Comparison of delivery outcomes in low-dose and high-dose oxytocin regimens for induction of labor following cervical ripening with a balloon catheter: A retrospective observational cohort study.

A variety of oxytocin regimens are used for labor induction and augmentation. Considering the increasing rates of labor induction, it is important to assess the most optimal oxytocin regimen without compromising maternal and fetal safety. The aim of this study was to compare delivery outcomes of low-dose and high-dose oxytocin induction protocols. This retrospective cohort study of 487 women comparing low-dose oxytocin protocol (n = 280) and high-dose oxytocin protocol (n = 207) in labor induction following cervical ripening by balloon catheter was performed in Helsinki University Hospital after implementation of a new oxytocin induction protocol. The study included two six-month cohorts from 2016 and 2019. Women with vital singleton pregnancies ≥37 gestational weeks, cephalic presentation, and intact amniotic membranes were included. The primary outcome was the rate of vaginal delivery. The secondary outcomes were the rates of maternal and neonatal infections, postpartum hemorrhage, umbilical artery blood pH-value, admission to neonatal intensive care, and induction-to-delivery interval. Statistical analyses were performed by using IBM SPSS Statistics for Windows (Armonk, NY, USA). The rate of vaginal delivery was higher [69.9% (n = 144) vs. 47.9% (n = 134); p<0.004] and the rates of maternal and neonatal infection were lower during the new high-dose oxytocin protocol [maternal infections 13.6% (n = 28) vs. 22.1% (n = 62); p = 0.02 and neonatal infection 2.9% (n = 6) vs. 14.6% (n = 41); p<0.001, respectively]. The rates of post-partum hemorrhage, umbilical artery blood pH-value <7.05 or neonatal intensive care admissions did not differ between the cohorts. The median induction-to-delivery interval was shorter in the new protocol [32.0 h (IQR 18.5-42.7) vs. 37.9 h (IQR 27.8-52.8); p<0.001]. In conclusion, implementation of the new continuous high-dose oxytocin protocol resulted in higher rate of vaginal delivery and lower rate of maternal and neonatal infections. Our experience supports the use of high-dose continuous oxytocin induction regimen with a practice of stopping oxytocin once active labor is achieved, and a 15-18-hour maximum duration for oxytocin induction in the latent phase of labor following cervical ripening with a balloon catheter.

Introduction

Oxytocin, a hormone secreted from the posterior pituitary, causes uterine contractions [1]. Oxytocin levels gradually increase during pregnancy and labor, and a four-fold rise of oxytocin levels occurs during vaginal delivery [2]. Oxytocin is the most common agent used for induction and augmentation of labor, administered by intravenous infusion according to uterine contraction frequency.

Currently, there is a wide variation in oxytocin regimens by administration with either continuous or pulsed infusions, linear or non‐linear incremental increases, and high‐dose or low‐dose regimens [3]. The optimal timing, dose and infusion type are still being debated over. High-dose oxytocin regimens may cause hyperstimulation associated with adverse maternal and neonatal outcomes, while low‐dose protocols may prolong the induction to delivery interval increasing the chance of maternal and neonatal infections [4, 5]. Evaluation of the best oxytocin regimen in induction of labor is challenging, as labor induction is influenced by various antenatal factors, such as parity, maternal height and weight, prior mode of delivery, cervical ripeness classified by Bishop’s score, fetal weight, and gestational age [6, 7]. Several studies on evidence-based labor management and induction of labor suggest that combination methods such as Foley catheter and either misoprostol or oxytocin are associated with a shorter labor durations than one method alone [8-10]. It is important to determine whether high‐dose oxytocin regimens can improve successful induction of labor without compromising maternal and fetal safety. Oxytocin has usually been assessed as an isolated intervention, and as different combination methods for labor induction become more popular, further research on oxytocin use alone and in combination with other methods in different regimens is warranted.

The aim of this study was to compare the delivery outcomes of two different oxytocin protocols following cervical ripening by balloon catheter in the same academic tertiary hospital following implementation of a new high-dose oxytocin protocol for labor induction.

Material and methods

This retrospective cohort study comparing low-dose and high-dose oxytocin protocols in induction of labor was performed in the Department of Obstetrics and Gynecology in Helsinki University Hospital, with approximately 13 500 deliveries annually. The rate of labor induction is 30%, and the overall rate of cesarean delivery is 20%. In Helsinki University Hospital, balloon catheter is the principal method used for cervical ripening, and in approximately 50% of the women labor induction is continued by amniotomy and oxytocin infusion.

The study included two six-month cohorts of women with vital singleton pregnancies at or beyond 37 gestational weeks, cephalic presentation, and intact amniotic membranes, undergoing induction of labor with cervical ripening by balloon catheter followed by amniotomy and oxytocin. The first cohort was obtained during the old oxytocin induction protocol (“old protocol”) between January 1st and June 30th 2016, and the second cohort was obtained during the new oxytocin induction protocol (“new protocol”) between January 1st and June 30th 2019. Women with multiple gestation, breech presentation, stillbirth, pre-labor rupture of membranes, preterm pregnancy, and ripe cervix with Bishop score > 6 were excluded from the study. Also, women who did not need oxytocin infusion during their labor induction were excluded. The potential bias of the study were the retrospective design and the decision to include only women undergoing induction of labor at term, rather than at any time during the third trimester. This bias was addressed by choosing two identical cohorts within two identical time periods during the two different oxytocin induction protocols. The study protocol was approved by the institutional review board (IRB) of the hospital region (Helsinki and Uusimaa Hospital District Committee for Obstetrics and Gynecology, HUS/3172/2018 and HUS/54/2019). Written informed consent was waived by the IRB according to national legislation (Medical Research Act 488/1999, chapter 2 a (23.4.2004/295), section 5 and 10a) and the retrospective nature of the study. All data were fully anonymized prior to access and the analyses. The study was performed in accordance with the Declaration of Helsinki and reported in compliance with the STROBE statement.

