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Excess risk of preterm birth with periconceptional iron supplementation in a malaria endemic area: analysis of secondary data on birth outcomes in a double blind randomized controlled safety trial in Burkina Faso.

ABSTRACT: BACKGROUND:Iron supplementation before a first pregnancy may improve the future health of mother and baby by reducing maternal anaemia. Iron supplementation could, however, increase malaria infections, notably in primigravidae who are most susceptible. The pathogenicity of other iron-utilizing pathogens could also increase, causing inflammation leading to increased risk of adverse birth outcomes. This paper reports pre-specified secondary birth outcomes from a safety trial in Burkina Faso in an area of high malaria endemicity. Primary outcomes from that trial had investigated effects of long-term weekly iron supplementation on malaria and genital tract infections in non-pregnant and pregnant women. METHODS:A double-blind, randomized controlled trial. Nulliparous, mainly adolescent women, were individually randomized periconceptionally to receive weekly either 60 mg elemental iron and 2.8 mg folic acid, or 2.8 mg folic acid alone, continuing up to the first antenatal visit for those becoming pregnant. Secondary outcomes were ultrasound-dated gestational age, fetal growth, placental malaria, chorioamnionitis and iron biomarkers. Seasonal effects were assessed. Analysis was by intention to treat. RESULTS:478 pregnancies occurred to 1959 women: 258/980 women assigned iron and folic acid and 220/979 women assigned folic acid alone. Malaria prevalence at the first antenatal visit was 53% (iron) and 55% (controls). Mean birthweight was 111 g lower in the iron group (95% CI 9:213 g, P?=?0.033). Mean gestational ages were 264 days (iron) and 269 days (controls) (P?=?0.012), with 27.5% under 37 weeks compared to 13.9% in controls (adjRR?=?2.22; 95% CI 1.39-3.61) P??5 mg/l was more common prior to births?

SUBMITTER: Brabin B

PROVIDER: S-EPMC6501288 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Excess risk of preterm birth with periconceptional iron supplementation in a malaria endemic area: analysis of secondary data on birth outcomes in a double blind randomized controlled safety trial in Burkina Faso.

Brabin Bernard B Gies Sabine S Roberts Stephen A SA Diallo Salou S Lompo Olga M OM Kazienga Adama A Brabin Loretta L Ouedraogo Sayouba S Tinto Halidou H

Malaria journal 20190506 1

<h4>Background</h4>Iron supplementation before a first pregnancy may improve the future health of mother and baby by reducing maternal anaemia. Iron supplementation could, however, increase malaria infections, notably in primigravidae who are most susceptible. The pathogenicity of other iron-utilizing pathogens could also increase, causing inflammation leading to increased risk of adverse birth outcomes. This paper reports pre-specified secondary birth outcomes from a safety trial in Burkina Fas ...[more]

PMID: 31060615

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Project description:BACKGROUND:In view of recent evidence from a randomized trial in Burkina Faso that periconceptional iron supplementation substantially increases risk of spontaneous preterm birth (<?37 weeks) in first pregnancies (adjusted relative risk?=?2.22; 95% CI 1.39-3.61), explanation is required to understand potential mechanisms, including progesterone mediated responses, linking long-term iron supplementation, malaria and gestational age. METHODS:The analysis developed a model based on a dual hit inflammatory mechanism arising from simultaneous malaria and gut infections, supported in part by published trial results. This model is developed to understand mechanisms linking iron supplementation, malaria and gestational age. Background literature substantiates synergistic inflammatory effects of these infections where trial data is unavailable. A path modelling exercise assessed direct and indirect paths influencing preterm birth and gestation length. RESULTS:A dual hit hypothesis incorporates two main pathways for pro-inflammatory mechanisms, which in this model, interact to increase hepcidin expression. Trial data showed preterm birth was positively associated with C-reactive protein (P?=?0.0038) an inflammatory biomarker. The malaria pathway upregulates C-reactive protein and serum hepcidin, thereby reducing iron absorption. The enteric pathway results from unabsorbed gut iron, which induces microbiome changes and pathogenic gut infections, initiating pro-inflammatory events with lipopolysaccharide expression. Data from the trial suggest that raised hepcidin concentration is a mediating catalyst, being inversely associated with shorter gestational age at delivery (P?=?0.002) and positively with preterm incidence (P?=?0.007). A segmented regression model identified a change-point consisting of two segments before and after a sharp rise in hepcidin concentration. This showed a post change hepcidin elevation in women with increasing C-reactive protein values in late gestation (post-change slope 0.55. 95% CI 0.39-0.92, P?<?0.001). Path modelling confirmed seasonal malaria effects on preterm birth, with mediation through C-reactive protein and (non-linear) hepcidin induction. CONCLUSIONS:Following long-term iron supplementation, dual inflammatory pathways that mediate hepcidin expression and culminate in progesterone withdrawal may account for the reduction in gestational age observed in first pregnancies in this area of high malaria exposure. If correct, this model strongly suggests that in such areas, effective infection control is required prior to iron supplementation to avoid increasing preterm births. Trial registration NCT01210040. Registered with Clinicaltrials.gov on 27th September 2010.

