Update of pre- and postnatal iron supplementation in malaria endemic settings.

This review focuses on pre- and post-natal iron supplementation in malaria endemic settings. Although iron supplementation can reduce iron deficiency, malaria infection may counteract this effect by the increase of hepcidin, and iron supplementation may further worsen malaria infection by providing additional iron for the parasites. However, most iron supplementation intervention studies in pregnant women with malaria have not shown a negative impact, although malaria treatment with iron supplementation may be beneficial in terms of improving birth outcomes. In infants and young children in malaria endemic settings, the adverse effects of iron supplementation has been well documented and malaria prevention and treatment with iron supplementation is recommended. Besides fostering the growth of malaria parasites, iron may also promote potential pathogens in the gut and cause an inflammatory response in young children. Overall, iron supplementation is beneficial for treating iron deficiency, but needs to be considered in the context of malaria prevention and treatment in pregnant women, infants and young children for safety and effectiveness.

Serum Micronutrients in Helminth-infected Pregnant Women and Children: Suggestions for Differential Supplementation During Anti-helminthic Treatment.

BACKGROUND: The prevalence of helminth infection, which is known to affect nutritional status of the host, varies with age. The complex interplay between ages, nutrient requirements, and infection necessitated the need to recommend micronutrient supplementation during helminth infection among different age groups. OBJECTIVE: The aim of this study was to determine the pattern of alteration in selected micronutrients in pregnant women and preschool- and school-aged children with helminth infection. METHODS: We screened 245 pregnant women and 349 children for helminth infection. Of these, 17 (6.9%) pregnant women and 102 (29.2%) children (42 preschool- and 60 school-aged) had helminth infection. Only Ascaris lumbricoides was found in pregnant women, whereas the children had A lumbricoides, hookworm, Fasciola hepatica, and Trichuris trichiura infections. The helminth-infected (HI) pregnant women, preschool-aged children, and school-aged children were matched with helminth-negative (HN) pregnant women (n = 21), preschool-aged children (n = 42), and school-aged children (n = 50) who served as controls. Venous blood samples were obtained and analyzed for iron (Fe), zinc (Zn), selenium (Se), and vitamins A and C. Statistical analysis was done using Student's t test, and P < 0.05 was considered statistically significant. FINDINGS: Serum levels of Fe, Zn, and Se were significantly lower in HI pregnant women than HN pregnant women. In preschool-aged children, serum levels of Fe, Zn, and vitamin A were significantly lower in the HI than in the HN group. Similarly, serum levels of Zn and vitamin A were significantly lower in HI school-aged children than in the HN group. However, serum levels of Se were significantly higher in HI children (both age groups) than in the corresponding HN group. CONCLUSION: Helminth infection alters different types of micronutrients in children and pregnant women. Results from the present study therefore suggest monitoring Fe, Zn, or vitamin A supplementation with an anti-helminthic regimen.

The association between malaria and iron status or supplementation in pregnancy: a systematic review and meta-analysis.

INTRODUCTION: Malaria prevention and iron supplementation are associated with improved maternal and infant outcomes. However, evidence from studies in children suggests iron may adversely modify the risk of malaria. We reviewed the evidence in pregnancy of the association between malaria and markers of iron status, iron supplementation or parenteral treatment. METHODS AND FINDINGS: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Global Health Library, and the Malaria in Pregnancy library to identify studies that investigated the association between iron status, iron treatment or supplementation during pregnancy and malaria. Thirty one studies contributed to the analysis; 3 experimental and 28 observational studies. Iron supplementation was not associated with an increased risk of P. falciparum malaria during pregnancy or delivery in Africa (summary Relative Risk = 0.89, 95% Confidence Interval (CI) 0.66-1.20, I(2) = 78.8%, 5 studies). One study in Asia reported an increased risk of P. vivax within 30 days of iron supplementation (e.g. adjusted Hazard Ratio = 1.75, 95% CI 1.14-2.70 for 1-15 days), but not after 60 days. Iron deficiency (based on ferritin and C-reactive protein) was associated with lower odds for malaria infection (summary Odds Ratio = 0.35, 0.24-0.51, I(2) = 59.2%, 5 studies). With the exception of the acute phase protein ferritin, biomarkers of iron deficiency were generally not associated with malaria infection. CONCLUSIONS: Iron supplementation was associated with a temporal increase in P vivax, but not with an increased risk of P. falciparum; however, data are insufficient to rule out the potential for an increased risk of P. falciparum. Iron deficiency was associated with a decreased malaria risk in pregnancy only when measured with ferritin. Until there is more evidence, it is prudent to provide iron in combination with malaria prevention during pregnancy.

