Treatment, prophylaxis and research priorities for developing countries.

PIP: An estimated two million new adult and pediatric HIV infections occurred worldwide during 1992, more than 50% of them in sub-Saharan Africa, 25% in Asia, and one-eighth in Latin America and the Caribbean. The remaining infections occurred in Europe, North America, and the industrialized countries of the Pacific Rim. Transmission by sexual intercourse and from an infected woman to her fetus/child remain major routes of transmission. The World Health Organization estimates that there will be a cumulative total of 30-40 million people infected with HIV by the year 2000. Over time, increasing numbers of people already infected with HIV and soon to be infected will develop AIDS and require higher levels of care. Obstacles to increasing access to cost-effective drugs for HIV/AIDS in developing countries, however, include weak drug distribution systems, the improper prescribing of available drugs by health workers, and the improper use of these drugs by patients who have not been appropriately educated by prescribing health workers. Currency shortages and lack of political will underlie these obstacles. This paper considers cost-effective prophylaxis and treatment of HIV-related infections including tuberculosis, candidiasis, penicilliosis, combined chemoprophylaxis, pruritus and diarrhea with wasting, and HIV infection. The prevention of HIV transmission is discussed under headings on heterosexual and perinatal transmission, followed by a discussion on increasing access to cost-effective drugs.^ieng

HIV-1 infection among women of reproductive age in a rural district in Malawi.

OBJECTIVES: To determine HIV-1 seroprevalence in pregnant women attending antenatal clinics in a rural district in Malawi, and to estimate the rate of HIV-1 infection in the district among women of reproductive age. DESIGN AND SETTING: Cross-sectional survey conducted from 1987 to 1990 of women enrolled at antenatal clinics at four sites (two towns and two villages). METHODS: Questionnaires were administered and sera screened at delivery. Population infection estimates were based on national census and survey data. RESULTS: Of 3953 pregnant women tested, 283 (7.2%) were HIV-1-seropositive. Women enrolled at town sites were significantly more likely to be HIV-1-infected than village women (11.3 versus 3.9%; P < 0.001). Higher infection rates were associated with age 20-29 years, first or second pregnancy, increased education or socioeconomic status, and living within 8 km of the clinic. It was estimated that over 7300 women of reproductive age were HIV-1-infected in this rural district. CONCLUSIONS: Seroprevalence rates in pregnant women in rural towns were intermediate between rates in villages and previously documented rates in cities in Malawi. Although village sites had lower seroprevalence rates, they accounted for over half the estimated HIV-1 infection in childbearing women in this district.

Maternal HIV infection and infant mortality in Malawi: evidence for increased mortality due to placental malaria infection.

OBJECTIVES: To examine the relationship between maternal HIV infection, placental malaria infection, and infant mortality as a first step in investigating the possibility of increased vertical transmission of HIV due to placental malaria infection. DESIGN: Retrospective analysis of data from a cohort study of mothers and infants in rural Malawi conducted from 1987 to 1990. METHODS: Pregnant women in Malawi were enrolled in a study examining chemoprophylaxis during pregnancy. At delivery, placental malaria infection status was determined. Infants born into this study were visited every 2 months for the first 2-3 years of life. Deaths were investigated using a standardized 'verbal autopsy' interview. Maternal serum collected during pregnancy was tested for antibodies to HIV-1 by enzyme-linked immunosorbent assay with Western blot confirmation. RESULTS: Overall, 138 (5.3%) of 2608 women in the study were HIV-1-seropositive. Infant mortality rates were 144 and 235 per 1000 live births for children born to HIV-seronegative and HIV-seropositive women, respectively (P < 0.001). In a multivariate model, the odds of dying during the post-neonatal period for an infant born to a mother with both placental malaria and HIV infection was 4.5 times greater than an infant born to a mother with only placental malaria, and between 2.7 and 7.7 times greater (depending on birthweight) than an infant born to a mother with only HIV infection. CONCLUSIONS: This study strongly suggests that exposure to both placental malaria infection and maternal HIV infection increases post-neonatal mortality beyond the independent risk associated with exposure to either maternal HIV or placental malaria infection. If confirmed, malaria chemoprophylaxis during pregnancy could decrease the impact of transmission of HIV from mother to infant.

