Background
Falciparum malaria is an important cause of maternal anaemia, intra-uterine growth retardation, intrauterine death, stillbirth, premature delivery, low birth weight (LBW), perinatal and neonatal morbidity and mortality [
1‐
5] and postpartum morbidity [
6‐
8]. In sub-Saharan Africa, poor nutrition, micronutrient imbalances (particularly vitamin A, zinc, iron and folate)[
1], HIV co-infection [
9‐
12], poverty and limited access to effective primary health care and emergency obstetric services [
13‐
15] exacerbate the impact of pregnancy-associated malaria.
In areas of high or moderate transmission, most malaria infections in pregnant women are asymptomatic and infected women do not present for treatment. In such areas, the World Health Organization recommends a combination of interventions to prevent malaria in pregnancy including insecticide-treated bednets (ITNs), intermittent preventive treatment in pregnancy (IPTp) and effective case management and treatment[
16,
17]. A small number of randomized controlled trials and prospective studies conducted in Kenya[
18,
19] and Malawi[
20,
21] in the 1990s demonstrated the efficacy, safety and cost-effectiveness[
22] of sulphadoxine-pyrimethamine (SP) IPTp in preventing maternal anaemia and LBW. The results of these studies led to a recommendation by the World Health Organization that, in areas of medium or high malaria transmission, IPTp with SP should be given on at least two occasions following quickening[
17]. Many countries in sub-Saharan Africa have subsequently introduced SP-IPTp into national malaria control programmes [
23‐
25], but levels of coverage are still only modest in most. Although strenuous efforts are being made to increase coverage levels with SP IPTp, its effectiveness is being threatened by increasing levels of resistance to SP across Africa[
23,
26‐
32] and in SE Asia[
33,
34]. Thus, some authors have suggested that SP should be combined with artemisinins or with cheaper and more readily available alternatives, such as chloroquine or amodiaquine[
35] to maintain the effectiveness of SP-IPTp or that other drug regimens should be used[
36]. Several antimalarials, notably chloroquine, proguanil, mefloquine and proguanil-atovaquone, have been evaluated for malaria chemoprophylaxis in pregnancy[
4,
37‐
43], but few clinical trials have attempted to evaluate alternatives to SP in IPTp regimens. Three IPTp clinical trials are currently underway in Benin, Malawi and Tanzania [
44‐
46] and will evaluate SP
vs mefloquine[
44]; SP alone
vs SP plus artesunate[
45]; and SP alone
vs SP plus azithromycin[
46] respectively. A phase III clinical trial among 900 pregnant women in Ghana concluded that amodiaquine alone or in combination with SP was effective in treating uncomplicated falciparum malaria[
47], but concerns about the safety and tolerability of amodiaquine in pregnancy[
48,
49] and widespread resistance, particularly in East Africa[
23], are likely to hinder development of amodiaquine-containing combinations for IPTp.
The future of SP for intermittent preventive treatment of malaria in pregnancy is tenuous, particularly in East and Southern Africa, and there are insufficient, reliable data on the safety and efficacy of alternative antimalarials for the prevention and treatment of malaria in pregnancy[
50]. Hence, there is an urgent need to evaluate new drug combinations, particularly in areas where multi-drug resistant falciparum malaria is common[
17]. This paper summarizes the current literature on this topic and suggests which antimalarial combinations should be considered for future phase II/III clinical trials among pregnant women in Africa. Key factors reviewed include evidence of safety, acceptability and favourable pharmacokinetic profile in pregnancy; the feasibility of producing fixed-dose co-formulations at costs affordable to most malaria-endemic countries; and the possibility of simple dosing regimens [
51‐
54]. The value of combining drugs with differing molecular targets, those likely to show synergy in combination and those having comparable or disparate elimination half-lives are also discussed[
55].
