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. 2007 Nov 29;2007:0903.

Malaria: prevention in travellers

Ashley M Croft 1
PMCID: PMC2943798  PMID: 19450348

Abstract

Introduction

Malaria transmission occurs most frequently in environments with humidity over 60% and ambient temperature of 25-30 °C. Risks increase with longer visits and depend on activity. Infection can follow a single mosquito bite. Incubation is usually 10-14 days but can be up to 18 months depending on the strain of parasite.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of non-drug preventive interventions in adult travellers? What are the effects of drug prophylaxis in adult travellers? What are the effects of antimalaria vaccines in travellers? What are the effects of antimalaria interventions in child travellers, pregnant travellers, and in airline pilots? We searched: Medline, Embase, The Cochrane Library and other important databases up to February 2006 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 69 systematic reviews, RCTs, or observational studies that met our inclusion criteria.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acoustic buzzers, aerosol insecticides, amodiaquine, air conditioning and electric fans, atovaquone-proguanil, biological control measures, chloroquine (alone or with proguanil), diethyltoluamide (DEET), doxycycline, full-length and light-coloured clothing, insecticide-treated clothing/nets, mefloquine, mosquito coils and vaporising mats, primaquine, pyrimethamine-dapsone, pyrimethamine-sulfadoxine, smoke, topical (skin-applied) insect repellents, and vaccines.

Key Points

Malaria transmission occurs most frequently in environments with a humidity over 60% and ambient temperature of 25-30 °C. Risks increase with longer visits, and depend on activity.

  • Infection can follow a single mosquito bite. Incubation is usually 10-14 days, but can be up to 18 months depending on the strain of parasite.

  • Complications are usually because of delayed or inappropriate treatment, but up to 88% of previously healthy travellers recover fully with prompt treatment. Older people have a worse prognosis.

Many of the studies on prevention of malaria have been performed on people other than travellers, such as residents of endemic malaria areas.

Various non-drug preventive measures may be effective, but some may have adverse effects.

Various drug treatments may be effective in preventing malaria, but we cannot be sure which is the most effective drug regimen, and most have adverse effects which can sometimes be serious.

  • Atovaquone-proguanil and doxycycline may be beneficial.

  • Chloroquine is considered to reduce the risk of malaria in travellers to areas where chloroquine resistance is low, although few studies have been done.

  • Mefloquine and chloroquine-proguanil may be beneficial, but their adverse effects must also be considered.

  • We don't know whether pyrimethamine-dapsone or pyrimethamine-sulfadoxine are effective.

  • Children may be at risk of encephalopathic adverse effects from topical insect repellents containing DEET. There is consensus that chloroquine is effective and safe in preventing malaria in children, but we don't know whether this is the case for any other treatments.

Insecticide-treated bed nets may be effective in preventing malaria in pregnant women.

  • We found no RCT evidence about insecticide-treated clothing in pregnant women, but evidence in non-pregnant adults that it is effective is likely to be generalisable to pregnant women. However, there are attendant risks.

  • There is consensus that chloroquine may be beneficial in pregnant women.

Atovaquone-proguanil may have no more adverse effects than placebo in airline pilots, but we have no direct evidence assessing whether treatments are safe or effective in this occupational group. There is no reason to suggest that evidence of benefit of atovaquone-proguanil, chloroquine, or doxycycline in other adults would not be generalisable to airline pilots.

CAUTION

About this condition

Definition

Malaria is an acute parasitic disease of the tropics and subtropics, caused by the invasion and destruction of red blood cells by one or more of four species of the genus Plasmodium: P falciparum, P vivax , P ovale, and P malariae. The clinical presentation of malaria varies according to the infecting species, and according to the genetics, immune status, and age of the infected person. The most severe form of human malaria is caused by P falciparum, in which variable clinical features include spiking fevers, chills, headache, muscular aching and weakness, vomiting, cough, diarrhoea, and abdominal pain; other symptoms related to organ failure may supervene, such as acute renal failure, generalised convulsions, and circulatory collapse, followed by coma and death. P falciparum accounts for more than 50% of malaria infections in most East Asian countries, over 90% in sub-Saharan Africa, and almost 100% in Hispaniola. Travellers are defined here as visitors from a malaria-free area to a malaria-endemic area, who stay in the endemic area for less than 1 year.

Incidence/ Prevalence

Malaria is the most dangerous parasitic disease of humans, infecting about 5% of the world's population, and causing about one million deaths each year. The disease is strongly resurgent, owing to the effects of war, climate change, large-scale population movements, increased breeding opportunities for vector mosquitoes, rapidly spreading drug and insecticide resistance, and neglect of public health infrastructure. Malaria is currently endemic in more than 100 countries, which are visited by more than 125 million international travellers each year. Cases of malaria acquired by international travellers from industrialised countries probably number 25,000 annually. Of these, about 10,000 are reported and 150 are fatal.

Aetiology/ Risk factors

Humans acquire malaria from sporozoites transmitted by the bite of infected female anopheline mosquitoes. Of about 3200 mosquito species so far described, some 430 belong to the genus Anopheles . Of these, about 70 anopheline species are known to transmit malaria, with about 40 species considered important vectors. When foraging, blood-thirsty female mosquitoes fly upwind searching for the scent trail of an attractive host. Female anophelines are attracted to their human hosts over a range of 7-20 m, through a variety of stimuli, including exhaled carbon dioxide, lactic acid, other host odours, warmth, and moisture. Larger people tend to be bitten by mosquitoes more than smaller individuals. Women receive significantly more mosquito bites in trials than men. Children secrete lower levels of chemical attractants than adults, and therefore usually receive fewer mosquito bites than adults. Malaria transmission does not usually occur at temperatures below 16 °C or above 35 °C, or at altitudes greater than 3000 m above sea level at the equator (lower elevations in cooler climates), because sporozoite development in the mosquito cannot take place. The optimal conditions for transmission are a humidity of over 60%, and an ambient temperature of 25-30 °C. Most of the important vectors of malaria breed in small temporary collections of fresh surface water exposed to sunlight and with little predation, and in sites such as residual pools in drying river beds. Although rainfall provides breeding sites for mosquitoes, excessive rainfall may wash away mosquito larvae and pupae. Conversely, prolonged droughts may be associated with increased malaria transmission if they reduce the size and flow rates of large rivers sufficiently to produce suitable Anopheles breeding sites. Anopheline mosquitoes vary in their preferred feeding and resting locations, although most bite in the evening and at night. The Anopheles mosquito will feed by day only if unusually hungry. Anopheles adults usually fly not more than 2-3 km from their breeding sites, although a flight range of up to 7 km has been observed. One cross sectional study of about 7000 children under the age of 10 years found that, during months of peak transmission, living within 3 km of an Anopheles breeding site significantly increased the risk of malaria compared with living 8-10 km away (RR 21.00, 95% CI 2.87 to 153.00). Exceptionally, strong winds may carry Anopheles up to 30 km or more. In travellers, malaria risk is related to destination, activity, and duration of travel. A retrospective cohort study (5898 confirmed cases) conducted in Italian travellers between 1989 and 1997 found that the malaria incidence was 1.5/1000 for travel to Africa, 0.11/1000 for travel to Asia, and 0.04/1000 for travel to Central and South America. A survey of approximately 170,000 Swedish travellers found that the prevalence of malaria was lowest among travellers to Central America and the Caribbean (0.01/1000), and higher among travellers to East, Central, and West Africa (prevalence among travellers to East Africa 2.4/1000, Central Africa 3.6/1000, and West Africa 3.0/1000). A survey of 2131 German travellers to sub-Saharan Africa found that solo travellers were at almost a ninefold greater risk of infection than those on package tours. A case control study (46 cases, 557 controls) reported that a visit to the tropics for longer than 21 days doubled the malaria risk compared with visits lasting 21 days or less.

Prognosis

Malaria can develop after just one anopheline mosquito bite. Human malaria has a usual incubation period that ranges from 10-14 days (P falciparum, P vivax, and P ovale) to about 28 days (P malariae). Certain strains of P vivax and P ovale can have a much longer incubation period of 6-18 months. About 90% of malaria attacks in travellers occur at home. About 36% of cases that develop after returning home do so more than 2 months after the traveller's return. People returning from an endemic area with any fever pattern should be considered to have malaria until proved otherwise. Once malaria infection occurs, older travellers are at greater risk of poor clinical outcomes and death. In US travellers between 1966 and 1987, the case fatality rate was 0.4% for people aged 0-19 years, 2.2% for ages 20-39 years, 5.8% for ages 40-69 years, and 30.3% for those aged 70-79 years. Complications and death from malaria are mainly due to inappropriate treatment, or to delayed initiation of treatment. If malaria is diagnosed and treated promptly, about 88% of previously healthy travellers will recover completely.

Aims of intervention

To reduce the risk of infection; to prevent illness and death, with minimal adverse effects of treatment.

Outcomes

Rates of clinical malaria and death, and adverse effects of treatment. Proxy measures include numbers of mosquito bites and rates of mosquito catches in indoor areas. One experimental study in rabbits has suggested that Anopheles stephensi biting behaviour is not affected by their P falciparum infection status. This suggests that numbers of A stephensi mosquito bites may be a reasonable measure of P falciparum malaria risk in humans. Long-term residents of malaria endemic areas acquire partial immunity to infected mosquito bites, with only a small proportion of such bites progressing to a new infection (in children aged 6 months to 6 years, monitored for 18 months in western Kenya, only 7.5% of infected bites produced a clinical episode of malaria). In non-immune travellers, the likelihood of malaria infection after a single infected bite is much higher (US marines who spent 1-14 nights in Liberia experienced a 44% malaria acquisition rate).

