Malaria in pregnancy: Modern approaches—Spotlight commmentary

This is the authors' abstract. We don't add key points for this paper.

In 2022, there were an estimated 249 million malaria cases across 85 countries and regions endemic to malaria, marking a rise of 5 million cases compared with 2021.1 Though there have been significant advances in malaria treatment in the last 15 years, it can still be considered a neglected tropical disease (NTD) despite not appearing on the formal WHO NTDs list, as emphasized by Bournissen et al. (Br J Clin Pharmacol 2022).2 The vast majority of global malaria cases and fatalities occur in Africa. Certain groups, including people with HIV, pregnant women and children under the age of five, face the greatest susceptibility to severe malaria infections. In sub-Saharan Africa, an estimated 12.7 million pregnant women are exposed to malaria during gestation, representing a third of all pregnancies in the region—this represents an increase of 0.7 million from the previous year,1 possibly representing lingering ill effects of the COVID-19 pandemic on health services. Malaria infection during pregnancy contributes to almost 1 million low birth weight deliveries each year, and it is estimated that that number could be cut in half by intermittent preventive treatment of malaria in pregnancy (IPTMp).1 We will highlight several recent papers published in the British Journal of Clinical Pharmacology addressing malaria in pregnancy, with a focus on Plasmodium falciparum (which sequesters in the placenta and therefore causes the highest morbidity and mortality in pregnancy of all strains), exploring key insights and advancements in prevention and treatment strategies, and prevailing guidance. Pregnant women have a well-documented increased susceptibility to malaria due to altered immune responses and physiological changes. Histological examinations of placentas infected with P. falciparum have unveiled a spectrum of vasculo-placental irregularities. These anomalies encompass augmented perivillous fibrinoid accumulations, compromised integrity of the syncytiotrophoblast, thickening of the trophoblast basal lamina, escalated formation of syncytial knots and the aggregation of mononuclear immune cells within intervillous spaces.3 In addition, once a malaria parasite has entered a placental cell, the cell expresses a pregnancy-specific surface antigen called the VAR2CSA protein, which is not recognized by the immune system, contributing to parasite immune evasion, dense placental sequestration (when it attaches to chondroitin sulphate A in the intervillous space) and pregnancy-associated increased susceptibility. Together, these changes contribute to the emergence of placental insufficiency, intrauterine growth restriction, preterm delivery and instances of low birth weight from malaria in pregnancy.4 The epidemiology bears out this increased susceptibility in pregnancy, and there are worrisome upward trends despite public health efforts. For example, data from Ghana's District Health Information Management System (DHIMS II) show that in spite of the augmentation of strategies aimed at controlling malaria during pregnancy such as the implementation of intermittent preventive treatment utilizing sulfadoxine-pyrimethamine (IPTp-SP), the distribution and utilization of insecticide-treated nets (ITNs), routine folate and iron supplementation, and the prompt and efficient management of cases within the framework of antenatal care (ANC), there have been slight upward trajectories observed in the prevalence of maternal anaemia and instances of low birth weight over the past decade.3, 5, 6 A significant element contributing to this disheartening data is the inadequacy of public health infrastructure, coupled with an underdeveloped pharmacovigilance system. This deficiency results in poor education around and limited accessibility of malaria-specific interventions in pregnancy.6 The perception of being at low risk further decreases people's enthusiasm for medication uptake, compounded by unreliable or unavailable information regarding the true efficacy and safety of drug regimens, particularly in pregnancy.7 Pre-exposure prophylaxis has been hailed as a significant advance for HIV, but uptake and utilization may lag in many high burden settings for individual (e.g., low risk perception) and systemic (e.g., cost and accessibility) reasons. Similar preventive strategies are currently available as part of the toolkit of defence against malaria, potentially with similar uptake barriers and a different risk–benefit balance depending on whether the pregnant person is living in a high transmission area or a low transmission area. Intermittent preventive treatment in pregnancy (IPTp) is chief among them, as it is specifically targeted to pregnant women living in areas where malaria is endemic and offers the option to prevent/abrogate effects of maternal malaria on the developing foetus. IPTp involves the administration of antimalarial