Women and Birth 32 (2019) 356–363
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
a,b, c d a,e
Lotta Selin *, Ulla-Britt Wennerholm , Maria Jonsson , Anna Dencker ,
c f b g a,h
Gunnar Wallin , Eva Wiberg-Itzel , Elisabeth Almström , Max Petzold , Marie Berg
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.
Aim To ascertain the effect on caesarean section rate of high-dose versus low-dose oxytocin for
Keywords:
augmentation of delayed labour in nulliparous women.
Augmentation of labour
Methods Multicentre parallel double-blind randomised controlled trial (ClinicalTrials.gov: NCT01587625) in
Delayed labour
six labour wards in Sweden. Healthy nulliparous women at term with singleton cephalic fetal presentation,
Oxytocin
fi
Caesarean spontaneous labour onset, con rmed delay in labour and ruptured membranes (n = 1351) were randomised to
Nulliparous labour augmentation with either high-dose (6.6 mU/minute) or low-dose (3.3 mU/minute) oxytocin infusion.
Findings: 1295 women were included in intention-to-treat analysis (high-dose n = 647; low-dose n = 648).
Caesarean section rates didnot differ betweengroups (12.4% and 12.3%, 95% ConfidenceInterval À3.7 to 3.8).
Womenwith high-dose oxytocin had: shorter labours (À23.4 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: [email protected] (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/).
L. Selin et al. / Women and Birth 32 (2019) 356–363 357
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 21
Eligible for inclusion were healthy, 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 vaginal
1. Introduction
bleeding during labour, delayed labour progress with fetal head
station below the ischial spines in second stage, suspected dispropor-
Delayed labour progress is common in nulliparous women, and
tion between fetal head and maternal pelvis, abnormal vertex
is among the leading indications for emergency caesarean section
<À
1–4 presentation, suspected fetal growth restriction ( 2 standard
(CS). Synthetic oxytocin is one of the most frequently used 22
5 deviations [SD]), abnormal fetal heart rate (FHR) (suspicious or
medications in obstetric care and the common routine for
pathological cardotocograph), heavy meconium stained amniotic
augmentation of labour. However, the effectiveness of oxytocin
fl fi >
3,6,7 uid, uterine tachysystole (de ned as 5 contractions during 10 min
for treating abnormal progress has been questioned. Despite
for >20 min), maternal fever, and known hypersensitivity to oxytocin
that, over time an increased use of oxytocin during labour has been
8,9 therapy. If any eligible women were already receiving oxytocin they
noted. An unstructured manner of using the drug prevails, and
were not included in the study, and women could be admitted to the
its use can lead to hyperactive uterine contractions, which have
fi
10–12 study when delayed progress was identi ed at any stage of dilation
been associated with negative effects on the fetus. Therefore,
–
13 (greater than 3 4 cm), or even in the second stage.
oxytocin has been designated as a high-alert medication.
Checklists and standardised protocols for the use of oxytocin have
2.3. Randomisation and procedure
been recommended with the aim of reducing adverse neonatal
outcomes.14,15
The study was conducted according to the study protocol with
A meta-analysis of 8 trials comparing high and low dose
two exceptions: women were asked to participate when delayed
oxytocin for induction of labour found no difference in CS rates,
labour was confirmed instead of being asked to participate at
although more “uterine hyperstimulation” was noted in the high
16 admission and, there was a change to a computer-generated
dose group. Knowledge and consensus are lacking, however,
randomisation system instead of using sealed envelopes.
regarding the proper dosage when oxytocin is used for accelerating
fi
17 Delayed labour was de ned in accordance with the Swedish
slow progress of labour. Women’s experience of childbirth and 23
National recommendations, by using a three-hour partogram action
pain in relation to oxytocin dosage is also insufficiently studied.
fi
17,18 line for delay during the rst stage of labour or an arrest of the descent
Systematic reviews on the dosage of oxytocin have found that a
of the fetal head for one to two hours during the second stage of labour.