Methods

BMJ Clinical Evidence search and appraisal February 2007. The following databases were used to identify studies for this systematic review: Medline 1966 to February 2007, Embase 1980 to February 2007, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials 2007, Issue 1. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and National Institute for Health and Clinical Excellence (NICE) and AMED for studies on bath/body oils and dietary supplementation. We also searched for retractions of studies included in the review. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the contributor for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews, RCTs, and prospective and retrospective cohort studies in any language, at least single blinded, and containing more than 20 individuals of whom more than 80% were followed up. There was no minimum length of follow-up required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We also searched for cohort studies on specific harms of named interventions. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the reviews as required. Additional hand searches were performed by the contributor of his own files and the Journal of Travel Medicine, Journal of the Royal Army Medical Corps, and Transactions of the Royal Society of Tropical Medicine and Hygiene. As BMJ Clinical Evidence was unable to perform a second appraisal of results retrieved by the contributor's search, we may have missed studies that could affect our overall assessment of the interventions in this review. Evidence from case control and observational studies have been included in some sections where randomised studies did not exist or where they did not address specific questions. In some sections, evidence of harms has been extracted from case series. In the questions on preventive and prophylactic interventions in adults, we have excluded studies in pregnant women or airline pilots, because these populations are covered by separate questions. Where no data were available in travellers, we have included systematic reviews and RCTs in people in malaria-endemic settings, as we believe that the results of these studies are generalisable to travellers.

Glossary

Aedes

Genus of day-biting mosquitoes which transmit various infections (dengue fever, yellow fever), but not malaria.

Anopheles

Genus of evening- and night-biting mosquitoes which transmit malaria.

Biological control measures

Antimosquito interventions based on modifying the local flora or fauna.

Carbamate

Class of synthetic insecticides (for example, carbosulfan) used to treat bed nets.

Electronic buzzers

Commercial devices which emit high-frequency sound waves, commonly marketed as insect repellents.

Plasmodium falciparum infection

The most severe and life-threatening form of human malaria.

Plasmodium vivax infection

A less severe form of human malaria, sometimes with a long incubation period of 6 to 18 months.

Protective efficacy

((R1  – R2 )/R1 ) x 100 where R1 is the incidence of the event in the control population and R2 is the incidence of the event in the immunised population. This is the same as the relative risk reduction.

Malaria (severe, life threatening)

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients.To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

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BMJ Clin Evid. 2007 Nov 29;2007:0903.

Aerosol insecticides in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of aerosol insecticides to prevent malaria in travellers. One large questionnaire survey in travellers found insufficient evidence on the effects of aerosol insecticides in preventing malaria. Two community RCTs in residents of malaria-endemic areas found that indoor spraying of aerosol insecticides reduced clinical malaria.

Benefits

We found no systematic review or RCTs in travellers (see comment below). One large questionnaire survey of 89,617 European tourists returning from East Africa measured malaria incidence with a two-stage self-completed questionnaire administered during the return flight and again 12 weeks later. It found that commercially available personal aerosol insecticides did not significantly reduce the incidence of malaria (P = 0.55). Two community RCTs in lifelong residents of malaria-endemic areas found that indoor residual spraying of synthetic pyrethroids reduced clinical malaria.

Harms

The RCTs gave no information on adverse effects.

Comment

Clinical guide:

Historically, indoor residual spraying has not been recommended for short-stay travellers, and we found weak evidence from a large observational study that aerosol insecticides did not reduce the risk of malaria in travellers. However, we found evidence from RCTs of benefit from indoor residual spraying of synthetic pyrethroids in preventing malaria in residents of malaria-endemic areas. It is possible that this benefit may also be seen in travellers if the same insecticides are used in the same conditions.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Biological control measures in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of biological control measures to prevent malaria in travellers.

Benefits

We found no systematic review or RCTs of biological control measures in preventing malaria in travellers (see comment below).

Harms

We found no RCTs.

Comment

One systematic review (search date 1997) identified two cohort studies based on mosquito counts. It found no evidence that growing the citrosa plant, and encouraging natural predation of insects by erecting bird or bat houses reduced bites to humans from infected anopheline mosquitoes. The only known way to reduce mosquito populations naturally is to eliminate sources of standing water — such as blocked gutters, tree-stump holes, and discarded tyres, cans, and bottles.

Clinical guide:

There is no reliable evidence about the effects of biological control measures in preventing malaria in travellers.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Air conditioning and electric fans in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of air conditioning or electric fans to prevent malaria in travellers. One large questionnaire survey found that air conditioning reduced the incidence of malaria. One small observational study found that electric ceiling fans reduced total catches of culicine mosquitoes in indoor spaces. However, it found no significant difference in total catches of anopheline mosquitoes.

Benefits

We found no systematic review or RCTs (see comment below). One questionnaire survey of 89,617 European tourists returning from East Africa measured malaria incidence with a two-stage self-completed questionnaire administered during the return flight and again 12 weeks later. It found that sleeping in an air-conditioned room significantly reduced the incidence of malaria (P = 0.04).

Harms

We found no RCTs.

Comment

One cohort study (6 experimental huts in villages in Pakistan) of various antimosquito interventions found that an electric ceiling fan run at high speed significantly reduced total catches of blood-fed culicine mosquitoes (P less than 0.05). However, it did not significantly reduce total catches of blood-fed anopheline mosquitoes. These studies support the finding that mosquitoes are reluctant to fly in windy conditions, but suggest that anopheline mosquitoes may be more tolerant than culicine mosquitoes of air turbulence.

Clinical guide:

There is weak evidence of possible benefit from air conditioning in preventing malaria in travellers. There is no reliable evidence about the effects of electric fans in preventing malaria in travellers.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Electronic buzzers in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of electronic buzzers to prevent malaria in adults.

Benefits

We found no systematic review or RCTs with clinical malaria as an outcome.

Harms

We found no RCTs.

Comment

We found one non-randomised controlled trial (18 houses in Gabon) of a commercially available ultrasound-emitting device. The trial lasted 6 weeks and used total mosquito catches as an outcome. Most mosquitoes were culicine. It found no significant difference in mosquito catches between the ultrasound-emitting device and a sham device (P = 0.48).

Clinical guide:

There is weak evidence suggesting that electronic buzzers may be of no benefit in preventing malaria in travellers.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Mosquito coils and vaporising mats in non-pregnant adult travellers

Summary

We found one systematic review but no RCTs on the effects of coils to prevent malaria in travellers, and no RCTs on the effects of vaporising mats. One case control study of coils in travellers found no evidence of a protective effect against malaria. Two case control studies of coils in residents found no evidence of a protective effect against malaria.

Benefits

We found one systematic review (search date 2003) that evaluated the use of coils to prevent malaria. It identified no RCTs. We found no systematic review and no RCTs examining the effect of vaporising mats on the incidence of clinical malaria. We found three case control studies. The first case control study (603 British travellers to the Gambia between September and December, 48% of whom burnt mosquito coils) found that, when assessing people with and without malaria, there was no significant difference in coil use between groups (OR 0.65, 95% CI 0.32 to 1.34). In the second case control study (457 urban residents in southern India, surveyed during the rainy season), approximately 13% of participants used mosquito coils to prevent malaria, and approximately 43% used vaporising mats; the use of these devices did not significantly reduce malaria rates (OR 0.85, 95% CI 0.57 to 1.28). The use of other repellent methods such as nets, oils, and creams was included in this final figure. The third case control study (406 village residents in a high-transmission area of southern Laos) found that non-use of a mosquito coil did not increase the risk of malaria acquisition (OR 1.35, 95% CI 0.06 to 2.91, P = 0.38).

Harms

The systematic review found one trial, which reported irritation of the eyes and nose after coil use. The studies in the systematic review and the subsequent case control studies did not report on other potential adverse effects of exposure to the substances emitted by coils or vaporising mats. These potential adverse effects need investigation.

Comment

One RCT of coils (residential houses in a squatter area in Malaysia) and one observational study (6 experimental huts in villages in Pakistan) of pyrethroid vaporising mats found that these devices reduced numbers of culicine mosquitoes in indoor spaces.

Clinical guide:

There is evidence that mosquito coils and vaporising mats may be of no benefit in preventing malaria in travellers. Because of their unknown safety profile, these devices should not be used indoors.

Substantive changes

Coils and vaporising mats in non-pregnant adult travellers Two case control studies added. Categorisation unchanged (Unknown effectiveness)

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Outdoor smoke in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of outdoor smoke to prevent malaria. One controlled clinical trial found that outdoor smoke repelled mosquitoes during the evening.

Benefits

We found no systematic review or RCTs of outdoor smoke that assessed effects on malaria acquisition.

Harms

We found no RCTs.

Comment

One controlled clinical trial, in which five small fires were tended on five successive evenings in a village in Papua New Guinea, found a smoke-specific and species-specific effect from different types of outdoor smoke. Catches of one anopheline species were reduced by 84% by burning betelnut (95% CI 62% to 94%), by 69% by burning ginger (95% CI 25% to 87%), and by 66% by burning coconut husks (95% CI 17% to 86%). There may be an irritant and toxic effect of outdoor smoke on the eyes and respiratory system, but this effect was not quantified in the controlled clinical trial.

Clinical guide:

There is weak evidence of benefit from certain types of outdoor smoke in repelling mosquitoes. This may translate into clinical benefit by reducing bites, which is likely to reduce malaria infection. However, there is currently no evidence about the effects of outdoor smoke on malaria risk in travellers.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Insecticide-treated bed nets in non-pregnant adult travellers

Summary

We found no systematic review or RCTs in travellers. One systematic review in adult and child residents of malaria-endemic settings found that insecticide-treated bed nets reduced the number of mild episodes of malaria, and reduced child mortality.

Benefits

We found no systematic review or RCTs in travellers. We found one systematic review (search date 2003), which identified 21 RCTs in malaria-endemic settings (stable transmission area greater than 1 infective bite/person/year; non-traveller children and adults). It found that, over 4–29 months, bed nets sprayed or impregnated with a pyrethroid insecticide such as permethrin were associated with lower rates of mild episodes of malaria compared with no or untreated bed nets (insecticide-treated nets v no nets: 4 RCTs; RRR 50%; insecticide-treated nets v untreated nets: 3 RCTs; RRR 39%, CIs not calculated for either analyis, as the analyses included both cluster and non-cluster randomised trials). It found that bed nets sprayed or impregnated with a pyrethroid insecticide such as permethrin significantly reduced child mortality (impregnated nets v no nets: 3 RCTs; RR 0.83, 95% CI 0.76 to 0.90; impregnated nets v untreated nets: 1 RCT; RR 0.77, 95% CI 0.86 to 0.95).

