{"paper_id":"27a13bd3-209c-4cdd-8163-f745e31e5f13","body_text":"1\n1 Co-developing a comprehensive disease \n2 policy model with stakeholders: the case \n3 of malaria during pregnancy\n4 Authors: Fernandes, Silke;  Briggs Andrew; Hanson, Kara\n5 Abbreviations:\n6 CEA=Cost effectiveness analysis\n7 DALY=disability-adjusted life years\n8 Total word count: 3200 words\n9\n10\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.\n\n2\n1 Abstract\n2 Introduction: Understanding the holistic impact of malaria during pregnancy is essential for \n3 improving maternal and child outcomes in malaria endemic settings. To be able to design \n4 appropriate research and conduct robust policy analyses, a comprehensive model of the \n5 underlying disease, representing the current understanding of mechanisms and consequences \n6 is essential. This study aimed to illustrate a methodology to co-develop a disease model with \n7 expert stakeholders using malaria during pregnancy as a case study. \n8 Methods: An initial steering group was convened to develop a first model of malaria during \n9 pregnancy and its consequences for mother and child based on their understanding of the \n10 literature. Subsequently, this model was refined using a Delphi process to gain consensus \n11 amongst twelve experts, representing the disciplines of health economics, mathematical \n12 modelling, epidemiology and clinical medicine, working in the field of malaria during pregnancy. \n13 Experts reviewed drafts of the conceptual model and provided feedback in two rounds of semi-\n14 structured questionnaires with the aim of identifying the most important health outcomes and \n15 relationships in both mother and child  as well as the most relevant stratifiers for the model. \n16 Consensus on any final disagreement was reached after two consensus meetings.  \n17 Results: The final model is a comprehensive disease model of malaria during pregnancy, \n18 including ten maternal and ten child outcomes with four stratifiers. The model developed in \n19 this study should be of value to malaria researchers, funders, evaluators and decision makers, \n20 though some adaptation will be required for each specific context and purpose. In addition, the \n21 methodology and process followed in this study is replicable and can guide researchers aiming \n22 to develop a conceptual model for other conditions.\n23 Discussion & Conclusion: The model resulting from this study highlights the complexity \n24 required to depict appropriately the consequences of malaria during pregnancy for both the \n25 mother and the child. It also demonstrates how to conduct a rigorous process to develop a \n26 disease model. In addition the study has helped to identify a number of areas with scarce data \n27 and need for further research. \n28 Funding: This study from part of the IMPROVE and IMPROVE-2 studies, which received financial \n29 support from the EDCTP2 programme under Horizon 2020 (TRIA.2015-1076, TRIA.2015-1076b); \n30 the UK Department of Health and Social Care, the UK Foreign Commonwealth and \n31 Development Office, the UK Medical Research Council, and Wellcome Trust, through the Joint \n32 Global Health Trials scheme (MR/P006922/1); and the Swedish International Development \n33 Cooperation Agency.\n34\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n3\n1 Introduction\n2 Most diseases work via complex biological processes that create observable interrelated health \n3 outcomes.   Understanding these relationships is essential for many types of research and the \n4 embedded policy analyses that are informed by that research.  For example, trials of \n5 comparative effectiveness and associated cost-effectiveness analysis would benefit from an \n6 understanding of all the relevant outcomes, and the interconnections among them, both in \n7 designing the most appropriate research study and in analysing the results of that study to \n8 understand which treatment options are most appropriate in a given context. \n9\n10 Cost effectiveness analyses (CEA) are required by many global and national bodies to inform \n11 policy change. Some health interventions have multiple health effects (for example, both \n12 morbidity and mortality);  and some have effects on more than one population group.  To \n13 capture such disparate benefits in a way that facilitates comparison between alternative uses of \n14 scare resources, health benefits of interventions are translated into a common metric such as a \n15 Quality Adjusted Life Year (QALY) or Disability Adjusted Life Year (DALY).\n16\n17 Complexity is increased when a disease such as malaria is combined with pregnancy, as the \n18 disease and its treatments now have the potential to impact both mother and child.  In this \n19 paper, we use malaria in pregnancy as a case study to illustrate how a structured approach to \n20 co-developing a disease model with relevant stakeholders can result in a more robust model, \n21 that will carry greater influence with the scientific community because of the multi-disciplinary \n22 input into its development.  \n23\n24 In 2012 a taskforce recommended the development of a conceptual model as the foundation \n25 for developing an economic model (1). A conceptual model entails a systematic approach to \n26 provide a visual framework for analysis that shows how specific health outcomes and pathways \n27 relate and interact with each other (1). Documented approaches to the development of \n28 conceptual frameworks include literature reviews, consultation with stakeholders (qualitative \n29 and quantitative), methods of incorporating stakeholder views and piloting to refine the \n30 framework (2, 3).