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This systematic review and meta-analysis evaluated intravenous oxytocin dosing regimens for preventing postpartum hemorrhage following cesarean delivery, analyzing data from 35 studies involving 7333 women. The findings indicated that bolus plus infusion regimens may slightly reduce mean blood loss, while bolus only regimens of 10 IU may decrease the need for additional uterotonics compared to 5 IU. However, the overall evidence was limited and inconclusive, highlighting the need for further research to establish optimal dosing regimens.

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Oxitocina

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Systematic Reviews ajog.

org

Intravenous oxytocin dosing regimens for

postpartum hemorrhage prevention following cesarean
delivery: a systematic review and meta-analysis
Laura C. Phung, MD; Elise K. Farrington, MD; Mairead Connolly, MD, MPH;
Alyce N. Wilson, MD, MPH; Brendan Carvalho, MBBCh, FRCA; Caroline S. E. Homer, PhD;
Joshua P. Vogel, PhD

OBJECTIVE: To compare the available evidence on intravenous oxytocin dosing regimens for the prevention of postpartum hemorrhage
following cesarean delivery.
DATA SOURCES: We searched Ovid MEDLINE, Embase, Global Index Medicus, Cumulative Index of Nursing and Allied Health Literature,
Cochrane Controlled Register of Trials, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for eligible studies pub-
lished until February 2020.
STUDY ELIGIBILITY CRITERIA: We included any randomized or nonrandomized study published in peer-reviewed journals that compared
at least 2 different dosing regimens of intravenous oxytocin for postpartum hemorrhage prevention in women undergoing cesarean
delivery.
METHODS: Two authors independently assessed the eligibility of studies, extracted the data, and assessed the risk of bias. The primary
outcome was incidence of postpartum hemorrhage 1000 mL. Other review outcomes included use of additional uterotonics, blood loss,
and adverse maternal events. Data were analyzed according to the type of intravenous administration (bolus only, infusion only, or bolus
plus infusion) and total oxytocin dose. A meta-analysis was performed on randomized trials and the results were reported as risk ratios or
mean differences with 95% confidence intervals. The Grading of Recommendations, Assessment, Development, and Evaluations scale
was used to rate the certainty of evidence. Findings from dose-finding trials and nonrandomized studies were reported narratively.
RESULTS: A total of 35 studies (7333 women) met our inclusion criteria and included 30 randomized trials and 5 nonrandomized studies.
There were limited data available from the trials for most outcomes, and the results were not conclusive. Compared with bolus plus infusion
regimens, bolus only regimens probably result in slightly higher mean blood loss (mean difference, 52 mL; 95% confidence interval, 0.4e104
mL; moderate certainty). Among the bolus plus infusion regimens, initial bolus doses <5 IU may reduce nausea (risk ratio, 0.26; 95%
confidence interval, 0.11e0.63; low certainty) when compared with doses of 5e9 IU. Total oxytocin doses of 5e9 IU vs total doses of 10e19
IU may increase the use of additional uterotonics (risk ratio, 13.00; 95% confidence interval, 1.75e96.37; low certainty). Effects on other
outcomes were generally inconclusive.
CONCLUSION: There are limited data available for comparisons of IV oxytocin regimens for postpartum hemorrhage prevention following
cesarean delivery. Bolus plus infusion regimens may lead to minor reductions in mean blood loss and initial bolus doses of <5 IU may
minimize nausea. Bolus only regimens of 10 IU vs bolus only regimens of 5 IU may decrease the need for additional uterotonics, however,
further comparative trials are required to understand the effects on other key outcomes, particularly hypotension.
Key words: abdominal delivery, birth, blood loss, dosing, drug administration, pregnancy, uterine atony, uterotonics

Introduction accounting for nearly 20%1 of the PPH is uterine atony,3 hence increasing
Postpartum hemorrhage (PPH) is one of 295,000 maternal deaths that occur the use of uteronics for all women during
the leading causes of maternal mortality, worldwide.2 The most common cause of delivery has been a key component of

From the Maternal, Child and Adolescent Health Program, Burnet Institute, Melbourne, Australia (Drs Phung, Farrington, Connolly, Wilson, Homer, and
Vogel); Faculty of Medicine, Dentistry and Health Sciences, Melbourne Medical School, The University of Melbourne, Melbourne, Australia (Drs Phung,
Farrington, and Connolly); School of Population and Global Health, Faculty of Medicine, Dentistry, and Health Sciences, The University of Melbourne,
Melbourne, Australia (Drs Wilson and Vogel); and Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, Stanford, CA (Dr
Carvalho).
Received Jan. 23, 2021; revised April 14, 2021; accepted April 30, 2021.
The authors report no conﬂict of interest.
This study received no ﬁnancial support.
Corresponding author: Laura C. Phung, MD. lauracphung@gmail.com
0002-9378/$36.00 ª 2021 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.ajog.2021.04.258

250 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

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ajog.org Systematic Reviews

Eligible studies were those that

AJOG at a Glance included women who gave birth at any
Why was this study conducted? gestational age to a live or stillborn baby
The World Health Organization guidelines state that there is insufficient evidence via CD and included both planned and
to recommend a specific oxytocin dosing regimen to prevent women from intrapartum CDs. Women were eligible
experiencing postpartum hemorrhage following a cesarean delivery. This sys- if they received IV oxytocin for PPH
tematic review was conducted to identify and compare intravenous oxytocin prevention either at or around the third
dosing regimens administered during cesarean deliveries and to determine stage of labor, recognizing that admin-
whether any regimens are superior. istration of oxytocin during the third
stage may not be possible or practical
Key findings during a CD, particularly during an
We found limited and generally low-quality data for most outcomes and further emergency CD.
research is required. Bolus plus infusion regimens, with an initial bolus dose of Studies comparing at least 2 different
<5 international units (IU), may have minor benefits. Bolus only regimens of 10 IV dosing regimens of oxytocin during
IU vs 5 IU may decrease the use of additional uterotonics, although the effects on CD were eligible. Trials with coad-
adverse events (particularly hypotension) is unknown. ministered interventions were eligible,
provided that the use of cointerventions
What does this add to what is known? was identical in all trial arms.
This study compared data on all oxytocin regimens administered during cesarean
delivery for postpartum hemorrhage prevention. It provides valuable information Outcomes of interest
for clinical guidelines and future research. We prespecified 25 outcomes based on
those used in the WHO recommenda-
tions on uterotonics for PPH preven-
global efforts to reduce PPH-associated of studies are important to help guide tion,4 the PPH core outcome set,11 and
morbidity and mortality.4 clinical practice and address the priority the 2019 Cochrane network meta-
In 2018, the World Health Organiza- identified by the WHO Guideline analysis on uterotonics for PPH pre-
tion (WHO) recommended that 10 in- Development Group. The aim of this vention.5 The primary review outcome
ternational units (IU) of oxytocin should systematic review was, therefore, to was incidence of PPH 1000 mL, with
be administered to all women during identify and compare IVoxytocin dosing secondary outcomes including PPH
delivery, irrespective of the mode of de- regimens during CD and determine 500 mL, maternal death, severe
livery (vaginal or cesarean delivery whether any regimens are superior. maternal morbidity (intensive care unit
[CD]).4 This recommendation was [ICU] admissions), severe maternal
informed by a Cochrane network meta- Methods morbidity (shock), use of additional
analysis of uterotonic agents for PPH We conducted a systematic review in uterotonics, satisfactory uterine tone,
prevention by Gallos et al.5 Based on accordance with the Preferred Reporting use of surgical or invasive nonsurgical
further evidence from observational Items for Systematic Reviews and Meta- interventions, blood transfusion, mean
studies suggesting dose-dependent Analyses (PRISMA) guidance9 (Appendix volumes of blood loss, change in he-
adverse effects,4 the WHO recommen- A). We followed a prespecified protocol moglobin measurements before vs after
dations specified that when used for PPH registered with the International Prospec- birth, any adverse maternal events
prevention during CD, 10 IU oxytocin tive Register of Systematic Reviews (including nausea, vomiting, headache,
should be administered as a divided dose (CRD42020175544),10 and outlined any hypotension, chest pain, myocardial
using a smaller initial intravenous (IV) deviations in Appendix B. Ethics ischemia, cardiac arrythmia, dyspnea,
bolus followed by infusion.4 However, approval was not required because this bradycardia, tachycardia, or water
the WHO Guideline Development was a systematic review of publicly intoxication), breastfeeding at hospital
Group acknowledged that there was available data. discharge, maternal sense of well-being,
insufficient evidence from randomized and maternal satisfaction.
controlled trials and specified that Eligibility criteria
identifying an optimal IV oxygocin Randomized controlled trials (RCTs) and Information sources, search strategy,
regimen for PPH prophylaxis during CD nonrandomized studies of interventions and study selection
was a high research priority.4 (NRSIs) published in peer-reviewed A search strategy was developed in
Previous reports have synthesized ev- journals were eligible for inclusion consultation with an information
idence on oxytocin dosing regimens for without date restrictions. Conference specialist (Supplemental Table 1). Be-
PPH prevention during CD, however, abstracts were not included. We included tween February 14, 2020, and February
none of these were systematic reviews or studies written in English and those 19, 2020, we searched the following 7
were published nearly a decade ago.6e8 written in other languages if we were able electronic databases: Ovid MEDLINE,
An up-to-date review and comparison to obtain adequate translations. Embase, Global Index Medicus,

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 251

Cumulative Index of Nursing and Allied risk of bias for each included study. In 50 IU) for comparison in pairwise
Health Literature, Cochrane Central addition, we assessed the risk of bias of analyses. In addition, among trials using
Register of Controlled Trials, blood loss measurements using a similar bolus plus infusion regimens, we iden-
ClinicalTrials.gov, and WHO Interna- approach to Gallos et al5 (Supplemental tified trials that studied the effects of
tional Clinical Trials Registry Platform. Table 2). Extracted data about the re- using different initial bolus doses by
Recovered citations were de-duplicated view outcomes from RCTs were entered varying the initial bolus dose while
using Endnote (Clarivate Analytics, into the Review Manager 5 software keeping the infusion component iden-
Philadelphia, PA)12 and imported into (Cochrane)16 for the meta-analysis. Data tical between trial arms. Hence, we also
Covidence (Covidence, Melbourne, from NRSIs were reported narratively. analyzed (3) the effects of different initial
Australia)13 for screening. Each unique bolus doses among trials using bolus
citation was reviewed and independently Data synthesis plus infusion regimens. To accomplish
assessed by 2 review authors (L.C.P., We identified the following 3 types of this, we grouped the initial bolus doses as
E.K.F., and M.C.) for inclusion, initially studies: comparative RCTs with 2 <5 IU, 5 IU, or 10 IU for comparison in
based on titles and abstracts and then on arms, dose-finding RCTs, and NRSIs. pairwise analyses.
the full-text articles of potentially eligible In line with the 2019 international
citations. Disagreements were resolved Comparative randomized controlled trials. consensus statement recommendation of
through discussion or consultation with For comparative RCTs, we first assessed a 2- to 4-hour maintenance infusion,8 we
another reviewer (J.P.V.). We also trial populations and methods used performed a subgroup analysis on studies
screened the reference lists of all between trials to judge whether they that used a maintenance infusion be-
included studies, in addition to the were sufficiently similar to warrant a tween 2 and 4 hours only. Owing to
reference list of the Gallos et al5 network meta-analysis. A random-effects model limited available data, we were only able
meta-analysis for additional eligible was used to assess all outcomes with >1 to perform this for the analysis of initial
studies. trial. Results from dichotomous data bolus doses in a bolus plus infusion
were presented as a summary risk ratio regimen.
Data extraction and assessment of risk (RR) with 95% confidence intervals (CI) We planned to conduct subgroup
of bias and as mean differences (MDs) for analyses by type of CD (planned vs
For each study, 2 reviewers (L.C.P., continuous data. For all meta-analyses intrapartum), previous oxytocin admin-
E.K.F., M.C.) double-extracted data us- we used the Grading of Recommenda- istration, and previous risk of PPH,
ing a predesigned and pretested elec- tions Assessment, Development, and however, these were not possible because
tronic spreadsheet (Google Sheets). Data Evaluation (GRADE) approach17 to rate of limited available data. We performed
about the study design, year of publica- the certainty of evidence as very low, low, sensitivity analyses for risk of bias (only
tion, period of recruitment, number of moderate, or high using GRADEpro including studies with an overall low risk
participants, maternal age, gestational software (Evidence Prime, Inc, Ontario, of bias) and method of blood loss esti-
age, primary and secondary review out- Canada).18 We planned to assess publi- mation (only including studies that used
comes, and potential effect modifiers cation bias using funnel plots if there were calculated or volumetric assessment of
(type of CD, previous oxytocin admin- 10 or more studies included in the meta- blood loss). When making statements on
istration during childbirth, and previous analysis, however, this was not done the effects of an intervention, we adopted
risk for PPH) were extracted. Disagree- because of the limited number of studies. standardized language derived from San-
ments between the reviewers at the title We conducted separate meta-analyses tesso et al.19
and abstract, and full-text stages were for (1) type of IV administration (bolus
4% and 9%, respectively, and were only, infusion only, or bolus plus infu- Dose-finding trials and nonrandomized
resolved through discussion or consul- sion) and (2) total oxytocin dose studies.
tation with another reviewer (J.P.V.). We administered. We calculated the total The dose-finding RCTs used a 1-arm up-
attempted to contact the study authors oxytocin dose for each trial arm by and-down sequential allocation method
for all studies for which further infor- adding all preplanned doses of oxytocin in which the oxytocin dose for the next
mation was required. described in the study methods, participant was adjusted according to the
Each included study was assessed for including any doses used in a bolus, response of the preceding participant.20
risk of bias by at least 2 review authors short infusion, and maintenance infu- For example, if the first participant had
(L.C.P., E.K.F., M.C.). RCTs were assessed sion (studies were not included for a satisfactory response, the next partici-
using the Cochrane Risk Of Bias 2.0 analysis of total oxytocin dose if there pant was allocated either an equal or
(ROB 2.0, Cochrane, London, United was insufficient information to deter- lower dose using a biased-coin technique.
Kingdom) tool,14 and NRSIs were mine the total dose). Considering the Dose-finding trials did not make explicit,
assessed using the Risk Of Bias In Non- available evidence (and to standardize pairwise comparisons between dosing
randomized Studies of Interventions the analyses), trial arms were grouped regimens, hence findings from these trials
(ROBINS-I, Cochrane) tool.15 We made into 5 total oxytocin dose categories (<5 were reported narratively. Eligible NRSIs
an explicit judgment about the overall IU, 5e9 IU, 10e19 IU, 20e49 IU, and were also reported narratively.