Project description:BackgroundProviding balanced energy-protein (BEP) supplements is a promising intervention to improve birth outcomes in low- and middle-income countries (LMICs); however, evidence is limited. We aimed to assess the efficacy of fortified BEP supplementation during pregnancy to improve birth outcomes, as compared to iron-folic acid (IFA) tablets, the standard of care.Methods and findingsWe conducted an individually randomized controlled efficacy trial (MIcronutriments pour la SAnté de la Mère et de l'Enfant [MISAME]-III) in 6 health center catchment areas in rural Burkina Faso. Pregnant women, aged 15 to 40 years with gestational age (GA) <21 completed weeks, were randomly assigned to receive either fortified BEP supplements and IFA (intervention) or IFA (control). Supplements were provided during home visits, and intake was supervised on a daily basis by trained village-based project workers. The primary outcome was prevalence of small-for-gestational age (SGA) and secondary outcomes included large-for-gestational age (LGA), low birth weight (LBW), preterm birth (PTB), gestational duration, birth weight, birth length, Rohrer's ponderal index, head circumference, thoracic circumference, arm circumference, fetal loss, and stillbirth. Statistical analyses followed the intention-to-treat (ITT) principle. From October 2019 to December 2020, 1,897 pregnant women were randomized (960 control and 937 intervention). The last child was born in August 2021, and birth anthropometry was analyzed from 1,708 pregnancies (872 control and 836 intervention). A total of 22 women were lost to follow-up in the control group and 27 women in the intervention group. BEP supplementation led to a mean 3.1 percentage points (pp) reduction in SGA with a 95% confidence interval (CI) of -7.39 to 1.16 (P = 0.151), indicating a wide range of plausible true treatment efficacy. Adjusting for prognostic factors of SGA, and conducting complete cases (1,659/1,708, 97%) and per-protocol analysis among women with an observed BEP adherence ≥75% (1,481/1,708, 87%), did not change the results. The intervention significantly improved the duration of gestation (+0.20 weeks, 95% CI 0.05 to 0.36, P = 0.010), birth weight (50.1 g, 8.11 to 92.0, P = 0.019), birth length (0.20 cm, 0.01 to 0.40, P = 0.044), thoracic circumference (0.20 cm, 0.04 to 0.37, P = 0.016), arm circumference (0.86 mm, 0.11 to 1.62, P = 0.025), and decreased LBW prevalence (-3.95 pp, -6.83 to -1.06, P = 0.007) as secondary outcomes measures. No differences in serious adverse events [SAEs; fetal loss (21 control and 26 intervention) and stillbirth (16 control and 17 intervention)] between the study groups were found. Key limitations are the nonblinded administration of supplements and the lack of information on other prognostic factors (e.g., infection, inflammation, stress, and physical activity) to determine to which extent these might have influenced the effect on nutrient availability and birth outcomes.ConclusionsThe MISAME-III trial did not provide evidence that fortified BEP supplementation is efficacious in reducing SGA prevalence. However, the intervention had a small positive effect on other birth outcomes. Additional maternal and biochemical outcomes need to be investigated to provide further evidence on the overall clinical relevance of BEP supplementation.Trial registrationClinicalTrials.gov NCT03533712.

Project description:In Burkina Faso, onchocerciasis was no longer a public health problem when the WHO Onchocerciasis Control Programme in West Africa closed at the end in 2002. However, epidemiological surveillance carried out from November 2010 to February of 2011, showed a recrudescence of infection in the Cascades Region. This finding was made at a time when ivermectin, a drug recommended for the treatment of both onchocerciasis and lymphatic filariasis, had been distributed in this area since 2004 for the elimination of lymphatic filariasis. It was surprising that ivermectin distributed for treating lymphatic filariasis had not prevented the recrudescence of onchocerciasis. Faced with this situation, the aim of our study was to evaluate the effectiveness of ivermectin on the onchocerciasis parasite. The percentage reduction in microfilarial load after treatment with ivermectin was used as a proxy measure for assessing possible resistance. A cohort study was carried out with 130 individuals who had tested positive for microfilariae of Onchocerca volvulus in 2010 using microscopic examination of skin-snip biopsies from five endemic villages. Subjects were followed from July 2011 to June 2012. The microfilarial load of each individual was enumerated by skin-snip biopsy in 2010, prior to the first ivermectin treatment against onchocerciasis under community guidelines. All individuals received two ivermectin treatments six months apart. In 2012, the microfilarial loads were determined again, six months after the second round of ivermectin and the reductions in parasite loads were calculated to measure the impact of the drug. The percentage reduction of the microfilarial loads ranged from 87% to 98% in the villages. In all villages, there was a statistically significant difference between the average microfilarial loads in 2010 and 2012. The level of reduction of microfilarial loads suggests that ivermectin is effective against the recrudescent population of O. volvulus in Cascades Region of Burkina Faso. Further investigations would be necessary to determine the causes of the recrudescence of onchocerciasis. (For French language abstract, see S1 Alternative Language Abstract-Translation of the Abstract into French by the authors.).

