Table 1:

Summary table of studies included in the literature review and conceptual framework

Reference	Stage in conceptual framework	Risk factor	Findings
Achan J et al. (2012)	First stage	Maternal coinfection	In this study, Lopinavir-ritonavir-based antiretroviral therapy, as compared with nonnucleoside reverse-transcriptase inhibitor-based antiretroviral therapy, was seen to reduce the incidence and recurrence of malaria.
Adam I et al. (2011)	First stage Second stage	Maternal gravidity Placental pathology	In this study, placental malaria was significantly associated with preeclampsia. At univariate analysis, primigravidae were associated with preeclampsia.
Adamo AM & Oteiza (2010)	First stage	Maternal nutrition	This study found that zinc deficiency during gestation may increase the risk of behavioural and neurological disorders in infancy, adolescence and adulthood.
Agostoni et al. (2010)	First stage Third stage	Maternal malnutrition Nutritional deficiencies	This expert panel presented guidelines on the nutrition of preterm infants. This commentary discusses the conflicting data surrounding iron supplementation, and highlights studies that have found adversities associated with excessive iron supplementation.
Agudelo OM et al. (2014)	Second stage	Hypoxia	The authors found that the hypoxia markers, COX-1 and COX-2, were significantly higher in women with PM, when compared to uninfected controls.
Altshuler G (1993)	Second stage	Hypoxia Impaired vascularisation	A thorough review of studies associating neurodevelopmental disorders with placental pathology.
Aucott et al. (2008)	First stage Third stage	HPA axis disturbances Low birthweight	This study aimed to evaluate the relationship between cortisol concentrations and short-term outcomes in low birthweight infants. The authors found that infants with high cortisol concentrations had significantly higher odds of severe intraventricular haemorrhage.
Basiloius et al. (2015)	Second stage Third stage	Placental insufficiency White matter damage	A systematic review summarising the neurological outcomes of placental insufficiency in animal models, including reduced hippocampal and corpus callosum size, hypomyelination and neuronal apoptosis.
Basu S et al. (2017)	First stage	Maternal nutrition	This study found that maternal iron deficiency anaemia was associated with lower fetal hippocampal volumes and brain-derived neurotrophic factor, and that the degree of affection was proportional to the severity of maternal anaemia.
Bergman K et al. (2007)	First stage	Maternal mental health	In this study, maternal stress during pregnancy was negatively correlated with mental development and positively associated with fearfulness in infants.
Black MM et al. (2017)	Third stage	Cognition and behavioural deficits	This review used proxy measures of stunting and poverty and found that ∼250 million children in LMICs are at risk of not reaching their developmental potential. The majority of these infants reside in SSA (94.8 million) and South Asia (88.8 million).
Black RE et al. (2008)	Third stage	Nutritional deficiencies	A comprehensive review of the health consequences of maternal and child undernutrition. In particular, a 1.73-point decrease in IQ was seen for every 10g/L decrease in haemoglobin in children.
Blencowe H et al. (2013)	Third stage	Birth outcomes Cognition and behavioural deficits	This study found that approximately 2.7% and 4.4% of preterm births who survived beyond the first month had moderate/severe and mild neurodevelopmental impairment, respectively.
Boeuf P et al. (2013)	Third stage	Birth outcomes	This study found alterations of amino acid transport in PM cases, particularly in cases with local inflammation. The authors conclude that, as opposed to PM, inflammation is more likely to blame for compromised amino acid transport and subsequent IUGR.
Boeuf P et al. (2008)	Second stage	Hypoxia	This study found significantly higher levels of the hypoxia marker, hypoxia inducible factor-1α, in PM cases. However, the authors conclude that there was little evidence to suggest PM itself causes hypoxia.
Boivin MJ et al. (2007)	Third stage	Disease susceptibility Cognition and behavioural deficits	In a Ugandan cohort, 21.4% of children who had cerebral malaria had cognitive deficits after discharge.
Bouyou-Akotet MK et al. (2005)	First stage	Maternal mental health	This study found significantly higher cortisol concentrations among P. falciparum-infected women, relative to uninfected women. Furthermore, cortisol levels were significantly higher among P. falciparum-infected primigravidae relative to uninfected primigravidae.