Discussion
The pharmacokinetics, dosing regimen, efficacy and safety profile of antimalarials currently used to treat and prevent falciparum malaria in adults and children are well-described. This is not the case in pregnancy where the limited data available in each of these areas makes it difficult to predict which drugs are likely to be the best candidates for treating and preventing infection. Many antimalarials are contra-indicated in pregnancy (e.g. primaquine, doxycycline, halofantrine, tafenoquine), whilst the safety of several promising candidates remains unclear[
58]. In malaria-endemic countries, where antenatal HIV prevalence is high, the increased risk of serious adverse events associated with some antimalarials (e.g. severe skin reactions with SP in women with co-infection[
54]) and drug interactions with anti-retrovirals used for the prevention of mother to child HIV transmission (e.g. SP interacts with nevirapine and zidovudine[
118]) are also important factors to consider. Malaria in pregnancy is unique and characterized by placental sequestration of
P. falciparum-infected erythrocytes following their adherence to placental chondroitin sulphate A (CSA)[
119] and hyaluronic acid[
120], which essentially allows the placenta to act as a 'privileged site' for parasite replication[
36]. Pregnant women in all transmission areas have an increased susceptibility to malaria and other infections due to changes in cellular mediated immune responses [
121‐
123], which persist into the postpartum period[
6,
8]. Physiological changes such as increased intravascular volume, delayed gastric emptying time, elevated oestrogen and cortisol levels and increased body fat content alter the absorption, distribution and elimination of many antimalarials during pregnancy[
81]. For example the pharmacokinetics of atovaquone, proguanil, cycloguanil and dihydroartemisnin are significantly altered in pregnant women with malaria compared to healthy volunteers or adults and children with malaria[
81,
101]. For candidate IPTp combinations there is the added complication that there is still some debate as to how IPTp actually works: repeated short courses of antimalarials may act mainly by intermittent suppressive chemotherapy ('prophylactic effect'); by intermittent treatment of repeated infections ('treatment effect'); or by some combination of these effects[
36,
55]. Similar issues are also being debated about IPTi [
124]. Given the early success of SP-IPTp in high transmission areas, the slow parasite clearance times and long elimination half-lives of each of the component drugs[
125], it seems likely that the 'prophylactic effect' is the predominant mode of action, at least in this combination.
How then to decide which antimalarials are likely to be effective for IPT in pregnancy and which combinations should be prioritized for investigation in clinical trials (Table
1)? If the effect of IPTp is mainly prophylactic, then short-acting drugs such as quinine and the artemesinins would be expected to provide little direct benefit in asymptomatic pregnant women living in high-transmission areas since rapid parasite elimination is unnecessary. Drugs with long half-lives such as mefloquine, piperaquine or lumefantrine would, therefore, appear better choices, but monotherapy with any of these agents would be inappropriate given global patterns of drug resistance and the consensus on the need for combination therapies [
51‐
54]. There is some evidence that combining short-acting artemisinins with longer-acting agents is likely to delay the emergence of resistance to the slowly-eliminated component[
51,
53,
55]. Conversely, some authors advise combining drugs with similar elimination half-lives due to the risk of resistance emerging to the longer-acting drug because of it's persistence alone at sub-therapeutic levels once the rapidly eliminated drug has been excreted[
54]. Combining drugs that have different molecular targets is also preferable to reduce the risk of resistance[
51,
54]. Acceptability, cost, possibility of a fixed-dose formulation, and a simple dosing regimen are other important considerations[
53].
Table 1
Pharmacology of selected candidates for IPTp
Artemether
| Inhibits falciparum sarcoplasmic-endoplasmic reticulum calcium ATPase | 3 – 7 h (converted to DHA) | Appears safe in the second and third trimester Widely available in a cheap, fixed dose co-formulation with lumefantrine (Coartem©/Riamet©) |
Artemisinin
| Inhibits falciparum sarcoplasmic-endoplasmic reticulum calcium ATPase | 2 – 3 h (converted to DHA) | Appears safe in the second and third trimester Fixed dose co-formulations unavailable |
Artesunate
| Inhibits falciparum sarcoplasmic-endoplasmic reticulum calcium ATPase | 2 – 5 mins (converted to DHA) | Appears safe in the second and third trimester Fixed dose co-formulations unavailable |
Atovaquone
| Selective inhibitor of parasite mitochondrial metabolism | 48 – 72 h | Appears safe in the third trimester Available only in fixed dose co-formulation with proguanil (Malarone©), which is expensive outside specific donation programmes |
Azithromycin
| Exact mode of action unknown | 68 h | Safe in all trimesters where has been used extensively in STI treatment Expensive; fixed dose co-formulations unavailable |
Chlorproguanil
| Folic acid antagonist (inhibits dihydrofolate reductase) | 32 h | Cheap; appears safe in the third trimester and likely to be safe earlier in pregnancy based on experience with proguanil Available only in fixed dose co-formulation with dapsone (Lapdap©), which WHO have recommended be used with caution in areas of high G6PD deficiency |
Dapsone
| Folic acid antagonist (inhibits dihydropteroate synthase) | 31 h | Cheap; appears safe in the third trimester Available in fixed dose co-formulation with chlorproguanil (Lapdap©), which WHO have recommended be used with caution in areas of high G6PD deficiency |
Dihydroartemisinin (DHA)
| Inhibits falciparum sarcoplasmic-endoplasmic reticulum calcium ATPase | 40 – 60 mins | Likely to be safe in the second and third trimester Available in SE Asia, China in a cheap fixed dose co-formulation with piperaquine (Artekin©/Eurartekin©) |
Lumefantrine
