Antibiotic Prophylaxis to Prevent Obesity-Related Induction Complications in Nulliparae at Term (APPOINT): A Pilot Randomized Controlled Trial
Phase: EARLY_PHASE1
Conditions: Obesity, Induction of Labor Affected Fetus / Newborn
Sponsor: University of Oklahoma

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
Antibiotic Prophylaxis to Prevent Obesity-Related Induction Complications in Nulliparae 
at Term (APPOINT): A Pilot Randomized Controlled Trial
Rodney K Edwards, MD, MS; Sabrina N Wyatt, MD; Stephanie L Pierce, MD, MS; Sarah 
Grimes, MD; Michelle L Norris, RN, BSN; Christina Zornes, MHR; Pravina Kota, MS; Katherine 
A Loeffler, BA; Jennifer D Peck, PhD
Abstract
Obesity increases the risk of pregnancy complications, including among others puerperal 
infections and cesarean delivery, and risk rises with increasing body mass index (BMI). Since 
obese women are more likely to have comorbidities that would necessitate delivery prior to their 
due date (i.e. prior to 40 weeks gestation), and class III obesity specifically is an indication for 
delivery by 39 weeks, these patients have a high rate of labor induction. In nulliparous women 
from the general population (obese and non-obese), labor induction at 39 weeks (compared to 
expectant management) is associated with less morbidity and a lower cesarean rate. Antibiotic 
prophylaxis, standard before cesarean delivery, is associated with less post-cesarean infection 
if azithromycin is added to the standard cefazolin. In this placebo-controlled pilot trial, we will 
estimate the parameters necessary to calculate the sample size for a planned multicenter 
clinical trial of prophylactic antibiotics administered at the start of labor inductions of obese 
nulliparous women at term.
Specific Aims
The aim of this study is to estimate the parameters necessary to calculate the sample size for a 
clinical trial of prophylactic antibiotics administered at the start of labor inductions of obese 
nulliparous women at term.
Background and Significance
More than one-third of American adults are obese (1). Obesity, defined as a body mass index 
(BMI) ≥30 kg/m2, increases the risk of pregnancy complications including hypertensive 
disorders, gestational diabetes, macrosomia, puerperal infection, cesarean delivery, and 
stillbirth (2-6). Risk of complications rises with increasing BMI (7), and women with class III 
obesity (BMI ≥40) have a risk of stillbirth that increases more sharply with advancing gestational 
age compared to women with lesser obesity (8). 
Consequently, since June 2014, the Section of Maternal-Fetal Medicine at the University of 
Oklahoma Health Sciences Center has had a policy of delivering women at 39 weeks for the 
indication of class III obesity. We recently evaluated this practice change in a before-and-after 
cohort study and found that the policy did not affect the overall cesarean rate among women 
with class III obesity or rates of maternal or neonatal morbidity (9). In addition, a large (n >6000) 
randomized controlled trial of labor induction at 39 weeks versus expectant management (until 
41 weeks) in low-risk nulliparous (including both lean and obese) women demonstrated that 
labor induction did not adversely affect neonatal morbidity but reduced the cesarean delivery 
and maternal morbidity rates (10). Therefore, we anticipate an increase in the rate of labor 
inductions. 

