
Operative vaginal delivery: 
 18.5% vs 20.7% 
197939 
112 
•
Multiparous or
nulliparous (45%)** 
•
Favorable cervix
40 weeks 
42 weeks 
Operative vaginal delivery: 
        2.3% vs 4.8% 
198940 
345 
•
Multiparous or
nulliparous (54%)
•
Favorable cervix
40 weeks 
42 weeks 
Nulliparas: 
Cesarean: 1.0% vs 3.4% 
Operative vaginal delivery: 
 3.0% vs 3.4% 
Multiparas: 
Cesarean: 1.2% vs 0%  
Operative vaginal delivery: 
 1.2% vs 0% 
199940 
194 •
Nulliparous†
39 weeks 
42 weeks 
Cesarean: 6.4% vs 5.6%  
Operative vaginal delivery: 
 53.4% vs 33.3% 
(p=.03) 
200541 
226 
•
Multiparous or
nulliparous (45%)
•
Favorable cervix
39-40 
weeks 
42 weeks 
Nulliparas:  
Cesarean: 13.3% vs 10.3% 
Multiparas: 
Cesarean:   2.8% vs 3.8% 
2.4.1 Randomized Trials of Elective Induction at Term versus Expectant Management 
There have been several small randomized clinical trials comparing elective induction of labor at 37-40 
weeks’ gestation with expectant management until 41-42 weeks (Table 3).37-42  None of these studies 
found an increased frequency of cesarean section among induced participants.  However, these trials have 
significant limitations.  First, all were underpowered to detect the magnitude of increase in cesarean rate 
that would be considered clinically relevant. In addition, because two trials only included women with a 
favorable Bishop score, the generalizability of the data to women with an unfavorable score is limited.  
* Excluded women in EIOL group who had spontaneous labor before 39 weeks and women in EM group  if failed to go into
spontaneous labor by 42 weeks 
** Excluded women in either group with spontaneous labor before 40 weeks or who required a cesarean 
†    Excluded women in EIOL group who had spontaneous labor before 39 weeks and women in EM group if induced before 42 
weeks or failed to go into spontaneous labor by 42 weeks 

July 20, 2017 
7 
Nevertheless, meta-analysis of these data generated by randomized trials reveals a reduction in the 
frequency of cesarean section with induction (RR 0.89; 95% CI 0.81 to 0.97).2  Although it did not 
address elective induction, the Hypertension and Pre-eclampsia Intervention Trial At Term (HYPITAT), a 
randomized trial comparing induction to expectant management for women with hypertensive disease of 
pregnancy, also demonstrates that labor induction may not increase the risk of cesarean (14% in the 
induction of labor group versus 19% in the expectant management group (RR 0.75; 95% CI 0.55-1.04).43  
2.5 Rationale for a Randomized Clinical Trial 
Given the reported increased risks of adverse events in pregnancies extending beyond 39 weeks it has 
been hypothesized that a policy of planned elective induction at 39 weeks could improve outcomes for the 
infant and the mother.  For multiparous patients, especially those with a favorable cervix, it is perhaps 
easy to justify an elective induction at 39 weeks given the low risk of cesarean section.  However, for 
nulliparous patients the current evidence, derived mainly from retrospective observational studies, does 
not allow a clear recommendation.  Nevertheless, a trend towards an increased rate of elective labor 
induction in pregnancies at 39 weeks has been reported, indicating that practitioners are more commonly 
using elective induction at this gestational age,43 even as others caution against routine elective induction 
prior to 41 weeks given the reported increased risk of cesarean delivery.19,44,45,46  Ultimately, a randomized 
controlled trial is necessary to satisfactorily understand whether elective induction of labor of nulliparas at 
39 weeks improves neonatal and maternal outcomes. 

July 20, 2017 
8 
3 Study Design 
3.1 Primary Research Question 
This randomized trial will address the primary research question: does elective induction of labor in 
nulliparous women at 39 weeks improve perinatal outcome compared with expectant management? 
3.2 Secondary Research Questions 
Secondary research questions this study will address are:  
• 
Does elective induction of labor in nulliparous women at 39 weeks reduce the risk of any of the 
maternal outcomes listed in Section 4.7.2? 
• 
Does elective induction of labor in nulliparous women at 39 weeks reduce the risk of any of the 
fetal and neonatal outcomes listed in section 4.7.3? 
• 
Does elective induction of labor in nulliparous women at 39 weeks modify the utilization of the 
medical resources listed in section 4.7.4? 
• 
If the two groups show a difference in the incidence of the primary outcome or cesarean, does the 
proposed effect of elective induction of labor in nulliparous women at 39 weeks vary according to 
any of the subgroups listed in section 5.5? 
3.3 Design Summary 
The study is a randomized controlled multi-center clinical trial of 6000 women at 38 weeks 0 days to 38 
weeks 6 days randomized to one of two arms at participating MFMU Network clinical centers. 
• 
Elective induction of labor between 39 weeks 0 days and 39 weeks 4 days  
• 
Expectant management (unless a medical indication arises) until at least 40 weeks 5 days. 
3.4 Eligibility Criteria 
3.4.1 Inclusion Criteria 
1. Nulliparous - no previous pregnancy beyond 20 weeks  
2. Singleton gestation.  Twin gestation reduced to singleton, either spontaneously or therapeutically, 
is not eligible unless the reduction occurred before 14 weeks project gestational age (see below). 
3. Gestational age at randomization between 38 weeks 0 days and 38 weeks 6 days inclusive based 
on clinical information and evaluation of the earliest ultrasound as described in Gestational Age 
Determination in Section 3.4.2 below.   
3.4.2 Gestational Age Determination 
Gestational age is determined using criteria proposed by the American Congress of Obstetricians and 
Gynecologists, the American Institute of Ultrasound in Medicine and the Society for Maternal-Fetal 
Medicine47 and is denoted “project gestational age”.  The “project EDC”, which is based on the project 
gestational age, cannot be revised once a determination has been made.  If the pregnancy is conceived by 
in-vitro fertilization, project gestational age is calculated from the date of embryo transfer and the embryo 
age at transfer.  If the pregnancy is conceived spontaneously (including ovulation induction and artificial 

July 20, 2017 
9 
insemination) information from the earliest dating ultrasound and the last menstrual period are used to 
determine project gestational age.  The following algorithm is used:   
• 
The first day of the last menstrual period (LMP) is determined, and a judgment made as to 
whether or not the patient has a “sure” LMP date. 
• 
If the LMP date is unsure, measurement(s) obtained at the patient’s first dating ultrasound 
examination is used to determine the project gestational age. The first dating ultrasound must 
have been conducted before 14 weeks 0 days by crown rump length (CRL).  
• 
If the LMP date is sure, project gestational age is determined by a comparison between the 
gestational age by LMP and by the earliest dating ultrasound.  The first dating ultrasound must 
have been conducted before 21 weeks 0 days by LMP.  If the ultrasound confirms the gestational 
age by LMP as in the table below, the LMP-derived gestational age is used to determine the 
project gestational age.  Otherwise, project gestational age will be determined based upon the 
ultrasound measurement. 
Table 4. Cutoffs for Using LMP to Determine Gestational Age for Sure LMP 
Gestational age at first ultrasound by LMP 
Ultrasound method of 
measurement 
Ultrasound agreement with LMP 
Up to 8 weeks 6 days 
CRL 
± 5 days 
9 weeks 0 days to 13 weeks 6 days 
CRL 
± 7 days 
14 weeks 0 days to 15 weeks 6 days 
Per institution 
± 7 days 
16 weeks 0 days to 20 weeks 6 days 
Per institution 
±  10 days 
3.4.3 Exclusion Criteria 
1. Project gestational age at date of first ultrasound is > 20 weeks 6 days  
2. Plan for induction of labor prior to 40 weeks 5 days 
3. Plan for cesarean delivery or contraindication to labor 
4. Breech presentation 
5. Signs of labor (regular painful contractions with cervical change) 
6. Fetal demise or known major fetal anomaly 
7. Heparin or low-molecular weight heparin during the current pregnancy 
8. Placenta previa, accreta, vasa previa 
9. Active vaginal bleeding greater than bloody show  
10. Ruptured membranes  
11. Cerclage in current pregnancy 
12. Known oligohydramnios, defined as AFI < 5 or MVP < 2 
13. Fetal growth restriction, defined as EFW < 10th percentile 
14. Known HIV positivity because of modified delivery plan  

