Supplementary Appendix

This appendix has been provided by the authors to give readers additional information about their work.

Supplement to: 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
 Supplementary  Appendix  

LABOR INDUCTION VERSUS EXPECTANT MANAGEMENT IN LOW-RISK NULLIPAROUS

WOMEN

Grobman, et al.

This appendix has been provided by the authors to give readers additional information about their
work.

Table of Contents

Investigators and Study Personnel ............................................................................................... 2  

Eligibility Criteria ........................................................................................................................... 3  

Baseline Cervical Exam and Scoring System to Derive the Modified Bishop Score .................... 5  

Patient Management .................................................................................................................... 6  

Compliance with Group Assignment ............................................................................................ 7  

Reasons for Non-compliance with Group Assignment ................................................................. 7  

Secondary Outcomes and Definitions .......................................................................................... 8  

Details of Sub-components of the Primary Perinatal Outcome .................................................. 10  

Additional Secondary Outcomes ................................................................................................ 11  

Sensitivity Analysis ..................................................................................................................... 12  

 2

Investigators  and  Study  Personnel  

In addition to the authors, other members of the Eunice Kennedy Shriver National Institute of Child Health
and Human Development Maternal-Fetal Medicine Units Network are as follows:
Northwestern University, Chicago, IL – A. Peaceman, B. Plunkett (NorthShore University), K. Paycheck
(NorthShore University), M. Dinsmoor (NorthShore University)
University of Alabama at Birmingham, Birmingham, AL – S. Harris, J. Sheppard, J. Biggio, L.Harper,
S.Longo (Ochsner), C. Servay (Ochsner)
University of Utah Health Sciences Center, Salt Lake City, UT – M. Varner, A. Sowles, K. Coleman (Utah
Valley Hospital), D. Atkinson (Utah Valley Hospital), J. Stratford (McKay-Dee Hospital), S. Dellermann
(McKay-Dee Hospital), C. Meadows (McKay-Dee Hospital), S. Esplin (Intermountain Med Ctr), C.
Martin (Intermountain Med Ctr), K. Peterson (Intermountain Med Ctr), S. Stradling (LDS Hospital)
Stanford University, Stanford, CA – C. Willson, D. Lyell, A. Girsen, R. Knapp
Columbia University, New York, NY – R. Wapner, C. Gyamfi, S. Bousleiman, M. Talucci, V. Carmona, L.
Plante (Drexel University), C. Tocci (Drexel University), B. Leopanto ( Drexel University), M. Hoffman
(Christiana Care), L. Dill-Grant (Christiana Care), K. Palomares (St. Peter’s Univ. Hosp.), S. Otarola
(St. Peter’s Univ. Hosp.), D. Skupski (NYP Queen), R. Chan (NYP Queens)
Brown University, Providence, RI – D. Allard, T. Gelsomino, J. Rousseau, L. Beati, J. Milano, E. Werner
University of Texas Medical Branch, Galveston, TX – A. Salzar, M. Costantine, G. Chiossi, L. Pacheco, A.
Saad, M. Munn, S. Jain, S. Clark
University of North Carolina at Chapel Hill, Chapel Hill, NC – K. Clark, J. Thorp, S. Timlin, K. Eichelberger
(Greenville Memorial Hospital), A. Moore (Greenville Memorial Hospital), C. Beamon (WakeMed
Health & Hospitals), H. Byers (WakeMed Health & Hospitals)
UT Health- University of Texas Medical School at Houston--Children's Memorial Hermann Hospital,
Houston, TX – F. Ortiz, L. Garcia (Harris Health System, Lyndon B. Johnson Hospital), B. Sibai
The Ohio State University, Columbus, OH – A. Bartholomew, C. Buhimschi, M. Landon, F. Johnson, L.
Webb, D. McKenna (Miami Valley Hospital), K. Fennig (Miami Valley Hospital), K. Snow (Miami Valley
Hospital), M. Habli (Good Samaritan Hospital), M. McClellan (Good Samaritan Hospital), C. Lindeman
(Good Samaritan Hospital)
MetroHealth Medical Center-Case Western Reserve University, Cleveland, OH – W. Dalton, D. Hackney
(University Hospital Cleveland), H. Cozart, A. Mayle, B. Mercer
University of Texas Southwestern Medical Center, Dallas, TX – L. Moseley, J. Gerald, L. Fay-Randall, M.
Garcia, A. Sias, J. Price
University of Colorado, Denver, CO – K. Hale, J. Phipers, K. Heyborne
University of Pennsylvania, Philadelphia, PA – J. Craig, S. Parry
Duke University, Durham, NC – T. Bishop, J. Ferrara
University of Pittsburgh, Pittsburgh, PA – M. Bickus, S.. Caritis
The George Washington University Biostatistics Center, Washington, DC – L. Doherty, J. de Voest
Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD – S.
Tolivaisa, M. Miodovnik

