Talk:Abnormal Development - Malaria

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Cite this page: Hill, M.A. (2021, May 12) Embryology Abnormal Development - Malaria. Retrieved from


Ngai M, Weckman AM, Erice C, McDonald CR, Cahill LS, Sled JG & Kain KC. (2020). Malaria in Pregnancy and Adverse Birth Outcomes: New Mechanisms and Therapeutic Opportunities. Trends Parasitol. , 36, 127-137. PMID: 31864896 DOI.

Malaria in Pregnancy and Adverse Birth Outcomes: New Mechanisms and Therapeutic Opportunities.

Abstract Malaria infection during pregnancy is associated with adverse birth outcomes but underlying mechanisms are poorly understood. Here, we discuss the impact of malaria in pregnancy on three pathways that are important regulators of healthy pregnancy outcomes: L-arginine-nitric oxide biogenesis, complement activation, and the heme axis. These pathways are not mutually exclusive, and they collectively create a proinflammatory, antiangiogenic milieu at the maternal-fetal interface that interferes with placental function and development. We hypothesize that targeting these host-response pathways would mitigate the burden of adverse birth outcomes attributable to malaria in pregnancy. Copyright © 2019 Elsevier Ltd. All rights reserved. KEYWORDS: L-arginine; adverse birth outcomes; complement activation; heme axis; malaria; nitric oxide; pregnancy PMID: 31864896 DOI: 10.1016/


Congenital Malaria in Newborns Presented at Tororo General Hospital in Uganda: A Cross-Sectional Study

Am J Trop Med Hyg. 2019 May;100(5):1158-1163. doi: 10.4269/ajtmh.17-0341.

Hangi M1, Achan J2, Saruti A3, Quinlan J4, Idro R1.

Despite recent large-scale investments, malaria remains a major public health concern. Few studies have examined congenital malaria, defined as the presence of malaria parasitemia within the first 7 days of life, in endemic areas. This study aimed to determine the prevalence, to describe the clinical presentation, and to examine factors associated with congenital malaria in newborns aged up to 7 days attending Tororo General Hospital in Uganda. A total of 261 mother/baby pairs were recruited in this cross-sectional study. Giemsa-stained thick blood smears for malaria parasites and rapid malaria diagnostic tests were performed on capillary blood samples from all newborns and mothers, as well as on placental and cord samples from newborns delivered in the hospital. The prevalence of congenital malaria in the newborns was 16/261 (6.1%). No single clinical feature was associated with congenital malaria. However, there were associations between congenital malaria and maternal parasitemia (P < 0.001), gravidity of one (P = 0.03), maternal age < 19 years (P = 0.01), cord blood parasitemia (P = 0.01), and placental malaria (P = 0.02). In conclusion, congenital malaria is not rare in Uganda and there are no obvious clinical features associated with it in the newborn. Based on these findings, we recommend strengthening malaria prevention during pregnancy to reduce the occurrence of congenital malaria in newborns.

PMID: 30860019 PMCID: PMC6493922 [Available on 2020-05-01] DOI: 10.4269/ajtmh.17-0341

Association of Malaria Infection During Pregnancy With Head Circumference of Newborns in the Brazilian Amazon

JAMA Netw Open. 2019 May 3;2(5):e193300. doi: 10.1001/jamanetworkopen.2019.3300.

Dombrowski JG1, Souza RM1,2, Lima FA1, Bandeira CL1, Murillo O1, Costa DS1, Peixoto EPM1, Cunha MDP3, Zanotto PMA3, Bevilacqua E4, Grisotto MAG5, Pedroso de Lima AC6, Singer JDM6, Campino S7, Clark TG7,8, Epiphanio S9, Gonçalves LA1, Marinho CRF1.

IMPORTANCE: Malaria during pregnancy is associated with adverse events for the fetus and newborn, but the association of malaria during pregnancy with the head circumference of the newborn is unclear.

OBJECTIVE: To investigate the association of malaria during pregnancy with fetal head growth.