July 20, 2017 
10 
15. Major maternal medical illness associated with increased risk for adverse pregnancy outcome  
(for example, any diabetes mellitus, lupus, any hypertensive disorder, cardiac disease, renal 
insufficiency) 
16. Refusal of blood products 
17. Participation in another interventional study that influences management of labor at delivery or 
perinatal morbidity or mortality 
18. Delivery planned elsewhere at a non-Network site 
3.5 Informed Consent Criteria 
Each center will develop its own consent forms according to the requirements of its own institutional 
review board using the model consent form in Appendix B.  Each center will also develop its own patient 
research authorization documents, as required by the HIPAA Privacy Rule, following the guidelines of its 
own institution.  A copy of the signed consent form will be provided to the patient.   
Women who are not fluent in English will be enrolled by a person fluent in their language.  Both verbal 
and written informed consent and authorization will be obtained in that language; if this is not possible 
the patient will be excluded. 
3.6 Randomization Method 
Randomization for consenting women will occur at 38 weeks 0 days to 38 weeks 6 days of gestation.  
Consenting women will be assigned to induction of labor at 39 weeks 0 days to 39 weeks 4 days or 
expectant management in a 1:1 ratio according to a randomization sequence prepared and maintained 
centrally by the Biostatistical Coordinating Center (BCC).   
The simple urn method will be used to generate the randomization sequences because it provides a high 
probability of balance in treatment assignments, it is unpredictable, and it allows an explicit 
randomization analysis to be conducted with relative ease.48  Randomization will be stratified by clinical 
site to assure balance between the two treatment groups with respect to anticipated differences in the 
clinic populations and possible differences in patient management.

July 20, 2017 
11 
4 Study Procedures 
4.1 Screening for Eligibility and Consent 
All nulliparous women with a singleton gestation between 34 and 38 weeks are potentially eligible for 
screening.  Inclusion/exclusion criteria will be reviewed with the patient’s chart.   
If a patient appears to meet the criteria for the trial, she will be told about the study and asked for written 
informed consent to participate in the trial.  Consent may be obtained anytime from 34 weeks 0 days to 38 
weeks 6 days of gestation. 
Each patient must undergo a digital cervical exam between 72 hours prior to randomization and 24 hours 
after randomization.  The three components of the modified Bishop score must be obtained during this 
exam.  Table 5 provides the scoring system that uses the following three components to derive the 
modified Bishop score: 
• 
Cervical dilation 
• 
Cervical length or effacement 
• 
Fetal station 
 
Table 5. Scoring System for the Modified Bishop Score 
4.2 Randomization   
Eligibility should be verified again before randomization.  Eligible and consenting patients will be 
randomized by certified research staff using an internet based randomization system maintained by the 
BCC.  Randomization will occur when the patient is from 38 weeks 0 days to 38 weeks 6 days of 
gestation.  The patient will be assigned either to the induction of labor group or the expectant 
management group.  
If the patient has had a digital cervical exam within the past 72 hours, and all components of the modified 
Bishop score are documented (cervical dilation, cervical effacement or cervical length, and fetal station), 
randomization may be done in person or over the telephone.  If the patient has not had a digital cervical 
exam within the past 72 hours, or if components of the modified Bishop score are not documented, she 
must be randomized in person and have a digital cervical exam within that same day. 
Station 
(in relation to the spines) 
-3 cm 
-2 cm 
-1 - 0 cm 
1 - 2 cm 
0 
1 
2 
3 
Dilation 
(of the cervix) 
0 cm 
1-2 cm 
3-4 cm 
>4 cm 
0 
2 
4 
6 
Length 
(of the cervix) 
3 cm 
2 cm 
1 cm 
0 cm 
0 
1 
2 
3 

July 20, 2017 
12 
4.3 Baseline Procedures 
In addition to information collected for eligibility, project gestational age, and project EDC determination, 
the following information will be obtained at randomization from a patient interview followed by a 
review of her chart: 
•
Components of the modified Bishop score: cervical dilation, cervical length or effacement, and
fetal station from digital cervical exam
•
Demographic information: age, race, ethnicity, insurance status
•
Medical history: first clinic weight, current weight, height, chronic disease history
•
Obstetrical history including outcome(s) of any prior pregnancies
•
Social history: marital status, alcohol use, and tobacco use
•
Current pregnancy complications
4.4 Study Procedures 
Women randomized to induction of labor will undergo induction via oxytocin at 39 weeks 0 days to 39 
weeks 4 days.  Those with an unfavorable cervix (modified Bishop score < 5) will first undergo cervical 
ripening (method left to the discretion of the patient’s physician) in conjunction with or followed by 
oxytocin stimulation unless a contraindication arises. 
Women randomized to expectant management will have at least weekly follow-up visits with their 
providers and, unless a medical indication is present, will continue pregnancy until at least 40 weeks 5 
days of gestation.  Antepartum fetal testing will be initiated no later than 41 weeks 6 days according to 
policies at each center. All patients will undergo induction via oxytocin by 42 weeks 2 days.  
4.5 Patient Management and Follow-up 
Patients in the induction of labor group (as well as patients in the expectant management group that 
undergo induction of labor) should be allowed adequate time to labor before considering the induction 
“failed” and proceeding to cesarean section.  An induction will be considered “failed” if at least 12 hours 
have elapsed since both rupture of membranes and use of a uterine stimulant and the patient remains in 
latent labor.  It is expected that the fetal heart rate will be monitored while the patient is being induced 
(including ripening) and during labor and that patients will stay in the hospital until delivery once the 
induction (including ripening) is started.  Mechanical ripening using a Foley catheter without saline 
infusion is permitted without monitoring and may be used in an outpatient setting according to policies at 
each center.   
For patients in the expectant management group, only a valid medical indication should warrant delivery 
before 40 weeks and 5 days.  Otherwise, no attempt will be made to alter or mandate clinical management 
of the subjects.   
Women will be asked about pain experienced during childbirth and asked to complete a questionnaire on 
feelings of control during childbirth.  All women will be contacted at six weeks postpartum to determine 
unanticipated outpatient or inpatient visits for them or their infants since discharge and to complete the 
same questionnaire about feelings of control again.  

