High Dose and Low Dose Oxytocin Regimen as Determinants of Successful Induction: A multicenter comparative study

Background Induction of labor by Oxytocin is a routine obstetric procedure. However, little is known regarding the optimal dose of oxytocin so as to bring successful induction. This study is aimed at comparing the effect of high dose versus low dose oxytocin regimen on success of induction. Methods Hospital based comparative cross-sectional study was conducted in four selected hospitals in Ethiopia from October 1, 2017 to May 30, 2018. A total of 216 pregnant women who undergo induction of labor at gestational age of 37 weeks and above were included. Data was entered into Epi-data version 3.1 and then exported to SPSS version 20 for cleaning and analysis. Chi-square test and logistic regression were done to look for determinants of successful induction. The result is presented using 95% con�dence interval of crude and adjusted odds ratios. P-value < 0.05 was used to declare statistical signi�cance. Result Mean “Induction to delivery time” was 5.9 hours and 6.3 hours for participants who received high dose Oxytocin and low dose Oxytocin respectively. Higher successful induction (72.2% versus 61.1%) and lower Cesarean Section rate (27.8% vs. 38.9) was observed among participants who received low dose Oxytocin compared to high dose. Favourable bishop score [AOR 4.0 95% CI 1.9, 8.5], elective induction [AOR 0.2 95% CI 0.1, 0.4], performing arti�cial rupture of membrane [AOR 10.1 95% CI 3.2, 32.2], neonatal birth weight of < 4Kg [AOR 4.3, 95% CI 1.6, 11.6] and being parous [AOR 2.1 95% CI 1.1, 4.0] were signi�cantly associated with success of induction. Conclusions : In this study, oxytocin regimen didn’t show signi�cant association with success of induction. But, high dose oxytocin regimen is signi�cantly associated with slightly shorter induction to delivery time. Favourable bishop score, emergency induction, performing arti�cial rupture of membrane and delivery to non-macrosomic neonate are positive determinants of


Introduction
Induction of labor (IOL) refers to the iatrogenic stimulation of uterine contractions before the onset of spontaneous labor to accomplish vaginal delivery (VD) [1,2].Use of Oxytocin for labor induction is one of the most frequently used medications in obstetrics.This synthetic polypeptide hormone has been used to stimulate uterine contractions since 1950s after synthesized for the rst time in 1953 by Vincent du Vigneaud [2][3].
Oxytocin regimen can be classi ed as high-dose or low-dose based on different parameters.These are amount of starting dose, rate of incremental dose and intervals of escalation [4,5].The high-dose regimens varied across the different trials; starting doses ranged from 4-10 mili-unit/minute (mU/min), with increases in dose ranging from 4-7 mU/min and maximum rates ranging from 4-90 mU/min.The Low-dose regimen commences infusion at a range of 1-4 mU/min, with rate increases ranging from 1-2 mU/min and maximum rates ranging between 1-31.7mU/min as mentioned in one systematic review which reviewed many randomized trials [4].Intervals of escalation of oxytocin doses vary from 15 to 60 minutes across the trials [1,[4][5][6][7][8][9][10][11][12].
Worldwide, there is neither agreement on standard oxytocin regimen nor strong evidence to recommend a particular dosage of oxytocin regimen for labor induction [5,12].However, one meta-analysis conducted in 1998 supports the use of a low-dose oxytocin infusion for IOL [3].In Ethiopia, although very few studies were conducted to assess rate and determinants of induction success, there was no comparative study done to evaluate the effects of the two oxytocin protocols on success of induction.The present study is, therefore aimed at comparing the effect of these oxytocin regimens on success of induction.

Study area and study period
Comparative cross-sectional study was conducted in 4 hospitals namely Jimma University Medical Centre (JUMC), Shanan Gibe general hospital, Arbaminch General Hospital and Kuyu General Hospital from October 1 to May 30,2018.JUMC is the specialized teaching referral hospital where high dose oxytocin regimen is used for IOL while the three general hospitals use low dose oxytocin regimen.

Study population
Pregnant women with singleton gestation who undergo induction of labor at gestational age (GA) of 37 weeks and above were recruited while those pregnant mothers with Intra Uterine Fetal Death (IUFD), critically ill pregnant mothers, pregnant mothers with lethal congenital anomaly, pregnancies complicated by cord prolapse, induced pregnancy for whom C/S was done for non-obstetric indication like social reason were excluded from the study.

Sample size & sampling technique
The required sample size was determined by using double population proportion considering the following parameters: Proportion of C/S among laboring mothers who received high dose of oxytocin (10.4%) and proportion of C/S among laboring mothers who received low dose of oxytocin (25.7%) [7], 5% level of signi cance, power of 80% and 1:1 ratio of exposed to un-exposed.Considering 10% for non-response, 108 laboring mothers were recruited for each group.Thus, 108 pregnant women were recruited from JUMC while the rest 108 (36 from each) pregnant women were recruited from three general hospitals.All pregnant women who had undergone induction of labor during study period were recruited consecutively using inclusion criteria.

Data collection, entry and analysis
Data was collected by trained midwifes using pretested structured questionnaire.Data like induction to delivery time, outcomes of induction (successful or failed), and mode of delivery, Oxytocin regimen, Bishop Scores and gestational age were collected from records of patient while socio -demographic data were collected by interviewing patients.
Data were edited and entered into Epi data version 3.1 and then exported to SPSS version 20 for cleaning and analysis.Chi-square test was conducted to compare participants who received high dose oxytocin and low dose oxytocin in terms of outcome data (route of delivery and outcomes of induction).Bivariate and multivariable logistic regression analyses were conducted to identify determinants of the successful induction.Findings were presented using 95%CIs of crude and adjusted odds ratios.P-value < 0.05 was used to declare statistical signi cance.

