Continued versus discontinued oxytocin after the active phase of labor: An updated systematic review and meta-analysis.

OBJECTIVE: To systematically assess the effect of discontinued vs continued oxytocin after active stage of labour is established.
METHODS: Pubmed, Embase, and the Cochrane Library were systematically searched to 18 April 2021. The risk ratio or mean difference with corresponding 95% confidence interval were computed to investigate the effect of intervention or control on maternal and fetus outcomes. This review was registered in the International Prospective Register of Systematic Reviews: CRD42021249635.
RESULTS: Discontinuing oxytocin when the active labour was established might decrease the risk of cesarean delivery [RR (95% CI): 0.84 (0.72-0.98), P = 0.02]. However, when we restricted our analysis to women who performed cesarean section after the active phase was reached, the difference was no longer significant [RR (95% CI): 0.82 (0.60-1.10), P = 0.19]. The incidence of uterine tachysystole [RR (95% CI): 0.36 (0.27-0.49)], postpartum hemorrhage [RR (95% CI): 0.78 (0.65-0.93)], and non-reassuring fetal heart rate [RR (95% CI): 0.66 (0.58-0.76)] were significantly lower in the oxytocin discontinuation group. We also found a possible decrease in the risk of chorioamnionitis in discontinued oxytocin group [RR (95% CI): 2.77 (1.02-5.08)]. An increased duration of active [MD (95% CI): 2.28 (2.86-41.71)] and second [MD (95% CI): 5.36 (3.18-7.54)] phase of labour was observed in discontinued oxytocin group, while the total delivery time was not significantly different [MD (95% CI): 20.17 (-24.92-65.26)].
CONCLUSION: After the active labor is reached, discontinuation of oxytocin could be considered a new recommendation for the improved maternal and fetal outcomes without delaying labour.

Introduction

Approximately one in every four term pregnant women have their labor induced [1-3]. Oxytocin, first synthesized in 1954, has been used widely for induction of labor [4]. Its application needs a balance between the effect on labor progression and the risk of uterine hyperstimulation, defined as more than five contractions in 10 minutes [5]. Frequent contractions, along with too short relaxation period, may lead to insufficient oxygen supplied to the fetus and abnormal fetal heart rate (FHR), which may require immediate intervention by instrumental assistance or cesarean delivery [6]. Also, oxytocin use may increase the maternal risk of uterine rupture and postpartum hemorrhage [7, 8]. A preliminary study indicates that oxytocin use raises the risk of unsuccessful breastfeeding [9]. Additionally, prolonging oxytocin use duration down-regulates the sensibility of oxytocin receptors in uterine myometrium, which lead to decreased efficiency of labour induction and increased the risks of maternal complications [10]. Few but existed, excessive oxytocin can cause seizure, hyponatremia, water retention, myocardial ischemia, and coma [11]. Furthermore, its use also has been doubted that whether oxytocin usage might have bad effect on children’s behavior development over the long term since it can cross the placenta barrier [12].

Recently, oxytocin has gained increasing concern and is considered as 1 of the 12 most dangerous medications in hospital [13]. Although extensively used, no consensus exists regarding the optimal administration scheme, as well as the duration of oxytocin infusion. Some protocols for oxytocin administration have been studied, such as high versus low dose, pulsatile/intermittent versus continuous administration, automatic feedback system, and discontinuing of oxytocin when the active labour is established [14-18]. Of them, stopping oxytocin when the active stage of labour is established rather than continuing infusion until delivery gains growing interest and are often studied.

Four meta-analyses have been published on this issue and suggests that the labour will continue even if oxytocin stimulation is stopped [19-22]. However, related maternal and neonatal outcomes between continued oxytocin (OC) versus discontinued oxytocin (OD) are highly controversial and inconclusive. Whether discontinued oxytocin does have some advantages over the conventional administration therefore remains uncertain. In recent three years, some additional trails have been published concerning this important but inconclusive issue. This review and meta-analysis aims to systematically analyze and integrate the updated evidence on discontinued versus continued oxytocin for induction of labor and provide high-quality evidence for improving maternal and fetus outcomes as well as guiding future clinical practice.

Methods

This review was done according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [23]. This review was registered in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42021249635.

1) Literature search

Literature searching was performed systematically of Pubmed, Embase, and the Cochrane Library to 18 April 2021 for relevant articles comparing discontinued versus continued oxytocin for the induction of labour without language restrictions. We combined MeSH terms ‘oxytocin’, ‘Labor, Induced’ with any related free terms for research searching. Manual search of reference lists from screened articles was also performed for other potential eligible studies.

2) Study selection

After removing the duplicate, the title and abstract of screened studies were assessed for potentially applicable articles. Then the full text of relevant studies were obtained and assessed, and the studies that accords with the eligibility criteria were included for this review. This process was independently conducted by two reviewers, any disagreement can be resolved by consulting with the third reviewer. The inclusion criteria were: (1) Study type: Randomized controlled trial (RCT); (2) Population: women who use oxytocin stimulation for induced labor; (3) Intervention: discontinuting oxytocin when the active stage of labor is established; (4) Comparison: continuting of oxytocin infusion till delivery. The exclusion criteria were: (1) abstracts, reviews, case reports, letters, or observational studies; (2) studies presented with insufficient original data, and (3) studies with duplicate data or repeated analysis.

3) Data extraction and quality assessment

Two reviewers were responsible for the data extraction process independently. If divergence occurred, the authors discussed it with the third reviewer to reach a consensus. The following items were extracted: (1) General information: the first author, publication year, country, sample size; (2) Study characteristics: study design, inclusion and exclusion criteria, definition of active phase, oxytocin regimen, protocol adherence; (3) Maternal and fetal outcomes: caesarean delivery, duration of the active stage of labor (mean ± SD), duration of the second stage of labor (mean ± SD), delivery time (mean ± SD), vaginal instrumental delivery, uterine tachysystole, epidural use, chorioamnionitis, third- or fourth-degree perineal tear, postpartum haemorrhage, exclusive breastfeeding at discharge, non-reassuring FHR, apgar score at 5 mint <7, arterial umbilical pH< 7.10, neonatal asphyxia, NICU admission.

