New WHO recommendations on the management of sickle‐cell disease in pregnancy

In 2025, the World Health Organization (WHO) has published a new evidence-based clinical practice guideline to support the provision of high-quality care for women with sickle-cell disease (SCD) in the perinatal period [1]. The guideline aims to provide actionable guidance that can improve outcomes for women with SCD and their babies, while placing a spotlight on the complex interaction between SCD and pregnancy. Several of the systematic reviews of interventions underpinning the guideline recommendations are published Pregnancy. SCD is a common autosomal recessive haemoglobin disorder affecting almost 7.74 million people worldwide [2]. SCD is associated with severe anaemia, vaso-occlusive crises, cerebrovascular disease, opportunistic infections and premature death [3]. The number of people living with SCD increased by 41.4% between 2000 and 2021 [2]. SCD affects people in many countries, but is highly prevalent in sub-Saharan Africa and significantly impacts populations in other historically malaria-endemic regions [2]. While effective management and curative treatments are available, people in countries with the highest prevalence of SCD often lack access to adequately resourced care [4]. In 2020, 95% of maternal mortality occurred in low- and middle-income countries (LMICs) [5], many of which are countries with high rates of SCD [6]. Despite the associated severe complications, improvements in disease management have led to decreasing infant and child mortality and more women with SCD reaching reproductive age [7]. The normal physiological changes of pregnancy (such as immune-adaptation and hypercoagulable state) may exacerbate SCD's characteristic pathophysiology and compound the risks to a woman's health [7, 8], leading to a 4- to 11-fold higher rate of maternal death than that found in the general pregnant population [9, 10]. Women with SCD are also at greater risk of complications of pregnancy such as pre-eclampsia, stillbirth, preterm birth and small-for-gestational-age babies [8]. Although their pregnancies are deemed to be high-risk, there is little guidance available to support optimal care for pregnant women with SCD in moderate- and high-prevalence contexts [11, 12]. The new guideline is part of a wider WHO project to address non-communicable disease (NCD)-related morbidity and mortality in women in pregnancy, childbirth and the postnatal periods. It addresses one of five high-priority topics identified in July 2021 by a WHO Steering Group. Guidelines will also be developed to address cardiovascular conditions; diabetes; mental health conditions and substance misuse; and respiratory conditions in the perinatal period. A scoping process undertaken to inform the development of the new guideline identified only five national guidelines that included recommendations on care for pregnant women with SCD, all of which were from high-income countries [13-17]. During the guideline development process, one further US guideline was published [18], and WHO African Region included some guidance on care for pregnant women in a new technical package for SCD management [12]. The new WHO guideline on the management of SCD in pregnancy [1] is the first to provide comprehensive, evidence-based recommendations focussed on perinatal care for women with SCD that is applicable to all contexts globally. The new recommendations are based on comprehensive appraisal of the scientific evidence, in accordance with GRADE methodology [19]. They are designed to inform health policymaking and support health-care workers in the provision of quality care for women and their babies. While the guideline is global in scope, it is intended to serve LMICs in particular, where the burden of SCD is greatest. The guideline development group (GDG) identified eight questions to be addressed by the new guideline, described in Population (P), Intervention (I), Comparison (C), Outcome (O) (PICO) format (see Box 1). These questions focus on the most pressing issues facing women with SCD and their caregivers. Consideration of the eight topics aims to reduce the burden of the condition for pregnant women with SCD and reduce perinatal morbidity and mortality, while addressing the effectiveness, safety, acceptability, feasibility and cost-effectiveness of the most important interventions during the perinatal period. Figure 1 summarises the guideline development process. New systematic reviews were undertaken to answer these PICO questions. The systematic reviews of effectiveness evidence on antenatal medication and transfusion management, intrapartum management and postpartum management have been published in this journal [20-22]. Other topics are published as web annexes to the guideline [23]. In addition, a qualitative evidence synthesis (QES) was conducted to explore the views and preferences of women with SCD during the maternity care journey and of the health-care providers caring for these women [24]; and a systematic review of economic evaluations was undertaken to provide evidence on resource use and cost-effectiveness [25] (see Figure 1). The eight systematic reviews of effectiveness evidence considered randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) from all countries with no language restrictions. Despite this broad scope, there was scant evidence directly addressing the PICO questions. Only one review, on antenatal medication and transfusion management for pregnant women with SCD, identified any RCTs (on prophylactic transfusion and iron supplementation) [20]. This review also identified evidence from NRSIs, but there were several interventions (pain management, folic acid, vitamin D, aspirin, anticoagulants and antibiotics) for which no studies were identified. Two other reviews, on additional foetal monitoring [23] and mode of birth for women with SCD [21], identified one NRSI each. The other five reviews (on pain management plans for women with SCD, fluid management plans and thromboprophylaxis for pregnant women hospitalized with SCD [23], timing of delivery for pregnant women with SCD [21], and interpregnancy management for women with SCD [22]) identified no eligible intervention studies. The included RCTs, which together included 86 women, were from Nigeria and the United States. The combined NRSIs