high-dose (4–10 mU/min) compared to low-dose (1–4 mU/min)
If a delayed labour was diagnosed together with intact membranes,
oxytocin regimen for treating delayed labour progress may reduce
18 17 amniotomy was performed. One hour later, an assessment was
the risk of CS by 15%, or by as much as 46%, without any
performed and, if there was no further progress, augmentation with
negative maternal or neonatal outcomes. However, the evidence
oxytocin infusion was indicated. The woman received written and oral
for prioritising high-dose oxytocin is weak, and the Cochrane
information about the study from the midwife.
review on this topic (based on only four trials) recommended
17 Consenting women were randomly allocated to receive a
further research. The need for further investigations has been
regimen of either a high-dose or a low-dose of oxytocin (33.2 or
highlighted, especially on neonatal outcomes and on women’s
m
18,17 16.6 g oxytocin in 1000 ml isotonic saline solution), respectively).
childbirth experiences in relation to oxytocin dosage. More
These doses were chosen based on the definitions for low and high
randomised controlled trials (RCTs) are justified to determine the 17
dose included in the latest Cochrane review on this topic.
effect of oxytocin augmentation on the likelihood of CS and other
Randomisation was generated by an external information technol-
outcomes including women’s satisfaction with care, which has
ogy-consultant using a computer-generated randomisation se-
been emphasised by the British Maternal and Foetal Medicine
quence, with allocation 1:1 ratio. There was no stratification by
Society.19
maternity unit. Randomisation and preparation of the oxytocin
The overall aim of the study was to ascertain the effect on
infusion according to the allocated dosage were handled by
caesarean section rate of high-dose versus low-dose oxytocin for
external staff, not working at the labour ward. Allocation was
augmentation of delayed labour in nulliparous women. The
blinded for responsible staff, the woman in labour and for the
hypothesis, based on weak evidence form a previous Cochrane
17 research team. The random codes were revealed after completion
review, was that a high-dose oxytocin regimen, compared to a
of data collection and after the data file was closed.
low-dose, will reduce the number of CSs without negative
In the high-dose group, the infusion started with 6.6 mU
maternal and neonatal outcomes.
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. Methods 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
2.1. Study design and setting 29.7 mU oxytocin/min. The recommended standard dose in
Sweden for oxytocin augmentation corresponds to the low-dose
23
A parallel double-blind, multicentre, randomised controlled regimen in this study. When more than 1000 ml of infusion with
trial (RCT) was conducted in accordance with the CONSORT oxytocin was needed, the next oxytocin infusion, which was given
20
guidelines in four maternity units in Sweden including six labour to women in both groups, was the recommended standard dose
wards: (removed for anonymity). The wards entered the study at (3.3 mU oxytocin/min) as clinicians would not know which
different time points between September 2013 and June 2016. Data strength had been given the first time. This was required for only
collection was completed in October 2016. Supplementary data on 32 women (10 in high dose group and 22 in low dose group), 2.5%
the participating labour wards are shown in Table S1. of the total and 1.5% of the high dose group.
358 L. Selin et al. / Women and Birth 32 (2019) 356–363
1 1
In both groups the infusion was increased until adequate uterine hospital (Obstetrix or Cosmic ). Data from the checklist protocol
contractions were obtained, and progress of labour was established were reported in a shared internet database by the local research
(i.e.dilationof cervixand descentof the fetal head),oroccurrence ofa midwife. Delayed labour progress defined by the midwife or the
maximum of five contractions in 10 min. The monitoring and obstetrician in charge of each woman was verified retrospectively
documentation of labour progress included assessment of maternal by the local research midwives. All manually entered data were
and fetal status and followed the study protocol and established double-checked.
