Women are particularly susceptible to malaria during first and second pregnancies, even though they may have developed immunity over years of residence in endemic areas. Plasmodium falciparum-infected red blood cells (IRBCs) were obtained from human placentas. These IRBCs bound to purified chondroitin sulfate A (CSA) but not to other extracellular matrix proteins or to other known IRBC receptors. IRBCs from nonpregnant donors did not bind to CSA. Placental IRBCs adhered to sections of fresh-frozen human placenta with an anatomic distribution similar to that of naturally infected placentas, and this adhesion was competitively inhibited by purified CSA. Thus, adhesion to CSA appears to select for a subpopulation of parasites that causes maternal malaria.

https://science.sciencemag.org/content/sci/272/5267/1502.full.pdf

Adherence of Plasmodium falciparum to Chondroitin Sulfate A in the Human Placenta

Pregnant women in malarious areas may experience a variety of adverse consequences from malaria infection including maternal anemia, placental accumulation of parasites, low birth weight (LBW) from prematurity and intrauterine growth retardation (IUGR), fetal parasite exposure and congenital infection, and infant mortality (IM) linked to preterm-LBW and IUGR-LBW. We reviewed studies between 1985 and 2000 and summarized the malaria population attributable risk (PAR) that accounts for both the prevalence of the risk factors in the population and the magnitude of the associated risk for anemia, LBW, and IM. Consequences from anemia and human immunodeficiency virus infection in these studies were also considered. Population attributable risks were substantial: malaria was associated with anemia (PAR range = 3-15%), LBW (8-14%), preterm-LBW (8-36%), IUGR-LBW (13-70%), and IM (3-8%). Human immunodeficiency virus was associated with anemia (PAR range = 12-14%), LBW (11-38%), and direct transmission in 20-40% of newborns, with direct mortality consequences. Maternal anemia was associated with LBW (PAR range = 7-18%), and fetal anemia was associated with increased IM (PAR not available). We estimate that each year 75,000 to 200,000 infant deaths are associated with malaria infection in pregnancy. The failure to apply known effective antimalarial interventions through antenatal programs continues to contribute substantially to infant deaths globally.

The burden of malaria in pregnancy in malaria-endemic areas.

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.

Cytoadhesion of infected red blood cells (iRBC) is mediated through parasite-encoded, clonally variant surface antigens (VSA) and is a central process in the pathogenesis of Plasmodium falciparum malaria. Pregnancy-associated malaria (PAM) has been linked to VSA-mediated adhesion of iRBC to the glycosaminoglycan chondroitin sulphate A (CSA) in the placental intervillous space. Several studies have pointed to members of the PfEMP1 VSA family as mediators of CSA-specific iRBC sequestration in the placenta. Here, we report marked upregulation of a single var gene in several P. falciparum parasite isolates after selection for adhesion to CSA in vitro. The gene belongs to a highly conserved and common var gene subfamily (var2csa). The var2csa genes are structurally distinct from all other var genes in the parasite genome in lacking both CIDR and DBL-gamma domains. These domains have previously been implicated in PfEMP1-mediated adhesion to CD36 and CSA. We also show that var2csa was transcribed at higher levels in three placental parasite isolates compared with transcription in parasites from peripheral blood of two children with P. falciparum malaria. This var gene thus has the properties expected of a gene encoding the parasite adhesion molecule that initiates the pathology associated with PAM.

Selective upregulation of a single distinctly structured var gene in chondroitin sulphate A-adhering Plasmodium falciparum involved in pregnancy-associated malaria

Mortality and morbidity from malaria were measured among 3000 children under the age of 7 years in a rural area of The Gambia, West Africa. Using a post-mortem questionnaire technique, malaria was identified as the probable cause of 4% of infant deaths and of 25% of deaths in children aged 1 to 4 years. The malaria mortality rate was 6.3 per 1000 per year in infants and 10.7 per 1000 per year in children aged 1 to 4 years. Morbidity surveys suggested that children under the age of 7 years experienced about one clinical episode of malaria per year. Calculation of attributable fractions showed that malaria may be responsible for about 40% of episodes of fever in children. Although the overall level of parasitaemia showed little seasonal variation, the clinical impact of malaria was highly seasonal; all malaria deaths and a high proportion of febrile episodes were recorded during a limited period at the end of the rainy season.