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
Nulliparous women with class III obesity undergoing induction of labor at our center have a rate 
of puerperal infection (chorioamnionitis, endometritis, and/or cesarean wound infection) of 20% 
(9). In addition, chorioamnionitis is associated with an increased likelihood of cesarean delivery 
due to labor dystocia (11). In our population of class III obese nulliparous women undergoing 
labor induction, the cesarean delivery rate is 52% (9). Women with lesser degrees of obesity 
also have increased rates of infection and cesarean delivery than lean women. 
Antibiotic prophylaxis is standard practice before cesarean delivery, since it results in lower 
rates of post-cesarean infection (endometritis and wound infection). A recent multicenter 
randomized controlled trial compared standard prophylaxis with intravenous cefazolin prior to 
the procedure to cefazolin and azithromycin; women in the trial were from the general obstetric 
population and were undergoing cesarean after labor and without the diagnosis of 
chorioamnionitis (12). The primary outcome (composite of endometritis and/or wound infection) 
was less likely with the expanded spectrum prophylaxis—12.0% compared to 6.1%, relative risk 
0.51 (95% confidence interval 0.38-0.68). Both endometritis and wound infection, individually, 
also were significantly less likely with expanded spectrum prophylaxis. There are also data 
regarding antibiotic prophylaxis during the postpartum period. One trial showed that giving 
antibiotic prophylaxis for 48 hours postpartum in women with obesity (class I, II and III) who 
underwent cesarean delivery was associated with a decreased risk of surgical site infection – 
15.4% in the placebo group vs 6.4% in the group receiving antibiotics, relative risk 0.41 (95% 
confidence interval 0.22-0.71) (13).
Antibiotic prophylaxis is not standard during labor inductions except as it relates to prevention of 
early-onset neonatal infection with group B streptococci (GBS) (14). That prophylaxis is with a 
narrow spectrum agent (penicillin or ampicillin). As mentioned above, there is a clear benefit of 
giving pre-operative antibiotic prophylaxis for patients undergoing cesarean delivery and also 
evidence for a reduction in surgical site infection in obese women receiving post-operative 
antibiotic prophylaxis. Therefore it is plausible that giving prophylactic antibiotics during labor 
induction to obese women, who are at higher risk for infection complications during and after 
labor and delivery, may decrease their risk for complications. We hypothesize that antibiotic 
prophylaxis given at the start of a labor induction in nulliparous women with obesity may reduce 
the rates of cesarean delivery and puerperal infection in this high-risk group. We propose to 
undertake a pilot randomized controlled trial to estimate the parameters necessary to calculate 
the sample size for a large, multicenter trial to test this hypothesis. 
Experimental Design and Methods
Trial Design
We will enroll consenting women delivering at The Children’s Hospital at OU Medical Center 
who meet enrollment criteria. Patients may be given information about the study during a third 
trimester prenatal care visit. However, they will be enrolled in the hospital before their labor 
induction is started. 
The study will be registered with clinicaltrials.gov. 

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
Inclusion criteria

BMI ≥30

No prior deliveries at or beyond 20 weeks gestation

Undergoing induction of labor

Gestational age 37 weeks or more

Age 15-45
Exclusion criteria

Fetal death prior to labor induction

Known fetal anomaly

Multiple gestation

Ruptured membranes for more than 12 hours

Chorioamnionitis or other infection requiring antibiotics at the start of the labor induction

Previous myometrial surgery

Allergy to azithromycin or beta-lactam antibiotics
Intervention
Women will be randomized 1:1 to receive either cefazolin 2 grams intravenously at the start of 
the labor induction and every 8 hours thereafter for a maximum of three doses and azithromycin 
500 mg intravenously once at the start of the labor induction or like placebos of each drug. We 
will enroll 300 patients total: 100 with class I obesity (BMI 30-34), 100 with class II obesity (BMI 
= 35-39), and 100 with class III obesity (BMI = 40 or above). There will be a separate 
randomization scheme for each obesity class. The allocation tables for the randomization 
sequences will be computer-generated in randomly chosen blocks of size 4 and 6  and provided 
to the research pharmacist, who will prepare and deliver the treatment packets in the randomly 
assigned order.. Investigators, clinical personnel and patients will be blinded to allocation. The 
research pharmacist will not be blinded to allocation.

Patients undergoing intrapartum cesarean delivery:
o
Per our institutional guideline, patients in whom intrapartum cesarean delivery is 
indicated will receive cefazolin 2 grams intravenously and azithromycin 500 mg 
intravenously within 60 minutes prior to skin incision, regardless of their assigned 
study group

Patients with chorioamnionitis diagnosed intrapartum:
o
Per our institutional guideline, patients with an intrapartum diagnosis of 
chorioamnionitis will be treated with ampicillin 2 grams intravenously every 6 
hours and gentamicin (dose based on weight) every 8 hours. If they deliver 
vaginally, both of those drugs will be discontinued after the first postpartum dose. 
If they undergo cesarean delivery, clindamycin 900 mg intravenously every 8 
hours will be started, and all three drugs will be continued for 24-48 hours 
postpartum. These antibiotic drugs (used to treat chorioamnionitis) will be in 
addition to receiving the assigned study drugs or placebo. Patients with 
chorioamnionitis who undergo cesarean delivery will also receive prophylactic 
azithromycin 500mg intravenously at the time of cesarean.

