Placental but Not Peripheral Plasmodium falciparum Infection During Pregnancy Is Associated With Increased Risk of Malaria in Infancy

Boudova, Sarah; Divala, Titus; Mungwira, Randy G.; Mawindo, Patricia; Tomoka, Tamiwe; Laufer, Miriam K.

doi:10.1093/infdis/jix372

Cited by 29 publications

(34 citation statements)

References 13 publications

(16 reference statements)

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“…Similarly, in a recent study of intermittent preventive therapy for malaria during pregnancy (IPTp), Bardaji et al found that infants born to mothers who experienced clinical malaria during pregnancy were at increased risk of malaria in the first year of life compared to infants born to uninfected women. In contrast, Boudova et al found that there was no difference in the risk of malaria infection or clinical malaria between children born to Malawian mothers with or without maternal peripheral malaria parasitaemia during pregnancy after controlling for PM. The varied associations described above highlight the challenges of separating multiple overlapping, yet biologically distinct definitions of malaria exposure in pregnancy (eg, peripheral malaria infection vs PM and PM defined by detection of parasites by microscopy vs molecular techniques vs histopathologic assessment).…”

Section: Maternal Malaria Predicts An Increased Risk Of Malaria Durinmentioning

confidence: 90%

Malaria in pregnancy shapes the development of foetal and infant immunity

Harrington

Kakuru

Jagannathan

2018

Parasite Immunology

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Malaria, particularly Plasmodium falciparum, continues to disproportionately affect pregnant women. In addition to the profoundly deleterious impact of maternal malaria on the health of the mother and foetus, malaria infection in pregnancy has been shown to affect the development of the foetal and infant immune system and may alter the risk of malaria and nonmalarial outcomes during infancy. This review summarizes our current understanding of how malaria infection in pregnancy shapes the protective components of the maternal immune system transferred to the foetus and how foetal exposure to parasite antigens impacts the development of foetal and infant immunity. It also reviews existing evidence linking malaria infection in pregnancy to malaria and nonmalarial outcomes in infancy and how preventing malaria in pregnancy may alter these outcomes. A better understanding of the consequences of malaria infection in pregnancy on the development of foetal and infant immunity will inform control strategies, including intermittent preventive treatment in pregnancy and vaccine development.

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Section: Maternal Malaria Predicts An Increased Risk Of Malaria Durinmentioning

confidence: 90%

Malaria in pregnancy shapes the development of foetal and infant immunity

Harrington

Kakuru

Jagannathan

2018

Parasite Immunology

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“…124 Consistent with this model, several studies have reported that infants born to women with PM are themselves at higher risk of malaria during early life. [8][9][10][11]125,126 However, this association has not been observed in all cohorts, [127][128][129] and indeed one study found that infants of primagravidas with PM actually have a lower risk of parasitemia during infancy. 7 A parsimonious explanation for the repeated observation of higher infant malaria risk following in utero exposure is that these studies are confounded by variability in exposure.…”

Section: Doe S In Utero Anti G En E Xp Osure Impac T the De Velopmementioning

confidence: 98%

The immune response to malaria in utero

Feeney

2019

Immunological Reviews

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Malaria caused by Plasmodium falciparum is a leading killer of infants and children. Efforts to develop a protective vaccine have been hindered by the parasite's numerous evasion strategies, which include the induction of immunoregulatory mechanisms in the human host.Indeed, several promising vaccine candidates that induce robust protection in malaria-naive populations have been shown to have much lower efficacy when administered to individuals residing in endemic settings, 1,2 suggesting that immunomodulatory mechanisms induced by prior malaria exposure may pose a critical barrier to vaccine-mediated protection. In endemic regions, many individuals are first exposed to malaria in utero, when P. falciparum-infected red blood cells sequester in the placenta and parasite antigens cross the syncytiotrophoblast barrier, gaining entry into the fetal circulation.Therefore, even during the neonatal period, vaccination may be influenced by prior malaria exposure. Here, we examine the consequences of in utero antigen exposure for fetal immune development and postnatal immunity. The worldwide burden posed by malaria-related complications of pregnancy is profound. More than 125 million pregnancies occur annually in regions at risk for malaria transmission, 3 and one in four pregnant women in sub-Saharan Africa have evidence of infection with malaria at parturition. 4 Although most placental malaria (PM) infections are attributable to P. falciparum, recent evidence indicates that P.vivax is also associated with poor pregnancy outcomes, and some data suggest that it too may sequester in the placenta. 5,6 Pregnancy-associated malaria results in tremendous obstetrical and pediatric morbidity, AbstractMalaria causes tremendous early childhood morbidity and mortality, providing an urgent impetus for the development of a vaccine that is effective in neonates. However, the infant immune response to malaria may be influenced by events that occur well before birth. Placental malaria infection complicates one quarter of all pregnancies in Africa and frequently results in exposure of the fetus to malaria antigens in utero, while the immune system is still developing. Some data suggest that in utero exposure to malaria may induce immunologic tolerance that interferes with the development of protective immunity during childhood. More recently, however, a growing body of evidence suggests that fetal malaria exposure can prime highly functional malariaspecific T-and B-cells, which may contribute to postnatal protection from malaria. In utero exposure to malaria also impacts the activation and maturation of fetal antigen presenting cells and innate lymphocytes, which could have implications for global immunity in the infant. Here, we review recent advances in our understanding of how various components of the fetal immune system are altered by in utero exposure to malaria, discuss factors that may tilt the critical balance between tolerance and adaptive immunity, and consider the implications of these findings for malaria prevention strateg...