   
 3

Eligibility  Criteria  
Inclusion Criteria
• Nulliparous - no previous pregnancy beyond 20 weeks 0 days
• Singleton gestation. Twin gestation reduced to singleton, either spontaneously or therapeutically,
is not eligible unless the reduction occurred before 14 weeks 0 days project gestational age (see
below).
• 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 below
Exclusion Criteria
• Project gestational age at date of first ultrasound is > 20 weeks 6 days
• Plan for induction of labor prior to 40 weeks 5 days
• Plan for cesarean delivery or contraindication to labor
• Breech presentation
• Signs of labor (regular painful contractions with cervical change)
• Fetal demise or known major fetal anomaly
• Heparin or low-molecular weight heparin use during the current pregnancy
• Placenta previa, accreta, vasa previa
• Active vaginal bleeding greater than bloody show
• Ruptured membranes
• Cerclage in current pregnancy
• Known oligohydramnios, defined as amniotic fluid index < 5 cm or maximal vertical pocket < 2 cm
• Fetal growth restriction, defined as EFW < 10th percentile
• Known HIV positivity because of modified delivery plan
• Major maternal medical illness associated with increased risk for adverse pregnancy outcome
(e.g. any diabetes mellitus, lupus, any hypertensive disorder, cardiac disease, renal insufficiency)
• Refusal of blood products
• Participation in another interventional study that influences management of labor at delivery or
perinatal morbidity or mortality
• Delivery planned elsewhere at a non-Network site
Study Criteria for Determination of Gestational Age
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
47
Medicine 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 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.
 4

• 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.

Cutoffs for Using LMP to Determine Gestational Age for Sure LMP
Gestational age at first ultrasound by Ultrasound method of Ultrasound agreement with
LMP measurement 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

   
 5

Baseline  Cervical  Exam  and  Scoring  System  to  Derive  the  Modified  Bishop  Score  
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. The table below provides the scoring system that uses the following three components to derive
the modified Bishop score:
• Fetal station
• Cervical dilation
• Cervical length or effacement

Scoring System for the Modified Bishop Score

Using cervical length
Fetal station -3 cm -2 cm -1 - 0 cm 1 - 2 cm
(in relation to the ischial spines)
0 1 2 3

Cervical dilation 0 cm 1-2 cm 3-4 cm >4 cm

0 2 4 6

Cervical length* 3 cm 2 cm 1 cm 0 cm
(>2.5cm) (>1.5 -2.5cm) (>0.5 -1.5 cm) (≤ 0.5 cm)

0 1 2 3

Cervical Effacement* 0%-<25% 25%-<75% ≥ 75%

1 2 3

*Either cervical length or cervical effacement was used in the determination of modified Bishop score
based on which was used in documentation of the cervical examination.

