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Re-orienting anti-malarial drug development to better serve pregnant women

Abstract

Malaria is one of the most serious infectious diseases affecting predominantly low- and middle-income countries, where pregnant women are among the populations at risk. There are limited options to prevent or treat malaria in pregnancy, particularly in the first trimester, and existing ones may not work optimally in areas where the threat of drug resistance is rising. As malaria elimination is a key goal of the global health community, the inclusion of pregnant women in the adult population to protect from malaria will be key to achieving success. New, safe, and effective options are needed but it can take decades of evidence-gathering before a medicine is recommended for use in pregnancy. This is because pregnant women are typically not included in pre-registration clinical trials due to fear of causing harm. Data to support dosing and safety in pregnancy are subsequently collected in post-licensure studies. There have been growing calls in recent years that this practice needs to change, amplified by the COVID-19 pandemic and increasing public awareness that newly developed medicines generally cannot be administered to pregnant women from the onset. The development of new anti-malarials should ensure that data informing their use in pregnancy and breastfeeding are available earlier. To achieve this, a mindset change and a different approach to medications for pregnant women are needed. Changes in non-clinical, translational, and clinical approaches in the drug development pathway, in line with recent recommendations from the regulatory bodies are proposed in this Comment. The new approach applies to any malaria-endemic region, regardless of the type of Plasmodium responsible for malaria cases. By incorporating intentional and systematic data collection from pre-registration stages of development through post-licensure, it will be possible to inform on the benefit/risk balance of a new anti-malarial earlier and help ensure that the needs of pregnant individuals are addressed in a more timely and equitable manner in the future.

Background

Malaria is an infectious disease predominantly of low- and middle-income countries. The latest World Health Organization (WHO) World Malaria Report [1] states that in 2020 there were an estimated 241 million cases of infection in 87 malaria endemic countries, resulting in 627,000 deaths, and more than a third of pregnant women in 33 African countries with moderate to high transmission had malaria. Data from regions outside of Africa are scarce, but more than 90 million pregnant women were estimated to be at risk of malaria in the Asia–Pacific region [2]. These are estimates and subject to change as malaria elimination progresses. For example, China was listed as a ‘malaria-endemic’ country with over 21 million pregnancies at risk [3], while the WHO has now certified the country as malaria-free [4]. The WHO envisages a 90% reduction in malaria incidence and mortality globally by 2030 compared with 2015 levels [5]. The inclusion of pregnant women in the adult population will be key to successful elimination campaigns as was recently highlighted in The Lancet Commission on Malaria Eradication [6].

Malaria poses specific risks both to pregnant women and the neonates. Firstly, altered immune response during pregnancy is thought to lead to increased susceptibility to infection [7]. Then, malaria in pregnancy (MiP) increases the risk of a severe form of the disease for the mother, and consequently severe anaemia [8]. Despite the increasing knowledge of the consequences of MiP [9], estimates of malaria-related maternal mortality in Africa are scarce and more studies are needed. However, there are numerous reports on the adverse effects of MiP on birth outcomes which include miscarriage, stillbirth, preterm birth, neonatal mortality, and babies born small for gestational age or with a low birthweight. It has been estimated, using meta-analysis, that 20% of all stillbirths in sub-Saharan Africa are attributed to Plasmodium falciparum malaria annually [10]. Malaria is also associated with a three–fourfold increased risk of miscarriage and preterm birth [11]. It has been estimated, using meta-analysis, that the prevalence of babies born small for gestational age is 32% [12]. According to the World Malaria Report [1], MiP resulted in an estimated 819,000 newborns with low birthweight in 33 African countries with moderate-to-high transmission in 2020. Low birthweight is linked to poor health outcomes and long-term morbidity risk [12]. Modelling suggests that prevention of malaria before conception or very early in pregnancy results in a greatly reduced incidence of low birthweight, especially in primigravidae [13]. Moreover, Plasmodium vivax, less prevalent globally but the dominant human malaria parasite in regions outside of Africa, also presents a major risk for pregnancy [14, 15].