PIP: Researchers analyzed data on 2608 women attending one of four prenatal clinics in Mangochi District in Malawi during 1987-1990 to study the relationship between maternal HIV infection, placental malaria infection, and infant mortality. 5.8% (138) of the women were HIV-1 seropositive. HIV-1 seroprevalence increased from 2.3% to 5.8% between 1987 and 1993. Infants born to HIV-1 positive mothers were much more likely to die during the first year of life than those born to HIV-1 negative mothers (235/1000 vs. 144/1000 live births; p 0.001). The excess deaths occurred during the postneonatal period (49 vs. 44, p = 0.3, for neonatal mortality, compared to 186 vs. 100, p 0.001, for postneonatal mortality). In the postneonatal period, diarrhea or gastrointestinal illness was more common as a cause of death among infants of HIV-1 positive mothers than those of HIV-1 negative mothers (8.7% vs. 3.6%; relative risk = 2.4; p = 0.0002). The researchers stratified the effect of maternal HIV infection on postneonatal death according to birth weight and placental malaria infection to control for potential confounding. They found that, when compared with normal birth weight infants born to seronegative mothers with no placental malaria infection, low birth weight infants born to HIV-1 positive mothers with placental malaria had an 11.49 increased odds of dying during the postneonatal period. The multivariate analysis showed that an infant born to an HIV-infected mother with placental malaria was 4.5 times more likely to die during the first year of life than an infant born to a mother with only placental malaria and 2.7-7.7 times (depending on birth weight) more likely to die than an infant born to a mother with only HIV infection. These findings suggest that malaria chemoprophylaxis during pregnancy would reduce the likelihood of HIV transmission from mother to infant in addition to reducing the burden of malaria infection during pregnancy, malaria-associated low birth weight, and their subsequent effect on child survival.

The effect of Plasmodium falciparum malaria on HIV-1 RNA blood plasma concentration.

OBJECTIVES: This study was undertaken to determine the relative effect of malaria infection on HIV concentration in blood plasma, and prospectively to monitor viral concentrations after antimalarial therapy. DESIGN: A prospective, double cohort study was designed to compare the blood HIV-1 RNA concentrations of HIV-positive individuals with and without acute malaria illness. Subjects were followed for 4 weeks after successful malaria therapy, or for 4 weeks from enrollment (controls). METHODS: Malawian adults with symptomatic Plasmodium falciparum parasitemia (malaria group) and asymptomatic, aparasitemic blood donors (control group) were tested for HIV-1 antibodies to identify appropriate study groups. The malaria group received antimalarial chemotherapy only and were followed with sequential blood films. In both groups, blood plasma HIV-1 RNA viral concentrations were determined at enrollment and again at 1, 2 and 4 weeks. RESULTS: Forty-seven malaria patients and 42 blood donors were enrolled. At enrollment blood plasma HIV-1 RNA concentrations were approximately sevenfold higher in patients with malaria than in blood donors (medians 15.1 x 10(4) and 2.24 x 10(4) copies/ml, respectively, P = 0.0001). No significant changes in median HIV-1 concentrations occurred in the 21 blood donors followed to week 4 (P = 0.68). In the 27 subjects successfully treated for malaria who were followed to week 4, a reduction in plasma HIV-1 RNA was observed from a median of 19.1 x 10(4) RNA copies/ml at enrollment, to 12.0 x 10(4) copies/ml at week 4, (P = 0.02). Plasma HIV-1 concentrations remained higher in malaria patients than controls (median 12.0 x 10(4) compared with 4.17 x 10(4) copies/ml, P = 0.086). CONCLUSIONS: HIV-1 blood viral burden is higher in patients with P. falciparum malaria than in controls and this viral burden can, in some patients, be partly reduced with antimalarial therapy.

Developing effective strategies for malaria prevention programs for pregnant African women.

The control of malaria in pregnant African women, one of several child survival strategies applied through antenatal care, has been particularly challenging. Prevention and control recommendations for typical areas of high Plasmodium falciparum transmission have promoted the use of antimalarial chemoprophylaxis to prevent placental infection. Persistently low program coverage coupled with diminishing intervention effectiveness have forced a re-evaluation of the relative importance of malaria in pregnancy. The Mangochi Malaria Research Project (MMRP), a prospective evaluation of malaria prevention in pregnant women in rural Malawi conducted during 1987-1990, contributed to establishing new criteria for policy and program development for malaria prevention in pregnancy. The principle findings of the MMRP include: 1) populations at risk of the adverse consequences of malaria in pregnancy include women with low parity, women infected with human immunodeficiency virus, pregnancy during the high malaria transmission season, and the use of a malaria drug that is suboptimally efficacious; 2) the estimated maximum benefits of an antimalarial intervention that clears placental and umbilical cord parasitemia are a 5-12% reduction of low birth weight (LBW), an approximately 35% reduction in the risk of LBW for risks that are actually preventable once a woman has become pregnant (e.g., risks such as infectious disease or poor nutrition during gestation), and a 3-5% reduction in the rate of infant mortality; 3) the intervention must be capable of rendering the woman malaria parasite free, including clearance of parasites from the placental vascular space and umbilical cord blood; 4) other diseases adversely affect pregnancy outcome and, while the control of malaria in pregnancy may not warrant independent programming, if coupled with prevention programs to provide a range of antenatal services, the incremental costs of malaria control may prove to be highly cost-effective; and 5) the choice of a regimen must balance intervention efficacy with safety, availability, affordability, and simplicity of delivery, and several antimalarials may meet these criteria. The Malawi Ministry of Health has modified its malaria prevention in pregnancy recommendations and now faces the challenge of effective programming to improve child survival.