Brabin BJ (1983)	Second stage	Impaired oxygen, nutrient, antibody transfer	It was seen that the maximum parasite rate of pregnant women recruited at ANC visits in Western Kenya occurred at 13–16 weeks’ gestation. It is likely that the presence of parasites at this time can disrupt vasculogenesis and impair placental transfer.
Brabin BJ (1991)	First stage Third stage	Maternal gravidity Birth outcomes	This study found that the risk of LBW is increased among primigravidae in malaria-endemic areas, significantly correlating with parasite rate at delivery.
Buehler MR (2011)	Second stage Third stage	Cytokine production Neuropsychiatric disorders	This paper details a model describing the impact of pro-inflammatory cytokines on fetal brain development, and the relation of cytokines to neuropsychiatric disorders, including autism and schizophrenia.
Chawanpaiboon S et al. (2018)	Third stage	Birth outcomes	A systematic review of global, regional and national levels of preterm birth in in 2014. There was an estimated 14.84 million live preterm births.
Conroy AL et al. (2019)	Third stage	Cognition and behavioural deficits	A case report of the neurodevelopmental outcomes in placental malaria-discordant dizygotic twins. The PM-exposed twin showed consistent delays across cognitive, motor and language domains, relative to the unexposed twin.
Conroy AL et al. (2013)	Second stage	Complement activation	This study investigated the role of complement. Complement is seen to be elevated in PM cases and, interestingly, blocking C5a in murine model improved feto-placental vessel development and fetal growth and survival and reduced placental vascular resistance.
Cusick SE et al. (2014)	First stage	Maternal nutrition	Vitamin D insufficiency is associated with severe malaria in children; the authors suggest a potential role for vitamin D deficiency in the aetiology of severe malaria.
Darling AL et al. (2017)	First stage Third stage	Maternal nutrition Cognition and behavioural difficulties	In this study, the offspring of women who were Vitamin D insufficient during gestation had adversities in motor and social development, relative to offspring of women who were Vitamin D sufficient. Maternal 25(OH)D deficiency was associated with mental and motor deficits in infants 16–18 months, poorer gross and fine motor development at 30 months, and lower social development at 42 months. However, associations were not seen at older ages.
Dellicour et al. (2010)	First stage	Maternal parity, gravidity, age	Using global estimates, it was concluded that 85.3 million pregnancies occurred in areas with P. falciparum transmission in 2007.
Djontu JC et al. (2016)	Second stage	Cytokine production	This study investigated the expression of cytokines in mothers and infants exposed to PM. Placental and peripheral malaria infection correlated positively with peripheral plasma levels of IL-6.
Dombrowski JG et al. (2017)	Third stage	Reduced growth	This study from Brazil found that P. falciparum infection during pregnancy significantly increased the odds of the occurrence of small head and microcephaly in exposed infants, relative to unexposed infants.
Duthie & Reynolds (2013)	First stage	HPA axis disturbances	A comprehensive review of changes to the HPA axis during pregnancy, and the impact on fetal outcomes. With relation to this framework, the HPA axis is dysregulated by maternal stress, increasing transfer of glucocorticoids from mother to fetus, which are associated with LBW and adverse infant neurodevelopmental outcomes
Fitri LE et al. (2015)	Second stage Third stage	Cytokine production Low birthweight	This study investigated the influence of concentrations of IL-17 and IL-10 in malaria-infected placentas on fetal weight. The authors concluded that sequestration of parasites directly causes LBW in PM cases, while cytokines act indirectly.
Fox et al. (2012)	Third stage	Autoantibodies Cognition and behavioural deficits	This review discusses the possible association between maternal autoantibody production during gestation, and infant neurodevelopmental consequences.
Fried M et al. (1998)	Second stage	TH1 response	In this study, cytokine concentrations were measured in PM positive and negative placentas. Significantly higher TNF-α and TGF-β concentrations and significantly lower IL-10 concentrations were seen in PM positive placentas, leading authors to conclude that maternal malaria increases the concentration of type-1 cytokines.
Gelaye B et al. (2016)	First stage	Maternal mental health	This systematic review summarised the prevalence of perinatal depression and its association with infant/child outcomes in LMICs.