The WHO recommends the following to control malaria in pregnancy: the use of an insecticide-treated bed nets (ITNs); effective case management with timely diagnosis and adequate treatment; intermittent preventive treatment using sulfadoxine-pyrimethamine (SP). Unless they sleep under an ITN, most women are not adequately protected in early pregnancy. This is because neither SP nor any of the six available artemisinin-based combination therapy (ACT) regimens, the standard of care in malaria, are recommended for use in first-trimester pregnancy. Quinine in combination with clindamycin is the WHO recommended treatment, but it is poorly tolerated [16]. If these drugs are not available or fail, only then an ACT or oral artesunate in combination with clindamycin is recommended [5]. Despite the WHO recommendation, ACT is being adopted by national guidelines as first-line treatment for first trimester pregnancy in some malaria-endemic countries [17]. Moreover, it is important to point out that the malaria epidemiological context outside of Africa poses unique challenges for pregnant women at risk of P. vivax malaria [2, 15]. The blood-stage of P. vivax infection can in most regions of the world still be treated with chloroquine, a drug that is considered safe in pregnancy [5]. The liver-stage of P. vivax infection is treated with primaquine and in some countries with the recently registered tafenoquine. Both drugs are recommended with glucose-6-phosphate dehydrogenase (G6PD) deficiency testing to assess the potential risk of haemolysis. However, G6PD status of the fetus cannot be determined antenatally in most malaria endemic settings [5, 15], hence pregnant women may be ineligible for these essential treatments to prevent P. vivax relapse.

To better address the needs of pregnant women, the malaria research community is working towards the following goals: (1) to generate evidence on the dosing and safety of currently available therapies; (2) to increase the options to prevent and treat malaria in pregnancy; and (3) to allow inclusion of pregnant women in community-wide approaches to eliminate and ultimately eradicate malaria. New tools especially in the first trimester of pregnancy and sustained dedicated funding are needed to support the realisation of these goals. This Comment, highlights the approaches that should be adopted to include pregnant women in the development of new anti-malarials. These proposals are based on the recommendations of the Task Force on Research Specific to Pregnant Women and Lactating Women [18] led by the National Institutes of Health, the ConcePTION project led by the Innovative Medicines Initiative [19] and the guidance provided by the regulatory bodies. Although this Comment does not focus on lactating women, historically they also have been excluded from clinical research in most disease areas. In the case of malaria, it has been suggested that most existing first-line treatments appear safe during lactation, however data remain limited, and more research is needed[20].

Safe and effective medicines for both prevention and treatment of malaria during pregnancy are urgently needed. The pipeline of new medicines in development must factor in the needs of pregnant individuals from the outset. From a research and development perspective, this requires the collection of supporting data and appropriate inclusion of pregnant and lactating women in the development of new medicines earlier than is currently practiced. The benefit/risk balance, underpinned by relevant data, will guide regulators, funders, healthcare professionals and patients to informed decisions in addressing the medical needs of all segments of the population at risk of malaria.

Anti-malarials suitable for use in all stages of pregnancy are limited

The WHO defines a “positive pregnancy experience” as “maintaining physical and sociocultural normality, maintaining a healthy pregnancy for mother and baby (including preventing or treating risks, illness and death), having an effective transition to positive labour and birth, and achieving positive motherhood (including maternal self-esteem, competence and autonomy)” [21]. Current WHO guidelines for malaria recommend intermittent preventative treatment in pregnancy (IPTp) as part of antenatal care in the second and third trimesters, in combination with ITNs [5]. While multiple artemisinin-based combinations are recommended by the WHO from the second trimester for malaria treatment during pregnancy, for the first trimester quinine plus clindamycin are recommended. In pregnancy, the benefit/risk balance when taking any medicine must be considered from the perspective of both the mother and the child. Given the potential for harm, the safety requirements are more stringent than for non-pregnant adults and should be well defined by the relevant authorities. This explains partly the limited anti-malarial options for pregnant women today and the challenges in developing new ones.