PIP: During 1987-90, a prospective evaluation of malaria prevention in pregnant women in rural Malawi, the Mangochi Malaria Research Project, was conducted. It aimed to address systematically the evolving obstacles to effective program strategies. The findings contribute to the establishment of new criteria for decision-making in policy and program development for malaria prevention and control in pregnancy. The project resulted in five key lessons learned. Populations at risk of the adverse effects of malaria during pregnancy are low-parity women, HIV-infected women, women pregnant during the high malaria transmission season, and pregnant women using a less effective malaria drug. The estimated maximum benefits of an antimalarial intervention include a 5-12% reduction in low birth weight (LBW), an approximate 35% reduction in the risk of LBW for risks that are preventable once a woman has conceived (i.e., infectious disease or poor nutrition during pregnancy), and a 3-5% reduction in infant mortality. The antimalarial intervention must be able to make the pregnant women malaria-parasite free and to effect clearance of parasites from the placental vascular space and umbilical cord blood. Since other diseases also adversely affect pregnancy outcome, the control of malaria should be integrated with prevention programs to provide a range of prenatal services. When choosing a regimen, the health provider must balance the regimen's efficacy with safety, availability, affordability, and ease of delivery. Several antimalarial regimens appear to meet these criteria. Based on the findings of the project, the Malawi Ministry of Health has changed its recommendations for malaria prevention in pregnancy.

Risk factors for anemia in young children in rural Malawi.

Anemia is an increasingly recognized health problem in African children. To determine the prevalence of and risk factors for anemia in young children, we enrolled 252 pregnant women and studied their newborn infants in Mangochi District in southern Malawi. At the first follow-up visit after birth at approximately two months of age, the mean hematocrit value of the 252 infants was 29.5%, and 64 infants (25%) were anemic (hematocrit value < 25%). Placental malaria infection was the strongest risk factor for an infant having anemia at the first follow-up (relative risk = 2.0, P = 0.003). Infants who had Plasmodium falciparum parasitemia at the first follow-up had lower hematocrit values than infants without parasitemia (median 28% versus 31%; P = 0.02). Neither the mother's hematocrit at enrollment, her hematocrit at delivery, sex of the infant, nor fever illness in the infant was associated with having a hematocrit less than 25% at the first follow-up. Although infants with hematocrit values less than 25% were more likely than infants with higher hematocrit values to die during the first year of life, this difference was not statically significant (relative risk = 1.7, P = 0.15). In rural Malawi, anemia commonly affects young infants, is acquired early in life, and is probably a risk factor for death in infancy. Strategies to reduce anemia in infants must address P. falciparum infection, both during pregnancy and in the first few months of life.

Comparability of treatment groups and risk factors for parasitemia at the first antenatal clinic visit in a study of malaria treatment and prevention in pregnancy in rural Malawi.

The problems of Plasmodium falciparum infection in pregnant women have been described in numerous sub-Saharan African countries, but the frequency of parasitemia at the first antenatal visit and risk factors for infection have not been fully investigated. During a prospective antimalarial treatment and prophylaxis trial in pregnant women in Malawi (three groups receiving a chloroquine regimen and one group receiving a mefloquine regimen), we examined women at their first antenatal clinic visit to evaluate these issues and to verify that subjects in the study treatment/prevention arms were similar. Among 4,127 women with enrollment blood smear results, 1,836 (44.5%) were parasitemic. The highest infection rates and densities were observed in primigravidas (66% infected, geometric mean parasite density [GMPD] = 1,588 parasites/mm3 of whole blood), followed by second pregnancies (46% infected, GMPD = 615 parasites/mm3) and subsequent pregnancies (29% infected, GMPD = 238 parasites/mm3), (P < 10(-6) for both infection prevalence and density, by chi-square test for trend). Significant risk factors for parasitemia at first antenatal clinic visit in a multivariate model included low gravidity, high transmission season, no use of prophylaxis before first antenatal clinic visit, young age (< 20 years), human immunodeficiency virus (HIV) infection, low hematocrit, short stature, and second trimester (compared with third trimester). Women in the different treatment arms of the study were generally similar in many characteristics; statistically significant differences, where present, were small. Targeting malaria control efforts to women in their first or second pregnancy and during the high transmission season will be an important strategy to reach most parasitemic women and minimize resource expenditure. Women infected with HIV had a 55% increased risk of parasitemia at their first antenatal clinic visit and may represent an additional important risk group whose numbers may be increasing and who may benefit from identification and management for malaria.

