Malarious patients experience asymptomatic parasitemia; acute febrile illness (with cerebral damage, anemia, respiratory distress, hypoglycemia); chronic debilitation (anemia, malnutrition, nervous system-related sequelae); and complications of pregnancy (anemia, low birth weight, increased infant mortality). These manifestations in patients, communities, and countries reflect intrinsic (human, parasite, mosquito) and extrinsic (environmental, social, behavioral, political, and economic conditions as well as disease-control efforts) determinants. At a minimum, between 700,000 and 2.7 million persons die yearly from malaria, over 75% of them African children. Between 400 and 900 million acute febrile episodes occur yearly in African children under 5 yr of age living in endemic areas. Although about half of these children are parasitemic, all merit consideration of malaria-specific therapy, which is becoming more problematic because of parasite resistance to drugs. These numbers will more than double over the next 20 yr without effective control. Fewer than 20% of these febrile episodes and deaths come to the attention of any formal health system. The relatively few ill patients who have any contact with the health services represent the "ears of the hippopotamus." Greatly intensified research activities and control of the intolerable burden of malaria are mandatory if economic development is to accelerate in Africa. In particular, support should be targeted to understanding and preventing malaria-induced anemia, hypoglycemia, effects on pregnancy, and neurologic and developmental impairment. To decrease and stop transmission of this intolerable scourge, there is an urgent need for malaria vaccines, newer drugs, and better vector control methods as well as the ability to improve current technologies and use them more efficiently.

The ears of the hippopotamus: manifestations, determinants, and estimates of the malaria burden.

We reviewed evidence of the clinical implications and burden of malaria in pregnancy. Most studies come from sub-Saharan Africa, where approximately 25 million pregnant women are at risk of Plasmodium falciparum infection every year, and one in four women have evidence of placental infection at the time of delivery. P falciparum infections during pregnancy in Africa rarely result in fever and therefore remain undetected and untreated. Meta-analyses of intervention trials suggest that successful prevention of these infections reduces the risk of severe maternal anaemia by 38%, low birthweight by 43%, and perinatal mortality by 27% among paucigravidae. Low birthweight associated with malaria in pregnancy is estimated to result in 100 000 infant deaths in Africa each year. Although paucigravidae are most affected by malaria, the consequences for infants born to multigravid women in Africa may be greater than previously appreciated. This is because HIV increases the risk of malaria and its adverse effects, particularly in multigravidae, and recent observational studies show that placental infection almost doubles the risk of malaria infection and morbidity in infants born to multigravidae. Outside Africa, malaria infection rates in pregnant women are much lower but are more likely to cause severe disease, preterm births, and fetal loss. Plasmodium vivax is common in Asia and the Americas and, unlike P falciparum, does not cytoadhere in the placenta, yet, is associated with maternal anaemia and low birthweight. The effect of infection in the first trimester, and the longer term effects of malaria beyond infancy, are largely unknown and may be substantial. Better estimates are also needed of the effects of malaria in pregnancy outside Africa, and on maternal morbidity and mortality in Africa. Global risk maps will allow better estimation of potential impact of successful control of malaria in pregnancy.

