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International audience; Background - Iron deficiency is a common nutritional deficiency that impacts maternal health and fetal development and is also associated with increased uptake of toxic metals. Women in sub-Saharan Africa are highly exposed to both iron deficiency and metals in the environment. As research on the developmental origins of health and disease increasingly shows impacts of pre-conception maternal health on pregnancy and fetal health, these environmental exposures are of concern. Objectives - This study investigated the association between iron status pre-pregnancy and blood metal concentrations in the first trimester of pregnancy with potential implications for iron supplementation. Methods - Pre-conception and first trimester blood samples taken from 262 Beninese women were tested for serum ferritin, inflammation markers, manganese (Mn), cadmium (Cd), lead (Pb), copper, zinc, selenium, mercury and arsenic. Associations between serum ferritin adjusted for inflammation and metal concentrations were analyzed using multivariate linear regression. Results - Women with iron deficiency before conception (13%) were more likely to remain iron deficient in the first trimester (4%) (adjusted OR = 41.2, 95%CI 6.2; 275.0) even within the context of routine iron supplementation during pregnancy. Lower pre-pregnancy serum ferritin concentrations were significantly related to higher concentrations of Mn, Cd and Pb in the first trimester. Every 1% increase in serum ferritin concentration was associated with a 0.13% decrease in Mn (adjusted β = -0.13, 95%CI -0.18; -0.07), a 0.22% decrease in Cd (adjusted β = -0.22, 95%CI -0.28; -0.15) and a 0.06% decrease in Pb concentration (adjusted β = -0.06, 95%CI -0.12; -0.006). Discussion - These results suggest that increasing iron stores prior to pregnancy may prevent excessive uptake of toxic concentrations of the metals Mn, Cd and Pb and argue in favour of testing the effects of iron supplementation prior to pregnancy on metal concentrations.

Background Malaria in early pregnancy occurs at a time when the placenta is developing, with possible consequences for placental function and fetal growth. We assessed the association between first trimester malaria and fetal growth documented through repeated ultrasound scans. Methods The RECIPAL preconceptional cohort included 411 Beninese pregnant women followed from 7 weeks’ gestation (wg) until delivery. Among them, 218 had 4 scans for fetal monitoring at 16, 22, 28, and 34 wg. Multivariate seemingly unrelated regression models were used to assess association of microscopic malaria in the first trimester ( Results Of 39% (86/218) of women with at least 1 microscopic malarial infection during pregnancy, 52.3% (45/86) were infected in the first trimester. Most women (88.5%) were multiparous. There was no association between adjusted z-scores for fetal growth parameters and first trimester malaria. Parity, newborn sex, socioeconomic level, and maternal body mass index significantly influenced fetal growth. Conclusions In a context where malaria infections in pregnancy are well detected and treated, their adverse effect on fetal growth may be limited. Our results argue in favor of preventing and treating infections as early as the first trimester.

Background In the context of global malaria elimination efforts, special attention is being paid to submicroscopic Plasmodium falciparum infections. In pregnant, sub-Saharan African women, such infections are more prevalent than microscopic infections, and are thought to have adverse effects on both mothers’ and newborns’ health. However, no study has studied the dynamics and determinants of these infections throughout pregnancy. Retard de Croissance Intra-uterin et Paludisme (RECIPAL), a preconception cohort study carried out in Benin between 2014 and 2017, represented a unique opportunity to assess this issue. Methods We used data from 273 pregnant Beninese women who were followed-up from preconception to delivery. We studied the dynamics of and factors influencing submicroscopic (and microscopic) P. falciparum infections during the 3 trimesters of pregnancy, using an ordinal logistic mixed model. Results The incidence rate of submicroscopic P. falciparum infections during pregnancy was 12.7 per 100 person-months (95% confidence interval [CI] 10.8–14.9), compared to 6.7 per 100 person-months (95% CI 5.5–8.1) for microscopic infections. The prevalences were highest in the first trimester for both submicroscopic and microscopic infections. After adjustment for potential confounding factors, we found that those of young age and those with a submicroscopic P. falciparum infection prior to pregnancy were at significantly higher risks of submicroscopic and microscopic infections throughout pregnancy, with a more pronounced effect in the first trimester of pregnancy. Conclusions The first trimester of pregnancy is a particularly high-risk period for P. falciparum infection during pregnancy, especially for the youngest women. Malaria prevention tools covering the preconception period and early pregnancy are urgently needed to better protect pregnant women and their newborns., In a preconception malaria cohort study, the prevalence of submicroscopic versus microscopic Plasmodium falciparum infections was higher throughout pregnancy, most markedly in the first trimester, and young women with submicroscopic infections before pregnancy had a higher subsequent risk of infection.

