This study provides evidence that early pregnancy malaria parasitaemia may alter placentation and lead to intrauterine growth restriction. These observations have important implications for future research directions and could ultimately inform the timing of malaria parasitaemia prevention and control efforts. The effects of early pregnancy malaria parasitaemia could be seen on both uterine and umbilical artery blood flow, indicating alterations in placentation and villous angiogenesis, respectively. Primigravidae with early pregnancy malaria parasitaemia had greater than three times the risk of subsequent IUGR and greater than five times the risk of repeat IUGR episodes compared to multigravidae with no early pregnancy malaria parasitaemia. The effects of early pregnancy malaria parasitaemia on foetal growth were less pronounced among multigravidae, suggesting that the effects of early pregnancy malaria parasitaemia are worse for primigravidae than multigravidae, as described at term
. This difference may also reflect the increased intensity of infection among primigravidae compared to multigravidae, as previously suggested
. While the findings of the current study, designed as a pilot for a larger subsequent trial, should be interpreted with caution due to small sample size, the results support recent evidence of early pregnancy malaria parasitaemia and restricted foetal growth from Thailand
Differential effects of early pregnancy malaria parasitaemia on uterine artery RI between women with low and normal MUAC were found, suggesting important interactions between malaria parasitaemia and nutritional status on placental development
[4, 5]. The effects of malaria parasitaemia on foetal growth have previously been shown to vary by nutritional status
, but the joint effects of malaria parasitaemia and nutritional status during pregnancy on the foetus are not well understood. Extravillous trophoblast invasion is highly regulated and is critical to establishing physiologic uteroplacental blood flow. Malaria parasitaemia in the placenta could dysregulate trophoblast invasion via relative placental hypoxia
[27, 28]; increases in inflammatory cells and mediators (such as TNFα)
[29–31]; functional folate deficiency
[32, 33]; and/or, increased complement activation
[34, 35]. Maternal nutritional status at baseline did not have a significant, independent effect on uterine artery resistance in the current study. However, maternal nutritional status has been demonstrated to affect placental development, with differential effects based on the timing and type of nutritional insult
[36–38]. Decreased uterine artery resistance (i.e. increased uterine artery blood flow) with early pregnancy malaria or undernutrition may be an adaptive response to increase oxygen and nutrients to the placenta/foetus
. However, among undernourished women with early pregnancy malaria, these adaptations may not occur, leading to increased uterine artery resistance.
Increased uterine artery resistance has been previously shown to be associated with restricted foetal growth
. In the fully adjusted IUGR model, early pregnancy malaria was found to be associated with IUGR among primigravidae. However, maternal nutritional status at enrolment was not found to be independently associated with IUGR, as previously demonstrated in the current cohort
. Neither was there found to be an interaction between early pregnancy malaria and maternal undernutrition at baseline in the IUGR models. These findings indicate that, in this cohort, early pregnancy malaria had a more important impact on foetal growth than maternal nutritional status at baseline.
Altered uterine artery resistance with early pregnancy malaria parasitaemia indicates that placental malaria parasitaemia may be associated with diseases of trophoblast hypo-invasion, such as pre-eclampsia
. Evidence consistent with increased trophoblast invasion among nourished women with early pregnancy malaria parasitaemia was also found. Placental bed biopsies are necessary to determine if the effects of early pregnancy malaria parasitaemia on trophoblast invasion are physiological or pathological. The findings demonstrate that malaria parasitaemia prior to 20 weeks’ gestation affects placentation and may contribute to poor pregnancy outcomes due to dysregulation of trophoblast invasion.
Among primigravidae, early pregnancy malaria parasitaemia led to decreased umbilical artery resistance, which may indicate increased angiogenesis in the villous tree of the placenta
. Adaptive villous branching and capillarisation occur in hypoxic placental environments, including term preeclampsia
, high altitude
, and anaemia
. Branching angiogenesis is associated with increased vascular endothelial growth factor (VEGF) expression
, previously shown to be associated with placental malaria parasitaemia and maternal hypertension
. Increased villous angiogenesis may explain the previously reported high placental to foetal weight ratio among primigravidae with placental malaria parasitaemia
Primigravidae with early pregnancy malaria parasitaemia had an increased risk of subsequent IUGR, compared to multigravidae with no early pregnancy malaria parasitaemia. Primigravidae are known to have increased severity of malaria infection and worse pregnancy outcomes than multigravidae in malaria endemic areas
[24, 25]. The findings support limited, but growing, evidence that early pregnancy malaria parasitaemia adversely affects birth weight
[49–52] and foetal growth
. The adverse effect of early pregnancy malaria parasitaemia on foetal growth in primigravidae appeared to occur despite a blood flow profile consistent with moderate alterations in placentation and increased angiogenesis. This suggests that the effects of early pregnancy malaria parasitaemia on foetal growth among primigravidae occur at the time of infection and may be mediated via mechanistic pathways other than changes in blood flow, such as inflammatory cells and cytokines
, or acute changes in blood flow during active parasitaemia
. In the current study, a foetus frequently demonstrated signs of IUGR at one or more study time points, yet did not at other time points, suggestive of differential rates of foetal growth during gestation. Further, there was no association between early pregnancy malaria and low birth weight (data not shown), possibly due to the frequent identification and treatment of sub-clinical malaria parasitaemia in the study cohort.