Gibson RS et al. (1991)	Third stage	Disease susceptibility Nutritional deficiencies	This cross-sectional study investigated zinc status in children in a subdistrict of Papua New Guinea. Authors believe that suboptimal zinc status seen may be due to the high prevalence of malaria.
Gibson RS et al. (1998)	First stage	Maternal nutrition	This study assessed zinc status and infection among rural Malawian women. Hair zinc concentrations was significantly associated with malaria infection (p=0.01).
Girardi G et al. (2006)	Second stage	Immuno-inflammatory cells Complement activation	Using a mouse model of spontaneous miscarriage and IUGR, the authors demonstrate that complement activation is a necessary intermediary in placental and fetal injury.
Giurgescu C (2009)	First stage	Maternal mental health HPA axis disturbances	This review highlights the association between maternal cortisol levels and preterm birth.
Guyatt HL et al. (2004)	First stage	Maternal parity, gravidity, age	A comprehensive review on the pathological effects of malaria in pregnancy; data from 15 studies indicate an overall prevalence of malaria of 32.3% among pregnant women.
Harrington W et al. (2009)	First stage	SP resistance	A prospective delivery cohort examining the IPTp on level of parasitaemia and inflammation in the placenta. The use of IPTp was associated with an increase in resistant parasites, increased parasitaemia and more intense placental inflammation.
Imamura T et al. (2002)	Second stage	Placental pathology	This study investigated tissue factor expression and fibrin deposition in P. falciparum infected placentas. The tissue occupancy ratio of fibrin was found to be 5-fold higher in infected relative to uninfected placentas. The authors conclude that perivillous fibrin clot formations narrow and plug the intervillous space, interrupting placental blood supply.
Kauye F et al. (2014)	First stage	Maternal mental health	This study found that common mental disorders at out-patients services in Malawi were commonly misdiagnosed as malaria.
Keelan JA et al. (1999)	Second stage Third stage	Cytokine production Preterm birth	This study investigated inflammation in the gestational tissue of women with preterm labour. Significantly higher cytokine concentrations were seen in amniotic and chorionic-decidual tissues from women with preterm deliveries.
Keim SA et al. (2014)	First stage Third stage	Maternal malnutrition Cognition and behavioural deficits	This study investigated the impact of maternal and cord blood 25(OH)D concentrations on child development and behaviour. IQ at 7y was associated with both maternal and cord blood 25(OH)D concentrations.
Kuban KC et al. (2009)	Third stage	Reduced growth	An investigation into developmental correlates of congenital microcephaly and at 2-years in extremely preterm infants. In this cohort, the authors found that congenital microcephaly is only a risk factor for cognitive impairment if microcephaly persists to 2-years.
Lang B et al. (2005)	Second stage	Autoantibodies	In a cohort of Kenyan children, levels of antibodies to the voltage-gated calcium channels increased with the severity of malaria.
Lang B et al. (2003)	Second stage	Autoantibodies	A review discussing the associations between autoantibodies and central nervous system disorders.
Le Hesran Y et al. (1997)	Third stage	Disease susceptibility	This study conducted in Cameroon found that offspring exposed to PM were more likely to develop a malaria infection between 4–6 months of age and have higher parasite prevalence rates at 5–8 months of age.
Lee AC et al. (2017)	Third stage	Birth outcomes	This review found that, in 2012, approximately 23.3 million infants in low- and middle-income countries were born small for gestational age.
Liew J et al. (2015)	Second stage	Autoantibodies	This study investigated the autoantibody profile of patients infected with P. knowlesi relative to uninfected patients.
Loureiro B et al. (2017)	First stage Third stage	Maternal nutrition White matter damage Cognition and behavioural deficits	In this study, infants with severe anaemia at birth displayed white matter injuries, which were related to global developmental delay, behavioural and learning problems.
Martinez E et al. (1998)	Second stage Third stage	Cytokine production White matter damage	In this study, amniotic fluid IL-6 was an independent risk factor for periventricular leukomalacia and intraventricular haemorrhage.