The problem of malaria and malaria control in pregnancy in sub-Saharan Africa.

Plasmodium falciparum infection in pregnant women frequently leads to placental infection and low birth weight (< 2,500 grams) of the infant, particularly in the areas of high malaria transmission found in sub-Saharan Africa. Low birth weight is widely known to be an important risk factor for early infant mortality. To reduce the risk that maternal infection poses to child survival, many antenatal clinic programs recommend and provide antimalarial chemoprophylaxis, often with chloroquine (CQ) as a recommended element for antenatal care. Prior to the 1980s, despite widespread advocacy for this intervention, little was known about the effect of this intervention strategy. As an introduction to the Mangochi Malaria Research Project, which examined the efficacy of several antimalarial regimens using CQ or mefloquine in pregnant women in Malawi, we describe the background of knowledge regarding malaria infection in pregnant African women and the important elements of an intervention and prevention strategy.

Transplacental transmission of Plasmodium falciparum in rural Malawi.

Malaria during pregnancy may result in fetal exposure to malaria when parasites are transmitted across the placenta. To document the rate of transplacental passage of Plasmodium falciparum and to identify the risk factors for congenitally acquired malaria infection, we examined umbilical cord blood for malaria parasites from 2,080 newborn infants born to mothers enrolled in a study of malaria prophylaxis during pregnancy. Cord blood parasitemia was detected in 140 (6.7%) newborn infants with a geometric mean density of 187 parasites/microliter (range 12-99, 752 parasites/microliter). The likelihood of umbilical cord blood parasitemia was closely linked to the parasite density of placental malaria infection and the density of maternal peripheral blood parasitemia at the time of delivery; all babies born to women with both placental and peripheral blood parasitemia densities > or = 10,000/microliter had cord blood parasitemia. In a multivariate logistic regression model, male sex, premature delivery, and placental and maternal peripheral blood malaria parasitemia were independently associated with a baby being born with umbilical cord blood parasitemia. In this setting, highly endemic for malaria, transplacental transmission of malaria from infected placentae occurs frequently and is directly related to the density of maternal malaria infection.

The effect of placental malaria infection on perinatal mortality in rural Malawi.

Perinatal deaths (fetal or infant deaths from the 28th week of pregnancy up to the seventh day after birth) occur as a result of adverse conditions during pregnancy, labor, and delivery, or in the first few days of life. Placental malaria infection is known to increase the risk of delivery of a low birth weight infant, thus, potentially increasing the risk of perinatal and infant mortality. To better understand the relationship among the adverse events in pregnancy, including placental malaria infection, adverse conditions in labor, and birth weight to perinatal mortality, we investigated the perinatal mortality among a cohort of infants born to rural Malawian women for whom placental malaria infection status and birth weight were documented. Among the 2,063 mother-singleton infant pairs, there were 111 perinatal deaths (53.8 perinatal deaths per 1,000 births). The risk of perinatal death increased as birth weight decreased. Risk factors identified for perinatal mortality among all infants excluding birth weight included abnormal delivery (cesarean section, breech, or vacuum extraction), a history of a late fetal or neonatal death in the most recent previous birth among multiparous women, reactive maternal syphilis serology, nulliparity, and low socioeconomic status. Placental malaria infection was not associated with increased perinatal mortality, but was associated with lower perinatal mortality among normal birth weight (> or = 2,500 g) infants (odds ratio = 0.35, 95% confidence interval = 0.14, 0.92). Interventions to address these risk factors could have a substantial impact on reducing perinatal mortality in this population.

Infant and second-year mortality in rural Malawi: causes and descriptive epidemiology.