Harms

The review gave no information on adverse effects.

Comment

Clinical guide:

Permethrin remains active for about 4 months.Mosquitoes are increasingly tolerant of pyrethroid insecticides, and there is some evidence that using a carbamate insecticide (such as carbosulfan) to treat bed nets may deter mosquitoes more effectively than using a pyrethroid insecticide to treat nets. Although the systematic review analysing insecticide-treated bed nets was undertaken in non-traveller children and adults, the results are likely to be generalisable to other groups, such as travellers. Therefore, the evidence suggests that insecticide-treated bed nets are likely to be of benefit in preventing malaria in travellers.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Insecticide-treated clothing in non-pregnant adult travellers

Summary

Three RCTs in soldiers and refugee householders who were not receiving chemoprophylaxis found that permethrin-treated fabric (clothing or sheets) reduced the incidence of malaria. However, one controlled trial in soldiers receiving chemoprophylaxis found no significant difference in the incidence of malaria between those wearing permethrin-treated uniforms and control soldiers, although the presence of background chemoprophylaxis may have masked the effect of permethrin-treated uniforms.

Benefits

We found no systematic review but found two RCTs and one controlled clinical trial. The first RCT (172 Colombian soldiers patrolling a malaria-endemic area for a mean of 4.2 weeks) found that permethrin-impregnated uniforms significantly reduced the incidence of malaria compared with non-impregnated uniforms (3/86 [3%] with impregnated uniforms v 12/86 [13%] with non-impregnated uniforms; RR 0.25, 95% CI 0.07 to 0.85). The second RCT (102 refugee households in northwestern Pakistan) found that permethrin-treated wraps and top sheets significantly reduced the risk of falciparum malaria compared with placebo over 4 months (RR 0.56, 95% CI 0.41 to 0.78). The third RCT (198 Somali refugees) found that permethrin-impregnated clothing significantly reduced malaria infection rates over 3 months compared with placebo (proportion infected: 38% with permethrin-treated clothing v 66% with placebo; P = 0.0002; absolute numbers not reported). One non-randomised controlled trial (663 non-immune Thai soldiers patrolling a malaria-endemic area for 6 months) found that permethrin-treated uniforms did not significantly reduce the incidence of malaria compared with placebo-treated uniforms (68/249 [27%] with permethrin treated uniforms v 118/414 [29%] with placebo-treated uniforms; RR and CI not reported). All participants were given the same chemoprophylaxis throughout the study.

Harms

The first RCT also included an analysis of permethrin-impregnated uniforms compared with non-impregnated uniforms in 286 soldiers patrolling a leishmaniasis-endemic area for a mean 6.6 weeks. It found that 2/229 (1%) participants wearing permethrin-impregnated uniforms experienced irritation and itching. No comparative information was given for soldiers wearing non-impregnated uniforms. Neither the second RCT nor the non-randomised study reported on adverse effects. The third RCT reported that no adverse effects were observed in any of the participants.

Comment

In the first RCT, the entire uniform (hat, shirt, undershirt, trousers, and socks) was treated with a single application of permethrin. All participants were instructed to wear the uniform continuously, day and night, with the sleeves rolled down. Each participant washed his own uniform two or three times during the study, using soap and water. Topical (skin-applied) insect repellents were not used. In the second RCT, the chaddar (a veil or wrap) and top sheets of participants were treated with 1 g/m2 permethrin. In the third study, the uniform shirt and trousers of participants were sprayed evenly at high pressure, until entirely saturated with an emulsion containing 151 mL permethrin in 7.5 L water. Re-treatment was not reported in any of the studies.

Clinical guide:

There is some evidence of benefit from insecticide-treated clothing in preventing malaria. Trials in soldiers may not be generalisable to other travellers, because tourists or business travellers may be less likely than soldiers to wear their impregnated garments continuously.

Substantive changes

Insecticide-treated clothing in non-pregnant adult travellers One RCT added, which found that permethrin-treated clothing reduced malaria incidence in non-pregnant refugees. Categorisation of insecticide-treated clothing in travellers unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Lifestyle changes (including full-length clothing, light clothing, behaviour modification) in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of full-length or light-coloured clothing to prevent malaria in travellers. One case control study in expatriates found that wearing clothes covering arms or legs reduced the incidence of malaria. One controlled trial in military personnel and one large questionnaire survey in travellers reported that wearing long trousers and long-sleeved shirts reduced the incidence of malaria.

Benefits

Full-length clothing:

We found no systematic review or RCTs. We found one non-randomised controlled trial (two co-located squadrons of US Air Force personnel exposed to malaria for 1 month during World War II, with one squadron wearing long-sleeved shirts and trousers continuously and the other wearing short-sleeved shirts and shorts continuously).The trial found that wearing long-sleeved shirts and trousers significantly reduced the incidence of malaria (2/150 [1%] with long-sleeved shirts v 62/150 [41%] with short-sleeved shirts; RR and CI not reported). The trial provided no information on denominators, the design or conduct of the study, statistical analysis, or confounders. We also found one case control study (144 expatriates staying in the Central African Republic for more than 4 months), which found that wearing clothes covering arms or legs in the evening or at night significantly reduced malaria acquisition (OR 0.13, 95% CI 0.02 to 0.65, P = 0.01). We also found one large questionnaire survey (89,617 European tourists returning from East Africa), which found that wearing long-sleeved shirts and trousers significantly reduced the incidence of malaria (P = 0.02).

Other lifestyle changes:

We found no studies (see comment below).

Harms

None.

Comment

Other lifestyle changes:

Other lifestyle changes include not travelling to malaria-endemic regions during the rainy season (when most malaria transmission occurs) and not going outdoors in the evening or at night.

Clinical guide:

Travellers who take day trips from a malaria-free city to a malaria-endemic region may be at minimal risk if they return to the city before dusk. Some authors suggest wearing light-coloured rather than dark clothing, as insects prefer landing on dark surfaces. However, we found no reliable evidence about the effects of wearing light-coloured clothing. Full-length clothing may prevent malaria in travellers.

Substantive changes

Lifestyle changes (including full-length clothing, light clothing, behaviour modification) in non-pregnant adult travellers One case control study added;categorisation unchanged (Unknown effectiveness).

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Skin-applied chemical repellents in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of skin-applied chemical repellents to prevent malaria in travellers. However, two RCTs and one case control study of DEET-containing repellent soap in residents in Asia and South America found that use of soap was associated with reduced malaria incidence. Extensive clinical experience of DEET has led to the consensus that it is likely to be beneficial in preventing malaria. DEET has been reported to cause systemic and skin adverse reactions, particularly with prolonged use. Picaridin is a newer, and possibly safer and more effective, chemical repellent than DEET, but it has not yet been evaluated against clinical outcomes.

Benefits

We found no systematic review or RCTs on the effects of skin-applied chemical repellents to prevent malaria in travellers. However, we found two RCTs, one case control study,and one field study of repellent soap (containing 20% DEET and 0.5% permethrin) in residents. The first RCT, which randomised communities in rural Ecuador and Peru (8272 people over 1 year), found no significant difference in the incidence of malaria between repellent soap compared with no soap (protective efficacy of repellent soap 0% in Ecuador and 26% in Peru; reported as non-significant).The RCT reported that continuous soap use was only carried out by 50–70% of participants. The second RCT (127 Afghan refugee village households in Pakistan, 1148 people, over 6 months) found that repellent soap significantly reduced the number of people experiencing one or more episodes of P falciparum malaria compared with placebo lotion, (23/618 [4%] using repellent soap v 47/530 [9%] using placebo lotion; OR 0.44, 95% CI 0.25 to 0.76). The case control study (96 cases of P falciparum and P vivax malaria, resident in Nangahar province, eastern Afghanistan) found that recalled use of repellent soap around the likely time of infection (10 days before) significantly reduced malaria infection (OR 0.08, 95% CI 0.01 to 0.61, P less than 0.001). The field study of picaridin in Burkina Faso (more than 49,000 mosquitoes collected, over 96 nights, of which more than 95% were of the Anopheles gambiae complex) found that, after 10 hours of exposure, picaridin reduced the number of mosquitoes landing on the test humans compared with DEET ( 3698 mosquitoes with picaridon v 6836 mosquitoes with DEET; significance not reported for this comparison).

Harms

We found one case series of systemic toxic reactions (confusion, irritability, insomnia) in US national park employees after repeated and prolonged use of DEET. We found 14 case reports of contact urticaria and irritant contact dermatitis (mostly in soldiers) as a result of DEET. The risk of absorption is especially high if DEET is left in the antecubital fossa overnight. DEET also damages leather and some synthetic clothing fibres, and degrades plastics, such as eyeglass frames.Unlike DEET, picaridin is odourless and non-sticky, and does not damage plastics or fabrics; it has shown no evidence of carcinogenicity or teratogenicity in animal studies. The first RCT reported that skin irritation was rare. The second RCT reported that one person had skin irritiation.The case control study reported that one person described a burning sensation while using the soap.The field study gave no information on adverse effects.

Comment

Larger RCTs are needed to compare DEET versus other topical (skin-applied) repellents and placebo in preventing malaria.

Clinical guide:

Five decades of experience of DEET have led to consensus that it is effective in preventing malaria in travellers. Picaridin may be a more effective repellent than DEET, but it has not yet been evaluated against clinical outcomes.

Substantive changes

Skin applied chemical repellents in non-pregnant adult travellers Two RCTs, one case control study, and one field study added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Skin-applied plant-based repellents in non-pregnant adult travellers

Summary

We found no evidence on the effects of skin-applied plant-based repellents to prevent malaria in travellers. We found one RCT assessing the effects of skin-applied plant-based repellants on mosquito landing catches, providing insufficient evidence to assess whether these substances are effective in preventing malaria.