   
 6

Patient  Management  
General considerations
Participants were enrolled from both University Hospitals and non-University (i.e., community) hospitals.
Antepartum and intrapartum providers included midwives, as well as family practice physicians and
obstetrician gynecologists. In some cases, participants were cared for and delivered by an “in-house”
physician, while in other cases obstetric providers were not stationed on the labor unit and came in for
delivery. Trainee (e.g., student, resident, and fellow) involvement occurred for some but not all patients.
Patients Randomized to Induction of Labor
When a participant with a favorable cervix was randomized to induction of labor and had not gone into
spontaneous labor or had an induction of labor or cesarean delivery for a medical indication prior to her
scheduled induction date between 39 weeks 0 days and 39 weeks 4 days project gestational age, she
was expected to be scheduled to undergo induction via oxytocin. Those with an unfavorable cervix
(modified Bishop score < 5) were expected to first undergo cervical ripening (method left to the discretion
of the patient’s obstetric provider) in conjunction with or followed by oxytocin unless a contraindication
arose.
The fetal heart rate was expected to be monitored while the patient was being induced (including
methods that employ pharmacologic ripening) as well as during labor, and patients were expected to stay
in the hospital until delivery once the induction (including ripening) was started. Fetal monitoring may
have included continuous wireless monitoring or intermittent monitoring per policies at each
center. Mechanical ripening using a Foley catheter without saline infusion and without concurrent
oxytocin was permitted without monitoring and could be used in an outpatient setting according to policies
at each center. Although not mandated, it was suggested to providers that women should be allowed at
least 12 hours in the latent phase after completion of any ripening, rupture of membranes, and use of
oxytocin before considering the induction “failed” and proceeding to cesarean delivery absent any acute
maternal or fetal indication.
Otherwise, no attempt was made to alter or mandate specific clinical management of the participants,
whether they were undergoing labor induction or were in spontaneous labor.
Patients Randomized to Expectant Management
If a participant was randomized to expectant management, she was expected to have at least weekly
follow-up visits with her provider and, unless a valid medical indication was present, to continue
pregnancy until at least 40 weeks 5 days. Antepartum fetal testing was expected to be initiated no later
than 41 weeks 6 days according to policies at each center.
All participants were expected to undergo delivery by 42 weeks 2 days project gestational age if
spontaneous labor or medical indications for delivery had not occurred. If undergoing induction of labor,
the management guidelines were identical to those randomized to the induction of labor group (above).
Otherwise, no attempt was made to alter or mandate specific clinical management of the subjects
whether they were undergoing labor induction or were in spontaneous labor.

   
 7

Compliance  with  Group  Assignment  

In the induction group, compliance to the intended protocol was defined as non-medically-indicated
induction occurring between 39 weeks 0 days to 39 weeks 4 days, spontaneous labor or medically-
indicated induction or cesarean on or before 39 weeks 4 days, or delivery after 39 weeks 4 days due to
medically-indicated delay (e.g., due to active herpes simplex virus) in delivery timing. In the expectant-
management group, compliance with the protocol was defined as spontaneous labor or medically-
indicated induction or cesarean on or before 42 weeks 2 days.

Reasons  for  Non-­‐compliance  with  Group  Assignment  

Reasons for non-compliance in the induction group included elective induction before 39 weeks 0 days
due to an induction scheduling error (n=2), elective induction after 39 weeks 4 days due to an induction
scheduling error or unavailability of labor and delivery room (n=37), delivery after 39 weeks 4 days due to
patient or provider preference (n=144), and cesarean without labor or medical indication (n=1). Reasons
for non-compliance in the expectant-management group included elective induction before 40 weeks 5
days due to a scheduling error (n=1), elective induction before 40 weeks 5 days due to patient or provider
preference (n=135), and cesarean without labor or medical indication (n=4).