Community information based on causes and circumstances of death in infants and young children in Malawi was obtained in a prospective cohort of babies delivered to women enrolled in a malaria-prevention-in-pregnancy study. Vital status information was obtained through home visits every two months; for children who died, questions were asked concerning age and date of death, symptoms preceding death, care sought, location of death (home versus facility), and duration of illness. Of 3,274 liveborn singleton infants, 181, 397, and 152 deaths occurred in the neonatal, postneonatal, and second year of life, respectively. For neonates, proportionate mortality was greatest for sepsis/tetanus (16.7%) and fever (8.6%); however, for more than half of neonatal deaths evaluated the cause was not identified. Up to 30% of neonatal deaths may have been related to prematurity. In the postneonatal period, gastrointestinal illness (39.6%), fever (18.3%), and respiratory illness (14.7%) were the leading causes. Most postneonatal illnesses lasted 1 week or less. Two-thirds of postneonatal deaths occurred outside of a health care facility, although 80% were brought to a facility for care during their illness. Infectious disease syndromes continued to be important in the second year of life, with gastrointestinal (31.6%), fever (23.5%), and measles (20.6%) the most commonly reported causes of death. In this area of rural sub-Saharan Africa, neonatal mortality contributes substantially to infant mortality, and prematurity is considered to be an important component of early neonatal deaths; infectious disease syndromes predominate in the postneonatal and second year of life. Strategies to reduce infant deaths in sub-Saharan Africa must consider these factors, as well as the observations that most children who died had brief illnesses, were taken to a health care facility before death, yet died at home.

Rates and risk factors for mortality during the first two years of life in rural Malawi.

Developing nations in sub-Saharan Africa experience childhood mortality rates that are much higher than any other region of the world. In a rural Malawian community we investigated risk factors for deaths occurring during the neonatal (birth-28 days), postneonatal (29-365 days), infant (birth-365 days), and second-year (366-730 days) periods among a cohort of 3,724 infants monitored from birth. The neonatal mortality rate in this cohort was 48.6 per 1,000 live births (LB); the postneonatal mortality rate was 108.7/1,000 LB. The overall infant mortality rate was 157.3 deaths/1,000 LB and the mortality rate for the first two years of life was 223.7 deaths/1,000 LB. The predominate risk factors for neonatal deaths identified in multivariate analysis were low (hazard ratio [HR] = 2.3) and very low birth weight (HR = 12.7), first pregnancy (HR = 1.8) and maternal syphilis infection (HR = 2.4). Maternal infection with human immunodeficiency virus (HIV) (HR = 1.5) predominated for postneonatal deaths. Low (HR = 1.4) and very low (HR = 5.0) birth weight, first pregnancy (HR = 1.6), maternal HIV infection (HR = 2.4), and the combination of low education and low socioeconomic status (SES) of the mother (HR = 2.0) were the most important factors during the infant period. Maternal HIV infection (HR = 3.3) and the combination of low education and low SES of the mother (HR = 2.6) were the predominate risk factors for mortality occurring during the second year. Factors that were significant in univariate analysis but not significant in the final multivariate models included prematurity, previous adverse reproductive outcome, dying during high malaria transmission season, and being born at home. Interventions to prevent maternal HIV infection and low birth weight and treatment of syphilis infection would have a great impact on reducing early childhood deaths. Improving the delivery of health care and education to women during their first pregnancy and to the most socially disadvantaged women may also help reduce the burden of early childhood mortality in communities such as the one studied in Malawi.

Evaluation of maternal practices, efficacy, and cost-effectiveness of alternative antimalarial regimens for use in pregnancy: chloroquine and sulfadoxine-pyrimethamine.

With the knowledge that an efficacious antimalarial administered to pregnant women would markedly reduce placental malaria and its associated risk of low birth weight (LBW), investigations were conducted to identify an antimalarial regimen practical for nationwide implementation through the antenatal clinic (ANC) system. Maternal practices, including ANC utilization and malaria treatment and prevention during pregnancy were evaluated as part of a national malaria knowledge, attitudes, and practices survey. A second study was conducted to evaluate the efficacy and cost of selected alternative antimalarial regimens. Women in their first or second pregnancy were placed on chloroquine (CQ) treatment (25 mg/kg) followed by weekly CQ (300 mg) (CQ/CQ); sulfadoxine-pyrimethamine (SP) treatment followed by CQ (300 mg weekly) (SP/CQ); or SP treatment during the second trimester and repeated at the beginning of the third trimester (SP/SP). With 87% of women attending ANC two or more times during pregnancy, most pregnant women in Malawi could be reached with an antimalarial intervention. Among 159 women in their first or second pregnancy receiving CQ/CQ, SP/CQ, and SP/SP, placental malaria parasitemia rates were 32%, 26%, and 9%, respectively (P = 0.006, by chi-square test). The SP/SP regimen was also markedly more cost-effective in preventing infant deaths, costing $75 per infant death prevented, compared with $481 for SP/CQ and $542 for CQ/CQ. These investigations suggest that a regimen consisting of two treatment doses of SP during pregnancy is an efficacious and cost-effective intervention to prevent placental malaria, and LBW-associated mortality, that can be delivered to pregnant women through ANCs in settings similar to those found in rural Malawi.