Risk of bias assessment was performed independently by two reviewers in accordance with the risk of bias tool in Cochrane Handbook based on items below: random sequence generation; allocation concealment; blinding of participants, personnel, and outcome assessment; incomplete outcome data; selective reporting; other bias [24]. Each item was categorized as low, unclear or high risk of bias. Furthermore, two reviewers assessed the quality of the evidence for each outcome independently using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) approach [25], and the evidence was downgraded from ’high quality’ for limitations based on the following items: study limitations, consistency of effect, imprecision, indirectness, and publication bias. For the quality assessment process, reviewers resolved the divergence by discussion or the arbitration of the third reviewer.

4) Data synthesis

Data synthesis process was performed using Review Manager 5.3 statistical software. The risk ratio (RR) or mean difference (MD) with their 95% confidence interval (CI) were calculated separately for dichotomous or continuous data. I2 statistic was used for assessing heterogeneity, I2 ≤ 50 indicated an acceptable heterogeneity and a fixed-effect model was used to combine the data; or else, the random-effect model was used when a substantial heterogeneity (I2 > 50) was detected across the studies. Publication bias across studies included in cesarean delivery analysis was assessed using Begg’s and Egger’s tests with Stata 14.0 software. The P-value of <0.05 was considered as significant statistically. Since no substantive heterogeneity was detected between primary outcome (cesarean delivery), none of subgroup analysis or sensitivity analysis were made.

Results

1) Study selection

A total of 2606 studies were searched through electronic database and manual search. After removing duplicated documents, 2461 studies were screened by title and abstract. Then, 21 studies were further assessed by reading full-text, and 13 studies [18, 26–37] that in accordance with inclusion criteria were selected for this meta-analysis (Fig 1).

Fig 1

The flow chart of literature selection process.

2) Study characteristics

The detailed characteristics of included studies are shown in Table 1, and the detailed oxytocin protocols in each study see Table 2. Protocol adherence for OD and OC Groups were shown in Table 3. A total of thirteen RCTs including 1696 in OD group and 1678 in OC group. These studies were published between 2004 and 2021. And the sample size of involved studies ranged from 90 to 1200 women. The definition of the active phase of labour concerning cervical dilation extent was 4 cm in 2 studies [30, 32], 5 cm in 7 studies [17, 18, 29, 33–35, 37], 6 cm in 1 study [28], 4–5 cm in 1 study [26], 4–6 in 1 study [31], and not defined in 1 study [36]. Women of the OD group received placebo with saline/ringer’s solution in 5 studies [26, 28, 30, 31, 37], while other studies simply discontinued the oxytocin inclusion once active labor was established. In the OC group, oxytocin was used until delivery on the same dose in 9 studies [18, 27, 29, 31, 33–37], used at the standard concentration in 1 study [28], used titrated to target 3–5 contractions/10 minutes in 1 study [32], and 2 studies did not specify oxytocin dose [26, 30]. The publication bias for primary outcome (cesarean section) was observed among the twelve studies with the p-value of 0, see the funnel plot (Fig 2). The risk of bias assessment result for this systematic review is shown in Fig 3 Risk of bias summary and Fig 4 Risk of bias graph. And the details for GRADE assessment are presented in Table 4. The GRADE assessment for each outcome ranged from very low certainty to moderate certainty.

Table 1

Characteristics of the included studies.

Study year	Country	Sample size	Inclusion criteria	Defination of active phase	Intervention group	Control group
Bahadoran 2011 [26]	Iran	104	Singleton gestations ≥ 37 weeks, Bishop <5, BMI <26	Dilatation of 4 cm and 80% effacement, or 5 cm without considering effacement	Oxytocin+500 cc of Ringer’s solution	Oxytocin until delivery
Begum 2013 [27]	Bangladesh	100	Singleton gestations ≥ 37 weeks	Cervical dilatation of 5 cm	Oxytocin was discontinued after the active phase	Oxytocin until delivery on the same dose
Bioe 2021 [28]	Denmark and Netherlands	1200	Singleton gestations ≥ 37 weeks or PROM without progression in labour	Ruptured membranes with cervical dilatation of 6 cm and 100% effacement, and at least 3 contractions/10 minutes.	Oxytocin+500mL of 0.9% of NaCl solution	Oxytocin until delivery at the standard concentration
Bor 2016 [29]	Denmark	200	Singleton gestations ≥ 37 weeks, cervical dilation ≤ 4cm	Cervical dilatation of 5 cm	Oxytocin was discontinued after the active phase	Oxytocin until delivery on the same dose
Chookijkul 2016 [30]	Thailand	340	Singleton gestations ≥ 37 weeks, estimated fetal weight < 4000 g, Bishop > 4	Cervical dilatation of 4 cm with good uterine contraction	Oxytocin+500mL of 0.9% of NaCl solution	Oxytocin until delivery
Chopra 2015 [31]	India	106	Singleton gestations ≥ 36 weeks	Cervical dilatation of 4–6 cm	Oxytocin+500mL of 0.9% of NaCl solution	Oxytocin until delivery on the same dose
Daniel-Spiegel 2004 [18]	Israel	104	Singleton gestations ≥41 weeks, or PROM >24 hours, or IUGR, or diabetes	Cervical dilatation of 5 cm	Oxytocin was discontinued after the active phase	Oxytocin until delivery on the same dose
Diven 2012 [32]	USA	252	Singleton gestations ≥ 36 weeks	Cervical dilatation of 4 cm, and regular contractions	Oxytocin was discontinued after the active phase	Oxytocin titrated to target 3–5 contractions /10 minutes until delivery
Eissa 2019 [33]	Egypt	90	Singleton gestation ≥ 37 weeks, postdated pregnancy (>42 weeks), Bishop ≥ 6, PROM at term, mild preeclampsia/hypertension ≥ 39 weeks, oligohydramnios	Cervical dilatation of 5 cm	Oxytocin was discontinued after the active phase	Oxytocin until delivery on the same dose
Mitra 2019 [34]	India	200	Women ≥ 18 years old, primigravida, singleton gestations ≥ 37 weeks with cervical dilation ≤ 3cm and PROM	Cervical dilatation of 5 cm	Oxytocin+500mL of 0.9% of NaCl solution	Oxytocin until delivery on the same dose
Ozturk 2015 [35]	Turkey	130	Nulliparous singleton gestations ≥ 36 weeks	Cervical dilatation of 5 cm	Oxytocin was discontinued after the active phase	Oxytocin until delivery on the same dose
Rashwan 2011 [36]	Egypt	200	Singleton gestations ≥ 37 weeks, Bishop >4	Not defined	Oxytocin was discontinued after the active phase	Oxytocin until delivery on the same dose
Ustunyurt 2007 [37]	Turkey	342	Singleton gestations ≥ 37 weeks	Cervical dilatation of 5 cm, and regular contractions at 3 min intervals	Oxytocin+500mL of 0.9% of NaCl solution	Oxytocin until delivery on the same dose

