Malaria in pregnancy: small babies, big problem

doi:10.1016/j.pt.2011.01.007

Trends in Parasitology

Volume 27, Issue 4, April 2011, Pages 168-175

https://doi.org/10.1016/j.pt.2011.01.007 Get rights and content

Placental malaria is hypothesized to lead to placental insufficiency, which causes fetal growth restriction (FGR). In this review, recent discoveries regarding the mechanisms of pathogenesis by which malaria causes FGR are discussed in the wider context of placental function and fetal growth. Placental malaria and associated host responses can induce changes in placental structure and function, affecting pregnancy-associated growth-regulating hormones and predisposing the offspring to hypertension and vascular dysfunction. Risk factors associated with FGR are highlighted, and potential interventions and studies to uncover remaining mechanisms of pathogenesis are proposed. Together, these strategies aim to decrease the burden of FGR associated with malaria in pregnancy.

Section snippets

Malaria during pregnancy and fetal growth

Each year more than 125 million pregnant women are at risk of malaria infection, which can have serious consequences for them and their offspring, especially in first- and second- time mothers [1]. In highly endemic settings up to 50% of low birth weight (LBW) deliveries can be attributed to malaria in pregnancy, leading to approximately 100 000 infant deaths annually, many of which are consequences of FGR [2], defined in Box 1 Here recent findings in placental malaria (PM) and placental

Placental development and vascularization

During early pregnancy (up to 18–20 weeks of gestation), placental extravillous trophoblasts invade the uterus, transforming maternal spiral arteries and increasing placental blood supply [11]. Remodeling of uterine and placental vasculature is essential for appropriate placental function and fetal growth. Placental vascular development is controlled partly by angiogenic factors including the angiopoietins (ANG-1, ANG-2) and vascular endothelial growth factor (VEGF) and its soluble receptor

Placental malaria, angiogenesis, hypertension and fetal growth

Maternal Plasmodium falciparum infections peak at 13–18 weeks of gestation, and it is hypothesized that malaria might impair trophoblast invasion, contributing to the development of FGR 14, 15 (Figure 1, Figure 2). The effects of malaria on early placental development are largely unknown, but a Doppler ultrasound study at 32–35 weeks showed a relationship between concurrent malaria infection and abnormal uterine blood flow; altered uterine vascular resistance was predictive of LBW, preterm

Hormones

Throughout gestation, placental hormones play important roles in regulation of fetal growth and the maintenance of pregnancy [21]. These hormones influence the maternal immune system and regulate placental functions including nutrient transport. In the placenta, growth-regulating hormones are synthesized predominantly by the syncytiotrophoblast which lines the intervillous spaces, forming the interface between maternal and fetal circulations. Key hormones include insulin-like growth factors

Nutrient transport and maternal nutrition

Fetal growth is dependent on the placental delivery of nutrients including amino acids, lipids and glucose. Their delivery can be regulated by the number and activity of specific transporters or transport proteins, such that only modest decreases in transport can affect fetal growth. For example, decreased activity of system A amino acid transporters, one of the most important and widely studied families of amino acid transport proteins in the placenta, is associated with both the occurrence

Placental pathology and inflammation

PM involves the sequestration of parasites in the intervillous space. These parasites can cause maternal mononuclear cells and the syncytiotrophoblast to produce chemokines 15, 40, leading to recruitment of additional monocytes. The resulting inflammatory cytokines could then lead to the formation of fibrin deposits. On histology, active PM includes parasites in the IVS, with or without malaria pigment in fibrin and/or monocytes, whereas in past infection pigment alone is detected.