Treatment

A clear picture of the total burden of malaria in the early stages of pregnancy is lacking. However, malaria in the first trimester of pregnancy is associated with miscarriage, and the risk is higher for women with symptomatic and asymptomatic malaria (adjusted odds ratio 4·0 and 2·7, respectively) than for women who did not have malaria in the first trimester [11]. Women of reproductive age take ACT whilst there might be insufficient evidence on the safety of these medicines during the first trimester, should they become pregnant. Although non-clinical data have raised concerns [22], a meta-analysis of prospective observational studies concluded that compared to quinine, artemisinin treatment (mainly artemether-lumefantrine, AL) in the first trimester is not associated with an increased risk of miscarriage or stillbirth [23]. However, AL is not yet recommended by the WHO for first-trimester pregnancy despite being used for two decades. As the general risk of fetal malformations is high during first trimester pregnancy, a body of evidence is needed to support the safety claim for a new drug. Better alignment with the WHO, and other stakeholders, on what evidence is required is key to expediting access to medicines by pregnant women particularly in first trimester. Furthermore, beyond the first trimester optimization of the dosing regimen might be necessary to achieve equal efficacy to non-pregnant population as has been recently suggested for AL based on pharmacokinetic modelling [24].

Intermittent preventative therapy

To date, 33 African countries have adopted IPTp to reduce the burden of MiP. In 2020, 57% of women visiting antenatal care clinics received at least one dose, but only 32% received three doses, well below the coverage target of 80% [1]. Pregnancies frequently occur in regions with a prevalence of parasite drug resistance markers to SP, the drug combination recommended for IPTp. So far, even in those areas, SP remains associated with reductions in low birthweight [25]. Although the precise relationship between the resistance markers and SP efficacy is not yet clear, this continues to be a cause for concern and the need for additional drug combinations for use in IPTp is pressing [26, 27]. Innovative approaches like monoclonal antibodies [28] and vaccines specific for pregnancy-associated malaria [29] might offer alternatives as they are generally considered lower risk options than chemical entities.

Community-wide campaigns

In population-based elimination strategies, such as Mass Drug Administration (MDA) campaigns, a large proportion of the target population will consist of individuals with no clinical manifestations of acute malaria infection who will be exposed to the drug without gaining immediate benefit, analogous to population-wide immunisation campaigns for vaccine-preventable infectious diseases. Consequently, the safety threshold required is much higher than for treatment of symptomatic malaria infection. Pregnant women are currently excluded from such campaigns due to the more stringent benefit/risk balance that exists at the individual level for this population. Given that the success of elimination strategies may depend on the inclusion of pregnant women it will be essential to have a range of medicines considered safe in all stages of pregnancy [30]. Moreover, as asymptomatic malaria infection in pregnant women is associated with an increased likelihood of anaemia [31], there will be an added benefit to individuals participating in the elimination campaigns in averting this adverse consequence of untreated asymptomatic infection.

The need for additional antimalarial choices for pregnant individuals in first trimester of pregnancy, as well as the need to support drug resistance and malaria elimination efforts, are urgent. The research community has a major role to play in meeting these needs. It must expedite the availability of more drug options appropriate for use in all stages of pregnancy and systematically generate the necessary evidence throughout the discovery, development and post-licensure of new antimalarials to address this population.

A paradigm shift towards the inclusion of pregnant women in clinical research

In recent years, there has been a growing awareness that the labelling of most medications does not contain sufficient information about the use in pregnancy [20, 32]. Historically, just 1.3% of pharmacokinetic (PK) trials registered from the 1960s to 2013 included pregnant women [33] and only 1% of pharmaceutical industry-sponsored Phase IV trials were designed specifically for pregnant women [34]. Of over 500 anti-malarial drug trials conducted between 1966 and December 2006, only 31 evaluated anti-malarials specifically in pregnant women and recommended dose regimens for pregnant women are all derived from studies in non-pregnant adults [35]. As pregnant women are not typically included during the development of medicines, data regarding safe use in pregnancy are collected in costly post-registration studies (e.g., pregnancy exposure registries, case–control studies and surveillance). In many malaria-endemic countries there are challenges to this approach due to the lack of robust pharmacovigilance systems, patients not being routinely followed-up, or limited resources. Therefore, it takes time to make efficacy and safety data of anti-malarials in pregnant population available via much needed meta-analyses and evidence synthesis [36, 37].