The primary outcome was the rate of vaginal delivery. The secondary outcomes were the rates of maternal and neonatal infections, postpartum hemorrhage, umbilical artery blood gas pH-value, admission to neonatal intensive care, and induction to delivery interval. The data on baseline characteristics and delivery outcomes were obtained from the hospital database.

Induction of labor was started by cervical ripening with a single 60–80 ml balloon catheter (Rüsch 2-way Foley Couvelaire tip catheter size 22 Ch, Teleflex Medical, Athlone, Ireland). Light traction was applied by taping the catheter on the inner thigh. The balloon was retained for a maximum of 24 hours. When Bishop score ≥ 6 was reached, labor induction was continued by amniotomy and oxytocin induction if spontaneous contractions and onset of labor had not occurred.

Helsinki University Hospital used the old low-dose intermittent oxytocin protocol in the induction of labor until January 2017, after which it was replaced by the new high-dose continuous oxytocin protocol. The oxytocin protocols are described in Tables 1 and 2.

Table 1

The old intravenous low-dose oxytocin infusion protocol.

Concentration: Oxytocin (Syntocinon®) 5 IU diluted in 500 ml of 0.9% saline (0,01 IU/ml)
Time; hours:minutes	Dose	Dose	Total Oxytocin	Total Volume infused (ml)
	mIU/min	ml/h	units infused (mIU)
0:30	2,5	15	75	7.5
1:00	4,2	25	200	20
1:30	5,8	35	375	37.5
2:00	7,5	45	600	60
2:30	9,2	55	875	87.5
3:00	10,8	65	1200	120
3:30	12,5	75	1575	157.5
4:00	14,2	85	2000	200
4:30	15,0	90	2450	245
5:00	15,0	90	2900	290
5:30	15,0	90	3350	335
6:00	15,0	90	3800	380
Break 2–6 hours, after which another 6-hour infusion repeated as above

Maximum dose: 15 mIU/min

Maximum continuous duration: 6 hours

Total maximum dose infused: 3.8 IU x 2 = 7.6 IU

Table 2

The new intravenous high-dose oxytocin infusion protocol.

Oxytocin (Syntocinon®) 8,3 μg = 5 IU diluted in 500 ml of 0.9% saline (0,01 IU/ml)
Time; hours:minutes	Dose	Dose	Total Oxytocin	Total Volume infused (ml)
	mIU/min	ml/h	units infused (mIU)
00:20	2,5	15	50	5.0
00:40	4,2	25	133	13.3
01:00	5,8	35	250	25.0
01:20	7,5	45	400	40.0
01:40	9,2	55	583	58.3
02:00	10,8	65	800	80.0
02:20	12,5	75	1050	105.0
02:40	14,2	85	1333	133.3
03:00	15,8	95	1650	165.0
03:20	17,5	105	2000	200.0
03:40	19,2	115	2383	238.3
04:00	20,0	120	2783	278.3
04:20	20,0	120	3183	318.3
04:40	20	120	3583	358.3
05:00	20	120	3983	398.3
05:20	20	120	4383	438.3
05:40	20	120	4783	478.3
06:00	20	120	5183	518.3
06:20	20	120	5583	558.3
06:40	20	120	5983	598.3
07:00	20	120	6383	638.3
07:20	20	120	6783	678.3
07:40	20	120	7183	718.3
08:00	20	120	7583	758.3
08:20	20	120	7983	798.3
08:40	20	120	8383	838.3
09:00	20	120	8783	878.3
09:20	20	120	9183	918.3
09:40	20	120	9583	958.3
10:00	20	120	9983	998.3
10:20	20	120	10383	1038.3
10:40	20	120	10783	1078.3
11:00	20	120	11183	1118.3
11:20	20	120	11583	1158.3
11:40	20	120	11983	1198.3
12:00	20	120	12383	1238.3

Maximum dose: 20 mIU/min

Maximum continuous duration: 12(-18) hours

Total dose infused: 12.38 UI

In the old oxytocin protocol, oxytocin infusion was started 2 hours after amniotomy in the absence of spontaneous regular contractions. Oxytocin (Syntocinon® 8,3 μg [5 IU]) diluted in 500 ml of NaCl 0.9%) infusion was started at 2.5 mIU/min (15 ml/h), and the dose was increased by 1.7 mIU/min (10 ml/h) increments in every 30 minutes up to 15 mIU/min (90 ml/h) (Table 1). Oxytocin infusion was continuously administered for 6 hours, with the total maximum dose of 3.8 IU was infused, followed by a break of 2–6 hours and another 6 hours of oxytocin infusion, or until contractions deemed adequate or active labor was reached. Oxytocin was altogether administered for 12–18 hours, with a break of 2–6 hours following each six-hour infusion, after which induction was considered failed.

