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close this bookGuidelines for the Treatment of Malaria (WHO; 2006; 266 pages) View the PDF document
View the documentGlossary
View the documentAbbreviations
open this folder and view contents1. Introduction
View the document2. The clinical disease
open this folder and view contents3. Treatment objectives
open this folder and view contents4. Diagnosis of malaria
open this folder and view contents5. Resistance to antimalarial medicines9
open this folder and view contents6. Antimalarial treatment policy
close this folder7. Treatment of uncomplicated P. Falciparum malaria10
View the document7.1 Assessment
View the document7.2 Antimalarial combination therapy
View the document7.3 The choice of artemisinin-based combination therapy options
View the document7.4 Practical aspects of treatment with recommended ACTs
View the document7.5 Incorrect approaches to treatment
View the document7.6 Additional aspects of clinical management
View the document7.7 Operational issues in treatment management
View the document7.8 Management of treatment failures
View the document7.9 Treatment in specific populations and situations
View the document7.10 Coexisting morbidities
open this folder and view contents8. Treatment of severe falciparum malaria14
open this folder and view contents9. Treatment of malaria caused by P. vivax, P. ovale or P. malariae19
View the document10. Mixed malaria infections
open this folder and view contents11. Complex emergencies and epidemics
open this folder and view contentsAnnexes

7.9 Treatment in specific populations and situations

7.9.1 Pregnant women

Pregnant women with symptomatic acute malaria are a high-risk group, and must receive effective antimalarials. Malaria in pregnancy is associated with low birth weight, increased anaemia and, in low-transmission areas, an increased risk of severe malaria. In high-transmission settings, despite the adverse effects on fetal growth, malaria is usually asymptomatic in pregnancy. There is insufficient information on the safety and efficacy of most antimalarials in pregnancy, particularly for exposure in the first trimester, and so treatment recommendations are different to those for non-pregnant adults. Organogenesis occurs mainly in the first trimester and this is therefore the time of greatest concern for potential teratogenicity, although nervous system development continues throughout pregnancy. The antimalarials considered safe in the first trimester of pregnancy are quinine, chloroquine, proguanil, pyrimethamine and sulfadoxine-pyrimethamine. Of these, quinine remains the most effective and can be used in all trimesters of pregnancy including the first trimester. In reality women often do not declare their pregnancies in the first trimester and so, early pregnancies will often be exposed inadvertently to the available first-line treatment. Inadvertent exposure to antimalarials is not an indication for termination of the pregnancy.

There is increasing experience with artemisinin derivatives in the second and third trimesters (over 1000 documented pregnancies). There have been no adverse effects on the mother or fetus. The current assessment of benefits compared with potential risks suggests that the artemisinin derivatives should be used to treat uncomplicated falciparum malaria in the second and third trimesters of pregnancy, but should not be used in the first trimester until more information becomes available. The choice of combination partner is difficult. Mefloquine has been associated with an increased risk of stillbirth in large observational studies in Thailand, but not in Malawi. Amodiaquine, chlorproguanil-dapsone, halofantrine, lumefantrine and piperaquine have not been evaluated sufficiently to permit positive recommendations. Sulfadoxine-pyrimethamine is safe but may be ineffective in many areas because of increasing resistance. Clindamycin is also safe, but both medicines (clindamycin and the artemisinin partner) must be given for 7 days. Primaquine and tetracyclines should not be used in pregnancy.

Despite these many uncertainties, effective treatment must not be delayed in pregnant women. Given the disadvantages of quinine, i.e. the long course of treatment, and the increased risk of hypoglycaemia in the second and third trimesters, ACTs are considered suitable alternatives for these trimesters. In practice, if first-line treatment with an artemisinin combination is all that is immediately available to treat in the first trimester of pregnancy pregnant women who have symptomatic malaria, then this should be given. Pharmaco-vigilance programmes to document the outcome of pregnancies where there has been exposure to ACTs, and if possible documentation of the development of the infant, are encouraged so that future recommendations can stand on a firmer footing.