A paradigm shift towards the inclusion of pregnant women in clinical research is underway and necessary changes are starting to be proposed in some disease areas [38]. Several bodies have endorsed the shift, including the Council for International Organizations of Medical Sciences [39], the WHO [40], and regulatory agencies as reflected in updates of relevant guidance in recent years. In 2018, a Task Force on Research Specific to Pregnant Women and Lactating Women (PRGLAC) recommended to the US Congress the inclusion and integration of pregnant women and lactating women into the clinical research agenda [18] on the basis that the exclusion of these populations to-date has significantly limited scientific knowledge of therapeutic product safety, effectiveness and dosing. In line with these recommendations, the inclusion of pregnant women in clinical research should be extended to new anti-malarial drug development to accelerate access by this population to new medications in malaria-endemic countries. Consultations with the malaria community stakeholders, support from the pharmaceutical industry and funders will be important in implementing the new recommendations into practice.

Proposed approaches to discovery and development of future anti-malarial drugs suitable for pregnant women

To tackle the urgent lack of anti-malarial options for prevention and treatment during all stages of pregnancy, there must be a commitment to systematically change the way the malaria research community approaches the discovery and development of new drugs. Adoption of the following practices is proposed (Fig. 1):

  • Validation and routine use of predictive embryo and foetal development in vitro assays to efficiently screen and prioritize lead compounds based on their non-teratogenic profile before investing in more expensive Developmental and Reproductive Toxicity (DART) studies in animals. This early screening approach should not constitute an absolute no-go criterion where it might limit progress in addressing other critical unmet medical needs in malaria.

  • Appropriate sequencing of DART studies to support the intentional inclusion of pregnant women in clinical studies during drug development. These studies evaluate the effects of potential drugs on one complete life cycle, from conception in one generation through the following generation. The timing and extent of DART studies is usually left to the discretion of the sponsor, depending on the target population [41]. Performing these studies earlier to use the results for decision-making would ensure that finite funding is channelled to clinical development of drugs most suitable for use during pregnancy.

  • Utilising translational science approaches, such as physiologically-based pharmacokinetic (PBPK) models of pregnancy, to better anticipate how drug dosing might need to be adjusted for women in the second or third trimester, prior to including them in a clinical trial [42], or to semi-quantitatively assess the possibility of foetal exposure to the tested drug [43, 44]. Similarly, PBPK lactation models can be used to better anticipate the passage of anti-malarials into breast milk and inform on the need for a clinical study to assess safety for the newborn [45].

  • Once compounds with appropriate non-clinical profile are progressed to clinical development, and there is sufficient safety and efficacy data in non-pregnant adults, simultaneous commencement of Phase I pharmacology trials for pregnant or lactating women parallel to Phase III trials for non-pregnant population.

  • If the benefit/risk assessment is favourable, offering an option to women who inadvertently become pregnant while enrolled in a clinical trial to continue receiving treatment with appropriate follow-up including the newborn.

Fig. 1
figure 1

Proposed changes to the antimalarial research and development to better integrate the needs of pregnant individuals in the future. PAST APPROACH (top): Women of non-child-bearing potential (WONCBP) and women of child-bearing potential (WOCBP) with highly effective contraceptive use are included in clinical studies. The timing and extent of non-clinical Developmental and Reproductive Toxicity (DART) studies depends on the intended patient population. Generally, embryofoetal development (EFD) studies start in time to support clinical Phase II but pre-/postnatal development (PPND), as well as fertility and early-embryonic development (FEED) studies may be completed even post-licensure. Data on safety in pregnancy are collected passively in post-licensure registries. Pharmacokinetic (PK) data in pregnant and lactating women are rarely reported at the time of new medicine approval. FUTURE APPROACH (bottom): Lead compounds would be prioritized for progression to clinical development based on their non-teratogenic potential in in vitro assays, e.g., mammalian embryo exposure to compounds in a whole embryo culture (WEC) assay, or a zebrafish foetal development model. By performing the DART studies earlier and in relevant sequence, further selection of drugs for full development would be possible based on the risks identified in animal species. This would support earlier inclusion of WOCBP in clinical trials, with appropriate level of contraception [47], and pregnant women. Inadvertent pregnancies would be followed-up to assess maternal health, growth and development of the child. Utilising physiologically-based pharmacokinetic (PBPK) pregnancy or lactation models would inform on potential human foetal exposure or passage of the tested drug through the placenta and breastmilk, and hence support the justification for starting doses to be tested in clinical PK trials involving pregnant or lactating women. The PK trials would be initiated in parallel to the Phase III development for the general malaria population, once there is sufficient safety and efficacy evidence to derive an acceptable benefit/risk balance to start including pregnant or lactating women in the development of new drugs. Providing appropriate dosage and preliminary safety data in pregnant and lactating women in the first label of the registered medicine would expedite the commencement of further clinical studies and registries to fully characterize safety and efficacy. In particular, active pregnancy registries that capture inadvertent exposures in the first trimester, could help bridge the knowledge gap and provide some confidence to extend studies to this patient population