Table 2

Detailed oxytocin protocol in each study.

	Oxytocin dilution	Starting dose	Increasing dose	Maximal dose
Bahadoran 2011	5 IU in 500 mL of Ringer’s solution	6 mIU/minute	6 mIU/30 min until regular contractionsa	NRb
Begum 2013	5 IU in 500 mL of Ringer’s solution or 2.5 IU in 5% dextrose	10 droups/minute	Until regular contractionsa	20 mIU/min
Bioe 2021	10 IU in 1000 mL of 0.9% NaCl or 5 IU in 50 mL of 0.9% NaCl	3.3 mIU/min	3.3 mIU/20 min until regular contractionsa	30/33 mIU/ min in Denmark / Netherlands
Bor 2016	5 IU in 500 mL of 0.9% NaCl	3.3 mIU/minute	3.3 mIU/20 min until regular contractionsa	30 mIU/min
Chookijkul 2016	NRb	NRb	NRb	NRb
Chopra 2015	NRb	3 mIU/minute	3.3 mIU/30 min until regular contractionsa	42 mIU/min
Daniel-Spiegel 2004	5 IU in 500 mL of 0.9% NaCl	1 mIU/minute	1 mIU/20 min until regular contractionsa	20 mIU/min
Diven 2012	30 IU in 500 mL of 0.9% NaCl	NRb	Until regular contractionsa	NRb
Eissa 2019	5 IU in 500 mL of Ringer’s solution	2 mIU/minute	2 drops/20 min until 3–4 contractions/10min	20 mIU/min
Mitra 2019	1.5 IU in 500 mL of 0.9% NaCl	3 mIU/minute	3 mIU/30 min until 3–4 contractions/10min	15 mIU/min
Ozturk 2015	Oxytocin in 0.9% NaCl at a 1% concentration	1–2 mIU/minute	2 mIU/15 min until regular contractionsa	40 mIU/min
Rashwan 2011	5 IU in 500 mL of 0.9% NaCl	1 mIU/minute	1 mIU/20 min until regular contractionsa	20 mIU/min
Ustunyurt 2007	5 IU in 500 mL of 0.9% NaCl	2 mIU/minute	2 mIU/15 min until regular contractionsa	NRb

aRegular contractions: 3–5 contractions per 10 min;

bNR: not reported.

Table 3

Protocol adherence for OD and OC groups.

Study	Failure Protocol in ODa group	N (%) with failure protocol	Failure Protocol in OCb group	N (%) with failure protocol
Bahadoran [26]	NRc	NRc	NRc	NRc
Begum [27]	NRc	0/50	NRc	0/50
Bioe [28]	Slow labour progress, uterine tachysystole, FHR abnormalities, and others	311/607 (51.2%) had oxytocin restarted	Slow labour progress, uterine tachysystole, FHR abnormalities, and others	197/591 (33.3%) had oxytocin discontinued
Bor [29]	No cervical dilatation in two hours	36/100 (36.0%) had oxytocin restarted	Non-reassuring FHR, or others	3/100 (3.0%) had oxytocin discontinued
Chookijkul [30]	Poor uterine contraction	16/170 (9.4%) had oxytocin restarted	Non-reassuring FHR	15/170 (8.8%) had oxytocin discontinued
Chopra [31]	Inadequate uterine contractions (<3/10min) for two hours or more, or if cervical dilation did not improve	NRc	Non-reassuring FHR, or others	NRc
Daniel-Spiegel [18]	Inadequate uterine contractions for two hours or more, or if cervical dilation did not improve	4/52 (7.7%) had oxytocin restarted	Non-reassuring FHR	4/52 (7.7%) had oxytocin discontinued
Diven [32]	Lack of cervical change, or decrease in contraction frequency	89/125 (71.2%): - 31/125 not discontinued despite randomization—58/125 had oxytocin restarted	Non-reassuring FHR, or others	0/127
Eissa [33]	NRc	NRc	NRc	NRc
Mitra [34]	Arrest of labour	7/100 (7%) had oxytocin restarted	Uterine tachysystole, fetal distress	15/100 (15%) had oxytocin discontinued
Ozturk [35]	Lack of cervical change, or decrease in contraction frequency	0/66	Non-reassuring FHR, or others	0/64
Rashwan [36]	NRc	NRc	NRc	NRc
Ustunyurt [37]	No cervical change for two hours despite adequate contractions	11/168 (6.5%) had oxytocin restarted	Non-reassuring FHR	8/174 (4.6%) had oxytocin discontinued

aOD: discontinued oxytocin;

bOC: continued oxytocin;

cNR: not reported

Fig 2

The funnel plot of studies included in cesarean section analysis.