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
Primary outcomes (there will be two)

Cesarean delivery rate

Puerperal infection rate (chorioamnionitis, endometritis and/or cesarean wound infection)
Secondary outcomes

Other maternal complications
o
Individual infections above
o
Postpartum hemorrhage
o
Blood transfusion
o
Intensive care unit admission
o
Indications for cesarean delivery
o
Length of maternal hospital stay
o
Length of neonatal hospital stay
o
Maternal hospital readmission within 30 days after delivery

Neonatal complications (established composite of neonatal morbidities)
Definitions

Chorioamnionitis will be defined clinically by 1) a maternal temperature of 38.0 degrees 
Celsius or higher plus one or more of a) maternal heart rate over 100, b) baseline fetal 
heart rate over 160, c) fundal tenderness, d) purulent amniotic fluid, or 2) antibiotics 
administered for that indication.

Endometritis will be defined clinically by 1) a maternal temperature of 38.0 degrees 
Celsius or higher plus uterine tenderness and/or foul-smelling lochia; or 2) antibiotics 
administered for that indication within 30 days after delivery.

Cesarean wound infection will be defined according to the Centers for Disease Control 
and Prevention’s National Healthcare Safety Network definitions for surgical site 
infections if occurring within 30 days after delivery and classified accordingly as 
superficial, deep and/or organ space (15). 
Gender/Minority/Pediatric Inclusion for Research
Since only women become pregnant and undergo labor induction, all subjects in this study will 
be pregnant woman and fetus/infant dyads. The inclusion of minorities is anticipated in keeping 
with the racial/ethnic distribution of our obstetric population. Therefore, we anticipate including 
about 15% African-Americans, 45% Caucasians, 29% Hispanics, and 11% of other ethnicities.
Human Participants
Women with scheduled labor inductions will be screened by study personnel for eligibility. They 
will be approached about participation when they present for their scheduled induction. Since 
these women will not be in labor and it will be emphasized that participation is not required, 
coercion should not be an issue. Those women agreeing to participate will be consented by 
trained study personnel in their preferred language. We will have both English and Spanish 
consent forms. 
Because we will have consent forms in both English and Spanish, and since our patient 
population is 29% Hispanic, we anticipate enrolling non-English speaking participants. In 

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
addition to the Spanish consent form, hospital translation services will be utilized.
This study will include 300 female patients ages 15-45 who will meet the above enrollment 
criteria. We will recruit 100 women with class I obesity, 100 women with class II obesity, and 
100 women with class III obesity. No specimens will be collected. Clinical data will be recorded 
at the time of enrollment. Clinical data will also be abstracted later from the medical record. A 
data collection form is attached.
The patient’s treating physician will discuss the treatment options and the risks and benefits of 
participating in this clinical trial. The patient will have the opportunity to review the consent and 
ask questions, and these questions will be answered to the patient’s satisfaction. Patients will 
be given adequate time to consider participation in the study and will in no way be coerced into 
participating.
Participants will be contacted via phone by a member of the research team at 30 days after 
delivery to assess for occurrence of any of the primary or secondary outcomes at a location 
outside of our institution.
Risks/Benefits
Risks to participants are largely those that would occur during the labor induction that the 
patient would be undergoing if not enrolled in the study. These risks will be similar in women 
with each class of obesity (I, II, and III) and include risk of prolonged labor or cesarean delivery; 
these risks would be present during the labor induction whether or not the patient is enrolled in 
the study. There is a risk of allergic or other adverse reaction to the prophylactic antibiotics that 
are the study intervention, however known allergy to either study drug will be an exclusion 
criteria for participation in the study. The likelihood of allergic reaction should be on the order of 
1 in 100,000 to 1 in 1,000,000. 
The potential benefits of enrolling in the study would result from being randomized to the active 
drug group if our hypothesis turns out to be true related to one or both of the primary outcomes. 
The above risks are reasonable in relation to benefits, since the likelihood of adverse events is 
low and since most similar patients not included in the study will be exposed to the same 
antibiotics during the delivery admission.
To protect the privacy and confidentiality of research subjects, we will assign each participant a 
study ID number in REDCap. This ID number will be linked to the patient’s name and medical 
record number only via a key that will be maintained in a locked file drawer in the research 
coordinator’s locked office. Once data collection is complete, the key will be destroyed, and the 
de-identified data will not be able to be linked to participants. Researchers will protect against 
loss of confidentiality by keeping all data containing PHI in a locked cabinet or on a password-
protected, encrypted computer. Only key personnel will have access to PHI. Interactions and 
data analysis will be held in a private area.
Data and Safety Monitoring Plan
All adverse events will be reviewed by the PI and co-investigators and reported to the IRB 
according to institutional guidelines. All research data will be stored on a password-protected 
computer in the administrative offices of the Section of Maternal-Fetal Medicine. Any paper 
records and CRFs will be stored in a locked file drawer in the locked office of the research 
coordinator that is also located in the administrative offices of the Section of Maternal-Fetal 
Medicine. Since this study is a pilot which initially included only 100 participants, we did not 