The overall aim of the above approach is to provide an initial data package that would inform on the benefit/risk balance for pregnant individuals at the time of new medicine registration for the general malaria population, and to support the collection of further evidence more expeditiously than currently practiced. Safety and efficacy interventional clinical trials in the third and second trimester of pregnancy and eventually in the first trimester should become routine practice. Active registries could help to capture data on the safety of inadvertent exposure to anti-malarials for the mother and the child, particularly in the first trimester.

To successfully adopt the drug research and development strategies described here, involvement of ethics committees [46], regulatory authorities, the WHO and normative bodies, investigators, patient communities and industry/development partners will be key. Such consultations would help determine what evidence is required to conduct clinical trials in pregnant women in pre-marketing setting; understanding that requirements for specific drugs might differ on case-by-case basis. Moreover, these consultations will expose existing barriers and explore ways to overcome them, including appropriate incentives to accelerate access to medicines by pregnant individuals as the proposed approach may require a greater upfront financial investment.

Conclusions

Defeating malaria will not be possible without the intentional inclusion of pregnant and lactating individuals in clinical research. The malaria research community must prioritize the acceleration of discovery, development, and delivery of new, high-quality anti-malarial options for women of reproductive age who can and do become pregnant. In the near-term, data gathering on the safety and effectiveness of existing anti-malarials should continue. Furthermore, re-combining existing drugs to improve anti-malarial options appropriate for pregnant individuals and to make these more accessible, should be investigated. In the medium- to long-term, innovative strategies to identify new anti-malarial medicines that better serve the needs of pregnant women across all trimesters, as well as lactating women, must be explored. This can be achieved by adapting non-clinical and clinical approaches for the earlier inclusion of these patient populations in drug development research. Finally, the malaria elimination goals will be reached and lives saved from this preventable disease only by addressing the needs of the entire population at risk of malaria.

Availability of data and materials

Not applicable.

Abbreviations

ACT:

Artemisinin-based combination therapy

AL:

Artemether-lumefantrine

DART:

Developmental and reproductive toxicity

EFD:

Embryofoetal development

FEED:

Fertility and early-embryonic development

IPTp:

Intermittent preventative treatment in pregnancy

ITN:

Insecticide-treated net

MDA:

Mass Drug Administration

MiP:

Malaria in pregnancy

PBPK:

Physiologically-based pharmacokinetic

PK:

Pharmacokinetic

PPND:

Pre-/post-natal development

PRGLAC:

Task force on research specific to pregnant women and lactating women

SP:

Sulfadoxine-pyrimethamine

WEC:

Whole embryo culture

WOCBP:

Women of child-bearing potential

WONCBP:

Women of non-child-bearing potential

References

  1. WHO. World Malaria Report 2021. Geneva, World Health Organization, 2020. 2021. https://www.who.int/publications/i/item/9789240040496 Accessed 28 Jan 2022.

  2. Chico RM, Cano J. Devising a strategy for prevention of malaria in pregnant women in the Asia Pacific. Lancet Infect Dis. 2019;19:919–20.

    Article  Google Scholar 

  3. Dellicour S, Tatem AJ, Guerra CA, Snow RW, ter Kuile FO. Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study. PLoS Med. 2010;7:e1000221.

    Article  Google Scholar 

  4. Burki T. Triumph in China as it is certified malaria-free by WHO. Lancet Infect Dis. 2021;21:1220–1.

    Article  Google Scholar 

  5. WHO. Guidelines for malaria, Revision 1. Geneva, World Health Organization. 2021. WHO/UCN/GMP/2021.01 Rev.1. https://www.who.int/publications/i/item/guidelines-for-malaria. Accessed 28 March 2022.

