The REDUCED-I Pilot Trial: REDucing the Utilization of CEsarean Sections With Induction
Phase: NA
Conditions: Induced; Birth
Sponsor: University of Calgary

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
Protocol ID: REB21-0614 
NCT05037617 
Version 3, October 15, 2021 
 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
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BACKGROUND: The cesarean section (CS) epidemic appears to be continuing unabated and 
rising rates are being observed in the developing world. Recent data suggests that 21% of births 
worldwide are by CS and that this rate has doubled since 2000(1). While there is no doubt that 
CS is lifesaving in many circumstances for both mothers and babies, CS rates have risen 
significantly without any corresponding improvement in outcomes. CS, while protective of some 
pelvic floor outcomes, increases the rates of abnormal placentation in subsequent pregnancies, 
which increases the risk of severe maternal morbidity and hysterectomy(2). Reducing the risk of 
CS has proved challenging, and no clearly effective interventions have been identified in clinical 
trials(3, 4). Modelling studies suggest that the target population to reduce the overall CS rate 
should be first time mothers(5). 
 Currently the rate of CS in first time mothers with singleton fetuses ≥35 weeks with 
cephalic presentation being induced in Alberta is 32.6%(6). This has increased from 23.1% in 
1992 and a recent study from our group found that increasing CS for fetal distress are the most 
important factor in explaining this rise(7). Induction of labor often overstimulates uterine 
contractions (hyperstimulation) and can lead to fetal distress. Therefore, an intervention to 
decrease uterine hyperstimulation may lead to a reduction in fetal distress and therefore CS.  
Additionally, uterine hyperstimulation can lead to the reduction of oxygen transport to the fetus 
potentially leading to asphyxia and hypoxic-ischemic encephalopathy (HIE) which can result in 
chronic neurodevelopmental impairment.  
 
For the vast majority of women who are induced in Alberta (and worldwide), this is 
accomplished by intravenous oxytocin. An approach that could reduce uterine hyperstimulation 
with induction of labor is to discontinue the oxytocin infusion once the active phase of labor is 
reached. This is consistent with bench research that shows that oxytocin stimulates prostaglandin 
production in the chorio-decidua, which induces positive feedback loops to continue 
production(8). Furthermore, this idea has been tested in a number of small single centre clinical 
trials with encouraging results. The 10 trials to date have been summarized by two meta-
analyses(9, 10). The number of randomized subjects was modest n=1,538 and the sample sizes 
ranged from 100-250. Most of trials were not of high quality with either high or unclear risk of 
bias. Only two of the trials were in populations comparable to Canada: one in Europe and one in 
the USA(11, 12).  All trials that reported CS rates documented a reduction with oxytocin 
discontinuation; pooled OR 0.64 (0.48–0.87). The USA trial observed a reduction in the rate of 
CS with oxytocin discontinuation compared to continuing from 19.2% (24/125) to 25.2% 
(32/127) and the European trial the rates were 15% (15/100) vs 22% (22/100). The baseline rates 
of CS are comparable to our population and the differences they observed were clinically 
significant. The meta-analyses also observed reductions in the rates of uterine hyperstimulation 
with oxytocin discontinuation 0.53 (0.33–0.84). While these results are promising, a definitive 
large randomized controlled trial (RCT) is required to assess important safety outcomes. We 
propose an initial small pilot study, which will allow us to refine our protocol and will ensure the 
success of a large multi-centre cluster RCT.  Additionally, we also wish to examine serial urine 
prostaglandin (PG) metabolite levels in a subset of the study population. Our group has 
completed a large study of PG metabolites (unpublished data) in over 200 women pre-labor and 
in labor. We have found that prostaglandin F and E metabolites are increased during induced and 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
Page 3 of 8 
 
 
 
spontaneous labor. We hypothesize that patients who do not need oxytocin restarted may have 
higher levels or will not have a drop in their urinary PG metabolites. This data could help with 
improving compliance in future trials. This will also permit a precision medicine approach 
whereby in the larger trial, the intervention can be offered to those women most likely to benefit. 
AIMS: In this REDucing the Utilization of Cesarean sections with Induction (REDUCE-I) Pilot 
Trial, we propose to answer the following question: Does discontinuation of oxytocin during the 
active stage of labor (≥6 cm dilation) decrease the rate of cesarean section (CS) in induced 
primiparous women, at term (≥37 weeks), with a cephalic presenting singleton fetus without 
increasing maternal or neonatal morbidity?   
METHODS: The REDUCE-I Pilot Trial is a randomized controlled trial (RCT). 
 