July 20, 2017 
13 
4.6 Adverse Event Reporting 
Detailed information concerning adverse events will be collected and evaluated throughout the conduct of 
the protocol.  
The NICHD Project Scientist and the BCC will be notified within seventy-two hours of any maternal 
death, perinatal death, or life-threatening maternal event by email/phone/fax, if the event occurred in a 
MFMU Network hospital.  For any maternal death, perinatal death, or life-threatening maternal event 
occurring outside a MFMU Network hospital, the adverse event must be reported to the NICHD and the 
BCC within twenty-four hours of being notified.  These and other adverse events deemed serious, 
unexpected and definitely, possibly or probably related, will be immediately (within twenty-four hours of 
notification) forwarded by the BCC to the DSMC Chair, NIH representative, and any other DSMC 
member who requests notification.  If a death is reported, a copy of the patient’s medical record will be 
made.   
Adverse events which do not qualify under the above definition must be reported to the BCC within 7 
days of being notified.  These adverse events will be collected and sent to the Chair, NIH representative, 
and any other requesting DSMC member on a monthly basis.  The Chair decides whether the adverse 
event reports should be disseminated to the rest of the committee, and whether a follow-up call or meeting 
is required.  NICHD representatives may also request follow-up of specific events.  All adverse events 
will be considered along with other interim safety data in the DSMC deliberations. 
4.7 Study Outcome Measures and Ascertainment 
4.7.1 Primary Outcome 
The primary outcome is a composite of severe neonatal morbidity and perinatal mortality (any one of the 
following): 
•
Antepartum, intrapartum, or neonatal death
•
Intubation, continuous positive airway pressure (CPAP) or high-flow nasal cannula (HFNC) for
ventilation or cardiopulmonary resuscitation within first 72 hours
•
Apgar ≤ 3 at 5 minutes
•
Neonatal encephalopathy as defined by Shankaran et al.49
•
Seizures
•
Sepsis.  The diagnosis of sepsis will require the presence of a clinically ill infant in whom
systemic infection is suspected with a positive blood, CSF, or catheterized/suprapubic urine
culture; or, in the absence of positive cultures, clinical evidence of cardiovascular collapse or an
unequivocal X-ray confirming infection.
•
Pneumonia confirmed by X-ray or positive blood culture.
•
Meconium aspiration syndrome
•
Birth trauma (bone fractures, brachial plexus palsy, other neurologic injury, retinal hemorrhage,
or facial nerve palsy)
•
Intracranial hemorrhage (intraventricular hemorrhage grades III and IV, subgaleal hematoma,
subdural hematoma, or subarachnoid hematoma)
•
Hypotension requiring pressor support

July 20, 2017 
14 
4.7.2 Maternal Secondary Outcomes 
1. Cesarean delivery and indication  
2. Incisional extensions at cesarean section, including J shape or T shape; or cervical traumas 
3. Operative vaginal delivery and indication 
4. Chorioamnionitis, defined as a clinical diagnosis before delivery 
5. Third or fourth degree perineal laceration 
6. Maternal death 
7. Admission to intensive care unit (ICU) 
8. Preeclampsia/gestational hypertension 
9. Postpartum hemorrhage, defined as any of the following:  
• 
Transfusion 
• 
Non-elective hysterectomy 
• 
Use of two or more uterotonics other than oxytocin 
• 
Other surgical interventions such as uterine compression sutures, uterine artery ligation, 
embolization, hypogastric ligation, or balloon tamponade  
• 
Curettage 
10. Interval from randomization to delivery 
11. Gestational age at delivery 
12. Maternal postpartum infection, defined as any of the following:  
• 
Clinical diagnosis of endometritis 
• 
Wound reopened for hematoma, seroma, infection or other reasons 
• 
Cellulitis requiring antibiotics 
• 
Pneumonia 
• 
Pyelonephritis 
• 
Bacteremia unknown source 
• 
Septic pelvic thrombosis 
13. Maternal venous thromboembolism (deep venous thrombosis or pulmonary embolism) 
4.7.3 Fetal and Neonatal Secondary Outcomes 
1. Birth weight  
2. Duration of respiratory support including ventilator, CPAP, high-flow nasal cannula (HFNC) 
3. Cephalohematoma 
4. Shoulder dystocia 
5. Transfusion of blood products or blood  
6. Hyperbilirubinemia requiring phototherapy or exchange transfusion 

July 20, 2017 
15 
7. Hypoglycemia (glucose < 35 mg/dl) requiring IV therapy   
8. Admission to neonatal intensive care unit (NICU) or intermediate care unit 
4.7.4 Utilization of Medical Resources  
1. Number of hours on the labor and delivery unit 
2. Maternal postpartum length of hospital stay 
3. Neonatal length of hospital stay 
 
 

July 20, 2017 
16 
5 Statistical Considerations  
5.1 Data Relevant to the Primary Outcome 
To estimate the rate of the primary outcome in the expectant management group, data from the MFMU 
Network’s APEX study were evaluated.  APEX was an observational study of approximately one-third of 
all deliveries at 25 hospitals in the MFMU Network, collected over a three-year period.  For this analysis 
only nulliparous women with a singleton pregnancy delivered at 39 weeks 0 days to 42 weeks 0 days 
were included; those with diabetes, hypertension before 38 weeks, previa and abruption were excluded, 
yielding a cohort of 24,683 women.  A composite outcome as close as possible to the proposed composite 
primary outcome for this trial was evaluated in these women.  However, APEX only included pregnancies 
with fetal heart tones on admission for delivery and therefore stillbirth would be slightly underestimated.  
In addition, presence of thick meconium was used as a surrogate for meconium aspiration syndrome.  The 
outcome rate in this cohort was 2.3% excluding presence of thick meconium; with thick meconium 
present the outcome rate was 9.3%.  The real primary outcome rate could be expected to be between these 
two estimates.   
Also, among women in the FOX trial, risks of adverse neonatal outcome at term (neonatal composite 
outcome including death, respiratory distress, seizure, sepsis, intubation and ventilator support, 5 minute 
Apgar score of 3 or less or hypoxic ischemic encephalopathy) were 3.7% at 36-38 weeks, 3.5% at 39 
weeks, 3.8% at 40 weeks and 5.0% at ≥ 41 weeks.38   
Therefore the neonatal composite outcome rate for pregnancies expectantly managed beyond 39 weeks 
would be expected to be between 3.5% and 5%.  This is consistent with other literature presented in 
Chapter 1. 
5.2 Sample Size and Power 
5.2.1 Primary Outcome 
Table 6 shows the sample sizes per group (rounded up to the next 10) to detect a 35-40% reduction in the 
primary outcome, with 80% to 90% power, assuming type I error of 5% 2-sided and primary outcome rate 
in the expectant management arm between 3.5% and 5%.  Some women will labor after randomization 
but prior to when their randomized assignment could be implemented (i.e., before 39 weeks).  In addition, 
some women may undergo an elective induction off-protocol before 40 weeks, 5 days without a specific 
indication.  These ‘crossovers’ would therefore behave more like the elective induction group; and it is 
assumed that their primary outcome rate would be the same as that of the elective induction group.  This 
has the effect of reducing the effect size slightly depending on the proportion of crossovers: for example 
with 5% crossovers, the 40% nominal reduction becomes 39%.  
Sample sizes were adjusted to take into account that between 5 and 10% of the women in the expectant 
management group will behave more like the elective induction group.  The actual effect sizes are shown 
in parentheses in the table.  
Data from observational studies suggest that a policy of induction of labor at 39 weeks may result in an 
equivalent reduction in adverse outcome.6, 46  Using a type I error of 5% 2-sided and power of 85%, and 
an estimate that 7.5% of women in the expectant management group will be crossovers, 3000 women in 
each group (total N= 6000) would be needed to detect the actual reduction in primary outcome of 38%.   
If the primary outcome rate is as high as 5%, a sample size of 6000 patients is sufficient to detect a 33-
34% reduction in the primary outcome with at least 85% power, again assuming that 7.5% of women will 
be crossovers.   
 