Benefits

We found no systematic review or RCTs in travellers that assessed the effects of skin-applied plant-based repellants on malaria acquisition rates.

Harms

The studies did not report on the tolerability or potential adverse effects of the plant-based repellents used.

Comment

We found one small RCT and two very small non-randomised studies that assessed mosquito landings. The small RCT (unspecified number of adult volunteers in rural India, 683 anopheline mosquitoes collected over 10 nights) found that neem oil mixed at 2% strength in coconut oil applied at around 1800 hours to face, arms and legs gave better protection against anopheline landing over 12 hours than placebo coconut oil (0 mosquitoes in 2% neem oil v 144 mosquitoes in placebo control; percentage protection 100%; P value not reported). The first non-randomised study (5 adult volunteers in rural northeast Bolivia, 8855 mosquitoes collected, more than 80% anopheline, over 25 nights) compared lemon eucalyptus in isopropanol applied at 1830 hours to the legs versus control (baby oil in 10% ethanol). It found that lemon eucalyptus significantly reduced mosquito landing over 4 hours compared with control (97% protection, P value reported as significant). The study also found that 2% neem oil in alcohol did not significantly reduce mosquito landing over 4 hours compared with baby oil in ethanol (2% neem oil 57% protection; reported as non-significant). The second non-randomised study (8 adult volunteers in rural India, unspecified number of mainly culicine mosquitoes collected, over 20 nights) found that, when applied at dusk to hands, face, and feet, both 1 ml of Cymbopogan martinii martinii var. Sofia (palmarosa oil) and Cymbopogan citratus (lemon grass oil) each reduced mosquito landing compared with untreated controls from dusk to dawn (palmarosa oil 97.0% protection, lemon grass oil 96.9% protection; P value not reported). Using skin-applied plant-based repellents to prevent malaria may be more acceptable to certain travellers than using chemical repellents, and may also be safer. However, there is only weak evidence that these substances are effective for this indication.

Clinical guide:

As with chemical repellents, the duration of protection of plant-based repellents depends on a number of factors, including amount of repellent applied, ambient humidity, rate of sweating, etc. Under study conditions, a duration of protection of 11.0 hours has been recorded for both Cymbopogan martinii martinii var. Sofia (palmarosa oil) and Cymbopogan citratus (lemon grass oil).

Substantive changes

Skin-applied plant-based repellents in non-pregnant adult travellers New option added; no RCT evidence assessing malaria acquisition identified; categorised as Unknown effectiveness.

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Bath or chemical base oils in non-pregnant adult travellers

Summary

We found no evidence of sufficient quality on the effects of bath or chemical base oils to prevent malaria in travellers.

Benefits

We found no systematic review or RCTs in travellers, and no studies with clinical outcomes. We found one non-randomised controlled trial using mosquito landing catches as an outcome. The non-randomised study (8 adult volunteers in rural India, unspecified number of mainly culicine mosquitoes collected, over 20 nights) found that 1 ml of mylol, applied to hands, face, and feet, reduced mosquito landing compared with untreated controls from dusk to dawn (96% protection; P value not reported).

Harms

The study did not report on the adverse effects of mylol.

Comment

Clinical guide:

Bath oils, and possibly chemical base oils, seem to protect against insect biting not by a repellant action, but by forming a physical barrier between the human target and the insect.Using bath or chemical base oils to prevent malaria may be more acceptable to certain travellers than using chemical repellents, and may also be safer. However, there is only weak evidence that these substances are effective for this indication.

Substantive changes

Bath or chemical base oils in non-pregnant adult travellers New option added; no RCT evidence identified; categorised as Unknown effectiveness.

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Dietary supplementation in non-pregnant adult travellers

Summary

We found no evidence on the effects of dietary supplementation in preventing malaria in travellers. We found three non-randomised trials that did not show any repellent effect of vitamin B when mosquito landings were used as the outcome.

Benefits

We found no systematic review or RCTs in travellers that assessed effects of dietary supplementation on malaria acquisition rates.

Harms

We found no RCTs.

Comment

We found three non-randomised controlled trials (reported in two papers) that assessed effects on mosquito landing catches. The first non-randomised trial (18 North American adult volunteers, exposed in a sealed room to 100 female Aedes aegypti mosquitoes for 10 minutes) found no significant difference in the proportion of mosquitoes biting between 200 mg of thiamine chloride (vitamin B1) daily for 3 days and placebo (proportion of mosquitoes which bit people: 50% with thiamine chloride v 38% with controls; P value reported as not significant).The second non-randomised trial (23 North American adult volunteers, glass vial rolled between hands for 2 minutes then vial exposed to 28–32 female Anopheles stephensi mosquitoes for 2 minutes, crossover design) found no significant difference in the number of mosquito landings over 4 weeks after crossover between 1 week's treatment with vitamin B complex multivitamin tablet (that included vitamin C) daily and vitamin C 500 mg control (absolute figures not reported, P greater than 0.9). The second non-randomised trial (17 North American adult volunteers, glass vial rolled between hands for 2 minutes then vial exposed to 28–32 female Anopheles stephensi mosquitoes for 2 minutes, crossover design) found no significant difference between vitamin B1 100 mg three times daily for one day and vitamin C 250 mg control in the number of mosquito landings over 4 weeks after crossover (absolute figures not reported, P greater than 0.9 for both interventions v control).The studies gave no information on adverse effects.

Clinical guide:

There is evidence that dietary supplementation with vitamin B has no repellent effect on healthy mosquitoes. However, vitamin B1, along with garlic and other dietary and herbal agents, is popularly recommended as malaria prophylaxis. Dietary supplementation to prevent malaria may be more acceptable to some travellers than antimalaria drugs, but there is no evidence that it is effective for this indication.

Substantive changes

Dietary supplementation in non-pregnant adult travellers New option added. No RCT evidence identified. Categorised as Unknown effectiveness.

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Primaquine in non-pregnant adult travellers

Summary

One RCT found that primaquine had a protective efficacy of 94% for P falciparum and 85% for P vivax malaria in non-immune soldiers. It found that, in some people, primaquine was associated with severe epigastric pain, abdominal pain, or vomiting. Primaquine can cause potentially lethal acute intravascular haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and methaemoglobinaemia in people with normal G6PD activity. The small risk of severe haemolysis outweighs the possible benefit from using primaquine to prevent malaria.

Benefits

We found no systematic review but found one RCT. The RCT (176 non-immune Colombian soldiers, aged 18–42 years) compared primaquine (30 mg/day) versus placebo over a 16-week period. It found that the protective efficacy of primaquine was 94% (95% CI 78% to 99%) for P falciparum infection and 85% (95% CI 57% to 95%) for P vivax infection.

Harms

The RCT found that primaquine was associated with severe epigastric pain, abdominal pain, or vomiting in 3/122 (2.5%) of participants. There were no severe adverse effects with placebo. Although neither RCT reported any such events, it is important to note that primaquine can cause acute intravascular haemolysis in people with glucose-6-phosphate dehydrogenase (G6PD) deficiency, and methaemoglobinaemia in people with normal G6PD activity.

Comment

Primaquine versus chloroquine:

We found one non-randomised controlled trial (99 non-immune Indonesian males, aged 7–59 years, migrating to a malaria-endemic setting), which compared primaquine (0.5 mg/kg every 2 days) versus chloroquine (5 mg/kg weekly) over 16–19 weeks in an area of chloroquine resistance. It found that, compared with chloroquine, primaquine reduced P falciparum malaria (RR 0.25, 95% CI 0.08 to 0.83; P = 0.014) and P vivax malaria (RR 0.10, 95% CI 0.005 to 0.71; P = 0.012). It also found that primaquine was associated with significantly fewer adverse effects than chloroquine over 16 weeks (total adverse effects: 17 with primaquine v 114 with chloroquine; P less than 0.0001). We also found one systematic review (search date 2005) in Spanish, which is being translated and will be considered for inclusion in when we perform the next update of this review.

Clinical guide:

The small risk of severe and possibly fatal haemolysis makes the risk–benefit ratio unacceptable when using primaquine to prevent malaria. Severe haemolytic events have occasionally occurred in trials of primaquine/primaquine analogues, even when the participants had been carefully pre-screened for G6PD deficiency.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Chloroquine in non-pregnant adult travellers

Summary

We found no systematic review or RCTs on the effects of chloroquine in travellers. One RCT in Austrian workers residing in Nigeria found no significant difference in the incidence of malaria after 6–22 months between chloroquine and sulfadoxine–pyrimethamine. P falciparum resistance to chloroquine is now established in most malaria-endemic regions. However, clinical experience has led to the consensus that chloroquine is effective for preventing malaria in people travelling to areas where no chloroquine resistance has developed.

Benefits

We found no systematic review or RCTs in travellers. One RCT (173 Austrian industrial workers residing in Nigeria) found no significant difference in the incidence of malaria after 6–22 months between chloroquine and sulfadoxine–pyrimethamine.

Harms

The RCT found that chloroquine was associated with insomnia in 3/87 (3%) of people. Two people withdrew from the study because of adverse effects, one with skin rash and the other with visual disturbance. Retrospective questionnaire surveys have suggested that severe adverse effects from chloroquine are rare at prophylactic dosages.

Comment

Alcohol consumption, other medication, and comorbidities can modify the effects of antimalaria drugs. P falciparum resistance to chloroquine is now established in most malaria-endemic regions, although there are countries (principally in Central America and the Near East) where there has been no reported resistance.

Chloroquine versus primaquine:

See comment on primaquine.

Clinical guide:

Chloroquine is a low-cost drug, and decades of experience of using it to prevent malaria in regions where there is no parasite resistance to the drug have led to the consensus that it is effective in travellers to these regions (chiefly Central America and the Near East).