252 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

Results
FIGURE 1
Study selection and characteristics
The results of the search are summarized
Flow diagram
in the PRISMA flow diagram (Figure 1).
We identified 9631 records of which
6626 records were excluded at the title
and abstract screening stage and 195 at
the full-text review stage. The most
common reasons for exclusion were
duplicate study (n¼72) and wrong
article type (n¼37). No further articles
were identified through screening of the
reference lists. In total, 35 studies of 7333
women were included. We found 30
RCTs of which 26 were comparative
RCTs and 4 were dose-finding RCTs. We
found 5 NRSIs of which 4 were
comparative and 1 was a dose-finding
study. A summary of the study charac-
teristics and an overview of study com-
parisons are provided in Tables 1 to 4
and Supplemental Table 3. Among the 26
comparative RCTs included, 9 were at an
overall high risk for bias and 15 were at
low risk for bias (Supplemental Figures 1
and 2); the 4 dose-finding RCTs were
assessed to be at an overall high risk for
bias. Of the 5 NRSIs, 2 were assessed to
be at an overall critical risk of bias and
the remaining 3 as at moderate risk
(Supplemental Figures 3 and 4).

Comparative randomized controlled PRISMA flow diagram.

trials PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
We identified 26 comparative RCTs (64 Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet
Gynecol 2021.
trial arms) that included 5271 women.
Of these, 19 RCTs were 2-arm trials, and
7 RCTs were multi-arm trials (ranging
from 3e6 arms). Sample sizes ranged
from 28e2069 women, and 23 trials different initial bolus doses within a comparative studies (3 2-arm studies, 1
included women undergoing planned bolus plus infusion regimen, the initial 3-arm study) and 1 was a dose-finding
CD only. The types of IVadministrations bolus doses ranged from 0.5e10 IU. study. The most common type of IV
used were bolus only (14 arms), infusion administration was bolus only (4 arms).
only (23 arms), and bolus plus infusion Dose-finding trials and Doses ranged from 3e80 IU with the
(27 arms). There were 26 different total nonrandomized studies most common dose being 5 IU (2 arms).
doses of oxytocin used ranging from 1 We identified 4 dose-finding RCTs (180
IUe260 IU. The most common total women). The sample sizes ranged from Outcomes
doses were 5 IU (11 arms) and 10 IU (8 30e70 women. Two trials included The most commonly reported outcomes
arms). We could not calculate the total women undergoing planned CD only were the use of additional uterotonics
dose for 3 of the studies.25,27,35 Among and 1 trial included women undergoing (28 studies) and mean blood loss (20
those trial arms that used an infusion intrapartum CD only. All studies used studies). No data were available for 7
component, the total infusion duration either an initial bolus or infusion fol- outcomes (maternal deaths, ICU ad-
ranged from 5 minutes to 24 hours, and lowed by a maintenance infusion. We missions, shock, water intoxication,
the rate of oxytocin administration var- found 5 NRSIs that included 1840 breastfeeding after discharge, maternal
ied from 0.7 IU per hour to 120 IU per women with sample sizes ranging from sense of well-being, and maternal sense
hour. Among the 5 trials that compared 41e1122 women. Of these, 4 were of satisfaction (Supplemental Table 4).

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 253

TABLE 1
Characteristics of included studies
First author, Study
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year design n Country CD type Oxytocin dosing regimens

Comparative randomized controlled trials Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 All arms
Bhattacharya 2-arm RCT 80 India Planned Bolus Infusion — — — — Infusion (0.16 IU/
et al,21 2013 3 IU 3 IU min) after study
period
Butwick 5-arm RCT 75 United States Planned No Bolus Bolus Bolus Bolus — Infusion of 10 IU
et al,22 2010 bolus 0.5 IU 1 IU 3 IU 5 IU over 2 h once
adequate UT plus
infusion (0.16 IU/
min) after study
period
Cecilia et al,23 2-arm RCT 271 India Both Infusion Infusion — — — — —
2018 2.5 IU/h over 10 IU/h over
2e4 h 8e12 h
Derbel et al,24 2-arm RCT 87 Tunisia Planned Bolus Bolus — — — — Infusion of 25 IU
2016 10 IU 5 IU over 3 h
Duffield 2-arm RCT 51 United States Planned Infusion of 10 IU Infusion of 60 IU — — — — Bolus 1 IU
et al,25 2017 until discharge until discharge
Ghulmiyyah 3-arm RCT 189 Lebanon Planned 20 IU 30 IU 40 IU over 30 — — — Infusion of 30 IU
et al,26 2017 over 30 min over min then 20 IU then 10
30 min IU for 24 h total
Golparvar 2-arm RCT 84 Iran Planned Infusion Infusion — — — — —
et al,27 2014 15 IU/h 30 IU/h
Güngördük 2-arm RCT 720 Turkey Planned Placebo infusion Infusion of 30 IU — — — — Bolus 5 IU
et al,28 2010 over 4 h
Jonsson 2-arm RCT 103 Sweden Planned Bolus 5 IU Bolus 10 IU — — — — —
et al,29 2010
Kajendran 2-arm RCT 92 Sri Lanka Planned Infusion of 20 IU Placebo infusion — — — — Bolus 5 IU
et al,30 2017 over 4 h
Kikutani 2-arm RCT 90 Japan Planned Bolus 10 IU over Infusion 10 IU — — — — —
et al,31 2003 30 s over 5 min
Kim et al,32 3-arm RCT 60 Korea Planned Infusion of 20 IU Bolus 2 IU plus Bolus 5 IU plus — — — —
2011 over 40 min infusion of 10 IU infusion of 10
over 40 min IU over 40 min
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)

ajog.org
ajog.org
TABLE 1
Characteristics of included studies (continued)
First author, Study
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year design n Country CD type Oxytocin dosing regimens

Comparative randomized controlled trials Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 All arms
King et al,33 2-arm RCT 143 Canada Both Bolus 5 IU Placebo bolus — — — — Infusion of 40 IU
2010 over 30 min then
infusion of 20 IU
over 4 h
Kiran et al,34 3-arm RCT 90 India Planned Bolus 0.5 IU Bolus 1 IU Bolus 2 IU — — — Infusion 20 IU
2013 over 2 h
Kovacheva 2-arm RCT 60 United States Planned Bolus 3 IU every 3 Infusion of 30 IU — — — — Infusion of 30 IU
et al,35 2015 min until until adequate UT over 6 h
adequate UT or
maximum 3
boluses
Munn et al,36 2-arm RCT 321 United States Intra Infusion of 10 IU Infusion of 80 IU — — — — Infusion of 20 IU
2001 over 30 min over 30 min over 8 h
Murphy 2-arm RCT 115 Scotland Planned Placebo infusion Infusion of 30 IU — — — — Bolus 5 IU
et al,37 2009 over 4 h
Palacio et al,38 2-arm RCT 104 Spain Planned Bolus 1 IU plus Infusion of 20 IU — — — — —
2011 infusion of 2.5 IU/ at 700 mIU/min
h for 24 h plus 10 IU/h for
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

24 h
Pinder et al,39 2-arm RCT 34 United Planned Bolus 5 IU Bolus 10 IU — — — — —
2002 Kingdom
Qian et al,40 6-arm RCT 145 China Planned No infusion Infusion of 1 IU/h Infusion of 2 Infusion of 3 Infusion of 5 Infusion of 8 Bolus 1 IU
2019 for 1 h IU/h for 1 h IU/h for 1 h IU/h for 1 h IU/h for 1 h
Sarna et al,41 4-arm RCT 40 United States Planned Infusion of 5 IU Infusion of 10 IU Infusion of 15 Infusion of 20 — — —
1997 at 1 IU/min at 1 IU/min IU at 1 IU/min IU at 1 IU/min
Sartain et al,42 2-arm RCT 80 Australia Planned Bolus 2 IU Bolus 5 IU — — — — Infusion of 40 IU

Systematic Reviews
2008 over 4 h
Sheehan 2-arm RCT 2069 Ireland Planned Placebo infusion Infusion of 40 IU — — — — Bolus 5 IU
et al,43 2011 over 4 h
Taj and 2-arm RCT 50 India Planned Bolus 10 IU over Infusion of 10 IU — — — — —
Ommid,44 15 s over 5 min
2014
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
255
Systematic Reviews
256 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

TABLE 1
Characteristics of included studies (continued)
First author, Study
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year design n Country CD type Oxytocin dosing regimens

Comparative randomized controlled trials Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6 All arms
Tariq and 2-arm RCT 90 Pakistan Planned Bolus 5 IU over 10 Infusion of 5 IU — — — — —
Syed,45 2018 s over 5 min
Thomas 2-arm RCT 28 United Planned Bolus 5 IU over 1 s Infusion of 5 IU — — — — —
et al,46 2007 Kingdom over 5 min
Dose-finding randomized trials Initial dose Maintenance infusion to all patients
47
Balki et al, 2006 1-arm 30 Canada Intra Starting bolus 0.5 IU Infusion of 40 mIU/min for up to 8 h
DF RCT Subsequently up or down by 0.5 IU (based on response
of preceding patient)
Carvalho et al,48 2004 1-arm 40 USA Planned Starting bolus 0.5 IU Infusion of 40 mIU/min until discharge
DF RCT Subsequently up or down by 0.5 IU (based on response
of preceding patient)
George et al,49 2010 1-arm 40 Canada Planned Starting infusion at 0.4 IU/min Infusion of 30 IU until discharge
DF RCT Subsequently up or down by 0.1 IU for 1 h (based on
response of preceding patient)
Lavoie et al,50 2015 2-arm 70 — Arm 1: intra; Starting infusion of 18 IU/h until end of CD Infusion of 3.6 IU/h until discharge
DF RCT arm 2: planned Subsequently up or down by 3 IU/h (based on response
of preceding patient)
Nonrandomized studies of interventions Arm 1 Arm 2 Arm 3 All arms
Ahmadi et al,51 2018 2-arm NRSI 150 Iran — Infusion of 80 IU Infusion of 30 IU — —
Holleboom et al,52 2013 3-arm NRSI 1122 Netherlands Planned Bolus 5 IU Bolus 10 IU Bolus 5 IU plus —
infusion of 10 IU over
2h
Pursche et al,53 2012 2-arm NRSI 454 Germany Both Bolus 3 IU plus Infusion with at least — —
infusion at 100 mL/h 120 mL/h
Terblanche et al,54 2017 2-arm NRSI 73 Australia Planned Bolus 3 IU Bolus 5 IU — —
55
Beiranvand et al, 2019 2-arm 41 Iran Arm 1: intra; Bolus 1 IU bolus, plus — — Infusion 30 mU/min
DF NRSI arm 2: planned 0.5 IU every min until
adequate UT
CD, cesarean delivery; DF, dose-finding; GA, gestational age; intra, intrapartum; IU, international units; NRSI, nonrandomized studies of interventions; RCT, randomized controlled trial; UT, uterine tone.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

ajog.org
ajog.org Systematic Reviews

TABLE 2
Overview of study comparisons: type of intravenous administration
Type of IV administration Bolus only Infusion Bolus plus infusion
Bolus only No studies 5 RCTs (338 women, 5 RCTs (3141 women)
all 2-arm trials)21,31,44e46 Four 2-arm trials28,30,37,43
One 6-arm triala,40
1 NRSI (1122 women, 2-arm study)b,52
Infusion — No studies 5 RCTs (442 women)
Three 2-arm trials32,35,38
One 3-arm trialc,32
One 4-arm triald,22
1 NRSI (454 women, 2-arm study)53
Bolus plus infusion — — No studies
Dose-finding studies (4 RCTs, 1 NRSI) are not included in this table.
IV, intravenous; NRSI, nonradomized studies of intervention; RCT, randomized controlled trial.
a
Six-arm study comparing bolus only with bolus plus infusion (BþI) vs BþI vs BþI vs BþI vs BþI; b Three-arm study comparing bolus only with bolus and BþI; c Three-arm study comparing infusion
with BþI and BþI; d 4-arm study comparing infusion with BþI and BþI and BþI.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