Fig 3

Risk of bias summary.

Fig 4

Risk of bias graph.

Table 4

Details for GRADE assessment.

Outcome	Quality						Quality
	Design	Limitations	Inconsistency	Indirectness	Imprecision	Others
Caesarean delivery	randomised trials	very serious	no serious	no serious	no serious	reporting bias	Very low
Duration of the active phase of labour	randomised trials	very serious	very serious	no serious	no serious	none	Very low
Duration of the second phase of labour	randomised trials	very serious	no serious	no serious	no serious	none	Low
Delivery time	randomised trials	serious	very serious	no serious	no serious	none	Very low
Vaginal instrumental delivery	randomised trials	serious	no serious	no serious	serious	none	Low
Uterine tachysystole	randomised trials	serious	no serious	no serious	no serious	none	Moderate
Epidural use	randomised trials	serious	serious	no serious	serious	none	Very low
Chorioamnionitis	randomised trials	serious	no serious	serious	no serious	none	Low
Third- or fourth-degree perineal tear	randomised trials	no serious	no serious	no serious	serious	none	Moderate
Postpartum haemorrhage	randomised trials	serious	no serious	no serious	no serious	none	Moderate
Exclusive breast feeding at discharge	randomised trials	no serious	very serious	no serious	serious	none	Very low
Non-reassuring FHR	randomised trials	very serious	no serious	no serious	no serious	none	Low
Apgar score at 5 mint <7	randomised trials	serious	no serious	no serious	serious	none	Low
Arterial umbilical pH< 7.10	randomised trials	serious	no serious	no serious	serious	none	Low
Neonatal asphyxia	randomised trials	no serious	no serious	no serious	serious	none	Moderate
NICU admission	randomised trials	very serious	no serious	no serious	serious	none	Very low

3) Meta-analysis

3.1 Cesarean section

Totally, 12 studies with 3270 women that explored the association between discontinued oxytocin and cesarean section risk were analyzed (Fig 5). Discontinuting oxytocin infusion after the active labor may decrease the risk of cesarean delivery [RR (95% CI): 0.84 (0.72–0.98), P = 0.02]. And no statistical heterogeneity was detected. Notably, when we restricted our analysis to women who performed cesarean section after the active phase was reached, the difference was no longer significant [RR (95% CI): 0.82 (0.60–1.10), P = 0.19] (Fig 6). Furthermore, no intergroup differences were detected concerning the indication for cesarean delivery such as fetal distress, non-reassuring FHR, arrest of labour, dystocia, chorioamnionitis, and suspicion of uterine rupture (Table 5).

Fig 5

Pooled results for each outcome.

Fig 6

Pooled results for each outcome.

Table 5

The analysis of indication for cesarean delivery.

Aurthor	Fetal distress		Non-reassuring FHRa		Arrest of labour		Dystocia		Chorioamnionitis		Suspition of uterine rupture
	ODb	OCc	ODb	OCc	ODb	OCc	ODb	OCc	ODb	OCc	ODb	OCc
Bioe 2021	26/607	13/591	NRd	NRd	NRd	NRd	62/607	58/591	2/607	1/591	3/607	1/591
Bor 2016	3/100	7/100	2/100	3/100	12/100	15/100	12/100	15/100	1/100	0/100	0/100	2/100
Chookijkul 2016	NRd	NRd	12/47	13/54	NRd	NRd	NRd	NRd	NRd	NRd	NRd	NRd
Chopra 2015	0/53	0/53	NRd	NRd	0/51	1/53	NRd	NRd	NRd	NRd	NRd	NRd
Daniel-Spiegel 2004	NRd	NRd	1/52	3/52	2/52	3/52	NRd	NRd	NRd	NRd	NRd	NRd
Diven 2012	7/125	8/127	7/125	8/127	6/125	7/127	NRd	NRd	NRd	NRd	NRd	NRd
Eissa 2019	NR	NR	3/47	7/41	2/47	3/41	NRd	NRd	NRd	NRd	NRd	NRd
Mitra 2019	NR	NR	10/100	10/100	4/100	5/100	NRd	NRd	3/100	4/100	NRd	NRd
Ozturk 2015	2/66	2/64	NRd	NRd	0/66	1/64	NRd	NRd	NRd	NRd	NRd	NRd
Ustunyurt 2007	4/168	6/174	NRd	NRd	4/168	6/174	NRd	NRd	NRd	NRd	NRd	NRd
No. of events	42/1119	36/1109	35/471	44/474	30/709	41/711	74/707	73/691	6/807	5/791	3/707	3/691
No. of studies	6		6		8		2		3		2
Overall effect (P-value)	0.51		0.35		0.18		0.96		0.78		0.98
RR 95%CI	1.16 [0.75, 1.80]		0.82 [0.54, 1.24]		0.74 [0.47, 1.15]		0.99 [0.73, 1.35]		1.17 [0.38, 3.61]		0.98 [0.22, 4.34]

aFHR: fetal heart rate;

bOD: discontinued oxytocin;

cOC: continued oxytocin;

dNR: not reported

3.2 Maternal outcomes

Six studies including 2015 women reported the correlation between discontinued oxytocin and uterine tachysystole (Fig 7). A significant decrease in the uterine tachysystole risk was observed in the OD group versus the OC group [RR (95% CI): 0.36 (0.27–0.49), P<0.00001]. We found no evidence of statistical heterogeneity. To assess postpartum hemorrhage, eight studies including 2484 patients were employed (Fig 8). Its risk reduced significantly in the discontinued oxytocin group [RR (95% CI): 0.78 (0.65–0.93), P = 0.006]. No significant heterogeneity was found across included studies. Two studies including 1450 patients explored the effect of discontinued oxytocin on chorioamnionitis, and we found a possible increased risk of chorioamnionitis in OD group without significant heterogeneity [RR (95% CI): 2.27 (1.02–5.08), P = 0.05] (Fig 9). However, no intergroup differences were found for other maternal outcomes such as vaginal instrumental delivery, epidural use, third- or fourth-degree perineal tear, and exclusive breastfeeding at discharge, see pooled Table 6.