routines based on national and departmental guidelines. In a The primary outcome was the rate of CS in labour. Secondary
checklist protocol, frequency of contractions every 10 min and maternal outcomes were: instrumental vaginal birth, spontaneous
electronic FHR pattern (normal/suspicious/pathological cardioto- vaginal birth, main indication for CS and instrumental vaginal birth
24
cography [CTG]) were assessed and documented at everychange of (fetal distress, failure to progress or other indications), duration of
infusion rate, and once per hour after a therapeutic dose was labour (min), postpartum haemorrhage (>500 ml; >1000 ml),
obtained. Maternal blood pressure (at start of oxytocin infusion and manual removal of placenta, anal sphincter injury (grade 3 or
once per hour for an oxytocin rate 180 ml/h) was registered. 4), fever during labour (>38.0 grade for two occasions after
Adverse events (AEs) categorised as mild, moderate or severe were antipyretic medication), uterine tachysystole, total dose of
documented and evaluated. oxytocin (mg), maximum oxytocin dose per minute (mg/min),
total duration of oxytocin infusion (hour), oxytocin stopped or
2.4. Ethical issues reduced temporarily, oxytocin stopped or reduced temporarily due
to tachysystole together with suspicious or pathological FHR
The study was approved by (removed), and by (removed). All pattern. Neonatal outcomes included: Apgar score at 5 min <4 or
women gave informed, written consent to take part. An indepen- <7; metabolic acidosis (umbilical cord arterial pH < 7.05 and base
dent Data and Safety Monitoring Board (DSMB) secured the project excess À12 or umbilical cord arterial pH < 7.0), fetal distress
management through periodical reviews and an interim analysis of (pathological CTG), intrapartum thick meconium stained amniotic
study specific data. A security team was established for the fluid, admission to neonatal intensive care unit (NICU) and number
assessment of serious adverse events (SAEs). At each maternity of days stayed at NICU. Women’s total experience of labour pain
unit there was a local principal investigator and a local research and their childbirth experience using the Childbirth Experience
25
midwife responsible in charge for continuous supervision of Questionnaire will be reported later.
security and labour management.
2.6. Analysis
2.5. Data collection
The sample size was based on an assumed decrease of the CS
Characteristics of study participants, and obstetric and neonatal rate from 17.5% to 13% i.e. a reduction of 25%. This required a total
data, were collected from the electronic medical record at each sample size of 2090 woman for 80% power at a significance level of
Fig. 1. CONSORT flow diagram.
L. Selin et al. / Women and Birth 32 (2019) 356–363 359
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
9
labour . A reduction of 25% was regarded as a clinically relevant On May 30, 2016 the DSMB recommended the Steering Committee
reduction. to stop the study because of futility as there was no statistically
The independent DSMB reviewed the data periodically, using a significant difference in CS between the high-dose or low-dose group.
group sequential method based on Haybittle-Peto rule to control The numeric difference between the two study groups was extremely
26
for benefits and harms and need for early stopping of the trial. small and the interim results suggested that it was unlikely to achieve
After the sixth planned safety review, DSMB recommended statistical significance with a completed study.
27
termination of the trial for futility. That interim analysis, which During the study period, 5141 women were assessed for
included 72 primary endpoint events (including CS) in the high- eligibility. A total of 1351 out of 2273 women who were eligible
dose group and 66 in the low-dose group (44% of those projected), (59.4%) were randomised and 1295 were analysed on an intention
demonstrated a less than 5% conditional power to demonstrate to treat (ITT) basis, 647 in the high-dose and 648 in the low-dose
superiority to a p value < 0.05 if the trial were carried to group. Recruitment and flow are shown in Fig. 1.
completion. The Executive Steering Committee and sponsor In total 56 women were excluded in the ITT analysis. Of these, 26
accepted this recommendation, and the trial was terminated on women were incorrectly included (induction of labour, gestational
June 8, 2016. By completion of follow-up of all included women, age < 37 weeks and 42 + 0, hepatitis, <18 years of age and breech
and finalisation of the trial database on March 20, 2017, a total of presentation); 27 women had been immediately excluded after
160 primary endpoint events (51% of those projected) were randomisation by the responsible midwife when detecting incor-
available for analysis. rectly inclusion and the woman was therefore deleted from the
Statistical analyses were performed using SPSS 24.0 for study. and three women withdrew consent after having been
Windows (SPSS Inc., Chicago, IL, USA) and SAS 9.4 (SAS Institute randomisation. Detailed information is given in Table S2.2.