Both

Plasmodium vivax and FGR

In contrast to P. falciparum, there is little evidence indicative of P. vivax-infected reticulocyte cyto-adhesion to the syncytiotrophoblast layer, despite a recent report showing P. vivax adhesion to placental cryo-sections [44]. Nevertheless, P. vivax infections have been associated with LBW and maternal anemia [45], although the impact is less severe than of P. falciparum. In addition to the current dogma of placental malaria, clues from pregnancy-associated P. vivax infections suggest that

Placental cytokine responses

Unlike normal pregnancy, which is characterized by a Th2 immune response, placental malaria initiates a Th1 response [33], potentially resulting in adverse fetal outcomes. Proinflammatory cytokines, in particular, are consistently elevated in malaria-infected placentas, especially those with chronic inflammation [46]. They have been associated with poor birth outcomes in several studies, but their effects on trophoblast function have been largely neglected. Cytokines and chemokines are produced

Functional consequences of placental parasite sequestration

Although novel insights point to a pathogenic role of systemic and endocrine changes distal to the site of infection, recent discoveries into the consequences of placental parasite adhesion reveal a more active role for local infection than was previously appreciated.

The sequestration of parasitized erythrocytes in the intervillous space is mediated by surface expression of variant surface antigen, var2CSA, which binds chondroitin sulphate-A expressed by the syncytiotrophoblast [46]. Adhesion

Timing of infection and its consequences

Recent studies 4, 6, 7, 55, 56, 57, 58 have begun to examine whether infection in early gestation, infection closer to delivery, or an accumulation of both, have the greatest influence on birth weight or indices of fetal growth. In a longitudinal study of fetal growth in utero, multiple episodes of malaria infection independently influenced fetal growth [7], although numbers were small. In a recent large study, increasing cumulative numbers of parasitemia episodes during pregnancy increased the

Placental and fetal hypoxia

Placental hypoxia has been hypothesized to be involved in the pathogenesis of FGR [46], given the combination of physical effects created by dense cellular accumulation in the intervillous space and thickening of syncytiotrophoblast basement membrane in chronic PM. However, a recent study suggests this is not the case, as no markers of placental hypoxia were associated with PM and FGR [59]. Fetal hypoxia can also occur independently of placental normoxia, and whether PM causes fetal hypoxia

Maternal anemia, malaria and FGR

Anemia is an independent risk factor for LBW and FGR [3]. Malaria is an important cause of anemia; the population attributable fraction of severe anemia (hemoglobin <70 g/l) due to malaria in high-transmission settings is around 25% [2], and PM-associated inflammation is strongly associated with anemia 62, 63. The mechanisms by which moderate to severe anemia causes FGR are not well understood. Potential contributing factors include deficiencies in hematinic factors including iron, folic acid

Interventions

Effective prevention of FGR associated with pregnancy malaria includes administration of intermittent preventive treatment (IPTp) [64] and the use of insecticide-treated nets [65]; pregnancy-specific vaccines are in early development, and evaluation of pre-erythrocytic vaccines such as RTS,S is under consideration. Because the impact of maternal malnutrition, HIV infection and malaria can be additive 5, 7, multiple interventions combined with malaria prevention could also improve birth weight;

Gaps in our knowledge and recommended future studies

Box 4 summarizes key areas for future research into the pathogenesis of FGR associated with PM. Evaluation of changes in placental gene transcription with PM is a key area for future research. In a genome-wide expression analysis of placental malaria, B-cell, antibody and macrophage-activation genes were upregulated [67], but metabolic genes potentially mediating FGR are tightly regulated and require a more targeted approach. Total placental extracts contain heterogeneous cell populations of

Conclusions

Recent studies provide evidence that PM perturbs placental function, leading to placental insufficiency. There are also indications that abnormal maternal vascular function and altered levels of growth-regulating hormones in response to PM can contribute to FGR. Placental inflammation appears to be central to FGR, and the timing and duration of infection probably determine its severity, in conjunction with maternal risk factors. Further work is required to disentangle causation from

Glossary

Ballard scores: a technique commonly used to assess gestational age at birth.
Extravillous trophoblast: a specialized trophoblast that migrates from villous tissue and invades through the maternal decidua and transforms maternal spiral arteries.
Fetal growth restriction, low birth weight, small for gestational age, preterm delivery and Rohrer's Ponderal index: these terms are defined in Box 1.
Infected erythrocytes: parasitized red blood cells during the blood stage of malaria infection
Intervillous space

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Cited by (154)