July 20, 2017 
17 
Table 6. Sample Sizes per Group for Different Primary Outcome Rates, Power and Effect Sizes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5.2.2 Cesarean Delivery 
Assuming that the rate of cesarean delivery is 30% in the expectant management group, a sample size of 
6000 women also yields more than 90% power to detect a nominal 15% increase or decrease even after 
adjusting for 7.5% crossovers.    
Reduction in Primary 
Outcome Rate 
(Reduction Adjusted 
for Crossover) 
Power % 
Nominal Primary Outcome Rate in Expectant Management  
Group 
3.5% 
4.0% 
4.5% 
5.0% 
0% Crossover 
35% (35%) 
80 
3030 
2650 
2350 
2120 
85 
3460 
3030 
2690 
2420 
90 
4050 
3540 
3150 
2840 
40% (40%) 
80 
2250 
1970 
1750 
1570 
85 
2570 
2250 
2000 
1800 
90 
3010 
2630 
2340 
2110 
5% Crossover 
35% (33.8%) 
80 
3320 
2900 
2580 
2320 
85 
3790 
3320 
2950 
2660 
90 
4440 
3880 
3450 
3110 
40% (38.8%) 
80 
2460 
2150 
1910 
1720 
85 
2810 
2460 
2190 
1970 
90 
3290 
2880 
2560 
2300 
7.5% Crossover 
35% (33.2%) 
80 
3480 
3040 
2710 
2440 
85 
3980 
3480 
3100 
2790 
90 
4660 
4070 
3620 
3260 
40% (38.1%) 
80 
2580 
2260 
2010 
1810 
85 
2950 
2580 
2290 
2060 
90 
3450 
3020 
2680 
2420 
10% Crossover 
35% (32.6%) 
80 
3650 
3200 
2840 
2560 
85 
4180 
3660 
3250 
2930 
90 
4890 
4280 
3810 
3430 
40% (37.5%)  
80 
2700 
2370 
2100 
1890 
85 
3090 
2710 
2410 
2170 
90 
3620 
3170 
2820 
2530 

July 20, 2017 
18 
5.3 Feasibility 
Given that the sample size estimates are based on a composite of rare outcomes, it is planned that the 
primary outcome rate in the expectant management group be examined in the first 1000 patients.  These 
data would be presented to the DSMC before any comparison by group, and the committee would be 
charged with making a recommendation regarding potential revision of the sample size in addition to 
addressing the feasibility of answering the primary research question. 
5.4 Interim Analysis 
The Data and Safety Monitoring Committee (DSMC) meets in person at least once per year and more 
often if recommended by the committee.  Before each of the annual meetings, a formal detailed report 
will be written by the Biostatistical Coordinating Center (BCC) which presents all baseline variables, 
protocol adherence, side effects, all adverse events reported, as well as center performance in terms of 
recruitment, data quality, loss to follow-up and protocol violations.   
Once sufficient patients have been accrued into the trial, the report will also include a formal interim 
analysis evaluating the primary outcome by treatment group.  For this evaluation, a cohort of patients is 
chosen consisting of all patients randomized before a certain date so that the analysis cohort does not 
depend on gestational age at delivery.   
The main statistical issue relevant to interim analysis is the problem of performing multiple tests of 
significance on accumulating data.  For this trial, the group sequential method of Lan and DeMets will be 
used to characterize the rate at which the type I error is spent.50  This method is flexible with regard to the 
timing of the interim analyses.  Asymmetric stopping boundaries will be used for the Lan-deMets 
procedure.  The upper boundary which describes the stopping rule for benefit will be based on 1-sided 
type I error of .025 and the Lan-deMets generalization of the O’Brien-Fleming boundary.   
The lower boundary will be based on a less stringent stopping rule: 1-sided type 1 error of .05 and the 
Lan-deMets generalization of the Pocock type boundary.   
It is often useful to calculate conditional power given the observed data to date, and conditional on the 
future data showing the originally assumed design effect. If this conditional power is low (under 10 
percent) the DSMC may consider termination for futility if the accrual rate is slow, with confidence that 
the Type II error is not greatly inflated.51  
It is recognized that any decision to terminate the study would not be reached solely on statistical grounds 
but on a number of complex clinical and statistical considerations.  
5.5 Analysis Plan 
All statistical analyses will be based upon the total cohort of patients randomized into the trial.  Although 
data on some patients may be missing, all relevant data available from each patient will be employed in 
the analyses.  Patients will be included in the treatment group to which they were randomly assigned 
regardless of compliance. 
The primary analysis will consist of a simple comparison of binomial proportions.  The relative risk and 
confidence interval will be reported.  The individual components of the composite outcome will also be 
examined.  If the treatment groups are found to differ on a pre-treatment factor known to be a risk factor 
for the outcome, the statistical analysis will adjust for these differences.  An evaluation of treatment by 
center interaction will be included.  An analysis adjusting by center also will be performed to ensure that 
center differences do not change the conclusion.   
If the two groups show a difference in the incidence of the primary outcome or cesarean, interactions will 
be evaluated and subgroup analyses conducted to determine whether the effect prevails throughout 

July 20, 2017 
19 
particular subgroups of patients.  Indeed, NIH guidelines require investigators to evaluate consistency 
between the genders and across racial subgroups (see Section 5.5.1).  It should be noted, however, that 
subgroup analyses have been greatly abused, particularly when there is no overall treatment difference.52  
There is a strong temptation to search for a specific subpopulation in which the therapy is nevertheless 
effective.  Yusuf et al. concluded “the overall ‘average’ result of a randomized clinical trial is usually a 
more reliable estimate of the treatment effect in the various subgroups examined than are the observed 
effects in individual subgroups.”53  Thus subgroup analyses will be interpreted with care.   
It is generally acknowledged that subgroup analysis that is pre-specified in the protocol has more validity 
than ad-hoc comparisons.  The following factors will be considered for subgroup analysis, if there is a 
significant interaction between the factor of interest and the treatment effect. 
•
Race/ethnicity (see below)
•
Modified Bishop score (< 5 and ≥ 5)
•
Body mass index (obese and non-obese)
•
Maternal age (< 35 and ≥ 35 years)
•
Admitting provider specialty (see below)
Loss to follow-up will be defined as no information regarding stillbirth or neonatal outcome.  There 
should be a low loss to follow-up rate.  It is possible that a woman would deliver at a non-Network 
hospital; however, a record release will be obtained at enrollment to ensure that delivery and neonatal 
information can be obtained.  However, to determine whether the results are robust, a sensitivity analysis 
will be performed including patients lost to follow up with different assumptions regarding their outcome.  
Since many of the secondary endpoints are dichotomous variables like the primary outcome, standard 
statistical methods for rates and proportions will be appropriate.  The Wilcoxon rank sum test will be used 
to compare continuous variables, and survival analysis methodology may be used to compare time-to-
event variables.  
In general, analyses of data will be conducted to address the primary and secondary research questions of 
the trial, and other interrelationships among elements of study data of interest to the investigators and of 
relevance to the objectives of the study. 
5.5.1 Racial/Ethnic Subgroup Analysis 
The racial/ethnic composition of patients of women recruited into the MFMU Network trials varies.  
Assuming for this trial that the composition is 25% African-American and 30% Hispanic, similar to the 
ongoing STAN trial, there is limited power (40-50%) to detect a 50% reduction in the primary outcome or 
cesarean in the separate subgroups.    
5.5.2 Admitting Provider Specialty Subgroup Analysis 
Although admitting provider specialty is not a baseline variable, this variable will be evaluated for 
subgroup analysis if the two groups show a difference in the incidence of the primary outcome or 
cesarean, and if the test for interaction is significant. Elective induction of labor may be perceived as an 
intervention more likely utilized by obstetricians than by midwives, therefore it is important to 
demonstrate whether a treatment effect is present among patients treated by obstetricians and among 
patients treated by midwives.  

