Drug treatment and prevention of malaria in pregnancy: a critical review of the guidelines

National and international malaria treatment guidelines were retrieved using PubMed Medical Subject Heading terms: “guidelines” and “malaria”. The Worldwide Web via Google was used with the following phrases: malaria treatment guidelines followed by the country name (e.g., Angola, Thailand) or organizations such as WHO, US Centers for Disease Control and Prevention (US CDC) and President’s Malaria Initiatives (PMI)-Malaria Operational Plans (MOP). The data analysis was limited to publications, literature and reports from December 2012 onwards about 2 years after the release of the second edition of WHO Guidelines for Treatment of Malaria [14]. It was assumed that 2 years would suffice for guideline dissemination and for countries to adopt WHO Guidelines.

Updated national guidelines emerged 2012 onwards and PMI-MOP reports for 2018–2019 published in English were included. Based on WHO regional classification [15], countries from Africa, Eastern Mediterranean, Southeast Asia, and Western Pacific regions known to have the highest estimated malaria prevalence were included. National guidelines/PMI-MOP reports written in languages other than English, guidelines published before 2012, and Pan-American Health Organization (PAHO) countries were excluded.

Except for malaria chemoprevention in pregnancy, there was no significant difference between the 3rd [1] and 2nd [14]. WHO Guidelines recommendations reported with regard to first-line treatment in uncomplicated and complicated falciparum malaria in all trimesters of pregnancy (Table 2). Since national guidelines in Malaysia (2013) and national guidelines in both India and Sri Lanka (2014) were published 1–2 years ahead of the 2015 WHO Guidelines [1] and 3–4 years after publication of the 2010 WHO Guidelines [14], both WHO Guidelines editions were used in this review (Table 2).

According to WHO recommendations on treatment of chloroquine-resistant falciparum malaria in pregnant women, the primary outcome measures evaluated were: (1) first-line drugs for treating either uncomplicated or complicated (severe) malaria infection during any trimesters of pregnancy; (2) IPTp-strategy with SP combination, guidance on folic acid supplementation and concomitant IPTp-SP with cotrimoxazole in HIV-positive pregnant women.

The authors independently carried out an assessment of outcome measures in a non-blinded standardized manner. Any discrepancy was resolved in consultation with another clinical pharmacologist.

PMI is a US Government initiative, one of the largest international sources of funding to control and eradicate malaria in PMI-supported countries. PMI works in partnership with host-country governments in SSA and GMS to: (a) provide effective therapeutic and prophylactic intervention to those at risk of malaria; (b) develop annual MOPs; and, (c) complement and expand malaria monitoring and evaluation strategies [16].

Contrary to WHO recommendations [1], oral quinine monotherapy instead of quinine plus clindamycin regimen was adopted by 23/35 (65.7%) guidelines/reports as first-line treatment for uncomplicated falciparum malaria in the first semester of pregnancy (Table 2).

As first-line treatment, artemether-lumefantrine (AL), an SPC, was the most common artemisinin-based combination recommended by 26/35 (74.3%) guidelines for treating uncomplicated malaria in second and third trimesters, and as the preferred option for completing treatment following parenteral artesunate/quinine for complicated malaria in second and third trimesters. The proportion of national guidelines/PMI reports that adopted oral quinine or quinine plus clindamycin for completing of initial parenteral quinine for complicated malaria in first trimester was 12/35 (34.3%) and 3/35 (8.6%), respectively (Table 2).

Intravenous artesunate has been approved by 18/35 (51.4%) and 31/35 (88.6%) of guidelines/reports for treating severe malaria in early (first trimester) and late (second and third trimesters) of pregnancy, respectively (Table 2).

Of the 23 guidelines/PMI reports to implement IPTp-SP strategy, emphasis on DOT was overlooked by 8 (34.8%). The standard dose of folic acid (400 µg daily) recommended by WHO Guidelines was adopted by 18/23 (78.3%) of SSA countries that implemented IPTp-SP strategy (Table 2). Of note, 17/23 (73.9%) did not include an explicit warning of adverse events potential if concomitant cotrimoxazole prophylaxis is used in HIV-positive pregnant women.