CCR5 contributes to adverse outcomes during malaria in pregnancy
2023, Cytokine
CCR5 is a chemokine receptor that mediates cell recruitment to sites of inflammation. It has been previously reported that the expression of CCR5 is increased in the placentas of women with malaria, a disease characterized by causing deliveries with low birth weight among other complications. CCR5 has been associated with pathology of protozoan infections during pregnancy but its role during malaria in pregnancy has not been elucidated. In the present work, we assessed the pregnancy outcome, placental structure, and levels of inflammatory markers of pregnant C57BL/6 and CCR5-/- mice infected or not with Plasmodium berghei NK65, with the purpose of determine the role of CCR5 in pregnancy associated malaria complications. We demonstrated that the expression of CCR5 mRNA increases in late pregnancy placentas of C57BL/6 when compared to uninfected controls. Infected pregnant C57BL/6 mice showed preterm birth, decreased fetal weight, placental inefficiency, and reduced placental vascular space. On the other hand, CCR5 deficiency led to increased levels of maternal parasitemia, reduced fetal weight and placental inefficiency compared to C57BL/6 mice. However, the infection did not cause additional changes in these parameters or in the incidence of preterm delivery in infected CCR5-/- mice in relation to C57BL/6 mice, showing that CCR5 may contribute to the adverse effects caused by infection during pregnancy. This improvement in pregnancy outcome, observed in infected CCR5-/- mice, was accompanied by lower placental levels of the inflammatory markers, such as TNF and NAG. Furthermore, it was observed that the placentas of CCR5-/- animals showed structural differences in relation to C57BL/6 mice, which could improve the efficiency of maternal-fetal exchanges, reflecting on fetal weight. Taken together, these results indicate that CCR5 expression contributes to the adverse outcomes caused by malaria in late pregnancy.
Safety of treating malaria with artemisinin-based combination therapy in the first trimester of pregnancy
2022, Reproductive Toxicology
There have been recent calls for the use of artemisinin-based combination therapies (ACTs) for uncomplicated malaria in the first trimester of pregnancy. Nevertheless, the 2021 WHO Guidelines for Malaria reaffirmed their position that there is not adequate clinical safety data on artemisinins to support that usage. The WHO’s position is consistent with several issues with the existing clinical data. First, first trimester safety results from multiple ACTs were lumped in a meta-analysis which does not demonstrate that each of the included ACTs is equally safe. Second, safety results from all periods of the first trimester were lumped in the meta-analysis which does not demonstrate the same level of safety for all subperiods, particularly gestational Weeks 6–8 which is likely to be the most sensitive period. Third, even if there is evidence of a lack of an effect on miscarriage rate for a particular ACT, it does not follow then there are no developmental effects for any ACT. In monkeys, artesunate caused marked embryonal anemia leading to embryo death but the long-term consequences of lower levels of embryonal anemia are not known. Fourth, there have been advances in the sensitivity and usage of rapid diagnostic tests that will lead to diagnoses of malaria earlier in gestation which is less well studied and more likely sensitive to artemisinins. Any clinical studies of the safety of ACTs in the first trimester need to evaluate the results of treatment with individual ACTs during different 1- to 2-week periods of the first trimester.
Mapping and characterizing areas with high levels of malaria in pregnancy in Brazil: A spatiotemporal analysis
2022, The Lancet Regional Health - Americas
Malaria in pregnancy (MiP) is a public health problem in the Brazilian Amazon region that requires special attention due to associated serious adverse consequences, such as low birth weight, increased prematurity and spontaneous abortion rates. In Brazil, there have been no comprehensive epidemiological studies of MiP. In this study, we aimed to explore the spatial and spatiotemporal patterns of MiP in Brazil and epidemiologically characterize this population of pregnant women over a period of 15 years.
We performed a national-scale ecological analysis using a Bayesian space-time hierarchical model to estimate the incidence rates of MiP between 1 January 2004 and 31 December 2018. We mapped the high-incidence clusters among pregnant women aged 10-49 years old using a Poisson model, and we characterized the population based on data from the Epidemiological Surveillance Information System for Malaria (SIVEP-Malaria).
We consolidated the data of 61,833 women with MiP in Brazil. Our results showed a reduction of 50·1% (95% CI: 47·3 to 52·9) in the number of malaria cases over the period analysed, with Plasmodium vivax malaria having the highest incidence. MiP was widely distributed throughout the Amazon region, and spatial and spatiotemporal analyses revealed statistically significant clusters in some municipalities of Amazonas, Acre, Rondônia and Pará. In addition, we observed that younger pregnant women had a higher risk of infection, and the administration of appropriate treatment requires more attention.