medication to pregnant women living in hyperendemic or holoendemic regions at defined intervals during their pregnancy, regardless of whether they are infected with the malaria parasite or showing symptoms of the disease. The primary objective of IPTp is to reduce adverse outcomes associated with malaria infection during pregnancy, such as maternal anaemia, low birth weight, preterm delivery and foetal demise/stillbirth. The most commonly used drug for IPTp is sulfadoxine-pyrimethamine (SP). SP is given as a single dose or multiple doses, at specific time points during pregnancy. The timing and number of doses can vary based on regional guidelines and recommendations from health authorities. There is no convincing evidence that SP at therapeutic doses causes an increased risk of abortion, stillbirth or malformation at therapeutic doses in humans.8 However, the emergence of resistance to SP has prompted the integration of new medications in IPTp regimens.9 Mefloquine, already widely used to treat malaria in pregnancy worldwide (though not as monotherapy), is one alternative in the realm of prevention, as evidenced by favourable outcomes recently demonstrated in Kisangani, Democratic Republic of Congo, an area of widespread SP resistance. A randomized, controlled trial by Labama Otuli N et al. (Br J Clin Pharmacol 2021) compared split-dose mefloquine (separated by a meal to enhance tolerability) to four doses of SP in pregnancy and found comparable tolerability between the two regimens but superior efficacy of mefloquine, with reduced risk of placental malaria, maternal parasitaemia and low birth weight infants.10 This is in accordance with numerous other studies reporting good tolerability of mefloquine. Although both SP and mefloquine are designated as safe for use in all trimesters according to the CDC, some older data suggests a marginal uptick in abortion occurrences among pregnant women taking mefloquine (which is known to cross the placenta) during the first trimester.8 It is important to note, however, that adherence is difficult to ensure in observational studies and that the foetal effects of maternal malaria itself include increased stillbirth and miscarriage. There has been overall reassuring data of mefloquine safety in pregnancy, and its pharmacokinetics do not appear to change in pregnancy. Currently, ACTs are the preferred pharmacological approach for addressing severe malaria worldwide. In pregnancy, ACTs are poised to extend their role from the recommended approach during the second and third trimesters of pregnancy to the recommended approach throughout pregnancy (including the first trimester). A recent review (Kiguba R et al. [Br J ClinPharmacol 2023]) documented that factors such as insufficient documentation of antimalarial resistance, coupled with the notable prominence of antimalarials within the category of substandard and falsified (SF) medical products in Africa, play a significant role in poor uptake of antimalarials.7 Out of 15 studies conducted across four East African countries, it was found that 24% of antimalarials did not meet at least one quality standard. This failure rate is significant and may contribute to a notable proportion of malaria-related deaths resulting from ineffective treatment.11 Even if malaria education were completely optimal, drugs that do not work—either because they are wrongly given in the setting of widespread resistance to them, as in the case of chloroquine, or because they are fake—do not inspire confidence. In addition, while ACT therapy may not be deemed cost-prohibitive in many Western nations, its affordability remains a significant barrier in developing countries. National healthcare strategies should prioritize measures to enhance accessibility and affordability of these drugs, particularly as the populations with the highest malaria burden often comprise the poorest individuals. Epidemiological initiatives could potentially integrate comprehensive programmes encompassing malaria and other infectious diseases, such as HIV, within communal diagnostic and treatment frameworks. However, establishing a robust pharmacovigilance network in these regions presents considerable challenges, attributed to deficiencies in various areas, including information dissemination, infrastructure, drug quality assurance, follow-up mechanisms and overall coherence of the system.12 The overall economic burden of malaria escalates when the disease is not promptly treated, as the disparity in costs (narrowly and broadly defined) between severe and mild cases far exceeds the differences in price between effective and ineffective drugs. The treatment landscape for severe malaria, both in general and during pregnancy, has been substantially improved in the past decade, largely owing to the implementation of ACTs, which have diminished mortality and are safe and well tolerated. However, the widespread adoption of ACTs is at the present moment confronted by a rising challenge: the