Effectiveness of routine antihelminthic treatment on anaemia in pregnancy in Rufiji District, Tanzania: a cluster randomised controlled trial.

OBJECTIVE: The aim of this study was to estimate the effect of an antihelminthic drug, given at booking and at term to antenatal care visits, on the prevalence of anaemia at term and 4 months post-partum in Rufiji district, Tanzania, the area with high prevalence of intestinal parasites. METHODS: A cluster randomised controlled trial was conducted on 3080 pregnant women. Out of these 1475 (study arm) received albendazole and 1605 (control arm) placebo. All women also received routine daily iron folate supplements (36 mg iron and 5 mg folate), and sulphadoxine pyramethamine (SP) to prevent malaria. Haemoglobin levels were assessed at booking, at term and 4 months post-partum. RESULTS: At term, median and mean haemoglobin level and the prevalence of severe (< 70 g/l) and moderate (70-104 g/l) anaemia did not differ. The reduction in the prevalence of anaemia from booking to term, was significantly larger in the study arm compared to control arm (26.1% vs. 18.8%; p < 0.001). At four months postpartum, mean haemoglobin was higher in the study arm compared to the control arm (118 vs. 113; p < 0.0001) while the reduction in proportion of women with anaemia (Hb <105 g/dl) was significantly lower (30.6 vs. 21.2; p < 0.0001) in the study arm compared to the control arm. CONCLUSION: These findings support WHO's recommendation for anthelmintic treatment during pregnancy. However benefits for deworming may be limited in areas with an antenatal iron supplementation programme or low intensity of hookworm infections and hence future research should be directed towards the cost-effectiveness of the de-worming compared to other interventions for reducing anaemia in pregnancy.

Risks for preterm delivery and low birth weight are independently increased by severity of maternal anaemia.

OBJECTIVE: To estimate the effect of the severity of maternal anaemia on various perinatal outcomes. DESIGN: A cross-sectional study. SETTING: Labour Ward, Muhimbili National Hospital, Dar es Salaam, Tanzania. METHODS: The haemoglobin of eligible pregnant women admitted for delivery between 15 November 2002 and 15 February 2003 was measured. Data on socio-demographic characteristics, iron supplementation, malaria prophylaxis, blood transfusion during current pregnancy, and current and previous pregnancy outcomes were collected and analysed. Anaemia was classified according to the World Health Organization (WHO) standards: normal--Hb > or = 11.0 g/dl; mild--Hb 9.0-10.9 g/dl; moderate--Hb 7.0-8.9 g/dl; and severe--Hb < 7.0 g/dl. Logistic regression analysis was performed to estimate the severity of anaemia. The following outcome measures were used: preterm delivery (<37 weeks), Apgar score, stillbirth, early neonatal death, low birth weight (LBW) (<2500 g) and very low birth weight (VLBW) (<1500 g). RESULTS: A total of 1174 anaemic and 547 non-anaemic women were enrolled. Their median age was 24 years (range 14-46 years) and median parity was 2 (range 0-17). The prevalence of anaemia and severe anaemia was 68% and 5.8%, respectively. The risk of preterm delivery increased significantly with the severity of anaemia, with odds ratios of 1.4, 1.4 and 4.1 respectively for mild, moderate and severe anaemia. The corresponding risks for LBW and VLBW were 1.2 and 1.7, 3.8 and 1.5, and 1.9 and 4.2 respectively. CONCLUSION: The risks of preterm delivery and LBW increased in proportion to the severity of maternal anaemia.

Prenatal iron supplementation in rural Vietnam.