Fig 7

Pooled results for each outcome.

Fig 8

Pooled results for each outcome.

Fig 9

Pooled results for each outcome.

Table 6

Pooled outcomes for this meta-analysis.

Outcome	No. of studies	No. of patients	Statistical method	Effect size	GRADE summary
1 Caesarean delivery	12	3270	Risk Ratio (M-H, Fixed, 95% CI)	0.84 [0.72,0.98]	Very low
2 Duration of the active phase of labour	9	1536	Mean Difference (IV, Random, 95% CI)	22.28 [2.86, 41.71]	Very low
3 Duration of the second phase of labour	8	2412	Mean Difference (IV, Fixed, 95% CI)	5.36 [3.18, 7.54]	Low
4 Delivery time	6	2090	Mean Difference (IV, Random, 95% CI)	20.17 [-24.92, 65.26]	Very low
5 Vaginal instrumental delivery	7	2246	Risk Ratio (M-H, Fixed, 95% CI)	0.93 [0.72, 1.20]	Low
6 Uterine tachysystole	6	2015	Risk Ratio (M-H, Fixed, 95% CI)	0.36 [0.27, 0.49]	Moderate
7 Epidural use	4	1754	Risk Ratio (M-H, Random, 95% CI)	1.04 [0.93, 1.17]	Very low
8 Chorioamnionitis	2	1450	Risk Ratio (M-H, Fixed, 95% CI)	2.27 [1.02, 5.08]	Low
9 Third- or fourth-degree perineal tear	2	1212	Risk Ratio (M-H, Fixed, 95% CI)	0.84 [0.51, 1.40]	Moderate
10 Postpartum haemorrhage	8	2482	Risk Ratio (M-H, Fixed, 95% CI)	0.78 [0.65, 0.93]	Moderate
11 Exclusive breast feeding at discharge	1	1158	Risk Ratio (M-H, Random, 95% CI)	1.03 [0.95, 1.12]	Very low
12 Non-reassuring FHR	11	2893	Risk Ratio (M-H, Fixed, 95% CI)	0.66 [0.58, 0.76]	Low
13 Apgar score at 5 mint <7	6	2291	Risk Ratio (M-H, Fixed, 95% CI)	0.94 [0.46, 1.94]	Low
14 Arterial umbilical pH< 7.10	5	2071	Risk Ratio (M-H, Fixed, 95% CI)	1.02 [0.71, 1.47]	Low
15 Neonatal asphyxia	2	1298	Risk Ratio (M-H, Fixed, 95% CI)	0.57 [0.17, 1.87]	Moderate
16 NICU admission	9	2920	Risk Ratio (M-H, Fixed, 95% CI)	0.81 [0.63, 1.06]	Very low

3.3 Neonatal outcomes

Eleven studies with a total of 2893 women reported the non-reassuring FHR result in discontinued versus continued oxytocin group (Fig 10). The pooled result demonstrated that the risk of non-reassuring FHR significantly decreased in the discontinued group [RR (95% CI): 0.66 (0.58–0.76), P<0.00001]. And we found no evidence of statistical heterogeneity. Other neonatal outcomes including Apgar score at 5 mint <7, arterial umbilical pH< 7.10, neonatal asphyxia, and NICU admission are not statistically different between groups (Table 6).

Fig 10

Pooled results for each outcome.

3.4 Induction delivery interval

The association between discontinued oxytocin infusion and the duration of active labor was analyzed in 9 studies involving 1536 patients (Fig 11). The pooled result indicated that discontinued may prolong the active stage of labor compared to continued oxytocin [MD (95% CI): 22.28 (2.86–41.71), P = 0.02]. The heterogeneity was statistically significant, then a random-effect modal was used. Similarly, the duration of the second labor was prolonged when the oxytocin is discontinued compared to continued group [MD (95% CI): 5.36 (3.18–7.54), P<0.00001, 8 trails, 2412 women] (Fig 12). The fixed-effect modal was chosen since no substantial heterogeneity was found. However, total delivery duration was not significantly different between discontinued and continued oxytocin groups [MD (95% CI): 20.17 (-24.92–65.26), P = 0.38, 6 trails, 2090 women] (Fig 13). The detected heterogeneity was significant, so we used a random-effect model for pooling the result.

Fig 11

Pooled results for each outcome.

Fig 12

Pooled results for each outcome.

Fig 13

Pooled results for each outcome.

Discussion

1) Main findings and interpretation

13 RCTs with 3374 women were included in this review for comparing OD and OC in the induction of labour after the active phase was reached. The pooled results indicated that the discontinued oxytocin could reduce the risk of cesarean section, uterine tachysystole, postpartum hemorrhage, and non-reassuring FHR, without evidence of increasing the maternal and neonatal complications. Surprisingly, we observed an uncertain effect of discontinuation of oxytocin on the risk of maternal chorioamnionitis. Furthermore, the duration of the active and second stage of labor was significantly increased in OD group, yet the total delivery time was similar between groups.