TABLE 3
Overview of study comparisons: total oxytocin dose
Dose <5 IU 5e9 IU 10e19 IU 20e49 IU ‡50 IU
<5 IU No 1 RCT (145 women) No studies No studies No studies
studies 1 IU vs 2 IU vs 3 IU
vs 4 IU vs 6 IU vs 9
IU40
1 NRSI (73 women)
3 IU vs 5 IU54
5e9 IU — No studies 3 RCTs (177 women) 4 RCTs (2996 women) No studies
5 IU vs 10 IU29,39 5 IU vs 35 IU28,37
5 IU vs 10 IU vs 5 IU vs 45 IU43
15 IU41 5 IU vs 25 IU30
3 NRSI (1122 women)
5 IU vs 10 IU vs
15 IU52
10e19 — — No studies 2 RCTs (331 women) No studies
IU 10 IU vs 30 IU23
12 IU vs 15 IU vs
20 IU32
20e49 — — — 3 RCTs (257 women)a 1 RCT (321 women)
IU 42 IU vs 45 IU42 30 IU vs 100 IU36
30 IU vs 35 IU24 1 NRSI (150 women)
20.5 IU vs 21 vs 30 IU vs 80 IU51
22 IU34
50 IU — — — — 3 RCTs (436 women)a
80 IU vs 90 IU
vs 100 IU26
60 IU vs 65 IU33
61 IU vs 260 IU38
Four dose-finding studies (4 RCTs, 1 NRSI) and 3 RCTs were not included because the total oxytocin dose could not be calculated.
IU, international unit; NRSI, nonrandomized studies of intervention; RCT, randomized controlled trial.
a
Studies compared outcomes within the same total oxytocin dose category and were not analyzed.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 257

TABLE 4
Overview of study comparisons: initial bolus dose in a bolus plus infusion regimen
Dose <5 IU 5 IU 10 IU
<5 IU 1 RCT (90 women) 3 RCTs (180 women) No studies
0.5 IU vs 1 IU vs 2 IU34 0.5 IU vs 1 IU vs 3 IU vs 5 IU22
2 IU vs 5 IU32
2 IU vs 5 IU42
5 IU — No studies 1 RCT (87 women)
5 IU vs 10 IU24
10 IU — — No studies
Dose-finding studies (4 RCTs, 1 NRSI) are not included in this table.
IU, international unit; NRSI, nonrandomized studies of intervention; RCT, randomized controlled trial.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

Synthesis of results mean change in hemoglobin (3 trials of 1.50; 95% CI, 0.27e8.34; low cer-
Meta-analysis. 2260 women; MD, e0.05 g/dL; 95% CI, tainty], and tachycardia [1 trial of 143
Type of intravenous administration. A e0.27 to 0.17 g/dL; high certainty) or women; RR, 0.96; 95% CI, 0.06e15.04;
total of 15 RCTs (3921 women) incidence of blood transfusion (3 trials low certainty]). The effects on use of
compared different types of IV admin- of 2870 women; RR, 1.55; 95% CI, additional uterotonics, mean blood
istration regimens (Table 2, 0.47e5.13; low certainty). The effects of loss, and nausea were inconclusive
Supplemental Table 5). The incidence of either dosing regimen on the outcomes because the certainty of evidence was
PPH 1000 mL was only reported for 1 of incidence of PPH 500 mL, use of very low. There were zero events re-
comparison (bolus only vs bolus plus additional uterotonics, and maternal ported for surgical interventions, chest
infusion). adverse effects (hypotension, nausea, pain, and dyspnea.
Bolus only vs infusion only. In 5 RCTs and chest pain) were inconclusive Total oxytocin dose. A total of 17 RCTs
(338 women), bolus only regimens were because the certainty of evidence was (4663 women) compared different total
compared with infusion only regimens. very low. There were zero events re- oxytocin doses (Table 3, Supplemental
No study reported on the outcome of ported for surgical or nonsurgical in- Table 6). The outcome of the incidence
incidence of PPH 1000 mL. The effects terventions, vomiting, bradycardia, of PPH 1000 mL was reported for 2
of either dosing regimen on the use of tachycardia, and dyspnea. A sensitivity comparisons (<5 IU vs 5e9 IU and 5e9
additional uterotonics, mean blood loss, analysis on risk of bias (including only IU vs 20e49 IU).
or maternal adverse effects (nausea, studies at an overall low risk of bias) Total oxytocin dose of <5 IU vs 5e9
vomiting, chest pain, and myocardial suggested no clear difference in mean IU. One RCT40 (145 women) compared
ischemia) are inconclusive because the blood loss. a total oxytocin dose of <5 IU with 5e9
certainty of evidence was very low. No Infusion only vs bolus plus infusion. In IU. It reported zero incidences of PPH
other outcomes were reported. 5 RCTs (442 women), infusion only 1000 mL with either dosing regimen.
Bolus only vs bolus plus infusion. In 5 regimens were compared with bolus The effects on the use of additional
RCTs (4580 women), bolus only regi- plus infusion regimens. No study re- uterotonics, satisfactory uterine tone,
mens were compared with bolus plus ported on the outcome of incidence of mean blood loss, or maternal adverse
infusion regimens. The effect of either PPH 1000 mL. There were no clear events (nausea, hypotension, chest pain)
dosing regimen on the outcome of differences in the incidence of satisfac- were inconclusive because the certainty
incidence of PPH 1000 mL was tory uterine tone (2 trials of 164 of evidence was very low. There were
inconclusive because the certainty of women; RR, 0.98; 95% CI, 0.90e1.06; zero events reported for blood trans-
evidence was very low (4 trials of 2976 low certainty), blood transfusion (1 trial fusions, vomiting, bradycardia, tachy-
women; RR, 1.44; 95% CI, 0.75e2.76; of 145 women; RR, 0.35; 95% CI, cardia, and dyspnea.
very low certainty), although bolus only 0.04e3.26; low certainty), or maternal Total oxytocin dose of 5e9 IU vs 10e19
regimens slightly increased the mean adverse events (vomiting [1 trial of 60 IU. Three RCTs (177 women) compared
blood loss (5 trials of 3068 women; MD, women; RR, 0.50; 95% CI, 0.06e4.18; a total oxytocin dose of 5e9 IU with
52 mL; 95% CI, 0.4e104 mL; moderate low certainty], headache [1 trial of 152 10e19 IU. No study reported on the
certainty) (Figure 2) and decreased the women; RR, 0.36; 95% CI, 0.01e8.71; incidence of PPH 1000 mL. The use of
incidence of satisfactory uterine tone (1 low certainty], hypotension [2 trials of a total dose of 5e9 IU vs 10e19 IU may
trial of 145 women; RR, 0.63; 95% CI, 263 women; RR, 0.60; 95% CI, result in a large increase in the use of
0.41e0.95; low certainty) (Figure 3). 0.34e1.05; moderate certainty], cardiac additional uterotonics (2 trials of 137
There were no clear differences in the arrythmia [1 trial of 60 women; RR, women; RR, 13.00; 95% CI, 1.75e96.37;

258 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

FIGURE 2
Bolus only vs bolus plus infusion: mean blood loss

CI, confidence interval; IV, intravenous; SD, standard deviation.

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

low certainty) (Figure 4). There was no probably reduces chest pain (1 trial of Different bolus doses in bolus plus infusion
clear difference in myocardial ischemia 271 women; RR, 0.05; 95% CI, regimens. A total of 5 RCTs using
(1 trial of 103 women; RR, 0.98; 95% CI, 0.00e0.81; moderate certainty) oxytocin regimens of bolus plus infusion
0.14e6.70; low certainty). The effect on (Supplemental Figure 5). There were no (357 women) compared different initial
mean blood loss was inconclusive clear differences in the incidence of bolus doses while keeping the infusion
because the certainty of evidence was blood transfusion (1 trial of 271 women; component identical for both trial arms
very low. There were zero events re- RR, 0.86; 95% CI, 0.28e2.62; low cer- (Table 4, Supplemental Table 7).
ported for hypotension. tainty), satisfactory uterine tone (1 trial Initial bolus dose of <5 IU vs 5 IU in a
Total oxytocin dose of 5e9 IU vs 20e49 of 271 women; RR, 1.05; 95% CI, bolus plus infusion regimen. In 3 RCTs
IU. Four RCTs (2996 women), 1.00e1.09; moderate certainty), or (180 women) in which a bolus plus
compared a total oxytocin dose of tachycardia (1 trial of 271 women; RR, infusion regimen was used, an initial
5e9 IU with 20e49 IU. The effects of 0.84; 95% CI, 0.26e2.69). The effects on bolus dose of <5 IU was compared with
either dosing regimen on the out- the use of additional uterotonics, mean that of 5 IU. No study reported on the
comes of incidence of PPH 1000 blood loss, nausea, or vomiting were incidence of PPH 1000 mL. Data from
mL, PPH 500 mL, use of additional inconclusive because the certainty of all 3 trials showed that initial bolus doses
uterotonics or blood transfusion, or evidence was very low. of <5 IU may reduce nausea (RR, 0.29;
mean blood loss were inconclusive Total oxytocin dose of 20e49 IU vs 50 95% CI, 0.10e0.81; low certainty)
because the certainty of evidence was IU. One RCT36 (321 women) compared (Supplemental Figure 7), but there were
very low. There was no clear differ- a total oxytocin dose of 20e49 IU with no clear differences in the use of addi-
ence in the change in hemoglobin 50 IU. It did not report on the inci- tional uterotonics (RR, 1.08; 95% CI,
(3 trials of 2260 women; MD, e0.05 dence of PPH 1000 mL. The use of 0.51e2.31; low certainty) or vomiting
g/dL; 95% CI, e0.27 to 0.17 g/dL; low doses of 20e49 IU compared with 50 (RR, 0.23; 95% CI, 0.05e1.04; low cer-
certainty). IU may increase the use of additional tainty). The effect on mean blood loss
Total oxytocin dose of 10e19 IU vs uterotonics (RR, 2.07; 95% CI, was very uncertain owing to very low
20e49 IU. Two RCTs (331 women) 1.42e3.01; low certainty) (Supplemental certainty about the evidence. There were
compared a total oxytocin dose of 10e19 Figure 6). There were no clear differ- zero events reported for surgical or
IU with 20e49 IU. Neither ences in mean blood loss (MD, 20 mL; nonsurgical interventions, blood trans-
study reported on the incidence of PPH 95% CI, e14 to 54 mL; low certainty) or fusions, and maternal adverse events
1000 mL. The use of a total dose of hypotension (RR, 1.05; 95% CI, (chest pain, cardiac arrythmia, dyspnea,
10e19 IU compared with of 20e49 IU 0.71e1.53; low certainty). hypotension).

FIGURE 3
Bolus only vs bolus plus infusion: satisfactory uterine tone

CI, confidence interval.

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 259

FIGURE 4
Total oxytocin dose of 5e9 IU vs 10e19 IU: use of additional uterotonics

CI, confidence interval.

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

Initial bolus dose of 5 IU vs 10 IU in a CD48e50 and that higher doses of suggested more women who received 5
bolus plus infusion regimen. One RCT24 oxytocin may be required during intra- IU experienced vomiting when
(87 women) that employed a bolus plus partum CD regardless of the type of compared with women who received 3
infusion regimen compared an initial administration.47,50 One dose-finding IU. One study52 (1122 women, critical
bolus dose of 5 IU with 10 IU. It did not NRSI55 (83 women) reported that small risk of bias) compared a total oxytocin
report on the incidence of PPH 1000 doses (1 IU as a bolus) may be adequate dose of 5 IU with that of 10 IU and 15 IU.
mL and there were no clear differences in to prevent uterine atony, with higher It suggested that increased doses of
mean blood loss (MD, 2 mL; 95% CI, doses needed during intrapartum CD. oxytocin may result in less PPH 1000
e135 to 138 mL; low certainty), cardiac Hypotension, secondary to oxytocin mL, the use of additional uterotonics and
arrythmia (RR, 0.34; 95% CI, 0.01e8.14; administration, was noted in all studies, blood transfusions, and may lead to
low certainty), or chest pain (RR, 0.41; however, was not explored in relation to more satisfactory uterine tone.52 One
95% CI, 0.08e2.00; low certainty). There specific doses or types of IV adminis- study51 (150 women, critical risk of bias)
were zero events reported for surgical or tration regimens. compared a total oxytocin dose of 30 IU
nonsurgical interventions and dyspnea. Nonrandomized studies. with that of 80 IU. It did not report on
We were largely unable to perform Type of intravenous administration. One the incidence of PPH 1000 mL but
sensitivity and subgroup analyses owing study52 (1122 women, critical risk of bias) suggested that 30 IU may lead to a sta-
to limited available data. However, where compared bolus only with bolus plus tistically significant increase in the use of
data permitted these analyses, no sig- infusion regimens. It suggested that more additional uterotonics and a decrease in
nificant effects were found except where women who received bolus only regi- satisfactory uterine tone. No significant
otherwise described. mens experienced PPH 1000 mL than differences were reported for any other
women who received bolus plus infusion outcomes including hypotension.
Narrative synthesis. regimens, greater use of additional ute-
We reviewed dose-finding RCTs and rotonics, and increased incidence in Comment
NRSIs separately. Findings from these blood transfusions. There were no sig- Main findings
studies are inconclusive, however, we nificant differences reported for any other We identified 35 studies of 7333 women
report the main findings below. The re- outcomes.52 Another study53 (454 comparing different IV oxytocin regi-
sults were not reported as statistically women, moderate risk of bias) compared mens for PPH prevention following CD.
significant unless otherwise noted. infusion only with bolus plus infusion The evidence in general was limited and
Dose-finding studies. A total of 4 dose- regimens. It did not report on the inci- data were lacking for most of the review
finding RCTs (180 women) studied the dence of PPH 1000 mL but suggested outcomes, with the data from 11 studies
different initial doses required to initiate that women who received infusion only at high or critical risk of bias. We did not
uterine contraction when followed by a regimens experienced a greater overall find any clear differences in the incidence
maintenance infusion. No study re- decrease in hemoglobin levels. of PPH 1000 mL, although data were
ported on the incidence of PPH 1000 Total oxytocin dose. One study54 (73 sparse for this outcome. Bolus plus
mL. The studies found that small doses women, moderate risk of bias) infusion regimens are possibly superior
(0.3 IU as a bolus or 0.27e0.29 IU/min compared a total oxytocin dose of 3 IU to bolus only regimens in terms of a
as a short infusion) may be adequate to with that of 5 IU. It did not report on the small reduction in mean blood loss
prevent uterine atony during planned incidence of PPH 1000 mL but (around 52 mL) and increased uterine

