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Contents lists available at ScienceDirect

Women and Birth

journal homepage: www.elsevier.com/locate/wombi

High-dose versus low-dose of oxytocin for labour augmentation:

a randomised controlled trial
Lotta Selina,b,* , Ulla-Britt Wennerholmc , Maria Jonssond , Anna Denckera,e ,
Gunnar Wallinc , Eva Wiberg-Itzelf , Elisabeth Almströmb , Max Petzoldg , Marie Berga,h
a
University of Gothenburg, Institute of Health and Care Sciences, Sahlgrenska Academy, Gothenburg, Sweden
b
NU-Hospital Group, Department of Obstetrics and Gynecology, Trollhättan, Sweden
c
University of Gothenburg, Department of Obstetrics and Gynecology, Institute for Clinical Sciences, Sahlgrenska Academy, Gothenburg, Sweden
d
Uppsala University, Department of Women’s and Children’s Health, Uppsala, Sweden
e
University of Gothenburg, Centre for Person-centred Care, Sahlgrenska Academy, Gothenburg, Sweden
f
Karolinska Institute, Soder Hospital, Department of Clinical Science and Education, Section of Obstetrics and Gynaecology, Stockholm, Sweden
g
University of Gothenburg, Health Metrics Unit, The Sahlgrenska Academy, Gothenmurg, Sweden
h
Sahlgrenska University Hospital, Obstetric Unit, Gothenburg, Sweden

A R T I C L E I N F O A B S T R A C T

Article history: Problem: Delayed labour progress is common in nulliparous women, often leading to caesarean section
Received 6 July 2018 despite augmentation of labour with synthetic oxytocin.
Received in revised form 8 September 2018 Background: High- or low-dose oxytocin can be used for augmentation of delayed labour, but evidence for
Accepted 10 September 2018
promoting high-dose is weak.
Available online xxx
Aim To ascertain the effect on caesarean section rate of high-dose versus low-dose oxytocin for
augmentation of delayed labour in nulliparous women.
Keywords:
Methods Multicentre parallel double-blind randomised controlled trial (ClinicalTrials.gov: NCT01587625) in
Augmentation of labour
Delayed labour
six labour wards in Sweden. Healthy nulliparous women at term with singleton cephalic fetal presentation,
Oxytocin spontaneous labour onset, confirmed delay in labour and ruptured membranes (n = 1351) were randomised to
Caesarean labour augmentation with either high-dose (6.6 mU/minute) or low-dose (3.3 mU/minute) oxytocin infusion.
Nulliparous Findings: 1295 women were included in intention-to-treat analysis (high-dose n = 647; low-dose n = 648).
Caesarean section rates did not differ between groups (12.4% and 12.3%, 95% Confidence Interval 3.7 to 3.8).
Women with high-dose oxytocin had: shorter labours ( 23.4 min); more uterine tachysystole (43.2% versus
33.5%); similar rates of instrumental vaginal births, with more due to fetal distress (43.8% versus 22.7%) and
fewer due to failure to progress (39.6% versus 58.8%). There were no differences in neonatal outcomes.
Discussion: Our study could not confirm results of two systematic reviews indicating, with weak evidence,
that use of high-dose oxytocin was associated with lower frequency of caesarean section.
Conclusion: We found no advantages for routine use of high-dose oxytocin in the management of delay in
labour. Low-dose oxytocin regimen is recommended to avoid unnecessary events of tachysystole and fetal
distress.
© 2018 The Authors. Published by Elsevier Ltd on behalf of Australian College of Midwives. This is an open
access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

oxytocin is usually used for augmentation of labour, but

Statement of significance does have side-effects.

What is already known

Problem
Evidence for promoting high-dose synthetic oxytocin for
Delayed labour progress is common in nulliparous women, augmentation of labour, above low-dose, is weak.
and often leads to emergency caesarean section. Synthetic
What this paper adds

* Corresponding author at: Institute of Health and Care Sciences, Sahlgrenska High-dose oxytocin as compared to low-dose was not
Academy at the University of Gothenburg, 405 30 Gothenburg, Sweden. associated with a lower frequency of caesarean section
E-mail address: lotta.selin@vgregion.se (L. Selin).