McDonald CR et al. (2015)	Third stage	Cognition and behavioural deficits	In a murine model of malaria, offspring born to malaria-infected pregnant mice displayed impaired non-spatial learning, memory and depressive-like behaviour in infancy that persisted through to adulthood.
McDonald CR et al. (2013)	Second stage Third stage	Complement activation Impaired vascularisation Cognition and behavioural deficits	A review discussing the role of the complement system in placental malaria, placental insufficiency and adverse neurodevelopmental outcomes.
McDonald CR et al. (2015)	Second stage Third stage	Complement activation Cognition and behavioural deficits	A review of the role of complement in pregnancy, and the possible consequences on infant neurodevelopmental outcomes.
Menendez C et al. (2000)	Third stage	Birth outcomes	This study investigated the impact of malaria-associated placental changes on birth weight. The severe fibrin deposition was significantly associated with increased risk of preterm LBW at univariate and multivariate analysis.
Moore JM et al. (1999)	First stage	Maternal coinfection	A study investigating cytokine production in HIV-positive/negative PM-infected/uninfected women. It was concluded that HIV-mediated cytokine dysregulation and impaired interferon-gamma responses increased the susceptibility of HIV-positive pregnant women to malaria.
Moormann AM et al. (1999)	Second stage Third stage	Cytokine production Intrauterine growth restriction	In this study, cytokine expression was compared in malaria infected and uninfected placentas. Significantly increased concentrations of IL-1β, IL-8, and TNF-α were seen in infected placentas, and increased TNF-α or IL-8 was associated with IUGR.
Mount AM et al. (2004)	First stage	Maternal coinfection	A comparison of serum concentrations of antibodies to placental type variant surface antigens among pregnant women. Concentrations of IgG to variant surface antigens were lower in HIV-infected women than in HIV-uninfected women.
Muehlenbachs A et al. (2010)	Second stage	Massive chronic intervillositis	This study developed a histological grading scheme for PM, including the presence of massive chronic intervillositis. The literature suggests massive chronic intervillositis is reported in 1.7–6.9% of PM cases.
Muehlenbachs A et al. (2006)	First stage Second stage	Maternal parity, gravidity and age Impaired oxygen, nutrient, antibody transfer	This cross-sectional study assessed levels of soluble vascular endothelial growth factor receptor 1 (also known as soluble Fms-like tyrosine kinase-1), a preeclampsia biomarker, in primigravidae with either PM, hypertension, or both. Levels were found to be significantly increased, suggesting soluble Fms-like tyrosine kinase-1 may be involved in the relationship between chronic PM and hypertension in primigravidae.
Mutabingwa TK et al. (2005)	Third stage	Disease susceptibility	This study found that infants who were born to mothers with PM were more likely to have malaria earlier than infants born to unexposed mothers. Offspring of multigravida mothers with PM were more likely to have malaria during infancy, while it appeared that offspring of primigravida had reduced susceptibility to PM.
Naing C et al. (2016)	First stage	Maternal coinfection	A meta-analysis on the coinfection of HIV and malaria. It is estimated that there is an estimated pooled prevalence of HIV and malaria coinfection of 12% among pregnant women.
Nosarti C et al. (2010)	Third stage	Birth outcomes White matter damage Cognition and behavioural deficits	This book discussed the evidence associating adverse birth outcomes (preterm birth and low birthweight) with an increase in the prevalence neurodevelopmental adversities.
Nzila A et al. (2014)	First stage	Environmental risk factors	A review investigating the impact of folate supplementation during pregnancy on SP efficacy. The authors summarise evidence suggesting the use of folate may negate SP efficacy.
Opsjln SL et al. (1993)	Second stage Third stage	Cytokine production Preterm birth	This study measured levels of TNF, IL-1 and IL-6 in human pregnancies; these cytokines were seen to increase at the onset of labour, suggesting they may play a role in the onset of normal labour. The authors suggest that higher levels of these cytokines in PM cases may be a risk factor for preterm labour.
Ordi J et al. (1998)	Second stage Third stage	Massive chronic intervillositis Low birthweight	In this study, massive chronic intervillositis is associated with PM, predominantly among primigravidae. Further, massive chronic intervillositis was associated with low birthweight.
