Abstract
Malaria is a major public health problem in the sub-Saharan Africa. According to the World Health Organization, Approximately 60% of the clinical cases of malaria and 90% of deaths from malaria occur in Africa, mostly in children under 5 years and pregnant women1,2. In addition to these acute disease and deaths, malaria also poses serious adverse outcome during pregnancy. It contributes significantly to maternal anaemia during pregnancy and adverse birth outcome such as abortions, intrauterine growth restriction, low birth weight, intrauterine fetal death and stillborn3,4. All these add their own tolls to the unacceptable maternal and infant mortality and morbidity in Africa. Approximately 50 million women residing in high endemic malaria zone get pregnant annually5. About 25 – 30 million of these women are in sub-Saharan Africa with stable transmission of Plasmodium falciparum throughout the year6.
In Nigeria, malaria accounts for about 60% of out-patient consultation and approximately 10,000 maternal death occur annually in the country due to malaria caused by Plasmodium falciparum3,4, the commonest and the most fatal of the species of plasmodia causing malaria in West Africa. Similarly, 8 – 14 % of low birth weight and 3 – 8 % 0f all infant death in Nigeria are due to malaria infestation3.
Pregnant women are more susceptible to malaria particularly during the first and to a lesser extent during the second pregnancy. The suppression of cell-mediated immunity and the predilection of Plasmodium falciparum for Chondroitin Sulphate A (CSA) an adhesion molecule in the placental by means of parasite variant surface antigens (VSA) expressed on the surface of infected erythrocytes is thought to explain why there is increased malaria infection in pregnancy, particularly in the primigravidae3,4,6. However, in multiparae, there is induced cytoadherence inhibiting VSA-CSA specific antibodies which confers on them some degree of resistance to placental parasitisation6. This placental parasitisation which is a common occurrence with an increased frequency in the first pregnancy, has been recognised as the most important factor that is responsible for most of the complications that occur in pregnancy due to malaria infection caused by Plasmodium falciparum. The sequestration of Plasmodium falciparum parasitized red blood cells in the placenta bed and intervillous spaces set the stage for inflammatory reaction with the release of mediators of inflammation that cause placental injury3,6. These pathological changes associated with heavy Plasmodium falciparum sequestered in the placenta bed leads to impaired fetomaternal blood flow that result in adverse pregnancy outcomes including abortion, low birth weight (LBW), intrauterine growth restriction (IUGR), fetal anemia, congenital malaria and perinatal mortality2,4,6. Maternal mortality may result from complicated malaria or complication of anaemia due to malaria infection2,3.
To prevent the adverse effects of malaria during pregnancy, the World Health Organization recommended weekly Chloroqiune as chemoprophylaxis for malaria in pregnancy7. This was implemented to replace weekly Pyrimethamine whose effect had earlier been found not to be better than that of placebo. However, in the mid 1990s, because of poor patient compliance with prophylaxis and increasing resistance of parasite strains to chloroquine, WHO replaced weekly chloroquine prophylaxis as the drug based strategy for the prevention of malaria during pregnancy and has now been adopted by almost all malaria-endemic countries in Africa. Sulfadoxine-Pyrimethamine is now recommended for all pregnant women living in areas with stable malaria transmission8. Sulfadoxine/Pyrimethamine is given during antenatal visits at curative doses (1500mg Sulfadoine and 75mg Pyrimethamine) at least twice during pregnancy, first dose given in the second trimester after 16 weeks or after quickening. The second dose should be given at least one month after the first dose but not after 36 weeks of gestation to prevent the possibility of neonatal jaundice that can be associated with sulphonamide if given close to delivery2,5.
Intermittent Preventive Treatment with Sulfadoxine/Pyrimethamine has proven efficacious in reducing the incidence of pregnancy-associated malaria and is currently a component of the national malaria prevention program in Nigeria9. However, Sulfadoxine-Pyrimethamine efficacy for the treatment of symptomatic malaria in children has dwindled in the last 5 years raising concern about its longevity for IPT treatment10,11,12. Resistance to Sulfadoxine-Pyrimethamine results from mutation in the dihydrofolate synthetase (DHFR) and the dihydropteroate reductase (DHPS) genes of the parasite13,14. Though the in-vitro detection of the resistant gene has been increasing in Africa, the frequency of these mutations does not predict the efficacy of SP in the prevention of malaria in African children11,12. However, parasites with triple DHFR mutation have an approximately 1000 fold reduction in their susceptibility to pyrimethamine, which translates into a reduction in the duration of the suppressive prophylaxis thus compromising efficacy6,15. Countries with moderate to high levels of sulfadoxine-pyrimethamine resistance urgently require quidance on whether to continue using sulfadoxine-pyrimethamine for IPT during pregnancy. Thus, this drug may soon be compromised, and an urgent need exists to assess alternative drug regimens for intermittent preventive treatment.
Chloroquine was introduced into clinical practice in 194716 for the prophylactic treatment of malaria. It remained in the mainstream of malaria therapy for more than 50 years. Resistance of P. falciparum to chloroquine16was first reported in the South-Asia and South America in the 1950s16. By the late 1970s16, the resistance had made its way into African continent when the resistance contributed to increased malaria transmissions and death. In 1993, Malawi was the first country in Africa to completely withdraw chloroquine and replaced it with sulfadoxine-pyrimethamine as the first-line treatment of uncomplicated malaria15. For more than 10 years, chloroquine was not used anywhere in Malawi. At that time, the clinical efficacy of chloroquine was less than 50%. However, after 10 years of complete abandonment,the malaria parasite has once again become susceptible to chloroquine17,18,19. A recent study from Malawi showed that chloroquine was effective at treating malaria in 99 percent of the children, while sulfadoxine-pyrimethamine was effective only in 21 percent20. The molecular marker of chloroquine-resistant falciparum malaria subsequently declined in prevalence and was undetectable by 2001, suggesting that chloroquine might once again be effective in Malawi20. This remarkable switch in efficacy may not have occurred in Nigeria as well as many African nations because they have continued to use chloroquine even after officially switching to newer drugs to treat malaria.
The loss of the chloroquine to resistance was a public health catastrophe for Africa. Chloroquine as an anti-malarial drug is inexpensive, rapid- and long-acting, and safe for all age groups and pregnant women. This prospective randomise-controlled double-blinded trial was therefore designed to ascertain whether chloroquine is still effective in preventing the adverse outcome of malaria during pregnancy in Nigeria.