https://www.thelancet.com/pdfs/journals/laninf/PIIS1473-3099(07)70021-X.pdf

Epidemiology and burden of malaria in pregnancy

Background. Infant and under-5 childhood mortality rates in developing countries have declined significantly in the past 2 to 3 decades. However, 2 critical indicators, maternal and newborn mortality, have hardly changed. World leaders at the United Nations Millennium Summit in September 2000 agreed on a critical goal to reduce deaths of children Objective. This review of community-based antenatal, intrapartum, and postnatal intervention trials in developing countries aimed to identify (1) key behaviors and interventions for which the weight of evidence is sufficient to recommend their inclusion in community-based neonatal care programs and (2) key gaps in knowledge and priority areas for future research and program learning. Methods. Available published and unpublished data on the impact of community-based strategies and interventions on perinatal and neonatal health status outcomes were reviewed. Evidence was summarized systematically and categorized into 4 levels of evidence based on study size, location, design, and reported impact, particularly on perinatal or neonatal mortality. The evidence was placed in the context of biological plausibility of the intervention; evidence from relevant developed-country studies; health care program experience in implementation; and recommendations from the World Health Organization and other leading agencies. Results. A paucity of community-based data was found from developing-country studies on health status impact for many interventions currently being considered for inclusion in neonatal health programs. However, review of the evidence and consideration of the broader context of knowledge, experience, and recommendations regarding these interventions enabled us to categorize them according to the strength of the evidence base and confidence regarding their inclusion now in programs. This article identifies a package of priority interventions to include in programs and formulates research priorities for advancing the state of the art in neonatal health care. Conclusions. This review emphasizes some new findings while recommending an integrated approach to safe motherhood and newborn health. The results of this study provide a foundation for policies and programs related to maternal and newborn health and emphasizes the importance of health systems research and evaluation of interventions. The review offers compelling support for using research to identify the most effective measures to save newborn lives. It also may facilitate dialogue with policy makers about the importance of investing in neonatal health.

/pdf/community-based-interventions-for-improving-perinatal-and-17rlant020.pdf

Community-Based Interventions for Improving Perinatal and Neonatal Health Outcomes in Developing Countries: A Review of the Evidence

This book marks the first step in a new review of health policy - a review that focuses specifically on sub - Saharan Africa. Several factors make this exercise particularly timely: 1) the concern that the economic downturn of the early 1980s may have adversely affected the health sector in Africa; 2) the need to evaluate the impact of primary health care strategies, especially the key elements of immunization and oral rehydration; 3) the completion of a substantial body of epidemiological and demographic analyses, which provides a much improved empirical basis for assessing health conditions and recent health trends; 4) the concern that the global emergence of Acquired Immune Deficiency Syndrome (AIDS) and its sharp impact in selected African foci have undermined development prospects in some countries; and 5) the potential value of explicitly seeking lessons from the Bank's experience with health sector operations in Africa. The chapters in this book were commissioned to address the third point - to assemble in one place lessons from the analyses of the epidemiological and demographic conditions that define the problems facing Africa's health systems. This book sets an important part of the agenda of work for African health officials over the next decade.

Disease and Mortality in Sub-Saharan Africa

Artemisinin-based combination treatments (ACTs) are now generally accepted as the best treatments for uncomplicated falciparum malaria. They are rapidly and reliably effective. Efficacy is determined by the drug partnering the artemisinin derivative and, for artesunate-mefloquine, artemether-lumefantrine, and dihydroartemisinin-piperaquine, this usually exceeds 95%. Artesunate-sulfadoxine-pyrimethamine and artesunate-amodiaquine are effective in some areas, but in other areas resistance to the partner precludes their use. There is still uncertainty over the safety of artemisinin derivatives in the first trimester of pregnancy, when they should not be used unless there are no effective alternatives. Otherwise, except for occasional hypersensitivity reactions, the artemisinin derivatives are safe and remarkably well tolerated. The adverse effect profiles of the artemisinin-based combination treatments are determined by the partner drug. Most malaria endemic countries have now adopted artemisinin-based combination treatments as first-line treatment of falciparum malaria, but in most of these only a minority of the patients that need artemisinin-based combination treatments actually receive them.

Artemisinin-based combination treatment of falciparum malaria.