Inc., Cary, NC, USA). Primary and secondary outcome data were Included in the ITT analysis were 58 women incorrectly
analysed on intention to treat (ITT) population and on per randomized according to inclusion/exclusion criteria: These
protocol (PP) population. Categorical variables are presented with women had either fever during labour, pathological or suspicious
n (%) and continuous variables with mean, standard deviation pathological CTG, fetal head station below the ichial spinae, thick
(SD), median, first quartile (q1) and third quartile (q3). For the meconium stained amniotic fluid, amniotomy after oxytocin
comparison between two groups Fisher’s Exact test was used for infusion, adominal pain or myoma. Furthermor 38 women without
dichotomous variables, Chi-square test was used for non-ordered delayed labour progress and 69 women who did not receive the
categorical variables and the Mann-Whitney U-test was used for allocated intervention were also included in the ITT analysis.
continuous variables. Calculation of difference between groups Detailed information is given in Table S2.1.
for confidence interval (CI) in continuous variables was based on The baseline characteristics were similar in the two groups
bootstrapping. (Table 1). There was no difference between the high-dose and the
For exploratory purposes, an interaction analysis was per- low-dose group with respect to the frequency of CS, 80 of 647
formed for relevant baseline variables and dose group in relation to women (12.4%) versus 80 of 648 women (12.3%) (difference
the primary outcome variable CS rate. If interactions were between groups 0.0, 95% CI À3.7 to 3.8) (Table 2). CS rate in the
significant (p < 0.05), subgroup analyses were performed. different participating labour wards is shown in Table S4.
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
a
Delayed labour n = 621 n = 636
Primary 340 (54.8%) 345 (54.2%)
Secondary 281 (45.2%) 291 (45.8%)
a
Delayed labour (stage) 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%)
b
Small for gestational age < À 2 SD 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.
360 L. Selin et al. / Women and Birth 32 (2019) 356–363
Secondary maternal and neonatal outcomes are presented in was 21.1% in the high-dose group compared with 15.9% in the low-
Tables 2 and 3. The main indication for CS was failure to progress dose group (difference 5.1%, 95% CI 0.8 to 9.5).
in both high-dose (55.0%) and low-dose groups (62.5%), but the The proportion of women experiencing any adverse events did
difference was not significant (difference À7.5%, 95% CI À24.0 to not differ significantly between the high-dose group and the low-
9.0). There were no significant differences in the rate of operative dose group, 31/647 (4.8%) and 39/648 (6.0%), respectively (P = 0.39).
vaginal birth or spontaneous vaginal birth between the two Three women in the high-dose group and one in the low-dose group
regimens. The main indication for operative vaginal birth was experienced a serious adverse event (SAE) (P = 0.37). None of the
fetal distress in the high-dose group (43.8% versus 22.7%, SAEs were regarded as drug-related. One woman with a SAE in the
difference 21.1%, 95% CI 7.1 to 35.1) and failure to progress in high-dose group did not receive treatment.
the low-dose group (39.6% versus 58.8%, difference À19.2, 95% CI
(-34.1 to À4.3). 3.1. Per protocol analysis
Labour duration was 23 min shorter with a high-dose regimen
of oxytocin (mean difference À23.4 min, 95% CI À45.1 to À1.5). No In the per protocol analysis 1130 of 1295 women in ITT analysis
statistically significant differences were observed in the neonatal were included, 96 incorrectly randomised women and 69 women
outcomes. In the low-dose group one perinatal death occurred in a who did not receive the allocated intervention were excluded.
child with severe hypoxic encephalopathy. It was regarded as not (Tables S2.1 + S2.2). The CS rate was 69/562 (12.3%) in the high-
being related to the study drug. dose group and 67/568 (11.8%) in the low-dose group (P = 0.87). The
The total dose of oxytocin used was significantly higher in the results were comparable with the results in ITT analyses (Table S3).