260 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

tone, although these findings were based bolus plus infusion regimen.7 Both re- compared, the authors similarly
on a few trials. In general, we found no views further reported more adverse described inadequate reporting of
clear indication of a superior total hemodynamic events with higher doses adverse events in trials of uterotonics for
oxytocin dose (largely because of insuf- of oxytocin, which is consistent with our PPH prevention.5 The international
ficient evidence). Although we found findings. Our findings are compatible consensus statement by Heesen et al8
doses of 10e19 IU is possibly better than with a 2019 international consensus also called for further large studies on
doses of 5e9 IU in terms of decreasing statement,8 which recommends using a 1 this topic.8 Any such trials should be
the use of additional uterotonics, there IU bolus followed by a 2.5e7.5 IU/h sufficiently powered for important
were limited data on adverse maternal infusion over 2e4 hours and the WHO health-related outcomes and should
events (particularly hypotension). Of recommendation of 10 IU oxytocin clearly specify the dosing regimen. Spe-
interest, both studies used in the meta- administered IVor intramuscular during cifically, trials comparing different
analysis of this outcome exclusively all births with doses divided into a small oxytocin doses of bolus plus infusion
compared 5 IU with 10 IU in a bolus only initial IV bolus with subsequent infusion regimens should be conducted. We
regimen. during CD.4 However, it is evident that consider it particularly important that
Oxytocin regimens were described good-quality trials comparing different future trials should report on the
using varying time intervals, which oxytocin dosing regimens are needed to outcome of PPH 1000 mL, an impor-
complicated meaningful comparison. guide practice. It is noteworthy to tant outcome for clinical guideline de-
However, available evidence suggests mention that national guidelines vary cision making.
that when administering oxytocin in a (Supplemental Table 8), probably We also found hypotension to be a
bolus plus infusion regimen, initial bolus reflecting the lack of clear evidence to poorly studied outcome, despite dose-
doses of <5 IU may lead to less nausea, guide practice. The 2017 American dependent hypotension being well
but the effects of lower vs higher initial College of Obstetricians and Gynecolo- described.21,29,42,46,62 Among RCTs, the
bolus doses on blood loss are not known. gists guidelines recommend using a effects of different dosing regimens on
The infusion component of bolus plus dilute IV infusion (bolus dose of 10 IU) hypotension were generally either
infusion regimens most commonly for PPH prevention without specifica- inconclusive or equivocal. No NRSI re-
continued for 2e4 hours. tion for mode of delivery.57 Australian ported significant differences in the
Findings from nonrandomized guidelines only recommend prophylac- incidence of hypotension. However, it
studies, although not conclusive owing tic oxytocin for all births without speci- would not seem unreasonable to expect
to a greater susceptibility to bias, were fying a dosing regimen.61 Carbetocin is an increased incidence of hypotension
broadly consistent with the findings of recommended in Canada during plan- with higher doses (particularly with
meta-analyses on RCTs. These generally ned CD,60 and a bolus only oxytocin bolus regimens), and it is likely that the
indicated that bolus plus infusion regi- regimen is recommended in the United combination of a bolus plus infusion
mens may be superior to bolus only Kingdom.58 French guidelines recom- regimen allows doses to exceed 5 IU
regimens and that higher oxytocin doses mend a oxytocin bolus plus infusion while avoiding significant hemodynamic
may be more effective but can increase regimen during CD, however, suggest an instability. Indeed, we consider it
adverse maternal events. Among the initial bolus dose of 5e10 IU.59 particularly important to prioritize
bolus plus infusion regimens, 4 dose- research in this area.
finding RCTs reported that small initial Strengths and limitations We also did not find any clear evidence
doses (0.3 IU as a bolus or 0.27e0.29 IU/ We used a systematic and methodologi- of diminishing returns from increasing
min as a short infusion) may be adequate cally robust approach to searching and doses and/or longer time periods of
to prevent uterine atony during planned analyzing literature without date or infusion despite it also being well
CD,48e50 with higher doses required at language restrictions. We included both described.22,26 Again, this was largely
intrapartum CD,47,50 but the evidence randomized and nonrandomized because of lack of good-quality data and
was not conclusive and should be inter- studies, which allowed for a more thor- is an area for which further research is
preted with caution. ough and nuanced investigation of required.
oxytocin dosing regimens. We also pre- We identified a wide range of dosing
Comparison with existing literature specified outcomes that aligned with regimens that added to the complexity of
Our findings are broadly consistent with WHO priority outcomes4 and the PPH this analysis and likely contributed to
previous work on IV oxytocin dosing core outcome set11 and used the latest high heterogeneity. Although we aimed
regimens for PPH prevention following and more sophisticated iterations of the to standardize comparisons by using
at CD, including a 2012 systematic re- Cochrane risk of bias tools (ROB 2.0 and total oxytocin dose, we were not able to
view7 of 7 RCTs (626 women) and a 2011 ROBINS-I).14,15 account for other factors such as rate of
literature review.6 Both reviews recom- Despite this, evidence was generally oxytocin administration or total infu-
mended the use of a small initial bolus limited for most outcomes. In a network sion time. We acknowledge that our dose
dose (ranging between 0.3 and 3 IU)6,7 meta-analysis by Gallos et al5 in which categories are somewhat arbitrary,
with 1 review further recommending a different uterotonic options were although necessary to standardize and

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 261

interpret comparisons. We also tried to Australia) for his assistance with the search 13. Covidence systematic review software.
minimize the effect of subjective judg- strategy; Dr Rangi de Silva, MBBS (Mercy Hos- Veritas Health Innovation. Available at: www.
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ments on blood loss by including this in insights on this topic; Dr Matthew Page, PhD 14. Sterne JAC, Savovic J, Page MJ, et al. RoB
our risk of bias assessment and per- (Monash University, Clayton, Australia) and Dr 2: a revised tool for assessing risk of bias in
forming sensitivity analyses. Tari Turner, PhD (Monash University) for their randomised trials. BMJ 2019;366:l4898.
Finally, the majority of studies insights on data analysis; and Liz Comrie- 15. Sterne JA, Hernán MA, Reeves BC, et al.
included only women undergoing plan- Thomson (Burnet Institute, Melbourne, Robins-I: a tool for assessing risk of bias in non-
Australia) for her insights on the entire research randomised studies of interventions. BMJ
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these findings may not be generalizable disclosure pertaining to this review. 16. Review manager (RevMan) [computer pro-
to other, higher-risk groups of women gram]. Version 5.3. Copenhagen: The Nordic
who may require a different oxytocin Cochrane Centre, The Cochrane Collaboration;
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32. Kim TS, Bae JS, Park JM, Kang SK. He- d4661. Shiny web app for visualizing risk-of-bias
modynamic effects of continuous intravenous 44. Taj A, Ommid M. Haemodynamic effects of assessments. Res Synth Methods 2021;12:
injection and bolus plus continuous intravenous oxytocin as intravenous bolus or infusion on 55–61.
injection of oxytocin in cesarean section. Korean women undergoing caesarean section. JK Sci 57. Committee on Practice Bulletins-Obstetrics.
J Anesthesiol 2011;61:482–7. 2014;16:52–6. Practice Bulletin No. 183: postpartum hemor-
33. King KJ, Douglas MJ, Unger W, Wong A, 45. Tariq M, Syed W. Comparison of haemo- rhage. Obstet Gynecol 2017;130:e168–86.
King RA. Five unit bolus oxytocin at cesarean dynamic effect of equivalent dose of oxytocin 58. Prevention and management of postpartum
delivery in women at risk of atony: a randomized, given as Bolus and in Fusion. Pak Armed Forces haemorrhage: Green-top Guideline No. 52.
double-blind, controlled trial. Anesth Analg Med J 2018;68:1517–21. BJOG 2017;124:e106–49.
2010;111:1460–6. 46. Thomas JS, Koh SH, Cooper GM. Haemo- 59. Sentilhes L, Vayssière C, Deneux-
34. Kiran S, Anand A, Singh T, Gupta N. To dynamic effects of oxytocin given as i.v. bolus or Tharaux C, et al. Postpartum hemorrhage:
estimate the minimum effective dose of oxytocin infusion on women undergoing caesarean sec- guidelines for clinical practice from the French
required to produce adequate uterine tone in tion. Br J Anaesth 2007;98:116–9. College of Gynaecologists and Obstetricians
women undergoing elective caesarean delivery. 47. Balki M, Ronayne M, Davies S, et al. Mini- (CNGOF): in collaboration with the French So-
Egypt J Anaesth 2013;29:161–5. mum oxytocin dose requirement after cesarean ciety of Anesthesiology and Intensive Care
35. Kovacheva VP, Soens MA, Tsen LC. delivery for labor arrest. Obstet Gynecol (SFAR). Eur J Obstet Gynecol Reprod Biol
A randomized, Double-blinded Trial of a “Rule of 2006;107:45–50. 2016;198:12–21.
Threes” algorithm versus continuous infusion of 48. Carvalho JC, Balki M, Kingdom J, 60. Leduc D, Senikas V, Lalonde AB. No. 235-
oxytocin during elective cesarean delivery. Windrim R. Oxytocin requirements at elective active management of the third stage of labour:
Anesthesiology 2015;123:92–100. cesarean delivery: a dose-finding study. Obstet prevention and treatment of postpartum hem-
36. Munn MB, Owen J, Vincent R, Wakefield M, Gynecol 2004;104:1005–10. orrhage. J Obstet Gynaecol Can 2018;40:
Chestnut DH, Hauth JC. Comparison of two 49. George RB, McKeen D, Chaplin AC, e841–55.
oxytocin regimens to prevent uterine atony at McLeod L. Up-down determination of the 61. Leung Y, Sgroi J, Vaughan J, et al. Man-
cesarean delivery: a randomized controlled trial. ED(90) of oxytocin infusions for the prevention of agement of postpartum haemorrhage (PPH).
Obstet Gynecol 2001;98:386–90. postpartum uterine atony in parturients under- Royal Australian and New Zealand College of
37. Murphy DJ, MacGregor H, Munishankar B, going Cesarean delivery. Can J Anaesth Obstetricians and Gynaecologists (RANZCOG).
McLeod G. A randomised controlled trial of 2010;57:578–82. 2017. Available at: https://ranzcog.edu.au/
oxytocin 5IU and placebo infusion versus 50. Lavoie A, McCarthy RJ, Wong CA. The ED90 RANZCOG_SITE/media/RANZCOG-MEDIA/
oxytocin 5IU and 30IU infusion for the control of of prophylactic oxytocin infusion after delivery of Women%27s%20Health/Statement%20and%
blood loss at elective caesarean section–pilot the placenta during cesarean delivery in laboring 20guidelines/Clinical-Obstetrics/Management-of-
study. ISRCTN 40302163. Eur J Obstet Gyne- compared with nonlaboring women: an up-down Postpartum-Haemorrhage-(C-Obs-43)-Review-
col Reprod Biol 2009;142:30–3. sequential allocation dose-response study. July-2017.pdf?ext¼.pdf 2017. Accessed Oct.
38. Palacio FJ, Morillas F, Ortiz-Gómez JR, Anesth Analg 2015;121:159–64. 29, 2020.
Fornet I, Bermejo L, Cantalejo F. [Efficacy of low- 51. Ahmadi F. A comparative study on infusion 62. Langesceter E, Rosseland LA. Maternal
dose oxytocin during elective cesarean section]. of usual dose of oxytocin and 80 units dose of hemodynamics during cesarean delivery. Acta
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APPENDIX A
PRISMA checklist
Section/topic R Checklist item Reported on page #
TITLE
Title 1 Identify the report as a systematic review, 1
meta-analysis, or both.
ABSTRACT
Structured summary 2 Provide a structured summary including, as applicable: 1
background; objectives; data sources; study eligibility
criteria, participants, and interventions; study appraisal
and synthesis methods; results; limitations;
conclusions and implications of key findings;
systematic review registration number.
INTRODUCTION
Rationale 3 Describe the rationale for the review in the context of 2
what is already known.
Objectives 4 Provide an explicit statement of questions being 2
addressed with reference to participants,
interventions, comparisons, outcomes, and study
design (PICOS).
METHODS
Protocol and registration 5 Indicate if a review protocol exists, if and where it can 2
be accessed (e.g., Web address), and, if available,
provide registration information including registration
number.
Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of 2
follow-up) and report characteristics (e.g., years
considered, language, publication status) used as
criteria for eligibility, giving rationale.
Information sources 7 Describe all information sources (e.g., databases with 2e3
dates of coverage, contact with study authors to
identify additional studies) in the search and date last
searched.
Search 8 Present full electronic search strategy for at least one Supplemental
database, including any limits used, such that it could Table 1
be repeated.
Study selection 9 State the process for selecting studies (i.e., screening, 2e3
eligibility, included in systematic review, and, if
applicable, included in the meta-analysis).
Data collection process 10 Describe method of data extraction from reports (e.g., 3
piloted forms, independently, in duplicate) and any
processes for obtaining and confirming data from
investigators.
Data items 11 List and define all variables for which data were sought 3
(e.g., PICOS, funding sources) and any assumptions
and simplifications made.
Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of 3
individual studies (including specification of whether
this was done at the study or outcome level), and how
this information is to be used in any data synthesis.
Summary measures 13 State the principal summary measures (e.g., risk ratio, 3
difference in means).
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)