Proposed interventions: We will use the modern definition to define the active stage of labor to 
be ≥6 cm dilation(13). The intervention will be to stop oxytocin infusion when a dilation of ≥6 
cm has been documented. The intervention will be continued until delivery unless contractions 
decrease to less than 2 in 10 minutes or if no further cervical dilation is noted 4 hours after 
discontinuation.  
 
Randomization: A computer-generated random allocation sequence will be created by the study 
statistician. Randomization will stratified by need for cervical ripening and randomization will 
be blocked. Randomization will take place prior to the initiation of oxytocin.  
 
Blinding: Once a patient is found to be ≥6 cm dilation, the study medication will be initiated. 
Pharmacy will make up identical vials of oxytocin or saline, which will be numbered according 
to the random allocation sequence created by the study statistician. Nurses will use the blinded 
vials for ongoing infusion. Patients and caregivers will be blinded. 
 
Inclusion/exclusion criteria: Primiparous women 18 years old or older, at term (≥37 weeks) 
with a cephalic presenting singleton fetus undergoing induction of labor with oxytocin. Multiple 
pregnancies and known fetal congenital or chromosomal anomalies will be excluded.  
 
Duration of treatment: The treatment period will continue until delivery. If the frequency of the 
patient’s contractions are reduced to less than 2 in 10 minutes or there has been no change in 
dilation for 4 hours then oxytocin can be restarted. 
 
In the event a physician or midwife makes a decision to stop the study medication, they have the 
option to become unblinded by making a request to pharmacy to make it easier for them to know 
at what dose to continue or re-start oxytocin. 
 
Duration of follow up:  Maternal and neonatal follow up until discharge. Postpartum 
readmission and outcomes will be obtained up to 4 weeks postpartum. 
 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
Page 4 of 8 
 
 
 
Primary outcomes: 1) CS in labor. 2) Uterine hyperstimulation (occurrence of >5 contractions 
in 10 minutes). 3) Proportion of screened subjects who agree to enroll in the trial. 
Secondary outcomes: Adverse neonatal and maternal outcomes including: 
Neonatal: a) Perinatal death; b) Neonatal asphyxia: intrapartum stillbirth or neonatal death from 
asphyxia (Perinatal Society of Australia and New Zealand coding)(14) or NICU admission and at 
least two of: i. Apgar score of ≤5 at 10 minutes; ii. Mechanical ventilation or chest compressions 
for resuscitation within 10 minutes; iii. Cord pH <7.00 (venous or arterial), or arterial base 
excess ≥12 at birth; c) moderate or severe asphyxia (Sarnat)(15) or meets criteria for therapeutic 
cooling; and d) sepsis or suspected sepsis. 
 
Maternal: a) postpartum hemorrhage (PPH); b) blood transfusion; c) postpartum uterine 
artery/pelvic artery embolization; d) postpartum hysterectomy; and e) postpartum maternal 
intensive care unit (ICU) admission. 
 
Compliance: Duration of oxytocin discontinuation. Rate of reintroduction of oxytocin infusion. 
 
Urine Prostaglandin metabolites: Urine samples will be collected every 2 hours during labor 
from a minimum of 13 women in the intervention group and a minimum of 13 women in the 
control group. Samples will be aliquoted, frozen, and stored at -80°C prior to analysis. The 
following five assays will be performed: Prostaglandin E2 ELISA kit (Cayman 514010); 
Prostaglandin E2 metabolite ELISA kit (Cayman 514531); Prostaglandin F2α ELISA 
Kit(Cayman 516011),PGF2a metabolite, 13,14-dihydro-15-keto Prostaglandin F2α ELISA Kit 
(Cayman 516671); and creatinine ELISA kit. Assays will be performed according to 
manufacturer instructions with appropriate dilutions.  
 
Measurement of Outcomes: The primary and secondary outcomes will be obtained by detailed 
chart review by an experienced nurse blinded to allocation. To assess neonatal outcomes, such as 
hypoxic-ischemic encephalopathy (HIE), data will be obtained by linkage to a specialized 
asphyxia database in Calgary. This database has collected data on all neonates in Calgary 
diagnosed with HIE since 2010. Loss to follow-up is not applicable for the current trial as data 
on all hospital-based deliveries are routinely captured in the medical chart. 
 
Sample Size: The proposed sample size is 200. Approximately 1250 primiparous women are 
induced each year at Foothills Medical Centre; their CS rate is approximately 30%.  A sample of 
200 subjects has 30% power to detect an absolute difference of 10% in CS rate and 44% power 
to detect a difference consistent with previous trials. While under-powered for clinical outcomes, 
this pilot RCT will allow us to determine an effect size in our population (which will be required 
to perform a sample size calculation for a larger trial) and will allow us to assess the feasibility of 
moving forward with a larger study. 
 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
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Recruitment: We would expect approximately 1250 primiparous women to be induced at 
Foothills Medical Centre (FMC) over the study period, therefore, we are anticipating 
approximately a 16% recruitment rate. 
 