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
assemble a Data and Safety Monitoring Board. With the inclusion of an additional 200 patients, 
we will convene a Data and Safety Monitoring Board. The DSMB will consist of three 
participants: two Obstetrics and Gynecology physicians and one statistician. No members of the 
DSMB will be co-investigators or key personnel on this study. The DSMB has met prior to this 
submission and has established a charter document (see attached). The DSMB will convene 
every six months to review data and assess risk-benefit ratio of the study intervention, and will 
also meet as needed to review any study-related adverse events.  Prior to each DSMB meeting, 
the PI will provide information regarding protocol adherence, outcome variables, adverse 
events, recruitment, and data quality. At the twice yearly review, the DSMB may vote to modify 
the protocol or terminate study. 
Statistical Analysis
We will enroll 300 women total: 100 women with class I obesity, 100 women with class II 
obesity, and 100 women with class III obesity. As previously mentioned, no sample size 
calculation has been performed since this is a pilot trial designed to estimate the parameters 
necessary to calculate the sample size for a large, multicenter trial. The enrollment numbers for 
the class I and II groups were chosen to match that of the original class III obese group. Since 
the sample sizes in each of the obesity classes will be 50 (n=50 in the placebo groups and n=50 
in the active drug groups), the confidence limit around the proportions will be less than or equal 
to ±13%. In addition, practically speaking we have chosen a small enough number so as to limit 
the number of patients exposed to the potential study-related risks, but substantial enough to 
allow meaningful estimation of study parameters. This plan for sample size and analysis has 
been created with the collaboration of our statistician. We will not stratify the randomization by 
whether or not prophylaxis against early-onset neonatal infection with GBS is indicated at the 
beginning of the labor induction (due to known colonization). However, we will perform a 
secondary analysis stratified by whether GBS prophylaxis was received.
In total there will be 150 each in the placebo and active drug groups (for each of the 
three obesity classes, there will be 50 each in the placebo and active drug groups). We 
anticipate the rate of GBS prophylaxis to be 25-30%. Even if it is as high as 40%, there will be 
90 women each in the placebo and active drug groups who were not also exposed to GBS 
prophylaxis.
For each of the three obesity classes separately, we will estimate the frequency of the primary 
outcomes in the placebo and active drug groups. Proportions and ninety-five percent confidence 
limits will be calculated for each of these outcomes. We will perform within-group comparisons 
of outcomes in the placebo and active drug groups for each of the three obesity classes 
individually. We will also perform a comparison of outcomes in the placebo and active drug 
groups using BMI as a continuous variable in order to determine whether there is a BMI cut 
point at which the antibiotic intervention significantly reduces infection complications. In addition 
to the co-primary outcome variables, this BMI evaluation will inform design of the next-step, 
larger multicenter trial. 

IRB NUMBER: 9939
IRB APPROVAL DATE: 03/02/2020
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