263.e1 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

APPENDIX A
PRISMA checklist (continued)
Section/topic R Checklist item Reported on page #
Synthesis of results 14 Describe the methods of handling data and combining 3
results of studies, if done, including measures of
consistency (e.g., I2) for each meta-analysis.
Risk of bias across studies 15 Specify any assessment of risk of bias that may affect 3
the cumulative evidence (e.g., publication bias,
selective reporting within studies).
Additional analyses 16 Describe methods of additional analyses (e.g., 3
sensitivity or subgroup analyses, meta-regression), if
done, indicating which were pre-specified.
RESULTS
Study selection 17 Give numbers of studies screened, assessed for 3e4 & Figure 1
eligibility, and included in the review, with reasons for
exclusions at each stage, ideally with a flow diagram.
Study characteristics 18 For each study, present characteristics for which data Table 1
were extracted (e.g., study size, PICOS, follow-up
period) and provide the citations.
Risk of bias within studies 19 Present data on risk of bias of each study and, if 4, Supplemental
available, any outcome level assessment (see item 12). Figures 1e4
Results of individual studies 20 For all outcomes considered (benefits or harms), Supplemental
present, for each study: (a) simple summary data for Tables 5e7
each intervention group (b) effect estimates and
confidence intervals, ideally with a forest plot.
Synthesis of results 21 Present results of each meta-analysis done, including 4, 9e11, Supplemental
confidence intervals and measures of consistency. Tables 5e7
Risk of bias across studies 22 Present results of any assessment of risk of bias across Supplemental Figures 1e4
studies (see Item 15).
Additional analysis 23 Give results of additional analyses, if done (e.g., 4, 9e11
sensitivity or subgroup analyses, meta-regression [see
Item 16]).
DISCUSSION
Summary of evidence 24 Summarize the main findings including the strength of 11e13
evidence for each main outcome; consider their
relevance to key groups (e.g., healthcare providers,
users, and policy makers).
Limitations 25 Discuss limitations at study and outcome level (e.g., 12e13
risk of bias), and at review-level (e.g., incomplete
retrieval of identified research, reporting bias).
Conclusions 26 Provide a general interpretation of the results in the 13
context of other evidence, and implications for future
research.
FUNDING
Funding 27 Describe sources of funding for the systematic review 1
and other support (e.g., supply of data); role of funders
for the systematic review.
For more information, visit: www.prisma-statement.org.
Supplemental Reference
Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009;6:e1000097.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e2

APPENDIX B
Deviations from protocol
Protocol Deviation Justification
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Primary outcomes: PPH 500 mL and PPH 1000 mL PPH 500 mL downgraded from primary outcome to We opted to downgrade PPH 500 mL from a primary
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2021. Elsevier Inc. Todos los derechos reservados.

secondary outcome to a secondary outcome, considering that the definition

of PPH after CD is PPH 1000 mL (as distinct from PPH
after vaginal birth).
Included dyspnea and chest pain as additional Additional adverse events reported in some trials.
secondary outcomes
Include only third stage administration of oxytocin Included administration of oxytocin at or around third Practicality considerations means oxytocin not always
stage able to be delivered at third stage during CD.
Random-effects model if I2 >30% Random-effects model for all analyses with >1 trial Given large heterogeneity of trials and as per Cochrane
handbook, random-effects model provided a more
conservative estimate.
Specific comparisons made between high dose vs low We further divided the comparison of studies into (1) The wide range of oxytocin regimens identified meant
dose bolus, and high dose vs low dose infusion type of IV administration and (2) total oxytocin dose that our original approach of high and low dose was not
using the categories of <5 IU, 5e9 IU, 10e19 IU, practical nor informative.
20e49 IU, 50 IU. Among studies comparing a bolus
plus infusion regimen, we further compared various
initial bolus doses when followed by an infusion.
GRADE approach used to rate certainty of evidence. More accurately report study findings and draw
conclusions from the data.
Subgroup analysis for studies with maintenance Explore hypothesis proposed by Heesen et al8 that
infusions lasting 2e4 h included maintenance infusion should be run for 2e4 h.
CD, cesarean delivery; GRADE, Grading of Recommendations, Assessment, Development, and Evaluations; PPH, postpartum hemorrhage.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

ajog.org
ajog.org Systematic Reviews

SUPPLEMENTAL FIGURE 1
Randomized trials: risk of bias assessment by study

Risk of bias
D1 D2 D3 D4 D5 D6 D7 Overall

Balki 2006 xx xx xx ++ ?? ?? ++ xx
Bhattacharya 2013 ++ ++ xx ++ ?? ++ xx
Butwick 2010 ++ ++ ++ ++ ?? ++ −− ++
Carvalho 2004 xx xx ++ ++ ?? ?? ++ xx
Cecilia 2018 ++ ++ ++ ++ ?? ++ xx ++
Derbel 2016 ++ ++ ++ ++ ?? ?? −− ++
Duffield 2017 ++ ++ ++ ++ ?? ++ −− ++
George 2010 xx xx ++ ++ ?? ++ xx
Ghulmiyyah 2017 −− ++ ++ ++ ?? ++ ++ −−
Golparvar 2014 ++ xx −− ++ ?? ++ xx
Güngördük 2010 ++ ++ ++ ++ ?? ?? ++ ++
Jonsson 2010 ++ ++ ++ ++ ?? ++ xx ++
Kajendran 2017 ++ ++ ++ ++ ?? ++ ++ ++
Kikutani 2003 −− ++ ++ −− ?? ?? −−
Kim 2011 −− −− −− ++ ?? ?? ++ xx
Study

King 2010 ++ ++ ++ ++ ?? ++ xx ++
Kiran 2013 ++ ++ ++ ++ ?? ?? −− ++
Kovacheva 2015 ++ ++ ++ ++ ?? ++ −− ++
Lavoie 2015 xx xx ++ ++ ?? ++ ?? xx
Munn 2001 ++ ++ −− ++ ?? ++ ?? −−
Murphy 2009 ++ ++ ++ ++ ?? ++ ++ ++
Palacios 2011 ++ ++ ++ ++ ?? ++ xx ++
Pinder 2002 −− ++ −− ++ ?? ?? −−
Qian 2019 ++ ++ −− ++ ?? ++ ++ −−
Sarna 1997 ++ ++ xx ++ ?? ?? −− xx
Sartain 2008 ++ ++ ++ ++ ?? ?? xx ++
Sheehan 2011 ++ ++ ++ ++ ++ ++ ++ ++
Taj 2014 −− −− ++ ++ ?? ?? xx xx
Tariq 2018 ++ ++ ++ ++ ?? ++ ++
Thomas 2007 −− ++ ++ −− ?? ?? xx −−
D1: DOMAIN 1: Randomisation Judgement
D2: DOMAIN 2: Deviations form the intended interventions
D3: DOMAIN 3: Missing outcome data x High
D4: DOMAIN 4: Measurement of the outcome − Some concerns
D5: DOMAIN 5: Selection of the reported result
D6: DOMAIN 6 (OTHER): Conflicts of interest and funding source + Low
D7: DOMAIN 7 (OTHER): Blood loss measurement
? No information
Not applicable

Generated using robvis.56

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e4

SUPPLEMENTAL FIGURE 2
Comparative randomized trials: risk of bias by domain

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet
Gynecol 2021.

SUPPLEMENTAL FIGURE 3
Nonrandomised studies of interventions: risk of bias by study
Risk of bias
D1 D2 D3 D4 D5 D6 D7 D8 D9 Overall

Ahmadi 2018 xx !! ++ ?? ++ −− ++ ++ ++ !!
Beiranvand 2016 ++ ++ ++ ++ −− −− ++ ++ ?? −−
Study

Holleboom 2013 −− !! −− ?? ++ xx ++ !! xx !!
Pursche 2012 ++ ++ ++ −− ++ ++ ++ ++ −−
Terblanche 2017 ++ ++ −− ++ ++ ++ ++ ++ ++ −−
D1: Bias due to confounding Judgement
D2: Bias in selection of participants into the study
D3: Bias in classification of interventions ! Critical
D4: Bias due to deviations from intended interventions x High
D5: Bias due to missing data
D6: Bias in measurement of outcomes − Some concerns
D7: Bias in selection of the reported result + Low
D8: Bias due to conflicts of interest and funding source
D9: Bias in the measurement of blood loss ? No information
Not applicable
56
Generated using robvis.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet
Gynecol 2021.

263.e5 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL FIGURE 4
Nonrandomized studies of interventions: risk of bias by domain

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet
Gynecol 2021.

SUPPLEMENTAL FIGURE 5
Total oxytocin dose of 10e19 IU vs 20e49 IU: chest pain

CI, confidence interval; IU, international unit.

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e6

SUPPLEMENTAL FIGURE 6
Total oxytocin dose of 20e49 IU vs ‡50 IU: use of additional uterotonics

CI, confidence interval; IU, international unit.

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SUPPLEMENTAL FIGURE 7
Initial bolus dose of <5 IU vs 5e9 IU: nausea

CI, confidence interval; IU, international unit.

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

263.e7 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL TABLE 1
Search strategy
Database(s): Ovid MEDLINE(R) and Epub ahead of print, in-process, and other nonindexed citations and daily 1946 to February 14, 2020
Number Searches Results
1 exp Oxytocin/ or (oxytocin or ocytocin or syntocinon or 28,066
pitocin or oxytocic).mp. [mp¼title, abstract, original
title, name of substance word, subject heading word,
floating sub-heading word, keyword heading word,
organism supplementary concept word, protocol
supplementary concept word, rare disease
supplementary concept word, unique identifier,
synonyms]
2 exp Cesarean Section/ or (c?esarean or csection* or c 129,383
section* or abdominal delivery or elective delivery or
CS).mp.
3 exp Postpartum Hemorrhage/ 6910
4 (h?em?or?hag* or pph or (blood adj2 loss) or bleed* or 538,153
uterine atony or atonic uterus).mp.
5 3 or 4 538,153
6 exp drug administration routes/ 603,411
7 ((oxytocin or oxytocic or syntocinon or pitocin or drug or 876,861
drugs) adj5 (administ* or delivery or route or routes or
dose or doses or dosing or dosage or dosages or
intravenous or bolus or infusion or iv)).mp.
8 6 or 7 1,338,847
9 1 and 2 and (5 or 8) 1565
Database(s): Embase ClassicþEmbase 1947 to February 14, 2020
1 exp Oxytocin/ or (oxytocin or ocytocin or syntocinon or 44,929
pitocin or oxytocic).mp. [mp¼title, abstract, heading
word, drug trade name, original title, device
manufacturer, drug manufacturer, device trade name,
keyword, floating subheading word, candidate term
word]
2 exp Cesarean Section/ or (c?esarean or csection* or c 204,077
section* or abdominal delivery or elective delivery or
CS).mp.
3 exp Postpartum Hemorrhage/ 14,406
4 (h?em?or?hag* or pph or (blood adj2 loss) or bleed* or 968,513
uterine atony or atonic uterus).mp.
5 3 or 4 968,513
6 exp drug administration routes/ 1,222,962
7 ((oxytocin or oxytocic or syntocinon or pitocin or drug or 3,561,354
drugs) adj5 (administ* or delivery or route or routes or
dose or doses or dosing or dosage or dosages or
intravenous or bolus or infusion or iv)).mp.
8 6 or 7 3,569,315
9 1 and 2 and (5 or 8) 4631
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e8