Mortality and morbidity from malaria among children in a rural area of The Gambia, West Africa

The incidence of placental malaria at parturition and its effects on the conceptus have been investigated in The Gambia, West Africa. Malarious placentae occurred in 1300 (20.2%) of 6427 singleton births, in 32 (18.6%) of 172 sets of twins and in none of six sets of triplets. Plasmodium falciparum infections predominated; P. malariae or P. ovale infections were found in only nine instances. In the large group of single births placental malaria occurred less frequently (12.0%) in residents of urban than of other, more rural, communities (27.1%). In the former group incidence showed no clear change with season; in the latter group it was highest in the trimester following the end of the rains and lowest in the second half of the dry season. In both residential groups it was more frequent in primiparae (urban 16.1%; other 46.9%) than in multiparae (urban 8.9%; other 20.3%). The sex of the child did not influence malaria incidence. Dense placental infections were more frequent in primiparae. Stillbirth rates of singleton infants were significantly higher for males than for females, but no clear and consistent relationship between stillbirth and placental malaria was detected. Mean singleton birthweights were depressed by about 170 g in the presence of malaria; the deficits were statistically significant only among first born infants and tended to diminish progressively with increasing maternal parity. No distinct gradient linking birthweight with ascending density of placental parasitaemia was observed. Singleton birthweights of 2.5 kg or less occurred more frequently in association with malarious than non-malarious placentae and the association was more marked among first born than later birth rank infants. Differences between the weights of malarious and non-malarious placentae were small and not significant. The findings of the study are discussed in relation to the widely prevalent view that pregnancy exacerbates maternal malaria by attenuating acquired immunity.

Malaria infection of the placenta in The Gambia, West Africa; its incidence and relationship to stillbirth, birthweight and placental weight

This communication describes the mortality and growth rates of children in a rural Gambian community. The observations were made in the village of Keneba, where since 1949 the staff of the M.R.C. Laboratories, Gambia, have investigated the health of Africans. Keneba is an African settlement in the West Kiang District of the Protectorate of the Gambia and is typical of the villages situated near the banks of the Gambia river. About 700 inhabitants-Mandinkas-live in dwellings made of mud, grass, or krint (a local bamboo), and maintain themselves almost entirely by agriculture. The food crops-rice, millet (Pennisetumt sp.), sorghum, maize, and findo (Digitaria sp.)-and the only cash crop -groundnuts-are grown throughout the wet months from late May to October. The men usually grow the dry-land crops, riecultivation being regarded almost exclusively as a responsibility of the women. Cattle, the trypanosome-resistant N'dama, are kept; throughout the period discussed in this communication they totalled just over 100. They are practically never killed for food, and, although milk is welcomed by the villagers, yields are low and little is left for human consumption when the requirements of calves have been satisfied. Goats and sheep are kept, but again these contribute little to the village food supplies, the flesh being eaten only during feasts. Fish is abundant in the river and is consumed readily when available, but fishing is regarded as a low-caste occupation and adds little to the food supply. Most infants are exclusively breast-fed for four to six months after birth. The earliest food supplements are paps, usually made of rice but sometimes of millet or sorghum, and to these fish and sauces of groundnuts and green leaves are gradually added. Boiled rice grains are also added to the diet, usually by the mother feeding the infant a very small quantity of her own portion during meals. When breast-feeding finally stops, usually between the 18th and 22nd months, the toddler is receiving a mixed diet of the adult pattern. A baseline survey made in April-May, 1950 (McGregor and Smith, 1952), showed that malaria was h-yperendemic, the crude parasite rate for all ages being 54.7%10 ; that approximately 36% and 33% of villagers were carriers of microfilariae of Wuchereria bancrofti and Anopheles perstans respectively ; that 2.5% of the population were suffering from trypanosomiasis; and that hookworm and ascaris infections abounded. Against this background of varied and heavy parasitization a reculrent shortage of the harvested cereals was at first noted. From mid-May until late July, when the early crops, maize, and digitaria were harvested, dwindling cereal stocks were reinforced by extensive collection of bush fruits, nuts, berries, and green leaves. Since 1950 the duration of this recurrent \"hungry season \" has been progressively reduced by gradual extension of rice cultivation, until in the agricultural year 1957-8 it was entirely eliminated, the cereal supplies lasting from the harvest of 1957 to that of 1958.