Ethical considerations
Ethical clearance to conduct the research was obtained from institutional review board of Jimma University and written consent was obtained from study participants.All the information collected from the study participants were handled con dentially by omitting their personal identi ers and the data was used for the research purpose only.Participants were told by the language they understand that they have the right to participate in or withdraw from the study.In this research, the following operational de nitions were used.

Operational de nitions
Successful Induction: If a woman delivered vaginally with or without aid of instrument after induction with oxytocin.

Socio-demographic, reproductive and obstetric characteristics of study participants
A total of 216 pregnant women participated in the study in four hospitals.A total of 3162 mothers have delivered in JUMC during the study period of which 302 mothers undergo induction making prevalence of induction 9.5% at JUMC.Mean age of study participants is 26 years and is similar among the two study groups.One third 78 (36.1%) of the study participants are rural dwellers.
Overall mean gestational age at delivery for all participants was 39.4 weeks which is also the same for the two study groups.Majority 176(82%) of the inductions were undergone on emergency basis.The top three indications for IOL in this study were PROM 128 (59.3%), hypertensive disorders of pregnancy (HDP) 49 (22.7%) and post-term pregnancy 27 (12.5%)while the others accounted for 12 (5.6%).The indication for IOL is similar among the two study groups.Majorities of the participants enrolled in LDG 65(60.2%)have favorable bishop score at initiation of induction unlike those enrolled in HDG which was observed only in 14(13%) (Table2) %) [5] and in one other double masked randomized oxytocin trial (6.0% & 6.1%) [9].However, rate of failed induction was generally higher in our study compared to those studies.This might be due to the fact that the studies were following different protocols in relation to total duration of hours waited to diagnose failed induction.In this study failure to acquire either adequate uterine contraction or failed to show favorable cervical changes despite being on oxytocin drip for a period of six to eight hours is used to diagnose failed induction.But other centers in literatures used to give more time ranging from 12 to 24 hours as latent phase can usually be prolonged but ended in vaginal delivery [1].

Mean Induction to Time & Mean Oxytocin to Vaginal Delivery
Mean "Induction to delivery" time for study participants were 5.9 hours and 6.3 hours for participants of HDG and LDG respectively while mean time elapsed from initiation of oxytocin to vaginal Delivery were 5.1 hours and 6 hours among HDG and LDG respectively.This shows that mothers receiving high dose oxytocin regimen will have slightly shorter duration of labor.This nding is similar to many literatures although majority of them showed signi cant shortening of induction to delivery time (2-3 hours) compared to our study [3,5,6,9,10,19].Similar effect was found when using oxytocin for augmentation [4].This might be due to frequent escalation of oxytocin dose among HDG compared to LDG (every 20 minutes Vs 30 minutes) till getting adequate uterine contraction or favorable cervical outcome.
The limitation to this study was confounders like parity, Bishop score, ripening agent & fetal weight are not controlled so as to look the real effect of oxytocin regimen on induction success.
Failed induction: If a woman deliver by C/S due to failure to acquire either adequate uterine contraction (≥3 contractions and duration lasting ≥40 seconds in ten minutes period) or failed to show favorable cervical changes (reach at least 4cm in dilatation and fully effaced) despite being on oxytocin drip for at least six to eight hours.Instrumental vaginal birth: When vaginal delivery is effected by either vacuum or obstetric forceps.Vaginal birth: Is vaginal delivery without any assistance by instruments like vacuum or forceps Induction to delivery time: The time it takes the mother from starting of oxytocin to delivery of the fetus either vaginally or abdominally.Low dose oxytocin regimen: Initial dose of 2 mu/min increased by 2 mU/min every 30 minute up to a maximum of 40 mU/minute.High dose oxytocin regimen: Initial dose of 6 mu/min increased by 6mU/min every 20 minute up to a maximum dose of 92.8 mu/min.Favorable bishop: Those Bishop score having value of greater than six Unfavorable bishop: Those Bishop score having value of less or equal to six[2]

Table 2 :
Reproductive and Obstetric characteristics of the participants in four hospitals,October 1, 2017

Table 3 :
Outcome of pregnant women undergoing IOL with high dose and low dose oxytocin regimen in four hospitals, October 1, 2017 to May 30, 2018.

Table 4 :
Labor outcomes among participants who received dose and low dose oxytocin regimen in four October 1, 2017 to May 30, 2018.On Bivariate logistic regression analysis age, residence and family income of the respondent, previous history of successful induction, cervical ripening with misoprostol, type of oxytocin regimen, gestational age at delivery and neonatal weight did not show any kind of association with successful induction of labour.However, previous parity [COR 2.1, 95%CI 1.2, 3.7], bishop score at initiation of oxytocin [COR 3.

Table 5 :
Multivariate Logistic Regression of factors associated with success of induction in four hospitalsDiscussionwith NRFHRP in this study and mere occurrence of NRFHRP necessitating C/S during labor may reduce the possible number of successful vaginal deliveries if labor has to be continued.The fact that the number of mothers undergoing C/S for NRFHRP among HDG was higher by 2.3 times than among the LDG (45% vs. 20%) may explain higher C/S & lower successful induction observed among HDG.Because misoprostol use is standard of management as it increases success of induction.Lastly, the fact that centers with low oxytocin regimen use oral misoprostol for cervical priming before oxytocin induction in contrary to high dose center which initiate direct oxytocin induction for prolonged PROM, and PROM being major indication of induction (60%), might have contributed to higher induction success rate and thus lower C/S rate among LDG .Rate of failed induction was nearly the same among HDG (17.6%) and LDG (15.7%).This similarity in rate among the two groups was also seen in one cohort study comparing the two oxytocin regimen (4.3% & 5.1