In the new continuous high-dose oxytocin protocol, Oxytocin (Syntocinon® 8,3 μg (5 IU)) diluted in 500 ml of NaCl 0.9%) infusion was started 1–2 hours following amniotomy with 2.5 mIU/min (15 ml/h) and the dose was increased by 1.7 mIU/min (10 ml/h) increments in every 20 minutes up to 20 mIU/min (120ml/h) or until contractions were deemed adequate (Table 2). When contractions were deemed adequate and active labor was reached, oxytocin was paused for 1–2 hours, and administration was later restarted for augmentation of labor if necessary. Oxytocin induction was continued continuously for a maximum of 12–18 hours, with the total maximum dose of 12.38 IU, after which induction of labor was deemed failed and cesarean section was performed [11].

Contractions were deemed adequate when 3–5 contractions occurred in 10-minute period. Active labor was defined as adequate contractions and cervical dilation of 6 cm or more. Continuous cardiotocography during oxytocin induction and labor was routinely used. GBS was routinely tested in all women by a rapid qualitative in vitro GBS test (Xpert® GBS, Cepheid, Sunnyvale, California, USA) at the time of admission. Administration of prophylactic Benzylpenicillin with the first dose of 4 million units intravenously, followed by 2.5 million units every 4 hours until delivery was routinely used for prophylaxis in GBS-positive women. In case of a penicillin allergy, clindamycin 900 mg was administered every 8 hours intravenously.

Maternal infections were categorized as intrapartum (during labor) and postpartum (within one week from delivery). The criteria for intrapartum infection were maternal fever ≥ 38°C during labor and at least one of the following criteria: fetal tachycardia ≥ 160 bpm, uterine tenderness, purulent amniotic fluid or vaginal discharge, total white cell count > 15E9/L. Postpartum infections included endometritis, cesarean or episiotomy wound infection, deep abdominal or pelvic infection, sepsis, and puerperal fever of unknown origin. Neonatal infections were categorized by a neonatologist into blood culture positive sepsis, clinical sepsis, and suspected sepsis. Neonatal clinical sepsis was defined as blood culture negative infection with symptoms and signs consistent with sepsis (respiratory distress, apnea, tachycardia, poor perfusion, low blood pressure, fever, hypoglycemia or hyperglycemia, irritability, feeding problems, lethargy, convulsions), abnormal blood values (C-reactive protein (>20 mg/l), leukocytosis or leucopenia, increased neutrophil precursors and thrombocytopenia), and positive reaction to a minimum of five-day antibiotic treatment. The cases of suspected sepsis had at least one symptom and at least one abnormal laboratory test value, and a positive response to antibiotic treatment.

Statistical analyses were performed by using IBM SPSS Statistics for Windows, Version 26.0 (Armonk, NY, USA). Categorical variables were analyzed for odds ratios (OR) with 95% confidence interval (CI). Categorical variables were compared by the chi-square test and Fisher’s exact test when appropriate. Data with continuous variables were performed by T-test when the data followed normal distribution and by a Mann-Whitney U test if the data did not follow normal distribution. Univariate and multivariate logistic regression analyses were performed to assess relative risk for intrapartum infection. Variables used in the multivariate analyses were parity, maternal age, height, body mass index (BMI), previous cesarean delivery, Bishop score, gestational age, indication for labor induction, duration of oxytocin infusion, and the induction to delivery interval ≥ 48 h. A p-value <0.05 was considered statistically significant.

Results

We identified 3290 and 3085 deliveries during the selected time periods of the old and new oxytocin induction protocol, examined 743 and 853 women who underwent induction of labor for eligibility, and confirmed 280 and 207 women eligible, respectively (Fig 1). A total of 487 women with the mean age of 32.1 (5.2 SD) years, the mean BMI 26.7 (6.0 SD) and the median gestational age of 41.3 (range 39.6–42.0) weeks were included in the study. The old protocol included 280 women (57.5%) and the new protocol included 207 (42.5%) women (Fig 1). The characteristics of the study population are presented in Table 3. Women in the new protocol were older, more often had pregestational diabetes, and lower Bishop score at the start of labor induction, while there were more post-term pregnancies in the old protocol cohort (Table 3). The indications for labor induction did not differ between the groups (Table 3).

Fig 1

Flowchart of the study population.

Table 3

Characteristics of the study population.

	Old protocol		New protocol		p-value
	n = 280	(%)	n = 207	(%)
Primiparous	210	75.0	140	68.0	0.09
Maternal age, mean (SD)	31.1	5.3	33.3	4.9	<0.001
Age ≥37 years	45	16.1	53	25.7	0.01
BMI, mean (SD)	26.4	5.5	25	6.7	0.26
BMI ≥35	25	8.9	23	11.2	0.42
IVF	23	8.2	24	11.7	0.21
Smoking	14	5.0	10	4.9	0.94
Post-term ≥ 41 weeks	48	17.7	13	6.3	<0.001
Pregestational DM	2	0.7	11	5.3	0.002
Gestational diabetes	94	33.6	70	34.0	0.93
Medicated gestational diabetes	24	8.6	24	11.7	0.26
Maternal height < 164 cm	117	41.8	68	33.2	0.05
Bishop < 3	114	40.7	104	50.5	0.03
GBS-colonization	63	23.2	44	21.4	0.64
Indication for labor induction
Post-term pregnancy	136	48.6	87	42.2	0.17
Diabetes	48	17.1	46	22.3	0.15
Hypertension or preeclampsia	28	10.0	20	9.7	0.92
Other	68	24.4	53	25.7	0.72

The median duration of oxytocin induction, including the possible breaks during the infusion, was 12.1 (range 8.6–18.1) hours in the new protocol, and 17.4 (range 13.1–24.4) hours in the old protocol; p< 0.001 (Fig 2). Active labor was more often reached in the new protocol compared to the old protocol [80.1% (n = 165) vs. 64.3% (n = 180); p <0.001]. The median induction to delivery interval was significantly shorter in the new protocol [32.0 (IQR 18.5–42.7) hours vs. 37.9 (IQR 27.8–52.8) hours; p<0.001]. The duration of active labor did not differ between the protocols [9.0 (IQR 6.3–12.9) hours vs. 9.5 (IQR 6.6–13.4) hours; p = 0.50].