SUPPLEMENTAL TABLE 1
Search strategy (continued)
Database(s): Ovid MEDLINE(R) and Epub ahead of print, in-process, and other nonindexed citations and daily 1946 to February 14, 2020
Number Searches Results
1 exp Oxytocin/ or (oxytocin or ocytocin or syntocinon or 44,929
pitocin or oxytocic).mp. [mp¼title, abstract, heading
word, drug trade name, original title, device
manufacturer, drug manufacturer, device trade name,
keyword, floating subheading word, candidate term
word]
2 exp Cesarean Section/ or (c?esarean or csection* or c 204,077
section* or abdominal delivery or elective delivery or
CS).mp.
3 exp Postpartum Hemorrhage/ 14,406
Database: CINAHL Complete
Interface: EBSCOhost Research Databases
Search Screen: Advanced Search
Date: February 14, 2020
(MM “Oxytocin”) or (oxytocin or ocytocin or syntocinon or pitocin or oxytocic) AND
(MH “Cesarean Sectionþ”) or (c#esarean or csection* or c section* or abdominal delivery or elective delivery or CS) AND
((MH “Postpartum Hemorrhage”) or (h#em#or#hag* or pph or (blood N2 loss) or bleed* or uterine atony or atonic uterus)) or ((MH “Drug
Administrationþ”) or (oxytocin or oxytocic or syntocinon or pitocin or drug or drugs) N5 (administ* or delivery or route or routes or dose or doses or
dosing or dosage or dosages or intravenous or bolus or infusion or iv))
(797 results)
Global Index Medicus, February 14, 2020
tw:((tw:(oxytocin OR ocytocin OR syntocinon OR pitocin OR oxytocic)) AND (tw:(c?esarean OR csection* OR c section* OR abdominal delivery OR
elective delivery OR cs)) AND (tw:(h?em?or?hag* OR pph OR blood loss OR loss of blood OR bleed* OR uterine atony OR atonic uterus OR administ*
OR delivery OR route OR routes OR dose OR doses OR dosing OR dosage OR dosages OR intravenous OR bolus OR infusion OR iv)))
(686 results)
CENTRAL
Search Name: MDRP (19 Feb)
Date Run: February 19, 2020, 02:16:59 PM
ID Search Hits
#1 MeSH descriptor: [Oxytocin] explode all trees 1802
#2 ((oxytocin or ocytocin or syntocinon or pitocin or 4706
oxytocic)):ti,ab,kw
#3 MeSH descriptor: [Cesarean Section] explode all trees 2989
#4 ((c?esarean or csection* or “c section*” or “abdominal 18,468
delivery” or “elective delivery” or CS)):ti,ab,kw
#5 MeSH descriptor: [Postpartum Hemorrhage] explode 621
all trees
#6 ((h*em*or*hag* or pph or “blood NEAR/2 loss” or 63,385
bleed* or “uterine atony” or “atonic uterus”)):ti,ab,kw
#7 MeSH descriptor: [Administration, Intravenous] 18,229
explode all trees
#8 (((oxytocin or oxytocic or syntocinon or pitocin or drug 149,407
or drugs) NEXT/5 (administ* or delivery or route or
routes or dose or doses or dosing or dosage or dosages
or intravenous or bolus or infusion or iv))):ti,ab,kw
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)

263.e9 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL TABLE 1
Search strategy (continued)
ID Search Hits
#9 #1 or #2 4706
#10 #3 or #4 18,468
#11 #5 or #6 63,385
#12 #7 or #8 162,486
#13 #9 and #10 and (#11 or #12) 1048
ICTRP, February 19, 2020
Oxytocin AND hemorrhage (207)
Oxytocin AND dose (163)
Oxytocin AND bleed (191)
ClinicalTrials.gov, February 19, 2020
oxytocin (other terms) j Post Partum Hemorrhage (condition) (151)
oxytocin (other terms) j Bleed (condition) (178)
oxytocin (other terms) j Caesarean (condition) j Dose (intervention) (41)
ICTRP, International Clinical Trials Registry Platform; MeSH, medical subject headings.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SUPPLEMENTAL TABLE 2
Assessment of risk of bias of methods of measuring blood loss
ROB assessment ROB assessment
(RCTs) (NRSIs) Description
Low Low Objective measurements such as calculated blood
loss, weighing sponges or volumetric assessment
High Critical Subjective measurement such as clinical or visual
estimates
Medium Moderate Mixture of objective and subjective measurements
Unclear Unclear Unspecified methods of measurement
NRSI, nonrandomized studies of intervention; RCT, randomized controlled trial.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e10

SUPPLEMENTAL TABLE 3
Dosing regimens of all included studies
Author, year n Oxytocin dosing regimens
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6

Comparative RCTs Study dose 30 mina Study dose 30 mina Study dose 30 mina Study dose 30 mina Study dose 30 mina Study dose 30 mina All arms
Bhattacharya 80 Bolus 3 IU Infusion of 3 IU — — — — Infusion (0.16
et al,21 2013 IU/min) after
study period
Butwick et al,22 75 Bolus 0 IU Bolus 0.5 IU Bolus 1 IU Bolus 3 IU Bolus 5 IU — Infusion 10 IU
2010 over 2 h once
adequate UT
plus infusion
(0.16 IU/min)
after study
period
Cecilia et al,23 271 2.5 IU/h over 1.25 IU 10 IU/h over 5 IU — — — — —
2018 2e4 h 8e12 h
Derbel et al,24 87 10 IU 14 IU 5 IU 9 IU — — — — Infusion of 25
2016 IU over 3 h
Duffield et al,25 51 Infusion 10 NEb Infusion of NEb — — — — Bolus 1 IU
2017 IU until d/c 60 IU until
d/c
Ghulmiyyah 189 20 IU over 30 min 30 IU over 30 min 40 IU over 30 min — — — Infusion of 30
et al,26 2017 IU then 20 IU
then 10 IU for
24 h total
Golparvar et al,27 84 15 IU/h 7.5 IU 30 IU/h 15 IU — — — — —
2014
Güngördük 720 Placebo 5 IU 30 IU over 12.5 IU — — — — Bolus 5 IU
et al,28 2010 infusion 4h
Jonsson et al,29 103 5 IU 10 IU — — — — —
2010
Kajendran et al,30 92 20 IU over 10 IU Placebo 5 IU — — — — Bolus 5 IU
2017 4h infusion
Kikutani et al,31 90 Bolus 10 IU Infusion 10 IU — — — — —
2003
Kim et al,32 2011 60 20 IU over 15 IU Bolus 2 IU 9.5 IU Bolus 5 IU 12.5 IU — — — —
40 min plus infusion plus infusion

ajog.org
of 10 IU over of 10 IU over
40 min 40 min
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
ajog.org
SUPPLEMENTAL TABLE 3
Dosing regimens of all included studies (continued)
Author, year n Oxytocin dosing regimens
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6

a a a a a
Comparative RCTs Study dose 30 min Study dose 30 min Study dose 30 min Study dose 30 min Study dose 30 min Study dose 30 mina All arms
King et al,33 2010 143 Bolus 45 IU Placebo 40 IU — — — — Infusion of 40
5 IU bolus IU over 30 min
then infusion
of 20 IU over 4
h
Kiran et al,34 2013 90 Bolus 0.5 5.5 IU Bolus 1 IU 6 IU Bolus 2 IU 7 IU — — — Infusion of 20
IU over 2 h
Kovacheva et al,35 60 Bolus 3 IU NEb Infusion of NEb — — — — Infusion of 30
2015 every 3 min 30 IU until IU over 6 h
until adequate UT
adequate UT
or max of 3
boluses
Munn et al,36 321 Infusion of 10 IU Infusion of 80 IU — — — — Infusion of 20
2001 over 30 min over 30 min IU over 8 h
Murphy et al,37 115 Placebo 5 IU Infusion of 8.75 IU — — — — Bolus 5 IU
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

2009 infusion 30 IU over

4h
Palacio et al,38 104 Bolus 1 IU 2.125 IU Infusion of 21 IU — — — — —
2011 plus infusion 20 IU at 700
at 2.5 IU/h for mIU/min plus
24 h 10 IU/h for
24 h
Pinder et al,39 34 Bolus 5 IU Bolus 10 IU — — — — —
2002
Qian et al,40 2019 145 No infusion 1 IU Infusion of 1 1.5 IU Infusion of 2 2 IU Infusion of 3 2.5 IU Infusion of 5 3.5 IU Infusion of 8 5 IU Bolus 1 IU

Systematic Reviews
IU/h for 1 h IU/h for 1 h IU/h for 1 h IU/h for 1 h IU/h for 1 h
Sarna et al,41 40 Infusion of 5 IU Infusion of 10 IU Infusion of 15 IU at 1 IU/ Infusion of 20 IU at 1 IU/ — — —
1997 at 1 IU/min at 1 IU/min min min
Sartain et al,42 80 Bolus 2 IU 7 IU Bolus 5 IU 10 IU — — — — Infusion of 40
2008 IU over 4 h
Sheehan et al,43 2069 Placebo 5 IU Infusion of 10 IU — — — — Bolus 5 IU
2011 infusion 40 IU over 4
h
263.e12

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
Systematic Reviews
263.e13 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL TABLE 3
Dosing regimens of all included studies (continued)
Author, year n Oxytocin dosing regimens
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Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6

a a a a a
Comparative RCTs Study dose 30 min Study dose 30 min Study dose 30 min Study dose 30 min Study dose 30 min Study dose 30 mina All arms
Taj and Ommid,44 50 Bolus 10 IU Infusion of 10 IU — — — — —
2014 over 15 s over 5 min
Tariq and Syed,45 90 Bolus 5 IU Infusion of 5 IU — — — — —
2018 over 10 s over 5 min
Thomas et al,46 28 Bolus 5 IU Infusion of 5 IU — — — — —
2007 over 1 s over 5 min
Initial dose
Dose-finding randomized trials (Dose in 30 min not estimable for all studies in this category) Maintenance infusion to all patients
47
Balki et al, 2006 30 Starting bolus 0.5 IU Infusion 40 mU/min for up to 8 h
Subsequently up or down by 0.5 IU (based on response of preceding patient)
Carvalho et al,48 40 Starting bolus 0.5 IU Infusion 40 mU/min until discharge
2004 Subsequently up or down by 0.5 IU (based on response of preceding patient)
George et al,49 40 Starting infusion at 0.4 IU/min Infusion 30 IU until discharge
2010 Subsequently up or down by 0.1 IU for 1 h (based on response of preceding
patient)
Lavoie et al,50 70 Starting infusion 18 IU/h until end CD Infusion 3.6 IU/h until discharge
2015 Subsequently up or down by 3 IU/h (based on response of preceding patient)

Nonrandomized studies of Arm 1 Arm 2 Arm 3

a a
interventions Study dose 30 min Study dose 30 min Study dose 30 mina All arms
51 b b
Ahmadi et al, 150 Infusion 80 IU NE Infusion 30 IU NE — —
2018
Holleboom et al,52 1122 Bolus 5 IU Bolus 10 IU Bolus 5 IU plus 7.5 IU —
2013 infusion of 10 IU
over 2 h
Pursche et al,53 454 Bolus 3 IU plus infusion of 3 IU in 3.3 IU Infusion with at least NEb — —
2012 500 mL at 100 mL/h 120 mL/h
Terblanche 73 Bolus 3 IU Bolus 5 IU — —
et al,54 2017
Beiranvand 41 Bolus 1 IU bolus, plus 0.5 IU NEb — — Infusion at 30 mU/min
et al,55 2019 every min until adequate UT
CD, cesarean delivery; d/c, discharge; IU, international unit; NE, not estimable; UT, uterine tone.

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a
Total oxytocin dose received by each arm within first 30 minutes; b Not estimable because the study does provide enough information to reasonably estimate total dose received in 30 minutes.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.
ajog.org Systematic Reviews

SUPPLEMENTAL TABLE 4
Available data by outcome
RCTs, number of NRSIs, number of Total, number of
Outcome trials (women)a trials (women)a trials (women)a
PPH 1000 mL 8 (3324) 1 (1100) 9 (4424)
PPH 500 mL 1 (115) 1 (1100) 2 (1215)
Additional uterotonics 25 (5053) 3 (1323) 28 (6376)
Uterine tone 10 (1177) 3 (479) 13 (1656)
Surgical or nonsurgical interventions 5 (385) 1 (1100) 6 (1485)
Blood transfusion 12 (3994) 1 (1100) 13 (5094)
Mean blood loss 18 (4329) 2 (1173) 20 (5502)
Change in hemoglobin 4 (2400) 2 (1096) 6 (3496)
Nausea 9 (727) 3 (162) 12 (889)
Vomiting 10 (778) 2 (156) 12 (934)
Headache 6 (477) 3 (162) 9 (639)
Hypotension 10 (1048) 3 (162) 13 (1210)
Chest pain 7 (687) 3 (1278) 10 (1965)
b
Myocardial ischemia 2 (173) 0 (0) 2 (173)
Arrythmiac 5 (416) 0 (0) 5 (416)
Bradycardia 3 (236) 0 (0) 3 (236)
Tachycardia 7 (794) 0 (0) 7 (794)
Maternal deaths 0 (0) 0 (0) 0 (0)
ICU admissions 0 (0) 0 (0) 0 (0)
Shock 0 (0) 0 (0) 0 (0)
Water intoxication 0 (0) 0 (0) 0 (0)
Breastfeeding after discharge 0 (0) 0 (0) 0 (0)
Maternal sense of well-being 0 (0) 0 (0) 0 (0)
Maternal satisfaction 0 (0) 0 (0) 0 (0)
Studies were not included if there were zero events in both arms or if standard deviations were not provided with mean values.
ICU, intensive care unit; NRSI, nonrandomized studies of intervention; PPH, postpartum hemorrhage; RCT, randomized controlled trial.
a
Includes extra doses of oxytocin, prostaglandins (carboprost, misoprostol), and ergometrine; b Includes troponin I rise and ST segment changes; c Includes electrocardiogram changes.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e14