DESIGN, SETTING, AND PARTICIPANTS: Two cohort studies were conducted at the general maternity hospital of Cruzeiro do Sul (Acre, Brazil) in the Amazonian region. One cohort study prospectively enrolled noninfected and malaria-infected pregnant women who were followed up until delivery, between January 2013 and April 2015. The other cohort study was assembled retrospectively using clinical and malaria data from all deliveries that occurred between January 2012 and December 2013. Data analyses were conducted from January to August 2017 and revised in November 2018. Clinical data from pregnant women and anthropometric measures of their newborns were evaluated. A total of 600 pregnant women were enrolled through volunteer sampling (prospective cohort study), and 4697 pregnant women were selected by population-based sampling (retrospective cohort study). After application of exclusion criteria, data from 251 (prospective cohort study) and 232 (retrospective cohort study) malaria-infected and 158 (prospective cohort study) and 3650 (retrospective cohort study) noninfected women were evaluated.

EXPOSURE: Malaria during pregnancy.

MAIN OUTCOMES AND MEASURES: The primary end point was the incidence of altered head circumference in newborns delivered from malaria-infected mothers compared with that from noninfected mothers. Secondary end points included measures of placental pathology relative to newborn head circumference.

RESULTS: In total, 4291 maternal-child pairs were analyzed. Among 409 newborns in the prospective cohort study, the mothers of 251 newborns had malaria during pregnancy, infected with Plasmodium vivax, Plasmodium falciparum, or both. Among 3882 newborns in the retrospective cohort study, 232 were born from mothers that had malaria during pregnancy. The prevalence of newborns with a small head (19 [30.7%] in the prospective cohort study and 30 [36.6%] in the retrospective cohort study) and the prevalence of microcephaly among newborns (5 [8.1%] in the prospective cohort study and 6 [7.3%] in the retrospective cohort study) were higher among newborns from women infected with P falciparum during pregnancy. Multivariate logistic regression analyses revealed that P falciparum infection during pregnancy represented a significant risk factor for the occurrence of small head circumference in newborns (prospective cohort study: odds ratio, 3.15; 95% CI, 1.52-6.53; P = .002; retrospective cohort study: odds ratio, 1.91; 95% CI, 1.21-3.04; P = .006). Placental pathologic findings corroborated this association, with more syncytial nuclear aggregates and inflammatory infiltrates occurring in placentas of newborns born with decreased head circumference.

CONCLUSIONS AND RELEVANCE: This study indicates that falciparum malaria during pregnancy is associated with decreased head circumference in newborns, which is in turn associated with evidence of placental malaria.

PMID: 31050780 DOI: 10.1001/jamanetworkopen.2019.3300


Experimental Malaria in Pregnancy Induces Neurocognitive Injury in Uninfected Offspring via a C5a-C5a Receptor Dependent Pathway

PLoS Pathog. 2015 Sep 24;11(9):e1005140. doi: 10.1371/journal.ppat.1005140. eCollection 2015.

McDonald CR1, Cahill LS2, Ho KT3, Yang J3, Kim H4, Silver KL4, Ward PA5, Mount HT6, Liles WC7, Sled JG2, Kain KC8.


The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.

PMID 26402732

Interactions between malaria and HIV infections in pregnant women: a first report of the magnitude, clinical and laboratory features, and predictive factors in Kinshasa, the Democratic Republic of Congo

Malar J. 2015 Dec;14(1):598. doi: 10.1186/s12936-015-0598-2. Epub 2015 Feb 18.

Wumba RD1, Zanga J, Aloni MN, Mbanzulu K, Kahindo A, Mandina MN, Ekila MB, Mouri O, Kendjo E.


