Evidence reviews for route of administration of oxytocin in the third stage of labour
Evidence review L
NICE Guideline, No. 235
Route of administration of oxytocin in the third stage of labour
Review question
Is intravenous administration of oxytocin more effective than intramuscular administration in the active management of the third stage of labour?
Introduction
Women may choose to have active or physiological management of the third stage or labour.
Active management includes clamping of the umbilical cord, administration of a medication (uterotonic) to increase contraction of the uterus and controlled cord traction to deliver the placenta. Oxytocin is a commonly used uterotonic administered for active management of the third stage of labour and the current guideline recommends that this is administered by intramuscular injection.
The aim of this review is to find out whether oxytocin is more effective if administered intravenously or intramuscularly, in the active management of the third stage of labour.
Summary of the protocol
See Table 1 for a summary of the Population, Intervention, Comparison and Outcome (PICO) characteristics of this review.
Table 1
Summary of the protocol (PICO table).
For further details see the review protocol in appendix A.
Methods and process
This evidence review was developed using the methods and process described in Developing NICE guidelines: the manual. Methods specific to this review question are described in the review protocol in appendix A and the methods document (supplementary document 1).
Declarations of interest were recorded according to NICE’s conflicts of interest policy.
During guideline development, the BNF notation for oxytocin dose changed to ‘units’, so this has been reflected in the evidence report. The evidence tables in appendix D reflect the dose notations as defined by the original study.
Effectiveness evidence
Included studies
Two studies were included for this review, 1 randomised controlled trial (RCT) (Biradar 2021) and 1 Cochrane systematic review (Oladapo 2020), which included 7 RCTs (Adnan 2018, Charles 2019, Dagdeviren 2016, Durocher 2019, Neri-Mejia 2016, Oguz 2014, Sangkhomkhamhang 2015).
Both studies compared intravenous (IV) administration of 10 units oxytocin to intramuscular (IM) injection of 10 units oxytocin. The route of administration of IV oxytocin varied: 5 included RCTs in the Cochrane systematic review administered an IV oxytocin bolus injection (Adnan 2018, Charles 2019, Neri-Mejia 2016, Oguz 2014, Sangkhomkhamhang 2015) and 3 included RCTs in the Cochrane systematic review administered an IV oxytocin slow infusion (Charles 2019, Dagdeviren 2016, Durocher 2019). One RCT administered a combined IV oxytocin bolus injection and IV oxytocin infusion (Biradar 2021).
The included studies are summarised in Table 2.
See the literature search strategy in appendix B and study selection flow chart in appendix C.
Excluded studies
Studies not included in this review are listed, and reasons for their exclusion are provided in appendix J.
Summary of included studies
Summaries of the studies that were included in this review are presented in Table 2.
Table 2
Summary of included studies.
See the full evidence tables in appendix D and the forest plots in appendix E.
Summary of the evidence
The evidence was stratified in a hierarchy by the following pre-specified variables: type of oxytocin IV administration (IV bolus injection and IV slow infusion) and women who had had oxytocin in the first stage of labour versus women who had not. There was insufficient evidence to stratify by body mass index (BMI), mode of birth and risk of postpartum haemorrhage (PPH) and no need to stratify by dosage of oxytocin as all studies administered 10 units oxytocin.
For overall estimates comparing IV oxytocin (administered by either bolus or infusion) to IM oxytocin, there was consistent evidence in favour of IV oxytocin on outcomes. There was low quality evidence of an important benefit in terms of primary PPH, severe PPH and need for additional uterotonics. There was low quality evidence showing a possible important benefit in terms of need for manual removal of placenta. The evidence contributing to the outcomes of maternal admission to intensive therapy unit (ITU) and side effects were from studies administering IV oxytocin by IV bolus injection only.
For oxytocin IV bolus injection compared to oxytocin IM injection, there was moderate quality evidence of a possible important benefit of IV bolus injection in terms of maternal admission to ITU and an important benefit in terms of severe PPH. For the same comparison, there was low quality evidence of an important benefit on a reduction in primary PPH and the need for manual removal of placenta and low quality evidence of no important difference on the need for additional uterotonics or on side effects.
For oxytocin delivered by IV slow infusion compared to oxytocin IM injection, there was moderate quality evidence of no important difference in terms of primary PPH, no evidence of an important difference for need for manual removal of placenta and low quality evidence of no important difference in terms of reducing severe PPH. There was high quality evidence that IV oxytocin delivered by slow infusion had a possible important benefit compared to IM oxytocin in terms of need for additional uterotonics.