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

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.

The efficacy of antimalarial regimens containing sulfadoxine-pyrimethamine and/or chloroquine in preventing peripheral and placental Plasmodium falciparum infection among pregnant women in Malawi.

To define an effective and deliverable antimalarial regimen for use during pregnancy, pregnant women at highest risk of malaria (those in their first or second pregnancy) in an area of Malawi with high transmission of chloroquine (CQ)-resistant Plasmodium falciparum were placed on CQ and/or sulfadoxine-pyrimethamine (SP). Of 38 pregnant women who received CQ treatment followed by weekly CQ prophylaxis (CQ/CQ) for at least 45 days prior to delivery, 32% had placental malaria infection, compared with 26% of 50 pregnant women who received a treatment dose of SP followed by weekly CQ prophylaxis (SP/CQ), and only 9% of 71 pregnant women who received a two-dose SP regimen (SP/SP; given once during the second trimester and repeated at the beginning of the third trimester) (P = 0.006, by chi-square test). During the peak transmission season from April to July, 47% of the women who received CQ/CQ had placental malaria infection at delivery, as compared with 37% of the women who received SP/CQ, and 10% of women who received SP/SP (P = 0.004, by chi-square test). Among women in their first or second pregnancy, two treatment doses of SP were highly effective in decreasing the proportion of women with placental malaria infection at delivery.

Antibodies to a Plasmodium falciparum blood-stage antigen as a tool for predicting the protection levels of two malaria-exposed populations.

To evaluate the ability of antibodies to Plasmodium falciparum ring-infected erythrocyte surface antigen (Pf155/RESA) epitopes to discriminate between individuals well protected or poorly protected against malaria, a receiver operating characteristic analysis was performed in two populations living in Madagascar and Malawi. The definition of protection was based on longitudinal measurements of clinical malarial attacks during the season of high malaria transmission in the Madagascar study, and on a cross-sectional measurement of parasitemia in the Malawi study. Antibodies to peptides reproducing the 4-mer, 8-mer, and 11-mer of the Pf155/RESA were tested for their reactivities using the Falcon assay screening test-enzyme-linked immunosorbent assay. Maximal detection of poorly protected individuals (specificity = 100%) corresponded to high cutoff antibody titers (range = 1.65-3.0 optical density [OD] units in the Madagascar study and 0.67-1.42 OD units in the Malawi study) and a sensitivity less than 50%. For a given sensitivity of 50%, specificity ranged from 55% to 62% in the Madagascar study, and from 67% to 94% in the Malawi study. The antibody cutoff titers corresponding to minimal misclassification rates ranged from 0.24 to 1.73 OD units in the Madagascar study and from 0.15 to 0.55 OD units in the Malawi study. For each antibody, the highest detectability value as measured by the area under the curve was obtained for anti-R11 in the Malawi study (0.838). In demonstrating such qualities, antibodies to Pf155/RESA epitopes could be used for screening poorly protected populations in which malaria control programs have to be implemented.

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

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.

PIP: During September 1987 to June 1990, 3380 pregnant women with parasitemia attending 4 prenatal care clinics in rural Mangochi District, Malawi, were assigned to 1 of 4 regimens of antimalarial treatment and/or prophylaxis. The women were followed through delivery to determine the antimalarial drug efficacy on peripheral parasitemia during pregnancy and parasitemia at the time of delivery in peripheral, placental, and umbilical cord blood. The regimens were 3 regimens for chloroquine (CQ), 1 of which was the current standard of care in Malawi, and a mefloquine (MQ) regimen. Parasite clearance was not achieved in 18.4% of the 1528 women with parasitemia at enrollment. 17.3% of the 1852 women who were aparasitemic at enrollment had breakthrough infections. Women using a CQ regimen faced a significantly greater risk of persistent and breakthrough parasitemia (odds ratio [OR ] = 30.9 and 11.1, respectively; p 0.0000001). The multivariate analysis found other significant risk factors for malaria to be first pregnancy (OR = 3.6 for persistent malaria and 1.5 for breakthrough malaria), enrollment in the rainy or post-rainy season (OR = 2-3.4 for persistent parasitemia and 1.2-2.7 for breakthrough malaria), maternal age of at most 25 years (OR = 2.3 for persistent malaria and 1.6 for breakthrough malaria), and seropositivity to HIV (OR = 1.9 for persistent malaria). At delivery, women on a CQ regimen faced a significantly higher risk of peripheral, placental, or umbilical cord parasitemia than those using MQ (OR = 8.7, 7.4, and 4.1, respectively; p 0.000001). In the multivariate model, other significant risk factors for malaria at delivery were first pregnancy, enrollment in the rainy or post-rainy season, maternal age of at most 25 years, and seropositivity to HIV. The most important determinant of falciparum malaria in pregnant women was use of an ineffective intervention (i.e., CQ in an area with CQ-resistant parasites). Based on these findings, the researchers recommend that antimalarial programs focus on highly efficacious drugs and targeting pregnant women during the season of high malaria exposure.