BACKGROUND: HIV and malaria are among the leading causes of morbidity and mortality during pregnancy in Africa. However, data from Congolese pregnant women are lacking. The aim of the study was to determine the magnitude, predictive factors, clinical, biologic and anthropometric consequences of malaria infection, HIV infection, and interactions between malaria and HIV infections in pregnant women. METHODS: A cross-sectional study was conducted among pregnant women admitted and followed up at Camp Kokolo Military Hospital from 2009 to 2012 in Kinshasa, the Democratic Republic of Congo. Differences in means between malaria-positive and malaria-negative cases or between HIV-positive and HIV-negative cases were compared using the Student's t-test or a non-parametric test, if appropriate. Categorical variables were compared using the Chi-square or Fisher's exact test, if appropriate. Backward multivariable analysis was used to evaluate the potential risk factors of malaria and HIV infections. The odds ratios with their 95% confidence interval (95% CI) were estimated to measure the strengths of the associations. Analyses resulting in values of P < 0.05 were considered significant. RESULTS: A malaria infection was detected in 246/332 (74.1%) pregnant women, and 31.9% were anaemic. Overall, 7.5% (25/332) of mothers were infected by HIV, with a median CD4 count of 375 (191; 669) cells/μL. The mean (±SD) birth weight was 2,613 ± 227 g, with 35.7% of newborns weighing less than 2,500 g (low birth weight). Low birth weight, parity and occupation were significantly different between malaria-infected and uninfected women in adjusted models. However, fever, anemia, placenta previa, marital status and district of residence were significantly associated to HIV infection. CONCLUSION: The prevalence of malaria infection was high in pregnant women attending the antenatal facilities or hospitalized and increased when associated with HIV infection.

PMID 25782811

Neonatal And Pediatric Healthcare Worldwide: A Report From UNICEF

Clin Chim Acta. 2015 Mar 11. pii: S0009-8981(15)00136-9. doi: 10.1016/j.cca.2015.03.004. [Epub ahead of print]

Guerrera G1.


The 2013 UNICEF annual report on child mortality concluded that between 1990 and 2013, the annual number of deaths among children under-5years of age has fallen to 6.6 million (uncertainty range, 6.3 to 7.0 million), corresponding to a 48% reduction from the 12.6 million deaths in 1990 (uncertainty range, 12.4 to 12.9 million). About half of under-5 deaths occur in only five countries: India, Nigeria, Democratic Republic of the Congo, Pakistan and China. By 2050, close to 40% of all live births will take place in Sub-Saharan Africa and 37% of the world's children under age five will live in the region. Most deaths can be attributable to preventable diseases. Pneumonia, diarrhea and malaria together killed roughly 2.2 million children under age five in 2012, accounting for a third of all under-five deaths. Emerging evidence has shown that children are at greater risk of dying before age five if they are born in rural areas, poor households, or to a mother denied basic education. While under-5 mortality was consistently reduced over the past 20years, few progresses in reducing neonatal mortality as well as maternal mortality have been done. UNICEF is a leading partner in the Global Alliance for Vaccines and Immunization (GAVI), a far-reaching public-private partnership dedicated to increasing children's access to vaccines in poor countries. Early diagnosis and appropriate low-cost therapy of maternal and neonatal diseases are the challenges of the coming years. Therefore, there is the need to promote new experimental and clinical researches and to translate results in clinical practice. Laboratory medicine is strategic for promoting and validating innovative methods for managing the most important causes of maternal, neonatal and under-5 deaths, as well as to consistently reduce the gap between bench and bedside. This may be achieved by a close cooperation between laboratory medicine and industries for the development of new diagnostic tools, especially low-cost disposables easily usable by everyone, namely mothers, for an earlier and specific therapeutic treatments of such diseases like sepsis and infections. Copyright © 2015. Published by Elsevier B.V. KEYWORDS: Millennium Development Goal 4 (MDG 4); UNICEF’s immunization program; laboratory medicine; maternal mortality rate; neonatal mortality rate; under-five mortality rate

PMID 25771105


Intravital placenta imaging reveals microcirculatory dynamics impact on sequestration and phagocytosis of Plasmodium-infected erythrocytes

PLoS Pathog. 2013 Jan;9(1):e1003154. doi: 10.1371/journal.ppat.1003154. Epub 2013 Jan 31.

de Moraes LV, Tadokoro CE, Gómez-Conde I, Olivieri DN, Penha-Gonçalves C. Source Instituto Gulbenkian de Ciência, Oeiras, Portugal.


