Could a Triple-Hit Hypothesis Explain the Pathway from Malaria in Pregnancy to Adverse Infant Neurodevelopmental Outcomes?

Harriet L. S. Lawford 1 , Mary C. Ghazawy 1 , Tessa R. Donaldson 2 , Jack Donaldson 3 , and  Samudragupta Bora 1 shared their researct at the Malaria World Congress in Melbourne this week and present their findings below.

  1. Mothers, Babies and Women’s Health Program, Mater Research Institute, Faculty of Medicine, The University of Queensland, Australia
  2. Department of Psychology, University of Canterbury, Christchurch, New Zealand
  3. Dunedin School of Medicine, University of Otago, Dunedin, New Zealand

Each year, millions of pregnant women in malaria-endemic areas are at risk of Plasmodium falciparum infection and the development of placental malaria. Given that malaria in pregnancy is known to contribute to a number of perinatal and infant deaths, this suggests that a significant proportion of live-births may have been exposed to placental malaria in utero. Whilst the neurodevelopmental consequences of cerebral malaria in children have been widely documented, there has been little focus on the impact of placental malaria on infant neurodevelopment.

This research gap is critical to address. Placental malaria is associated with adverse birth outcomes including preterm birth, low birthweight and intrauterine growth restriction, which themselves are well recognized independent risk factors for adverse short-term and long-term neurodevelopment. Furthermore, the additive effects of prenatal environmental and social factors on infant neurodevelopment remain poorly understood. Hence, we propose a Triple-Hit Hypothesis to explain the potential pathway from placental malaria to poor infant neurodevelopmental outcomes.

As per our hypothesis, prenatal socioeconomic, environmental and maternal factors represent the first-hit that influences the risk of developing placental malaria. Poverty and low socioeconomic status are known to increase the likelihood of malaria infection, as well as negatively influence access to and uptake of malaria treatment and prevention tools. The use of sulfadoxine-pyrimethamine in resistant areas has been seen to increase placental inflammation and parasitisation, as well as the proportion of resistant parasites, which can lead to more severe placental infection. Lastly, maternal factors, including parity and age, are known to influence the likelihood of placental malaria; the risk of placental malaria among primigravidae is 2-4 times higher than multigravidae, and is seen to increase with decreasing age

The second-hit is represented by the direct activation of maternal immuno-inflammatory factors in response to placental malaria and resultant placental dysfunction. The infiltration of maternal immune and inflammatory factors and placental histopathological changes, such as thickening of the trophoblastic basement membrane, can cause mechanical blockage of materno-foetal oxygen and nutrient exchange, leading to hypoxic conditions and oxidative stress as well as impaired placental vascularisation. Evidence from the literature also suggests activation of complement and a TH1/TH2 imbalance, further contributing to the maternal immunological response.

The severity of placental infection represents the third-hit, wherein the risk of poor neurodevelopment is indirectly impacted by the increased likelihood of adverse birth outcomes associated with infection. Low birthweight, preterm birth and intrauterine growth restriction are themselves risk factors for adverse foetal brain development, and adversities include long-term volumetric brain reductions and cognitive, motor and behavioural deficits. Furthermore, research has shown a direct link between maternal inflammation, placental pathology and poor neurological and neurodevelopmental outcomes.

Taken together, this involvement of both direct and indirect pathways culminate in a unique foetal phenotype, where not only do we expect to see the adverse birth outcomes commonly associated with placental malaria, but also adversities including increased risks of neurological, cognitive and behavioural deficits that may impact the quality of life in this high-risk population. Validation of the link between placental malaria and adverse neurodevelopment is needed.

For feedback and any further information, please contact: harriet.lawford@mater.uq.edu.au.

One thought on “Could a Triple-Hit Hypothesis Explain the Pathway from Malaria in Pregnancy to Adverse Infant Neurodevelopmental Outcomes?

Leave a Reply

Your email address will not be published. Required fields are marked *

 

This site uses Akismet to reduce spam. Learn how your comment data is processed.