Placental malaria-associated inflammation disturbs the insulin-like growth factor axis of fetal growth regulation

Abstract

Background: The pathogenetic mechanisms of fetal growth restriction associated with placental malaria are largely unknown. We sought to determine whether placental malaria and related inflammation were associated with disturbances in the insulin-like growth factor (IGF) axis, a major regulator of fetal growth.

Method: We measured IGF-1 and IGF-2 concentrations in plasma from 88 mother-neonate pairs at delivery and IGF binding proteins 1 and 3 (IGFBP-1 and IGFBP-3, respectively) in cord plasma from a cohort of Papua New Guinean women with and without placental malaria. Messenger RNA levels of IGF-1, IGF-2, and the IGF receptors were measured in matched placental biopsy specimens.

Results: Compared with those for uninfected pregnancies, IGF-1 levels were reduced by 28% in plasma samples from women with placental Plasmodium falciparum infection and associated inflammation (P = .007) and by 25% in their neonates (P = .002). Levels of fetal IGFBP-1 were elevated in placental malaria with and without inflammation (P = .08 and P = .006, respectively) compared with uninfected controls. IGF-2 and IGFBP-3 plasma concentrations and placental IGF ligand and receptor messenger RNA transcript levels were similar across groups.

Conclusion: Placental malaria-associated inflammation disturbs maternal and fetal levels of IGFs, which regulate fetal growth. This may be one mechanism by which placental malaria leads to fetal growth restriction.

Figure 1.

Maternal insulin-like growth factor (IGF) concentrations in women with and without placental malaria. Maternal IGF-1 and IGF-2 levels (mean ± SD) were measured in plasma samples of uninfected women (n = 34), women with placental malaria (PM; n = 31), and women with placental malaria with monocyte infiltrate (PMM; n = 27). Maternal IGF-1 concentrations differed significantly between groups (P = .03; analysis of variance [ANOVA]), with levels in the PMM group being significantly less than those in the uninfected control group (**P = .007 vs uninfected; t test) (A). Maternal IGF-2 concentrations did not differ between groups (P = .5; ANOVA) (B). Log maternal IGF-1 concentrations from mothers with PMM (n = 27) demonstrate a negative correlation with the degree of monocyte infiltration (log number of monocytes per 500 cells in the intervillous spaces) measured by placental histology (r = −.4; P = .05) (C).

Figure 2.

Fetal insulin-like growth factor (IGF) and IGF binding protein (IGFBP) levels. Concentrations of IGF-1, IGF-2, IGFBP-1, and IGFBP-3 were measured in cord plasma in uninfected (n = 31) placental malaria (PM; n = 30 for IGFBP-1; n = 31 for other analytes) and placental malaria with monocyte infiltrate (PMM; n = 26) Concentrations of IGF-2 (mean ± SD) did not differ significantly (P = .9; analysis of variance [ANOVA]) (A), whereas cord IGF-1 concentrations were significantly different between groups (P = .007; ANOVA) (B). **P = .002 for PMM group vs uninfected control group (t test). IGFBP-1 concentrations (median ± IQR) were normalized by log transformation. Log IGFBP-1 values differed significantly between groups (P = .005; ANOVA) (C). *P = .08 for PMM group vs uninfected control group (t test on log values); **P = .006 for PM group vs uninfected control group (t test on log values). IGFBP-3 concentrations (mean ± SD) were not statistically different between groups (P = .9; ANOVA) (D). The estimated level of free IGF-1 in cord blood (log ratio of IGF-1 to IGFBP-3) differed significantly between groups (P = .004; ANOVA) (E). *P ≤ .02 for PM group vs uninfected control group (t test); ***P < .001 for PMM group vs uninfected control group (t test).

Figure 3.

Relationship between fetal insulin-like growth factor (IGF-1) and birth weight. Among all deliveries in the groups (n = 88), log cord IGF-1 level and birth weight were positively correlated (r = .2; P = .06) (A). IGF-1 concentration (mean ± SD) differed significantly (analysis of variance F[5, 77], 2.9; P = .02) in cord blood from the uninfected control, placental malaria (PM), and placental malaria with monocyte infiltrate (PMM) pregnancies according to birth weight category (normal birth weight [NBW], ≥2.5 kg; low birth weight [LBW], <2.5 kg). *P = .02 for PMM group vs uninfected control group among NBW infants (t test); *P = .02 for PM group vs uninfected control group among LBW infants (t test); *P = .04 for PMM group vs uninfected control group for LBW infants (t test).