Project description:BackgroundIt has been reported that neural tube defects can be prevented with periconceptional folic acid supplementation. The effects of different doses, forms and schemes of folate supplementation for the prevention of other birth defects and maternal and infant outcomes are unclear.ObjectivesThis review updates and expands a previous Cochrane Review assessing the effects of periconceptional supplementation with folic acid to reduce neural tube defects (NTDs). We examined whether folate supplementation before and during early pregnancy can reduce neural tube and other birth defects (including cleft palate) without causing adverse outcomes for mothers or babies.Search strategyWe searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2010). Additionally, we searched the international clinical trials registry platform and contacted relevant organisations to identify ongoing and unpublished studies.Selection criteriaWe included all randomised or quasi-randomised trials evaluating the effect of periconceptional folate supplementation alone, or in combination with other vitamins and minerals, in women independent of age and parity.Data collection and analysisWe assessed trials for methodological quality using the standard Cochrane criteria. Two authors independently assessed the trials for inclusion, one author extracted data and a second checked for accuracy.Main resultsFive trials involving 6105 women (1949 with a history of a pregnancy affected by a NTD and 4156 with no history of NTDs) were included. Overall, the results are consistent in showing a protective effect of daily folic acid supplementation (alone or in combination with other vitamins and minerals) in preventing NTDs compared with no interventions/placebo or vitamins and minerals without folic acid (risk ratio (RR) 0.28, 95% confidence interval (CI) 0.15 to 0.52). Only one study assessed the incidence of NTDs and the effect was not statistically significant (RR 0.08, 95% CI 0.00 to 1.33) although no events were found in the group that received folic acid. Folic acid had a significant protective effect for reoccurrence (RR 0.32, 95% CI 0.17 to 0.60). There is no statistically significant evidence of any effects on prevention of cleft palate, cleft lip, congenital cardiovascular defects, miscarriages or any other birth defects. There were no included trials assessing the effects of this intervention on maternal blood folate or anaemia at term.We found no evidence of short-term side effects.Authors' conclusionsFolic acid, alone or in combination with vitamins and minerals, prevents NTDs but does not have a clear effect on other birth defects.

Project description:BackgroundNew hemocytometric parameters can be used to differentiate causes of acute febrile illness (AFI). We evaluated a software algorithm-Infection Manager System (IMS)-which uses hemocytometric data generated by Sysmex hematology analyzers, for its accuracy to detect bacteremia in AFI patients with and without malaria in Burkina Faso. Secondary aims included comparing the accuracy of IMS with C-reactive protein (CRP) and procalcitonin (PCT).MethodsIn a prospective observational study, patients of ≥ three-month-old (range 3 months- 90 years) presenting with AFI were enrolled. IMS, blood culture and malaria diagnostics were done upon inclusion and additional diagnostics on clinical indication. CRP, PCT, viral multiplex PCR on nasopharyngeal swabs and bacterial- and malaria PCR were batch-tested retrospectively. Diagnostic classification was done retrospectively using all available data except IMS, CRP and PCT results.FindingsA diagnosis was affirmed in 549/914 (60.1%) patients and included malaria (n = 191) bacteremia (n = 69), viral infections (n = 145), and malaria-bacteremia co-infections (n = 47). The overall sensitivity, specificity, and negative predictive value (NPV) of IMS for detection of bacteremia in patients of ≥ 5 years were 97.0% (95% CI: 89.8-99.6), 68.2% (95% CI: 55.6-79.1) and 95.7% (95% CI: 85.5-99.5) respectively, compared to 93.9% (95% CI: 85.2-98.3), 39.4% (95% CI: 27.6-52.2), and 86.7% (95% CI: 69.3-96.2) for CRP at ≥20mg/L. The sensitivity, specificity and NPV of PCT at 0.5 ng/ml were lower at respectively 72.7% (95% CI: 60.4-83.0), 50.0% (95% CI: 37.4-62.6) and 64.7% (95% CI: 50.1-77.6) The diagnostic accuracy of IMS was lower among malaria cases and patients <5 years but remained equal to- or higher than the accuracy of CRP.InterpretationIMS is a new diagnostic tool to differentiate causes of AFI. Its high NPV for bacteremia has the potential to improve antibiotic dispensing practices in healthcare facilities with hematology analyzers. Future studies are needed to evaluate whether IMS, combined with malaria diagnostics, may be used to rationalize antimicrobial prescription in malaria endemic areas.Trial registrationClinicalTrials.gov (NCT02669823) https://clinicaltrials.gov/ct2/show/NCT02669823.