high-dose group compared with the low-dose group (7.98 mg
versus 5.74 mg; mean difference 2.25 mg, 95% CI 1.48 to 3.02) and 3.2. Interaction analyses and subgroup analyses
the maximum dose per minute was higher in the high-dose group
(0.049 mg/min versus 0.031 mg/min; mean difference 0.018 mg/ The analyses show a significant interaction between the latent
min; 95% CI 0.015 to 0.021) (Table 3). There were more women with phase and the randomised groups (P = 0.028). No interaction
uterine tachysystole in the high-dose group (43.2% versus 33.5%; effects could be seen among the other baseline characteristics, for
difference 9.6%; 95% CI 4.2 to 15.1). The rate of women in whom example maternal age (P = 0.052), stage of labour (first and second)
oxytocin was stopped or reduced temporarily due to uterine (p = 0.49) and BMI (p = 0.32). In women with a prolonged latent
tachysystole together with suspicious or pathological FHR pattern phase (>18 h), the rate of CS was 7.7% in the high dose group
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 (À3.7;3.8)
Secondary outcomes
Spontaneous vaginal birth 471 (72.8%) 471 (72.7%) 1.00 0.1 (À4.9;5.1)
Instrumental vaginal birth 96 (14.8%) 97 (15.0%) 1.00 À0.1 (À4.2;3.9)
Indication for caesarean section 0.623
Fetal distress 21 (26.3%) 17 (21.3%) 5.0 (À9.4;19.4)
Failure to progress 44 (55.0%) 50 (62.5%) À7.5 (À24.0;9.0)
Other indications 15 (18.8%) 13 (16.3%) 2.5 (À10.5;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%) À19.2 (À34.1;À4.3)
Other indications 16 (16.7%) 18 (18.6%) À1.9 (À13.7; 9.9)
Duration of labour (minutes) 744 (209)732 (595; 873) 768 (196)759 (635; 891) 0.021 À23.4 (À45.3; À1.5)
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 À0.3 (À2.2;1.6)
Postpartum haemorrhage
>500 (ml) 252 (38.9%) 263 (40.7%) 0.55 À1.8 (À7.3:3.7)
>1000 (ml) 88 (13.6%) 93 (14.4%) 0.74 À0.8 (À4.7;3.1)
a
Manual removal of placenta 30 (5.3%) 20 (3.5%) 0.19 1.8 (À4.3; 0.8)
n = 567 n = 568
a
Anal sphincter injury (grade 3 or 4) 26 (4.6%) 29 (5.1%) 0.79 À0.5 (À3.2:2.2)
n = 567 n = 568
Intrapartum thick meconium stained amniotic fluid 34 (5.3%) 38 (5.9%) 0.72 À0.6 (À3.3;2.0)
Pathological cardiotocograph 199 (30.8%) 180 (27.8%) 0.27 2.9 (À2.2;8.0)
Perinatal mortality 0 (0.0%) 1 (0.2%) 1.00 À0.2 (À0.6;0.3)
Apgar score 5 min <4 1 (0.2%) 1 (0.2%) 1.00 0.0 (À0.6;0.6)
Apgar score 5 min <7 7 (1.1%) 10 (1.5%) 0.63 À0.5 (À1.9;0.9)
Metabolic acidosis (pH < 7.05 and base excess À12 or 5 (1.0%) 9 (1.7%) 0.28 À0.8 (À2.1;0.6)
pH < 7.0) n = 527 n = 527
Admission to neonatal intensive care unit (NICU) 45 (7.0%) 48 (7.4%) 0.84 À0.5 (À3.4;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 (À0.74;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.
