Fetal Responses during Placental Malaria Modify the Risk of Low Birth Weight

Abstract

Inflammation during placental malaria (PM) is associated with low birth weight (LBW), especially during the first pregnancy, but the relative contribution of maternal or fetal factors that mediate this effect remains unclear and the role of gamma interferon (IFN-␥) has been controversial. We examined the relationship of maternal and cord plasma levels of IFN-␥, tumor necrosis factor alpha, interleukin-10, ferritin, and leptin to birth weight for Tanzanian women delivering in an area where there is a high rate of malaria transmission. The placental levels of inflammatory cytokines, including IFN-␥, increased significantly during PM in primigravid and multigravid women but not in secundigravid women. PM also increased maternal peripheral levels of all inflammatory markers except IFN-␥ but had strikingly little effect on cord levels of these proteins. In a multivariate analysis, placental IFN-␥ was negatively associated (P ‫؍‬ 0.01) and cord ferritin was positively associated (P < 0.0001) with birth weight in infected (PM-positive [PM ؉ ]) first-time mothers. This relationship was not observed in other mothers, consistent with the epidemiology of PM and disease. Cord leptin had a strong positive relationship with birth weight in offspring of PM-negative women (P ‫؍‬ 0.02 to P < 0.0001) but not in offspring of PM ؉ women (all differences were not significant) in the three gravidity groups. The results confirmed that placental IFN-␥ is related to LBW due to PM during first pregnancies and suggest that fetal ferritin plays a protective role. Because fetal cells are a source of placental IFN-␥ and cord ferritin, the fetal response to PM may modify the risk of LBW.

CXC Ligand 9 Response to Malaria during Pregnancy Is Associated with Low-Birth-Weight Deliveries

“…The role of IFN-␥ has been controversial (6,10,15,23). In our genomewide expression profiles of malaria-infected placentas from primigravidae, transcription of chemokines, including CXCL13, CXCL9, and CCL18, was significantly upregulated and was negatively correlated with birth weight (18).…”

“…Several studies have related increased placental TNF-␣ levels to LBW, particularly in primigravid women (6,10,23), and intrauterine growth retardation has been associated with the upregulation of IL-8 and TNF-␣ transcription in the placenta (17). The role of IFN-␥ has been controversial (6,10,15,23).…”

“…The IFN-␥ network results in the upregulation of CXCL9 in various cells, including macrophages (13). We reported previously that placental IFN-␥ increases the risk of LBW (6,10), and CXCL9 transcript levels during inflammatory placental malaria (PM) are negatively associated with birth weight (18).…”

“…At the molecular level, placental malaria is associated with increased levels of cytokines and chemokines such as tumor necrosis factor alpha (TNF-␣), gamma interferon (IFN-␥), interleukin-10 (IL-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1␣ (MIP-1␣), MIP-1␤, and CXC ligand 8 (CXCL8) (1,4,6,10,17,18,23,25,26). In addition to soluble factors released by maternal immune cells, fetal tissue may also release mediators that contribute to placental inflammation, for example, IFN-␥ secreted by placental villi during maternal malaria (26).…”

Sulfadoxine-Pyrimethamine–Based Intermittent Preventive Treatment, Bed Net Use, and Antenatal Care during Pregnancy: Demographic Trends and Impact on the Health of Newborns in the Kassena Nankana District, Northeastern Ghana

“…14 In one study, cord blood smears were 20-fold less sensitive than placental smears for detecting placental malaria in Tanzanian women, 15 but were only 1.5 times less sensitive than placental blood smears in another study. 16 It seems remarkable that a single dose of S/P during pregnancy could significantly improve the health of the newborn, and that these effects should only be seen in first-born children.…”