  6. Feachem RGA, Chen I, Akbari O, Bertozzi-Villa A, Bhatt S, Binka F, et al. Malaria eradication within a generation: ambitious, achievable, and necessary. Lancet. 2019;394:1056–112.

    Article  Google Scholar 

  7. Rogerson SJ, Hviid L, Duffy PE, Leke RF, Taylor DW. Malaria in pregnancy: pathogenesis and immunity. Lancet Infect Dis. 2007;7:105–17.

    CAS  Article  Google Scholar 

  8. Desai M, ter Kuile FO, Nosten F, McGready R, Asamoa K, Brabin B, et al. Epidemiology and burden of malaria in pregnancy. Lancet Infect Dis. 2007;7:93–104.

    Article  Google Scholar 

  9. Rogerson SJ, Desai M, Mayor A, Sicuri E, Taylor SM, van Eijk AM. Burden, pathology, and costs of malaria in pregnancy: new developments for an old problem. Lancet Infect Dis. 2018;18:e107–18.

    Article  Google Scholar 

  10. Moore KA, Simpson JA, Scoullar MJL, McGready R, Fowkes FJI. Quantification of the association between malaria in pregnancy and stillbirth: a systematic review and meta-analysis. Lancet Glob Health. 2017;5:e1101–12.

    Article  Google Scholar 

  11. McGready R, Lee SJ, Wiladphaingern J, Ashley EA, Rijken MJ, Boel M, et al. Adverse effects of falciparum and vivax malaria and the safety of antimalarial treatment in early pregnancy: a population-based study. Lancet Infect Dis. 2012;12:388–96.

    CAS  Article  Google Scholar 

  12. Saito M, Briand V, Min AM, McGready R. Deleterious effects of malaria in pregnancy on the developing fetus: a review on prevention and treatment with antimalarial drugs. Lancet Child Adolesc Health. 2020;4:761–74.

    CAS  Article  Google Scholar 

  13. Walker PG, ter Kuile FO, Garske T, Menendez C, Ghani AC. Estimated risk of placental infection and low birthweight attributable to Plasmodium falciparum malaria in Africa in 2010: a modelling study. Lancet Glob Health. 2014;2:e460–7.

    Article  Google Scholar 

  14. Nosten F, McGready R, Simpson JA, Thwai KL, Balkan S, Cho T, et al. Effects of Plasmodium vivax malaria in pregnancy. Lancet. 1999;354:546–9.

    CAS  Article  Google Scholar 

  15. Brummaier T, Gilder ME, Gornsawun G, Chu CS, Bancone G, Pimanpanarak M, et al. Vivax malaria in pregnancy and lactation: a long way to health equity. Malar J. 2020;19:40.

    Article  Google Scholar 

  16. Saito M, Mansoor R, Kennon K, Anvikar AR, Ashley EA, Chandramohan D, et al. Pregnancy outcomes and risk of placental malaria after artemisinin-based and quinine-based treatment for uncomplicated falciparum malaria in pregnancy: a WorldWide Antimalarial Resistance Network systematic review and individual patient data meta-analysis. BMC Med. 2020;18:138.

    CAS  Article  Google Scholar 

  17. Al Khaja KAJ, Sequeira RP. Drug treatment and prevention of malaria in pregnancy: a critical review of the guidelines. Malar J. 2021;20:62.

    Article  Google Scholar 

  18. US Department of Health and Human Services. Task force on research specific to pregnant women and lactating women (PRGLAC). 2021. https://www.nichd.nih.gov/about/advisory/PRGLAC. Accessed 28 March 2022.

  19. ConcePTION. https://www.imi.europa.eu/projects-results/project-factsheets/conception. Accessed 28 March 2022.

  20. Saito M, Gilder ME, McGready R, Nosten F. Antimalarial drugs for treating and preventing malaria in pregnant and lactating women. Expert Opin Drug Saf. 2018;17:1129–44.

    CAS  Article  Google Scholar 

  21. WHO. Recommendations on antenatal care for a positive pregnancy experience. Geneva, World Health Organization. 2016. https://apps.who.int/iris/bitstream/handle/10665/250796/9789241549912-eng.pdf.

  22. Clark RL. Teratogen update: malaria in pregnancy and the use of antimalarial drugs in the first trimester. Birth Defects Res. 2020;112:1403–49.