July 20, 2017 
20 
6 Data Collection 
6.1 Data Collection Forms 
Data will be collected on standardized forms on which nearly all responses have been pre-coded.  Each 
form is briefly described below: 
• 
AR01   Screening Log. 
• 
AR02   Eligibility and Randomization Form is completed for all patients eligible and consenting 
for the study, and documents the project gestational age and randomization digital cervical exam. 
• 
AR04   Baseline Form is completed for all randomized patients.  This form includes detailed 
demographic and social data, and medical and obstetrical history. 
• 
AR05   Clinic and Hospital Visit Log documents scheduled and unscheduled clinic, urgent care 
and hospital visits, procedures and diagnostic tests, including the antepartum portion of the 
delivery admission. 
• 
AR08   Labor and Delivery Summary Form documents specific pregnancy complications since 
randomization, in addition to labor, delivery and postpartum information.  
• 
AR08A   Labour Agentry Questionnaire 
• 
AR09   Neonatal Baseline Form records date and time of birth, delivery data and status at 
delivery, for each fetus/infant. 
• 
AR10   Neonatal Outcome Form records outcome data for all infants admitted to the NICU or 
special care nursery. 
• 
AR11   Patient Status Form documents loss to follow up/withdrawal status, last date of contact 
for lost to follow-up patients. 
• 
AR12  Adverse Event Form records serious and non-serious adverse events. 
• 
AR13  Postpartum Follow-up Form  
• 
AR13A  Maternal Follow-up Log documents the reasons and diagnoses associated with maternal 
clinic, urgent care and hospital visits   
• 
AR13B  Infant Follow-up Log documents the reasons and diagnoses associated with infant clinic, 
urgent care and hospital visits   
6.2 Web Data Entry System 
For this protocol, web data entry screens corresponding to the study forms listed above will be developed 
and maintained by the staff of the BCC.  Clinical center staff will enter data into the MySQL database 
located at the BCC through a web data management system (MIDAS).  The data are edited on-line for 
missing, out of range and inconsistent values.  A Users’ Manual documenting this system is provided to 
the centers by the BCC.  
6.3 Centralized Data Management System 
Daily data conversions from the MySQL database create up-to-date SAS datasets.  Data are reviewed 
weekly using edit routines similar to those implemented on-line during data entry, as well as additional 
checks for data consistency within or across forms.  A database of resulting potential data problems is 

July 20, 2017 
21 
generated in MIDAS for initial review by BCC staff, who then evaluate the comments keyed in 
association with edits on missing or unusual values.  Valid edits will be flagged in MIDAS for resolution 
at the clinical centers.   
At regular intervals, specialized data reviews comparing data availability and consistency across forms 
are run by the BCC staff on the entire database or on a specific subset of data.  These reports are also 
submitted to the centers for correction or clarification. 
An audit trail, consisting of all prior versions of each data form as entered in the computer for each 
patient, is maintained so that the succession of corrections can be monitored. 
6.4 Performance Monitoring 
The BCC will present regular reports to the ARRIVE Subcommittee, the Steering Committee, and the 
Data and Safety Monitoring Committee.  These include: 
• 
Monthly Recruitment Reports - reports of the number of women screened and enrolled by month 
and by clinical center are provided monthly to the ARRIVE Subcommittee and all other members 
of the Steering Committee.  Weekly or bi-weekly reports are provided electronically if needed. 
• 
Quarterly Steering Committee Reports - reports detailing recruitment, baseline patient 
characteristics, data quality, incidence of missing data and adherence to study protocol by clinical 
center, are provided quarterly to the ARRIVE Subcommittee and all other members of the 
Steering Committee. 
• 
Data and Safety Monitoring Committee Reports - for every meeting of the DSMC, a report is 
prepared which includes patient recruitment, baseline patient characteristics, center performance 
information with respect to data quality, timeliness of data submission and protocol adherence (in 
addition to safety and efficacy data).  The reports also include adverse events, loss to follow-up 
and all outcome variables as described previously in this protocol. 

July 20, 2017 
22 
7 Study Administration 
7.1 Organization and Funding 
The study is funded by the Eunice Kennedy Shriver National Institute of Child Health and Human 
Development (NICHD).  The study is conducted by the NICHD Maternal-Fetal Medicine Units (MFMU) 
Network, consisting of fourteen clinical centers, the Biostatistical Coordinating Center (BCC) and the 
NICHD, and is administered under cooperative agreements between each of the centers and the NICHD.  
Each of the funded institutions is represented by a Principal Investigator.  A complete description of the 
organization of the MFMU Network is provided in the MFMU Network Policy Manual.   
7.1.1 Participating Clinical Centers 
The participating Principal Investigators of the clinical centers have agreed to abide by the study protocol, 
to have comparable staff, facilities and equipment and to ensure the proper conduct of the study at each of 
their centers including: recruitment and treatment of patients as specified in the protocol, accurate data 
collection and the transmission of information to the Steering Committee. 
7.1.2 Biostatistical Coordinating Center 
The BCC is responsible for all aspects of biostatistical design, data management, interim and final 
statistical analyses, and preparation of publications based on the study results.  The Principal Investigator 
of the BCC reports to the Steering Committee and the Data and Safety Monitoring Committee. 
7.1.3 NICHD 
In addition to its role as funding agency, the NICHD participates in the activities of the Network, 
including the development of protocols, administration and conduct of the studies and preparation of 
publications. 
7.1.4 Network Advisory Board 
Appointed by the NICHD, the members of the Network Advisory Board consist of a group of experts 
who are not affiliated with research being conducted by the Network and represent the disciplines of 
maternal-fetal medicine, neonatology and biostatistics/epidemiology.  The role of the board includes the 
review and prioritization of proposed studies, in addition to the identification of scientifically and 
clinically important questions and ideas that might be conducted by the Network.  The NICHD Project 
Scientist convenes and attends the meetings. 
7.2 Committees 
7.2.1 Steering Committee 
This committee consists of seventeen members.  The Principal Investigator from each of the fourteen 
clinical centers, the BCC, and the NICHD MFMU Network Project Scientist are all voting members. The 
Chair of the Steering Committee may vote to break a tie.  The Chair, a person independent of the 
participating institutions, is appointed by NICHD.  The Steering Committee has the responsibility for 
identifying topics for Network studies, designing and conducting study protocols and monitoring study 
implementation, recruitment and protocol adherence.  The committee receives recommendations from the 
Data and Safety Monitoring Committee and the Network Advisory Board. 
7.2.2 Protocol Subcommittee 
The subcommittee consists of a chair (who is an investigator from one of the clinical centers), 
investigators from one or more other clinical centers, BCC staff, nurse coordinators, outside consultants 

July 20, 2017 
23 
(if appropriate), and the NICHD Network Project Scientist.  The Protocol Subcommittee is responsible 
for the preparation and conduct of the study, and reporting the progress of the study to the Steering 
Committee. 
7.2.3 Publications Committee 
The Publications Committee is a standing committee of the Steering Committee.  The functions of this 
committee are to develop publication policies and to review all manuscripts and abstracts prior to 
submission.  The goals of this committee are fair and appropriate authorship credit and high quality 
publications. 
7.2.4 Data and Safety Monitoring Committee 
The Data and Safety Monitoring Committee (DSMC), a group of individuals not affiliated with any of the 
participating institutions, was established by the NICHD.  Before the trial can begin, the protocol must be 
approved by the committee.  During the conduct of the study, the committee is charged with monitoring 
the emerging results for efficacy and safety, in addition to center performance and protocol adherence.  
Recommendations by the committee can include protocol modification, early termination for efficacy, or 
for unexpected safety problems.  Recommendations are made to the NICHD and disseminated to the 
Steering Committee. 