Despite international recommendations to use malaria treatment and prevention in pregnant women in malaria-endemic areas, few studies have evaluated the efficacy of available antimalarial regimens. This issue is of particular concern in the face of spreading chloroquine (CQ)-resistance of Plasmodium falciparum in malarious areas of sub-Saharan Africa. In a prospective trial in rural Malawian pregnant women, we examined three regimens using CQ (including the existing national policy regimen) and one regimen using mefloquine (MQ). The efficacy of the regimens was determined by comparing rates of clearance of initial parasitemia; prevention of breakthrough infection; and parasitemia at delivery in maternal peripheral blood, placental blood, and in infant umbilical cord blood. Among 1,528 parasitemic women at enrollment, 281 (18.4%) had persistent infections; and among 1,852 initially aparasitemic women, 320 (17.3%) had breakthrough parasitemia on one or more follow-up visits. Compared with women on MQ, women on a CQ regimen were at significantly greater risk of persistent and breakthrough infection (odds ratios [OR] = 30.9 and 11.1, respectively, P < 10(-6)). Other significant risk factors for persistent and breakthrough infections in a multivariate model included first pregnancy; enrollment in the rainy or postrainy season; maternal age < or = 25 years; seropositivity to the human immunodeficiency virus (HIV) (persistent infections only); and no use of antimalarial prophylaxis before enrollment (breakthrough infections only). At delivery, compared with women on MQ, women on a CQ regimen were at significantly greater risk of peripheral, placental, or umbilical cord blood parasitemia (OR = 8.7, 7.4, and 4.1, respectively, P < 10(-6)). Additional risk factors for parasitemia at delivery in multivariate models included first pregnancy; delivery in the rainy or postrainy season; HIV-seropositivity; and maternal age < or = 25 years (risk for peripheral and placental blood parasitemia only). Maternal anemia (hematocrit < 30%) at enrollment or at delivery was not associated with persistent or breakthrough parasitemia or parasitemia at deliver in these multivariate models. While factors leading to increased malaria parasite exposure (high transmission seasons) and lowered or altered host immune response (low pregnancy number, young age, and HIV infection) are important risk factors for malaria in pregnant women, the use of an ineffective intervention (CQ in a setting with CQ-resistant parasites) was the most important determinant of P. falciparum parasitemia in these pregnant women. Strategies to reduce the impact of malaria in pregnant women must use efficacious interventions and may need to consider targeting the intervention to the most susceptible women during the seasons of high malaria exposure.

Malaria parasite infection during pregnancy and at delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi

In sub-Saharan Africa, women frequently report a variety of symptoms during pregnancy, some of which indicate possible illness. Given the adverse impact of malaria in pregnancy, these events may be important for at least two reasons: it may be possible to use reported fever illness as a determinant of which women need an antimalarial intervention, and, it is possible that adverse symptoms following the antimalarial intervention may be important determinants of continued adherence to the prevention regimen. In a cohort of pregnant women enrolled at first antenatal clinic visit in rural Malawi, we evaluated reported fever, determined parasitemia, and placed the women on antimalarial regimens containing chloroquine (CQ) or mefloquine (MQ). We then systematically evaluated reported symptoms following antimalarial drug use after initial therapeutic doses and subsequent prophylactic doses, and monitored women throughout their pregnancy and at delivery. Among 4,187 enrolled women, 1,048 (25%) reported at least one febrile episode during pregnancy before their first antenatal clinic visit. Factors associated with this reported fever included low parity, enrollment in the rainy season, human immunodeficiency virus seropositivity, use of antimalarial prophylaxis before enrollment, high socioeconomic status, normal (compared to low) maternal height and weight, and literacy. Fever before the first antenatal clinic visit was reported by 24.4% of parasitemic women and 25.4% of aparasitemic women; the sensitivity and specificity of fever to identify parasitemic women was 24% and 71%, respectively. In contrast, the sensitivity and specificity of first or second pregnancy to identify parasitemic women was 71% and 57%, respectively. Among women on a CQ or MQ regimen, approximately 60% reported side effects (e.g., itching, dizziness, and gastrointestinal disturbances) after a treatment dose and approximately 25% reported side effects after a prophylactic dose; rates and types of symptoms reported were similar in the CQ and MQ groups. Few serious side effects were observed and rates of fetal loss were low and similar in the groups. Reliance on fever illness will be wholly inadequate to identify parasitemic women; therefore, our findings support existing World Health Organization recommendations that presumptive treatment and prevention regimens should be offered to all pregnant women. When resources are inadequate to offer antimalarial prophylaxis to all pregnant women, women in their first or second pregnancy may be a more appropriate target group than pregnant women with reported fever. Education regarding expected minor side effects may reduce rates of poor compliance and improve the effectiveness of the prevention effort.

