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We conducted a prospective longitudinal study of fetal size in rural Papua New Guinea (PNG) involving 439 ultrasound-dated singleton pregnancies with no obvious risk factors for growth restriction. Sonographically estimated fetal weights (EFWs; N = 788) and birth weights (N = 376) were included in a second-order polynomial regression model (optimal fit) to generate fetal weight centiles. Means for specific fetal biometric measurements were also estimated. Fetal weight centiles from a healthy PNG cohort were consistently lower than those derived from Caucasian and Congolese populations, which overestimated the proportion of fetuses measuring small for gestational age (SGA; < 10th centile). Tanzanian and global reference centiles (Caucasian weight reference adapted to our PNG cohort) were more similar to those observed in our cohort, but the global reference underestimated SGA. Individual biometric measurements did not differ significantly from other cohorts. In rural PNG, a locally derived nomogram may be most appropriate for detection of SGA fetuses., (© The American Society of Tropical Medicine and Hygiene.)

Human immunodeficiency virus (HIV) is common in pregnant women in many malaria-endemic regions and may increase risk of placental parasitemia. Placental malaria is more common in primigravidae than multigravidae, but the relationship between HIV and malaria across gravidities is not well characterized. We recruited pregnant Malawian women during the second trimester and followed them until delivery. Parasitemia was assessed at enrollment, follow-up visits, and delivery, when placental blood was sampled. There was no difference in risk of parasitemia between HIV-positive and HIV-negative primigravidae. Among multigravidae, HIV-infected women had greater than twice the risk of parasitemia as HIV-uninfected women throughout follow-up. Human immunodeficiency virus was also associated with more frequent peripheral parasitemia in multigravidae but not primigravidae. Both HIV and primigravid status were independently associated with higher peripheral and placental parasite densities. Although risk of parasitemia is lower in multigravidae than primigravidae, the HIV effect on risk of malaria is more pronounced in multigravidae.

Plasmodium falciparum and human immunodeficiency virus (HIV) are both risk factors for low birth weight (LBW) and maternal anemia, and they may interact to increase risk of adverse pregnancy outcomes. In 2005 and 2006, we followed 831 pregnant women attending antenatal care clinics in southern Malawi through delivery. HIV was associated with increased risk of LBW (adjusted prevalence ratio [PR(adj)] = 3.08, 95% confidence interval [CI] = 1.40, 6.79). Having greater than or equal to three episodes of peripheral parasitemia was also associated with increased risk of LBW (PR(adj) = 2.68, 95% CI = 1.06, 6.79). Among multigravidae, dual infection resulted in 9.59 (95% CI = 2.51, 36.6) times the risk of LBW compared with uninfected multigravidae. HIV infection and placental parasitemia were each associated with increased risk of anemia. Thus, HIV infection and parasitemia are important independent risk factors for adverse pregnancy outcomes. Among multigravidae, HIV infection and placental parasitemia may interact to produce an impact greater than the sum of their independent effects.

Pregnant women are susceptible to malaria during pregnancy. Plasmodium falciparum, which sequesters in the placenta, causes the greatest disease, contributing significantly to maternal and infant mortality. Parasitized cells in the placenta express unique variant surface antigens (VSA), predominantly the VAR2CSA protein, and lack of immunity to these pregnancy-specific variant surface antigens explains some of the pregnancy-associated malaria susceptibility. Changes in acquired cellular immunity during pregnancy also appear important. Placental inflammatory responses, particularly monocyte infiltrates, predispose to fetal growth restriction and maternal anemia. Preventing malaria in pregnancy relies on insecticide treated bed nets, intermittent preventive treatment with antimalarials such as sulphadoxine-pyrimethamine, and potentially relies on the development of effective vaccines. The optimal deployment of each may depend heavily on the relationship between the timing of placental malaria infection and its deleterious consequences. Improved understanding of the relationship between pathogenesis, immunity, and pregnancy outcome will allow better targeting of our interventions to prevent the consequences of malaria in pregnancy.

Antibodies to variant surface antigens (VSA) including Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) have been associated with protective antimalarial immunity that appears to be variant-specific. This study of adult returned travelers with a single acute P. falciparum infection investigated whether a primary antibody response includes IgG specific for heterologous VSA. We found that 11 of 14 patients had IgG reactive with up to six P. falciparum lines expressing different heterologous PfEMP1 variants, measured by flow cytometry (reactivity greater than two times the mean of the negative control sera was defined as "positive"), with high reactivity (greater than four times the mean of the negative controls) detected in three patients. The dominant variant(s) recognized differed between seropositive individuals. Despite previous evidence that antibody responses to heterologous VSA are short-lived, seven patients had detectable IgG at > 20 weeks post-infection. Together these data suggest that a single P. falciparum infection can be sufficient to induce antibodies reactive with several PfEMP1 variants, although the repertoire of target epitopes they recognize may still be restricted.