Fig 2

Duration of oxytocin induction in the old and new protocols.

The maternal and neonatal delivery outcomes are presented in Table 4. The rate of vaginal delivery was higher in the new protocol [69.9% (n = 144) vs. 47.9% (n = 134); p<0.004]. There were more cesarean sections performed due to fetal distress and failed labor induction during the old protocol (Table 4). The rates of maternal and neonatal infection were lower during the new protocol [maternal infections 13.6% (n = 28) vs. 22.1% (n = 62); p = 0.02 and neonatal infection 2.9% (n = 6) vs. 14.6% (n = 41); p< 0.0001, respectively, Table 4]. In the old protocol, maternal or neonatal infection occurred in 29.3% (n = 82) of the labors, while in the new protocol the corresponding rate was 14.6% (n = 30); p<0.001. The rates of vaginal delivery, cesarean delivery, maternal and neonatal infections, and the respective durations of oxytocin induction are presented in Fig 3. The mean birthweight, the rates of post-partum hemorrhage and umbilical artery blood pH-value <7.05 did not differ between the cohorts (Table 4).

Table 4

Delivery outcomes.

	Old protocol		New protocol		p-value
	n = 280	(%)	n = 207	(%)
Vaginal delivery	134	47.9	144	69.9	<0.004
Instrumental vaginal birth	35	12.5	32	15.5	0.44
Cesarean section
Fetal distress	28	10	51	4.4	0.02
Failed induction (cx <6cm)	71	25.4	33	16.0	0.01
Labor dystocia (cx >6cm)	27	9.6	18	8.7	0.73
Other	20	7.1	2	1.0	0.001
III -IV grade perineal tear	4	1.4	4	1.9	0.66
Placental retention	14	5	4	1.9	0.08
Post-partum haemorrhage > 1000ml	61	21.8	59	28.6	0.08
Induction to delivery interval <24 h	51	18.2	74	35.9	<0.001
Induction to delivery interval <48 h	189	67.5	168	81.6	0.001
Fetal scalp blood sampling	77	27.5	13	6.3	<0.001
Birthweight [mean (SD)]	3673	487	3674	470	0.88
Birthweight ≥+2 SD	6	2.1	10	4.9	0.10
Apgar 5min <7	13	4.8	9	4.4	0.83
Umbilical artery pH <7.05	2	0.7	0		0.51
Umbilical artery BE <-12.0	5	1.9	3	1.5	1
Maternal infection	621	22.1	28	13.6	0.02
Intrapartum infection	46	16.4	22	10.7	0.07
Postpartum infection	18	6.4	6	2.9	0.08
Neonatal infection	41	14.6	6	2.9	<0.001
Maternal or neonatal infection	82	29.3	30	14.6	<0.001
Maternal and neonatal infection	21	7.5	5	2.4	0.01
Neonatal intensive care unit admission	24	8.6	23	11.2	0.34

1Two women who had an intrapartum infection presented with a separate post-partum cesarean wound infection later after being discharged from the hospital. Both women had antibiotic treatment and revision surgery.

Fig 3

The rates of vaginal delivery, cesarean delivery, and maternal and neonatal infections during the old and new oxytocin protocols.

Nulliparity OR 2.4 (95%CI 1.3–4.4), Bishop score < 3 OR 1.7 (95%CI 1.1–2.7), oxytocin infusion of more than 12 hours OR 2.9 (95%CI 1.6–5.2) and prolonged induction to delivery interval of 48 hours or more OR 2.9 (95%CI 1.8–4.7) were associated with maternal infection. After adjustment with parity, age, height, BMI, and induction indication, oxytocin infusion of >12 hours OR 2.4 (95%CI 1.2–4.7) and prolonged induction to delivery interval of 48 hours OR 2.3 (95% CI 1.3–4.1) remained significant. Neonatal infection was, after adjustment for parity, maternal age, BMI, height, and gestational age, associated with oxytocin infusion > 12 hours OR 2.7 (95% CI 1.1–6.9) and induction to delivery interval > 48 hours OR 2.2 (95% CI 1.1–4.6).

After implementation of the new continuous oxytocin protocol, the number of emergency cesarean deliveries following induction of labor have decreased, while the rate of labor induction is increasing (Fig 4) [12].

Fig 4

The rates of labor induction and emergency cesarean delivery in induced labor in Helsinki University Hospital 2009–2019.

The rate of labor induction in Helsinki University hospital has steadily increased over the last decade. The rate of emergency cesarean delivery has decreased from 22.1% in 2016 to 18.3% in 2019 since the implementation of the new oxytocin protocol in January 2017 [12].