L. Selin et al. / Women and Birth 32 (2019) 356–363 361
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 À0.392
6.60)n = 646 7.00)n = 641 (À0.732;À0.054)
a
Uterine tachysystole (number of women with any episode) 279 (43.2%) 215 (33.5%) 0.0005 9.6 (4.2;15.1)
n = 641 n = 641
a
Episodes of uterine tachysystole 2.14 (1.62)2.00 (1.00; 2.24 (1.59)2.00 (1.00; 0.31 À0.102
3.00)n = 279 3.00)n = 215 (À0.387;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%) À0.7 (À7.2;5.8)
n = 374 n = 318
> = 3 episodes 85 (22.7%) 70 (22.0%) 0.90 0.7 (À5.8;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 17
Definition of tachysystole: “more than five uterine contractions in 10 min for longer than 20 min”.
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,
birth as women in the low-dose group, with more due to fetal which also could create a problem for the validity of the study. In
distress (43.8% versus 22.7%) and fewer due to failure to progress order not to endanger the validity, both ITT analysis and analysis
(39.6% versus 58.8%), without any impact on the CS rate or on other “per protocol” were performed, with similar results. Another
maternal and neonatal outcomes. limitation is that the study was stopped early for futility. An
interim analysis found that it was unlikely to reach a significant
4.2. Strengths and limitations difference in CS rate with the original target sample size of 2090
women. Women in the low-dose group had a lower CS rate than
This study has several strengths. The use of oxytocin for assumed in our sample size calculation, which may be explained
augmentation has become routine in obstetric care, with few recent by the strict inclusion and exclusion criteria i.e our result showing
studies evaluating its effect on labour outcomes. Effects of early or a CS rate of 12.4% (high-dose group) versus 12.3% (low-dose
delayed oxytocin augmentation on obstetric and neonatal outcomes group) could reflect a study population of healthy nulliparous
6,28,29
have been investigated, but recent RCTs evaluating oxytocin women, in the active phase of spontaneous labour (regular
dosage for augmentation are missing. Our trial fills this gap. painful contractions and effaced cervix and dilation 3–4 cm),
The double-blind RCT design reduced the risk for biases and and with a healthy fetus on entering the study. An earlier Swedish
7
skewed distribution of confounders. The comparison groups were RCT by Dencker et al , comparing early and expectant oxytocin
well balanced. We had a common labour management protocol showed a similar low CS rate in the same kind of a population
and the same oxytocin regimens among the different participating (9.2% versus 10.8%). In addition the Swedish rates of CS have not
hospitals, which facilitated the analysis and interpretation of data. increased as much as in other western countries and is lower
Delayed labour diagnosis was checked retrospectively by a small (17.6% in 2016) than in other countries.
group of trained study midwives to avoid misclassification and to A limitation could be the decision to change the protocol by
ensure consistency in assessments. All manually entered data were approaching women to participate when their labour has been
362 L. Selin et al. / Women and Birth 32 (2019) 356–363
delayed, rather than at admission. Some women might have 6. Author contribution
declined participation in the study due to the difficulty of making a
decision just before initiation of the treatment. Determining the LS, MB, UBW, AD, EA, GW and MP contributed to the design of the
optimal time to ask a women in labour if she wants to participate in study protocol. Statistical expertise was provided by MP, who was
a study could be regarded as an ethical dilemma. We decided not to involved in the study design, in elaborating the Statistical Analysis
ask all the nulliparous women, eligible at admission, in order to Plan (SAP), and during the running of the study. LS coordinated and
avoid involving women with normal labour progress in the study. supervised the multicentre study together with MB (principal
investigator) and UBW (coordinating clinical investigator). The local
investigators GW, EA, EWI, and MJ were responsible for the running
4.3. Interpretation of the findings
of the trail in their own hospitals. LS analysed the data and prepared
17,18 the figures together with a statistician. LS, UBW and MB drafted the
Our hypothesis was based on two systematic reviews that
manuscript. All authors have contributed to the review of the article,
investigated the research field regarding augmentation of labour
and haveapprovedthefinalversionandtheinterpretationofthe data
with a high-dose compared to a low-dose of oxytocin for reducing
for publication. All authors assert the ownership of and responsibili-
the incidence of CS. These reviews, based on small numbers of trials
ty for the manuscript.