emergence of artemisinin resistance. To mitigate this concern, the use of preventive antimalarials with diverse mechanisms of action, such as SP or 8-aminoquinolines, becomes a key strategy to mitigate resistance, along with combining artemisinin with other slowly eliminated antimalarials—triple ACTs (TACTs). These include artemether-lumefantrine-amodiaquine and dihydroartemisinin-piperaquine-mefloquine combinations. Other new potential approaches include boosting artemisinin activity with drugs like carfilzomib (a proteasome inhibitor used in multiple myeloma treatment that offers proof of concept but has not been studied in pregnancy and may be difficult to access in endemic settings) as well as the formulation of new artemisinin derivatives such as artefenomel (for which the same is true). The data vacuum for these two novel therapeutics in pregnancy highlights well-documented challenges related to excluding pregnant women from clinical trials—assessment of the risk–benefit balance is difficult with no clinical data, even when preclinical data suggests limited risk in pregnancy. (And, as highlighted by the example of the artemisinins, risk–benefit balance in human pregnancies may well not correlate with preclinical evidence of embryotoxicity in animal species.) Furthermore, it is crucial to ensure the availability of and access to high-quality medications and foster a heightened awareness of the threat to global health that malaria represents, even within regions where the disease has lower degrees of endemicity, such as Asia and the Americas. As highlighted in a recent paper by Hanboonkunupakarn B et al. (Br J Clin Pharmacol 2022), a concerted effort is required that aims to collectively address the multifaceted dimensions of malaria prevention, treatment and resistance mitigation.13 While there are a few distinctions between the African countries, most of the national guidelines advocate a similar approach. The majority advocate for oral quinine in combination with clindamycin as the primary therapeutic approach for addressing uncomplicated malaria during the first trimester. For complicated malaria in the first trimester, most recommendations include artesunate with parenteral quinine.14 In contrast, during the second and third trimesters, the artemether-lumefantrine or artesunate-amodiaquine combination is generally the preferred choice for managing both uncomplicated and complicated malaria cases. Preventive regimens such as intermittent treatment during pregnancy with SP or mefloquine are recommended by most guidelines.14 In prevailing UK malaria guidelines (2016) and the aforementioned recommendations in African countries, quinine in combination with clindamycin has long been considered to be first line therapy for managing uncomplicated P. falciparum malaria during pregnancy.15 Regarding the first-trimester safety of the quinine + clindamycin regimen, observational data involving pregnant women with malaria treated with quinine during the first trimester have not yielded evidence of a heightened incidence of congenital anomalies attributable to quinine administration. However, several studies have found a relatively elevated occurrence of miscarriage and stillbirth among pregnant women taking quinine in comparison to those opting for ACT.8 It is crucial to note that these findings may not suggest foetal toxicity linked to quinine usage; rather, they may be attributed to the downstream consequences of less effective control of malaria infection. In fact, the quinine derivative hydroxychloroquine, commonly employed in the management of systemic lupus erythematosus (SLE), has been found to have a favourable safety profile throughout pregnancy and has been used in the prevention of preeclampsia and recurrent miscarriages from SLE and other vasculo-placental disorders, based on a recent review by Moreuil C et al. (Brit J ClinPharmacol 2020).16 Its use in pregnant women for the prevention and treatment of non-chloroquine-resistant forms of malaria can therefore be considered. Clindamycin, the other component of the recommended malaria treatment regimen in pregnancy, is considered safe for use in pregnancy by the WHO (pregnancy category B). Change may be on the horizon—ACT, which is the first-line treatment choice for malaria during the second and third trimesters of pregnancy, is now being more extensively explored and considered as a potential treatment during the first trimester. A 2023 Lancet systematic review and individual patient data meta-analysis revealed thatartemether–lumefantrine treatment during the first trimester was associated with a reduced occurrence of unfavourable pregnancy outcomes compared with quinine-based treatment, and there were no adverse pregnancy outcomes associated with artemisinin-based treatment (ABT) in the first trimester of pregnancy.17 The conclusion of this systematic review and individual patient data meta-analysis was that ABT (particularly artemether-lumefantrine) should be preferred over