    CAS  Article  Google Scholar 

  23. Dellicour S, Sevene E, McGready R, Tinto H, Mosha D, Manyando C, et al. First-trimester artemisinin derivatives and quinine treatments and the risk of adverse pregnancy outcomes in Africa and Asia: a meta-analysis of observational studies. PLoS Med. 2017;14:e1002290.

    Article  Google Scholar 

  24. Kloprogge F, Workman L, Borrmann S, Tékété M, Lefèvre G, Hamed K, et al. Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: a pharmacokinetic-pharmacodynamic meta-analysis. PLoS Med. 2018;15:e1002579.

    Article  Google Scholar 

  25. van Eijk AM, Hill J, Noor AM, Snow RW, ter Kuile FO. Prevalence of malaria infection in pregnant women compared with children for tracking malaria transmission in sub-Saharan Africa: a systematic review and meta-analysis. Lancet Glob Health. 2015;3:e617–28.

    Article  Google Scholar 

  26. Desai M, Hill J, Fernandes S, Walker P, Pell C, Gutman J, et al. Prevention of malaria in pregnancy. Lancet Infect Dis. 2018;18:e119–32.

    Article  Google Scholar 

  27. Taylor SM, Levitt B, Freedman B, Madanitsa M, Thwai KL, Kalilani-Phiri L, et al. Interactions between antenatal sulfadoxine-pyrimethamine, drug-resistant Plasmodium falciparum parasites, and delivery outcomes in Malawi. J Infect Dis. 2020;222:661–9.

    CAS  Article  Google Scholar 

  28. Gaudinski MR, Berkowitz NM, Idris AH, Coates EE, Holman LA, Mendoza F, et al. A monoclonal antibody for malaria prevention. N Engl J Med. 2021;385:803–14.

    CAS  Article  Google Scholar 

  29. Mordmüller B, Sulyok M, Egger-Adam D, Resende M, De Jongh WA, Jensen MH, et al. First-in-human, randomized, double-blind clinical trial of differentially adjuvanted PAMVAC, a vaccine candidate to prevent pregnancy-associated malaria. Clin Infect Dis. 2019;69:1509–16.

    Article  Google Scholar 

  30. Goncalves BP, Walker PG, Cairns M, Tiono AB, Bousema T, Drakeley C. Pregnant women: an overlooked asset to Plasmodium falciparum malaria elimination campaigns? Trends Parasitol. 2017;33:510–8.

    Article  Google Scholar 

  31. Yimam Y, Nateghpour M, Mohebali M, Abbaszadeh Afshar MJ. A systematic review and meta-analysis of asymptomatic malaria infection in pregnant women in Sub-Saharan Africa: a challenge for malaria elimination efforts. PLoS ONE. 2021;16:e0248245.

    CAS  Article  Google Scholar 

  32. Ayad M, Costantine MM. Epidemiology of medications use in pregnancy. Semin Perinatol. 2015;39:508–11.

    Article  Google Scholar 

  33. Illamola SM, Bucci-Rechtweg C, Costantine MM, Tsilou E, Sherwin CM, Zajicek A. Inclusion of pregnant and breastfeeding women in research—efforts and initiatives. Br J Clin Pharmacol. 2018;84:215–22.

    Article  Google Scholar 

  34. Shields KE, Lyerly AD. Exclusion of pregnant women from industry-sponsored clinical trials. Obstet Gynecol. 2013;122:1077–81.

    Article  Google Scholar 

  35. White NJ, McGready RM, Nosten FH. New medicines for tropical diseases in pregnancy: catch-22. PLoS Med. 2008;5:e133.

    Article  Google Scholar 

  36. Shibeshi W, Baye AM, Alemkere G, Engidawork E. Efficacy and Safety of artemisinin-based combination therapy for the treatment of uncomplicated malaria in pregnant women: a systematic review and meta-analysis. Ther Clin Risk Manag. 2021;17:1353–70.

    CAS  Article  Google Scholar 

  37. Saito M, Mansoor R, Kennon K, Anvikar AR, Ashley EA, Chandramohan D, et al. Efficacy and tolerability of artemisinin-based and quinine-based treatments for uncomplicated falciparum malaria in pregnancy: a systematic review and individual patient data meta-analysis. Lancet Infect Dis. 2020;20:943–52.