https://doi.org/10.1016/j.wombi.2018.09.002
1871-5192/© 2018 The Authors. Published by Elsevier Ltd on behalf of Australian College of Midwives. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: L. Selin, et al., High-dose versus low-dose of oxytocin for labour augmentation: a randomised controlled trial,
Women Birth (2018), https://doi.org/10.1016/j.wombi.2018.09.002
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and led to more uterine tachysystole (43.2% versus 33.5%), 2.2. Participants
and similar rates of instrumental vaginal births, with more
due to fetal distress (43.8% versus 22.7%) and fewer due to Eligible for inclusion were healthy,21 nulliparous women with
failure to progress (39.6% versus 58.8%). Low-dose oxytocin
normal singleton pregnancies at term (37 + 0 to 41 + 6 gestational
is preferable for use to avoid unnecessary events of
weeks), cephalic presentation, spontaneous onset of labour, active
tachysystole and fetal distress.
phase of labour (regular painful contractions and effaced cervix
and dilation 3–4 cm), confirmed delayed labour progress, and
ruptured membranes. Exclusion criteria were: age < 18 years, non-
Swedish speaking, previous uterine surgery, clinically significant
1. Introduction
vaginal bleeding during labour, delayed labour progress with fetal
head station below the ischial spines in second stage, suspected
Delayed labour progress is common in nulliparous women, and
disproportion between fetal head and maternal pelvis, abnormal
is among the leading indications for emergency caesarean section
vertex presentation, suspected fetal growth restriction (< 2
(CS).1–4 Synthetic oxytocin is one of the most frequently used
standard deviations [SD]),22 abnormal fetal heart rate (FHR)
medications in obstetric care5 and the common routine for
(suspicious or pathological cardotocograph), heavy meconium
augmentation of labour. However, the effectiveness of oxytocin
stained amniotic fluid, uterine tachysystole (defined as >5
for treating abnormal progress has been questioned.3,6,7 Despite
contractions during 10 min for >20 min), maternal fever, and
that, over time an increased use of oxytocin during labour has been
known hypersensitivity to oxytocin therapy. If any eligible women
noted. An unstructured manner of using the drug prevails,8,9 and
were already receiving oxytocin they were not included in the
its use can lead to hyperactive uterine contractions, which have
study, and women could be admitted to the study when delayed
been associated with negative effects on the fetus.10–12 Therefore,
progress was identified at any stage of dilation (greater than 3–
oxytocin has been designated as a high-alert medication.13
4 cm), or even in the second stage.
Checklists and standardised protocols for the use of oxytocin have
been recommended with the aim of reducing adverse neonatal
2.3. Randomisation and procedure
outcomes.14,15
A meta-analysis of 8 trials comparing high and low dose
The study was conducted according to the study protocol with
oxytocin for induction of labour found no difference in CS rates,
two exceptions: women were asked to participate when delayed
although more “uterine hyperstimulation” was noted in the high
labour was confirmed instead of being asked to participate at
dose group.16 Knowledge and consensus are lacking, however,
admission and, there was a change to a computer-generated
regarding the proper dosage when oxytocin is used for accelerating
randomisation system instead of using sealed envelopes.
slow progress of labour.17 Women’s experience of childbirth and
Delayed labour was defined in accordance with the Swedish
pain in relation to oxytocin dosage is also insufficiently studied.
National recommendations,23 by using a three-hour partogram
Systematic reviews on the dosage of oxytocin17,18 have found that a
action line for delay during the first stage of labour or an arrest of
high-dose (4–10 mU/min) compared to low-dose (1–4 mU/min)
the descent of the fetal head for one to two hours during the second
oxytocin regimen for treating delayed labour progress may reduce
stage of labour. If a delayed labour was diagnosed together with
the risk of CS by 15%,18 or by as much as 46%,17 without any
intact membranes, amniotomy was performed. One hour later, an
negative maternal or neonatal outcomes. However, the evidence
assessment was performed and, if there was no further progress,
for prioritising high-dose oxytocin is weak, and the Cochrane
augmentation with oxytocin infusion was indicated. The woman
review on this topic (based on only four trials) recommended
received written and oral information about the study from the
further research.17 The need for further investigations has been
midwife.
highlighted, especially on neonatal outcomes and on women’s
Consenting women were randomly allocated to receive a
childbirth experiences in relation to oxytocin dosage.18,17More
regimen of either a high-dose or a low-dose of oxytocin (33.2 or
randomised controlled trials (RCTs) are justified to determine the
16.6 mg oxytocin in 1000 ml isotonic saline solution), respectively).
effect of oxytocin augmentation on the likelihood of CS and other
These doses were chosen based on the definitions for low and high
outcomes including women’s satisfaction with care, which has
dose included in the latest Cochrane review on this topic.17
been emphasised by the British Maternal and Foetal Medicine
Randomisation was generated by an external information technol-
Society.19
ogy-consultant using a computer-generated randomisation se-
The overall aim of the study was to ascertain the effect on
quence, with allocation 1:1 ratio. There was no stratification by
caesarean section rate of high-dose versus low-dose oxytocin for
maternity unit. Randomisation and preparation of the oxytocin
augmentation of delayed labour in nulliparous women. The
infusion according to the allocated dosage were handled by
hypothesis, based on weak evidence form a previous Cochrane
external staff, not working at the labour ward. Allocation was
review,17 was that a high-dose oxytocin regimen, compared to a
blinded for responsible staff, the woman in labour and for the
low-dose, will reduce the number of CSs without negative
research team. The random codes were revealed after completion
maternal and neonatal outcomes.
of data collection and after the data file was closed.
In the high-dose group, the infusion started with 6.6 mU
2. Methods oxytocin/min (20 ml/h), and could be increased every 20 min by
6.6 mU to a maximum dose of 59.4 mU/min. In the low-dose group
2.1. Study design and setting the infusion started with 3.3 mU oxytocin/min (20 ml/h), and could
be increased every 20 min by 3.3 mU to a maximum dose of
A parallel double-blind, multicentre, randomised controlled 29.7 mU oxytocin/min. The recommended standard dose in
trial (RCT) was conducted in accordance with the CONSORT Sweden for oxytocin augmentation corresponds to the low-dose
guidelines20 in four maternity units in Sweden including six labour regimen in this study.23 When more than 1000 ml of infusion with
wards: (removed for anonymity). The wards entered the study at oxytocin was needed, the next oxytocin infusion, which was given
different time points between September 2013 and June 2016. Data to women in both groups, was the recommended standard dose
collection was completed in October 2016. Supplementary data on (3.3 mU oxytocin/min) as clinicians would not know which
the participating labour wards are shown in Table S1. strength had been given the first time. This was required for only