EVIDENCE: trials on the use of antimalarial medicines for the treatment of uncomplicated malaria in pregnant women

Interventions: oral AS+MQ, oral CQ alone, oral quinine, oral quinine + clindamycin

Summary of RCTs: four randomized and two quasi-randomized trials with 513 pregnant participants. There were fewer treatment failures with AS+MQ than with quinine in one trial (day 63: RR: 0.09; 95% CI: 0.02-0.38; 106 participants). Data for other comparisons are scant. Where trials reported adverse outcomes, there were no differences reported between treatments in terms of effect on the mother or the fetus.

Expert comment: systematic summaries of safety suggest that the artemisinin derivatives are safe in the second and third trimesters of pregnancy. One large observational study in Thailand suggests an increased risk of stillbirth associated with MQ but this was not found in a study conducted in Malawi. There are as yet insufficient safety data about the use of artemisinin derivatives in the first trimester of pregnancy.

Basis of decision: expert opinion.

Recommendations: for the first trimester of pregnancy: quinine +/- clindamycin.

For second and third trimesters:

1. the ACT being used in the country/region, or
2. artesunate + clindamycin,
3. quinine + clindamycin.

Summary of recommendations on the treatment of uncomplicated falciparum malaria in pregnancy



First trimester: quinine + clindamycina to be given for 7 days. ACT should be used if it is the only effective treatment available.

O, E

Second and third trimesters: ACT known to be effective in the country/region or artesunate + clindamycin to be given for 7 days or quinine + clindamycin to be given for 7 days.

O, E


a If clindamycin is unavailable or unaffordable, then the monotherapy should be given.

7.9.2 Lactating women

The amounts of antimalarials that enter breast milk and are therefore likely to be consumed by the breast-feeding infant are relatively small. The only exception to this is dapsone, relatively large amounts of which are excreted in breast milk (14% of the adult dose), and pending further data this should not be prescribed. Tetracyclines are also contraindicated because of their effect on the infant's bones and teeth.

Summary of recommendations on the treatment of uncomplicated falciparum malaria in lactating women



Lactating women should receive standard antimalarial treatment (including ACTs) except for tetracyclines and dapsone, which should be withheld during lactation.


7.9.3 Infants12

12 A detailed review of the available data on safety of antimalarials in infants is provided in Annex 3, section A3.17.

Choice of antimalarial drug

In endemic countries, malaria is common in infants and children under 2 years of age. Immunity acquired from the mother wanes after 3-6 months of age, and the case-fatality rate of severe malaria in infants is higher than in older children. Furthermore, there are important differences between infants and older children in the pharmacokinetics of many medicines. Accurate dosing is particularly important in infants. Despite this, few clinical studies focus specifically on this age range, partly because of ethical considerations relating to the recruitment of very young children to clinical trials, and also because of the difficulty of repeated blood sampling. In the majority of clinical studies, subgroup analysis is not used to distinguish between infants and older children. Infants are more likely to vomit or regurgitate antimalarial treatment than older children or adults. Taste, volume, consistency and gastrointestinal tolerability are important determinants of whether the child retains the treatment. Mothers often need advice on techniques of medicine administration and the importance of administering the medicine again if it is immediately regurgitated. With the increasing failure of chloroquine and sulfadoxine-pyrimethamine as front-line antimalarials, the challenge is now to find safe alternatives in this age group. Fortunately the artemisinin derivatives appear to be safe in, and well tolerated by young children, and so the choice of ACT will be determined largely by the safety and tolerability of the partner drug. The limited information available does not indicate particular problems with currently recommended ACTs in infancy.


Although dosing based on body area is recommended for many drugs in young children, for the sake of simplicity, dosing of antimalarials has been traditionally based on weight. The weight-adjusted doses of antimalarials in infants are similar to those used in adults. For the majority of antimalarials, however, the lack of an infant formulation necessitates the division of adult tablets, which leads to inaccurate dosing. There is a need to develop infant formulations for a range of antimalarials in order to improve the accuracy and reliability of dosing.