July 20, 2017 
24 
8 Study Timetable 
Figure 1. Timetable 
   July 2013   
 July 2014  
     July 2015 
   July 2016   
8.1 Training and Certification 
During the study start-up period, preparation of the final case report forms, manual of operations, and 
randomization sequence, in addition to implementation of the data entry and management system will 
take place.  Training will be held with the nurse coordinators in July and October 2013, with a projected 
study start date of October 2013.  Each participating center must be certified to start the trial before 
recruitment at that center can begin.  The certification requirements are designed to ensure that personnel 
involved in the trial are committed to the study and proficient in study procedures, and that the center has 
satisfied regulatory requirements.  Each center is required to obtain IRB approval for the study before 
they are certified to begin the trial.   
8.2 Recruitment and Data Collection Period 
Approximately 160,000 women deliver at MFMU Network centers annually.  The APEX study database 
was queried to determine what proportion of all deliveries would be eligible for ARRIVE.  A total of 
17,960 pregnancies out of 115,502 or 15.5% satisfied the eligibility criteria.  In addition, a pilot survey 
was conducted at four of the MFMU Network centers.  A total of 204 women were queried to find out 
whether they would consent to this trial if it were presented to them.  A total of 55% responded ‘yes’, 
13% responded ‘maybe’ and 32% responded ‘no’.  Assuming only 20% percent of the 160,000 deliveries 
are available (due to, for example, certain sites or care providers not participating), 15.5% satisfying 
eligibility criteria and a 55% consent rate, this translates to 2700 patients per year.  Assuming no limit on 
the ability to schedule inductions at 39 weeks, the study would easily be completed within 30 months.  
Training/Certification 
Recruitment 
Follow-up 
Data processing 

July 20, 2017 
25 
Allowing an additional six months (i.e., 3 years in total), with only 30 of the 36 sites participating, 
translates to 67 patients per year per hospital (1.3 women per hospital per week) which should be feasible.  
Thus the overall recruitment goal is 167 women per month.     
8.3 Final Analysis 
After a two-month period for completion of data entry for the trial and close-out of the delivery and 
primary outcome, the data set will be locked and available for the primary and other main analyses.  

July 20, 2017 
26 
Appendix A 
Design Summary 
Induction in Nulliparous Women at 39 Weeks to Prevent Adverse Outcomes:  A Randomized Controlled Trial 
OBJECTIVE:  To determine whether elective induction of labor in nulliparous women at 39 weeks improves adverse perinatal/neonatal outcome compared with expectant 
management .
ORGANIZATION 
SCHEDULED EVALUATIONS / DATA COLLECTION 
Clinical Centers: 
Subcommittee: 
UAB, Ohio State, UTSW, Utah, Brown, Columbia, Case Western, 
UT-Houston, UNC, Northwestern, UTMB-Galveston, Colorado, 
Duke, Stanford, Magee, U Penn 
William Grobman, MD (Chair) 
Randomization: 

Gestational age estimation

Digital cervical exam; Bishop score

Pregnancy, exposure and medical history
Post-randomization: 
Delivery: 
Postpartum: 

Weekly visit with provider (expectant
management group) 

Patient-centered outcomes questionnaire

Delivery and neonatal data

Central chart review for primary outcome

Patient-centered outcomes questionnaire
DESIGN 
Major Eligibility Criteria: 

Singleton gestation

Gestational age  38
0 to 38
6  wks

Nulliparous
MANAGEMENT PROTOCOL 
Groups: 

Induction of labor at 39 weeks

Expectant management with induction by 42 weeks, if
undelivered 
Induction Group 

Induction via oxytocin at 39
0-39
4 wks.

If unfavorable cervix (modified Bishop score <
5) start with cervical ripening
Random Allocation: 
Standard urn design; 1:1 allocation 
Expectant Mgmt Group 

Continue pregnancy until at least 40
5 wks
(unless indication for delivery) 

Start antepartum fetal testing no later than 41
6

All patients induced by 42
2 wks
Level of Masking: 
Unmasked 
Stratification: 

Clinical site
Sample Size: 

6000
OUTCOME MEASURES 
Assumptions: 

Outcome event=perinatal death /neonatal adverse outcome

Expectant management  event rate = 3.5%

Induction of labor group event rate = 2.28% (38% reduction)

Type 1 error = 5% two sided

Power =85%
Primary: 
Major Secondary: 

Neonatal adverse outcome/fetal death

Cesarean delivery

Maternal adverse outcomes

Gestational age at delivery

Utilization of medical resources
Interim Analysis: 

Lan-DeMets group sequential method
TIMETABLE (as originally planned) 
Enrollment 
Data Collection 
Closeout 

Oct 2013 to Sep 2016

Oct 2013 to Nov 2016

Dec 2016 to Mar 2017
TIMETABLE (revised) 

Oct 2013 to Oct 2017

Oct 2013 to Dec 2017

Jan 2018 to Apr 2018

July 20, 2017 
27 
Appendix B 
Sample Informed Consent Form 
Research Study Title:  A Randomized Trial of Induction Versus Expectant Management (ARRIVE) 
Sponsor:  Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) 
of the National Institutes of Health (NIH) 
Principal Investigator:  ___________________________Phone  (____)  ___ - ____ 
Introduction 
You are invited to take part in a research study.  This consent form provides the information about the 
risks and benefits of the study.  A member of the research team is available to answer your questions and 
to provide further explanations.  You are free to choose whether or not you will take part in the study.  If 
you agree to take part in the research, you will be asked to sign this consent form.  This process is known 
as informed consent.   
Research Purpose 
You are being invited to participate because you are pregnant, having your first baby, and are planning to 
labor.  The goal of the study is to determine whether coming to the hospital and having your labor started 
with medicine (i.e., labor induction) at 39 weeks of pregnancy can improve the baby’s health at birth 
when compared with waiting for labor to start on its own. 
Many doctors wait until 41 weeks for labor to start on its own.  However, some studies, but not all, have 
shown that being induced at 39 weeks of pregnancy may improve the baby’s outcome.  Some older 
studies have suggested a higher risk of cesarean, but other recent studies have not shown this increased 
risk.  No studies like this one have been done before in the United States.  This study is planning to enroll 
6,000 women across the country.  Half of the women will be induced at about 39 weeks of gestation and 
half will have the existing prenatal care (that is, waiting for start of labor). 
Procedures 
If you consent to the study, when you are within one to two weeks of your due date, you will be 
randomized (like flipping a coin) to one of two groups.  In one group (the “induction of labor” group), 
you will have your labor started through the use of medicine within a few days of reaching 39 weeks of 
pregnancy.  Depending upon how open your cervix is (the cervix is the opening to your uterus or birth 
canal), your doctor will decide the best way to start your labor. In the other group (the “expectant 
management group”) you will continue with your pregnancy until either you begin labor or your care 
provider determines that you need to be delivered or you reach 41-42 weeks of gestation (1-2 weeks after 
your due date).   
Regardless of which group you are in, your care provider will check your cervix (the opening of your 
uterus or birth canal) during a pelvic examination.  This may have already been done as a part of regular 
care within three days of your being randomized in which case it would not have to be repeated.  If you 
receive medication to help open your cervix or start your labor, your baby’s heart rate will be monitored 
all the time you are receiving the medication and when you are in labor.  Once you receive medication to 
help open your cervix or start your labor you should expect to stay in the hospital until delivery.  All other 
care during your pregnancy and during labor will be at the discretion of your care provider.  
After delivery, research staff will review your medical chart for clinical and outcome information such as 
any treatments or medicines given during labor and whether you had a vaginal delivery or cesarean 
section.  They will also review the medical chart of your newborn.  The research team will collect 
information regarding your hospital course and that of your newborn until hospital discharge.  