Compliance: Compliance to the treatment is a potential problem. Not all previous studies 
reported compliance but it is noteworthy that in the USA study that oxytocin was continued in 
25% of subjects randomized to discontinuation and restarted in a further 25%(12).  This may 
have been due to concerns regarding the potential adverse effects of longer labor. We note that 
all the previous studies were performed prior to the release of recent guidelines on labor 
management (13), which advocated for accepting slow progress in labor and allowing longer 
labors. These recent guidelines were the intervention we tested in the REDUCED trial, a 
clustered multi-centre trial which is now completed. Our results did not find any evidence of 
increased maternal or neonatal risks with longer labors. The intervention site for this study 
(Foothills Medical Centre [FMC]) was a control site but we plan to move toward adoption of the 
guidelines at FMC over the next 3-6 months (pandemic permitting). We anticipate that our data 
will alleviate physician concerns regarding longer labors and encourage patience in managing 
labor. 
 
Location: Two academic centres will be used for the pilot: FMC in Calgary will be the treatment 
site, and Royal Alexandra Hospital in Edmonton will be used as a contemporaneous non-
intervention control site. 
 
Statistical Analysis: The analysis will be conducted independently by the study statistician 
(Dr. Brant). The primary outcome will not be changed during analysis. The trial, with an explicit 
statement of the primary outcome, will be registered at clinicaltrials.gov. For dichotomous 
outcomes relative risks will be calculated and Fisher exact test will be used to assess statistical 
significance. For continuous outcomes mean differences will be assessed with t-tests after 
appropriate transformations. Sub-group analysis will be performed by need for cervical ripening. 
The analyses will be conducted after recruitment for the pilot study has been completed. We will 
conduct a differences-in-differences analysis using contemporanous control data from the Royal 
Alexandra Hospital in Edmonton to monitor for temporal trends in outcomes and changes in 
labor management. 
 
Timeline: This study will be completed in two years (see figure).  
 
EXPERTISE, EXPERIENCE & RESOURCES: We are a strong interdisciplinary and well-
established team with expertise in obstetrics, epidemiology, neonatology, molecular biology, 
clinical trials, and biostatistics. The principal applicant (Dr. Stephen Wood, 
Obstetrician/Epidemiologist) will be responsible for directing trial. The co-principal applicant 
(Dr. Amy Metcalfe, Epidemiologist) will co-manage the trial and will analyze the results of the 
Childbirth Experience Questionnaire 2 (CEQ2). The data will be collected and prepared for 
analysis by Ms. Selphee Tang and Ms. Susan Crawford (Epidemiologist for APHP). The 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
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neonatal HIE data will be obtained by the study neonatologist (Dr. Khorshid Mohammad). The 
co-principal applicant, Dr. Donna Slater will supervise the measurement of the urinary 
prostaglandins. The analysis will be carried out independently by the study statistician (Dr. 
Rollin Brant). Two clinical collaborators, Dr. Philippa Brain and Dr. Jennifer Soucie from the 
obstetrics group at FMC will aid in recruitment.  
ALIGNMENT WITH THE CHW STRATEGY AND RELEVANT PROJECT METRICS: 
Our research project is aligned with the Maternal and Child Health research program, which is 
outlined in University of Calgary’s Child Health and Wellness Strategy(19). Safely decreasing 
the cesarean section rate 
in induced women will 
benefit maternal and 
infant health. As 
described above, 
cesarean sections 
increase the risk of 
severe maternal 
morbidity and 
hysterectomy, and CS 
may impact the 
development of the 
normal neonatal 
microbiome, which may 
have long term effects on 
child health. In addition, 
discontinuation of oxytocin during the active phase of labor may decrease the risk of neonatal 
asphyxia, which can have devastating and long-term consequences to child health.  
Our project is relevant to the Better Beginnings grand challenge area in child health and 
wellness, which is related to optimizing maternal, fetal, newborn and child health with accurate 
prediction, prevention, and interventions. If successful, this trial will prevent cesarean sections, 
which will provide infants the best start in life and improvements to maternal health. We will be 
utilizing two approaches to solving this grand challenge. As a registry-based trial, we will be 
‘harnessing big data for optimal child outcomes’ given that we are using the Alberta Perinatal 
Health Program database, as well as the southern Alberta asphyxia database, to obtain most of 
the data for our project. Secondly, we will be ‘transforming health care for children and families’ 
as this clinical intervention is designed to change the way care is delivered.  
SUSTAINABILITY: If REDUCE-I suggests a safe reduction in the CS rates, we will apply to 
CIHR for a Project Scheme grant for a multi-center randomized controlled trial to test this 
intervention in our trial network from the REDUCED trial.  
 