2) Comparison with other studies

On this issue, 3 meta-analysis and 1 Cochrane systematic review has been published until now [19-22]. Vlachos, Saccone, and Hernández-Martínez et al. [19-21] found that discontinued oxytocin could significantly decrease the risk of cesarean delivery and uterine tachysystole. Our pooled result indicated that when the analysis was restricted in the women who really reached the active phase, the effect was not evident anymore. And this result coincides with a previous review by Boie et al. [22], yet our meta-analysis includes three most recent RCTs with 79% more women. Moreover, we found a decreased non-reassuring FHR risk in the OD group, which is opposite to the conclusion by Saccone et al. [20]. In our review, discontinued oxytocin increased the duration of active labor, while Vlachos and Hernández-Martínez et al. [19, 21] found no differences. The duration of second labor was also observed increased in OD group, which is not coincided with Saccone et al. [20]. In addition, the total delivery time was not different between groups, consist with previous reviews by Vlachos and Hernández-Martínez et al. [19, 21]. In contrast to Boie et al. [22], our review found an increased risk for chorioamnionitis in the discontinued oxytocin group. Of note, the p-value of 0.5 indicated that the conclusion should be interpreted with caution. And, we reported two additional outcomes compared to previous meta-analysis [19-22], the risk of neonatal asphyxia and exclusive breastfeeding at discharge were not significantly different between groups.

3) Strengths and limitations

One main strength of this review is that three recent trails are included with approximately 79% more women [22]. Additionally, the publication bias for the main outcome was also analyzed. The main limitation is the high heterogeneity of inclusion criteria and oxytocin protocol across included studies. Since no standard oxytocin scheme exists, starting dose, increasing dose, dilation from which oxytocin was discontinued, criteria for reestablish oxytocin and cesarean section were somewhat different between trails. And the subgroup analysis stratified by parity was not possible due to the limited data. Also, we observed a publication bias for the main result (cesarean section). In the future, includes more studies might be valuable, for example an ongoing trail in 20 maternity units in France with 2475 women [38].

4) Implication

Exploring the optimal scheme for the management of induced labour is of vital importance for improving health outcomes for both the women and infants. Since synthesized in 1954, oxytocin has been the most widely used agent for inducing of labour [4]. Though extensively used, its ideal regimen regarding initial dose, increments, and maximal dose is still a lack of consensus [17, 39, 40]. An important issue to consider is that the use of oxytocin for induced labor is accompanied by an adverse effect of uterine hyperstimulation, which may causes adverse outcomes for maternal and fetus [6-12]. A long episode of induced labor is associated with uterine atony and postpartum bleeding that can not be stopped by oxytocin, which may caused by desensitized oxytocin receptor [41]. There is evidence indicates that the oxytocin of more than 10 hours’ use may have no effect or even adverse effect on uterine contractility [10, 42]. Moreover, the process of labor is demonstrated as self‑sustaining after the active labor is established [18]. Accordingly, it seems rational to discontinue oxytocin infusion once establishing the active stage. However, there are not enough proof to know whether the oxytocin should be continued or stopped when the active stage is already established.

The result of our meta-analysis indicates that continued oxytocin leads to a decreased duration of active and second phase of labour, while the total delivery time is not different. However, this effect is accompanied by increased adverse outcomes for both maternal and neonatal, including uterine tachysystole, postpartum hemorrhage, and non-reassuring FHR. It might also be related to an increased risk of chorioamnionitis, yet the conclusion should be interpreted with caution. Taken together, continuing oxytocin infusion when active labour is already established might be inappropriate considering the adverse maternal and fetal outcomes. Future research are needed to confirm our conclusion and clarify the necessity of oxytocin discontinuation after the active labor is already established.

Conclusion

Once the active phase is established, continuation of oxytocin will not accelerate the total duration of labour and seems to lead to an increased risk of uterine tachysystole, postpartum hemorrhage, and non-reassuring FHR. In addition, a possible raised risk for chorioamnionitis is also observed. Therefore, it is the time for considering discontinuing its infusion after the active phase for avoiding those adverse maternal and neonatal outcomes.

PRISMA 2009 checklist.

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28 Dec 2021

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Reviewer #1: The regimens of oxytocin during labour vary widely between different guidelines or even individual medical centers, that is why this study about oxytocin administration beyond the active phase is interesting.

Please, provide an explanation for the following comments:

1- If oxytocin discontinuing could decrease the risk of cesarean delivery, how this effect decreased in women who had cesarean operation? Is that affected by other factors like previous cesarean section or other factors that require cesarean intervention?

2- Oxytocin is a drug, regarding dosing protocol: would not different doses result in different responses?

3- The included studies reported different inclusion criteria for the patients, which in turn can affect the analysis?

4- Chorioamnionitis is analyzed, but some patients were enrolled with PROM. How could these affect the result?

5- In table 5, provide a row / column with the total number of events of each arm of the study?

6- Many studies have multiple high risk of bias points, How such studies can be trusted to get an accurate and reliable analysis?

Reviewer #2: Overall, this is an interesting relevant research question and represent a valuable addition to the Labor management approaches. The authors have collected sufficient dataset from the eligible trials and analyzed relevant variables that directly linked to the handled question. The analysis and results interpretation were clear, direct, and illustrated in a well-organized structure. The discussion structure and sequence were enriching and highlighted the important issues related to the study results.

The objective is clearly stated through informative title reflect the true nature of the review; page (1) and the well- structured introduction context; page (2, 3). The methodology was detailed and suitable for the research idea. Performing manual search of references (page (3) method section, Literature search paragraph, last sentence) and Publication bias assessment using the GRADE approach (page (4) method section, Data abstraction, second paragraph, third sentence), are thought to reinforce the design and the quality assessment, respectively. The results were clearly illustrated and neutrally discussed, with useful summary in the pooled outcomes; table (6) page (14) and the analysis was sufficient as well. The authors discussed the oxytocin effect using not just maternal outcomes but also neonatal and delivery interval as well which provide more accuracy to the conclusion; page (16) paragraph 3.3 and 3.4. The thorough discussion was well-structured and handled the relevant literature with results implication along with the existed conflict between using Continued vs discontinued oxytocin based on the available evidence (page 17, paragraph 3). Figures and tables were clearly presented and correctly labelled.