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Chloroquine–proguanil in non-pregnant adult travellers

Summary

One RCT found no significant difference in the incidence of P falciparum malaria between chloroquine–proguanil and chloroquine plus pyrimethamine–sulfadoxine. One RCT found no significant difference in the incidence of P falciparum malaria between chloroquine–proguanil and proguanil alone. One RCT found no significant difference between chloroquine–proguanil and atovaquone–proguanil in preventing malaria. RCTs comparing adverse effects of chloroquine–proguanil versus atovaquone–proguanil found different results. One RCT found that chloroquine–proguanil increased adverse effects compared with three other common antimalaria drug regimens (doxycycline, mefloquine, and atovaquone–proguanil). Another RCT found no significant difference in adverse effects between chloroquine–proguanil and atovaquone–proguanil.

Benefits

Chloroquine–proguanil versus chloroquine plus sulfadoxine–pyrimethamine:

We found one open-label RCT (767 Scandinavian travellers to East Africa; 70% of trips were longer than 4 weeks; duration of follow-up not reported) comparing chloroquine–proguanil versus chloroquine plus sulfadoxine–pyrimethamine. It found no significant difference between treatments in rates of P falciparum malaria (4/384 [1.0%] with chloroquine–proguanil v 3/383 [0.7%] with chloroquine plus sulfadoxine–pyrimethamine; RR 1.3, 95% CI 0.3 to 5.9).

Chloroquine–proguanil versus proguanil alone:

We found one RCT (1625 Dutch travellers to Africa; 60% spent less than 6 weeks in tropical areas). It found no significant difference in incidence of P falciparum malaria 4 weeks after returning to the Netherlands between chloroquine 300 mg weekly plus proguanil 200 mg daily and proguanil alone (risk per 100 person months: 2.8, 95% CI 0.9 to 10.1 with chloroquine–proguanil v 6.0, 95% CI 2.6 to 14.0 with proguanil alone).

Chloroquine–proguanil versus atovaquone–proguanil:

See benefits of atovaquone–proguanil in adults.

Harms

Chloroquine–proguanil versus chloroquine plus sulfadoxine–pyrimethamine:

In the RCT conducted in Scandinavian travellers, adverse effects associated with chloroquine–proguanil were nausea (3%), diarrhoea (2%), and dizziness (1%).

Chloroquine–proguanil versus proguanil alone:

One cohort study (470 British soldiers in Belize) found that the risk of mouth ulcers almost doubled with chloroquine–proguanil compared with proguanil alone (P = 0.025).

Chloroquine–proguanil versus atovaquone–proguanil:

See harms of atovaquone–proguanil.

Chloroquine–proguanil versus doxycycline:

See harms of doxycycline.

Chloroquine–proguanil versus mefloquine:

See harms of mefloquine.

Comment

The incidence of confirmed P falciparum malaria in both trials was so low that a clinically important effect cannot be excluded. The RCT that compared adverse effects of four different drug regimens was not powered to assess malaria prevention. It found no cases of malaria with any treatment. The RCT tested the difference in tolerability between all four treatments but did not compare any two interventions versus each other directly.

Clinical guide:

Chloroquine–proguanil is a complex two-drug regimen, and consensus from two decades of use, together with more recent evidence from one RCT, suggests that it may have similar benefits to atovaquone–proguanil for preventing malaria in travellers. However, chloroquine–proguanil is poorly tolerated.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Doxycycline in non-pregnant adult travellers

Summary

One RCT in soldiers and one RCT in migrants with limited immunity found that doxycycline reduced the risk of malaria compared with placebo. The RCT in soldiers found a similarly low incidence of malaria with doxycyline and mefloquine. One of the RCTs found that, over 13 weeks, doxycycline was associated with nausea and vomiting, diarrhoea, cough, headache, and unspecified dermatological symptoms. We found no evidence on long-term safety. One RCT found that doxycycline had fewer adverse effects than mefloquine or chloroquine–proguanil, and had similar adverse-effect rates compared with atovaquone–proguanil.

Benefits

We found no systematic review but found two RCTs.

Doxycycline versus placebo:

The first RCT (136 Indonesian soldiers) compared doxycycline versus mefloquine versus placebo in a malaria-endemic setting (see comment below). It found that, in an area of drug resistance, doxycycline significantly reduced the risk of malaria compared with placebo after a 13–15 week period of prophylaxis (AR: 1/67 [2%] with doxycycline v 53/69 [77%] with placebo; RR 0.02, 95% CI 0.003 to 0.14). The second RCT (300 Indonesian migrants with limited immunity) comparing azithromycin versus doxycycline versus placebo found that doxycycline significantly reduced the incidence of malaria compared with placebo over 20 weeks (2/75 [3%] cases of P falciparum malaria with doxycycline v 29/77 [38%] with placebo; RR 0.07, 95% CI 0.02 to 0.29; NNT 3, 95% CI 2 to 4; 1/75 [2%] cases of P vivax malaria with doxycycline v 27/77 [35%] with placebo; RR 0.04, 95% CI 0.01 to 0.28).

Doxycycline versus mefloquine:

The first RCT (136 Indonesian soldiers) found that doxycycline and mefloquine were similarly effective at reducing the risk of malaria after a 13–15 week period of prophylaxis (AR: 1/67 [2%] with doxycycline v 0/68 [0%] with mefloquine; significance assessment not performed).

Harms

Doxycycline versus placebo:

The first RCT found that doxycycline was associated with gastrointestinal symptoms (including nausea and vomiting, abdominal pain, and diarrhoea) in 16/67 (24%) soldiers, unspecified dermatological problems in 22/67 (33%), cough in 21/67 (31%), and headache in 11/67 (16%) over 13 weeks.

Doxycycline versus mefloquine, chloroquine–proguanil, or atovaquone–proguanil:

The first RCT found that, compared with mefloquine, doxycycline reduced headache (11/67 [16%] with doxycycline v 25/68 [37%] with mefloquine; P less than 0.01) and dizziness (6/67 [9%] with doxycycline v 18/68 [26%]; P less than 0.01) over 13 weeks. One RCT (623 non-immune travellers to sub-Saharan Africa) compared four chemoprophylaxis regimens (doxycycline, mefloquine, chloroquine–proguanil, and atovaquone–proguanil) started 17 days before travel and continued for 4 weeks after return. It found that doxycycline reduced adverse effects compared with mefloquine and chloroquine–proguanil, and had similar adverse-effect rates compared with atovaquone–proguanil (severe adverse effects: 12% with chloroquine–proguanil v 11% with mefloquine v 7% with atovaquone–proguanil v 6% with doxycycline; P = 0.14; mild to moderate adverse effects: 45% with chloroquine–proguanil v 42% with mefloquine v 33% with doxycycline v 32% with atovaquone–proguanil; P = 0.048 for comparison of all 4 treatments). See comment below.

Observational studies:

One questionnaire survey (383 returned Australian travellers taking doxycycline) found that 15% reported nausea or vomiting, 12% reported diarrhoea, and 9% of female travellers reported vaginitis. Evidence from case reports suggests that, in sunny conditions, up to 50% of travellers using doxycycline may experience photoallergic skin rash.

Comment

Most drug trials in travellers have been conducted in soldiers, and the results may not be generalisable to tourists or business travellers. Both RCTs were three-arm, parallel studies. Only the doxycycline versus placebo comparisons are reported here. The RCT that compared adverse effects of four different drug regimens was not powered to assess malaria prevention. It found no cases of malaria with any treatment. The RCT tested the difference in tolerability between all four treatments but did not compare any two interventions versus each other directly.

Clinical guide:

Doxycycline is a low-cost, once-daily drug regimen for which there is evidence of benefit, but which is contraindicated in children and in pregnancy.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Mefloquine in non-pregnant adult travellers

Summary

One systematic review of one RCT in soldiers found that mefloquine reduced cases of malaria compared with placebo, and that mefloquine had a protective efficacy of 100%. Three RCTs in non-military travellers found that mefloquine increased neuropsychiatric adverse effects compared with placebo or alternative chemoprophylaxis.

Benefits

We found one systematic review and one subsequent RCT.

Mefloquine versus placebo:

We found one systematic review (search date 2002), which identified one RCT (203 Indonesian soldiers) comparing three interventions: mefloquine, doxycycline, and placebo, in a malaria-endemic setting (see comment below). It found that, compared with placebo, mefloquine had a protective efficacy of 100% (95% CI 93% to 100%) after up to 15 weeks of treatment (malaria cases: 0/202 person months of exposure with mefloquine v 53/109 person months of exposure with placebo).

Mefloquine versus atovaquone–proguanil:

The subsequent RCT (976 people) compared mefloquine plus placebo versus atovaquone–proguanil. It found no clinical cases of malaria among people included in the trial.

Mefloquine versus doxycycline:

See benefits of doxycycline.

Harms

Mefloquine versus placebo:

The review found significantly more withdrawals with mefloquine than with placebo (4 RCTs, 1382 people; RR 3.38, 95% CI 1.62 to 7.03). We found one additional RCT that exclusively examined adverse effects of a single dose of mefloquine versus placebo. It found that mefloquine increased the risk of neuropsychiatric adverse effects (mainly sleep disturbances, strange dreams, and inability to concentrate) compared with placebo (100 adult travellers; 13/59 [22%] with mefloquine v 3/31 [10%] with placebo; RR and CI not reported, see comment below).

Mefloquine versus chloroquine or doxycyline:

The systematic review identified 10 RCTs (275 people) of mefloquine for 2–15 weeks of treatment. It found no significant difference between mefloquine and alternative antimalaria prophylaxis (chloroquine or doxycycline) in withdrawal (29/863 [3%] with mefloquine v 20/798 [2%] with alternative prophylaxis; RR 1.32, 95% CI 0.75 to 2.31). Commonly reported adverse effects associated with mefloquine were headache (16%), insomnia (15%), and fatigue (8%). The review found more than 500 case reports of adverse effects of mefloquine, including four reports of death.

Mefloquine versus doxycycline:

See harms of doxycycline.