Delay in treating falciparum malaria may have fatal consequences, particularly for more severe infections. Every effort should be made to give oral treatment and ensure that it is retained. In situations where it is not possible to give parenteral treatment, a sick infant who vomits antimalarial medicine treatment repeatedly, has a seizure or is too weak to swallow reliably should be given artesunate by the rectal route, pending transfer to a facility where parenteral treatment is possible. Large trials assessing the impact of this strategy on mortality have recently been undertaken in remote rural areas, but results are not yet available. Pharmacological and trial evidence concerning the rectal administration of artesunate and other antimalarial drugs is provided in section 8.7.

Summary of recommendations on treatment of uncomplicated falciparum malaria in infants and young children



The acutely ill child requires careful clinical monitoring as they may deteriorate rapidly.


ACTs should be used as first-line treatment for infants and young children.

T, O, E

Referral to a health centre or hospital is indicated for young children who cannot swallow antimalarials reliably.


7.9.4 Travellers

Travellers who acquire malaria are often non-immune adults either from cities with little or no transmission within endemic countries, or visitors from non-endemic countries. Both are likely to be at a higher risk of malaria and its consequences because they have no immunity to malaria. Within the malaria endemic country they should in principle be treated according to national policy. Travellers who return to a non-endemic country and then develop malaria present particular problems and, have a high case fatality rate. Doctors may be unfamiliar with malaria and the diagnosis may be delayed, relevant anti-malarials may not be registered and/or therefore available. If the patient falls ill far from a major health facility, availability of antimalarials can be a life-threatening issue despite registration. On the other hand prevention of emergence of resistance and transmission are of less relevance outside malaria endemic areas. Thus monotherapy may be given if it can be assured to be effective. Furthermore cost of treatment is usually not a limiting factor. The principles underlying the recommendations given below are that effective medicines should be used to treat travellers; if the patient has taken chemoprophylaxis, then the same medicine should not be used for treatment. The treatment for P. vivax, P. ovale and P. malariae in travellers should be the same as for these infections in patients from endemic areas (see section 9).

In the management of severe malaria outside endemic areas, there may be delays in obtaining artesunate, artemether or quinine. If parenteral quinidine is available but other parenteral drugs are not, then this should be given with careful clinical and electrocardiographic monitoring (see section 8).

EVIDENCE: treatment of uncomplicated malaria in travellers returning to non-endemic areas

Interventions: atovaquone-proguanil, halofantrine, quinine, quinine + clindamycin, artemether-lumefantrine

Summary of RCTs: three RCTS (total 259 patients) report effective treatment with all interventions listed although the artemether-lumefantrine regimen was only 4 doses and therefore less effective. In one trial using halofantrine significant prolongation of the QT interval was noted.

Expert comment: halofantrine is not recommended because of significant cardiotoxicity compared to other treatments.

Basis of decision: RCTs and expert opinion.

Recommendation: the following antimalarials are suitable for use in travellers returning to non-endemic countries:

- artemether-lumefantrine (6-dose regimen),
- atovaquone-proguanil,
- quinine + doxycycline or clindamycin.

Summary of recommendations on the treatment of falciparum malaria in non-immune travellers



For travellers returning to non-endemic countries:a

- atovaquone-proguanil (15/6 mg/kg, usual adult dose, 4 tablets once a day for 3 days);

- artemether-lumefantrine (adult dose, 4 tablets twice a day for 3 days); - quinine (10 mg salt/kg bw every 8 h) + doxycyclineb (3.5 mg/kg bw once a day) or clindamycin (10 mg/kg bw twice a day); all drugs to be given for 7 days

O, E

For severe malaria:

- the antimalarial treatment of severe malaria in travellers is the same as shown in section 8;

- travellers with severe malaria should be managed in an intensive care unit;

- haemofiltration or haemodialysis should be started early in acute renal failure or severe metabolic acidosis;

- positive pressure ventilation should be started early if there is any breathing pattern abnormality, intractable seizure or acute respiratory distress syndrome.

O, E


a Halofantrine is not recommended as first-line treatment for uncomplicated malaria because of cardiotoxicity.

b Doxycycline should not be used in children under 8 years of age.


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