Background Harmful maternal and neonatal health outcomes result from malaria in pregnancy, the prevention of which primarily relies on intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP). The World Health Organization recommends IPTp-SP in sub-Saharan Africa, but implementation is highly heterogeneous and often suboptimal in terms of the number of doses and their timing. In this study, we assessed the impact of this heterogeneity on malaria in pregnancy, mainly with respect to submicroscopic Plasmodium falciparum infections. Methods We used data from 273 Beninese women followed throughout pregnancy. Screening for P. falciparum infections, using both microscopy-based and polymerase chain reaction (PCR)–based methods, was performed monthly, and information on IPTp-SP doses was collected. Gestational age was estimated by repeated ultrasound scans. Using a negative binomial model, we investigated the effect of IPTp-SP doses and timing after 17 weeks of gestation on the number of P. falciparum infections, focusing on submicroscopic infections detectable only by PCR. Results At least 2 IPTp-SP doses were taken by 77.3% of the women. The median gestational age at the first IPTp-SP dose was 22 weeks. A late first IPTp-SP dose (>21.2 weeks) was marginally associated with an increased number of P. falciparum infections (adjusted incidence rate ratio [aIRR] = 1.3; P = .098). The number of IPTp-SP doses was not associated with the number of submicroscopic infections (aIRR = 1.2, P = .543). Conclusions A late first IPTp-SP dose failed to provide optimal protection against P. falciparum, especially submicroscopic infections. This highlights the need for a new antimalarial drug for IPTp that could be taken early in pregnancy., In a cohort study, increased numbers of Plasmodium falciparum infections were found in pregnant women with suboptimal dose numbers and late first doses of intermittent preventive treatment with sulfadoxine-pyrimethamine (IPTp-SP). The timing of IPTp-SP primarily affects submicroscopic infections.

Background. The implication of the immune system in the physiopathology of pregnancy complicated by diabetes has been reported. Here, we investigated the effects of insulin treatment on the frequencies of immune cell subpopulations as well as T cell-derived cytokines in type 2 diabetic (T2D) pregnancy compared to gestational diabetes mellitus (GDM). Methods. Fifteen (15) women with GDM, twenty (20) insulin-treated T2D pregnant women, and twenty-five (25) pregnant controls were selected. Immune cell subpopulation frequencies were determined in blood using flow cytometry. The proliferative capacity of T cells was performed, and serum and cell culture supernatant cytokine levels were also quantified. Results. The frequencies of total CD3+ and CD4+ T cells and nonclassical monocytes significantly increased in insulin-treated T2D pregnant women compared to pregnant controls. The proportions of CD4+ T cells as well as B cells were significantly higher in women with GDM than in pregnant controls. GDM was associated with high frequencies of total CD3+ and CD4+ T cells and B cell expansion, suggesting a concomitant activation of cellular and humoral immunity. Concomitantly, Th1/Th2 ratio, determined as IFN-γ/IL-4, was shifted towards Th1 phenotype in women with GDM and insulin-treated T2D pregnant women. Besides, isolated T cells elicited similar proliferative capacity in the three groups of women. Insulin-treated T2D pregnant women and women with GDM exhibited a low serum IL-10 level, without any change in the number of Treg cells. Conclusion. Our study showed that, despite insulin treatment, pregnant women with T2D displayed a proinflammatory status consistent with high proportions of CD3+ and CD4+ T cells, upregulation of Th1 cytokines, and low IL-10 production, suggesting a reduced immune-suppressive activity of regulatory T cells. However, GDM, although associated with proinflammatory status, has shown increased humoral immunity consistent with high proportion of CD19+ B cells. Thus, the lack of response to insulin in diabetes during pregnancy and clinical implications of these immunological parameters deserves further investigations.