 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
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REFERENCES 
1. 
Boerma T, Ronsmans C, Melesse DY, Barros AJD, Barros FC, Juan L, et al. Global 
epidemiology of use of and disparities in caesarean sections. Lancet. 2018;392(10155):1341-8. 
2. 
Keag OE, Norman JE, Stock SJ. Long-term risks and benefits associated with cesarean 
delivery for mother, baby, and subsequent pregnancies: Systematic review and meta-analysis. 
PLoS Medicine / Public Library of Science. 2018;15(1):e1002494. 
3. 
Hartmann KE, Andrews JC, Jerome RN, Lewis RM, Likis FE, McKoy JN, et al. 
Strategies to Reduce Cesarean Birth in Low Risk Women. AHRQ Publications. 
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4. 
Betran AP, Torloni MR, Zhang JJ, Gulmezoglu AM, WHO Working Group on Caesarean 
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5. 
Le RC, Blondel B, Prunet C, Khireddine I, Deneux-Tharaux C, Goffinet F. Stabilising the 
caesarean rate: which target population? BJOG: an International Journal of Obstetrics & 
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6. 
Skiffington J, Metcalfe A, Tang S, Wood SL. Potential Impact of Guidelines for the 
Prevention of Cesarean Deliveries in a Contemporary Canadian Population. Journal of obstetrics 
and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 
2020. 
7. 
Wood S, Tang S. Changes in the Frequency of Cesarean Delivery in Nulliparous Women 
in Labor in a Canadian Population, 1992-2018. . 2021;137(2):263-70. 
8. 
Fuchs AR, Fuchs F, Husslein P, Soloff MS, Fernstrom MJ, Fuchs AR, et al. Oxytocin 
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9. 
Saccone G, Ciardulli A, Baxter JK, Quinones JN, Diven LC, Pinar B, et al. Discontinuing 
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10. 
Boie S, Glavind J, Velu AV, Mol BWJ, Uldbjerg N, de Graaf I, et al. Discontinuation of 
intravenous oxytocin in the active phase of induced labour. Cochrane Database of Systematic 
Reviews. 2018;8:CD012274. 
11. 
Bor P, Ledertoug S, Boie S, Knoblauch NO, Stornes I. Continuation versus 
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12. 
Diven LC, Rochon ML, Gogle J, Eid S, Smulian JC, Quinones JN. Oxytocin 
discontinuation during active labor in women who undergo labor induction. American Journal of 
Obstetrics & Gynecology. 2012;207(6):471.e1-8. 
13. 
Caughey AB, Cahill AG, Guise JM, Rouse DJ. Safe prevention of the primary cesarean 
delivery. Am J Obstet Gynecol. 2015;210(3):179-93. 
14. 
Chan A, King JF, Flenady V, Haslam RH, Tudehope DI. Classification of perinatal 
deaths: development of the Australian and New Zealand classifications. Journal of paediatrics 
and child health. 2004;40(7):340-7. 

The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction  
 
 
Ethics ID: REB21-0614 
Study Title: The REDUCE-I Pilot Trial: REDucing the Utilization of CEsarean sections with Induction 
PI: Dr. Stephen Wood  
Version 3 & Version date: October 15, 2021 
 
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15. 
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and 
electroencephalographic study. Archives of Neurology. 1976;33(10):696-705. 
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Walker KF, Dencker A, Thornton JG. Childbirth experience questionnaire 2: Validating 
its use in the United Kingdom. European Journal of Obstetrics & Gynecology and Reproductive 
Biology: X. 2020;5:100097. 
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Spong CY, Berghella V, Wenstrom KD, Mercer BM, Saade GR. Preventing the first 
cesarean delivery: summary of a joint Eunice Kennedy Shriver National Institute of Child Health 
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Obstetricians and Gynecologists Workshop. Obstetrics & Gynecology. 2012;120(5):1181-93. 
18. 
Wood S, Crawford S, Hicks M, Mohammad K. Hospital-related, maternal, and fetal risk 
factors for neonatal asphyxia and moderate or severe hypoxic-ischemic encephalopathy: a 
retrospective cohort study. The Journal of Maternal-Fetal & Neonatal Medicine. 2019:1-6. 
19.         University of Calgary. 2020. Child Health and Wellness Strategy. 59 pages.