July 20, 2017 
28 
You will be asked two questions about the pain you experienced during childbirth and asked to fill out 
one questionnaire soon after your baby is born.  The questionnaire will be about how you felt about the 
process of labor and giving birth.  Six weeks after your baby is born, research staff will contact you to 
find out about any unplanned hospital or clinic visits for you or your baby and you will be asked to fill out 
the same questionnaire about the process of labor again.  
Possible Risks 
During labor induction, the same types of complications that can occur during any labor can occur.  At 
present, it is not known whether labor induction at 39 weeks is associated with a greater chance of 
cesarean delivery.  Some older studies have suggested a higher risk of cesarean, but other recent studies 
have not shown this increased risk. 
Benefits 
If you decide to take part in this research study, you and your baby may not directly benefit.  Your 
participation may help doctors determine the best time to plan for delivery in the future. 
Alternative Procedures 
The alternative to this study is not to participate.  Women who do not take part in this study will continue 
with their pregnancies until either they begin labor or their care provider determines there is a reason that 
they need to be delivered before labor begins (i.e., the standard care during pregnancy). 
Costs 
There will be no cost to you to take part in the research study.  The costs of your labor, delivery and care 
after delivery will be billed to you or your insurance company in the usual manner. 
Compensation 
(THIS SECTION WILL BE CENTER SPECIFIC.) You will be paid $XX to compensate you for the time 
and travel associated with the research study. 
Payment for Injury or Harm 
(THIS SECTION WILL BE CENTER SPECIFIC.) This hospital is not able to offer financial 
compensation or absorb the costs of medical treatment in the event of injury resulting from the research.  
In the event of such injury, treatment will be provided but it is not provided free of charge.  Since this is a 
research study, payment for any injury resulting from your participation in this research study may not be 
covered by some health insurance plans. 
Right to Withdraw From the Research Study 
This study is voluntary and it is up to you to decide whether or not you want to participate.  You are free 
to withdraw your consent and stop taking part in this research study at any time without giving a reason.  
Refusal to take part or the decision to withdraw from the study will involve no penalty or loss of benefits 
to which you are otherwise entitled.  Your refusal will not affect your legal rights or quality of health care 
that you will receive at this hospital.  Any significant new information which becomes available during 
your participation in this research, and which may affect your health, safety, or willingness to continue in 
this research study, will be given to you. 
Right of the Investigator to Withdraw 
The researchers of this institution or the National Institutes of Health can withdraw you from this study 
without your approval.  A possible reason for withdrawal could be the early termination of the study by 
the National Institutes of Health. 
Confidentiality 

July 20, 2017 
29 
You have the right to privacy.  All information obtained from this research that can be identified with you 
will remain confidential within the limits of the law.   
The medical information collected on you for this research study will come from your medical record and 
from information you give the nurse, such as your previous pregnancies, height, weight, and whether you 
drink or smoke.  Other information collected about you includes whether you are married, whether you 
have a job, and type of medical insurance.  If we lose track of you, study staff may collect information 
from the internet including social network sites in order to find your contact information. 
The information collected for this research study will be held at the data coordinating center (George 
Washington University Biostatistics Center in Rockville, Maryland) in a database consisting of 
information from all of the participants in this study.  Your information in the database will only be used 
for statistical analysis and may appear in scientific publications but will not identify you.  The 
information at the data coordinating center does not include your name, address, social security number, 
hospital number, date of birth or any other personal identifiers.  Instead the data center will use a unique 
code for each person consisting of a number and the first letter of your first name.  The key to the code 
linking the data to you will be kept here in a locked file.  Only the research study staff employed for this 
study at this hospital will have access to the key to the code.  
The following individuals and/or agencies will be able to look at and copy your research records:  
•
The investigator, study staff and other medical professionals who may be evaluating the study.
•
Authorities from this institution, including the Institutional Review Board (IRB) which is a group
of people who are responsible for making sure the rights of participants in research are respected.
Members or staff of the IRB at this medical center may also contact you about your experience
with this research.  You do not have to answer any questions asked by the representative of the
board.
•
The Office for Human Research Protections (OHRP)
•
The Eunice Kennedy Shriver National Institute of Child Health and Human Development
(NICHD) which sponsors this study, including persons or organizations working with the
sponsors, such as the data coordinating center, the George Washington University Biostatistics
Center in Rockville, Maryland.
A copy of your or your baby’s medical chart may also be sent to research investigators at one of the other 
enrolling centers or the data coordinating center for review.  If your chart is sent, identifying information, 
such as name, address, social security number, or hospital number will be removed.   
The results of this research study will be provided to the sponsor, NICHD, (and/or its representatives).  In 
addition, data from this study will be put in a public data set that will be available to other research 
investigators.  This public data set will not contain any identifying patient data. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law.  This Web site will not include information that can identify you.  At most, the Web site will include 
a summary of the results.  You can search this Web site at any time. 
This permission does not end unless you cancel it, even if you leave the study.  You can cancel this 
permission any time except where a healthcare provider has already used or released your health 
information, or relied on your permission to do something.  Even if you cancel this authorization, the 
researchers may still use and disclose protected health information (PHI) they already have obtained 
about you as necessary to maintain the integrity or reliability of the research.  However, no new PHI will 
be collected from you after you revoke your authorization. 
To cancel your authorization, you will need to send a letter to Dr. ________ of the ________ stating that 
you are canceling your authorization.  This letter must be signed and dated and sent to this 

July 20, 2017 
30 
address:___________________.  If you are unable to write a letter ask one of the research staff to provide 
you with a letter that must be signed, dated, and sent to the above address.  A copy of this revocation will 
be provided to the Study Doctor and his or her research team.  Not signing this form or later canceling 
your permission will not affect your health care treatment outside the study, payment for health care from 
a health plan, or ability to get health plan benefits. 
Your protected health information will be treated confidentially to the extent permitted by applicable laws 
and regulations.  Federal law may allow someone who gets your health information from this study to use 
or release it in some way not discussed in this section and no longer be protected by the HIPAA Privacy 
Rule. 
By signing this form you authorize the Study Doctor and members of the research team to use and share 
with others (disclose) your PHI for the purpose of this study.  If you do not wish to authorize the use or 
disclosure of your PHI, you cannot participate in this study because your PHI is necessary to conduct this 
study. 
Questions  
The researchers are available to answer your questions about this research.  A representative of the 
Institutional Review Board is also available to answer questions about your rights as a participant in 
research or to answer your questions about an injury or other complication resulting from your 
participation in this research study.   
If you have questions or are hurt while taking part in this research study, you should contact 
________________ at (___) ___-____. 
If you have any questions about the informed consent process or any other rights as a research subject, 
please contact __________________, at (____) ___-____.  _______________ .   
Signatures 
By signing below, you indicate that you have read this consent form, the study has been explained to you, 
your questions have been answered, and you agree to take part in this study.  You do not give up any of 
your legal rights by signing this form.  A copy of this consent form will be given to you. 
The investigator or study team may wish to contact you in the future to request permission for additional 
research.  Please initial the appropriate statement to indicate whether or not you give permission for future 
contact. 
YES_____ I give permission to be contacted in the future for research purposes. 
NO_____ I do not give permission to be contacted in the future for research purposes. 
______________________              _______________________ 
______________ 
Participant     
    Signature 
 Date 
(Print Name) 
_______________________      
  ________________________ 
_______________ 
Person Obtaining Consent         
        Signature 
 Date 
(Print Name) 