\n31\n32 Economic evaluations of interventions can be complex and require contributions from a broad \n33 range of disciplines. Models based on a particular viewpoint can lead to poor validity and \n34 credibility.  A review of outcomes included in published economic models of malaria in \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n4\n1 pregnancy interventions reveals a disparate picture of outcomes included in DALY estimation \n2 (4-12).  Only four out of nine CEAs incorporated clinical malaria, maternal anaemia and low \n3 birth weight (5, 6, 9, 11), which are commonly measured in clinical trials, in the DALY \n4 estimation. One CEA did not include any child health outcome (8) and another no maternal \n5 health outcome (4). \n6 The Delphi consultation method is a well-established and tested approach used in research to \n7 elicit information from experts and has been used extensively in the social sciences (13-16).\n8 It is a particularly suitable method to incorporate a range of stakeholder views,  leading to \n9 improved quality and acceptance of an economic evaluation model and its findings(17) (1, 18, \n10 19) by seeking consensus amongst experts, avoiding the pitfall of only including outcomes and \n11 relationships measured in trials. \n12\n13 The aim of this study was to co-develop a conceptual model of prevention of P.falciparum \n14 malaria during pregnancy for pregnant women and their babies using a Delphi consensus study \n15 with experts in the field of malaria during pregnancy. The expert panel’s task was to identify \n16 the most important health outcomes and relationships in both mother and child and the most \n17 relevant stratifiers for the model.  In doing so, the study demonstrates that co-production of \n18 holistic disease models with expert stakeholders, representing the current understanding of a \n19 disease and potential treatment pathways, is feasible and represents a more robust approach \n20 than ad hoc model construction by individual academic teams.  \n21\n22 Methods\n23 This study used the Delphi methodology to co-develop a policy model of malaria during \n24 pregnancy with expert stakeholders. The expert panel in the Delphi methodology consists of \n25 people with relevant insight into the subject to be explored and can include technical experts, \n26 health providers, policy makers, patients or other suitable panellists. It is a very useful \n27 technique to gather input from various stakeholders in a time-efficient manner through a series \n28 of questionnaires. Responses from each round are collated, analysed and incorporated into the \n29 subsequent rounds of questions until consensus between the panellists has been reached, \n30 usually after two-to-three rounds, which is often followed by a final consensus meeting with \n31 stakeholders to resolve any final points (15, 16, 20). The experts remain anonymous in the \n32 process up until the final meeting if applicable, which promotes equal contribution \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n5\n1 independent of status and other factors and removes less favourable forces of group dynamics \n2 (15, 16). The \n3\n4 The different stages and methods in this study are illustrated in figure 1 and summarized \n5 below.  Full details of the approach are described in the supplementary materials. Experts in \n6 this study were first approached on 31 August 2022, all experts had consented by 5th of \n7 October 2022. The final consensus meeting took place on 8th September 2023. \n8\n9 Stage one: preparation\n10 During an initial preparation stage, a steering group with collective experience in health \n11 economics, conceptual modelling and epidemiology of malaria in pregnancy was convened. Its \n12 task was to short-list experts to be approached to be part of a Delphi panel as well as to advise \n13 on the preparation of a first draft of the conceptual model and questionnaire based on their \n14 understanding of the literature, ongoing research and natural history of malaria in pregnancy. \n15 Potential candidates for the Delphi panel were purposively selected for their varied expertise, \n16 knowledge of the literature and current research in malaria during pregnancy and approached \n17 by email. The authors paid particular attention to having a well-balanced panel with experts \n18 representing both maternal and child health, early and later exposure to malaria during \n19 pregnancy and various endemicity contexts. The study team aimed to include eight to ten \n20 experts in the Delphi panel, a group size shown to be effective and reliable for the Delphi \n21 method (15, 16). Experts received no incentive or financial reimbursement for their time \n22 participating in this study. \n23\n24 Stage two: Delphi consultation\n25 Twelve expert agreed to take part in the Delphi study and provided written informed consent \n26 (online). During the Delphi consultation stage, they were asked to refine the draft model using \n27 an a priori undetermined number of rounds of consultations until consensus in most questions \n28 was reached.  