For oxytocin delivered by a combined IV bolus injection and IV slow infusion compared to IM oxytocin, there was low quality evidence of no evidence of important difference in terms of need for additional uterotonics. No other outcomes were reported for this stratification.
For women who had oxytocin in the first stage of labour, there was moderate quality evidence that oxytocin IV bolus injection in the third stage of labour had no evidence of an important difference on primary PPH and high quality evidence that it had an important benefit in terms of reducing severe PPH compared to IM injection. For women who did not have oxytocin in the first stage of labour, there was low quality evidence that oxytocin IV bolus injection in the third stage of labour had no important difference on primary PPH and severe PPH compared to IM injection. There was insufficient evidence to stratify any other reported outcomes by women who had received oxytocin in the first stage of labour or not.
There was no evidence for women’s experience of labour and birth for any of the comparisons.
See appendix F for full GRADE tables.
Economic evidence
Included studies
A systematic review of the economic literature was conducted but no economic studies were identified which were applicable to this review question.
Economic model
No economic modelling was undertaken for this review because the committee agreed that other topics were higher priorities for economic evaluation. This was because recommendations were not expected to generate a significant resource impact to the NHS.
Unit costs
The committee’s discussion and interpretation of the evidence
The outcomes that matter most
The aim of this review was to determine the effectiveness of intravenous administration of oxytocin compared with intramuscular administration in the third stage of labour to prevent excessive bleeding after the birth of the baby. The committee therefore agreed that maternal admission to an ITU or high-dependency area, primary PPH and severe PPH were critical outcomes which would directly capture the effectiveness and safety of the intervention.
The committee agreed that need for manual removal of the placenta was an important outcome which would determine the effectiveness of the mechanism of action of the intervention as oxytocin helps to prevent blood loss after birth of the baby by stimulating the uterus to contract, closing the blood vessels to the placenta and helping the placenta to separate. The committee agreed that the need for additional uterotonics during the third stage or within the first 48 hours should be included as an important outcome as they wanted to know whether IV oxytocin would reduce the need for additional interventions in the third stage compared to IM oxytocin.
The committee included side effects during the third stage or within the first 24 hours as an important outcome as oxytocin administered intravenously as a bolus injection has been associated with hypotension and tachycardia. The committee agreed that women’s experience of labour and birth should be included as an important outcome to capture the acceptability of the intervention and any wider impacts on the woman associated with the differential route of administration of oxytocin.
The quality of the evidence
The quality of the evidence ranged from high to low, with most of the evidence being of low quality. Most of the included RCTs were of high quality, but some outcomes were downgraded for risk of bias where evidence came from studies at risk of selective reporting bias or where outcome assessors were not blinded. Evidence was not downgraded in cases where participants or study personnel were not blinded as the outcomes were measured objectively and the intervention was administered once, so the risk of bias due to deviations from the intervention was low. Outcomes were downgraded for imprecision in some cases where 95% confidence intervals (CIs) crossed the minimally important differences, indicating the effect size was small.
Benefits and harms
The committee discussed the evidence and used this alongside their expert opinion and clinical knowledge to make recommendations. Based on overall effect estimates, the committee agreed there was consistent evidence of benefits of IV oxytocin compared to IM oxytocin in the third stage of labour in terms of maternal admission to ITU, primary PPH, severe PPH, need for manual removal of placenta and need for additional uterotonics. The committee considered the outcomes stratified by type of administration and noted that IV bolus injection had important benefits in terms of primary PPH, severe PPH and need for manual removal of placenta compared to IM injection, whereas there was no difference or no evidence of important difference for IV infusion. There was no important difference in terms of side effects, with the data contributing to this outcome only from studies administering IV injection compared to IM injection.
The committee discussed the evidence from two large RCTs comparing IV oxytocin injection to IM oxytocin stratified by women who have had and have not had oxytocin in the first stage of labour. The committee acknowledged that the stratified analysis did not substantially change the effect estimate in terms of primary PPH, however, in terms of severe PPH, the effect estimate was larger in favour of IV injection for women who had had oxytocin compared to the non-stratified effect estimate and conversely there was no important difference found for women who had not had oxytocin in the first stage of labour. Based on this evidence and insufficient data to stratify other critical and important outcomes by women who had and had not had oxytocin in the first stage of labour, the committee agreed that the evidence supported a recommendation for oxytocin to be administered by IV injection in the third stage for women who had had oxytocin in the first stage of labour, but not for women who had not previously received oxytocin.