| Inhibits metabolism of haem within parasite acid food vacuole | 4 – 6 days | Safety in children and adults established but no data available in pregnancy Widely available in a cheap [through WHO pricing agreement], fixed dose co-formulation with artemether (Coartem©/Riamet©) |
Mefloquine
| Exact mode of action unknown | 2 – 4 weeks | Appears safe in the second and third trimester Expensive; fixed dose co-formulations unavailable |
Piperaquine
| Inhibits detoxification of haem | 3 – 4 weeks | Safety in children and adults established but no data available in pregnancy Available in SE Asia, China in a cheap, fixed dose co-formulation with dihydroartemisinin (Artekin©/Eurartekin©) |
Proguanil
| Folic acid antagonist (inhibits dihydrofolate reductase) | 12 – 21 h | Cheap; appears safe in all trimesters Available alone or in fixed dose co-formulation with atovaquone (Malarone©), which is expensive outside specific donation programmes |
Pyrimethamine
| Folic acid antagonist (inhibits dihydrofolate reductase) | 100 h | Cheap; widely available in fixed-dose combination with sulphadoxine Increasing resistance particularly in East Africa |
Sulphadoxine
| Folic acid antagonist (inhibits dihydropteroate synthase) | 200 h | Cheap; widely available in fixed-dose combination with pyrimethamine Increasing resistance particularly in East Africa |
Based on these criteria, dihydroartemisinin-piperaquine appears an appropriate candidate for IPTp and should be considered for phase II/III clinical trials in second and third trimester pregnant women. The combination is relatively inexpensive (around US$ 1.00 for an adult treatment course, which is comparable to Coartem
©)[
126]; combines a very short acting artemisinin with a longer acting partner with a different mode of action; and is available in fixed-dose co-formulation. Dihydroartemisinin is the active metabolite of many artemisinin compounds, which appear to be effective, well tolerated and safe after the first trimester; the evidence for the safety of piperaquine is, however, less clear, indicating the need for preliminary phase II studies.
Artemether-lumefantrine may also be a suitable candidate: a relatively inexpensive, fixed co-formulation is available and the partner drugs have different molecular targets. The 'prophylactic effect' conferred by lumefantrine may not be sufficient however, given its relatively short half-life compared to sulphadoxine, pyrimethamine, mefloquine or piperaquine.
Mefloquine in combination with artemether or artesunate has the advantage of a similar elimination profile to dihydroartemisnin-piperaquine and the safety of such combinations in the treatment of pregnancy-associated malaria is reasonably well-established. Indeed, the extensive data available on mefloquine use in pregnancy compared to piperaquine suggest that dihydroartemisinin-mefloquine could enter phase III trials ahead of dihydroartemisinin-piperaquine. Cost and the lack of fixed dose co-formulations (although these are currently under development) are disadvantages. Combining mefloquine with the relatively long acting azithromycin is another option and likely to have additional health benefits by reducing maternal and perinatal infections, which may offset cost concerns. Sexually-transmitted infections (STIs) are common in women of childbearing age in Africa and may go undiagnosed and untreated during pregnancy[
127]. Monthly azithromycin reduces STI incidence significantly in high-risk groups[
128] and is safe and effective for treating gonorrhoea as well as chlamydia infection during pregnancy[
71], which is associated with increased risk of stillbirth, prematurity and LBW[
129]. Mefloquine-azithromycin may, therefore, represent a promising, safe and effective combination for IPTp and should be considered urgently for evaluation in phase III clinical trials.
Patterns of SP resistance vary across sub-Saharan Africa so that new artemisinin-containing combinations with SP may be appropriate in West Africa, given that these would fulfil many of the criteria above. Such combinations are, however, unlikely to succeed in East and Southern Africa, given prevailing levels of resistance.
Are different types of drug combination needed in different areas of malaria transmission? Evidence for the effectiveness of IPTp comes primarily from studies conducted in areas of intense perennial transmission (stable malaria), but there may be a case for evaluating IPTp in areas of low transmission (unstable malaria). The World Health Organization recommends that IPTp be an integral part of national malaria control programmes in high/medium perennial or seasonal transmission areas but caution that there is insufficient evidence for introducing IPTp in low transmission settings where the principal focus should be on effective case management and insecticide-treated bednets[
17]. In areas of highly seasonal transmission there is some evidence to suggest that IPT given only during periods of high transmission may be effective, at least in infants[
112], but no studies to date have been reported from low transmission settings such as South America or Asia, where the burden of pregnancy-associated malaria is significant, but quite different from that observed in areas of stable malaria and where the contribution of
Plasmodium vivax infection also needs to be taken into consideration[
36]. In addition, combinations found to be efficacious in sub-Saharan Africa may be of limited benefit in Asia due to their inability to prevent relapse in
P. vivax infection[
130,
131].
Authors' contributions
AV participated in the conception and design of the review, coordinated the literature review and drafted the manuscript.
LV participated in the conception and design of the review, conducted the literature search, obtained full text articles and helped draft the manuscript.
JC participated in the design of the review and helped draft the manuscript.
BG participated in the conception and design of the review, provided additional information e.g. conference proceedings and helped draft the manuscript.
DC conceived the study, participated in its design and coordination and helped draft the manuscript.
All authors have read and approved the final manuscript.