Malaria in pregnancy is exquisitely aggressive, causing a range of adverse maternal and fetal outcomes prominently linked to Plasmodium-infected erythrocyte cytoadherence to fetal trophoblast. To elucidate the physiopathology of infected erythrocytes (IE) sequestration in the placenta we devised an experimental system for intravital placental examination of P. berghei-infected mice. BALB/c females were mated to C57Bl/6 CFP+ male mice and infected with GFP+ P. berghei IE, and at gestational day 18, placentas were exposed for time-lapse imaging acquisition under two-photon microscopy. Real-time images and quantitative measurements revealed that trophoblast conformational changes transiently restrain blood flow in the mouse placental labyrinth. The complex dynamics of placental microcirculation promotes IE accumulation in maternal blood spaces with low blood flow and allows the establishment of stable IE-trophoblast contacts. Further, we show that the fate of sequestered IE includes engulfment by both macrophagic and trophoblastic fetal-derived cells. These findings reinforce the current paradigm that IE interact with the trophoblast and provide definitive evidence on two novel pathogenesis mechanisms: (1) trophoblast layer controls placental microcirculation promoting IE sequestration; and (2) fetal-derived placental cells engulf sequestered IE.

PMID 23382682

Does malaria affect placental development? Evidence from in vitro models

PLoS One. 2013;8(1):e55269. doi: 10.1371/journal.pone.0055269. Epub 2013 Jan 31.

Umbers AJ, Stanisic DI, Ome M, Wangnapi R, Hanieh S, Unger HW, Robinson LJ, Lufele E, Baiwog F, Siba PM, King CL, Beeson JG, Mueller I, Aplin JD, Glazier JD, Rogerson SJ. Source Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia. Abstract BACKGROUND: Malaria in early pregnancy is difficult to study but has recently been associated with fetal growth restriction (FGR). The pathogenic mechanisms underlying malarial FGR are poorly characterized, but may include impaired placental development. We used in vitro methods that model migration and invasion of placental trophoblast into the uterine wall to investigate whether soluble factors released into maternal blood in malaria infection might impair placental development. Because trophoblast invasion is enhanced by a number of hormones and chemokines, and is inhibited by pro-inflammatory cytokines, many of which are dysregulated in malaria in pregnancy, we further compared concentrations of these factors in blood between malaria-infected and uninfected pregnancies. METHODOLOGY/PRINCIPAL FINDINGS: We measured trophoblast invasion, migration and viability in response to treatment with serum or plasma from two independent cohorts of Papua New Guinean women infected with Plasmodium falciparum or Plasmodium vivax in early pregnancy. Compared to uninfected women, serum and plasma from women with P. falciparum reduced trophoblast invasion (P = .06) and migration (P = .004). P. vivax infection did not alter trophoblast migration (P = .64). The P. falciparum-specific negative effect on placental development was independent of trophoblast viability, but associated with high-density infections. Serum from P. falciparum infected women tended to have lower levels of trophoblast invasion promoting hormones and factors and higher levels of invasion-inhibitory inflammatory factors. CONCLUSION/SIGNIFICANCE: We demonstrate that in vitro models of placental development can be adapted to indirectly study the impact of malaria in early pregnancy. These infections could result in impaired trophoblast invasion with reduced transformation of maternal spiral arteries due to maternal hormonal and inflammatory disturbances, which may contribute to FGR by limiting the delivery of maternal blood to the placenta. Future prevention strategies for malaria in pregnancy should include protection in the first half of pregnancy.

PMID 23383132

Malaria in pregnancy

Mediterr J Hematol Infect Dis. 2013;5(1):e2013010. doi: 10.4084/MJHID.2013.010. Epub 2013 Jan 2.