Minor issues:

1) In Method section in Data abstraction part, page (4) first paragraph; the author mentioned an extracted variable (setting, mentioned as a part of General information) that was not obtained in the characteristics table; page (7).

2) In Result section, there are two mistakes in the reported data compared with the labelled analysis figures.

- page (13), Maternal outcomes paragraph, Fifth sentence: ''Moreover, we found a possible increased risk of chorioamnionitis in the OD group without significant heterogeneity [RR (95% CI): 2.77 (1.02–5.08), P=0.05] (Fig 5e)''. RR is supposed to be 2.27 as shown in fig 5e. Also, the number of trials from which these results were analyzed and the number of patients are recommended to mentioned in this sentence.

- Page (16), Induction delivery interval paragraph, second sentence: ''The pooled result indicated that discontinuation may prolong the active stage of labor compared to continued oxytocin [MD (95% CI): 2.28 (2.86–41.71), P=0.02]''. RR is supposed to be 22.28 as shown in fig 5g.

3) In Discussion Section in Comparison and Implication parts (Page 17 and 18, respectively), there was a lack of reported statistical data of the results and conclusions discussed from the literature. The statistical data are important and reinforce the flow of the discussion.

In brief, the paper is generally well thought out and written, accessible data statistically analyzed in sufficient detailed manner, the conclusions well supported by the data presented in the results and figures, and with no conflict of interests. Thus, we recommend its acceptance, with some minor corrections regarding the issues previously mentioned.

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4 Feb 2022

Response to reviewers

Reviewer #1: The regimens of oxytocin during labour vary widely between different guidelines or even individual medical centers, that is why this study about oxytocin administration beyond the active phase is interesting. Please, provide an explanation for the following comments.

Dear reviewer#1:

Thank you for your comments concerning our manuscript entitled “Continued versus discontinued oxytocin after the active phase of labor: An updated systematic review and meta-analysis”. Those comments are all valuable and very helpful for revising and improving our paper, as well as the important guiding significance to our researches. We have studied these comments carefully and tried our best to revise and imporve the manuscript. We sincerely hope that it will meet with approval.

Response to the comments:

1- If oxytocin discontinuing could decrease the risk of cesarean delivery, how this effect decreased in women who had cesarean operation? Is that affected by other factors like previous cesarean section or other factors that require cesarean intervention?

Response: Thanks very much for your valuable comment. Women with a history of prior cesarean delivery were excluded in seven trials (Begum 2013; Chookijkul 2016; Chopra 2015; Diven 2012; Eissa 2019; Mitra 2019; Ustunyurt 2007). For the remnant six studies, they may include patients with previous cesarian delivery, but specific data were limited. So a separate analysis just on the history of cesarian delivery is not possible. We sincerely hope that, with further studies with a larger sample size that stratify by previous cesarean section, can deepen our understanding to this issue. And other factors that require cesarean intervention were already assessed by the authors when performing the study, the exact items are in the exclusion criteria of each study. Since we do not present with the exclusion criteria of 13 studies, we are sorry for confusing you. Thanks again for your careful comment.

2- Oxytocin is a drug, regarding dosing protocol: would not different doses result in different responses?

Response: Thanks for your comment. The drug protocols are somewhat different, but for all trials the procedure corresponded to a low-dose regimen, and this makes the impact to some extent mild across studies (Budden 2014). Though oxytocin has been used for induction of labor for many years, there is no consensus regarding the ideal dosing regimen. Thus, it is impossible to unify the usage dose in all trials around the world. Actually, we totally agree with your comment that different doses may have different responses, and we have discussed this content in 'Strengths and limitations' part. And we do hope, a consensus for oxytocin use may exist as soon as possible with the continuous progress of research in this field.

Reference: Budden A, Chen LJ, Henry A. High-dose versus low-dose oxytocin infusion regimens for induction of labour at term. Cochrane Database Syst Rev. 2014;(10):CD009701. doi:10.1002/14651858.CD009701.pub2

3- The included studies reported different inclusion criteria for the patients, which in turn can affect the analysis?

Response: The inclusion criteria for each trial is somewhat, but they all correspond to the application indication for induction of labor. Since the patients in each hospital are different, it is impossible to include exactly the same patients for every trial. And we do have the same worry as you that different inclusion criteria may affect the analysis, so we discussed this issue in the 'Strengths and limitations' part. In the furture, large multi-center research may help further answer this question.

4- Chorioamnionitis is analyzed, but some patients were enrolled with PROM. How could these affect the result?

Response: Thanks for your comment. There are 2 of the total 13 studies that included patients with PROM （Bioe 2021; Daniel-Spiegel 2004）. Since the primary results were not separately reported according to whether patients had PROM or not, it is not possible for us to do a separate analysis. Your opinion also inspired us a lot. As the application of oxytocin in the induction of labor becomes more and more clear, it may be beneficial to carry out such research in the PROM subgroup in the future for exploring the potential effect of oxytocin in chorioamnionitis. Thanks again for your hard work on our study.

5- In table 5, provide a row / column with the total number of events of each arm of the study?

Response: Thank you for your comment. We totally agree with your opinion and had added a column with the total number of events according to your suggestion, see Table 5. Thanks for your warm work on our article.

6- Many studies have multiple high risk of bias points, How such studies can be trusted to get an accurate and reliable analysis?