The effect of malaria and malaria prevention in pregnancy on offspring birthweight, prematurity, and intrauterine growth retardation in rural Malawi.

While there is broad evidence for the adverse effects of Plasmodium falciparum infection in pregnancy, and the World Health Organization recommends preventive strategies, there is markedly reduced efficacy in sub-Saharan Africa of the most widely available, affordable and used antimalarial drug for chemoprophylaxis-chloroquine (CQ). During 1987-1990, we studied pregnant women in an area of high malaria endemicity in rural Malawi to compare the efficacy of CQ (the drug recommended by national policy) with mefloquine (MQ, a relatively new and highly effective antimalarial) in preventing low birth weight (LBW) due to prematurity and intrauterine growth retardation (IUGR). Among 1,766 women monitored during at least their last six weeks of pregnancy with observed ingestion of their regimen and facility delivery of a live born singleton, their babies had a mean +/- SD birth weight of 2,905 +/- 461 gm and 16.8% had LBW. In a multivariate analysis, factors significantly associated with LBW included: first birth (odds ratio [OR] = 4.27), female infant (OR = 2.92), maternal human immunodeficiency virus infection (OR = 2.66), low maternal weight (OR = 1.95), and placental blood P. falciparum infection (OR = 1.71). Factors significantly associated with IUGR-LBW included first birth, female infant, low maternal weight, and placental malaria. Factors significantly associated with preterm-LBW included maternal syphilis infection, umbilical cord blood malaria, first birth, low maternal weight, and female infant. Use of an effective antimalarial (MQ) was protective against LBW through its effect on reducing placental and umbilical cord blood malaria infection. The proportion of LBW babies born to women on MQ (12.5% [parity-adjusted for the population of delivering women]) was significantly lower than the proportion born to women on CQ (15.5%; P = 0.05). Effective prevention of malaria in pregnant women in malaria-endemic settings may reduce the likelihood of LBW by 5-14%, and may reduce the amount of preventable LBW by more than 30%. When evaluating antenatal care programs, health policy makers must consider providing an effective preventive drug (either MQ or other drugs identified in additional studies, e.g., sulfa-pyrimethamine compounds) as a means to prevent low birth weight and its consequences.

Impairment of a pregnant woman's acquired ability to limit Plasmodium falciparum by infection with human immunodeficiency virus type-1.

In Africa, the human immunodeficiency virus (HIV) is the most serious emerging infection and Plasmodium falciparum malaria is one of the most prevalent infectious diseases. Both infections have serious consequences in pregnant women, their fetuses, and infants. We examined the association between HIV and P. falciparum in pregnant women enrolled in a malaria chemoprophylaxis study in rural Malawi. Pregnant women (n = 2,946) were enrolled at their first antenatal clinic visit (mean 5.6 months of pregnancy), placed on one of three chloroquine regimens, and followed through delivery. Plasmodium falciparum parasitemia was measured at enrollment, monthly thereafter, at delivery, and 2-6 months postpartum; placental and newborn (umbilical cord blood) infection was measured for hospital-delivered infants. Serum collected during pregnancy was tested for antibodies to HIV by enzyme-linked immunoassay with Western blot confirmation. Parasitemia was detected in 46% of 2,946 women at enrollment and 19.1% at delivery; HIV seroprevalence was 5.5%. The prevalence and geometric mean density (GMPD) of parasitemia at enrollment and at delivery were higher in HIV-seropositive(+) than in HIV-seronegative(-) women (at enrollment: 57% prevalence and a GMPD of 1,558 parasites/mm3 versus 44% and 670/mm3, respectively; P < 0.0001; and at delivery: 35% and 1,589/mm3 versus 18% and 373/mm3; P < 0.0005). Placental infection rates were higher in HIV(+) compared with HIV(-) women, (38% versus 23%; P < 0.0005). This association was strongest in multigravidas. Compared with infants born to HIV(-) women, newborns born to HIV(+) women had higher rates of umbilical cord blood parasitemia. Both HIV(+) and HIV(-) women had similar rates of parasitemia 2-6 months postpartum. The HIV infection diminishes a pregnant woman's capacity to control P. falciparum parasitemia and placental and newborn infection, the major determinants of the impact of P. falciparum on fetal growth and infant survival.