The national guidelines and PMI reports of several representative SSA and GMS countries recommend quinine monotherapy for 7 days as the preferred regimen, administered under full supervision, for treating uncomplicated malaria during first trimester (Table 2). The use of quinine alone is contrary to WHO Guidelines, which strongly recommend quinine in combination with clindamycin for 7 days [1]. Although quinine at the recommended dose is considered safe in first trimester [1], quinine use in pregnant women is associated with drawbacks [17, 18]. The clearance of quinine is increased in pregnant women compared to non-pregnant women [19, 20]. Meta-analysis findings of five randomized trials in pregnant women revealed that a 7-day course of quinine monotherapy was linked with a slower rate of malaria parasite clearance and higher rate of gametocyte carrier emergence risk compared to ACT [21] or quinine plus clindamycin regimens [17, 22, 23].

The gametocidal activity of quinine against falciparum malaria has been reported to be sub-optimal to prevent transmission in endemic areas [18, 24]. Nausea and vomiting often associated with quinine may exacerbate morning sickness [25]. A 7-day course of oral quinine should be administered under full supervision because of poor tolerability that may compromise patient compliance resulting in treatment failure [17, 26‐29]. Nonetheless, the reviewed data suggest a trend towards quinine monotherapy by two-thirds of national guidelines, although robust evidence supports the need to combine quinine with clindamycin. In real-world settings, a combination of oral quinine plus clindamycin for a 7-day treatment course has been reported to improve the therapeutic efficacy against multidrug-resistant P. falciparum in first trimester of pregnancy and to reduce the risk of therapeutic failure [22, 23, 26].

Moreover, this combined regimen is considered important in children and pregnant women in whom the use of doxycycline, the slow-acting partner schizonticide, is contra-indicated [26]. The explanation for quinine plus clindamycin regimen under-use is most likely the cost in endemic areas with resource constraints [22, 26]. Using International Medical Products Price Guide [30], the estimated current average cost of quinine plus clindamycin regimen (administered twice daily for 7 days) was equal to $4.05–5.95 (Table 3) in contrast to $18.5 for combined regimen [22] and $15.0 for clindamycin alone [26], reported two decades ago. These cost differences are because the estimated treatment cost was based on the supplier/buyer average price of generic clindamycin. In contrast, the treatment cost reported in previous studies [22, 26] was based on the price of proprietary clindamycin (Dalacin C). A meta-analysis of seven randomized controlled trials has affirmed that the quinine plus clindamycin regimen was safe and rarely associated with severe adverse events [23]. Perhaps neither the cost of such regimen nor adverse effects are the reasons for not recommending them by some guidelines/PMI reports. Treatment regimen complexity, including the duration, frequency of dosing, number of pills prescribed (Table 3), and poor tolerability by pregnant women with uncomplicated malaria who may require full supervision, are more likely barriers to universal endorsement of quinine plus clindamycin regimen. This controversy can be resolved by revising WHO Guidelines to include ACT as a first-line treatment option for uncomplicated malaria in first trimester as recommended by the WHO Malaria Policy Advisory Committee [31] based on growing evidence on artemisinin safety [32‐35]. US-CDC updated recommendation in 2018 states that during first trimester of pregnancy falciparum malaria should be treated with the currently available options of either mefloquine or quinine plus clindamycin. However, when neither of these options is available, AL should be considered for treatment [36].