The threshold for consensus for individual questions was set at 70%, consistent \n29 with previous Delphi studies (18, 21). In each round, the panel members were provided with a \n30 current draft of the model and were asked to perform the following tasks: \n31 1) Assess importance of the outcomes in the model, \n32 2) suggest additional outcomes that were missing, \n33 3) evaluate the accuracy of relationships between outcomes, \n34 4) suggest additional relationships between outcomes that were missing, \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n6\n1 5) order stratifiers for subgroup analysis by importance (a stratifier is defined as a \n2 variable which can partition the population in the model into subpopulations, e.g.  by gravidity \n3 or HIV status of the mother),\n4 6) suggest any additional stratifiers that were missing, and \n5 7) provide their opinion on additional aspects of the presentation of the model, e.g.  the \n6 visual presentation of low birth weight with its sub-categories (prematurity, intrauterine \n7 growth restriction and small for gestational age). \n8\n9 Nominal and ordinal categorical response options as well as free-text questions were used in \n10 both questionnaires with round two containing more of the latter (See appendix 2 and 3 for \n11 questionnaires used in round 1 and 2). The responses to each round were analysed by one \n12 researcher (SF) and incorporated into the next model draft and questionnaire. Categorical \n13 questions were analysed using simple descriptive statistics. Free text responses were explored \n14 using a simple thematic analysis, coding them manually into themes (22). After each round \n15 panellists received a summary report of the analysis (See appendix 4 and 5), ensuring \n16 anonymity was maintained. \n17\n18 Stage three: Consensus meeting \n19 In the final stage of the study, two online consensus meetings for experts in different time \n20 zones were held to present the findings of the second Delphi round and to discuss and vote on \n21 any remaining aspects of the model where consensus had not been reached during stage two.   \n22 The conceptual model was finalized by the first author following the consensus meeting.\n23\n24 Ethics\n25 Ethics approval for this study was received on 12 July 2022 by the Research Ethics Committee of \n26 the London School of Hygiene and Tropical Medicine (Reference number 27361). Informed \n27 written consent was received from all Delphi panel members. \n28\n29 Role of the funding source \n30 This study forms part of the PhD of SF supervised by KH, with an aim to be used in the cost-\n31 effectiveness analysis of the IMPROVE (TRIA.2015-1076) and IMPROVE-2 (TRIA.2015-1076b) \n32 trials. SF was funded on both IMPROVE trials to conduct the cost-effectiveness analysis into \n33 which this conceptual model will feed. \n34\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n7\n1 The study received financial support from the EDCTP2 programme under Horizon 2020 \n2 (TRIA.2015-1076, TRIA.2015-1076b); the UK Department of Health and Social Care, the UK \n3 Foreign Commonwealth and Development Office, the UK Medical Research Council, and \n4 Wellcome Trust, through the Joint Global Health Trials scheme (MR/P006922/1); and the \n5 Swedish International Development Cooperation Agency.\n6\n7 Results\n8 Key results of the different stages of this study are summarized here (see supplementary \n9 materials for additional detail). \n10\n11 Stage one: Preparation\n12 The first draft of the conceptual model developed by the steering group included outcomes for \n13 the mother and the child and relationships among them (Figure 2). Gravidity, timing of \n14 exposure to P.falciparum (i.e. first, second or third trimester) and HIV status were selected as \n15 the most relevant stratifiers for subpopulation analysis. The steering group identified 17 \n16 experts to be approached to participate in the study, of whom twelve agreed (71%). Amongst \n17 eleven experts the average years of experience working in malaria in pregnancy was 17.9 years \n18 (range 8-34) and the twelfth expert had over 15 years of experience in the economics of \n19 malaria. \n20\n21 Stage two: Delphi consultation\n22 Two rounds of consultation were required before sufficient consensus was reached.  Changes \n23 to the model made after each consultation round and the consultation meetings are illustrated \n24 in table 1 with only the most significant changes highlighted here. \n25\n26 After the first consultation round all outcomes included in figure 2 remained in the model. On \n27 recommendation of panel members \"severe disease” and “serious complications” were \n28 combined into a single outcome of “severe malaria” as experts pointed out the difficulty in \n29 differentiating between these two outcomes.  All experts agreed that “low birth weight” should \n30 be separated into “intrauterine growth restriction” and “preterm birth”, with five experts \n31 suggesting the addition of “small for gestational age”. Additional outcomes - all maternal -  to \n32 be incorporated into the next draft of the model were “asymptomatic parasitaemia”, “placental \n33 malaria” and “hypertension disorders of pregnancy”. Responses on rating stratifiers (gravidity, \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n8\n1 HIV status, timing of exposure) needed further exploration with transmission intensity \n2 suggested as an additional stratifier by seven experts. \n3\n4 In round two experts reached consensus regarding the inclusion of asymptomatic parasitaemia \n5 (100%, 12/12 agreed) and placental malaria (75%, 9/12 agreed) and their associated \n6 relationships. Whether to include or exclude “hypertension disorder of pregnancy” was unclear \n7 and had to be explored further during the consensus meeting. While all relationships associated \n8 with “hypertension disorder of pregnancy” were judged to be correct, it appeared that there \n9 was a difference in opinion regarding its importance and relevance amongst experts working in \n10 low- versus high endemicity settings.  \n11\n12 Experts were asked to vote for the two most important stratifiers for subpopulation analysis \n13 leading to the following ranking from most to least important with the number of votes in \n14 brackets: gravidity (10), transmission intensity (8), timing of exposure of P.falciparum (3) and \n15 HIV status (2). Summary reports of both Delphi consultation round analyses can be found in \n16 appendix 4 (round 1) and 5 (round 2) and intermediate model drafts after round 1 and 2 are \n17 depicted in figure S1 and S2 in appendix 1. \n18\n19 Stage three: consensus meeting\n20 All twelve experts completed both rounds of questionnaires and nine (75%) attended one of \n21 the consensus meetings, held on 31st August and 8th of September 2023. The most relevant \n22 topic discussed was “hypertension disorders of pregnancy” and its potential sequelae. All \n23 attending experts agreed to keep “hypertension disorder of pregnancy” in the model without \n24 splitting it further into “hypertension”, “pre-eclampsia” and “eclampsia”. However, they voted \n25 to add “long-term effects of hypertension disorders of pregnancy” as a further outcome to \n26 include long-term sequelae such as stroke or mental health disorders.  Other less contentious \n27 issues such as the relationship between “clinical malaria” and “anaemia” or relationships and \n28 labelling of child morbidities were also agreed during the consensus meeting. \n29\n30 Experts expressed the importance of adapting economic models to context and allowing the \n31 flexibility for them to evolve over time as more granular data become available. They also felt \n32 that in addition to developing a conceptual model of malaria during pregnancy to be used in \n33 future cost-effectiveness analysis, the work had helped to identify a number of areas where \n34 data are limited and that it will be important to share these with the research community. The \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n9\n1 final model is shown in figure 3, in which both child and maternal figures are combined, a \n2 suggestion made during the consensus meeting.\n3\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n10\n1 Discussion\n2 Summary\n3 This article presents a consensus-building study using the Delphi methodology with the goal of \n4 co-developing a conceptual model of malaria during pregnancy with a diverse group of expert \n5 stakeholders. The result is a comprehensive disease policy model including ten maternal and \n6 ten child outcomes with four stratifiers. To our knowledge, it is the first formal attempt to co-\n7 develop a disease model of this kind either in the field of malaria or in a disease area \n8 predominantly prevalent in low and middle income countries.   \n9\n10 The study has highlighted the complexity of the model required to depict appropriately the \n11 consequences of malaria during pregnancy to mothers and their offspring. Key contributors to \n12 the success of the study were the selection of the expert panel, thorough preparation of each \n13 stage as well as well as careful analysis and weighing-up of all responses. It was essential to be \n14 accurate with language, which sometimes had to evolve over various stages, while remaining \n15 accessible to a wide range of readers. \n16\n17 The process not only helped to develop the model to include relevant outcomes and \n18 relationships, but also improved the visual presentation and accessibility of the model, for \n19 example by adding symbols for the different timings of outcomes or appearance of arrows. \n20\n21 Strength and limitations\n22 This study has a number of strengths and limitations. The literature search conducted by the \n23 first author during the preparation stage was not a systematic review. Therefore some potential \n24 outcomes and relationships may have been missed out of the first draft of the model, however \n25 this was mitigated by the experts’ responses during the consultation rounds and consensus \n26 meetings. Experts for the Delphi panel were purposively selected to balance the experience, \n27 origin and focus area of work of panel members, however, the study may suffer from bias by \n28 omitting other experts with differing views. \n29\n30 The acceptance rate of experts was high (71%) with a 100% retention during the two \n31 consultation rounds;  and 75% of panellists attended one of the two consensus meetings. The \n32 use of the Delphi methodology preserved the anonymity of experts and allowed panellists to \n33 respond freely without being influenced by other opinions or dominant personalities. The final \n34 stage of the study using online consultation meetings was more susceptible to the effects of \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n11\n1 group dynamics, however, this did not appear to be a problem with all experts engaging equally \n2 and respectfully with each other in both meetings. \n3\n4 This study focused on P. falciparum malaria. To apply the model to other plasmodium species \n5 such as P.vivax, malariae or ovale  it would be necessary to review the model and consider \n6 inclusion of additional outcomes, relationships and stratifiers, informed by a literature search \n7 and expert consultation. \n8\n9 It may be a challenge to populate this comprehensive model for a cost-effectiveness study \n10 because of the range of outcomes and complexity of relationships. Nevertheless, this study has \n11 brought together experts from different fields and contexts to develop a model all could agree \n12 to. \n13\n14 Areas for future research\n15 During the study a number of areas requiring further research or development have emerged.  \n16 The most commonly used outcome in cost-effectiveness analysis of global health interventions, \n17 the DALY, is a composite outcome combining mortality and morbidity, and in the case of \n18 malaria during pregnancy can combine both maternal and child outcomes into one measure. \n19 However, not all outcomes lend themselves equally well to calculating reliable DALY estimates \n20 and all of them rely heavily on assumptions made in the Global Burden of Disease studies (23). \n21 For example, estimating DALYs arising from “Long-term neurological and other sequelae” could \n22 potentially be difficult as long-term follow up data are lacking from malaria trials, requiring \n23 assumptions.   Likewise, not all manifestations of severe malaria are equally associated with \n24 mortality or long-term morbidities, ultimately affecting the DALY. Placental malaria and \n25 asymptomatic parasitaemia were included in the model after the first consultation round, \n26 because for the experts, in particular epidemiologists, it is important to have these \n27 intermediate and often reported outcomes represented in the model for completeness and to \n28 depict important pathways.\n29\n30 Experts expressed very differing views regarding the inclusion of hypertension disorders of \n31 pregnancy, mostly shaped by different levels of awareness. The votes as well as the comments \n32 provided in the Delphi consultation indicated that experts working in lower endemicity settings \n33 were more aware of the link between malaria during pregnancy and hypertension disorder \n34 during pregnancy. The consensus meetings provided a useful platform to discuss these \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n12\n1 differences and the supporting evidence. Evidence from both Asia (24) and Africa points to an \n2 association, with a meta-analysis including four case-control studies from Africa suggesting that \n3 women experiencing malaria during pregnancy had 2.7 times higher odds of developing \n4 gestational hypertension disorder compared with those who did not (25). Ideally, the model \n5 should also differentiate hypertension disorder of pregnancy further into pre-eclampsia and \n6 eclampsia, but experts agreed that this level of detail will be difficult to find in the currently \n7 available data, but should be sought in the future. Experts commented that more effort should \n8 be made to collect data on hypertension disorder in pregnancy as blood pressure is always \n9 measured but often omitted from clinical trial databases. As above for “long-term neurological \n10 and other sequalae” the estimation of DALYs arising from hypertension disorder of pregnancy \n11 will require some assumptions on incidence and disability weights. \n12\n13 Some of the morbidities and outcomes can have lifelong consequences and be progressive. For \n14 example “neurocognitive and physical development impairment in <5” will likely impact the \n15 child for its entire life and influence its educational achievement and productivity. Likewise, for \n16 a women with severe malaria who develops severe anaemia and requires a blood transfusion  \n17 there is a risk that the blood supply is contaminated, which then increases the risk of a wide \n18 range of other morbidities associated with other infectious diseases. While it will not be \n19 possible to quantify these future consequences for a cost-effectiveness analysis with currently \n20 available data, it is certainly important to create awareness of the potential long term health \n21 problems.  \n22\n23 This study identified four important stratifiers: gravidity, transmission intensity, timing of \n24 exposure and HIV status. However, this does not preclude other variables from being important \n25 in certain analyses. Examples could be the sickle cell trait or the gender of the baby. At this \n26 point in time insufficient data are available to differentiate the consequences of the timing of \n27 exposure (e.g. first versus second, third trimester).  HIV status also requires further \n28 disaggregation of the data such as the CD4 count or whether the woman is receiving \n29 antiretrovirals. Currently, cost-effectiveness models of chemoprevention for malaria during \n30 pregnancy will naturally stratify by HIV status as different prevention interventions are given to \n31 HIV negative and positive women. \n32\n33 Currently, the model does not include potential treatment or prevention interventions to \n34 ensure it is widely applicable for different purposes. Depending on the type of intervention \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n13\n1 study and context, further outcomes, such as side-effects, or effects on other diseases, such as \n2 HIV transmission from mother to child in HIV positive women, might need to be incorporated \n3 into the model. Studies using QALYs might also need to include patient’s health perception, \n4 perceived quality of life and future outlook into the model. \n5\n6 Finally, an important outcome of this study is to identify areas where data are scarce and share \n7 these with the research community, to raise awareness of the need for comparable outcome \n8 measures reported by trials. \n9\n10 A number of these points highlight the urgent need for more granular data, and experts felt \n11 that despite the complexity of the model it was important to create awareness of the wide \n12 range of outcomes that can be prevented by preventing pregnant women from being exposed \n13 to P. falciparum.  More detailed data in the future should allow a move away from one size fits \n14 all models to models that are more adaptable and fluid.