Malaria Treatment and Prevention in Pregnancy: Indications for Use and Adverse Events Associated With Use of Chloroquine or Mefloquine

In 1984 the government of Malawi instituted a program to reduce malaria mortality and morbidity in children less than 5 years of age as a part of the Combatting Childhood Communicable Diseases (CCCD) program. To define the appropriate malaria therapy regimen, investigators used a quality assurance design in a simplified 7-day in vivo drug response study with follow-up observations on day 2 (D2), D3, and D7 after the initial day of the study (D0). The efficacy of oral chloroquine was assessed in 224 children who were enrolled at 6 sites, 2 in each of the 3 administrative regions of Malawi. Parasitological failure, defined as failure of parasitemia to decrease by 75% of the value by D3 or presence of any detectable parasitemia on D7, ranged from 41%-65% following administration of chloroquine 25 mg (base)/kg. However, only 8% of children who were parasitemic on D7 were febrile or judged to be ill. Considering these therapeutic results and the higher cost and limited availability of alternative therapies, chloroquine 25 mg/kg therapy was adopted as the primary therapy for malaria.

In vivo efficacy of chloroquine treatment for Plasmodium falciparum in Malawian children under five years of age.

The in vivo and in vitro response of Plasmodium falciparum to a single oral dose of mefloquine (25 mg/kg body weight (M25) or 15 mg/kg (M15] was studied in children under 5 years of age in Malawi. Of the children who received mefloquine, 35% vomited at least once, and 10% did not tolerate the drug because of vomiting. The therapy failure rates for the M25 group on day 7, 14, and 28 were 15%, 18%, and 42%, respectively, and these did not differ significantly from those for the M15 group (4%, 18%, and 59%). In contrast, 34 in vitro microtests (17 per group) showed schizont inhibition at less than or equal to 32 pmol mefloquine per test well. On day 7, the concentration of mefloquine in samples of blood was significantly lower in both the M25 and M15 groups for children who were parasitaemic on day 7 than in samples from those who were aparasitaemic. A positive blood smear on day 7 was strongly associated with a mefloquine concentration of less than 500 ng/ml blood on day 2 or day 7 (P less than 0.0003). Vomiting was associated with a low mefloquine concentration on day 2 but not day 7. These results suggest that mefloquine is effective against P. falciparum in Malawi but that for young children the therapy appears to be complicated by frequent vomiting.

Mefloquine therapy for Plasmodium falciparum malaria in children under 5 years of age in Malawi: in vivo/in vitro efficacy and correlation of drug concentration with parasitological outcome.

The roles of Plasmodium falciparum resistance to chloroquine and compliance in the protective efficacy of the antenatal chloroquine prophylaxis programme in Malawi were evaluated by interviewing pregnant women attending antenatal clinics and examining them for P. falciparum parasites in thick smears and chloroquine metabolites in urine. 36% of 642 women had urine chloroquine metabolite levels compatible with regular compliance to the weekly chloroquine dosage schedule. Among a subgroup of 288 pregnant women who were provided weekly prophylaxis under supervision for 4 consecutive weeks, P. falciparum infection rates were 37%, representing the failure of chloroquine to eliminate P. falciparum in Malawi. Among pregnant women not taking prophylaxis, the P. falciparum infection rate was 48%. Based on the P. falciparum infection rates among these 2 groups of women, the protective efficacy of CQ chloroquine was estimated as 23%. If the 36% of pregnant women who had chloroquine in their urines accurately estimates the proportion of women who comply with the prophylaxis programme in Malawi, the actual protective efficacy of the programme would be 8%. The cost of preventing one P. falciparum infection among pregnant women in the Malawi programme is estimated at US$ 10.87. This is an unacceptably high cost in much of Africa, and research is required to define more cost-effective interventions, including more effective drugs, and health education programmes to improve compliance among pregnant women.

Charles O. Khoromana

Papers

Malaria parasite infection during pregnancy and at delivery in mother, placenta, and newborn: efficacy of chloroquine and mefloquine in rural Malawi

Malaria Treatment and Prevention in Pregnancy: Indications for Use and Adverse Events Associated With Use of Chloroquine or Mefloquine

In vivo efficacy of chloroquine treatment for Plasmodium falciparum in Malawian children under five years of age.

Mefloquine therapy for Plasmodium falciparum malaria in children under 5 years of age in Malawi: in vivo/in vitro efficacy and correlation of drug concentration with parasitological outcome.

Antenatal chloroquine chemoprophylaxis in Malawi: chloroquine resistance, compliance, protective efficacy and cost