OBJECTIVE: To assess the potential impact of a national iron supplementation programme in rural Vietnam. METHODS: The study included questionnaires, focus group discussions of pregnant women and key informant interviews, together with measurements of haemoglobin (Hb) and a stool examination for soil-transmitted helminths. RESULTS: Iron supplementation significantly increased Hb concentration among participants in the second and third trimesters by 0.4 and 0.7 g/dl, respectively (P=0.017 and P<0.001). The risk of anaemia (Hb <10.0 g/dl) was increased significantly by hookworm infestation (P=0.041) and in summer season (P=0.001) and was decreased significantly by taking iron tablets (P=0.041). CONCLUSIONS: The results of this study show that an iron supplementation programme is beneficial as a part of a comprehensive anaemia programme for pregnant women in these communities. These results will be useful for developing improved iron-deficiency anaemia control programs for pregnant women.

A cohort study of haemoglobin and zinc protoporphyrin levels in term Zambian infants: effects of iron stores at birth, complementary food and placental malaria.

OBJECTIVE: To examine zinc-protoporphyrin (ZPP) and haemoglobin levels, and to determine predictors of iron deficiency anaemia (IDA) in Zambian infants. SUBJECTS AND METHODS: Ninety-one women and their normal birth weight (NBW) infants were followed bi-monthly during the first 6 months of life, and iron status, food intake, malaria parasitaemia and growth were monitored. At 4 months, the infants were divided into two groups, and the data were analysed according to whether or not they were exclusively breastfed. RESULTS: Almost two-third of infants were born with low iron stores as defined by ZPP levels, and this proportion increased with age. Over 50% had developed IDA by 6 months. Exclusive breastfeeding at 4 months could be a protective factor for IDA (odds ratio (OR): 0.2; 95% confidence interval (CI): 0.0-1.1). Exclusively breastfed infants had higher haemoglobin values at 4 and 6 months (mean difference 0.6; 95% CI: 0.1-1.2 g/dl and mean difference 0.9; 95% CI: 0.2-1.7 g/dl, respectively), compared with infants with early complementary feeding. In univariate analysis, past or chronic placental malaria appeared to be a predictor of IDA at 4 and 6 months, but the significance was lost in multivariate analysis. CONCLUSIONS: Zambian NBW infants are born with low iron stores and have a high risk to develop IDA in the first 6 months of life. Continuation of exclusive breastfeeding after 4 months is associated with a reduction of anaemia. The effect of placental malaria infection on increased risk of infant IDA could not be proven.

Pharmacokinetics of dihydroartemisinin following oral artesunate treatment of pregnant women with acute uncomplicated falciparum malaria.

OBJECTIVE: To determine the pharmacokinetic properties of dihydroartemisinin (DHA) following oral artesunate treatment in women with recrudescent multi-drug resistant falciparum malaria, in the second and third trimesters of pregnancy. METHODS: Serial plasma concentrations of artesunate and DHA were measured in 24 women after the final dose of a 3 day treatment with artesunate (4 mg kg(-1) day(-1)) and atovaquone (20 mg kg(-1) day(-1)) plus proguanil (8 mg kg(-1) day(-1)), daily. Conventional non-compartmental modelling and a population one-compartment pharmacokinetic model were applied to the data. RESULTS: Artesunate was very rapidly eliminated. For DHA the median [90% range] estimate of oral clearance (CI/F) was 4.0 [0.8-20.7] l hour(-1) kg(-1), total apparent volume of distribution (Vd/f) was 3.4 [0.9-60.7] l/kg, and terminal elimination half-life was 1.0 [0.6-2.4] h. CONCLUSION: The kinetics of DHA are modified by pregnancy. The plasma levels of the active antimalarial metabolite DHA are lower than reported previously in non-pregnant adults. Dose-optimisation studies in pregnant women are needed.

Haematinic treatment of anaemia increases the risk of Plasmodium vivax malaria in pregnancy.

Nutritional deficiency and malaria are 2 major causes of anaemia during pregnancy in tropical areas. The relationship between anaemia, its treatment with iron and folate, and malaria was studied in a prospective cohort of 2112 pregnant Karen women on the north-western border of Thailand between 1993 and 1997. The development of Plasmodium vivax malaria was associated with a past mean haematocrit > 30% (hazard ratio = 1.5, 95% CI 1.2-2, P = 0.001) and recent (< or = 30 d) iron and folate supplementation (hazard ratio = 1.7, 95% CI 1.1-2.6, P = 0.01). There were no associations with P. falciparum infections. Plasmodium vivax has a predilection for young erythrocytes, and these results suggest that pregnant women with larger numbers of circulating young red cells are at greater risk of developing P. vivax malaria. In P. vivax-endemic areas, systematic iron and folate supplementation confers both benefit and risk in pregnancy.