PIP: During September 1987 to July 1989, in Malawi, clinical investigators enrolled 2946 pregnant women into a chemoprophylaxis study at their first prenatal care visit (mean, 5.6 months) at 4 rural sites in Mangochi District. They prescribed 1 of 3 chloroquine regimens to the women and followed them through delivery. The investigators measured Plasmodium falciparum parasitemia at enrollment, monthly thereafter, at delivery, and 2-6 months postpartum. For hospitalized infants, they measured parasitemia in the placenta and in the umbilical cord blood of the newborn. They also aimed to examine the association between HIV infection and malaria in pregnant women. 152 (5.5%) of the 2781 women for whom HIV test results and malaria blood smear examinations were available had confirmed HIV infection. Malaria parasitemia stood at 42% at enrollment and 19.1% at delivery. At enrollment, HIV-positive women had a higher malaria parasite prevalence rate than HIV-negative women (54.4% vs. 41.7%; relative risk [RR] = 1.31; p = 0.002). They also had a higher geometric mean density of parasitemia (1558 vs. 670/sq mm; p 0.0005). The parasite pattern was similar at delivery (34.7% vs. 18.2% [RR = 1.91] and 1589 vs. 373/sq mm, respectively; p 0.0005). The placenta of infants born in the hospital to HIV-positive mothers also had a higher prevalence of malaria parasites than those born in the hospital to HIV-negative mothers (38.2% vs. 22.5%; RR = 1.7; p = 0.0003). The prevalence of umbilical cord blood malaria infection was higher in infants born in the hospital to HIV-positive mothers than their counterparts (25.5% vs. 6.8%; RR = 3.76). At 2-6 months postpartum, the prevalence and density of malaria parasitemia rate did not differ significantly by HIV status. Parasitemia prevalence and density were higher in multigravida HIV-positive women than HIV-negative women but were similar in primigravid HIV-positive and HIV-negative women. These findings suggest that HIV infection reduces a pregnant woman's capacity to control P. falciparum parasitemia and placental and newborn infection.

Malaria treatment and prevention in pregnancy: indications for use and adverse events associated with use of chloroquine or mefloquine.

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.

PIP: 4187 pregnant women with parasitemia attending 4 prenatal care clinics in rural Mangochi District, Malawi, were assigned to 1 of 4 regimens of antimalarial treatment and/or prophylaxis and followed through delivery. The aim was to examine maternal fever and to evaluate side effects and the frequency of adverse reproductive outcomes for their possible association with malaria or the antimalarial drug regimens. The regimens were 3 regimens for chloroquine (CQ), 1 of which was the current standard of care in Malawi, and a mefloquine (MQ) regimen. 25% of the pregnant women claimed to have had at least 1 febrile episode before their first prenatal care visit. Blood smear tests revealed the parasitemia prevalence rate at enrollment to be 44.4%. The sensitivity of fever to identify parasitemic pregnant women was 24%. Fever's specificity was 71%. Only high density parasitemia (10,000 parasites/sq m) was associated with fever (44.9% vs. 25.4% for no parasitemia; odds ratio [OR] = 2.54; p 0.000001). Other significant factors associated with high fever were low parity, enrollment in the rainy season, HIV seropositivity, use of antimalarial prophylaxis before enrollment, high socioeconomic status, normal maternal height and weight, and literacy. The sensitivity of first or second pregnancy to identify parasitemic women was 71%. Its specificity was 57%. About 60% of women from both CQ and MQ treatment groups had side effects after a treatment dose. About 25% had side effects after a prophylactic dose. The leading side effects were itching, dizziness, and gastrointestinal disturbances. There were few serious side effects. Among all women, the spontaneous abortion rate was 1.2% and the stillbirth rate was 3.9%. Women in the CQ and MQ treatment groups had similar abortion and stillbirth rates. Based on these findings, the researchers concluded that using fever as a means to identify parasitemic women is unreliable. They recommend antimalarial treatment and/or prophylaxis for all pregnant women, but when resources are limited it should be administered to women in their first or second pregnancy.