This nationwide study provides robust evidence that, despite the reduction in the number of MiP cases in the country, it remains a serious public health problem, especially for young pregnant women. Our analyses highlight focus areas for strengthening interventions to control and eliminate MiP.
FAPESP and CNPq - Brazil.
Pregnancy-associated malaria: Effects of cytokine and chemokine expression
2022, Travel Medicine and Infectious Disease
Malaria remains a serious public health problem. Malaria caused 409,000 deaths in 2019, and 67% were children under 5 years old. Malaria-infected mothers exhibit several complications, including babies with low birth weight, stillbirth, preterm delivery, poor fetal intrauterine growth and maternal anemia. This review aims to provide an update on the immune response in pregnant women and the role of cytokines and chemokines in modulating immunity after infection by the Plasmodium parasite.
This review collects information from articles indexed in the main databases associated with malaria in pregnancy and its relationship with the immune response and cytokines.
and Discussion: The most influential event in malaria pregnancies for pathology development is placental sequestration. During the gestation period, an imbalance in the immune response due to the over- and under-expression of cytokines promotes high rates of fetal mortality, miscarriage, maternal anemia, and low birth weight. In addition, hormones, parity, gestational age, and age of the mother are risks associated with malaria severity during pregnancy.
The pathology of malaria pregnancy is dependent on factors such as cytokine imbalances, placental sequestration and hormones, parity, gestational age and age of the mother. Thus, a better understanding of immune mechanisms will provide information to improve results for disease treatment.
Wrong place, wrong time: The long-run effects of in-utero exposure to malaria on educational attainment
2022, Economics and Human Biology
This paper investigates the long-term relationship between early life exposure to malaria and human capital accumulation in Brazil. The identification strategy relies on exogenous variation in the risk of malaria outbreaks in different states and seasons of the year to identify in utero exposure according to the timing and location of birth. I find consistent negative treatment effects of in utero exposure to malaria on educational attainment. The effects are stronger for exposure during the first trimester of pregnancy than during other periods of gestation. Effective anti-malaria policies can, thus, be an important factor contributing to reducing the educational inequality by targeting pregnant women, especially those in their first months of gestation.
The Angiopoietin-Tie2 axis contributes to placental vascular disruption and adverse birth outcomes in malaria in pregnancy
2021, EBioMedicine
Malaria during pregnancy is a major contributor to the global burden of adverse birth outcomes including fetal growth restriction, preterm birth, and fetal loss. Recent evidence supports a role for angiogenic dysregulation and perturbations to placental vascular development in the pathobiology of malaria in pregnancy. The Angiopoietin-Tie2 axis is critical for placental vascularization and remodeling. We hypothesized that disruption of this pathway would contribute to malaria-induced adverse birth outcomes.
Using samples from a previously conducted prospective cohort study of pregnant women in Malawi, we measured circulating levels of angiopoietin-1 (Angpt-1) and Angpt-2 by Luminex (n=1392). We used a preclinical model of malaria in pregnancy (Plasmodium berghei ANKA [PbA] in pregnant BALB/c mice), genetic disruption of Angpt-1 (Angpt1^+/− mice), and micro-CT analysis of placental vasculature to test the hypothesis that disruptions to the Angpt-Tie2 axis by malaria during pregnancy would result in aberrant placental vasculature and adverse birth outcomes.
Decreased circulating levels of Angpt-1 and an increased ratio of Angpt-2/Angpt-1 across pregnancy were associated with malaria in pregnancy. In the preclinical model, PbA infection recapitulated disruptions to the Angiopoietin-Tie2 axis resulting in reduced fetal growth and viability. Malaria decreased placental Angpt-1 and Tie2 expression and acted synergistically with reduced Angpt-1 in heterozygous dams (Angpt1^+/−), to worsen birth outcomes by impeding vascular remodeling required for placental function.
Collectively, these data support a mechanistic role for the Angpt-Tie2 axis in malaria in pregnancy, including a potential protective role for Angpt-1 in mitigating infection-associated adverse birth outcomes.
This work was supported by the Canadian Institutes of Health Research (CIHR), Canada Research Chair, and Toronto General Research Institute Postdoctoral Fellowship Award. The parent trial was supported by the European & Developing Countries Clinical Trials Partnership and the Malaria in Pregnancy Consortium, which was funded by the Bill & Melinda Gates Foundation. The funders had no role in design, analysis, or reporting of these studies.