some of which were quasi-randomised, indicated with weak
evidence that the use of high-dose oxytocin was associated with a
Acknowledgements
lowerfrequencyofCS.Ourstudy, aswell asthe retrospectivestudyby
5
Zhang et al, could not confirm their results. Maybe the differences in
We would like to thank the women who participated in the trial,
dose initiated and dose increases,ordifferentlevels ofrisk ofbias and
as well as all the staff from the participating labour wards. We also
involvement of both nulliparous and multiparous women in the
thank all the study midwives for their enthusiastic efforts in
different trials included in the two systematic reviews, mightexplain
recruitment, data acquisition and data recording: Pia Vikner,
our divergent results. It may also be that, in Sweden, a longer period
Madelen Jakobsson, Lena Rehnberg Brandt, Veronica Miranda-
of time in labour is permitted, compared with studies conducted in
Lemner, Maria Norrbäck, Anna Woxenius and Caroline Lindvall. We
other countries with more stringent regulations, where women have
also wish to acknowledge the assistance given by the DSMB:
a CS for “failure to progress” at a much earlier time.
Margareta Mollberg, Hans Wedel and Lars Ladfors. We thank Laith
It is known that a labour lasting too many hours can affect
–
30 33 Hussain-Alkhateeb and Mattias Molin who provided statistical
women’s birth experiences negatively. Our results showed a
help and Arvid Birkenmeier for the development of the computer-
modest reduction in the duration of labour (23 mins) in the high-
generated randomisation system, and for his continuous support of
dose group compared with a 1.5 h reduction in the meta-analysis by
18 our computerised CRF system.
Wei et al, and 1.3 h in the retrospective study carried out by Zhang
5
et al. We found a great variation in length of labour in both groups.
The influence of oxytocin use on neonatal outcomes has been Funding
15
widely discussed. The drug is not harmless and it can lead to
hyperactive uterine contractions with negative outcomes for both This study was supported by grants from Department of Research
12,34
mother and child. However, no harm has been observed when and Development, NU-Hospital Group, Sweden; the Fyrbodal
34
the drug is used in an appropriate way. Adverse neonatal Research and Development Council Region Västra Götaland,
outcomes did not differ significantly between the two dosage Sweden; The Health & Medical Care Committee of the Regional
groups despite the increased incidence of uterine tachysystole in Executive Board, Region Västra Götaland Sweden; the Swedish
the high-dose group and the longer labours in the low-dose group. Medical Research Council; some of the local coordinating centres
This can be explained by the rigorous control in both groups based fundedmidwiferytime forthe trial.The fundingsponsorshad norole
on the use of a checklist protocol. in the study design; in the collection, analysis and interpretation of
According to previous research, nulliparous women with a high data; in the writing of the report; and in the decision to submit the
body mass index (BMI) have an increased risk of CS due to delayed article for publication.
35–37
labour progress. In our study, with a small group of women
with obesity (BMI > 30), the interaction analysis of BMI or weight Full study protocol
gain during pregnancy did not reveal any differences in CS rate
between the two study regimens, although the study was not Available on request from the corresponding author.
powered for this. The impact of oxytocin dose for augmentation of
labour in relation to BMI thus needs to be further investigated. Ethics
The study was approved by (removed) and is registered at
5. Conclusion
ClinicalTrials.gov (Dremovedata)
We found no difference in CS rate between the high-oxytocin and
Appendix A. Supplementary data
low-oxytocin dose regimens for the treatment of delayed labour in
nulliparous women in this study. Women in the high-dose group
Supplementary data associated with this article can be found, in
received a larger total amount of oxytocin and had a shorter duration
the online version, at https://doi.org/10.1016/j.wombi.2018.09.002.
of labour (by 23 min), and had more events of tachysystole compared
to women in the low-dose group, without any impact on other
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