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REVIEW ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 2  |  Page : 39-43

Implications of placental malaria on neurocognition


1 Department of Physiology, University of Nigeria, Enugu; Department of Physiology, Edo University, Iyamho, Edo State, Nigeria
2 Department of Medicine, Ambrose Alli University, Ekpoma, Edo State, Nigeria
3 Department of Physiology, University of Nigeria, Enugu, Nigeria

Date of Web Publication14-Nov-2018

Correspondence Address:
Mr. Akhabue Kenneth Okojie
Department of Physiology, Edo University, Iyamho, Edo State
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/njecp.njecp_3_18

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  Abstract 


Malaria infection during pregnancy is associated with serious health consequences among mothers and offspring. There are over 125 million pregnant women in malaria endemic regions each year; yet, the impact of in utero malaria exposure on the neurological and cognitive development of their exposed infants is unknown. Recent evidence has shown that the complement system is involved in neurodevelopment in the normal physiological state. However, malaria infection results in the activation of the coagulation cascade and the production of thrombin, as well as increased leukocytes with bound serine proteases. Both thrombin and serine proteases are able to directly cleave C5 which leads to over activation of the complement system. The aim of this study is to identify gaps in knowledge of the implications of placental malaria on brain development and neurocognitive functions of offspring and to chart a course for gathering requisite knowledge to fill those gaps both through special studies and routine data-gathering exercises such as monitoring, surveillance, and evaluation.

Keywords: Behavior, cognition, complement system, malaria, pregnancy


How to cite this article:
Okojie AK, Okobi EO, Iyare EE. Implications of placental malaria on neurocognition. Niger J Exp Clin Biosci 2017;5:39-43

How to cite this URL:
Okojie AK, Okobi EO, Iyare EE. Implications of placental malaria on neurocognition. Niger J Exp Clin Biosci [serial online] 2017 [cited 2018 Dec 16];5:39-43. Available from: http://www.njecbonline.org/text.asp?2017/5/2/39/245405




  Introduction Top


There is a common saying that, in as much as a woman has lived on earth, malaria would have trailed her;[1] however, not until the 21st century, issues associated with malaria in pregnancy were not reported.[2],[3] It is estimated that 125 million pregnant women are at danger of malaria disease worldwide every year[4] with 584,000 deaths in African children and severe morbidity in pregnant women.[5] There is a very high frequency of malaria in pregnancy in Plasmodium falciparum endemic regions with poor clinical results than the nonpregnant women.[6],[7]

Placental malaria is as a result of red blood cells that have been infected by P. falciparum and adheres to tissue of the placenta. It is an entity of malaria in pregnancy. It is marked by sequestration and massive aggregation of infected red blood cells in the placenta.[8] The dispersion of infected red blood cells in infected pregnant woman differs in relation to the endemicity of malaria. In partially immune gravid women, the percentage of infected erythrocytes is generally more in placental than the peripheral blood.[9] Materno-fetal transfer is impaired when the placental is parasitized which results in decreased are of syncytium in contact with maternal blood.[10] In addition, substantial irregularity in the intervillous spaces could threaten the physiological function associated with placental leading to high possibility of maternal and fetal anemia, intrauterine growth retardation, low birth weight, and prematurity.[11],[12],[13]

Malaria in pregnancy is marked by aggregation of infected red blood cells in the intervillous spaces of placenta tissue, where infected erythrocytes stick to the lining of the endothelium. This sequestration or adhesion seen in placental malaria is mediated through a specific parasite-encoded variant surface antigen (VSA) present on the membrane of parasitized erythrocytes.[14] The VSA confines to the chondroitin sulfate A on the syncytiotrophoblast covering the intervillous space. Sequestration leads to the release of inflammatory white blood cells, causing death of placental tissue. Usually, to some extent, multigravida is protected against placental malaria which could be as a result of maternal antibodies that inhibit cytoadhesion of parasitized erythrocytes to the placenta.[15],[16] This protection is absent if a multigravida changes location and is at danger of infection, if they relocate back to the endemic regions.

A watershed report in 2007 projected about 200 million children, mainly in Sub-Saharan Africa and South Asia, do not attain their true developmental potential.[17],[18] Current hypothesis of early life programming supports the premise that many developmental delay and disorders may have their origin in utero.[19],[20],[21] Infections, including malaria, in early postnatal life, could have a role on the neurocognitive function as shown in recent findings; even though hunger and starvation as a result of poverty are known factors for the developmental setback. Lasting neurocognitive losses are seen in children that recover from serious malaria infection which is complicated by convulsion or coma.[22],[23] Although in utero exposure to different kinds of infections such as polio and measles is known to escalate the dangers of neurodevelopmental conditions in progeny,[24] very limited information is available on the implications of malaria during pregnancy on neurological and cognition in children exposed in utero.

The purpose of this review is to fill the void in knowledge on how placental malaria may impact on brain development and neurocognitive functions and provide relevant information to fill the voids.