Please cite this article in press as: L. Selin, et al., High-dose versus low-dose of oxytocin for labour augmentation: a randomised controlled trial,
Women Birth (2018), https://doi.org/10.1016/j.wombi.2018.09.002
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32 women (10 in high dose group and 22 in low dose group), 2.5% 2.5. Data collection
of the total and 1.5% of the high dose group.
In both groups the infusion was increased until adequate Characteristics of study participants, and obstetric and neonatal
uterine contractions were obtained, and progress of labour was data, were collected from the electronic medical record at each
established (i.e. dilation of cervix and descent of the fetal head), or hospital (Obstetrix1 or Cosmic1). Data from the checklist protocol
occurrence of a maximum of five contractions in 10 min. The were reported in a shared internet database by the local research
monitoring and documentation of labour progress included midwife. Delayed labour progress defined by the midwife or the
assessment of maternal and fetal status and followed the study obstetrician in charge of each woman was verified retrospectively
protocol and established routines based on national and by the local research midwives. All manually entered data were
departmental guidelines. In a checklist protocol, frequency of double-checked.
contractions every 10 min and electronic FHR pattern (normal/ The primary outcome was the rate of CS in labour. Secondary
suspicious/pathological cardiotocography24[CTG]) were assessed maternal outcomes were: instrumental vaginal birth, spontaneous
and documented at every change of infusion rate, and once per vaginal birth, main indication for CS and instrumental vaginal birth
hour after a therapeutic dose was obtained. Maternal blood (fetal distress, failure to progress or other indications), duration of
pressure (at start of oxytocin infusion and once per hour for an labour (min), postpartum haemorrhage (>500 ml; >1000 ml),
oxytocin rate  180 ml/h) was registered. Adverse events (AEs) manual removal of placenta, anal sphincter injury (grade 3 or
categorised as mild, moderate or severe were documented and 4), fever during labour (>38.0 grade for two occasions after
evaluated. antipyretic medication), uterine tachysystole, total dose of
oxytocin (mg), maximum oxytocin dose per minute (mg/min),
2.4. Ethical issues total duration of oxytocin infusion (hour), oxytocin stopped or
reduced temporarily, oxytocin stopped or reduced temporarily due
The study was approved by (removed), and by (removed). All to tachysystole together with suspicious or pathological FHR
women gave informed, written consent to take part. An indepen- pattern. Neonatal outcomes included: Apgar score at 5 min <4 or
dent Data and Safety Monitoring Board (DSMB) secured the project <7; metabolic acidosis (umbilical cord arterial pH < 7.05 and base
management through periodical reviews and an interim analysis of excess  12 or umbilical cord arterial pH < 7.0), fetal distress
study specific data. A security team was established for the (pathological CTG), intrapartum thick meconium stained amniotic
assessment of serious adverse events (SAEs). At each maternity fluid, admission to neonatal intensive care unit (NICU) and number
unit there was a local principal investigator and a local research of days stayed at NICU. Women’s total experience of labour pain
midwife responsible in charge for continuous supervision of and their childbirth experience using the Childbirth Experience
security and labour management. Questionnaire25 will be reported later.

Fig. 1. CONSORT flow diagram.