https://www.bmj.com/content/bmj/2/5268/1661.full.pdf

Growth and Mortality in Children in an African Village

A detailed study of the growth and health of 215 children under 5 years in the village of Keneba (Gambia) during 1962-1963 was conducted. At the same time outline information was collected in 3 adjacent villages--Jali Manduar and Kantongkunda. There were 99 live births during 1962-1963. It became obvious during the 1st year of the study that season exercised a marked effect on trends in body weight and it became necessary to define the seasons. Data from children who died during the survey period were excluded. Of the 99 liveborn babies 93 were measured within 3 days of birth. The data suggested that birth weights were on average lower during the wet than the dry months but the differences between the quarter years were not statistically significantly. There was no indication that the weight gains in the 1st 6 months of small babies differed from those of large babies. The seasonal effect was slight during the early months of life but became obvious at later ages. Children born in the early part of the year gained very well until nearly the end of their 1st rainy season when there was a short setback. Children born during the wet months grew well until the onset of the rains in the following year. Those born during the earlier part of the dry season received a marked check to growth soon after entering the wet months. Both season of birth and age dictated the average pattern of gain in weight during the 1st year of life. Until about 6 months of age season made little difference to rates of gain in Keneba but thereafter increments were about zero or slightly negative during the wet months with some catch up during the dry months. The Keneba babies grew much faster than American babies during the first 3 months of life but much more slowly during the 2nd half of the 1st year. By the end of the 2nd year the average rate of growth in height had practically caught up with the American standard. The data confirmed the previous finding that in general the growth of children who die is not very different from that of children who survive and that the events which precede death cause effects on body weight which are of relatively short duration.

The growth of young children in a Gambian village

The health of young children in a West African (Gambian) village.

Haemoglobin and haematocrit values were determined at approximately quarterly intervals during 2 years (1962–1963) in children under 5 years of age, in 4 adjacent rural villages in the Gambia, West Africa. Haemoglobin concentrations fell progressively from high levels (mean over 14·0 g. %) in the first month of life to low levels (mean, 9·0 g. %) at the 18th month. They remained low for the remainder of the second year and thereafter climbed slowly to reach a mean value of 10·5 g. % at 4 years of age. Values for haematocrit and MCHC behaved in a similar fashion. More detailed analysis showed that haematological characteristics varied substantially by season and place of residence. In 3 of the villages haemoglobin concentrations and haematocrit values varied with season in a regular and predictable way. Values rose throughout the dry season (December to May) into the early part of the rains (July), only to fall sharply in the latter part of the wet season (November). Season had less effect on MCHC values, although these were found to be higher in children with malaria parasitaemia. Severe anaemia was common and was usually of the “iron deficiency” type. In the children of the fourth village anaemia was less common and less severe and haemoglobin levels showed no distinct change with season. The haematological findings are discussed in the light of medical knowledge of the area studied. Malaria is probably the most important single factor responsible for both the frequency of severe anaemia and the seasonal variations in haematological indices. Many other factors may also contribute, notably the effect of a rapidly expanding blood volume in an infant whose birth weight was low, the frequency of infectious disease with attendant clinical illness, and the dietary limitations imposed partly by the influence of season upon agriculture and partly by haphazard care of young children.

W.Z. Billewicz

Papers

Malaria infection of the placenta in The Gambia, West Africa; its incidence and relationship to stillbirth, birthweight and placental weight

Growth and Mortality in Children in an African Village

The growth of young children in a Gambian village

The health of young children in a West African (Gambian) village.

Haemoglobin concentration and anaemia in young West African (Gambian) children.