Paintlia MK et al. (2008)	Second stage Third stage	Immuno-inflammatory cells Reduced myelination White matter damage	This study investigated neuroinflammation and white matter injury in a series of mouse models. The authors found evidence of hypomyelination and astrogliosis in the brain of offspring of murine neuroinflammation models. The authors conclude that cerebral white matter injury may be due to maternal immune activation, such as occurs in PM.
Postels DG et al. (2018)	Third stage	Disease susceptibility Cognition and behavioural difficulties	This study investigated electroencephalogram findings in survivors of cerebral malaria from Uganda and Malawi. It was seen that 44% and 11.3% of infants from Uganda and Malawi, respectively, had neurological sequelae at discharge.
Rijken MJ et al. (2012)	Second stage	Brain development	A Thailand-based longitudinal observational investigation into the effect of malaria in pregnancy in pregnancy on foetal cortical brain development. Foetuses of infected and uninfected women showed no difference in foetal cortical development or brain volumes during pregnancy. However, the cingulate sulcus matured significantly faster in foetuses of malaria infected women, suggesting some neurodevelopmental involvement.
Rogerson SJ and Boeuf (2007)	Second stage Third stage	Placental insufficiency Immuno-inflammation Birth outcomes	A comprehensive review on the relationship between malaria in pregnancy and foetal growth restriction. Of note, this review describes the role of intervillous monocytes, placental hypoxia, and impaired placental transfer that has been reported in the literature.
Rogerson SJ et al. (2018)	First stage Third stage	Maternal malnutrition Nutritional deficiencies	This review discusses, among other factors, the association between malaria in pregnancy and maternal and infant anaemia.
Saraf et al. (2015)	First stage Third stage	Maternal malnutrition Nutritional deficiencies	A systematic review on global maternal and newborn Vitamin D status. It was found that Vitamin D deficiency is present in 54% of pregnant women and 75% of newborns globally.
Sartelet H et al. (1996)	Second stage	Placental insufficiency	This study from Senegal found that pre-eclampsia was significantly associated with malaria in pregnancy (p<0–03).
Scherjon SA et al. (1998)	Third stage	Cognition and behavioural deficits	This study investigated neurodevelopmental outcomes in IUGR, preterm infants. Adverse neurodevelopmental outcomes at 3-years were significantly associated with low head circumference (p=0.01).
Schwarz NG et al. (2008)	Third stage	Disease susceptibility	This study from Gabon investigated the effect of PM on the risk of malaria in the first 30 months of their offspring’s life. Offspring of women with active PM at delivery were at significantly higher risk of clinical malaria in the first 30 months of life.
Shulman CE et al. (2001)	First stage Third stage	Maternal malnutrition Low birthweight	This study investigated the relationship between PM, anaemia and low birthweight. Overall, a significant interaction was seen between chronic or past malaria and severe anaemia, and their effects on birthweight.
Skinner-Adams TS et al. (1998)	First stage Second stage Third stage	Maternal coinfection Placental insufficiency Immuno-inflammation Long-term infant outcomes	This study investigated the antimalarial activities of six commonly used antiretroviral agents. P. falciparum growth in vitro was inhibited by the HIV–1 protease inhibitors saquinavir, ritonavir, and indinavir. This information suggests a potentially protective interaction between HIV, PM and infant outcomes.
Soni PN et al. (1993)	Second stage	Autoantibodies	This South African study investigated the presence of anticardiolipin antibodies and P. falciparum infection. The authors concluded that there is a high prevalence of these antibodies in acute falciparum malaria cases.
Steketee RW et al. (1996a)	First stage Third stage	Maternal coinfection Disease susceptibility	This Malawian study investigated the association between HIV and P. falciparum infection in pregnant women. Parasitaemia density and placental infection was significantly higher in HIV-infected women (p<0.001) and newborns of HIV-infected women had higher rates of umbilical cord blood parasitaemia.
Steketee RW et al. (1996b)	Third stage	Low birthweight	This study prospectively evaluated malaria prevention in pregnant women in rural Malawi between 1987–1990. In this population, it was found that clearing placenta and umbilical cord parasites resulted in a 3–5% reduction in infant mortality rate and reduce 35% of preventable LBW deliveries.