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2.6. Analysis For exploratory purposes, an interaction analysis was per-

formed for relevant baseline variables and dose group in relation to
The sample size was based on an assumed decrease of the CS the primary outcome variable CS rate. If interactions were
rate from 17.5% to 13% i.e. a reduction of 25%. This required a total significant (p < 0.05), subgroup analyses were performed.
sample size of 2090 woman for 80% power at a significance level of
p < 0.05. The rate of 17.5% was based on an earlier study of the same 3. Results
target group i.e. CS rate among nulliparous women with delayed
labour9 . A reduction of 25% was regarded as a clinically relevant On May 30, 2016 the DSMB recommended the Steering
reduction. Committee to stop the study because of futility as there was no
The independent DSMB reviewed the data periodically, using a statistically significant difference in CS between the high-dose or
group sequential method based on Haybittle-Peto rule to control low-dose group. The numeric difference between the two study
for benefits and harms and need for early stopping of the trial.26 groups was extremely small and the interim results suggested that
After the sixth planned safety review, DSMB recommended it was unlikely to achieve statistical significance with a completed
termination of the trial for futility.27 That interim analysis, which study.
included 72 primary endpoint events (including CS) in the high- During the study period, 5141 women were assessed for
dose group and 66 in the low-dose group (44% of those projected), eligibility. A total of 1351 out of 2273 women who were eligible
demonstrated a less than 5% conditional power to demonstrate (59.4%) were randomised and 1295 were analysed on an intention
superiority to a p value < 0.05 if the trial were carried to to treat (ITT) basis, 647 in the high-dose and 648 in the low-dose
completion. The Executive Steering Committee and sponsor group. Recruitment and flow are shown in Fig. 1.
accepted this recommendation, and the trial was terminated on In total 56 women were excluded in the ITT analysis. Of these,
June 8, 2016. By completion of follow-up of all included women, 26 women were incorrectly included (induction of labour,
and finalisation of the trial database on March 20, 2017, a total of gestational age < 37 weeks and 42 + 0, hepatitis, <18 years of
160 primary endpoint events (51% of those projected) were age and breech presentation); 27 women had been immediately
available for analysis. excluded after randomisation by the responsible midwife when
Statistical analyses were performed using SPSS 24.0 for detecting incorrectly inclusion and the woman was therefore
Windows (SPSS Inc., Chicago, IL, USA) and SAS 9.4 (SAS Institute deleted from the study. and three women withdrew consent after
Inc., Cary, NC, USA). Primary and secondary outcome data were having been randomisation. Detailed information is given in
analysed on intention to treat (ITT) population and on per protocol Table S2.2.
(PP) population. Categorical variables are presented with n (%) and Included in the ITT analysis were 58 women incorrectly
continuous variables with mean, standard deviation (SD), median, randomized according to inclusion/exclusion criteria: These
first quartile (q1) and third quartile (q3). For the comparison women had either fever during labour, pathological or suspicious
between two groups Fisher’s Exact test was used for dichotomous pathological CTG, fetal head station below the ichial spinae, thick
variables, Chi-square test was used for non-ordered categorical meconium stained amniotic fluid, amniotomy after oxytocin
variables and the Mann-Whitney U-test was used for continuous infusion, adominal pain or myoma. Furthermor 38 women without
variables. Calculation of difference between groups for confidence delayed labour progress and 69 women who did not receive the
interval (CI) in continuous variables was based on bootstrapping.

Table 1
Baseline characteristics of study groups.

Variable High dose of oxytocin Low dose of oxytocin

(n = 647) (n = 648)
Maternal age (years) 29.0 (4.8)29.0 (25.0; 32.0) 29.0 (4.6)29.0 (26.0; 32.0)
BMI at first antenatal visit 24.7 (4.3)23.8 (21.6; 27.0)n = 556 24.5 (4.6)23.7 (21.5; 26.1)n = 574
BMI  30 60 (10.8) 62 (10.8)
n = 556 n = 574
Weight gain during pregnancy (kg) 15.5 (6.2)15.0 (11.0; 19.0)n = 540 14.9 (5.9)15.0 (11.0; 18.0)n = 563
Gestational age (days) 282.0 (7.4)283.0 (277.0; 288.0) 281.7 (6.9)282.0 (278.0; 287.0)
Duration of latent phase (hours) 17.7 (17.3)12.0 (7.0; 23.0)n = 592 18.6 (17.3)13.0 (7.0; 25.0)n = 592
Cervical dilation at admission (cm) 3.47 (1.55)3.00 (3.00; 4.00)n = 604 3.50 (1.60)3.00 (3.00; 4.00)n = 608
Cervical dilation at delayed labour (cm) 6.64 (2.17)6.00 (5.00; 9.00)n = 621 6.75 (2.20)6.00 (5.00; 9.00)n = 636
Delayed laboura n = 621 n = 636
Primary 340 (54.8%) 345 (54.2%)
Secondary 281 (45.2%) 291 (45.8%)
Delayed labour (stage)a n = 621 n = 636
First stage 529 (85.2%) 527 (82.9%)
Second stage 92 (14.8%) 109 (17.1%)
Epidural anaesthesia 555 (85.8%) 553 (85.3%)
Vertex presentation n = 641 n = 639
Occiput anterior 562 (87.7%) 560 (87.6%)
Occiput posterior 64 (10.0%) 60 (9.4%)
Other (military, brow, face) 15 (2.3%) 19 (3.0%)
Birth weight (g) 3655 (442)3652 (3330; 3940) 3621 (430)3605 (3330; 3890)
Birth weight (> = 4500 g) 25 (3.9%) 20 (3.1%)
Small for gestational age < 2 SDb 7 (1.1%) 7 (1.1%)
Female gender in neonates 300 (46.4%) 301 (46.5%)

For categorical variables n (%) is presented.