included 4902 women and were conducted in Bahrain, Belgium, Brazil, Burkina Faso, Canada, Democratic Republic of Congo, France, Germany, Greece, Italy, Jamaica, Türkiye, the United Kingdom and the United States. When effect estimates were GRADE-assessed, they were largely low- and very-low certainty, indicating a lack of confidence that they reflect the true effect of the interventions. In the absence of direct evidence, the guideline Evidence Synthesis Group was guided by the GDG in seeking indirect evidence as appropriate on a question-by-question basis (for instance, from pregnant populations with other chronic conditions, or from the general population with SCD; alongside physiological understanding of SCD in the perinatal period). The QES included 11 studies, which were conducted in the United Kingdom (six studies), Brazil (three studies), France (one study) and Uganda (one study) [24]; and the systematic review of economic evaluations included three studies, from the UK and USA [25]. Although these reviews provided some insight from countries where SCD is a significant health burden (Brazil and Uganda), much of the evidence came from high-income, lower-prevalence contexts, and there was a stark lack of evidence from high-prevalence contexts (e.g., Nigeria, India). The lack of representation in the published literature of relevant populations raises serious equity concerns. Therefore, for qualitative and resource guideline domains, the evidence synthesis team also drew on indirect evidence where available. Over the course of four sets of meetings in 2023 and 2024, the GDG developed 20 recommendations in response to the PICO questions (see Box 1). The recommendations provide guidance on the use of dietary supplements (folic acid and iron), medications (hydroxycarbamide, thromboprophylaxis, infection prophylaxis) and prophylactic blood transfusion in pregnancy; pain management; fluid management and thromboprophylaxis in hospitalized women; foetal monitoring; mode and timing of birth; and interpregnancy care (see Box 2). The recommendations are accompanied by detailed remarks that reflect the GDG's deliberations. The remarks are an important part of the recommendations, articulating the rationale that underpins them and providing contextual considerations to support their implementation in different contexts (see Figure 1). The GDG also developed a set of considerations to underpin the guideline recommendations. These considerations acknowledge a range of critical issues associated with SCD for women and their families across the reproductive cycle and life course (see Box 3). The considerations also reflect existing WHO guidance that is applicable or should be adapted to provide high-quality care and a positive pregnancy experience for women with SCD [27, 28] (see Figure 1). Overall, the new WHO recommendations draw attention to SCD, and to the complex interaction between the pathophysiology of SCD and the normal physiological changes of pregnancy. The recommendations provide much-needed guidance for care providers that may improve outcomes for women with SCD and their babies. Successful introduction of evidence-based policies to improve the management of SCD will depend on well-planned, participatory and consensus-driven processes of integration and implementation. Implementation of the recommendations for the management of SCD in pregnancy should be part of a wider strategy to ensure that all women have access to respectful, woman-centred care throughout their life course. Pregnant women with SCD deserve skilful care that effectively manages the risks associated with their pregnancy, while supporting as positive an experience of pregnancy, childbirth and the postnatal period as possible. The new guideline, underpinned by the systematic reviews published in this journal and elsewhere [20-25], highlights the lack of direct research evidence available to inform quality care. There are important knowledge gaps warranting well-designed research, especially in high-prevalence contexts. Research priorities relating to all eight priority topics were identified by the GDG (see Box 4 and Figure 1). WHO guidelines in maternal and perinatal health follow a ‘living’ approach, whereby they are updated when new evidence becomes available [29]. Investment of time and resources in priority research areas would support ongoing improvement of outcomes for women with SCD and their babies and potentially feed into revised WHO recommendations with a stronger evidence base in the future. The authors would like to acknowledge the contribution of the Guideline Development Group, the External Review Group, the WHO Steering Group, Observers and the Evidence Synthesis Group in developing the guideline discussed. This work was funded by 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 (WHO), and the Global NCD Platform. The funding sources did not have any role in the writing of this article. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the views, decisions or policies of the institutions with which they are affiliated. Boxes 1, 2 and 4 quote WHO recommendations on the management of sickle-cell disease during pregnancy, childbirth and the interpregnancy period (2025) verbatim. Box 3 paraphrases the considerations underpinning the recommendations. The guideline is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO), which permits copying, redistribution and adaptation of the work for non-commercial purposes. Doris Chou is employed by the World Health Organization (WHO) and is funded by HRP. She has received a grant from Global NCD Platform and travel reimbursements to attend the Society for Maternal-Fetal Medicine meeting. Jenny Ramson and Myfanwy Williams are contractors for the WHO and have received travel reimbursements from WHO. Bosede Afolabi received funding from the Tertiary Education Trust Fund, Nigeria for a clinical trial (the PIPSICKLE trial examining the effectiveness of low-dose aspirin vs. placebo in preventing intrauterine growth restriction in pregnant women with sickle-cell disease). Bosede received honoraria from the American Society of Hematology for a presentation, and travel reimbursements from the American Society of Hematology and National Heart, Lung, and Blood Institute/National Institutes of Health (USA).

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