View all citing articles on Scopus

^*: These authors contributed equally.

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Trends in Parasitology

ReviewMalaria in pregnancy: small babies, big problem

Section snippets

Malaria during pregnancy and fetal growth

Placental development and vascularization

Placental malaria, angiogenesis, hypertension and fetal growth

Hormones

Nutrient transport and maternal nutrition

Placental pathology and inflammation

Plasmodium vivax and FGR

Placental cytokine responses

Functional consequences of placental parasite sequestration

Timing of infection and its consequences

Placental and fetal hypoxia

Maternal anemia, malaria and FGR

Interventions

Gaps in our knowledge and recommended future studies

Conclusions

Glossary

Lancet Infect. Dis.

Semin. Perinatol.

Drug Alcohol. Depend.

Best Pract. Res. Clin. Endocrinol. Metab.

J. Reprod. Immunol.

Microbes Infect.

Am. J. Obstet. Gynecol.

Hum. Pathol.

Lancet. Infect. Dis.

Placenta

Trans. R. Soc. Trop. Med. Hyg.

Infect. Genet. Evol.

Lancet

Placenta

Early Hum. Dev.

Semin. Perinatol.

Quantifying the number of pregnancies at risk of malaria in 2007: a demographic study

PLoS Med.

Adverse birth outcomes in a malarious area

Epidemiol. Infect.

The effect of dual infection with HIV and malaria on pregnancy outcome in western Kenya

AIDS

Anthropometry of fetal growth in rural Malawi in relation to maternal malaria and HIV status

Arch. Dis. Child. Fetal Neonatal Ed.

Impact of maternal malaria and under-nutrition on intrauterine growth restriction: a prospective ultrasound study in Democratic Republic of Congo

Epidemiol. Infect.

Sexually transmitted infections in pregnancy: prevalence, impact on pregnancy outcomes, and approach to treatment in developing countries

Sex Transm. Infect.

Endovascular trophoblast invasion: implications for the pathogenesis of intrauterine growth retardation and preeclampsia

Biol. Reprod.

Dysregulation of angiopoietins is associated with placental malaria and low birth weight

PLoS ONE

Complement inhibition keeps mothers calm and avoids fetal rejection

Immunol. Invest.

New approaches to pathogenesis of malaria in pregnancy

Parasitology

Impaired uteroplacental blood flow in pregnancies complicated by falciparum malaria

Ultrasound Obstet. Gynecol.

Hypertension and maternal–fetal conflict during placental malaria

PLoS Med.

C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria

PLoS ONE

Natural selection of FLT1 alleles and their association with malaria resistance in utero

Proc. Natl. Acad. Sci. U.S.A.

Placenta malarial infection as a risk factors for hypertensive disorders during pregnancy in Africa: a case-control study in an urban area of Senegal, West Africa

Am. J. Epidemiol.

Endocrine regulation of human fetal growth: the role of the mother, placenta, and fetus

Endocr. Rev.

Placental malaria-associated inflammation disturbs the IGF axis of fetal growth regulation

J. Infect. Dis.

Maternal peripheral blood level of IL-10 as a marker for inflammatory placental malaria

Malaria J.

Review. Sex and the human placenta: mediating differential strategies of fetal growth and survival

Placenta

Cortisol, prolactin, cytokines and the susceptibility of pregnant Sudanese women to Plasmodium falciparum malaria

Ann. Trop. Med. Parasitol.

Depressed natural killer cell cytotoxicity against Plasmodium falciparum-infected erythrocytes during first pregnancies

Clin. Infect. Dis.

Review
Malaria in pregnancy: small babies, big problem