For continuous variables Mean (SD)/Median (Q1; Q3)/n = is presented.
a
Delayed labour not confirmed in 38 women (included in ITT).
b
Small for gestational age was defined as more than 2 SDs below the Swedish gestational and gender-specific reference curve.

Please cite this article in press as: L. Selin, et al., High-dose versus low-dose of oxytocin for labour augmentation: a randomised controlled trial,
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allocated intervention were also included in the ITT analysis. the maximum dose per minute was higher in the high-dose group
Detailed information is given in Table S2.1. (0.049 mg/min versus 0.031 mg/min; mean difference 0.018 mg/
The baseline characteristics were similar in the two groups min; 95% CI 0.015 to 0.021) (Table 3). There were more women with
(Table 1). There was no difference between the high-dose and the uterine tachysystole in the high-dose group (43.2% versus 33.5%;
low-dose group with respect to the frequency of CS, 80 of 647 difference 9.6%; 95% CI 4.2 to 15.1). The rate of women in whom
women (12.4%) versus 80 of 648 women (12.3%) (difference oxytocin was stopped or reduced temporarily due to uterine
between groups 0.0, 95% CI 3.7 to 3.8) (Table 2). CS rate in the tachysystole together with suspicious or pathological FHR pattern
different participating labour wards is shown in Table S4. was 21.1% in the high-dose group compared with 15.9% in the low-
Secondary maternal and neonatal outcomes are presented in dose group (difference 5.1%, 95% CI 0.8 to 9.5).
Tables 2 and 3. The main indication for CS was failure to progress in The proportion of women experiencing any adverse events did
both high-dose (55.0%) and low-dose groups (62.5%), but the not differ significantly between the high-dose group and the low-
difference was not significant (difference 7.5%, 95% CI 24.0 to dose group, 31/647 (4.8%) and 39/648 (6.0%), respectively
9.0). There were no significant differences in the rate of operative (P = 0.39). Three women in the high-dose group and one in the
vaginal birth or spontaneous vaginal birth between the two low-dose group experienced a serious adverse event (SAE)
regimens. The main indication for operative vaginal birth was fetal (P = 0.37). None of the SAEs were regarded as drug-related. One
distress in the high-dose group (43.8% versus 22.7%, difference woman with a SAE in the high-dose group did not receive
21.1%, 95% CI 7.1 to 35.1) and failure to progress in the low-dose treatment.
group (39.6% versus 58.8%, difference 19.2, 95% CI (-34.1 to 4.3).
Labour duration was 23 min shorter with a high-dose regimen 3.1. Per protocol analysis
of oxytocin (mean difference 23.4 min, 95% CI 45.1 to 1.5). No
statistically significant differences were observed in the neonatal In the per protocol analysis 1130 of 1295 women in ITT analysis
outcomes. In the low-dose group one perinatal death occurred in a were included, 96 incorrectly randomised women and 69 women
child with severe hypoxic encephalopathy. It was regarded as not who did not receive the allocated intervention were excluded.
being related to the study drug. (Tables S2.1 + S2.2). The CS rate was 69/562 (12.3%) in the high-
The total dose of oxytocin used was significantly higher in the dose group and 67/568 (11.8%) in the low-dose group (P = 0.87).
high-dose group compared with the low-dose group (7.98 mg The results were comparable with the results in ITT analyses
versus 5.74 mg; mean difference 2.25 mg, 95% CI 1.48 to 3.02) and (Table S3).

Table 2
Labour outcome.