Takem EN, D'Alessandro U. Source Medical Research Council Unit, Fajara, The Gambia.


Pregnant women have a higher risk of malaria compared to non-pregnant women. This review provides an update on knowledge acquired since 2000 on P. falciparum and P.vivax infections in pregnancy. Maternal risk factors for malaria in pregnancy (MiP) include low maternal age, low parity, and low gestational age. The main effects of MIP include maternal anaemia, low birth weight (LBW), preterm delivery and increased infant and maternal mortality.P. falciparum infected erythrocytes sequester in the placenta by expressing surface antigens, mainly variant surface antigen (VAR2CSA), that bind to specific receptors, mainly chondroitin sulphate A. In stable transmission settings, the higher malaria risk in primigravidae can be explained by the non-recognition of these surface antigens by the immune system. Recently, placental sequestration has been described also for P.vivax infections. The mechanism of preterm delivery and intrauterine growth retardation is not completely understood, but fever (preterm delivery), anaemia, and high cytokines levels have been implicated.Clinical suspicion of MiP should be confirmed by parasitological diagnosis. The sensitivity of microscopy, with placenta histology as the gold standard, is 60% and 45% for peripheral and placental falciparum infections in African women, respectively. Compared to microscopy, RDTs have a lower sensitivity though when the quality of microscopy is low RDTs may be more reliable. Insecticide treated nets (ITN) and intermittent preventive treatment in pregnancy (IPTp) are recommended for the prevention of MiP in stable transmission settings. ITNs have been shown to reduce malaria infection and adverse pregnancy outcomes by 28-47%. Although resistance is a concern, SP has been shown to be equivalent to MQ and AQ for IPTp. For the treatment of uncomplicated malaria during the first trimester, quinine plus clindamycin for 7 days is the first line treatment and artesunate plus clindamycin for 7 days is indicated if this treatment fails; in the 2(nd) and 3(rd) trimester first line treatment is an artemisinin-based combination therapy (ACT) known to be effective in the region or artesunate and clindamycin for 7 days or quinine and clindamycin. For severe malaria, in the second and third trimester parenteral artesunate is preferred over quinine. In the first trimester, both artesunate and quinine (parenteral) may be considered as options. Nevertheless, treatment should not be delayed and should be started immediately with the most readily available drug.

PMID 23350023


Ultrasound evidence of early fetal growth restriction after maternal malaria infection

PLoS One. 2012;7(2):e31411. Epub 2012 Feb 9.

Rijken MJ, Papageorghiou AT, Thiptharakun S, Kiricharoen S, Dwell SL, Wiladphaingern J, Pimanpanarak M, Kennedy SH, Nosten F, McGready R. Source Shoklo Malaria Research Unit, Mae Sot, Tak, Thailand. Abstract BACKGROUND: Intermittent preventive treatment (IPT), the main strategy to prevent malaria and reduce anaemia and low birthweight, focuses on the second half of pregnancy. However, intrauterine growth restriction may occur earlier in pregnancy. The aim of this study was to measure the effects of malaria in the first half of pregnancy by comparing the fetal biparietal diameter (BPD) of infected and uninfected women whose pregnancies had been accurately dated by crown rump length (CRL) before 14 weeks of gestation. METHODOLOGY/PRINCIPAL FINDINGS: In 3,779 women living on the Thai-Myanmar border who delivered a normal singleton live born baby between 2001-10 and who had gestational age estimated by CRL measurement <14 weeks, the observed and expected BPD z-scores (<24 weeks) in pregnancies that were (n = 336) and were not (n = 3,443) complicated by malaria between the two scans were compared. The mean (standard deviation) fetal BPD z-scores in women with Plasmodium (P) falciparum and/or P.vivax malaria infections were significantly lower than in non-infected pregnancies; -0.57 (1.13) versus -0.10 (1.17), p<0.001. Even a single or an asymptomatic malaria episode resulted in a significantly lower z-score. Fetal female sex (p<0.001) and low body mass index (p = 0.01) were also independently associated with a smaller BPD in multivariate analysis. CONCLUSIONS/SIGNIFICANCE: Despite early treatment in all positive women, one or more (a)symptomatic P.falciparum or P.vivax malaria infections in the first half of pregnancy result in a smaller than expected mid-trimester fetal head diameter. Strategies to prevent malaria in pregnancy should include early pregnancy.

