A Review of Randomized Controlled Trials of Routine Antimalarial Drug Prophylaxis during Pregnancy in Endemic Malarious Areas

Article excerpt

Introduction

Although malaria in pregnancy has been extensively researched, debate concerning antimalarial chemoprophylaxis during pregnancy continues. First and second pregnancies are associated with a higher prevalence of Plasmodium falciparum parasitaemia in the first half of pregnancy in women living in endemic malarious areas (1). Malaria may contribute to antenatal anaemia (2), and slowing of fetal growth, especially in primigravidae (3). Clinical episodes in late pregnancy may cause preterm delivery in non-immune women, although in semi-immune women a few studies suggest that growth retardation occurs more frequently than preterm delivery (3)(4)(5). Elimination of malaria, for example, by residual spraying with insecticide, has been associated with an increase in mean birth weight (6). The presence of malaria parasites in the placenta is associated with low birth weight (7)(8); and maternal malaria infection, defined as the presence of parasites in the placenta or peripheral blood during labour, may be associated with a higher perinatal mortality (9).

In the past, WHO recommended routine malaria drug prophylaxis throughout pregnancy for women living in endemic malarious areas (10). Although routine chemoprophylaxis is still recommended, it is not always easy to ensure good compliance, even with targeted health promotion activities. Good compliance has been achieved in the context of special research studies (11)(12); other studies have demonstrated that good compliance may be difficult to achieve (13).

The potential efficacy of chemoprophylaxis with chloroquine is likely to be reduced with the emergence of chloroquine-resistant Plasmodium falciparum. Daily proguanil is an alternative, and good compliance has been reported in studies in Tanzania (Mutabingwa, personal, communication, 1992) and Nigeria (Fleming, personal communication, 1990). However, there is a question over whether a daily schedule would be widely acceptable in other settings. Pyrimethamine has few side-effects, but its use is limited by parasite drug resistance. The safety of other drugs, such as Maloprim (dapsone and pyrimethamine) or mefloquine, is less well established; and they are more expensive.

While the benefits of chemoprophylaxis in non-immune women are clear (14), the possible benefits in indigenous, semi-immune women are not so obvious. Currently, WHO recommends that "in settings where placental parasitaemia is associated with low birth weight, and an effective antimalaria drug can be provided on a regular basis, chemoprophylaxis may be considered" (15). The ambiguity of this statement reflects the current dilemma of policymakers balancing efficacy of a potential chemoprophylactic agent against its potential adverse effects and the problems in delivering it. Some of the efficacy of chemoprophylaxis is based on an effect on birth weight: whether this necessarily affects perinatal or infant mortality has recently been questioned (16). Prevention of preterm delivery, on the other hand, could have an important impact on neonatal mortality.(a)

Before recommending chemoprophylaxis, with whichever drug regimen, to all pregnant women living in a particular endemic malarious area, clear evidence is required of its efficacy. To assist in this assessment, we have conducted a systematic review of the existing evidence derived from randomized controlled trials of chemoprophylaxis.

Materials and methods

Inclusion criteria. The criteria for inclusion in this review were trials during pregnancy in which an attempt had apparently been made to conduct a randomized comparison either between a policy of routine antimalarial chemoprophylaxis and a policy of treatment of symptomatic malaria; or between alternative antimalarial chemoprophylaxis regimens.

Trial identification. Trials were identified through existing literature reviews and a database of perinatal trials. Reference was made to Kramer (3), who reviewed the determinants of birth weight, searching the literature from 1970 to 1984; Brabin (2), who reviewed the risks and severity of malaria in pregnant women, and documented recent and current field studies; and the Oxford Database of Perinatal Trials, and the Cochrane Pregnancy and Childbirth Group, which maintains a register of published, unpublished, ongoing and planned trials concerned with perinatal health (17). …