Mefloquine versus chloroquine–proguanil:

One RCT (623 non-immune travellers to sub-Saharan Africa) compared four chemoprophylaxis regimens (chloroquine–proguanil, mefloquine, doxycycline, and atovaquone–proguanil) started 17 days before travel and continued for 4 weeks after return.It found that mefloquine had similar adverse-event rates to chloroquine–proguanil, and more adverse effects than doxycycline or atovaquone–proguanil (severe adverse effects: 12% with chloroquine–proguanil v 11% with mefloquine v 7% with atovaquone–proguanil v 6% with doxycycline; P = 0.14; mild to moderate adverse effects: 45% with chloroquine–proguanil v 42% with mefloquine v 32% with atovaquone–proguanil v 33% with doxycycline; P = 0.048 for comparison of all 4 treatments). Mefloquine was associated with the highest rate of moderate to severe neuropsychological adverse effects (37% with mefloquine v 30% with chloroquine–proguanil v 24% with doxycycline v 20% with atovaquone–proguanil; P = 0.003). See comment below.

Mefloquine versus atovaquone–proguanil:

The subsequent RCT (976 non-immune tourists and business travellers) found no significant difference in the risk of adverse effects between mefloquine plus placebo and atovaquone–proguanil (324/483 [67%] with mefloquine plus placebo v 313/493 [63%] with atovaquone–proguanil; ARR +2.6%, 95% CI –3.4% to +8.5%). However, when adverse effects specifically attributable to the study drug were analysed, there were significantly more adverse effects caused by mefloquine plus placebo than by atovaquone–proguanil (204/483 [42%] with mefloquine plus placebo v 149/493 [30%] with atovaquone–proguanil; RR 1.40, 95% CI 1.18 to 1.66; NNH 9, 95% CI 6 to 17; see comment below). Specifically, mefloquine plus placebo increased the incidence of “strange or vivid dreams” compared with atovaquone–proguanil (66/483 [14%] with mefloquine plus placebo v 33/493 [7%] with atovaquone–proguanil), insomnia (65/483 [13%] v 15/493 [3%]), dizziness or vertigo (43/483 [9%] v 11/493 [2%]), anxiety (18/483 [4%] v 3/493 [1%]), depression (17/483 [4%] v 3/493 [1%]), visual difficulties (16/483 [3%] v 8/493 [2%]), and headache (32/483 [7%] v 19/493 [4%]). Another RCT (623 non-immune travellers to sub-Saharan Africa) compared four chemoprophylaxis regimens: mefloquine; chloroquine–proguanil; doxycycline; and atovaquone–proguanil. It found that mefloquine had more adverse effects than atovaquone–proguanil (see mefloquine versus chloroquine–proguanil, above, for full details of this trial).

Observational studies:

Retrospective questionnaire surveys in tourists and business travellers also found that sleep disturbance and psychosis were common with mefloquine. One review of 74 dermatological case reports found that up to 30% of mefloquine users developed a maculopapular rash, and 4–10% had pruritus. Ten cohort studies in tourists found that more women than men experienced adverse effects (including dizziness, sleep disturbance, headache, diarrhoea, and nausea) with mefloquine. One case control study (564 Dutch travellers between 1997–2000) found that the risk of psychiatric events was significantly higher among people taking mefloquine than in people not taking drug prophylaxis (mefloquine use: 21% in people with psychiatric events v 9% in controls; adjusted OR 3.5, 95% CI 1.4 to 8.7). This increase was greater among women (mefloquine use: 22% in women with psychiatric events v 7% in controls; adjusted OR 47.1, 95% CI 3.8 to 578.6). One retrospective questionnaire survey of 93,668 European travellers to East Africa found that elderly travellers experienced fewer adverse reactions (not reported) with mefloquine than younger travellers (P less than 0.05). A review of 516 published case reports suggested that many of mefloquine's adverse effects could be explained as a posthepatic syndrome owing to mefloquine use combined with concurrent insults to the liver (such as from alcohol, dehydration, oral contraceptive pills, recreational drugs, and other liver-damaging drugs), and that in some users mefloquine may also cause a symptomatic thyroid disturbance.

Comment

The RCT in Indonesian soldiers was a three-arm parallel RCT. It compared mefloquine (68 people) versus doxycycline (67 people) versus placebo (69 people). Only the comparison of mefloquine versus placebo is included here. Early RCTs of mefloquine prophylaxis were carried out in soldiers and suggested good tolerability, but military drug trials cannot be generalised owing to higher rates of co-medications and co-morbidities in non-military groups. RCTs in mefloquine prophylaxis in non-military travellers found an excess of neuropsychiatric adverse effects in the mefloquine arm. The second RCT had two mefloquine arms, with different formulations of the drug. The RCT comparing mefloquine versus atovaquone–proguanil suggested a higher rate of adverse effects with mefloquine than in previous studies, but this RCT only reported adverse effects occurring after starting active treatment, which was 3 weeks earlier in the mefloquine group than in the atovaquone–proguanil group.

Clinical guide:

Mefloquine is useful to treat malaria, but there is strong evidence of harm with its use at current dosages to prevent malaria, especially in women.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Atovaquone–proguanil in non-pregnant adult travellers

Summary

One RCT in migrants with limited immunity and one RCT in non-immune soldiers found that atovaquone–proguanil reduced the proportion of people with malaria compared with placebo. Another RCT found no significant difference between atovaquone–proguanil and chloroquine–proguanil in preventing malaria. A third RCT comparing atovaquone–proguanil versus mefloquine found no cases of clinical malaria throughout the trial, but found a higher rate of neuropsychiatric harm with mefloquine than with atovaquone–proguanil. One RCT found that atovaquone–proguanil reduced adverse effects compared with mefloquine and chloroquine–proguanil, and had similar adverse-effect rates compared with doxycycline. Another RCT found no significant difference in adverse effects between atovaquone–proguanil and chloroquine–proguanil.

Benefits

We found no systematic review, but found four RCTs.

Atovaquone–proguanil versus placebo:

We found two RCTs. The first RCT (299 Indonesian migrants with limited immunity) found that atovaquone–proguanil significantly decreased the proportion of people with malaria at 24 weeks compared with placebo (AR 3/150 [2%] with atovaquone–proguanil v 37/149 [25%] with placebo; P less than 0.001).The second RCT (180 non-immune Colombian soldiers) found lower rates of malaria with atovaquone–proguanil, used for the duration and for one week, after a 10–16 week residence in an endemic area, than with placebo (9/120 [8%] with atovaquone–proguanil v 19/60 [32%] with placebo; P value not reported ).

Atovaquone–proguanil versus chloroquine–proguanil:

One multicentre RCT (1083 travellers) comparing atovaquone–proguanil versus chloroquine–proguanil found no significant difference in the incidence of malaria after 9 weeks (1/511 [0.2%] case of P ovale malaria with atovaquone–proguanil v 3/511 [0.6%] cases of P falciparum malaria with chloroquine–proguanil; ARR 0.4%; RR 0.33, 95% CI 0.03 to 3.16).

Atovaquone–proguanil versus mefloquine:

See benefits of mefloquine in adults.

Harms

Atovaquone–proguanil versus placebo:

The RCT found that stomatitis (P less than 0.001) and back pain (P = 0.009) occurred significantly more frequently in the atovaquone–proguanil group, whereas abdominal pain (P = 0.02) and malaise (P = 0.01) occurred significantly more frequently with placebo (absolute numbers not reported).Four people had severe adverse effects that were possibly drug-related (3 people with abdominal pain and 1 with skin rash). In the second RCT, headache was more commonly reported with atovaquone–proguanil (7% with atovaquone–proguanil v 3% with placebo; absolute numbers and P values not reported), as was fever (5% with atovaquone–proguanil v 0% with placebo; absolute numbers and P values not reported) .I

Atovaquone–proguanil versus chloroquine–proguanil:

The multicentre RCT in travellers found no significant difference between atovaquone–proguanil and chloroquine–proguanil in the proportion of people who one or more adverse effect (311/511 [61%] with atovaquone–proguanil v 329/511 [64%] with chloroquine–proguanil; RR 0.95, 95% CI 0.85 to 1.04). Common adverse effects were mainly gastrointestinal (diarrhoea: 5% with atovaquone–proguanil v 7% with chloroquine–proguanil; mouth ulcers: 4% v 5%; abdominal pain: 3% v 6%; and nausea: 2% v 7%), neuropsychiatric (strange/vivid dreams: 4% with atovaquone–proguanil v 3% with chloroquine–proguanil; dizziness: 3% v 4%; insomnia: 2% v 2%), and visual difficulties (2% with atovaquone–proguanil v 2% with chloroquine–proguanil). Another RCT (623 non-immune travellers to sub-Saharan Africa) compared four chemoprophylaxis regimens (atovaquone–proguanil, chloroquine–proguanil, mefloquine, and doxycycline) started 17 days before travel and continued for 4 weeks after return. It found that atovaquone–proguanil reduced severe (requiring medical advice) adverse effects compared with chloroquine–proguanil, but did not report the significance of the difference between groups (11/164 [7%] with atovaquone–proguanil v 19/153 [12%] with chloroquine–proguanil; significance of between-group difference not reported). It also found lower rates of mild to moderate adverse effects with atovaquone–proguanil than with chloroquine–proguanil (32% with atovaquone–proguanil v 45% with chloroquine–proguanil; significance of between-group difference not reported).

Atovaquone–proguanil versus doxycycline:

See harms of doxycycline.

Atovaquone–proguanil versus mefloquine:

See harms of mefloquine in adults.

Comment

Clinical guide:

Atovaquone–proguanil is a high-cost, once-daily drug regimen for which there is evidence of benefit.

Substantive changes

Atovaquone–proguanil in non-pregnant adult travellers One RCT added. Categorisation unchanged (Likely to be beneficial).

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Amodiaquine in non-pregnant adult travellers

Summary

We found no RCTs on the effects of amodiaquine in preventing malaria in travellers. We found limited observational evidence that amodiaquine may cause neutropenia, liver damage, and hepatitis. Amodiaquine use is now restricted to treatment rather than prevention of malaria in resource-rich countries because of concern about adverse effects.

Benefits

We found no systematic review and no RCTs in travellers.

Harms

One retrospective cohort study in 10,000 British travellers taking prophylactic amodiaquine for 6–13 weeks reported severe neutropenia in about 1/2000 users. We found 28 case reports describing liver damage or hepatitis in travellers who had taken amodiaquine for about 2 months to treat or prevent malaria.