\n15\n16 Conclusions \n17 This study has demonstrated a more inclusive approach to developing disease policy models \n18 that are capable of assisting in the design of clinical trials (and other policy evaluations) and \n19 their associated health economic analysis.  In so doing, we believe that this integrated \n20 approach should become the gold-standard for disease modelling designed to inform health \n21 policy in different countries and contexts.  Co-development ensures wider perspectives are \n22 incorporated into the model than is usually possible for a single academic team, which should \n23 ensure the resulting model is more robust and fit for purpose.  A robust conceptual modelling \n24 co-design approach will also help identify data gaps, ensuring these are not overlooked as the \n25 modelling proceeds to the implementation phase.\n26\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n14\n1 Contributors\n2 All authors conceived the idea for the study. SF designed the study with input from KH and AB. \n3 SF conducted the Delphi consultations & meetings and subsequent data analysis. KH verified the \n4 data analysis. SF wrote the first draft of the manuscript. KH and AB critically reviewed and edited \n5 several drafts of the manuscript. All authors had full access to all the data in the study and had \n6 final responsibility for the decision to submit for publication. \n7 Declaration of interests\n8 We declare no competing interests. \n9 Acknowledgement: \n10\n11 The authors would like to take this opportunity to acknowledge and thank the members of the \n12 Delphi Panel and Steering group for giving up their precious time so selflessly to share their \n13 invaluable wisdom with the study team. \n14\n15 Delphi panel members (in alphabetical order): Prof. Grant Dorsey (University of California San \n16 Francisco, United States of America), Prof. Kevin Kain (University of Toronto, UHN-Toronto \n17 General Hospital, Canada), Dr. Kassoum Kayentao (Malaria Research and Training Center-\n18 University of Sciences, Techniques, and Technologies of Bamako, Mali), Prof. Feiko ter Kuile \n19 (Liverpool School of Tropical Medicine, United Kingdom), Prof. Rose McGready (Shoklo Malaria \n20 Research Unit, Thailand), Dr. George Mtove (National Institute for Medical Research, Tanzania), \n21 Dr. Catherine Pitt (London School of Hygiene and Tropical Medicine, United Kingdom), Prof. \n22 Stephen Rogerson (University of Melbourne, Australia), Dr. Makoto Saito (WorldWide \n23 Antimalarial Resistance Network), Dr. Steve Taylor (Duke University, United States of America), \n24 Prof. Halidou Tinto (Institut de Recherche en Sciences de la Santé, Clinical Research Unit of \n25 Nanoro, Burkina Faso) and Dr. Holger Unger (Menzies School of Health Research, Darwin, \n26 Australia). \n27\n28 Steering group members: Prof. Kara Hanson (London School of Hygiene and Tropical Medicine), \n29 Prof. Andy Briggs (London School of Hygiene and Tropical Medicine), Prof. Feiko ter Kuile \n30 (Liverpool School of Tropical Medicine), Silke Fernandes (London School of Hygiene and \n31 Tropical Medicine)\n32\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n15\n1 Overview of figures, tables and appendices\n2 Figures in main paper:\n3  Figure 1: Methodology used in the study\n4  Figure 2: Conceptual model: Draft 1 – steering group\n5  Figure 3: Final model  after Delphi consultation meetings\n6 Figures in appendix 1:\n7  Figure S1: Conceptual model: Draft 2- Delphi consultation post round 1\n8  Figure S2: Conceptual model: Draft 3- Delphi consultation post round 2\n9 Table:\n10  Table 1: Changes to the model made after each consultation round and consultation \n11 meetings\n12 Appendices:\n13  Appendix 1: Detailed methods and results\n14  Appendix 2: Questionnaire Delphi consultation round 1\n15  Appendix 3: Questionnaire Delphi consultation round 2\n16  Appendix 4: Summary report Delphi consultation round 1\n17  Appendix 5: Summary report Delphi consultation round 2\n18\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n16\n1 Table 1: Changes to the model made after each consultation round and consultation meetings\n \n \nChanges made after Delphi consultation \nround 1\nChanges made after Delphi consultation \nround 2\nChanges made after Delphi consultation \nmeetings (final model)\n\"MOTHER Exposure to P.falciparum while \npregnant\" changed to \"MOTHER presence of \nP.falciparum while pregnant\"\n  \nAddition of \"asymptomatic parasitaemia\"   \n\"With and without Placental malaria\" added to \n\"clinical malaria\" and \"asymptomatic \nparasitaemia\"\n  \n\"Long term neurological sequelae\" changed to \n\"long term sequelae\" to include other long-term \ndisabilities resulting from manifestations of \nsevere malaria\n\"Long term sequelae\" changed to long term \nneurological and other sequelae\"\ngreen colour (for long-term consequence to \nthe mother) added to \"long-term neurological \nand other sequelae\"\n\"Death in utero after maternal death\" added to \n\"miscarriage/stillbirth\"\n\"miscarriage/stillbirth/death in utero after \nmaternal death\" changed to \n\"miscarriage/stillbirth/death in utero\"\n \n\"Hypertensions disorders of pregnancy\" added Outcome \"hypertension disorders of pregnancy\" \nrelabelled to \"hypertension disorders of \npregnancy and post-partum\", footnote added: \n\"includes pre-eclampsia, eclampsia and \ngestational hypertension\"\nAdditional outcome \"Long-term effects of \nhypertension disorders of pregnancy\" added \nas a consequene of \"Hypertension disorders \nor preganncy and post-partum\"\nOutcomes\n\"Severe