SUPPLEMENTAL TABLE 5
Summary of funding from randomized studies: type of IV administration
Patient or population: women undergoing cesarean delivery
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Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance
Outcomes Anticipated absolute effects (95% CI)a (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Type of IV administration: bolus only vs infusion only
Risk with infusion only Risk with bolus only
Use of additional 359 per 1000 327 per 1000 RR, 0.91 78 4 Effect is inconclusive ROB: RR, 0.88 Not estimablei
uterotonics (187e578) (0.52e1.61) (2 RCTs) Very lowb,c (0.44e1.75)
Mean blood loss The mean blood loss was MD, 0 mL (e309 to 309) — 28 4 Effect is inconclusive Not estimablej Not estimablei
600 mL in both arms (1 RCT) Very lowb,c
Nausea 80 per 1000 200 per 1000 RR, 2.50 50 4 Effect is inconclusive Not estimablej Not estimablei
(42e936) (0.53e11.70) (1 RCT) Very lowb,c
Vomiting 40 per 1000 120 per 1000 RR, 3.00 50 4 Effect is inconclusive Not estimablej Not estimablei
(13e1000) (0.33e26.92) (1 RCT) Very lowb,c
Chest pain Unable to calculate because there were zero events in RR, 7.00 80 4 Effect is inconclusive Not estimablej Not estimablei
infusion arm (0.37e131.28) (1 RCT) Very lowb,c
Myocardial Unable to calculate because there were zero events in RR, 11.00 80 4 Effect is inconclusive Not estimablej Not estimablei
ischemia infusion arm (0.63e192.56) (1 RCT) Very lowbed
Type of IV administration: bolus only vs bolus plus infusion only
Risk with bolus plus infusion Risk with bolus only
PPH 1000 mL 119 per 1000 172 per 1000 RR, 1.44 2976 4 Effect is inconclusive Not requiredk Not estimablei
(89e329) (0.75e2.76) (4 RCTs) Very lowe,f
Use of additional 120 per 1000 209 per 1000 RR, 1.75 3125 4 Effect is inconclusive ROB: RR, 1.60 Not estimablei
uterotonics (145e304) (1.21e2.54) (5 RCTs) Very lowe,f (0.99e2.58)
PPH 500 mL 179 per 1000 259 per 1000 RR, 1.45 110 (1 RCT) 4 Effect is inconclusive Not estimablej Not estimablei
(127e532) (0.71e2.98) Very lowc,g
Blood transfusion 9 per 1000 14 per 1000 RR, 1.55 2870 44 May make no clear Not requiredk Not estimablei
(4e46) (0.47e5.13) (3 RCTs) Lowf,h difference
Blood loss The mean blood loss ranged MD, 52 mL more — 3068 444 Bolus only regimens ROB: MD, 53 mL Not estimablei
from 569e693 mL (0.4 more to 104 more) (5 RCTs) Moderateh probably slightly (e4 to 111 mL)
increases blood loss
Blood loss: not
requiredj
Change in The mean change in MD, 0.05 g/dL less — 2260 4444 Makes no clear Not requiredk Not estimablei

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hemoglobin hemoglobin ranged (0.27 less to 0.17 more) (3 RCTs) High difference
0.88e11.9 g/dL
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
ajog.org
SUPPLEMENTAL TABLE 5
Summary of funding from randomized studies: type of IV administration (continued)
Patient or population: women undergoing cesarean delivery
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance
Outcomes Anticipated absolute effects (95% CI)a (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Nausea 92 per 1000 200 per 1000 RR, 2.18 145 4 Effect is inconclusive Not estimablej Not estimablei
(76e525) (0.83e5.73) (1 RCT) Very lowc,g
Hypotension 142 per 1000 200 per 1000 RR, 1.41 145 4 Effect is inconclusive Not estimablej Not estimablei
(81e492) (0.57e3.47) (1 RCT) Very lowc,g
Chest pain 50 per 1000 137 per 1000 RR, 2.74 145 4 Effect is inconclusive Not estimablej Not estimablei
(44e434) (0.87e8.67) (1 RCT) Very lowc,g
Satisfactory 767 per 1000 483 per 1000 RR, 0.63 145 44 Bolus only regimens Not estimablej Not estimablei
uterine tone (314e728) (0.41e0.95) (1 RCT) Lowf,g may decrease
incidence
Surgical or Unable to calculate because zero events occurred in either arms 92 — — — —
nonsurgical (1 RCT)
interventions
Vomiting Unable to calculate because zero events occurred in either arms 145 — — — —
(1 RCT)
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

Bradycardia Unable to calculate because zero events occurred in either arms 145 — — — —
(1 RCT)
Tachycardia Unable to calculate because zero events occurred in either arms 145 — — — —
(1 RCT)
Dyspnea Unable to calculate because zero events occurred in either arms 145 — — — —
(1 RCT)
Type of IV administration: infusion only vs bolus plus infusion
Risk with bolus plus infusion Risk with infusion only
Use of additional 143 per 1000 270 per 1000 RR, 1.88 441 4 Effect is inconclusive ROB: RR, 1.59 RR, 1.39

Systematic Reviews
uterotonics (132e551) (0.92e3.84) (5 RCTs) Very lowfeh (0.71e3.54) (0.87e2.22)
Mean blood loss The mean blood loss ranged MD, 20 mL more — 283 4 Effect is inconclusive ROB: MD, 43 mL MD, 90 mL
between 455e693 mL (13 less to 53 more) (3 RCTs) Very lowb,f (e12 to 97 mL) (e2 to 182 mL)
Blood loss: MD, 9 mL
(2e17 mL)
Nausea 53 per 1000 49 per 1000 RR, 1.05 277 4 Effect is inconclusive ROB: RR, 3.45 RR, 2.88
(17e145) (0.28e3.97) (3 RCTs) Very lowb,c (0.44e27.20) (0.12e69.49)
263.e16

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
Systematic Reviews
263.e17 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL TABLE 5
Summary of funding from randomized studies: type of IV administration (continued)
Patient or population: women undergoing cesarean delivery
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance
Outcomes Anticipated absolute effects (95% CI)a (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Hypotension 186 per 1000 111 per 1000 RR, 0.60 263 444 Probably makes no Not requiredk Not estimablei
(63e195) (0.34e1.05) (2 RCTs) Moderatef clear difference
Satisfactory 927 per 1000 918 per 1000 RR, 0.98 164 44 May make no clear Not requiredk Not estimablei
uterine tone (834e1000) (0.90e1.06) (2 RCTs) Lowd,f difference
Blood transfusion 41 per 1000 14 per 1000 RR, 0.35 143 44 May make no clear Not estimablej Not requiredl
(2e134) (0.04e3.26) (1 RCT) Lowc difference
Vomiting 100 per 1000 50 per 1000 RR, 0.50 60 44 May make no clear Not estimablej Not estimablei
(6e418) (0.06e4.18) (1 RCT) Lowc difference
Headache 13 per 1000 5 per 1000 RR, 0.36 152 44 May make no clear Not estimablej Not requiredl
(0e110) (0.01e8.71) (1 RCT) Lowc difference
Cardiac arrythmia 67 per 1000 100 per 1000 RR, 1.50 60 44 May make no clear Not estimablej Not estimablei
(18e556) (0.27e8.34) (1 RCT) Lowc difference
Tachycardia 14 per 1000 14 per 1000 RR, 0.96 143 44 May make no clear Not estimablej Not requiredl
(1e215) (0.06e15.04) (1 RCT) Lowc difference
Surgical Unable to calculate as zero events in both arms 75 — — — —
interventions (1 RCT)
Chest pain Unable to calculate as zero events in both arms 75 — — — —
(1 RCT)
Dyspnea Unable to calculate as zero events in both arms 75 — — — —
(1 RCT)
Sensitivity analysis of risk of bias included studies only at overall low risk of bias.
Sensitivity analysis of method of blood loss measurement included studies only at low risk of bias for that domain.
Subgroup analysis included only studies using a bolus plus infusion regimen, for which the infusion duration ranged between 2 to 4 hours.
GRADE working group grades of evidence were as follows:
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
CI, confidence interval; IV, intravenous; MD, mean difference; PPH, postpartum hemorrhage; RCT, randomized controlled trial; ROB, risk of bias; RR, risk ratio.
a
The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI); b Downgraded for very serious risk of bias; c Downgraded for very serious imprecision; d Downgraded
for serious indirectness; e Downgraded for very serious inconsistency; f Downgraded for serious imprecision; g Downgraded for serious risk of bias; h Downgraded for serious inconsistency; i Not estimable because no studies used maintenance infusion for 2 to 4

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hours in both arms; j Not estimable because it was a single study; k Not required as all studies at low risk of bias; l Not required because all studies used maintenance infusion for 2 to 4 hours in both arms.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.
ajog.org
SUPPLEMENTAL TABLE 6
Summary of findings from randomized studies: total oxytocin dose
Patient or population: women undergoing cesarean delivery
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Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance of
Outcomes Anticipated absolute effectsa (95% CI) (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Total oxytocin dose: <5 IU vs 5e9 IU
Risk with 5e9 IU Risk with <5 IU
PPH 1000 Unable to calculate because zero events were recorded in either arm 145 — — — —
(1 RCT)
Use of additional 120 per 1000 379 per 1000 RR, 3.16 145 4 Effect is Not estimablei Not estimablej
uterotonics (172e838) (1.43e6.98) (1 RCT) Very lowbed inconclusive
Mean blood loss The mean blood loss MD, 20 mL more — 145 4 Effect is Not estimablei Not estimablej
ranged from (116 less to 156 more) (1 RCT) Very lowbed inconclusive
642e661 mL
Nausea 100 per 1000 116 per 1000 RR, 1.16 145 4 Effect is Not estimablei Not estimablej
(43e315) (0.43e3.15) (1 RCT) Very lowb,c,e inconclusive
Hypotension 100 per 1000 221 per 1000 RR, 2.21 145 4 Effect is Not estimablei Not estimablej
(89e551) (0.89e5.51) (1 RCT) Very lowb,c,e inconclusive
4 Not estimablei Not estimablej
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

Chest pain 60 per 1000 84 per 1000 RR, 1.40 145 Effect is
(23e304) (0.39e5.06) (1 RCT) Very lowb,c,e inconclusive
Satisfactory uterine tone 900 per 1000 621 per 1000 RR, 0.69 145 4 Effect is Not estimablei Not estimablej
(522e747) (0.58e0.83) (1 RCT) Very lowbed inconclusive
Blood transfusion Unable to calculate because zero events were recorded in either arm 145 — — — —
(1 RCT)
Vomiting Unable to calculate because zero events were recorded in either arm 145 — — — —
(1 RCT)
Bradycardia Unable to calculate because zero events were recorded in either arm 145 — — — —
(1 RCT)

Systematic Reviews
Tachycardia Unable to calculate because zero events were recorded in either arm 145 — — — —
(1 RCT)
Dyspnea Unable to calculate because zero events were recorded in either arm 145 — — — —
(1 RCT)
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
263.e18
Systematic Reviews
263.e19 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL TABLE 6
Summary of findings from randomized studies: total oxytocin dose (continued)
Patient or population: women undergoing cesarean delivery
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance of
Outcomes Anticipated absolute effectsa (95% CI) (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Total oxytocin dose: 5e9 IU vs 10e19 IU
Risk with Risk with
10e19 IU 5e9 IU
Use of additional Unable to calculate because zero events were recorded RR, 13.00 137 44 5e9 IU may
uterotonics in the 10e19 IU arm (1.75e96.37) (2 RCTs) Lowb,d increase
ROB: RR, 18.64 Not estimablej
incidence
(1.11e312.11)
Mean blood loss The mean blood loss MD, 58 mL more — 133 4 Effect is ROB: MD, 45 mL Not estimablej
ranged 540e578 mL (9 mL less to 124 mL more) (2 RCTs) Very lowd,f inconclusive (e109 to 199 mL)
Blood loss: not Not estimablej
requiredk
Myocardial ischemia 39 per 1000 38 per 1000 RR 0.98 103 44 May make no Not estimablei Not estimablej
(5e263) (0.14e6.70) (1 RCT) LOWe clear
difference.
Hypotension Unable to calculate as zero events in both arms 60 — — — —
(1 RCT)
Total oxytocin dose: 5e9 IU vs 20e49 IU
Risk with Risk with
20e49 IU 5e9 IU
PPH 1000 mL 129 per 1000 186 per 1000 RR, 1.44 2831 4 Effect is Not estimablei Not estimablej
(97e357) (0.75e2.76) (4 RCTs) Very lowc,d,g inconclusive
Use of additional 110 per 1000 177 per 1000 RR, 1.60 2980 4 Effect is Not estimablei Not estimablej
uterotonics (109e285) (0.99e2.58) (4 RCTs) Very lowc,d,h inconclusive
PPH 500 mL 179 per 1000 259 per 1000 RR, 1.45 110 (1 RCT) 4 Effect is Not estimablei Not estimablej
(127e532) (0.71e2.98) Very lowb,e inconclusive
Blood transfusion 9 per 1000 13 per 1000 RR, 1.55 2980 4 Effect is Not estimablei Not estimablej
(4e45) (0.47e5.13) (4 RCTs) Very lowc,d,h inconclusive
Mean blood loss The mean blood loss MD, 53 mL more — 2923 4 Effect is Not estimablei Not estimablej
ranged from 455e610 (4 less to 111 more) (4 RCTs) Very lowc,g inconclusive
mL