quinine and clindamycin for malaria treatment in the first trimester of pregnancy, on the basis of stronger efficacy and comparable safety. Artemether-lumefantrine currently holds a WHO pregnancy category C classification, a designation established using information from its 2009 approval. However, more than a decade of accumulated data necessitates a re-evaluation of this categorization to accurately reflect the current understanding. There is a notable disconnect between preclinical embryotoxicity studies of antimalarials (most of which demonstrate embryotoxic effects in at least one animal species, sometimes with an animal:human exposure ratio < 1) and data from first-trimester human exposures (in which there has been no conclusive evidence of foetal harm in over a thousand cases of first trimester exposure). Non-artemisinin antimalarials exhibit embryotoxic effects in preclinical studies, ranging from embryonic loss to musculoskeletal malformations, with clindamycin being an exception. Artemisinin derivatives have also been linked to embryo deaths, as well as heart and musculoskeletal anomalies, in more than one animal species.8, 18 It is now understood that the preclinical work overestimated foetal harm of artemisinins in a manner not recapitulated in humans, prompting the recent WHO recommendation that artemether-lumefantrine and artesunate be used in the first trimester of pregnancy for the treatment of uncomplicated and complicated malaria, respectively. There is a notable dearth of clinical studies investigating the pharmacokinetics and pharmacodynamics of antimalarial drugs specifically during pregnancy. Physiologic changes (including increased plasma volume, changes in total body water and fat, increases in cardiac output and glomerular filtration rate, decreased protein binding, slowed GI transit, higher gastric pH and changes in metabolizing enzymes) may affect the PK of antimalarials in pregnancy. Likewise, immunologic changes in pregnancy (to prevent rejection of the foetus) can affect malaria susceptibility, disease burden and pharmacodynamics. Most available data indicate reduced plasma concentrations of antimalarial drugs due to increased volume of distribution in pregnant individuals, but no dosing guidance on dose adjustment in pregnancy exists, posing challenges for providers in determining appropriate dosages in this setting. As a result, pregnant women often receive the same drug doses as non-pregnant individuals, underscoring the complexities of treatment optimization in this population.19 At present, the WHO recommends two malaria vaccines: R21 and RTS,S/AS01. These vaccines target P. falciparum, the most lethal malaria parasite globally, which predominates in Africa. Favourable results from vaccine trials in young children have led to WHO prequalification and plans for broader implementation beginning in 2024. As they are safe and efficacious in children, their use could reasonably be extended to pregnant individuals. However, neither vaccine is currently approved for use in pregnancy due to the omission of pregnant individuals from these vaccine trials (which enrolled only children under 5 years of age), leading to a gulf between the proven efficacy of vaccines and pregnant individuals' ability to access and benefit from them. It is quite possible that, if a vaccine was found to be safe and effective, the risk–benefit ratio would favour vaccination in pregnancy over IPTp. The potential value of vaccinating pregnant mothers could be amplified if the vaccine also provided protection to their infants via transplacental antibody transfer; placental malaria vaccines (most targeting the aforementioned VAR2CSA protein) have been studied in the first trimester of pregnancy and have shown promise but are not yet available. Importantly, as access to healthcare, therapeutics, preventives and vaccines lags, strategies such as vector control can help circumvent the need for some of these approaches. In conclusion, malaria remains a significant global health challenge, with its brutal impact magnified in pregnancy and early childhood. Despite commendable advances in malaria therapeutics over the last 15 years, it continues to be in many important senses a NTD. Addressing the complex challenges posed by malaria in pregnancy requires a combination of improved public health infrastructure, expanded pharmacovigilance systems, revisited and updated evidence-based guidelines, and innovative strategies to improve therapeutics and uptake and combat antimalarial resistance. Through collaborative efforts between healthcare providers, researchers, drug developers, policymakers and communities, we can strive to reduce the burden and terrible toll of malaria on global maternal health. Both co-authors participated equally in writing the manuscript. Permission to reproduce material from other sources/permission has been obtained to use any copyrighted material and the source of the material has been acknowledged. None to declare.