Discussion

In Helsinki University hospital, two different oxytocin regimens for labor induction were used over the past five years; the old protocol with high starting and low continuing dose of 6-hour intermittent infusion, and a new protocol with high starting dose and continuous 12–18 –hour infusion. During the old protocol, breaks of 2–6 hours between each six-hour intermittent infusion were applied, prolonging the induction to delivery interval. In addition to higher dose, the new protocol included a change to continuous infusion, instituting a practice of stopping oxytocin once active labor is achieved, and instituting a maximum duration of induction before it was considered to have failed. The rate of vaginal delivery was higher (70% vs. 48%; p<0.004), and the rates of maternal and neonatal infections were lower (14% vs. 22%; p = 0.02 and 3% vs. 15%; p<0.001, respectively) during the new protocol. After the implementation of the new protocol, the rate of cesarean delivery in induced labor has decreased while the rate of labor induction is increasing [12]. A recent review by Dasanayakea and Goonewardene described a successful implementation of a new oxytocin protocol in a tertiary teaching hospital in 2006 with improved birth outcomes [13, 14], similar to our experience.

The standard regimen of oxytocin for women whose labor requires augmentation is started with 1–2 mU/minute dose, and increased over 30-minute intervals, the standard maximum dose is 32 mU/minute [3, 15]. The Cochrane review defines high‐dose oxytocin regimen as infusion to deliver more than 100 mU oxytocin in the first 40 minutes and more than 600 mU in two hours, and low dose regimen as infusion to deliver less than 100 mU oxytocin in the first 40 minutes and 600 mU in two hours [16]. In our study, in the old protocol 75 mU of oxytocin was infused during the first 40 minutes, and 600 mU during the first two hours. In the new protocol, 100 mU of oxytocin were infused during the first 40 minutes, and 800 mU during the first two hours. The maximum dose of the old protocol was 15 mU/ml with a total oxytocin dose of 7.6 IU over the 12-hour infusion, and the maximum dose of the new protocol was 20 mU/min with a total oxytocin dose of 12.38 IU over the 12-hour infusion.

The Cochrane review on spontaneous labor and oxytocin regimens concluded that high‐dose oxytocin was associated with a reduction in the length of labor and caesarean section rate, and an increase in spontaneous vaginal delivery, but these associations did not remain significant after adjustment [4]. In the Cochrane review, or in the randomized trial on high and low dose oxytocin in induction of labor of 2391 women, no evidence was found that high‐dose oxytocin increases either vaginal delivery within 24 hours or the caesarean section rate [5, 16]. Controversially, in our study the rates of cesarean section in both nulliparous and multiparous women were lower in the continuous high-dose regimen compared to the older low dose intermittent regimen, differently to the previous studies [16, 17]. Furthermore, we found a higher rate of women progressing into active phase of labor, and a shorter induction to delivery interval in the new high-dose protocol, as previously reported [18]. Discontinuation of oxytocin infusion in the active phase of labor, with cervical dilation of 6 cm and adequate uterine contractions, has been associated with lower risk of cesarean delivery and reduction of uterine tachysystole [19, 20]. This has been implemented in our hospital along with the new protocol. It is possible that all these oxytocin policy changes of the new protocol could have also contributed to the improved outcomes, in addition to the differences in oxytocin dosing.

It has been speculated, that prolonged exposure to oxytocin may desensitize oxytocin receptors, resulting in increased risk of postpartum hemorrhage [21, 22]. In our study, the rates of post-partum hemorrhage were similar in the short intermittent and continuous protocols, and no uterine ruptured occurred.

Cesarean delivery is recommended after approximately 15 hours of oxytocin infusion with no cervical change [23, 24]. After that an increase in adverse maternal and neonatal outcomes may occur, as seen in our study during the old protocol. In the new protocol, the decision on failed induction and cesarean delivery is performed at 12–18 hours from start of oxytocin [23-25]. However, it was noted that also during the new protocol, some women underwent prolonged induction of labor with duration of oxytocin induction of more than 18 hours against the hospital protocol. This may have been due to the newly implemented protocol that some obstetricians were not yet familiar or comfortable with.

The strength of this study is the setting in a tertiary academic hospital undergoing two different oxytocin protocols, and the detailed extensive patient data. The major weakness and bias of the study is the retrospective design. However, this study was a retrospective observational cohort on implementation of a new management protocol. The decision to include only women undergoing induction of labor at term, rather than at any time during the third trimester, is also a potential bias. We also regret not having the exact data on hyperstimulation. However, the rates of CTG changes and fetal distress leading to emergency cesarean delivery were recorded, and these rates were higher in the old protocol. Unfortunately, the data on CTG changes in labors leading to vaginal delivery were not recorded. Furthermore, we regret not having the data on maternal satisfaction during different protocols, as no trial has reported on maternal or caregiver satisfaction in the different oxytocin regimens. Another challenge with the study were also the relative terminology of “low dose" and "high dose" in studies on oxytocin for labor induction and augmentation, as well as the lack of standardized dosing. The authors acknowledge that the "high dose" of our new protocol still is lower than the dose used in in the literature in this area, including the recent review on oxytocin protocols in 12 countries, the Cochrane review, and the new European oxytocin guideline [3, 16, 26]. Encouraged by these results and the recent literature, the authors are considering updating the maximum dose of our protocol higher, in line with the recent European guideline [26].

Conclusion

Implementation of the new oxytocin protocol with a high starting dose of 140 mU/minute and continuous 12 (-18)-hour infusion with a maximum dose of 20 mU/minute, along with instituting a practice of stopping oxytocin once active labor is achieved and defining a maximum duration of induction before it was considered to have failed, resulted in higher rate of vaginal delivery and lower rate of maternal and neonatal infections compared to the previous low-dose oxytocin regimen. No difference in complications, such as post-partum hemorrhage, low 5-minute Apgar score, fetal asphyxia, or admission to neonatal intensive care unit were seen. Following implementation of the new oxytocin protocol, the rates of cesarean deliveries and maternal and neonatal infections in induced labor in our hospital have decreased. Our experience supports the use of high-dose continuous oxytocin induction regimen with a practice of stopping oxytocin once active labor is achieved, and a 15–18-hour maximum duration for oxytocin induction in the latent phase of labor following cervical ripening with a balloon catheter.