disease\" and \"serious complications\" \ncombined into \"severe malaria\" and WHO \ndefinition added\n  \nRelationships to and from \"hypertension \ndisorders of pregnancy\" added\n Relationship from \"Hypertension disorders of \npregancy and post-partum\" to \"Long-term \neffects of hypertension disorders of \npregnancy\" added\nMother\nRelationships\nRelationship from maternal death to \"death in \nutero after maternal death\" added\n  \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n17\nRelationship to and from \"asymptomatic \nparasitaemia\" added\n  \nRelationship from maternal anaemia to \"severe \nmalaria\" added\n  \nRelationship between maternal anaemia and \nclinical malaria made bi-directional\nBidirectional relationship between \"clinical \nmalaria\" and maternal anaemia\" reversed to \nunidirectional (malaria to anaemia) and an arrow \nfrom \"maternal anaemia\" to \"clinical malaria\" \nindicating \"contributes to progression\"\n Arrow from \"maternal anaemia\" to \"clinical \nmalaria\" indicating \"contributes to \nprogression\" removed\n\"Small for gestational age\" added and \nvisualization of \"low birth weight\" changed\n  \n\"short-, mid- and long-term morbidities\" \nchanged to \"neonatal, infant, <5 and older \nchild/adult morbidities\"\n\"Neonatal, infant, <5 and older child/adult \nmorbidities\" changed to \"Other morbidities in \nneonates, infants, <5, older children and adults\"\nShape of \"Other morbidities in neonates, \ninfants, <5, older children and adults\" changed \nfrom large arrow to an oval shape as other \noutcomes\n\"CHILD with in utero exposure to P.falciparum\" \nchanged to \"CHILD Presence of P.falciparum in \nutero\"\n \"CHILD Presence of P.falciparum in utero\" \nrelabelled to \"CHILD Presence of/ exposure to \nP.falciparum in utero\"\n \n \"Neonatal, infant and <5 mortality\" combined \ninto 1 large outcome box and relabelled as \n\"Neonatal, infant, <5 mortality & mortality in \nolder children & adults\"\ngreen colour added to box \"Neonatal, infant, \n<5 mortality & mortality in older children & \nadults\"\n \"Modified incidence of malaria in <5\" changed to \n\"Increased incidence of malaria in <5\"\n \nOutcomes\n  \"Neurocognitive development impairment in \n<5\" relabelled to \"Neurocognitive &physical \ndevelopment impairment in <5\"\nChild\nRelationship\nArrow from \"neonatal, infant, <5 and older \nchild/adult morbidities\" to \"neonatal, infant and \n<5 mortality\" added\nStarting position of arrow from \"neonatal, infant, \n<5 and older child/adult morbidities\" to \n\"neonatal, infant and <5 mortality\" changed from \nback of the box to the middle\n \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n18\n  Arrows from   \n1) \"CHILD Presence of/exposure to \nP.falciparum in utero\", 2)\"Fetal anaemia\", 3) \n\"Congenital malaria\" to \"Other morbidities in \nneonates, infants, <5, older children and \nadults\" added\nSymbols in addition of colour code for the \ntiming of health effects added\n  \nRed on timeline changed from \"neonate/ 28 \ndays postpartum\" to \"neonate/mother 28/42 \ndays postpartum\"  to reflect the postpartum \nperiod in which maternal death are counted\ndescription box moved below model  \nDesign\nDesign of certain arrows and lines changed to \nhelp with distinguising them\nDesign of arrows and lines changed again as \nprevious change was confusing to expert\n \nOther\nStratifiers\n\"Transmission intensity\" added as a stratifier to \nthe next round in addition to \"HIV \nstatus\",\"Gravidity\" and \"Timing of exposure\"\nOut of the four stratifiers \"Transmission \nintensity\", \"HIV status\",\"Gravidity\" and \"Timing of \nexposure\", Transmission intensity and gravidity \nwere considered most important by experts.\nDescription box listing potential other \nstratifiers added below the model\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n19\n1 Figures\n2 Figure 1: Methodology used in the study\n3 Figure 1 illustrates the methodology used in this Delphi consultation study, which can be split \n4 into three stages: preparation, Delphi consultation and consensus meeting. \n5\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n20\n1 Figure 2: Conceptual model: Draft 1- steering group\n2 2a) Maternal outcomes\n3\n4 2b) Child outcomes\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n21\n1\n2 Figure 2 shows the maternal and child outcomes included in the first draft of the conceptual \n3 model developed by the four members of the steering group to be used as a starting point for \n4 the first round of the Delphi consultation. Outcomes were divided into maternal and child \n5 outcomes. Outcomes affecting morbidity are shown at the top, while mortality outcomes at the \n6 bottom. The colour coding of the outcomes represents the different timings of the health \n7 effects. \n8 Abbreviations: IUGR=Intrauterine growth restriction\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n22\nFigure 3- Final model  after Delphi consultation meetings\nFigure 3: The final agreed conceptual model of malaria during pregnancy following two consensus meetings attended by nine experts. The model \ncombines both maternal and child outcomes. Outcomes were divided into maternal and child outcomes. Outcomes affecting morbidity are shown at \n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n23\nthe top, while mortality outcomes at the bottom. The colour and shape coding of the outcomes represents the different timings of the health \neffects. \nAbbreviations: w/=with; w/o=without; WHO=World Health Organization\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n24\nReferences \n1. Roberts M, Russell LB, Paltiel AD, Chambers M, McEwan P, Krahn M, Force I-\nSMGRPT. Conceptualizing a model: a report of the ISPOR-SMDM Modeling Good \nResearch Practices Task Force--2. Value Health. 