In 2006, WHO [37] recommended the use of ACT, including AL, artesunate–amodiaquine (AS–AQ), and artesunate–mefloquine (AS–MQ), to treat uncomplicated falciparum malaria in second and third trimesters, but not during first trimester, until safety data becomes available. Except for dihydroartemisinin–piperaquine (DHA–PPQ) combination, ACT was considered first-line treatment in second and third trimesters [14]. In 2015, WHO recommended the use of ACT, including DHA–PPQ, as first-line treatment in second and third trimesters [1]. More recent data from SSA and many GMS countries confirm that exposure to ACT (AL or artemisinin derivatives) were not associated with adverse pregnancy outcomes during first trimester [32‐36, 38] as well as in second and third trimesters [25, 32, 36, 38‐41]. Adverse effects of AL, such as asthenia, poor appetite, dizziness, nausea, and vomiting, occur significantly less often with AL compared to other ACT [42]. In addition to WHO recommendations [1], several guidelines of non-endemic-malaria countries have adopted AL as the preferred treatment option for falciparum malaria in second and third trimesters [36, 43‐46].

Among artemisinin-based combinations recommended by the WHO [1], AL as first-line choice has been widely recommended by approximately three-quarters of guidelines/PMI reports for treatment of uncomplicated and complicated falciparum malaria in second and third trimesters, both in endemic and non-endemic regions (Table 2). This finding harmonizes with the recent World Malaria Report for treating uncomplicated confirmed falciparum malaria in the general population [15]. As first-line treatment, AL is recommended in 24 of 46 (52%) SSA countries and 11 of 20 (55%) Southeast Asian and Western Pacific countries, respectively [15]. The extensive use of AL is due to efficacy, safety, moderate cost (compared to other ACT; Table 3); availability as a flavoured, dispersible, paediatric formulation is a distinct advantage for infants, toddlers and preschool children [47]. However, in countries, such as Cambodia where ACT resistance is a problem, national guidelines for first-line therapy need to be updated regularly because of emergent AS–MQ resistance and treatment failure. A recent randomized clinical trial carried out in Bangladesh, Cambodia, Laos, Burma, and the Democratic Republic of Congo has affirmed the safety of triple ACT, such as DHA–PPQ plus mefloquine versus AL plus amodiaquine, might provide effective treatment and delay emergence of multidrug anti-malarial resistance [48].

Sub-optimal exposure to lumefantrine, the partner component of artemether in AL (SPC) that may compromise therapeutic efficacy, is a concern with a 3-day course of AL in treating malaria during late pregnancy [49, 50]. The plasma concentrations of lumefantrine treatment were approximately 20% less in pregnant than in non-pregnant women [50], due to pregnancy-related physiological changes in drug absorption, and biotransformation (primarily due to altered hepatic cytochrome P450 isoenzymes), and increased apparent volume of drug distribution [11]. Prolonging AL treatment duration from the recommended twice daily for 3-days regimen to the extended 5-days regimen (twice daily for 5 days) was associated with acceptable tolerability and adequate safety. It enhanced overall lumefantrine exposure during late trimesters of pregnancy [49, 50] and among the general population in artemisinin resistance-emergent regions [51]. Further clinical trials evaluating the 5-days extended AL regimen for malaria treatment are awaited [50].

The oral bioavailability of lumefantrine, a lipophilic drug, is enhanced if it is administered along with milk or fat-rich meal [1]. Fat-rich food increased the bioavailability of artemether and lumefantrine by threefold and sixfold, respectively [52]. The therapeutic concentration of lumefantrine must be sustained for four 48-h asexual life cycles of P. falciparum and to be at least twice the minimum parasiticidal concentration on day 7 after the start of treatment in order to optimize the cure rates and to reduce the emergence of resistance and early stages of gametocyte development [53]. Ingestion of a fat-rich diet to enhance AL oral bioavailability has received little attention by most of the national guidelines/PMI reports (Table 2). Except for Ethiopia [54], Saudi Arabia [45], South Africa [46], and Sri Lanka [55], the vast majority of national guidelines have not addressed this crucial issue, an essential factor for ensuring lumefantrine plasma concentrations up to day 7 of treatment.