  Maternal Infection and in Utero Environment Top


Pregnancy is a unique state which gives fetus the opportunity to live and develop in the womb even though the fetus has paternal alloantigens which is seen as external by the mother.[25] Although the physiological process accountable for the harmonious coexistence between fetus and mother is not fully known, it is believed that the continuous existence of the fetus is dependent on the perturbations of maternal immune reaction during pregnancy.[26],[27] These maternal immune perturbations, although not immediately detrimental to the in utero fetal survival, may alter fetal immune responses which may become detrimental and long lasting in the early postnatal period or later in the life of the offspring. Such detrimental effects may include altered responses to vaccination[28],[29] and susceptibility to postnatal infections[30] and the development of immunopathological disorders such as allergy.[31] A number of studies have shown the role of in utero environment on brain development and lasting neurocognitive and neurobehavioral end results.[32] In utero neurodevelopment is marked by precisely monitored critical phases of neurogenesis, cell migration, synapse formation, and synaptic pruning. The complement system can perform or alter these signals. Therefore, maternal complement system reactions to infection during pregnancy possess the ability to interfere with these important processes in fetal brain development.[33],[34],[35] Recent assumptions indicate that neurodevelopmental conditions could have been as a result of early life programming during pregnancy.[19],[20],[21] Various reports have shown the role of in utero bacterial or viral infections on neurogenesis in murine models of developmental disorders in children.[36],[37],[38]

P. falciparum infection leads to extreme complement system activation, and during pregnancy, this undue complement activation in the intervillous space exposes the developing fetus, syncytiotrophoblasts, and placenta to extreme complement system activation products.[39] P. berghei ANKA and lipopolysaccharide exposure in utero resulted in elevated levels of cytokines in amniotic fluid, placental, and fetal brain occurring only within few hours,[40],[41] indicating that infection during pregnancy could immediately alter fetal environment. Studies from murine models suggest that progeny exposed to infection during pregnancy may have lasting behavioral disorder including interruption of regular neurodevelopment.[41],[42] Moreover, the infection in this study did not result in congenital fetal infection, indicating that only the stimulation of maternal defense system is enough to alter neurodevelopment.


  Complement System during Pregnancy Top


The complement system is made up of more than 50 proteins which generally function in a depressed constant condition of activation. It constitutes the first line of defense against invading pathogens. The complement cascade can be activated by any of the following: classical pathways which is precipitated by immune complexes; alternate or properdin pathway which is precipitated by contact with various microorganisms; and mannose-binding lectin pathway which is stimulated by the binding of lectin to mannose in bacteria. These pathways assemble on C3 protein which leads to successive cleavage of C5a which will subsequently initiate convening of membrane attack complex (MAC) which is important for complement function. However, despite the obviously known cascade pathways, thrombin and serine proteases can directly activate C5. P. falciparum infection is known to trigger coagulation cascade resulting in thrombin formation, surge in white blood cells accompanied by bound serine proteases.[42] Overactivation of the complement system is implicated with different disease conditions.

Elevations of maternal plasma C3a, C4a, and C5a concentrations have been reported in normal pregnancy.[44] It is believed that steroid hormones are responsible for the systemic increment in anaphylatoxins during pregnancy.[44] There is an increase in oxygen radical species production as a result of oxidative burst on neutrophils by C5a.[45] These findings have also been described in normal pregnancies.[46] The physiological activation of the complement system during pregnancy may be a compensatory mechanism aimed at protecting the host against infection.

Complement components play an important role as the first line of defense, thereby making them present at tissue levels. As a result of this, if unregulated during infection, it will impact on the feta-maternal interface which will undermine fetal survival.[25] A major issue associated with the complement cascade is the release of biologically active products which usually cannot differentiate self from components and foreign agents which leads to tissue injury through MAC and inflammation. This will alter the subtle equilibrium between the fetus and mother which ordinarily is functionally structured to allow for a peaceful harmony between fetus and mother during pregnancy.


  Placental Malaria on Neurocognition and Neurobehavior Top


Usually, standard placental growth is necessary for excellent fetal development. Malaria infection has been reported to interfere with complement system conciliate pathways which regulates brain development in utero.[41],[42] Prenatal environment is important in brain development which plays a role in cognitive and behavioral in life.[47],[48] Different studies have shown the impact of prenatal infection on brain development both in murine models and in children,[36],[38] with little or no information on malaria.

The complement system could be the final common pathway necessary for healthy placental, fetal development, and in utero neurodevelopmental process but when overactivated it leads to dysregulated in utero environment which may result in compromised neurodevelopment. Although the precise role of the complement system is unknown in fetal brain development, recent studies have linked it with initial brain developmental mechanisms which include neurogenesis, cell migration, and synaptic pruning.[49],[50],[51] Recent studies have shown that experimental model of malaria in pregnancy results in a continual neurocognitive shortfall in memory and affective-like behavior which persisted into adulthood.[39],[41] They also reported diminished regional brain levels of primary biogenic amines and BDNF.[40]


  Conclusion Top


It is estimated that 125 million gravidae are at danger of malaria disease worldwide every year, and these pregnancies are very common in resource-limited parts of the world where most of the women have restricted access to antenatal care services. The complement system could play a role in neurocognitive impairment resulting from malaria. Neurocognitive impairment due to malaria infection in utero will have a great social-economic burden on the family, especially in resource-limited settings.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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