Variable High dose of oxytocin Low dose of oxytocin p Difference between groups
(n = 647) (n = 648) Mean (95% CI)
Primary outcome
Caesarean section 80 (12.4%) 80 (12.3%) 1.00 0.0 ( 3.7;3.8)
Secondary outcomes
Spontaneous vaginal birth 471 (72.8%) 471 (72.7%) 1.00 0.1 ( 4.9;5.1)
Instrumental vaginal birth 96 (14.8%) 97 (15.0%) 1.00 0.1 ( 4.2;3.9)
Indication for caesarean section 0.623
Fetal distress 21 (26.3%) 17 (21.3%) 5.0 ( 9.4;19.4)
Failure to progress 44 (55.0%) 50 (62.5%) 7.5 ( 24.0;9.0)
Other indications 15 (18.8%) 13 (16.3%) 2.5 ( 10.5;15.5)
Indication for instrumental vaginal birth 0.006
Fetal distress 42 (43.8%) 22 (22.7%) 21.1 (7.1;35.1)
Failure to progress 38 (39.6%) 57 (58.8%) 19.2 ( 34.1; 4.3)
Other indications 16 (16.7%) 18 (18.6%) 1.9 ( 13.7; 9.9)
Duration of labour (minutes) 744 (209)732 (595; 873) 768 (196)759 (635; 891) 0.021 23.4 ( 45.3; 1.5)
From active phase of labour to birth n = 645 n = 648
Fever during labour >38.0 grade 16 (2.5%) 18 (2.8%) 0.87 0.3 ( 2.2;1.6)
Postpartum haemorrhage
>500 (ml) 252 (38.9%) 263 (40.7%) 0.55 1.8 ( 7.3:3.7)
>1000 (ml) 88 (13.6%) 93 (14.4%) 0.74 0.8 ( 4.7;3.1)
Manual removal of placentaa 30 (5.3%) 20 (3.5%) 0.19 1.8 ( 4.3; 0.8)
n = 567 n = 568
Anal sphincter injury (grade 3 or 4)a 26 (4.6%) 29 (5.1%) 0.79 0.5 ( 3.2:2.2)
n = 567 n = 568
Intrapartum thick meconium stained amniotic fluid 34 (5.3%) 38 (5.9%) 0.72 0.6 ( 3.3;2.0)
Pathological cardiotocograph 199 (30.8%) 180 (27.8%) 0.27 2.9 ( 2.2;8.0)
Perinatal mortality 0 (0.0%) 1 (0.2%) 1.00 0.2 ( 0.6;0.3)
Apgar score 5 min <4 1 (0.2%) 1 (0.2%) 1.00 0.0 ( 0.6;0.6)
Apgar score 5 min <7 7 (1.1%) 10 (1.5%) 0.63 0.5 ( 1.9;0.9)
Metabolic acidosis (pH < 7.05 and base excess  12 or 5 (1.0%) 9 (1.7%) 0.28 0.8 ( 2.1;0.6)
pH < 7.0) n = 527 n = 527
Admission to neonatal intensive care unit (NICU) 45 (7.0%) 48 (7.4%) 0.84 0.5 ( 3.4;2.5)
Stay in NICU (days) 5.62 (5.05)5.00 (3.00; 6.00) 4.73 (3.24)4.50 (2.00; 7.00) 0.56 0.89 ( 0.74;2.75)
n = 45 n = 48

For categorical variables n (%) is presented.For continuous variables Mean (SD)/Median (Q1; Q3)/n = is presented.
For comparison between groups Fisher’s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables and the Mann–Whitney U-test was used for
continuous variables. Calculation of confidence interval for continuous variables is based on bootstrapping of 10,000 replicates picking the 2.5 and 97.5 percentiles of the
10,000 mean differences as confidence interval.
a
Percentage of vaginal births.

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Table 3
Oxytocin given by treatment arm.

Variable High dose of oxytocin Low dose of oxytocin P Difference

(n = 647) (n = 648) between groups
Mean (95% CI)
Total dose of oxytocin (microgram) 7.98 (8.29)5.35 (2.70; 5.74 (5.54)4.00 (2.00; <.0001 2.25 (1.48;3.02)
10.10)n = 646 7.30)n = 639
Maximum dose of oxytocin per min (mg/min) 0.049 (0.034)0.044 0.031 (0.019)0.028 <.0001 0.018 (0.015;
(0.022; 0.066)n = 634 (0.017; 0.042)n = 615 0.021)
Total duration of oxytocin infusion (hour) 4.78 (3.07)4.00 (2.50; 5.17 (3.16)4.50 (2.80; 0.013 0.392
6.60)n = 646 7.00)n = 641 ( 0.732; 0.054)
Uterine tachysystolea (number of women with any episode) 279 (43.2%) 215 (33.5%) 0.0005 9.6 (4.2;15.1)
n = 641 n = 641
Episodes of uterine tachysystolea 2.14 (1.62)2.00 (1.00; 2.24 (1.59)2.00 (1.00; 0.31 0.102
3.00)n = 279 3.00)n = 215 ( 0.387;0.180)
Oxytocin stopped or reduced temporarily (number of women with any episode) 374(57.9%) 318(49.6%) 0.0034 8.3 (2.7;13.9)
n = 646 n = 641
No of women with episodes of stopped or reduced oxytocin
1-2 episodes 289 (77.3%) 248 (78.0%) 0.7 ( 7.2;5.8)
n = 374 n = 318
> = 3 episodes 85 (22.7%) 70 (22.0%) 0.90 0.7 ( 5.8;7.2)
n = 374 n = 318
a
Oxytocin stopped or reduced due to tachysystole together with suspicious or pathological 136 (21.1%) 102 (15.9%) 0.021 5.1 (0.8;9.5)
Fetal Heart Rate pattern (number of women with any episode) n = 646 n = 641

For categorical variables n (%) is presented.