Severe malaria in pregnancy needs a fast-acting and very effective treatment to save the mother’s life so that the risk/benefit equation overcomes any concerns about the safety of parenteral AS. Artesunate is first-line anti-malarial drug recommended for treatment of complicated (severe) malaria in all trimesters of pregnancy by international guidelines [1, 56], based on evidence from various studies [17, 18, 28]. In contrast to quinine, artesunate had shorter parasite clearance time and lower gametocyte carriage rate in falciparum malaria [57]. Artesunate is well tolerated [58] and has a better safety profile on the risk of miscarriage [33, 58] or significant congenital malformations [33] if administered during pregnancy compared to quinine. Unlike quinine, artesunate does not require an initial loading dose in severe malaria [1]. Moreover, quinine is associated with a higher risk of hypoglycaemia compared to artesunate, particularly in second and third trimesters, which may be refractory to intravenous glucose and may even be fatal [18, 28].

Whereas 18 of 35 (51.4%) of the reviewed guidelines/PMI reports have adhered to international guidelines regarding intravenous artesunate as a first-line option for treating complicated malaria in first trimester of pregnancy [1, 56], almost all guidelines have adopted intravenous artesunate for treating complicated malaria in the second and third trimesters. The guidelines for Benin [54] and Sudan [59] recommend either parenteral quinine or artesunate whereas in Cote d’Ivoire [54] parenteral quinine is recommended to treat complicated malaria during second and third trimesters. Paradoxically, however, in Cote d’Ivoire [54] parenteral artesunate is recommended for complicated malaria in general population. However, severe and refractory quinine-induced hypoglycaemia is more likely to occur in late than early trimesters [1], unless parenteral quinine is administered concomitantly along with glucose. The reluctance of some guidelines to recommend artesunate for treating complicated malaria in the first trimester can be attributed to safety risk controversy over artesunate; quinine during early trimester is associated with potentially less hypoglycaemic risk than during late trimesters [1]. Moreover, drug cost seems to be a deterrent for not recommending artesunate, since intravenous artesunate per treatment course costs $22.92 compared to $5.04 for intravenous quinine (Table 3). High drug cost is an impediment, especially in countries with limited healthcare budgets.

Based on robust evidence, WHO [8, 9] has proposed the IPTp strategy to mitigate adverse effects of malaria on maternal and fetal outcomes. IPTp should be implemented in malaria-endemic regions with high (stable) transmission as in Africa, where falciparum malaria is more prevalent. The IPTp policy requires that SP is administered to pregnant women (regardless of whether malaria parasites are identified in peripheral blood film or otherwise) at each scheduled antenatal visits starting as early as possible at the beginning of the second trimester around 13th week of gestation. Subsequent doses are to be administered at monthly intervals until delivery. The IPTp-SP strategy should be implemented as DOT of three SPC tablets (each tablet containing 500 mg/25 mg SP) [1, 8], administered by attending healthcare personnel as an integral component of antenatal care. DOT requirement of IPTp-SP policy is a vital strategy to ensure that the full preventive dose (i.e., three SPC of SP) is indeed ingested. Among 23 African countries that are required to implement IPTp-SP, the DOT requirement has not been explicitly stated in 8 (37.8%) national guidelines/reports, including that of Angola [54], Benin [54], Ghana [54], Liberia [54], Madagascar [54], Sierra Leone [54], Zambia [54], and Somalia [60] (Table 2). Although several guidelines adopt the DOT approach, its implementation in real-world practice is uncertain. Recently, poor adherence to DOT has been reported in Kenya, Nigeria and Tanzania, although DOT has been explicit in malaria guidelines of these countries [61]. National malaria plans of Ethiopia [54], South Africa [46] and Sudan [59] do not include IPTp-SP strategy as a part of their national malaria plans because of the relatively low intensity of malaria transmission in these countries, and in Rwanda due to increased parasite resistance to SP [54]. Antenatal healthcare providers should carefully adhere to the recommended DOT policy to ensure that the IPTp-SP strategy is effectively implemented. It is worth noting that WHO has not recommended IPTp strategy in countries with low transmission or high SP resistance, which is a gap in care for pregnant women, and involves other strategies, such as frequent testing and treating.