Project description:Provision of routine iron supplements to prevent anaemia could increase the risk for lower genital tract infections as virulence of some pathogens depends on iron availability. This trial in Burkina Faso assessed whether weekly periconceptional iron supplementation increased the risk of lower genital tract infection in young non-pregnant and pregnant women.Genital tract infections were assessed within a double blind, controlled, non-inferiority trial of malaria risk among nulliparous women, randomised to receive either iron and folic acid or folic acid alone, weekly, under direct observation for 18 months. Women conceiving during this period entered the pregnancy cohort. End assessment (FIN) for women remaining non-pregnant was at 18 months. For the pregnancy cohort, end assessment was at the first scheduled antenatal visit (ANC1). Infection markers included Nugent scores for abnormal flora and bacterial vaginosis (BV), T. vaginalis PCR, vaginal microbiota, reported signs and symptoms, and antibiotic and anti-fungal prescriptions. Iron biomarkers were assessed at baseline, FIN and ANC1. Analysis compared outcomes by intention to treat and in iron replete/deficient categories.A total of 1954 women (mean 16.8 years) were followed and 478 (24.5%) became pregnant. Median supplement adherence was 79% (IQR 59-90%). Baseline BV prevalence was 12.3%. At FIN and ANC1 prevalence was 12.8% and 7.0%, respectively (P?<?0.011). T. vaginalis prevalence was 4.9% at FIN and 12.9% at ANC1 (P?<?0.001). BV and T. vaginalis prevalence and microbiota profiles did not differ at trial end-points. Iron-supplemented non-pregnant women received more antibiotic treatments for non-genital infections (P?=?0.014; mainly gastrointestinal infections (P?=?0.005), anti-fungal treatments for genital infections (P?=?0.014) and analgesics (P?=?0.008). Weekly iron did not significantly reduce iron deficiency prevalence. At baseline, iron-deficient women were more likely to have normal vaginal flora (P?=?0.016).Periconceptional weekly iron supplementation of young women did not increase the risk of lower genital tract infections but did increase general morbidity in the non-pregnant cohort. Unabsorbed gut iron due to malaria could induce enteric infections, accounting for the increased administration of antibiotics and antifungals in the iron-supplemented arm. This finding reinforces concerns about routine iron supplementation in highly malarious areas.Trial registration number NCT01210040 . Registered with Clinicaltrials.gov on 27 September 2010.

Project description:BackgroundWith limited resources and spatio-temporal heterogeneity of malaria in developing countries, it is still difficult to assess the real impact of socioeconomic and environmental factors in order to set up targeted campaigns against malaria at an accurate scale. Our goal was to detect malaria hotspots in rural area and assess the extent to which household socioeconomic status and meteorological recordings may explain the occurrence and evolution of these hotspots.MethodsData on malaria cases from 2010 to 2014 and on socioeconomic and meteorological factors were acquired from four health facilities within the Nanoro demographic surveillance area. Statistical cross correlation was used to quantify the temporal association between weekly malaria incidence and meteorological factors. Local spatial autocorrelation analysis was performed and restricted to each transmission period using Kulldorff's elliptic spatial scan statistic. Univariate and multivariable analysis were used to assess the principal socioeconomic and meteorological determinants of malaria hotspots using a Generalized Estimating Equation (GEE) approach.ResultsRainfall and temperature were positively and significantly associated with malaria incidence, with a lag time of 9 and 14 weeks, respectively. Spatial analysis showed a spatial autocorrelation of malaria incidence and significant hotspots which was relatively stable throughout the study period. Furthermore, low socioeconomic status households were strongly associated with malaria hotspots (aOR = 1.21, 95% confidence interval: 1.03-1.40).ConclusionThese fine-scale findings highlight a relatively stable spatio-temporal pattern of malaria risk and indicate that social and environmental factors play an important role in malaria incidence. Integrating data on these factors into existing malaria struggle tools would help in the development of sustainable bottleneck strategies adapted to the local context for malaria control.

Dataset Information

Excess risk of preterm birth with periconceptional iron supplementation in a malaria endemic area: analysis of secondary data on birth outcomes in a double blind randomized controlled safety trial in Burkina Faso.

Publications

Excess risk of preterm birth with periconceptional iron supplementation in a malaria endemic area: analysis of secondary data on birth outcomes in a double blind randomized controlled safety trial in Burkina Faso.

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