For continuous variables Mean (SD)/Median (Q1; Q3)/n = is presented.
For comparison between groups Fisher’s Exact test (lowest 1-sided p-value multiplied by 2) was used for dichotomous variables and the Mann–Whitney U-test was used for
continuous variables.
Calculation of confidence interval for continuous variables is based on bootstrapping of 10,000 replicates picking the 2.5 and 97.5 percentiles of the 10,000 mean differences as
confidence interval (CI).
a
Definition of tachysystole: “more than five uterine contractions in 10 min for longer than 20 min”.17

3.2. Interaction analyses and subgroup analyses The double-blind RCT design reduced the risk for biases and
skewed distribution of confounders. The comparison groups were
The analyses show a significant interaction between the latent well balanced. We had a common labour management protocol
phase and the randomised groups (P = 0.028). No interaction and the same oxytocin regimens among the different participating
effects could be seen among the other baseline characteristics, for hospitals, which facilitated the analysis and interpretation of data.
example maternal age (P = 0.052), stage of labour (first and second) Delayed labour diagnosis was checked retrospectively by a small
(p = 0.49) and BMI (p = 0.32). In women with a prolonged latent group of trained study midwives to avoid misclassification and to
phase (>18 h), the rate of CS was 7.7% in the high dose group ensure consistency in assessments. All manually entered data were
compared with CS 11.9% in the low dose group (P = 0.20). In women double-checked by team members, who also filled in missing data.
with latent phase 18 h the CS rate was 14.9% in the high dose This was time-consuming, but ensured the quality of the data. The
group compared to 12.8% in the low dose group (p = 0.48). external validity of the study was strengthened by the multicentre
approach and the fact that the trial was conducted in different
4. Discussion regions of Sweden, which increased the opportunity to generalise.
A limitation, which might be a threat to the external validity was
4.1. Main finding that we excluded 56 women (4%) from the ITT analysis due to not
fulfilling inclusion criteria (for instance induction of labour, pre- or
In this randomised controlled clinical trial there was no post-term labour, breech presentation or incorrect randomisation
difference in CS rate between the high-oxytocin and low-oxytocin detected immediately after randomisation and without interven-
dose regimens for the treatment of delayed labour. A subgroup tion). The midwife or obstetrician responsible for the care of the
analysis investigating treatment with oxytocin in delayed labour in women had no contact with the randomisation procedure when
either first or second stage did not change these findings. Women the decision not to include the woman in the study was made
in the high-dose group received a larger total amount of oxytocin directly after randomisation.
and had a shorter duration of labour (by 23 min) and more events One weakness of our study is the number of women
of tachysystole. They had similar rates of instrumental vaginal randomised but not fulfilling inclusion or exclusion criteria, which
birth as women in the low-dose group, with more due to fetal also could create a problem for the validity of the study. In order
distress (43.8% versus 22.7%) and fewer due to failure to progress not to endanger the validity, both ITT analysis and analysis “per
(39.6% versus 58.8%), without any impact on the CS rate or on other protocol” were performed, with similar results. Another limitation
maternal and neonatal outcomes. is that the study was stopped early for futility. An interim analysis
found that it was unlikely to reach a significant difference in CS rate
4.2. Strengths and limitations with the original target sample size of 2090 women. Women in the
low-dose group had a lower CS rate than assumed in our sample
This study has several strengths. The use of oxytocin for size calculation, which may be explained by the strict inclusion and
augmentation has become routine in obstetric care, with few recent exclusion criteria i.e our result showing a CS rate of 12.4% (high-
studies evaluating its effect on labour outcomes. Effects of early or dose group) versus 12.3% (low-dose group) could reflect a study
delayed oxytocin augmentation on obstetric and neonatal outcomes population of healthy nulliparous women, in the active phase of
have been investigated,6,28,29 but recent RCTs evaluating oxytocin spontaneous labour (regular painful contractions and effaced
dosage for augmentation are missing. Our trial fills this gap. cervix and dilation 3–4 cm), and with a healthy fetus on entering

Please cite this article in press as: L. Selin, et al., High-dose versus low-dose of oxytocin for labour augmentation: a randomised controlled trial,
Women Birth (2018), https://doi.org/10.1016/j.wombi.2018.09.002
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L. Selin et al. / Women and Birth xxx (2018) xxx–xxx 7