PMID 22347473

Consequences of gestational malaria on birth weight: finding the best timeframe for intermittent preventive treatment administration

PLoS One. 2012;7(4):e35342. Epub 2012 Apr 13.

Huynh BT, Fievet N, Briand V, Borgella S, Massougbodji A, Deloron P, Cot M. Source UMR216, Institut de Recherche pour le Développement, Paris, France.


To investigate the consequences of intermittent preventive treatment (IPTp) timing on birth weight, we pooled data from two studies conducted in Benin between 2005 and 2010: a prospective cohort of 1037 pregnant women and a randomised trial comparing sulfadoxine-pyrimethamine (SP) to mefloquine in 1601 women. A total of 1439 women (752 in the cohort and 687 in the SP arm of the randomised trial) who delivered live singletons were analysed. We showed that an early intake of the first SP dose (4 months of gestation) was associated with a lower risk of LBW compared to a late intake (6-7 months of gestation) (aOR = 0.5 p = 0.01). We also found a borderline increased risk of placental infection when the first SP dose was administered early in pregnancy (aOR = 1.7 p = 0.1). This study is the first to investigate the timing of SP administration during pregnancy. We clearly demonstrated that women who had an early intake of the first SP dose were less at risk of LBW compared to those who had a late intake. Pregnant women should be encouraged to attend antenatal visits early to get their first SP dose and a third dose of SP could be recommended to cover the whole duration of pregnancy and to avoid late infections of the placenta.

PMID 22514730

Effect of malaria on placental volume measured using three-dimensional ultrasound: a pilot study

Malar J. 2012 Jan 5;11:5.

Rijken MJ, Moroski WE, Kiricharoen S, Karunkonkowit N, Stevenson G, Ohuma EO, Noble JA, Kennedy SH, McGready R, Papageorghiou AT, Nosten FH. Source Shoklo Malaria Research Unit, PO Box 46, Mae Sot, Tak 63110, Thailand.


BACKGROUND: The presence of malaria parasites and histopathological changes in the placenta are associated with a reduction in birth weight, principally due to intrauterine growth restriction. The aim of this study was to examine the feasibility of studying early pregnancy placental volumes using three-dimensional (3D) ultrasound in a malaria endemic area, as a small volume in the second trimester may be an indicator of intra-uterine growth restriction and placental insufficiency. METHODS: Placenta volumes were acquired using a portable ultrasound machine and a 3D ultrasound transducer and estimated using the Virtual Organ Computer-aided AnaLysis (VOCAL) image analysis software package. Intra-observer reliability and limits of agreement of the placenta volume measurements were calculated. Polynomial regression models for the mean and standard deviation as a function of gestational age for the placental volumes of uninfected women were created and tested. Based on these equations each measurement was converted into a z -score. The z-scores of the placental volumes of malaria infected and uninfected women were then compared. RESULTS: Eighty-four women (uninfected = 65; infected = 19) with a posterior placenta delivered congenitally normal, live born, single babies. The mean placental volumes in the uninfected women were modeled to fit 5th, 10th, 50th, 90th and 95th centiles for 14-24 weeks' gestation. Most placenta volumes in the infected women were below the 50th centile for gestational age; most of those with Plasmodium falciparum were below the 10th centile. The 95% intra-observer limits of agreement for first and second measurements were ± 37.0 mL and ± 25.4 mL at 30 degrees and 15 degrees rotation respectively. CONCLUSION: The new technique of 3D ultrasound volumetry of the placenta may be useful to improve our understanding of the pathophysiological constraints on foetal growth caused by malaria infection in early pregnancy.

PMID 22222152