26 Jan 2022

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1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: I Don't Know

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: No

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: General:

This study covers an interesting topic comparing the delivery outcomes of low-dose and high-dose oxytocin protocols for labour induction following cervical ripening by balloon catheter. Overall, the authors show that:

- The new high-dose protocol increases the rate of vaginal delivery.

- The new high-dose protocol reduces the rates of maternal and neonatal infection

- There was no difference between the rates of post-partum hemorrhage, umbilical artery blood pH-value <7.05 or neonatal intensive care admissions.

The study addresses how findings relate to previous research in the area. The introduction is supported by literature, it summarises the main controversies around oxytocin use (timing, dose infusion type, hyperstimulation, infection). Authors discuss limitations of the study.

Weaknesses: A weakness of the study is the lack of uterine hyperstimulation data, which authors also recognise as being a limitation of the study.

Suggested revisions

Major issues:

1. Title: It would be recommended for authors to add the study design in the title. For example: “Comparison of delivery outcomes in low-dose and high-dose oxytocin regimens for induction of labor following cervical ripening with a balloon catheter: A retrospective observational cohort study.”

2. Abstract:

a. Methods: Specify how many patients in each group i.e. low-dose oxytocin protocol (n= x) and high dose oxytocin protocol (n= y).

b. Results: Authors should add induction to delivery interval in results section of abstract as results from other secondary outcomes are stated.

3. Tables and figures:

a. Table 3: There are 206 patients in new protocol group in Table 3 as well as in Figure ,1 whereas the text states it is 207 patients. Adding a flow chart in the results section may be useful in clarifying this.

b. Table 4: Table 3 has total number of patients in each group at top of the table but table 4 does not.

c. Table 4: Authors should clarify the maternal infection value in old protocol (n=62) and subgroups intrapartum infection (n=46) and postpartum infection (n=18) as they do not add up. Furthermore, it might be useful to mention that the subgroups of maternal infection (intrapartum and postpartum infection) are not significantly different between the two protocols.

d. Table 4: It would be useful to also present CTG changes/fetal distress regardless of mode of delivery if data is available.

4. Methods:

a. If the authors have used the STROBE guidelines, please mention it in the methods. If it has not been used, please report this study in compliance with STROBE statement.

b. It would be recommended to state if any efforts were made to address potential risk of bias.

5. Results:

a. Could authors report numbers of individuals at each stage of study (examined for eligibility, confirmed eligible etc).

b. Page 14 lines 197-199: “In the old protocol, maternal or neonatal infection occurred in 29.3 % (n=82) of the labors, while in the new protocol the corresponding rate was 14.6 % (n=21); p<0.001”. This does not match results presented in table 4. In table 4 maternal or neonatal infection in the old protocol is reported in 82 patients (29.3%), and in 30 patients (14.6%) in the new protocol with a p value <0.0001.

c. Page 14 lines 201-203: The authors report that “The median birthweight, the rates of post-partum hemorrhage and umbilical artery blood pH-value <7.05 did not differ between the cohorts (Table 4).” However, in table 4 the mean SD birthweight is shown.

6. Discussion:

a. Page 17 lines 236-239 “The rate of vaginal delivery was higher, and the rates of maternal and neonatal infections were lower during the new protocol. After the implementation of the new protocol, the rate of cesarean delivery in induced labor has decreased while the rate of labor induction is increasing.” It would be useful for the authors to add p values.

7. Conclusion:

a. Page 20 lines 295-296: “No difference in complications, such as post-partum hemorrhage, or neonatal primary outcomes were seen.” It is not specified in the text what neonatal primary outcomes are, the primary outcome is defined as rate of vaginal delivery.

Minor issues:

8. Results page 3 line 24 and page 14 line 193: “p=0.004” whereas in table 4 it is p<0.004.

9. Page 11 lines 145-146 “Neonatal infections were by a neonatologist categorized...”. This could be rephrased to “Neonatal infections were categorized by a neonatologist...”.

10. Page 17 lines 239-240: There is a word missing “A recent review by described”

11. Figure 2: please add labels to axes

12. Figure 3: label years axis. I would also suggest adding a dotted line under the arrow to show more precisely when the new oxytocin protocol was implemented.

Reviewer #2: The manuscript compares delivery outcomes following an institutional change in practice from a low-dose oxytocin protocol to one with a higher dose. Overall the quality of the scientific work is very good and the outcomes discussed are important and add to the existing literature on this topic. The methods and results are explained very well and put into context quite clearly for the reader. I support acceptance of this manuscript with the following minor revisions:

1. I note that there were several changes made to the institutional protocol, in addition to the dose of oxytocin, which could potentially contribute to the differences between groups outlined in the results section. These included 1) removal of oxytocin breaks from the protocol 2) instituting a practice of stopping oxytocin once active labour is achieved and 3) instituting a maximum duration of induction before it was considered to have failed. It is possible that these policy changes could have also contributed to the improved outcomes the authors demonstrate in the new protocol, in addition to the differences in oxytocin dosing.