the study. An earlier Swedish RCT by Dencker et al7, comparing maternal and neonatal outcomes. Both groups had similar rates of
early and expectant oxytocin showed a similar low CS rate in the instrumental vaginal birth; in the high-dose group, the main
same kind of a population (9.2% versus 10.8%). In addition the indication was fetal distress and in the low dose group the main
Swedish rates of CS have not increased as much as in other western indication was failure to progress. We found no advantages for the
countries and is lower (17.6% in 2016) than in other countries. routine use of high-dose of oxytocin in the management of delay in
A limitation could be the decision to change the protocol by labour. Low-dose oxytocin regimen is to be recommended to avoid
approaching women to participate when their labour has been unnecessary events of tachysystole and fetal distress.
delayed, rather than at admission. Some women might have
declined participation in the study due to the difficulty of making a 6. Author contribution
decision just before initiation of the treatment. Determining the
optimal time to ask a women in labour if she wants to participate in LS, MB, UBW, AD, EA, GW and MP contributed to the design of
a study could be regarded as an ethical dilemma. We decided not to the study protocol. Statistical expertise was provided by MP, who
ask all the nulliparous women, eligible at admission, in order to was involved in the study design, in elaborating the Statistical
avoid involving women with normal labour progress in the study. Analysis Plan (SAP), and during the running of the study. LS
coordinated and supervised the multicentre study together with
4.3. Interpretation of the findings MB (principal investigator) and UBW (coordinating clinical
investigator). The local investigators GW, EA, EWI, and MJ were
Our hypothesis was based on two systematic reviews17,18 that responsible for the running of the trail in their own hospitals. LS
investigated the research field regarding augmentation of labour analysed the data and prepared the figures together with a
with a high-dose compared to a low-dose of oxytocin for reducing statistician. LS, UBW and MB drafted the manuscript. All authors
the incidence of CS. These reviews, based on small numbers of have contributed to the review of the article, and have approved
trials some of which were quasi-randomised, indicated with weak the final version and the interpretation of the data for publication.
evidence that the use of high-dose oxytocin was associated with a All authors assert the ownership of and responsibility for the
lower frequency of CS. Our study, as well as the retrospective study manuscript.
by Zhang et al,5 could not confirm their results. Maybe the
differences in dose initiated and dose increases, or different levels Acknowledgements
of risk of bias and involvement of both nulliparous and multiparous
women in the different trials included in the two systematic We would like to thank the women who participated in the trial,
reviews, might explain our divergent results. It may also be that, in
as well as all the staff from the participating labour wards. We also
Sweden, a longer period of time in labour is permitted, compared thank all the study midwives for their enthusiastic efforts in
with studies conducted in other countries with more stringent
recruitment, data acquisition and data recording: Pia Vikner,
regulations, where women have a CS for “failure to progress” at a Madelen Jakobsson, Lena Rehnberg Brandt, Veronica Miranda-
much earlier time.
Lemner, Maria Norrbäck, Anna Woxenius and Caroline Lindvall. We
It is known that a labour lasting too many hours can affect also wish to acknowledge the assistance given by the DSMB:
women’s birth experiences negatively.30–33 Our results showed a Margareta Mollberg, Hans Wedel and Lars Ladfors. We thank Laith
modest reduction in the duration of labour (23 mins) in the high- Hussain-Alkhateeb and Mattias Molin who provided statistical
dose group compared with a 1.5 h reduction in the meta-analysis by help and Arvid Birkenmeier for the development of the computer-
Wei et al,18 and 1.3 h in the retrospective study carried out by Zhang generated randomisation system, and for his continuous support of
et al.5 We found a great variation in length of labour in both groups. our computerised CRF system.
The influence of oxytocin use on neonatal outcomes has been
widely discussed.15 The drug is not harmless and it can lead to
Funding
hyperactive uterine contractions with negative outcomes for both
mother and child.12,34 However, no harm has been observed when
This study was supported by grants from (removed). The
the drug is used in an appropriate way.34 Adverse neonatal
funding sponsors had no role in the study design; in the collection,
outcomes did not differ significantly between the two dosage
analysis and interpretation of data; in the writing of the report; and
groups despite the increased incidence of uterine tachysystole in
in the decision to submit the article for publication.
the high-dose group and the longer labours in the low-dose group.
This can be explained by the rigorous control in both groups based
on the use of a checklist protocol. Full study protocol
According to previous research, nulliparous women with a high
body mass index (BMI) have an increased risk of CS due to delayed Available on request from the corresponding author.
labour progress.35–37 In our study, with a small group of women
with obesity (BMI > 30), the interaction analysis of BMI or weight Ethics
gain during pregnancy did not reveal any differences in CS rate
between the two study regimens, although the study was not The study was approved by (removed) and is registered at
powered for this. The impact of oxytocin dose for augmentation of ClinicalTrials.gov (Dremovedata)
labour in relation to BMI thus needs to be further investigated.
Appendix A. Supplementary data
5. Conclusion
Supplementary data associated with this article can be found, in
We found no difference in CS rate between the high-oxytocin and the online version, at https://doi.org/10.1016/j.wombi.2018.09.002.
low-oxytocin dose regimens for the treatment of delayed labour in
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Please cite this article in press as: L. Selin, et al., High-dose versus low-dose of oxytocin for labour augmentation: a randomised controlled trial,
Women Birth (2018), https://doi.org/10.1016/j.wombi.2018.09.002
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Please cite this article in press as: L. Selin, et al., High-dose versus low-dose of oxytocin for labour augmentation: a randomised controlled trial,
Women Birth (2018), https://doi.org/10.1016/j.wombi.2018.09.002