Comment

Clinical guide:

Amodiaquine is useful to treat malaria, but there is evidence of harm with its use at current dosages to prevent malaria. Amodiaquine use is now restricted to treatment rather than prevention of malaria in resource-rich countries because of concern about adverse effects.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Pyrimethamine–dapsone in non-pregnant adult travellers

Summary

We found no RCTs in travellers. One RCT in Thai soldiers found insufficient evidence to compare pyrimethamine–dapsone versus proguanil-dapsone. We found limited observational evidence that pyrimethamine–dapsone may cause agranulocytosis.

Benefits

We found no systematic review or RCTs in travellers. One RCT in Thai soldiers comparing pyrimethamine–dapsone versus proguanil-dapsone found no significant difference in P falciparum infection rates over 40 days (10% with proguanil-dapsone v 11% with pyrimethamine–dapsone; results presented graphically, P value not reported). It found a significantly lower P vivax infection rate with proguanil-dapsone than with pyrimethamine–dapsone (2% with proguanil-dapsone v 12% with pyrimethamine–dapsone; results presented graphically, P less than 0.001).

Harms

The RCT in Thai soldiers found that less than 2% reported any drug-related symptoms from pyrimethamine–dapsone. One retrospective cohort study in 15,000 Swedish travellers taking pyrimethamine–dapsone reported agranulocytosis in about 1/2000 users.

Comment

Clinical guide:

Pyrimethamine–dapsone is not currently licensed to prevent malaria.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Pyrimethamine–sulfadoxine in non-pregnant adult travellers

Summary

We found no RCTs of pyrimethamine–sulfadoxine alone. One RCT found no significant difference between chloroquine–proguanil and chloroquine plus pyrimethamine–sulfadoxine in the incidence of P falciparum malaria. One retrospective observational study suggested that pyrimethamine–sulfadoxine was associated with severe cutaneous reactions. Pyrimethamine–sulfadoxine is not currently licensed in the UK for the prevention of malaria.

Benefits

We found no systematic review or RCTs of pyrimethamine–sulfadoxine alone.

Sulfadoxine–pyrimethamine plus chloroquine versus chloroquine–proguanil:

See benefits of chloroquine–proguanil in adults.

Harms

One retrospective observational study in 182,300 US travellers taking weekly prophylactic pyrimethamine–sulfadoxine reported severe cutaneous reactions (erythema multiforme, Stevens–Johnson syndrome, and toxic epidermal necrolysis) in 24 people (1/5000–1/8000) after a mean of 3.4 weeks of use. The associated mortality was about 1/11,000–1/25,000 users.

Comment

Clinical guide:

Pyrimethamine–sulfadoxine is not currently licensed in the UK for the prevention of malaria.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Vaccines in adult and child travellers

Summary

We found no systematic review or RCTs on antimalarial vaccines in travellers. One systematic review in residents found no significant difference in episodes of clinical malaria between blood-stage vaccines and placebo. Another review in residents found that one pre-erythrocytic vaccine (RTS,S) reduced clinical episodes of malaria compared with placebo, but found no significant difference between three other pre-erythrocytic stage vaccines (CS-NANP, CS102 peptide, ME-TRAP) and placebo. A third review of antimalaria vaccines in residents of malaria-endemic areas found that the SPf66 vaccine reduced first attacks of P falciparum malaria compared with placebo.

Benefits

We found no systematic review or RCTs of antimalaria vaccines in travellers. We found three systematic reviews assessing antimalaria vaccines in residents. The first review (search date 2006) identified two RCTs (137 people) assessed the effects of blood-stage vaccines on clinical malaria in residents of malaria-endemic regions. The largest RCT (120 children aged 5–9 years) identified by the review assessed participants exposed to natural challenge. It found no significant difference in episodes of clinical malaria between MSP/RESA (a blood-stage vaccine) and placebo (RR 1.64, 95% CI 0.94 to 2.85 in non-pre-treated participants; RR 1.25, 95% CI 0.71 to 2.20 in those pre-treated with sulfadoxine–pyrimethamine). The second review (search date 2006, 11 RCTs, more than 3000 people) found that one pre-erythrocytic vaccine (RTS,S) significantly reduced clinical episodes of malaria compared with placebo (2 RCTs, 1911 participants, RR 0.76 95% CI 0.66 to 0.88).However, the review found no significant difference in clinical episodes of malaria between three other pre-erythrocytic stage vaccines (CS-NANP, CS102 peptide, ME-TRAP ) and placebo (RRs non-significant for all vaccines v placebo). The third review (search date 2005, 10 RCTs, 9698 people) found that SPf66 vaccine significantly reduced new episodes of clinical P falciparum malaria compared with placebo (9 RCTs, 7399 people, RR 0.90, 95% CI 0.84 to 0.96). However, when examined geographically, subgroup analyses found no significant difference in new episodes of clinical malaria in Africa between SPf66 and placebo (4 RCTs, 2371 people, RR 0.98, 95% CI 0.90 to 1.07) or in Asia (1 RCT, 1221 people, RR 1.06, 95% CI 0.90 to 1.25). The review found that SPf66 significantly reduced new episodes of clinical malaria in South America (4 RCTs, 3087 people, RR 0.72, 95% CI 0.63 to 0.82).

Harms

Vaccine-related adverse effects with the blood-stage and pre-erythrocytic vaccines were mainly increased rates of local reactions (mainly injection-site pain, swelling, arm motion limitation, headache, and malaise). RCTs assessing SPf66 vaccine identifed by the third review also reported increases in local reactions, and also found systemic reactions (whole-body reactions including fever, headache, gastric symptoms, and dizziness) in as many as 67% of participants receiving the vaccine.

Comment

Clinical guide:

There is currently no licensed vaccine to prevent malaria.

Substantive changes

Vaccines against malaria Three systematic reviews assessing antimalaria vaccines in residents added. Categorisation unchanged for vaccines in travellers (Unknown effectiveness)

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Topical (skin-applied) insect repellents containing DEET (diethyl-3-methyl-benzamide) in child travellers

Summary

We found no RCTs on the effects of DEET in preventing malaria in child travellers. However, many years of clinical experience have led to the consensus that using the topical insect repellent DEET is likely to beneficial in preventing malaria. Case reports in young children found serious adverse effects with DEET.

Benefits

We found no systematic review or RCTs.

Harms

We found 13 case reports of encephalopathic toxicity in children aged under 8 years after excessive use (not clearly defined) of topical (skin-applied) insect repellents containing DEET (diethyl-3-methyl-benzamide).

Comment

Clinical guide:

Infants and young children have thinner skin and greater surface area to mass ratio. Decades of experience of using DEET to prevent malaria in children have led to consensus that it is effective, but needs to be used with caution. Some authors advise that ethylhexanediol should be issued as a topical (skin-applied) insect repellent in preference to DEET in children aged 1–8 years.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Antimalaria drugs in child travellers

Summary

Decades of experience of using chloroquine to prevent malaria, in areas where there is no parasite resistance to the drug, have led to the consensus that it is effective in this setting. We found insufficient evidence about the effects of other antimalaria drugs in preventing malaria in child travellers.

Benefits

We found one RCT (multicentre study; 221 non-immune travellers aged 2–17 years), which compared atovaquone–proguanil versus chloroquine–proguanil. It found no cases of malaria in either arm (see comment below). We found no RCTs on the effects of other antimalaria drugs on preventing malaria in child travellers.

Harms

The RCT found no significant difference between atovaquone–proguanil and chloroquine–proguanil in one or more adverse events after about 20–50 days of use (most commonly diarrhoea, abdominal pain, vomiting, nausea, or oral ulceration; 39/110 [35%] with atovaquone–proguanil v 41/111 [37%] with chloroquine–proguanil, RR and CI not reported).

Comment

The RCT was not powered to detect clinically important differences in drug efficacy. Doxycycline is contraindicated in children under 12, as it may cause staining in growing teeth.

Clinical guide:

Chloroquine is a low-cost drug, and decades of experience of using it to prevent malaria, in areas where there is no parasite resistance to the drug, have led to the consensus that it is effective in travellers to these areas, and is safe in children.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Insecticide-treated bed nets in pregnant travellers

Summary

We found no RCTs on the effects of insecticide-treated bed nets in preventing malaria in pregnant travellers. One RCT of pregnant residents of a malaria-endemic area found insufficient evidence on the effects of permethrin-treated bed nets in preventing malaria. Although we found no evidence specifically in pregnant travellers, it is likely that the evidence of benefit from insecticide-treated bed nets in preventing malaria in non-pregnant adults can be generalised to pregnant women travellers.

Benefits

We found no systematic review or RCTs in pregnant travellers. We found one systematic review (search date 2006), which identified five RCTs, four conducted in Africa comparing insecticide-treated bed nets versus no nets, and one conducted in Thailand comparing insecticide-treated bed nets versus untreated nets. The review did not perform a meta-analysis for the outcome of incidence of malaria, which was assessed in three RCTs. The first RCT (503 pregnant women living in Kenya) found no significant difference in the incidence of clinical malaria during pregnancy between insecticide-treated bed nets and no nets (OR 0.85, 95% CI 0.47 to 1.54; absolute numbers not reported). The second RCT (2991 pregnant women living in Kenya) also found no significant difference in the incidence of clinical malaria during pregnancy between insecticide-treated bed nets and no nets (HR 0.72, 95% CI 0.19 to 2.75; absolute numbers not reported). The third RCT (341 pregnant women living in Thailand, followed for a mean of 16.6 weeks, at 3 sites in a malaria-endemic area) found that, at one study site (but not at the other two), permethrin-impregnated bed nets significantly reduced the incidence of malaria in pregnancy compared with untreated nets (RR 0.39, 95% CI 0.37 to 0.82; absolute numbers not reported). The review also found no significant difference in parasite densities between insecticide treated-bed nets and no nets (2 RCTs in Africa, OR 0.93, 95% CI 0.77 to 1.11; absolute numbers not reported). The review did not present results for the outcome of parasite density from the RCT conducted in Thailand comparing insecticide-treated nets versus untreated nets.

