Background: A threshold of ≥ 500 ml blood loss within 24 hours of childbirth has conventionally been used to initiate postpartum haemorrhage (PPH) treatment. We assessed the cost-effectiveness of initiating PPH treatment at lower blood loss thresholds, alone and in combination with any other abnormal haemodynamic marker (pulse, systolic and diastolic blood pressure, shock index), compared with the conventional ≥ 500 ml threshold. Methods: A decision tree model was developed to assess the cost per disability-adjusted life years (DALYs) averted from a healthcare provider perspective when the WHO first-response treatment bundle was initiated using alternative criteria. Sensitivity and specificity of scenarios for identifying women at high risk of a composite outcome of maternal mortality or severe morbidity was estimated using a World Health Organization individual participant data meta-analysis. Direct medical costs (2022 US$) were derived from randomised trial data in Kenya, Nigeria, South Africa, and Tanzania. Findings: Treatment initiation based on lower blood loss thresholds could avert additional composite outcomes. Use of lower blood loss thresholds in combination with any other abnormal haemodynamic marker was more cost-effective than blood loss alone. Combining blood loss thresholds (stepwise from 450 to 300 ml) with any other abnormal haemodynamic marker could avert 15-27% of composite outcomes, increase costs by 9-30% per woman, and have a cost of US$260-479 per DALY averted, compared to using 500 ml blood loss alone. Scenarios were more cost-effective for vaginal births, and cost-saving for populations with a composite outcome incidence >= 9%. Interpretation: Expanding the conventional criteria for initiating PPH treatment to include lower blood loss thresholds in combination with any other abnormal haemodynamic marker is cost-effective in improving maternal health outcomes, particularly for obstetric populations with high incidence of PPH mortality and severe morbidity. Further research is warranted in women undergoing caesarean birth.

IG, IY, GJH, AD, ZPQ, AC, and OTO were co-authors for E-MOTIVE trial, the largest included trial in the WHO individual participant data that underpinned this cost-effectiveness analysis. GJH previously received consultancy payments as inventor of the MaternaWell Tray for blood loss monitoring after birth, but has no current or future financial interest. LS has received consulting fees and payment/honoraria from Ferring Pharmaceuticals, Bayer, GlaxoSmithKline, Pfizer, Organon and Norgine. All other authors declare no competing interests.

This study was funded by The Gates Foundation (INV-063940) and the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), a co-sponsored programme executed by the World Health Organization.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Eligible studies for the WHO individual participant data meta-analysis must have had prior ethics committee approval and the data holder had to be able to enter into a legal data sharing agreement with WHO. Institutional review board approval was not required for this study because only previously collected, de-identified data were used. All contributing studies had received appropriate ethical approvals, and no new participant recruitment or data collection was undertaken for the current study.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All model parameters used for this study are available in the manuscript and supplementary material, extracted from the sources as cited. The individual participant data (IPD) that served as the basis for this article were shared with the WHO exclusively for the purpose of conducting this IPD meta-analysis to reappraise the definition of PPH. Researchers interested in accessing data from the original studies should contact the corresponding authors of those studies directly. Access will be subject to the approval of data owners and applicable data sharing agreements.