The committee also discussed the feasibility and acceptability of administering oxytocin by IV injection, as IM injections are quick to administer and do not require an IV access to be sited using a cannula. The committee also discussed that to reduce the possible haemodynamic effects of IV oxytocin it should be administered slowly (over a few minutes), and a slow IV injection would therefore be more time-consuming for the midwife to administer compared to an IM injection. The committee raised concerns that IV administration in midwifery-led settings may be less acceptable as inserting cannulas during third stage of labour may be less commonplace than in obstetric units and it increases the medicalisation of birth which women in these settings may wish to avoid. The committee were also concerned by the need for 2 midwives to be present during the third stage in order to check and administer the slow IV injection while also ensuring that the baby was safe and well, as in their experience this may not be feasible in all settings due to resource constraints. These considerations confirmed the committee’s evidence-based recommendation to offer oxytocin by slow IV injection only to women who had had oxytocin during labour and therefore would have existing IV access. The committee noted that, although 2 midwives may still be needed during the third stage to check and administer the IV oxytocin, it would remove the need to insert and check a cannula during the third stage. The committee noted the lack of evidence in terms of women’s experience of labour and birth, but agreed that, in their experience, women would prefer to avoid having an intramuscular injection which can be painful, if IV access was already established and another option was as safe and effective.
Cost effectiveness and resource use
The committee noted that there was no difference in the acquisition costs to the NHS of oxytocin whether given by IM or IV injection. The committee recognised that putting in IV access solely for the purposes of administering IV oxytocin would be resource intensive, requiring 2 midwives to be present to insert the access, check it and administer a flush and then the oxytocin. The committee also discussed the related practical difficulties of recommending IV oxytocin for all women with current levels of staffing. Therefore, they confirmed that the recommendations should restrict the use of IV oxytocin to women who had already received oxytocin in labour and who therefore have IV access is situ.
Recommendations supported by this evidence review
This evidence review supports recommendation 1.10.14.
References – included studies
Biradar 2021
Biradar, Aruna M., Yaliwal, Rajasri G., Kori, Shreedevi S. et al. (2021) Randomised control trial of 3 iu intravenous oxytocin bolus with 7 iu oxytocin infusion versus 10 iu intramuscular oxytocin in the third stage of labour in the prevention of postpartum hemorrhage. International Journal of Women’s Health and Reproduction Sciences 9(3): 171–175Hilton 2016Oladapo 2020
Oladapo, Olufemi T., Okusanya, Babasola O., Abalos, Edgardo et al. (2020) Intravenous versus intramuscular prophylactic oxytocin for reducing blood loss in the third stage of labour. Cochrane Database of Systematic Reviews 2020(12): cd009332 [PMC free article: PMC8236306] [PubMed: 33169839]
Effectiveness
Appendices
Appendix A. Review protocols
Appendix B. Literature search strategies
Appendix C. Effectiveness evidence study selection
Appendix D. Evidence tables
Appendix E. Forest plots
Appendix F. GRADE tables
Appendix G. Economic evidence study selection
Appendix H. Economic evidence tables
Economic evidence tables for review question: Is intravenous administration of oxytocin more effective than intramuscular administration in the active management of the third stage of labour?
No evidence was identified which was applicable to this review question.
Appendix I. Economic model
Economic model for review question: Is intravenous administration of oxytocin more effective than intramuscular administration in the active management of the third stage of labour?
No economic analysis was conducted for this review question.
Appendix J. Excluded studies
Excluded studies for review question: Is intravenous administration of oxytocin more effective than intramuscular administration in the active management of the third stage of labour?
Excluded effectiveness studies
Table 5
Excluded studies and reasons for their exclusion.
Excluded economic studies
No economic evidence was identified for this review.
Appendix K. Research recommendations – full details
Research recommendations for review question: Is intravenous administration of oxytocin more effective than intramuscular administration in the active management of the third stage of labour?
No research recommendations were made for this review question.
Final
Evidence reviews underpinning recommendation 1.10.12 in the NICE guideline
This evidence review was developed by NICE
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