Malaria during pregnancy, which is characterized by the accumulation of infected erythrocytes in the placenta, often has severe consequences for the mother and newborn. We assessed the effect of the genetic trait South-East Asian ovalocytosis (SAO) on placental malaria in women from Papua New Guinea. In children, this trait confers protection against cerebral malaria, but not against mild malaria disease, malaria parasitemia, or severe malaria anemia. Using a case-control approach, we found that SAO women suffer from placental malaria, and SAO-infected erythrocytes can sequester in the placenta, but heavy placental infections tended to be less common in SAO than in control pregnant women. Reduced prevalence and severity of placental infection associated with SAO were observed only for primigravid women, who are the group at highest risk of suffering from severe manifestations of placental malaria. Furthermore, we found that the prevalence of the SAO trait was lower among pregnant women than among non-pregnant controls.

Since quinine does not inhibit the growth of Plasmodium falciparum ring stages or mature schizonts, parasites may continue to emerge from sequestration sites after starting treatment. We used polymerase chain reaction amplification of P. falciparum merozoite surface protein 1 (MSP-1) and MSP-2 alleles to distinguish genotypes infecting 58 children with severe malaria. To examine changes in parasite populations in peripheral blood over time, we compared changes in number and spectrum of genotypes in samples on admission to a hospital to those obtained up to 24 hours later. Thirty-four children lost genotypes, 21 retained genotypes, and 3 gained an extra P. falciparum genotype at one locus but not the other. The lack of novel genotypes emerging suggests that among children with severe malaria the dominant clones sequestered in deep organs are usually the same as those in peripheral circulation.

In sub-Saharan Africa, human immunodeficiency virus (HIV) and malaria are among the leading causes of morbidity during pregnancy. We reviewed available information collected since the first report 15 years ago that HIV impaired the ability of pregnant women to control malaria parasitemia. Results from 11 studies showed that HIV-infected women experienced consistently more peripheral and placental malaria (summary relative risk = 1.58 and 1.66, respectively), higher parasite densities, and more febrile illnesses, severe anemia, and adverse birth outcomes than HIV-uninfected women, particularly in multigravidae. Thus, HIV alters the typical gravidity-specific pattern of malaria risk by shifting the burden from primarily primigravidae and secundigravidae to all pregnant women. The proportional increase of malaria during pregnancy attributable to HIV was estimated to be 5.5% and 18.8% for populations with HIV prevalences of 10% and 40%, respectively. Maternal malaria was associated with a two-fold higher HIV-1 viral concentrations. Three studies investigating whether placental malaria increased mother-to-child HIV-1 transmission showed conflicting results, possibly reflecting a complex balance between placental malarial immune responses and stimulation of HIV-1 viral replication. Further investigations of interactions between antiretroviral drugs, prophylaxis with cotrimoxazole, and antimalarial drugs in pregnant women are urgently needed. Although much has been learned in the past 15 years about the interaction between malaria and HIV-1 during pregnancy, many issues still require further information to improve our understanding. There is a clear need to strengthen the deployment of existing malaria and HIV prevention and intervention measures for pregnant women., (Copyright 2004 The American Society of Tropical Medicine and Hygiene)

Maternal anemia and low birth weight (LBW) may complicate malaria in pregnancy, and placental monocyte infiltrates have been associated with LBW, and anecdotally with anemia. We examined placental pathology from 357 Malawian women. Intervillous monocyte infiltrates were frequent in placental malaria and were not seen in uninfected placentas. Histology was grouped according to a 5-point scale. Dense monocyte infiltrates and presence of intramonocytic malaria pigment were associated with anemia and LBW. Of factors associated with LBW and/or anemia in univariate analysis, gravidity (P = 0.002), number of antenatal clinic (ANC) visits (P < 0.001), malaria pigment in fibrin (P = 0.03), and monocyte malaria pigment (P = 0.0001) remained associated with lower birth weight by multivariate analysis. Associated with maternal anemia were HIV infection (P < 0.0001), intervillous monocyte numbers (P < 0.0001), number of ANC visits (P = 0.002), and recent febrile symptoms (P = 0.0001). Pigment-containing placental monocytes are associated with anemia and LBW due to malaria, and may have a causative role in their development.

Malaria and anemia are common in pregnant African women. We screened 4,764 Malawian women at first antenatal visits for malaria and anemia. A total of 42.7% had a malaria infection, which was more common and of higher density in primigravidae (prevalence = 47.3%, geometric mean = 332 parasites/microl) and teenagers (49.8%, 390/microl) than in multigravidae (40.4%, 214/microl) or older women (40.6%, 227/microl). However, 35% of gravida 3+ women were parasitemic. A total of 57.2% of the women was anemic (hemoglobin < 11 g/dl), with moderate anemia (7.0-8.9 g/dl) in 14.9% and severe anemia (< 7 g/dl) in 3.2%. Prevalences of malaria and anemia were highest in the rainy season. Women with moderate/severe anemia had higher parasite prevalences and densities than women with mild/no anemia. Logistic regression showed that age, season, and trimester of presentation were significantly associated with the prevalence of malaria, but gravidity was not. In this urban setting, age and season are more important than gravidity as predictors of malaria at first antenatal visit, and parasitemia is frequent in women of all gravidities.