   
 8

Secondary  Outcomes  and  Definitions    

Fetal and Neonatal Secondary Outcomes
1. Birth weight
2. Duration of respiratory support including ventilator, continuous positive airway pressure, high-flow
nasal cannula
3. Cephalohematoma (bleeding between the periosteum and skull)
4. Shoulder dystocia
5. Blood transfusion (other than for hyperbilirubinemia)
6. Hyperbilirubinemia requiring phototherapy or exchange transfusion
7. Hypoglycemia (glucose < 35 mg/dl) requiring IV therapy
8. Admission to neonatal intensive care unit or intermediate care unit
Maternal Secondary Outcomes
1. Cesarean delivery and indication
2. Incisional extensions at cesarean delivery, including J shape or T shape; or cervical traumas
3. Operative (vacuum or forceps) vaginal delivery and indication
4. Chorioamnionitis, defined as suspected or clinical diagnosis from start of labor to delivery
5. Third or fourth degree perineal laceration
6. Maternal death
7. Admission to intensive care unit
8. Preeclampsia/gestational hypertension
Gestational hypertension
Blood pressure elevation after 20 weeks of gestation in absence of proteinuria or systemic findings as defined
below
Preeclampsia without severe features
Elevated blood pressure (blood pressure ≥ 140 mm Hg systolic or ≥ 90 mm Hg diastolic) on 2 occasions at least 4
hours apart after 20 weeks gestation in a woman with previously normal blood pressure
AND
Proteinuria (≥ 300 mg per 24-hour urine collection [or this amount extrapolated from a timed collection] OR
protein/creatinine ratio ≥ 0.3 mg/dL OR dipstick reading 1+ [used only if other quantitative methods not available])
OR
in the absence of proteinuria, new-onset hypertension with the new onset of thrombocytopenia (platelet count <
100,000/microliter) OR renal insufficiency (serum creatinine > 1.1 mg/dL or a doubling of the serum creatinine
concentration in the absence of other renal disease) OR impaired liver function (elevated blood concentrations of
liver transaminases to twice normal concentration) OR pulmonary edema OR cerebral or visual symptoms
Preeclampsia with severe features
Elevated blood pressure (blood pressure ≥ 160 mm Hg systolic or ≥ 110 mm Hg diastolic), hypertension can be
confirmed within a short interval (minutes)
AND
Proteinuria (≥ 300 mg per 24-hour urine collection [or this amount extrapolated from a timed collection] OR
protein/creatinine ratio ≥ 0.3 mg/dL OR dipstick reading 1+ [used only if other quantitative methods not available])
OR
in the absence of proteinuria, new-onset hypertension with the new onset of thrombocytopenia (platelet count <
100,000/microliter) OR renal insufficiency (serum creatinine > 1.1 mg/dL or a doubling of the serum creatinine
concentration in the absence of other renal disease) OR impaired liver function (elevated blood concentrations of
liver transaminases to twice normal concentration) OR pulmonary edema OR cerebral or visual symptoms
Eclampsia
Preeclampsia with eclamptic seizures
 9

9. Postpartum hemorrhage, defined as any of the following:

• Blood transfusion
• Non-elective hysterectomy
• Use of two or more uterotonics (methergine, prostaglandin F2-alpha, prostaglandin E1) other
than oxytocin
• Other surgical interventions such as uterine compression sutures (B-lynch stitch), uterine
artery ligation, vascular embolization, hypogastric artery ligation, or uterine balloon or packing
• 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)
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
Patient-reported Outcomes
1. Feelings of control during childbirth, as measured by the Labour Agentry Scale
(Hodnett ED, Simmons-Tropea DA. The Labour Agentry Scale: psychometric properties of an
instrument measuring control during childbirth. Res Nurs Health 1987;10:301-10.)
2. Two questions regarding pain experienced during childbirth using a visual analog scale
(Ludington E, Dexter F. Statistical analysis of total labor pain using the visual analog scale and
application to studies of analgesic effectiveness during childbirth. Anesth Analg 1998;87:723-7.)
3. Breastfeeding and formula feeding

   
 10

Details  of  Sub-­‐components  of  the  Primary  Perinatal  Outcome  

Sub-components of the Primary Perinatal Outcome

Outcome Induction Expectant-
Group Management
(N = 3059) Group
(N = 3037)
no. (%)
Perinatal death 2 (0.1) 3 (0.1)
Antepartum stillbirth 1 (0.0) 1 (0.0)
Intrapartum stillbirth 0 (0.0) 0 (0.0)
Neonatal death 1 (0.0) 2 (0.1)
Respiratory support 91 (3.0) 127 (4.2)
Mechanical ventilation 15 (0.5) 18 (0.6)
Continuous positive airway pressure or high 84 (2.7) 117 (3.9)
flow nasal cannula
Cardiorespiratory resuscitation 4 (0.1) 4 (0.1)
Infection 9 (0.3) 12 (0.4)
Confirmed sepsis 5 (0.2) 1 (0.0)
Confirmed pneumonia 5 (0.2) 11 (0.4)
Birth trauma 14 (0.5) 18 (0.6)
Clavicular fracture 6 (0.2) 8 (0.3)
Skull fracture 0 (0.0) 1 (0.0)
Other fracture 0 (0.0) 0 (0.0)
Brachial plexus palsy 8 (0.3) 9 (0.3)
Other neurologic injury* 0 (0.0) 1 (0.0)
Facial nerve palsy 1 (0.0) 1 (0.0)
Retinal hemorrhage 0 (0.0) 0 (0.0)
Intracranial or subgaleal hemorrhage 9 (0.3) 7 (0.2)
Intraventricular hemorrhage grades III or IV 1 (0.0) 0 (0.0)
Subdural hematoma 7 (0.2) 2 (0.1)
Subarachnoid hematoma 2 (0.1) 0 (0.0)
Subgaleal hematoma 4 (0.1) 7 (0.2)
* Vocal cord paralysis
 