Suchdev PS et al. (2017)	First stage Second stage	Maternal malnutrition Immuno-inflammation	This review assessed the relationship between nutrition, inflammation and child neurodevelopment in low-resource settings. These authors hypothesise a bidirectional relationship between inflammation and nutrition, wherein nutrition can directly impact immune function and the inflammatory response.
Suguitan AL et al. (2003)	Second stage Third stage	Cytokine production Preterm birth	This study measured concentrations of IFN-γ, TNF-α, IL-4 and IL-10 in placental plasma of malaria-infected and -uninfected Cameroonian women with premature and full-term deliveries. Elevated TNF-α and IL-10 were considered risk factors for malaria-associated preterm birth.
Sylvester B et al. (2016)	Third stage	Disease susceptibility	This Tanzanian study found that, in the first 2 years of life, exposure to P. falciparum in utero both reduced the time from birth to first clinical malaria episode and increased their frequency.
ter Kuile et al. (2004)	First stage	Maternal coinfection	This review includes 11 studies indicating higher peripheral and placental malaria in HIV-infected women. Malaria in pregnancy was associated with a higher HIV-1 viral concentrations, though reports of mother-to-child-transmission was conflicting.
Umbers AJ et al. (2011)	Second stage	Impaired oxygen, nutrient, antibody transfer	This study investigated concentrations of insulin growth factors-1 and -2, to determine whether PM and inflammation were associated with disturbances in the insulin-like growth factor axis, and thus played a role in fetal growth restriction. insulin growth factor-1 was significantly reduced in PM cases (p=0.007) and in their neonates (p=0.002).
Umbers AJ et al. (2013)	Second stage	Impaired vascularisation	Trophoblast invasion, migration and viability were measured in pregnant women with malaria infection. Trophoblast invasion (p=0.06) and migration (p=0.004) was reduced in response to serum of malaria-infected pregnant women, relative to uninfected women pregnant.
Veerhuis R et al. (2011)	Second stage	Complement activation	This review discusses the role of complement in central nervous system development, and evidence of the production of neurotoxic substances in response to complement activation.
Walther B et al. (2012)	Third stage	Reduced growth	This study investigated immune responses in 12-month-old offspring of PM cases. Lower growth rates were seen in infants born to mothers with PM; infants had significantly lower weight (p=0.032) and head circumference (p=0.041) at 12 months. No differences were seen at birth, implying that reduced growth at 12 months was associated with PM.
WBG (2016)	First stage	Low socioeconomic status	This report estimated global poverty. In 2013, ∼389 million people survived on <USD$1.90/day.
Weobong B et al. (2014)	First stage	Maternal mental health	This study investigated the adverse maternal and infant consequences of antenatal depression in Ghana. Interestingly, antenatal depression was associated with significant reductions in bed net use (p=0.005).
WHO (2017)	First stage	Maternal malnutrition	The WHO estimates that ∼10.9% of women of reproductive age in the African region are underweight (body mass index <18.5 kg/m2) and a median prevalence of 47.3% pregnant women are anaemic in the African region.
WHO (2018)	First stage		The latest World Malaria Report at the time of publication.
Yamada M et al. (1989)	Second stage	Complement activation	This study assessed 20 placentas from PM cases in Malawi. It was seen that 15% of placentas stained strongly for the complement factor, C3.
Yoon BH et al. (1997)	Second stage Third stage	Cytokine production White matter damage	This study investigated cytokine expression in the amniotic fluid of women with complicated preterm gestations. Significant differences were seen in the concentrations of IL-1β and IL-6 between infants with and without white matter lesions, support the authors’ hypothesis that inflammatory cytokines play a role in the genesis of brain white matter lesions.
Zimmerman AW et al. (2007)	Second stage	Autoantibodies	In this study, serum reactivity to prenatal, postnatal, and adult rat brain proteins was tested in mothers with autistic children and maternal and child controls. Reactivity to prenatal rat brain proteins was seen in autistic children and their mothers, and children with other neurodevelopmental disorders. These patterns of reactivity differed to controls and suggest a role of maternal antibodies in the development of autism and possibly other
			neurodevelopmental disorders, as well as evidence of transfer of autoantibodies across the placenta.