Cytoadherence of Plasmodium falciparum-infected erythrocytes to the microvascular endothelium is believed to be a key factor in the development of cerebral malaria. Erythrocyte rosette formation has been correlated with malaria severity in studies from east and west Africa. We cultured fresh isolates from Malawian children with severe (n = 76) or uncomplicated (n = 79) malaria to pigmented trophozoite stage and examined rosette formation and adherence to CD36, intercellular adhesion molecule-1 (ICAM-1), chondroitin sulfate A (CSA), and thrombomodulin (TM). Most (126 of 148) isolates bound to CD36, and 76 of 136 bound to ICAM-1. Fewer bound to CSA (40 of 148) or TM (23 of 148). After controlling for parasitemia, there was an inverse association between binding to CD36 (P = 0.004) or ICAM-1 (P = 0.001) and disease severity. Parasites from children with severe malaria anemia bound least to CD36, whereas ICAM-1 binding was lowest in children with cerebral malaria. There was no difference in rosette formation between any of the groups. In Malawian children, there was no evidence of a positive association between adherence to any of the receptors examined and disease severity. The negative association found raises the possibility that adherence to certain receptors could instead be an indicator of a less pathogenic infection.

The association between cytoadherence of Plasmodium falciparum-infected erythrocytes and the severity of malaria has been evaluated. In this study, we investigate adherence to C32 melanoma cells, CD36, intracellular adhesion molecule-1 (ICAM-1), thrombospondin (TSP), E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and chondroitin sulfate A (CSA) of 36 P. falciparum isolates from patients suffering from acute falciparum malaria. Adherence to purified adhesion molecules varied greatly among different parasite isolates. All isolates but one adhered to CD36, but none bound to E-selectin and VCAM-1 beyond control levels. Some P. falciparum isolates adhered to ICAM-1 and to CSA, a newly identified receptor for adherence. There was no correlation between in vitro binding to any one receptor and the patients' conditions. In addition, we investigated the characteristics of adherence to CSA and to C32 melanoma cells. Infected erythrocytes continued to adhere after trypsin digestion and soluble CSA inhibited adherence to C32 melanoma cells in a dose-dependent manner. The results imply a role for CSA in the natural infection of P. falciparum.

Some strains of Plasmodium falciparum form erythrocyte rosettes that are believed to result from a lectin interaction between malaria-infected and uninfected erythrocytes. The sulfated glycoconjugate heparin and certain heparin derivatives have been observed to disrupt rosettes. To investigate this interaction further, we have studied the effects of four sulfated glycoconjugates on 15 fresh isolates of P. falciparum from Papua New Guinea. A broader range of sulfated glycoconjugates has been tested against a laboratory strain. A concentration of 1,000 micrograms/ml of dextran sulfate (molecular weight [MW] 500,000) was the most potent disrupter of rosettes. Fucoidan, heparin, and dextran sulfate (MW 5,000) were of decreasing effectiveness in 14 of 15 fresh isolates. The same relationship was true for the laboratory strain. Pentosan polysulfate and sulfatide also disrupted rosettes; chondroitin sulfates A, B, and C and keratan sulfate gave either minimal or no rosette disruption. Thus, some sulfated glycoconjugates are potent disrupters of P. falciparum erythrocyte rosettes. Sulfated glycoconjugates that are potent disrupters of P. falciparum rosettes may prove useful in identifying ligands involved in rosette formation.

The relationship between antigenic variation, cytoadherence, rosette formation, and the pathogenesis of malaria has led to great interest in the diversity of these properties in Plasmodium falciparum isolates from different communities. In this study, we extend previous investigations by delineating the spectrum of agglutinating phenotypes, adherence to C32 melanoma cells, human umbilical vein endothelial cells (HUVEC), CD36, and intracellular adhesion molecule-1 (ICAM-1), and rosette-forming ability of a group of 20 P. falciparum isolates from Papua New Guinean children. Agglutination phenotypes were determined by using both the children's convalescent serum and a panel of adult immune sera. The wide range of variant antigenic types in the community was demonstrated by the failure of the agglutination assays to identify any two isolates with the same agglutinating phenotype in this, the largest study of its kind. Comparison of agglutination profiles from fresh and cryopreserved isolates demonstrated the general acceptability of cryopreservation before testing, but cautioned that some isolates may undergo selection and phenotypic change during the process. Nineteen isolates were able to bind to at least one of the four ligands studied and showed marked variation in both avidity and specificity of binding. The purified proteins ICAM-1 and CD36 proved to be the most useful assay ligands for investigating field isolates, with 18 isolates binding to at least one protein and 14 to both. No correlation was found between the binding of isolates to any two ligands nor between the binding of a standardized inoculum and the level of the patient's presenting parasitemia. All isolates from the study group were found to form rosettes (at a mean rate of 14.6% of cultured trophozoites involved in rosettes). A lack of correlation between rosette formation and CD36 binding suggests that the previously reported role of CD36 as a rosette formation receptor may not be important for isolates from Papua New Guinea.