Response: Thanks for the comment. We examined the quality of the overall body of the evidence for the outcomes using GRADE. As you said, our GRADE assessments ranged from very low certainty to moderate certainty. Overall, some of the included trials had some design limitations. Luckily, we found high consistency for our primary outcome, cesarean delivery rate. And this, indicates a highly reliable conclusion. However, the effects on other outcomes should be interpreted with caution. And in the future, further high-quality studies are needed to confirm our conclusion. Appreciate your warm work on this article earnestly.

Again, we appreciate your warm work earnestly and thank you very much for your comments and suggestions to our paper. All the authors have studied your comments carefully, we think it is important guidance to our paper. Exploring the optimal scheme for the management of induced labor is of vital importance for improving health outcomes for both women and infants. Though extensively used, its ideal regimen regarding initial dose, increments, and maximal dose of oxytocin is still a lack of consensus. In recent years, discontinuing oxytocin infusion when the active phase of labor is reached gains much attention. However, there is not enough proof to know whether the oxytocin should be continued or stopped when the active stage is already established. As you said, there are some design limitations of studies on this topic, and we do hope to poll the related data and decrease this bias by expanding the sample size through the meta-analysis. In the future, large multi-center research may help further answer this question. Once again, thank you for your hard work during this special time of the COVID-19 pandemic, hope all is well with you and your family.

Thank you and best regards.

Sincerely yours,

Nie Xiaocui

________________________________________

Reviewer #2: Overall, this is an interesting relevant research question and represent a valuable addition to the Labor management approaches. The authors have collected sufficient dataset from the eligible trials and analyzed relevant variables that directly linked to the handled question. The analysis and results interpretation were clear, direct, and illustrated in a well-organized structure. The discussion structure and sequence were enriching and highlighted the important issues related to the study results.

The objective is clearly stated through informative title reflect the true nature of the review; page (1) and the well- structured introduction context; page (2, 3). The methodology was detailed and suitable for the research idea. Performing manual search of references (page (3) method section, Literature search paragraph, last sentence) and Publication bias assessment using the GRADE approach (page (4) method section, Data abstraction, second paragraph, third sentence), are thought to reinforce the design and the quality assessment, respectively. The results were clearly illustrated and neutrally discussed, with useful summary in the pooled outcomes; table (6) page (14) and the analysis was sufficient as well. The authors discussed the oxytocin effect using not just maternal outcomes but also neonatal and delivery interval as well which provide more accuracy to the conclusion; page (16) paragraph 3.3 and 3.4. The thorough discussion was well-structured and handled the relevant literature with results implication along with the existed conflict between using Continued vs discontinued oxytocin based on the available evidence (page 17, paragraph 3). Figures and tables were clearly presented and correctly labelled.

Dear reviewer#2:

Thank you very much for your comments concerning our manuscript entitled “Continued versus discontinued oxytocin after the active phase of labor: An updated systematic review and meta-analysis”. Those comments are all valuable and very helpful for revising and improving our paper. We have studied these comments carefully and tried our best to revise and imporve the manuscript. We sincerely hope that it will meet with approval. Again, we appreciate your positive evaluation of our work. Thank you for your hard work in this difficult time of the COVID-19 pandemic, hope all is well with you and your family.

Response to the comments:

1) In Method section in Data abstraction part, page (4) first paragraph; the author mentioned an extracted variable (setting, mentioned as a part of General information) that was not obtained in the characteristics table; page (7).

Response: Thanks for your comment. The ‘setting’ we mentioned means the background of the study, it includes the author, publication year, and country of the study. We are so sorry that our inaccurate word confused you and we have deleted this word from the ‘Data abstraction part’. Thanks again.

2) In Result section, there are two mistakes in the reported data compared with the labelled analysis figures.

- page (13), Maternal outcomes paragraph, Fifth sentence: ''Moreover, we found a possible increased risk of chorioamnionitis in the OD group without significant heterogeneity [RR (95% CI): 2.77 (1.02–5.08), P=0.05] (Fig 5e)''. RR is supposed to be 2.27 as shown in fig 5e. Also, the number of trials from which these results were analyzed and the number of patients are recommended to mentioned in this sentence.

- Page (16), Induction delivery interval paragraph, second sentence: ''The pooled result indicated that discontinuation may prolong the active stage of labor compared to continued oxytocin [MD (95% CI): 2.28 (2.86–41.71), P=0.02]''. RR is supposed to be 22.28 as shown in fig 5g.

Response: Thank you very much for your careful comment. We are so sorry for the mistake and made corrections in accordance with your comment. Also, we added the number of trials from which these results were analyzed in the sentence. Thanks.

3) In Discussion Section in Comparison and Implication parts (Page 17 and 18, respectively), there was a lack of reported statistical data of the results and conclusions discussed from the literature. The statistical data are important and reinforce the flow of the discussion.

Response: Thanks for your comment. We totally agree with your comment that statistical data are very important and we had put them in the initial version of our manuscript. However, when we submitted the manuscript to the journal, the 'Instruction for authors' part suggests we delete the repeat comment to make the article concise and readable. So deleted this content when we submitted the article since all the statistical data had been presented in Table 6.

We tried our best to improve the manuscript and made some changes in the manuscript according to your comments. We hope the corrections will meet with approval. Again, we appreciate your warm work earnestly during this hard time of COVID-19, and we hope all is good for you and your family. Looking forward to hearing from you.

Thank you and best regards.

Sincerely yours,

Nie Xiaocui

________________________________________

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

11 Apr 2022

Continued versus discontinued oxytocin after the active phase of labor: an updated systematic review and meta-analysis.

PONE-D-21-15843R1

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Reviewer #1: All comments have been addressed

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Reviewer #1: Yes

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22 Apr 2022

PONE-D-21-15843R1

Continued versus discontinued oxytocin after the active phase of labor: An updated systematic review and meta-analysis.

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