IntroductionNeonatal sepsis outreaches all causes of neonatal mortality worldwide and remains a major societal burden in low and middle income countries. In addition to limited resources, endemic morbidities, such as malaria and prematurity, predispose neonates and infants to invasive infection by altering neonatal immune response to pathogens. Nevertheless, thoughtful epidemiological, diagnostic and immunological evaluation of neonatal sepsis and the impact of gestational malaria have never been performed.Methods and analysisA prospective longitudinal multicentre follow-up of 580 infants from birth to 3 months of age in urban and suburban Benin will be performed. At delivery, and every other week, all children will be examined and clinically evaluated for occurrence of sepsis. At delivery, cord blood systematic analysis of selected plasma and transcriptomic biomarkers (procalcitonin, interleukin (IL)-6, IL-10, IP10, CD74 and CX3CR1) associated with sepsis pathophysiology will be evaluated in all live births as well as during the follow-up, and when sepsis will be suspected. In addition, whole blood response to selected innate stimuli and extensive peripheral blood mononuclear cells phenotypic characterisation will be performed. Reference intervals specific to sub-Saharan neonates will be determined from this cohort and biomarkers performances for neonatal sepsis diagnosis and prognosis tested.Ethics and disseminationEthical approval has been obtained from the Comité d’Ethique de la Recherche – Institut des Sciences Biomédicales Appliquées (CER-ISBA 85 - 5 April 2016, extended on 3 February 2017). Results will be disseminated through international presentations at scientific meetings and publications in peer-reviewed journals.Trial registration numberClinicalTrials.gov registration number: NCT03780712.

Background In sub-Saharan Africa, malaria in the first half of pregnancy is harmful for both the mother and her fetus. However, malaria in the first trimester of pregnancy, when women are usually not protected against malaria, has been little investigated. For the first time, we assessed the effects of malaria in the first trimester on maternal and birth outcomes using a preconceptional study design. Methods From June 2014 to March 2017, 1214 women of reproductive age were recruited and followed monthly until 411 became pregnant. The pregnant women were then followed from 5–6 weeks of gestation until delivery. Path analysis was used to assess the direct effect (ie, not mediated by malaria in the second or third trimester) of malaria in the first trimester on maternal anemia and poor birth outcomes. The cumulative effect of infections during pregnancy on the same outcomes was also evaluated. Results The prevalence of malaria infections in the first trimester was 21.8%. Malaria in the first trimester was significantly associated with maternal anemia in the third trimester (adjusted odds ratio 2.25, 95% confidence interval 1.11–4.55). While we did not find evidence of any direct effect of first trimester malaria infections on birth outcomes, their association with infections later in pregnancy tended to increase the risk of low birth weights. Conclusions Malaria infections in the first trimester were highly prevalent and have deleterious effects on maternal anemia. They highlight the need for additional preventive measures, starting in early pregnancy or even before conception.

Background While malaria morbidity and mortality have declined since 2000, viral central nervous system infections appear to be an important, underestimated cause of coma in malaria-endemic Eastern Africa. We aimed to describe the etiology of non-traumatic comas in young children in Benin, as well as their management and early outcomes, and to identify factors associated with death. Methods From March to November 2018, we enrolled all HIV-negative children aged between 2 and 6 years, with a Blantyre Coma Score ≤ 2, in this prospective observational study. Children were screened for malaria severity signs and assessed using a systematic diagnostic protocol, including blood cultures, malaria diagnostics, and cerebrospinal fluid analysis using multiplex PCR. To determine factors associated with death, univariate and multivariate analyses were performed. Results From 3244 admissions, 84 children were included: malaria was diagnosed in 78, eight of whom had a viral or bacterial co-infection. Six children had a non-malarial infection or no identified cause. The mortality rate was 29.8% (25/84), with 20 children dying in the first 24 h. Co-infected children appeared to have a poorer prognosis. Of the 76 children who consulted a healthcare professional before admission, only 5 were prescribed adequate antimalarial oral therapy. Predictors of early death were jaundice or increased bilirubin [odd ratio (OR)= 8.6; 95% confidential interval (CI): 2.03–36.1] and lactate > 5 mmol/L (OR = 5.1; 95% CI: 1.49–17.30). Antibiotic use before admission (OR = 0.1; 95% CI: 0.02–0.85) and vaccination against yellow fever (OR = 0.2, 95% CI: 0.05–0.79) protected against mortality. Conclusions Infections were found in all children who died, and cerebral malaria was by far the most common cause of non-traumatic coma. Missed opportunities to receive early effective antimalarial treatment were common. Other central nervous system infections must be considered in their management. Some factors that proved to be protective against early death were unexpected.