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Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
ajog.org
SUPPLEMENTAL TABLE 6
Summary of findings from randomized studies: total oxytocin dose (continued)
Patient or population: women undergoing cesarean delivery
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance of
Outcomes Anticipated absolute effectsa (95% CI) (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Change in hemoglobin The mean change in MD, 0.05 g/dL less — 2260 44 Makes no Not estimablei Not estimablej
hemoglobin ranged from (0.27 less to 0.17 more) (3 RCTs) Lowc,d clear
0.88e12.1 g/dL difference
Total oxytocin dose: 10e19 IU vs 20e49 IU
Risk with Risk with
20e49 IU 10e19 IU
Use of additional 45 per 1000 15 per 1000 RR, 0.32 331 4 Effect is RR, 1.01 (0.06 Not estimablej
uterotonics (5e46) (0.10e1.02) (2 RCTs) Very lowc,d,f inconclusive e15.94)
Blood transfusion 51 per 1000 44 per 1000 RR, 0.86 271 44 May make no Not estimablei Not estimablej
(14e135) (0.28e2.62) (1 RCT) Lowe clear
difference
Nausea 100 per 1000 200 per 1000 RR, 2.00 60 4 Effect is Not estimablei Not estimablej
(47e856) (0.47e8.56) (1 RCT) Very lowc,e,f inconclusive
Vomiting 150 per 1000 50 per 1000 RR, 0.33 60 4 Effect is Not estimablei Not estimablej
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

(9e276) (0.06e1.84) (1 RCT) Very lowc,e,f inconclusive

Chest pain 74 per 1000 4 per 1000 RR, 0.05 271 444 10e19 IU may Not estimablei Not estimablej
(0e60) (0.00e0.81) (1 RCT) Moderated reduce
incidence
Tachycardia 44 per 1000 37 per 1000 RR, 0.84 271 44 May make no Not estimablei Not estimablej
(11e119) (0.26e2.69) (1 RCT) Lowe clear
difference
Mean blood loss The mean blood ranged MD, 9 mL less — 60 4 Effect is Not estimablei Not estimablej
from 448e457 mL (17 less to 0.7 less) (1 RCT) Very lowc,d,f inconclusive

Systematic Reviews
Satisfactory uterine tone 949 per 1000 996 per 1000 RR, 1.05 271 444 Probably Not estimablei Not estimablej
(949e1000) (1.00e1.09) (1 RCT) Moderated makes no
clear
difference
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
263.e20
Systematic Reviews
263.e21 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

Number of Certainty of (risk of bias, method Subgroup analyses

Relative effect women evidence of blood loss (maintenance of
Outcomes Anticipated absolute effectsa (95% CI) (95% CI) (studies) (GRADE) Comments measurement) infusion for 2e4 h)
Total oxytocin dose: 20e49 IU vs 50 IU
Risk with Risk with 20e49 IU
50 IU
Use of additional 190 per 1000 393 per 1000 RR, 2.07 321 44 20e49 IU may Not estimablei Not estimablej
uterotonics (270e572) (1.42e3.01) (1 RCT) Lowb,d increase
incidence
Mean blood loss The mean blood ranged MD, 20 mL more — 321 44 May make no Not estimablei Not estimablej
from 937e957 mL (14 less to 54 more) (1 RCT) Lowf clear
difference
Hypotension 241 per 1000 253 per 1000 RR, 1.05 321 44 May make no Not estimablei Not estimablej
(171e368) (0.71e1.53) (1 RCT) Lowb,d clear
difference
Sensitivity analysis of risk of bias included studies only at overall low risk of bias.
Sensitivity analysis of method of blood loss measurement included studies only at low risk of bias for that domain.
Subgroup analysis included only studies using a bolus plus infusion regimen for which the infusion duration ranged between 2 and 4 hours.
GRADE Working Group grades of evidence:
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
CI, confidence interval; MD, mean difference; PPH, postpartum hemorrhage; RCT, randomized controlled trial; ROB, risk of bias; RR, risk ratio.
a
The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI); b Downgraded for serious risk of bias; c Downgraded for serious indirectness; d Downgraded for
serious imprecision; e Downgraded for very serious imprecision; f Downgraded for very serious risk of bias; g Downgraded for very serious inconsistency; h Downgraded for serious inconsistency; i Not estimable because it was a single study; j Not estimable
because no studies used maintenance infusion for 2 to 4 hours in both arms
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

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SUPPLEMENTAL TABLE 7
Summary of findings from randomized studies: initial bolus dose in a bolus plus infusion regimen
Patient or population: women undergoing cesarean delivery
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Sensitivity analyses analyses

Relative Number of Certainty of (risk of bias, method (maintenance
effect women evidence of blood loss infusion for
Outcomes Anticipated absolute effectsa (95% CI) (95% CI) (studies) (GRADE) Comments measurement) 2e4 h)
Initial bolus dose in a bolus plus infusion regimen: <5 IU vs 5 IU
Risk with <5 IU Risk with 5 IU
Use of additional 133 per 1000 147 per 1000 RR, 1.08 179 44 May make no clear ROB: RRe 1.01 RR, 1.01
uterotonics (69e311) (0.51e2.31) (3 RCTs) Lowb difference (0.45-2.24) (0.45e2.24)
Nausea 253 per 1000 66 per 1000 RR, 0.29 179 44 <5 IU may reduce ROB: RR, 0.15 RR, 0.15
(28e160) (0.10e0.81) (3 RCTs) Lowc,d incidence (0.04e0.54) (0.04e0.54)
Vomiting 120 per 1000 26 per 1000 RR, 0.23 179 44 May make no clear ROB: RR, 0.17 RR, 0.17
(6e119) (0.05e1.04) (3 RCTs) Lowc,d difference (0.02e1.32) (0.02e1.32)
Mean blood loss The mean blood loss ranged MD, 4 mL more — 40 4 Effect is inconclusive Not estimablef Not estimableg
from (4 less to 13 more) (1 RCT) Very lowd,e
446e451 mL
Surgical or Unable to calculate because zero events were recorded in either arm 59 — — — —
nonsurgical (1 RCT)
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

interventions
Blood transfusion Unable to calculate because zero events were recorded in either arm 59 — — — —
(1 RCT)
Chest pain Unable to calculate because zero events were recorded in either arm 59 — — — —
(1 RCT)
Cardiac arrythmia Unable to calculate because zero events were recorded in either arm 59 — — — —
(1 RCT)
Dyspnea Unable to calculate because zero events were recorded in either arm 59 — — — —
(1 RCT)

Systematic Reviews
Hypotension Unable to calculate because zero events were recorded in either arm 40 — — — —
(1 RCT)
Initial bolus dose in a bolus plus infusion regimen: 5 IU vs 10 IU
Risk with 10 IU Risk with 5 IU
Mean blood loss The mean blood loss ranged MD, 2 mL more — 87 44 May make no clear Not estimablef Not requiredh
from 875e877 mL (135 less to 138 more) (1 RCT) Lowc,d difference
Chest pain 114 per 1000 47 per 1000 RR, 0.41 87 44 Effect is inconclusive Not estimablef Not requiredh
Lowb
263.e22

(9e227) (0.08e2.00) (1 RCT)

Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021. (continued)
Systematic Reviews
263.e23 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SUPPLEMENTAL TABLE 7
Summary of findings from randomized studies: initial bolus dose in a bolus plus infusion regimen (continued)
Patient or population: women undergoing cesarean delivery
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

Sensitivity analyses analyses

Relative Number of Certainty of (risk of bias, method (maintenance
effect women evidence of blood loss infusion for
Outcomes Anticipated absolute effectsa (95% CI) (95% CI) (studies) (GRADE) Comments measurement) 2e4 h)
Cardiac arrythmia 23 per 1000 8 per 1000 RR, 0.34 87 44 May make no clear Not estimablef Not requiredh
(0e185) (0.01e8.14) (1 RCT) Lowb difference
Surgical or nonsurgical Unable to calculate because zero events were recorded in either arm 87 — — — —
interventions (1 RCT)
Dyspnea Unable to calculate because zero events were recorded in either arm 87 — — — —
(1 RCT)
Sensitivity analysis of risk of bias included studies only at an overall low risk of bias.
Sensitivity analysis of method of blood loss measurement included studies only at low risk of bias for that domain.
Subgroup analysis included only studies using a bolus plus infusion regimen, for which the infusion duration ranged between 2e4 hours.
GRADE Working Group grades of evidence.
High certainty: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate certainty: we are moderately confident in the effect estimate; the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low certainty: our confidence in the effect estimate is limited; the true effect may be substantially different from the estimate of the effect.
Very low certainty: we have very little confidence in the effect estimate; the true effect is likely to be substantially different from the estimate of effect.
CI, confidence interval; MD, mean difference; RCT, randomized controlled trial; ROB, risk of bias; RR, risk ratio.
a
The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI); b Downgraded for very serious imprecision; c Downgraded for serious risk of bias; d Downgraded for
serious imprecision; e Downgraded for very serious risk of bias; f Not estimable because it was a single study; g Not estimable because no studies used maintenance infusion for 2 to 4 hours in both arms; h Not required because all studies used maintenance infusion
for 2 to 4 hours in both arms.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.

ajog.org
ajog.org
SUPPLEMENTAL TABLE 8
Guidelines on oxytocin dosing recommendations with cesarean deliveries
Country Governing body Recommendation
Descargado para jose luis mosquera agudelo (jolumo85@hotmail.com) en Universidad Libre de ClinicalKey.es por Elsevier en septiembre 07, 2021.

International WHO (2018) 10 IU IV or IM during all births, with doses to be divided

as a small IV bolus and an infusion at CD.4

International International consensus statement (2019) 1 IU bolus followed by 2.5e7.5 IU/h infusion for around
2e4 h during planned CD.8
United States ACOG (2017) Dilute IV infusion (bolus dose of 10 IU).
No specification for CD.57
United Kingdom RCOG (2016) Oxytocin 5 IU IV by slow injection during CD.58
France CNGOF (2016) Oxytocin at 5e10 IU IV by slow injection during CD plus
maintenance infusion not exceeding 10 IU/h which can
be stopped after 2 h based on clinical judgment.59
Canada SOCG (2018) Carbetocin 100 mg as IV bolus over 1 min during
elective CD.60
Australia and New Zealand RANZCOG (2017) Prophylactic oxytocin recommended for all births. No
recommendation on dose or dosing regimen provided.
No specification for CD.61
ACOG, American College of Obstetricians and Gynecologists; CD, cesarean delivery; CNGOF, French National College of Obstetricians and Gynecologists; IV, intravenous; IM, intramuscular; IU, international units; RANZCOG, Royal Australian and New Zealand College
of Obstetricians and Gynaecologists; RCOG, Royal College of Obstetricians and Gynaecologists; SOGC, Society of Obstetricians and Gynaecologists of Canada; WHO, World Health Organization.
Phung. Oxytocin dosing regimens for postpartum hemorrhage prevention following cesarean delivery. Am J Obstet Gynecol 2021.
SEPTEMBER 2021 American Journal of Obstetrics & Gynecology

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Oxitocina

Uploaded by

Oxitocina

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Systematic Reviews ajog.

Intravenous oxytocin dosing regimens for

250 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

Eligible studies were those that

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 251

252 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

Comparative randomized controlled PRISMA flow diagram.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 253

year design n Country CD type Oxytocin dosing regimens

year design n Country CD type Oxytocin dosing regimens

year design n Country CD type Oxytocin dosing regimens

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 257

258 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

CI, confidence interval; IV, intravenous; SD, standard deviation.

CI, confidence interval.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 259

CI, confidence interval.

260 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 261

262 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263

263.e1 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e2

secondary outcome to a secondary outcome, considering that the definition

Generated using robvis.56

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e4

263.e5 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

CI, confidence interval; IU, international unit.

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e6

CI, confidence interval; IU, international unit.

CI, confidence interval; IU, international unit.

263.e7 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e8

263.e9 American Journal of Obstetrics & Gynecology SEPTEMBER 2021

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e10

Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6

Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6

2009 infusion 30 IU over

Arm 1 Arm 2 Arm 3 Arm 4 Arm 5 Arm 6

Nonrandomized studies of Arm 1 Arm 2 Arm 3

SEPTEMBER 2021 American Journal of Obstetrics & Gynecology 263.e14

Number of Certainty of (risk of bias, method Subgroup analyses

Number of Certainty of (risk of bias, method Subgroup analyses

Number of Certainty of (risk of bias, method Subgroup analyses

Number of Certainty of (risk of bias, method Subgroup analyses

Number of Certainty of (risk of bias, method Subgroup analyses

Number of Certainty of (risk of bias, method Subgroup analyses

(9e276) (0.06e1.84) (1 RCT) Very lowc,e,f inconclusive

Number of Certainty of (risk of bias, method Subgroup analyses

Sensitivity analyses analyses

(9e227) (0.08e2.00) (1 RCT)

Sensitivity analyses analyses

International WHO (2018) 10 IU IV or IM during all births, with doses to be divided

as a small IV bolus and an infusion at CD.4

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