 
 11

Additional  Secondary  Outcomes  

Additional Secondary Outcomes

Outcome Induction Expectant- Relative Risk P
Group Management (95%CI)* Value†
(N = 3059) Group
(N = 3037)
Neonatal
Cephalohematoma – no. (%) 83 (2.7) 90 (3.0) 0.92 (0.68-1.23) 0.56
Shoulder dystocia – no. (%) 59 (1.9) 65 (2.1) 0.90 (0.64-1.28) 0.56
Duration of respiratory support – no. (%) 0.01‡§
0 day║ 2968 (97.0) 2911 (95.9)
1 day 55 (1.8) 70 (2.3)
>1 day 36 (1.2) 56 (1.8)
Length of hospital stay – no. (%)¶ 0.002‡§
<2 days 321 (10.5) 315 (10.4)
2 days 2030 (66.4) 1904 (62.8)
3 days 457 (14.9) 498 (16.4)
4 days 142 (4.6) 189 (6.2)
>4 days 107(3.5) 128 (4.2)
Maternal
Indication for cesarean delivery – no.
Dystocia 259 289
Non-reassuring fetal status 275 332
Other 35 53
Indication for operative vaginal delivery –
no.
Dystocia 101 94
Non-reassuring fetal status 119 156
Other 1 6
Venous thromboembolism – no. (%) 2 (0.1) 1 (0.0) 1.99 (0.26-26.8) 1.00
Uterine incisional extension at cesarean 28 (0.9) 48 (1.6) 0.58 (0.36-0.92) 0.02§
delivery – no. (%)¶
Breastfeeding status at 4-8 wk after delivery
– no. (%)¶
Breastfeeding 916 (33.2) 891 (33.1) reference
Breastfeeding and formula feeding 863 (31.3) 831 (30.8) 1.01 (0.89-1.15)# 0.88
Formula 981 (35.5) 972 (36.1) 0.98 (0.86-1.12)# 0.78
* Exact confidence intervals and p-values are provided for rare outcomes.
† The P-values and 95% CIs presented in this table have not been adjusted for multiplicity of comparisons
of secondary outcomes; those P-values that remain significant after adjustment using the false
discovery method are identified with superscript.
‡ Cochran-Armitage trend test.
§ Significant after controlling for multiple comparisons using the false discovery method.
║ One neonate had cardiorespiratory resuscitation and 0 days on mechanical ventilation, continuous
positive airway pressure or high flow nasal cannula.
¶ Neonatal length of hospital stay missing in 5 (2 induction group (IOL); 3 expectant-management group
(EM)); incisional extensions at cesarean section missing in 9 (5 IOL; 4 EM); breastfeeding status at 4-8
wk after delivery missing in 642 (299 IOL; 343 EM).
# Odds ratios from multinomial logistic regression.
   
 12

Sensitivity Analysis

Primary Perinatal Outcome

IOL EM RR (95%CI)
As analyzed with 10 missing data (3 in IOL 132 / 3059 164 / 3037
0.80 (0.64-1.00)
group and 7 in EM group) (4.3%) (5.4%)
Assumed percent of the missing with the
outcome is either 0% or approximately 30%:
IOL: 0/3 (0%) 132 / 3062 164 / 3044
0.80 (0.64-1.00)
EM: 0/7 (0%) (4.3%) (5.4%)
IOL: 1/3 (33%) 133 / 3062 164 / 3044
0.81 (0.65-1.01)
EM: 0/7 (0%) (4.3%) (5.4%)
IOL: 0/3 (0%) 132 / 3062 166 / 3044
0.79 (0.63-0.99)
EM: 2/7 (29%) (4.3%) (5.5%)
IOL: 1/3 (33%) 133 / 3062 166 / 3044
0.80 (0.64-1.00)
EM: 2/7 (29%) (4.3%) (5.5%)