The requirement to administer daily dose of folic acid in the IPTp-SP strategy merits further attention. The recommended dose of folic acid in early pregnancy (400 µg daily) along with iron is for prevention of maternal anaemia. However, women with high risk or family history of neural tube defects should receive 5000 µg (5 mg) daily instead, to prevent neural tube defects, ideally administered before pregnancy, but if in first trimester when it would not conflict with IPTp since it is not recommended in the first trimester. The therapeutic dilemma over folic acid is among those women who have severe anaemia, especially associated with risk of severe malaria, who may require iron and higher dose of folic acid in excess of the usual recommended dose; WHO Guidelines are not clear on how this should be managed. According to WHO recommendations [8], folic acid supplement at a dose of 400 µg daily should be administered to pregnant women on IPTp-SP since it assures desired benefits without compromising IPTp-SP effectiveness. However, dose ≥ 5000 µg per day should be avoided because it antagonizes the anti-malarial efficacy of folate antagonists (SP) by pharmacodynamic antagonism [8, 62]. Almost all guidelines/PMI reports that adopted IPTp-SP strategy in their national guidelines have adhered to the WHO-recommended dose of folic acid, except for Angola [54], Cameroon [54] and Mozambique [54] PMI reports, which advocate ≥ 1000 µg daily. The guidelines need to be clear on moderate and severe anaemia, which is common in pregnant women especially in Asia where higher doses of folic acid may be justified along with other interventions, such as de-worming and vitamin A supplementation.

Falciparum malaria in pregnancy causes several harmful severe effects on maternal and fetal outcomes. WHO IPTp-SP strategy is recommended to prevent or mitigate malaria-related outcomes [8]. In pregnant women, HIV infection is associated with a significant increase in the prevalence of malaria [63, 64]. In HIV-positive pregnant women, cotrimoxazole prophylaxis is required to prevent Pneumocystis jirovecii opportunistic infection [65]. Of note, IPTp-SP strategy is inappropriate in HIV-infected pregnant women who are already on cotrimoxazole prophylaxis to avoid the exacerbation risk of sulfonamide-related adverse effects, especially severe cutaneous reaction [66]. WHO IPTp-SP strategy remains valid even in areas where quintuple mutations linked to SP resistance are prevalent in P. falciparum [9]. However, a recent meta-analysis showed that IPTp-SP might not be effective in areas where the prevalence of sextuple mutation is common, and alternative strategies to replace IPTp-SP is a pressing research priority to control malaria in pregnancy [67]. Therefore, it may be arguable whether WHO IPTp-SP strategy remains valid. DHA–PPQ is a valuable alternative to replace SP in IPTp [68], and more recent meta-analysis data have confirmed that previous concerns about repolarization-related cardiotoxicity need not limit its use for the prevention and treatment of malaria [69]. However, concurrent use of cotrimoxazole and DHA–PPQ is best avoided. Moreover, cotrimoxazole prophylaxis has been demonstrated to be non-inferior to WHO IPTp-SP strategy in pregnant women with HIV regarding infant mortality, LBW, placental malaria, maternal death, and treatment-limiting adverse events [70]. Despite the clinical importance of IPTp-SP contra-indication in such patients, this therapeutic issue has received scant attention in several guidelines. Seventeen of 23 (73.9%) PMI reports stating IPTp-SP policy, do not provide guidance on adverse consequences of drug–drug interactions between SP and cotrimoxazole (Table 2). Although more than one million HIV-positive women at risk of contracting malaria become pregnant every year in SSA countries, such as Kenya, Malawi, Mozambique, Tanzania, and Zambia [71], the national guidelines of these countries have overlooked and never addressed this important public health issue (Table 2).

First, non-inclusion of several national guidelines of Eastern Mediterranean and Asian countries known to be endemic with malaria such as Yemen, Syria, Iran, Iraq, Pakistan, and Afghanistan; second, non-inclusion of Francophone countries in North Africa, and Hispanophone and Lusophone countries of PAHO in Central and South America eliminated the national guidelines of many countries with high malaria prevalence.