While these protocol changes are outlined by the authors in the Discussion section, it should be acknowledged that these may be confounding the study findings. The conclusion currently reads that the improved outcomes seen with their protocol change were the result of higher dose alone. I think that the Discussion could be modified slightly to highlight the possible contribution of these confounding factors and that the conclusion should reflect the change in protocol which includes but is not limited to a change from low dose to higher dose oxytocin. I don't think this takes away from the overall important findings of the paper.

2. The other point that might bear acknowledging in the manuscript is that "low dose" and "high dose" are relative terms in these types of studies. The "high dose" used here is lower than that used in other published studies. Lack of standardized dosing is one of the difficulties with the literature in this area, including the Cochrane review and other systematic reviews and meta analyses previously published. The findings here are specific to an institutional change from one protocol to another, which is important, particularly as it showed a clear benefit in terms the primary and secondary outcomes, but this finding may not be generalizable. I appreciate that the authors shared their protocol in its entirety, which would make adaptation by other institutions feasible.

The authors were not able to make all data publicly available due to restrictions from their Institutional Policy. They do provide contact information for those seeking access to the raw data, which I find acceptable.

Overall this is a strong paper and makes an important contribution to the existing literature. I did notice a few minor English grammatical errors, though the paper is overall well written and very clear. I congratulate the authors on their work.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #1: No

Reviewer #2: Yes: Harrison Banner

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10 Mar 2022

Reviewer’s comments to the authors and authors’ response:

Reviewer #1

Major issues:

1. Title: It would be recommended for authors to add the study design in the title. For example: “Comparison of delivery outcomes in low-dose and high-dose oxytocin regimens for induction of labor following cervical ripening with a balloon catheter: A retrospective observational cohort study.”

Authors’s response: Thank you, this has been done.

2. Abstract:

a. Methods: Specify how many patients in each group i.e. low-dose oxytocin protocol (n= x) and high dose oxytocin protocol (n= y).

Authors’s response: Number of patients in each protocol have now been added in the methods section of the Abstract (lines 6-7).

b. Results: Authors should add induction to delivery interval in results section of abstract as results from other secondary outcomes are stated.

Authors’s response: The median (IQR) induction-to-delivery interval results have been added in the results section of the Abstract (lines 21-22). To still meet the limited 300-word count of the Abstract after these additions, we have slightly edited the abstract. All the removed words have been indicated with tracked changes.

3. Tables and figures:

a. Table 3: There are 206 patients in new protocol group in Table 3 as well as in Figure ,1 whereas the text states it is 207 patients. Adding a flow chart in the results section may be useful in clarifying this.

Authors’s response: There has been an unfortunate typo. The correct number of patients in the new protocol is 207, and this has now been corrected in Table 3 and Figure 2 (former Fig 1). We have also added a flow chart in the Results section (the new Fig 1).

b. Table 4: Table 3 has total number of patients in each group at top of the table but table 4 does not.

Authors’s response: The total number of patients has been added in each group at top of Table 4.

c. Table 4: Authors should clarify the maternal infection value in old protocol (n=62) and subgroups intrapartum infection (n=46) and postpartum infection (n=18) as they do not add up. Furthermore, it might be useful to mention that the subgroups of maternal infection (intrapartum and postpartum infection) are not significantly different between the two protocols.

Authors’s response: Maternal intrapartum infection occurred in 62 women and post-partum infection in 46 women in the old protocol. Two of the women who had an intrapartum infection presented with a separate post-partum cesarean wound infection later, a few days after being discharged from the hospital. Both women had antibiotic treatment and revision surgery. This has now been clarified in the footnotes of Table 4.

d. Table 4: It would be useful to also present CTG changes/fetal distress regardless of mode of delivery if data is available.

Authors’s response: The authors regret that we don’t have the data on hyperstimulation as discussed in the limitations of the study. CTG changes and fetal distress leading to emergency cesarean delivery have been recorded, however, unfortunately the data on CTG changes in women who had vaginal delivery were not recorded. We have now emphasized this in the limitations paragraph of the Discussion (lines 282-286).

4. Methods:

a. If the authors have used the STROBE guidelines, please mention it in the methods. If it has not been used, please report this study in compliance with STROBE statement.

Authors’s response: The STROBE guideline has been used, and this is now stated in the Methods (lines 81-82).

b. It would be recommended to state if any efforts were made to address potential risk of bias.

Authors’s response: The authors acknowledge the potential bias being the retrospective design and the decision to include only women undergoing induction of labor at term, rather than at any time during the third trimester. We tried to address this bias by choosing two identical cohorts within two identical time periods during the two different oxytocin protocols. This has been discussed in the limitation of the study (lines 278-282), we now added it in the Methods as well (lines 71-74).

5. Results:

a. Could authors report numbers of individuals at each stage of study (examined for eligibility, confirmed eligible etc).

Authors’s response: We identified 3290 and 3085 deliveries during the selected time periods of the old and new protocol, examined 743 and 853 women for eligibility, and confirmed 280 and 207 women eligible, respectively. This has now been added in the beginning of the Results (157-159). We have also added the flowchart (Fig 1).

b. Page 14 lines 197-199: “In the old protocol, maternal or neonatal infection occurred in 29.3 % (n=82) of the labors, while in the new protocol the corresponding rate was 14.6 % (n=21); p<0.001”. This does not match results presented in table 4. In table 4 maternal or neonatal infection in the old protocol is reported in 82 patients (29.3%), and in 30 patients (14.6%) in the new protocol with a p value <0.0001.