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“…Several prior studies have reported associations between active PM de ned as detection of parasites in placental blood or tissue and an increased risk of malaria during infancy [9][10][11][24][25][26]. Active PM detected by microscopy was associated with a higher risk of malaria infection in Ugandan infants [24], an increased rate of rst parasitemia in Beninese infants [11], and a higher risk of rst episode of malaria in Gabonese infants [25].…”

Section: Discussionmentioning

confidence: 96%

“…There is evidence that PM may impact infants after birth [6][7][8]. Several observational studies have reported associations between PM and increased risks of malaria, non-malaria febrile illnesses, and anemia in infancy, possibly due to immune tolerance induced by in-utero exposure to malaria antigens [9][10][11][12][13]. However, most of these studies de ned PM as the detection of malaria parasites in placental blood by microscopy which has limited sensitivity and does not account for past placental infections characterized by the presence of malaria pigment [14].…”

mentioning

confidence: 99%

Infant Sex Modifies Associations Between Placental Malaria and Risk of Malaria in Infancy

Kakuru

Roh

Kajubi

et al. 2020

Preprint

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Background Placental malaria (PM) has been associated with a higher risk of malaria during infancy. However, it is unclear whether this association is causal, and is modified by infant sex, and whether intermittent preventive treatment in pregnancy (IPTp) can reduce infant malaria by preventing PM.MethodsData from a birth cohort of 656 infants born to HIV-uninfected mothers randomized to IPTp with dihydroartemisinin-piperaquine (DP) or sulfadoxine-pyrimethamine (SP) was analyzed. PM was categorized as no PM, active PM (presence of parasites), mild-moderate past PM (>0-20% high powered fields [HPFs] with pigment), or severe past PM (>20% HPFs with pigment). The association between PM and incidence of malaria in infants stratified by infant sex was examined. Causal mediation analysis was used to test whether IPTp can impact infant malaria incidence via preventing PM. ResultsThere were 1088 malaria episodes diagnosed among infants during 596.6 person years of follow-up. Compared to infants born to mothers with no PM, the incidence of malaria was higher among infants born to mothers with active PM (adjusted incidence rate ratio [aIRR] 1.30, 95% CI 1.00-1.71, p=0.05) and those born to mothers with severe past PM (aIRR 1.28, 95% CI 0.89-1.83, p=0.18), but the differences were not statistically significant. However, when stratifying by infant sex, compared to no PM, severe past PM was associated a higher malaria incidence in male (aIRR 2.17, 95% CI 1.45-3.25, p<0.001), but not female infants (aIRR 0.74, 95% CI 0.46-1.20, p=0.22). There were no significant associations between active PM or mild-moderate past PM and malaria incidence in male or female infants. Male infants born to mothers given IPTp with DP had significantly less malaria in infancy than males born to mothers given SP, and 89.7% of this effect was mediated through prevention of PM.ConclusionPM may have more severe consequences for male infants, and interventions which reduce PM could mitigate these sex-specific adverse outcomes. More research is needed to better understand this sex-bias between PM and infant malaria risk.Trial registrationTrial registration: ClinicalTrials.gov, NCT02793622. Registered 8 June 2016, https://clinicaltrials.gov/ct2/show/NCT02793622

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Placental but Not Peripheral Plasmodium falciparum Infection During Pregnancy Is Associated With Increased Risk of Malaria in Infancy

Cited by 29 publications

References 13 publications

Malaria in pregnancy shapes the development of foetal and infant immunity

Malaria in pregnancy shapes the development of foetal and infant immunity

The immune response to malaria in utero

Infant Sex Modifies Associations Between Placental Malaria and Risk of Malaria in Infancy

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