July 20, 2017 
31 
ASSENT FOR FEMALES UNDER 18 YEARS of AGE (if required by Center IRB): 
I agree __________ 
I do not agree__________ to participate in this study.  
This has been explained to me by ________________________. 
_____________________________      
   _____________________ 
Signature of Minor 
Date 
_____________________________      
_____________________ 
Print Name of Subject        
Age 
Please provide either one or both parental signatures as instructed by your IRB. 
_____________________________      
    _____________________ 
Signature of Mother/Guardian      
     Date 
_____________________________      
  _____________________ 
Signature of Father/Guardian        
Date 
A witness unrelated to the study is necessary if the participant can comprehend but cannot read (i.e., 
blind), or cannot sign (i.e., unable to use hands) the consent form. 
______________________        
   ________________________ 
_______________ 
Witness’ Name              
        Signature 
        Date 
   (Print Name) 

July 20, 2017 
32 
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ARRIVE Trial Protocol Changes 
There were 3 modifications to the protocol: 
1. December 23, 2014
2. April 27, 2017
3. July 20, 2017
ARRIVE Protocol Changes – December 23, 2014 
1.
Section 3.4.2 Gestational Age Determination - the dating criteria were updated for a sure
last menstrual period (LMP) to use criteria proposed by the American Congress of
Obstetricians and Gynecologists, the American Institute of Ultrasound in Medicine and
the Society for Maternal-Fetal Medicine (Committee opinion no 611: method for
estimating due date. Obstet Gynecol 2014;124:863-6). The changes compare the
gestational age by LMP and by the earliest dating ultrasound:
Gestational age at first ultrasound 
by LMP 
Ultrasound method 
of measurement 
Ultrasound 
agreement with LMP 
Up to 8 weeks 6 days 
CRL 
± 5 days 
9 weeks 0 days to 13 weeks 6 days 
CRL 
± 7 days 
14 weeks 0 days to 15 weeks 6 days 
Per institution 
± 7 days 
16 weeks 0 days to 20 weeks 6 days 
Per institution 
±  10 days 
2.
Section 3.4.3 Exclusion Criteria: Added breech presentation as an exclusion criterion.
ARRIVE Protocol Changes – April 27, 2017 
1.
The following research questions and secondary outcomes were deleted from the
protocol to keep the primary manuscript more focused and allow secondary papers to
focus on these outcomes.
a.
Section 3.2 Secondary Research Questions – deleted:
i.
Does elective induction of labor in nulliparous women at 39 weeks modify
the patient-centered outcomes listed in section 4.7.2?
b.
Section 4.7.2 Maternal Secondary Outcomes (and Appendix A Design Summary)
– deleted:
i.
Patient-reported outcomes including feelings of control during childbirth,
as measured by the Labour Agentry Scale,50 and two questions regarding
pain experienced during childbirth using a visual analog scale51
c.
Section 4.7.3 Fetal and Neonatal Secondary Outcomes – deleted:
i.
Macrosomia > 4500 g, large for gestational age (LGA) defined as > 90th
percentile weight for gestational age, assessed specifically by sex and
race of the infant based on United States birth certificate data52
ii.
Small for gestational age defined as < 5th  and < 10th percentile weight for
gestational age, assessed specifically by sex and race of the infant based
on United States birth certificate data52

d. Section 4.7.4 Utilization of Medical Resources – deleted: 
i. Number of clinic visits post randomization to admission for delivery  
ii. ER/urgent care/triage visits post randomization to delivery 
iii. Non-stress tests, biophysical profiles (BPPs), modified BPPs, ultrasounds 
done other than BPP, Doppler, contraction stress tests 
iv. Epidural use 
v. Intrauterine pressure catheter (IUPC) or fetal scalp electrode placement 
vi. Use of induction and ripening agents, maximum dose of oxytocin 
vii. Antepartum hospital admission 
viii. Length of neonatal intensive care unit or intermediate care stay  
ix. Post discharge resource utilization including inpatient and outpatient visits 
for mother or baby 
2. Section 3.2 Secondary Research Questions – clarification regarding when subgroup 
analyses would be performed, to be consistent with the analysis plan: 
a. Added:  ‘If the two groups show a difference in the incidence of the primary 
outcome or cesarean’ before ‘Does the proposed effect of elective induction of 
labor in nulliparous women at 39 weeks vary according to any of the subgroups 
listed in section 5.5?’ 
3. Section 4.7.1 Primary Outcome – clarification of the definition of the primary component 
intracranial hemorrhage to include: 
a. Intraventricular hemorrhage grades III and IV, subgaleal hemorrhage, subdural 
hematoma, or subarachnoid hematoma 
4. Section 5.5 Analysis Plan: 
a. Added ‘or cesarean’ to the following sentences: 
i. If the two groups show a difference in the incidence of the primary 
outcome or cesarean, interactions will be evaluated and subgroup 
analyses conducted to determine whether the effect prevails throughout 
particular subgroups of patients. 
ii. Assuming for this trial that the composition is 25% African-American and 
30% Hispanic, similar to the ongoing STAN trial, there is limited power 
(40-50%) to detect a 50% reduction in the primary outcome or cesarean 
in the separate subgroups. 
b. Added the following subgroups: 
i. Maternal age (< 35 and ≥ 35 years) 
ii. Admitting provider specialty 
c. Added the following paragraph regarding admitting provider specialty subgroup 
analysis: 
i. Although admitting provider specialty is not a baseline variable, this 
variable will be evaluated for subgroup analysis if the two groups show a 
difference in the incidence of the primary outcome or cesarean, and if the 
test for interaction is significant. Elective induction of labor may be 
perceived as an intervention more likely utilized by obstetricians than by 
midwives, therefore it is important to demonstrate whether a treatment 
effect is present among patients treated by obstetricians and among 
patients treated by midwives. 

5.
Appendix A Design Summary:
a.
Added two clinical centers: Magee and U Penn
b.
Enrollment period extended to October 2017
6.
Throughout – changed ‘Program Scientist’ to ‘Project Scientist’
ARRIVE Protocol Changes – July 20, 2017 
1.
Section 4.7.1 Primary Outcome - wording of a few components of the primary outcome
was changed to be consistent with the data forms:
a.
‘cardiorespiratory support’ was changed to ‘cardiopulmonary resuscitation’
b.
‘facial nerve injury’ was changed to ‘facial nerve palsy’
c.
‘subgaleal hemorrhage’ was changed to ‘subgaleal hematoma’
2.
Section 4.7.2 Maternal Secondary Outcomes - typographical errors corrected:
a.
Removed an ‘and’ and added an ‘or’ to the following sentence: ‘Other surgical
interventions such as uterine compression sutures, uterine artery ligation,
embolization, and hypogastric ligation, or balloon tamponade’
3.
Section 4.7.3 Fetal and Neonatal Secondary Outcomes - definition of a secondary
outcome was changed to be consistent with the manual, and a typographical error was
corrected:
a.
‘Hypoglycemia (glucose < 40 mg/%) requiring IV therapy’ was changed to
‘Hypoglycemia (glucose < 35 mg/dl) requiring IV therapy’