2012;15(6):804-11.\n2. McMeekin NJM. Conceptual models in health economic evaluation: a new role.: \nUniversity of Glasgow; 2021.\n3. Cruz Rivera S, Kyte DG, Aiyegbusi OL, Keeley TJ, Calvert MJ. Assessing the \nimpact of healthcare research: A systematic review of methodological frameworks. \nPLoS Med. 2017;14(8):e1002370.\n4. Becker-Dreps SI, Biddle AK, Pettifor A, Musuamba G, Imbie DN, Meshnick S, \nBehets F. Cost-effectiveness of adding bed net distribution for malaria prevention to \nantenatal services in Kinshasa, Democratic Republic of the Congo. Am J Trop Med \nHyg. 2009;81(3):496-502.\n5. Fernandes S, Sicuri E, Halimatou D, Akazili J, Boiang K, Chandramohan D, et al. \nCost effectiveness of intermittent screening followed by treatment versus intermittent \npreventive treatment during pregnancy in West Africa: analysis and modelling of results \nfrom a non-inferiority trial. Malaria journal. 2016;15(1):493.\n6. Fernandes S, Sicuri E, Kayentao K, van Eijk AM, Hill J, Webster J, et al. Cost-\neffectiveness of two versus three or more doses of intermittent preventive treatment for \nmalaria during pregnancy in sub-Saharan Africa: a modelling study of meta-analysis \nand cost data. The Lancet Global health. 2015;3(3):e143-53.\n7. Sicuri E, Bardaji A, Nhampossa T, Maixenchs M, Nhacolo A, Nhalungo D, et al. \nCost-effectiveness of intermittent preventive treatment of malaria in pregnancy in \nsouthern Mozambique. PloS one. 2010;5(10):e13407.\n8. Sicuri E, Fernandes S, Macete E, Gonzalez R, Mombo-Ngoma G, Massougbodgi \nA, et al. Economic evaluation of an alternative drug to sulfadoxine-pyrimethamine as \nintermittent preventive treatment of malaria in pregnancy. PloS one. \n2015;10(4):e0125072.\n9. Choi SE, Brandeau ML, Bendavid E. Cost-effectiveness of malaria preventive \ntreatment for HIV-infected pregnant women in sub-Saharan Africa. Malaria journal. \n2017;16(1):403.\n10. Hansen KS, Ndyomugyenyi R, Magnussen P, Clarke SE. Cost-effectiveness \nanalysis of three health interventions to prevent malaria in pregnancy in an area of low \ntransmission in Uganda. Int Health. 2012;4(1):38-46.\n11. Fernandes S, Were V, Gutman J, Dorsey G, Kakuru A, Desai M, et al. Cost-\neffectiveness of intermittent preventive treatment with dihydroartemisinin-piperaquine \nfor malaria during pregnancy: an analysis using efficacy results from Uganda and \nKenya, and pooled data. The Lancet Global health. 2020;8(12):e1512-e23.\n12. Paintain L, Hill J, Ahmed R, Umbu Reku Landuwulang C, Ansariadi A, Rini \nPoespoprodjo J, et al. Cost-effectiveness of intermittent preventive treatment with \ndihydroartemisinin-piperaquine versus single screening and treatment for the control of \nmalaria in pregnancy in Papua, Indonesia: a provider perspective analysis from a \ncluster-randomised trial. The Lancet Global health. 2020;8(12):e1524-e33.\n13. Earp JA, Ennett ST. Conceptual models for health education research and \npractice. Health Educ Res. 1991;6(2):163-71.\n14. Meyrick J. The Delphi method and health research. Health Education. 2003.\n15. Dalkey NC. The Delphi Method: An Experimental Study of Group Opinion. Santa \nMonica, CA: RAND Corporation; 1969.\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n25\n16. Jones J, Hunter D. Qualitative Research: Consensus methods for medical and \nhealth services research. BMJ. 1995;311(7001):376.\n17. Squires H, Chilcott J, Akehurst R, Burr J, Kelly MP. A Framework for Developing \nthe Structure of Public Health Economic Models. Value Health. 2016;19(5):588-601.\n18. Tabberer M, Gonzalez-McQuire S, Muellerova H, Briggs AH, Rutten-van Molken \nM, Chambers M, Lomas DA. Development of a Conceptual Model of Disease \nProgression for Use in Economic Modeling of Chronic Obstructive Pulmonary Disease. \nMedical decision making : an international journal of the Society for Medical Decision \nMaking. 2017;37(4):440-52.\n19. Tappenden P. Conceptual Modelling For Health Economic Model Development. \n2012.\n20. Linstone HA, Turoff M. Introduction. In The Delphi method: Techniques and \napplications. 2002.\n21. Woodcock T, Adeleke Y, Goeschel C, Pronovost P, Dixon-Woods M. A modified \nDelphi study to identify the features of high quality measurement plans for healthcare \nimprovement projects. BMC Med Res Methodol. 2020;20(1):8.\n22. Braun V, Clarke V. Using thematic analysis in psychology. Qualitative Research \nin Psychology. 2006;3:77-101.\n23. Das P, Samarasekera U. The story of GBD 2010: a \"super-human\" effort. Lancet. \n2012;380(9859):2067-70.\n24. Harrington WE, Moore KA, Min AM, Gilder ME, Tun NW, Paw MK, et al. \nFalciparum but not vivax malaria increases the risk of hypertensive disorders of \npregnancy in women followed prospectively from the first trimester. BMC Med. \n2021;19(1):98.\n25. Mruma HA, McQuillan R, Norrie J. The association of malaria infection and \ngestational hypertension in Africa: Systematic review and meta-analysis. J Glob Health. \n2020;10(2):020417.\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint \n\n . CC-BY 4.0 International licenseIt is made available under a \nperpetuity. \n is the author/funder, who has granted medRxiv a license to display the preprint in(which was not certified by peer review)preprint \nThe copyright holder for thisthis version posted September 12, 2024. ; https://doi.org/10.1101/2024.09.10.24313438doi: medRxiv preprint","source_license":"CC-BY-4.0","license_restricted":false}