Authors’s response: Thank you for pointing this out, the mistake (n=21 instead of n=30) and p> 0.001 in the the Results and Table 4 have been corrected (line 190).

c. Page 14 lines 201-203: The authors report that “The median birthweight, the rates of post-partum hemorrhage and umbilical artery blood pH-value <7.05 did not differ between the cohorts (Table 4).” However, in table 4 the mean SD birthweight is shown.

Authors’s response: Thank you, this sentence has now been corrected, the birthweight is expressed as mean (SD), not median (line 192).

6. Discussion:

a. Page 17 lines 236-239 “The rate of vaginal delivery was higher, and the rates of maternal and neonatal infections were lower during the new protocol. After the implementation of the new protocol, the rate of cesarean delivery in induced labor has decreased while the rate of labor induction is increasing.” It would be useful for the authors to add p values.

Authors’s response: We have now added the p-values and the rates to this sentence in the Discussion (lines 229-231).

7. Conclusion:

a. Page 20 lines 295-296: “No difference in complications, such as post-partum hemorrhage, or neonatal primary outcomes were seen.” It is not specified in the text what neonatal primary outcomes are, the primary outcome is defined as rate of vaginal delivery.

Authors’s response: This has been rephrased: “No difference in complications, such as post-partum hemorrhage, low 5-minute Apgar score, fetal asphyxia or admission to neonatal intensive care unit were seen” (lines 302-304).

Minor issues:

8. Results page 3 line 24 and page 14 line 193: “p=0.004” whereas in table 4 it is p<0.004.

Authors’s response: Thank you, this has been corrected

9. Page 11 lines 145-146 “Neonatal infections were by a neonatologist categorized...”. This could be rephrased to “Neonatal infections were categorized by a neonatologist...”.

Authors’s response: We have rephrased this as suggested (lines 134-135).

10. Page 17 lines 239-240: There is a word missing “A recent review by described”

Authors’s response: Thank you, this has been corrected as “A recent review by Dasanayakea and Goonewardene described..” (lines 233-234).

11. Figure 2: please add labels to axes

Authors’s response: The axes of Fig 2 have now been labeled

12. Figure 3: label years axis. I would also suggest adding a dotted line under the arrow to show more precisely when the new oxytocin protocol was implemented.

Authors’s response: We have added label to the x-axis and a dotted line under the arrow in Fig 3.

Reviewer #2:

Minor revisions:

1. I note that there were several changes made to the institutional protocol, in addition to the dose of oxytocin, which could potentially contribute to the differences between groups outlined in the results section. These included 1) removal of oxytocin breaks from the protocol 2) instituting a practice of stopping oxytocin once active labour is achieved and 3) instituting a maximum duration of induction before it was considered to have failed. It is possible that these policy changes could have also contributed to the improved outcomes the authors demonstrate in the new protocol, in addition to the differences in oxytocin dosing.

While these protocol changes are outlined by the authors in the Discussion section, it should be acknowledged that these may be confounding the study findings. The conclusion currently reads that the improved outcomes seen with their protocol change were the result of higher dose alone. I think that the Discussion could be modified slightly to highlight the possible contribution of these confounding factors and that the conclusion should reflect the change in protocol which includes but is not limited to a change from low dose to higher dose oxytocin. I don't think this takes away from the overall important findings of the paper.

Authors’s response: Thank you for this excellent comment. We have now highlighted these confounding factors as a part of the new protocol in the Discussion and in the Conclusion (Discussion lines 226-229 and 261-264, Conclusion lines 298-300 and 307-309).We also edited the conclusion paragraph of the Abstract accordingly (lines 24-28).

2. The other point that might bear acknowledging in the manuscript is that "low dose" and "high dose" are relative terms in these types of studies. The "high dose" used here is lower than that used in other published studies. Lack of standardized dosing is one of the difficulties with the literature in this area, including the Cochrane review and other systematic reviews and meta analyses previously published. The findings here are specific to an institutional change from one protocol to another, which is important, particularly as it showed a clear benefit in terms the primary and secondary outcomes, but this finding may not be generalizable. I appreciate that the authors shared their protocol in its entirety, which would make adaptation by other institutions feasible.

Authors’s response: Thank you for pointing this out. The authors acknowledge our “high” oxytocin dose still remains lower compared to several other institutions, the Cochrane review and the recent European guideline. However, at the time of implementation of the new protocol in Finland, our current dose was considered extremely high compared to other national institutions. We have now discussed this topic and the lack of standardized dosing in the Discussion (lines 288-295). Encouraged by the results of this study, we are considering updating the maximum oxytocin dose of our institutional protocol higher, similar to the recommendation in the current European guideline (lines 293-295).

We thank the editor and reviewers for these valuable comments which have much improved the manuscript.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

8 Apr 2022

Comparison of delivery outcomes in low-dose and high-dose oxytocin regimens for induction of labor following cervical ripening with a balloon catheter: a retrospective observational cohort study

PONE-D-21-36119R1

Dear Dr. Kruit,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Nnabuike Chibuoke Ngene, Dip HIV Med; MMed(FamMed); FCOG; MMed(O&G); Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: No

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

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7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

13 Apr 2022

PONE-D-21-36119R1

Comparison of delivery outcomes in low-dose and high-dose oxytocin regimens for induction of labor following cervical ripening with a balloon catheter: a retrospective observational cohort study

Dear Dr. Kruit:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Thank you for submitting your work to PLOS ONE and supporting open access.

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on behalf of

Dr. Nnabuike Chibuoke Ngene

Academic Editor

PLOS ONE