Malaria in pregnancy: Modern approaches—Spotlight commmentary

Abstract

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.

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.

None to declare.