Harms

The review gave no information on adverse effects.

Comment

One non-randomised controlled trial (36 pregnant and 36 non-pregnant Gambian women sleeping alone under a bed net in 6 identical huts, for 3 consecutive nights) found that pregnant women were twice as likely as non-pregnant women to be bitten by anopheline mosquitoes (mean bites/night: 6.3 for pregnant women v 3.1 for non-pregnant women; P = 0.0002).

Clinical guide:

Although we found no evidence specifically in pregnant travellers, it is likely that the evidence of benefit from insecticide-treated bed nets in preventing malaria in non-pregnant adults can be generalised to pregnant women travellers (see bed nets in non-pregnant adults). Pregnant travellers are specified as a different group because malaria is more common and more severe in pregnant women, and because antimalaria drugs may have toxic effects on the fetus. Contracting malaria significantly increases the likelihood of miscarriage.

Substantive changes

Insecticide-treated bed nets in pregnant travellers One systematic review added;recategorised as Likely to be beneficial.

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Insecticide-treated clothing in pregnant travellers

Summary

We found no RCTs in pregnant travellers of the effects of insecticide-treated clothing. However, it is likely that the evidence of benefit from insecticide-treated clothing in preventing malaria in non-pregnant adults can be generalised to pregnant women travellers.

Benefits

We found no systematic review or RCTs.

Harms

We found no evidence relating to pregnant travellers.

DEET (diethyl-3-methyl- benzamide):

See harms of topical (skin-applied) insect repellents in pregnant travellers.

Comment

See comment on insecticide-treated bed nets in pregnant travellers.

Clinical guide:

Although we found no evidence specifically in pregnant travellers, it is likely that the evidence of benefit from insecticide-treated bed nets in preventing malaria in non-pregnant adults can be generalised to pregnant women travellers (see insecticide-treated clothing in non-pregnant adults).

Substantive changes

Insecticide-treated clothing in pregnant travellers Evidence re-evaluated. Recategorised as Likely to be beneficial.

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Skin-applied insect repellents in pregnant travellers

Summary

We found no RCTs in pregnant travellers. It is unclear which skin-applied chemical repellents are safe in pregnancy. However, it is likely that the evidence of benefit from skin-applied insect repellants in preventing malaria in non-pregnant adults can be generalised to pregnant women travellers.

Benefits

We found no systematic review or RCTs.

Harms

We found little evidence in pregnant travellers.

DEET:

We found one case report indicating an adverse fetal outcome (mental retardation, impaired sensorimotor coordination, and craniofacial dysmorphology) in a child whose mother had applied DEET daily throughout her pregnancy. One RCT in pregnant women (897 refugees in a Thai forest area of low malaria endemicity) comparing DEET (median dose 214.2 g/pregnancy) versus a cosmetic cream found no differences in weekly reporting of headache, dizziness, or nausea and vomiting over 2–6 months. It also found no adverse effects on infant survival, growth, or development at either birth or 1 year (survival: 95.2% with DEET v 94.0% with cosmetic cream; P = 0.57; mean weight at 1 year 7983 g with DEET v 7984 g with cosmetic cream). Some animal studies have found that DEET crosses the placental barrier. Animal studies of reproductive effects of DEET are inconclusive.

Comment

See comment on insecticide-treated bed nets in pregnant travellers. The RCT in refugees reported that DEET significantly increased the proportion of women reporting skin warmth (359/449 [80%] with DEET v 258/448 [58%] with cosmetic cream; RR 1.39, 95% CI 1.27 to 1.52), although the clinical significance of this is unclear.

Clinical guide:

Although we found no evidence specifically in pregnant travellers, it is likely that the evidence of benefit from insecticide-treated bed nets in preventing malaria in non-pregnant adults can be generalised to pregnant women travellers (see skin-applied insect repellants in non-pregnant adults). However, there is inconclusive evidence regarding the safety of DEET in pregnant travellers. Some authors advise that only plant-derived skin-applied insect repellents are safe in pregnancy because of a potential risk of mutagenicity from DEET. However, we found no evidence on the effects of other repellents.

Substantive changes

Skin-applied insect repellents in pregnant travellers Evidence re-evaluated. Recategorised as Trade-off between benefits and harms.

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Antimalaria drugs in pregnant travellers

Summary

One systematic review identified no RCTs on the effects of antimalaria drugs in pregnant travellers. It found that, in pregnant residents of malaria-endemic settings, antimalaria drugs reduced malaria and episodes of fever compared with no prophylaxis. It found no significant difference in perinatal deaths or preterm births. We found insufficient evidence on the safety of chloroquine, doxycycline, and mefloquine in pregnancy. Decades of experience of using chloroquine to prevent malaria, in areas where there is no parasite resistance to the drug, have led to the consensus that it is effective in this setting.

Benefits

We found no systematic review or RCTs in pregnant travellers. We found one systematic review (search date 2006) of antimalaria drugs in pregnant women living in malaria-endemic settings. It found that antimalaria prophylaxis significantly reduced the proportion of women infected at least once compared with no prophylaxis (1 RCT, 337 women; AR 5/167 [3%] with prophylaxis v 37/170 [22%] with no prophylaxis; RR 0.14, 95% CI 0.06 to 0.34), and significantly reduced the number of episodes of fever (1 RCT, 227 women; 21/119 [18%] with prophylaxis v 45/108 [42%] with no prophylaxis; RR 0.42, 95% CI 0.27 to 0.66). It found no significant difference between antimalaria prophylaxis and no prophylaxis in the number of perinatal deaths (4 RCTs, 2890 women; 66/1464 [4%] with prophylaxis v 64/1426 [4%] with no prophylaxis; RR 1.02, 95% CI 0.73 to 1.43), in the number of preterm births (1 RCT, 199 women; 4/102 [4%] with prophylaxis v 8/97 [8%] with no prophylaxis; RR 0.48, 95% CI 0.15 to 1.53), or in mean birth weight (4 RCTs, 2671 women; WMD +24 g, 95% CI –55 g to +105 g; random effects analysis).

Harms

The review gave no information about adverse effects.

Chloroquine:

One RCT (1464 pregnant long-term residents of Burkina Faso) gave no information on adverse effects.

Doxycycline:

Case reports found that doxycycline taken in pregnancy or while breast feeding may damage fetal or infant bones or teeth.

Mefloquine:

One RCT (339 long-term Thai residents) found that mefloquine significantly increased the proportion of women reporting dizziness compared with placebo (28% with mefloquine v 14% with placebo; P less than 0.005). However, it found no other significant adverse effects on the mother, the pregnancy, or on infant survival or development over 2 years' follow-up.

Comment

See comment on insecticide-treated bed nets in pregnant travellers. Mefloquine is secreted in small quantities in breast milk, but it is believed that levels are too low to harm infants. Because of the potential for damage to fetal or infant bones or teeth, doxycycline is contraindicated in pregnant or breastfeeding women.

Clinical guide:

Chloroquine is a low-cost drug, and decades of experience of using it to prevent malaria, in areas where there is no parasite resistance to the drug, have led to the consensus that it is effective in travellers to these areas, and safe in pregnant women.

Substantive changes

No new evidence

BMJ Clin Evid. 2007 Nov 29;2007:0903.

Antimalaria drugs in airline pilots

Summary

There is no reason to suggest that evidence of benefit of atovaquone–proguanil, chloroquine, or doxycycline in other adults would not be generalisable to airline pilots. We found one small RCT reporting on the adverse effects of atovaquone–proguanil in non-travelling volunteers, under aircraft cabin-pressure conditions. It found no significant difference in adverse effects between atovaquone–proguanil and placebo. Another RCT of adverse effects found no evidence that mefloquine affected flying performance after 3 weeks of treatment.

Benefits

We found no systematic review or RCTs (see comment below). One retrospective questionnaire survey (28 Israeli pilots taking doxycycline and 15 non-aviator crew taking mefloquine) found no cases of malaria at 4 weeks.

Harms

Atovaquone–proguanil:

One small crossover RCT reporting on adverse effects (24 male and female non-travelling Dutch volunteers, assessed in a hypobaric chamber) found that atovaquone–proguanil did not significantly affect vigilance, sustained attention, complex information processing, sleepiness, sleep quality, or sleep time compared with placebo. No serious adverse effects were reported. There were 12 mild adverse events (including diarrhoea) with atovaquone–proguanil, and 17 adverse events with placebo (significance assessment not performed). There was one case of nosebleeding during the trial period, and one of night sweating.

Doxycycline:

One retrospective questionnaire survey (28 Israeli pilots) found that 39% experienced adverse effects from up to 2 months of doxycycline treatment (abdominal pain: 7/28 [25%]; fatigue: 5/28 [18%]; see comment below).

Mefloquine:

One placebo-controlled RCT of adverse effects (23 trainee commercial pilots) found no evidence that mefloquine significantly affected flying performance after 3 weeks of treatment (mean total number of errors recorded by the instrument coordination analyser: 12.6 with mefloquine v 11.7 with placebo). One retrospective questionnaire survey (15 Israeli non-aviator aircrew) found that 13% of respondants experienced adverse effects from mefloquine after up to 2 months of treatment (dizziness, nausea, and abdominal pain: 2/15 [13%]; abdominal discomfort: 1/15 [7%]; see comment below).

Comment

Clinical guide:

There is no reason to suggest that evidence of benefit of atovaquone–proguanil, chloroquine, or doxycycline in other adults would not be generalisable to airline pilots (see question on drug prophylaxis in adults). There is evidence that atovaquone–proguanil does not harm airline pilots compared with placebo. Airline pilots are specified as a different population because, as an occupational group, they are subject to health and safety legislation that is highly prescriptive about certain drugs.

Substantive changes

Antimalaria drugs (atovaquone–proguanil, doxycycline) in airline pilots Evidence re-evaluated. Recategorised as Likely to be beneficial.

Articles from BMJ Clinical Evidence are provided here courtesy of BMJ Publishing Group

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