    CAS  Article  Google Scholar 

  38. Eke AC, Olagunju A, Momper J, Penazzato M, Abrams EJ, Best BM, et al. Optimizing pharmacology studies in pregnant and lactating women using lessons from HIV: a consensus statement. Clin Pharmacol Ther. 2021;110:36–48.

    Article  Google Scholar 

  39. van der Graaf R. New CIOMS guidelines on research with pregnant & breastfeeding women. UMC Utrecht Julius Center. 2016. https://gfbr.global/wp-content/uploads/2017/04/CIOMS-revision-pregnant-women-Rieke.pdf. Accessed 28 March 2022.

  40. Pan American Health Organization, WHO. Zika ethics consultation: ethics guidance on key issues raised by the outbreak. PAHO/KBR/16-002. 2017. https://iris.paho.org/bitstream/handle/10665.2/28425/PAHOKBR16002_engpdf?sequence=11&isAllowed=y. Accessed 28 March 2022.

  41. Food and Drug Administration. S5(R3) detection of reproductive and developmental toxicity for human pharmaceuticals guidance for industry. 2021. https://www.fda.gov/media/148475/download. Accessed 28 March 2022.

  42. Abduljalil K, Badhan RKS. Drug dosing during pregnancy-opportunities for physiologically based pharmacokinetic models. J Pharmacokinet Pharmacodyn. 2020;47:319–40.

    Article  Google Scholar 

  43. Zhang Z, Imperial MZ, Patilea-Vrana GI, Wedagedera J, Gaohua L, Unadkat JD. Development of a novel maternal-fetal physiologically based pharmacokinetic model. I: insights into factors that determine fetal drug exposure through simulations and sensitivity analyses. Drug Metab Dispos. 2017;45:920–38.

    CAS  Article  Google Scholar 

  44. De Sousa MM, Lui G, Zheng Y, Pressiat C, Hirt D, Valade E, et al. A physiologically-based pharmacokinetic model to predict human fetal exposure for a drug metabolized by several CYP450 pathways. Clin Pharmacokinet. 2017;56:537–50.

    Article  Google Scholar 

  45. Nauwelaerts N, Deferm N, Smits A, Bernardini C, Lammens B, Gandia P, et al. A comprehensive review on non-clinical methods to study transfer of medication into breast milk—a contribution from the ConcePTION project. Biomed Pharmacother. 2021;136:111038.

    CAS  Article  Google Scholar 

  46. Kaye DK. The moral imperative to approve pregnant women’s participation in randomized clinical trials for pregnancy and newborn complications. Philos Ethics Humanit Med. 2019;14:11.

    Article  Google Scholar 

  47. Clinical Trial Facilitation Group (CTFG). Recommendations related to contraception and pregnancy testing in clinical trials. 2014. https://www.hma.eu/fileadmin/dateien/Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf. Accessed 28 March 2022.

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Acknowledgements

We thank Dr Timothy Wells for critical feedback on this Commentary. We are grateful to all members of MMV Malaria in Mothers and Babies (MiMBa) group and MMV partners for their expert contributions to the proposal described here.

Funding

MMV receives funding and support from government agencies, private foundations, international organizations, corporate foundations, and private individuals (see http://www.mmv.org/ for details) including the Bill & Melinda Gates Foundation, the UK Foreign Commonwealth and Development Office, the EDCTP and UNITAID. MMV was reimbursed for tafenoquine development costs, paid from the proceeds of the US Priority review Voucher awarded to GSK. MMV is entitled to royalty payments on sales of paediatric Coartem dispersible outside of malaria-endemic countries and the public sector. The funders had no role in the preparation of this manuscript.

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All authors contributed equally to the conceptualisation and writing of the proposal for new approaches to discovery and development of antimalarials suitable for pregnant women described in this Commentary. All authors read and approved the final manuscript.

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Correspondence to Wiweka Kaszubska.

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El Gaaloul, M., Tornesi, B., Lebus, F. et al. Re-orienting anti-malarial drug development to better serve pregnant women. Malar J 21, 121 (2022). https://doi.org/10.1186/s12936-022-04137-2

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Keywords

  • Malaria in pregnancy
  • Equity in R&D
  • Inclusion of women
  • Antimalarial drugs
  • New medicines