Albendazole therapy and reduced decline in haemoglobin concentration during pregnancy (Sierra Leone).

WHO recommends that anthelmintic treatment be included in strategies to improve maternal nutrition in areas where hookworms are endemic and anaemia is prevalent. At present, few countries have adopted this recommendation, partly owing to the lack of data to support the adverse effects of hookworms on maternal health. A longitudinal study was conducted on 125 women in Sierra Leone (in 1995/96) to measure the impact of single-dose albendazole (400 mg) and daily iron-folate supplements (36 mg iron and 5 mg folate) on haemoglobin and serum ferritin concentration during pregnancy. Women who received both albendazole and iron-folate supplements experienced no significant change (P > 0.05) in the prevalence of anaemia and iron-deficiency anaemia between the first and third trimesters. These prevalence levels significantly increased (P < 0.05) in women who received either albendazole or iron-folate supplements or neither. After controlling for baseline haemoglobin concentration and season, the mean decline in haemoglobin concentration between the first and third trimester in women who received albendazole was 6.6 g/L less than in women who received the control (P = 0.0034). The corresponding value for iron-folate supplements was 13.7 g/L haemoglobin (P < 0.001). The effects of albendazole and iron-folate supplements were additive. These findings lend support to WHO's recommendation for anthelmintic treatment during pregnancy.

Chloroquine prophylaxis, iron-folic acid supplementation or case management of malaria attacks in primigravidae in western Uganda: effects on maternal parasitaemia and haemoglobin levels and on birthweight.

The effects of weekly chloroquine prophylaxis, daily iron-weekly folic acid supplementation or passive case management on maternal haemoglobin and parasitaemia and on birthweight were examined in primigravidae in a randomized, double-blind placebo-controlled intervention trial in 1996-98 in Hoima District, western Uganda. Iron-folic acid supplementation significantly increased mean birthweight as compared to case management (P = 0.03). Low birthweight (< 2.5 kg) occurred in 2% of babies of women receiving chloroquine prophylaxis for > or = 8 weeks and in 9% in the case management group (RR = 0.36, 95% CI 0.13-1.00, P = 0.009). Parasitaemia at enrolment significantly correlated with low birthweight in the case management group as compared to the intervention groups (P = 0.02). Women in the case management group who were parasitaemia and had haemoglobin levels < 100 g/L at delivery had babies with lower mean birthweight as compared to babies in the other groups (P = 0.04). Low haemoglobin level at enrolment, irrespective of parasitaemia status, was a predictor of low birthweight in the case management group only (P = 0.04). Chloroquine prophylaxis and iron-folic acid supplementation significantly increased maternal haemoglobin levels during pregnancy as compared to case management (P = 0.01 and 0.007, respectively) and the increase correlated to the duration of the intervention.

Malaria in pregnancy and its consequences for the infant in rural Malawi.

Maternal malaria and anaemia, pregnancy and infant outcomes are reviewed among a cohort of mothers and their babies living in Chikwawa district, southern Malawi. Overall, 4104 women were screened at first antenatal visit and 1523 at delivery. Factors independently associated with moderately severe anaemia (MSA; < 8 g haemoglobin/dl) in primigravidae were malaria (relative risk = 1.9; 95% confidence interval = 1.6-2.3) and iron deficiency (relative risk = 4.2; 95% confidence interval = 3.5-5.0). Only iron deficiency was associated with MSA in multigravidae. After controlling for antimalarial use, parasitaemia was observed in 56.3% of the HIV-infected primigravidae and 36.5% of the non-infected (P = 0.04). The corresponding figures for multigravidae were 23.8% and 11.0%, respectively (P = 0.002). Over 33% of the infants born alive to primigravidae were of low birthweight (LBW; < 2500 g), and 23.3% of all newborns had foetal anaemia (< 12.5 g haemoglobin/dl cord blood). LBW was significantly associated in primigravidae with pre-term delivery, placental malaria and frequency of treatment with sulfadoxine-pyrimethamine (SP), and in multigravidae with pre-term delivery, adolescence, short stature and MSA. LBW was significantly reduced with a second SP treatment in primigravidae, and with iron-folate supplementation in multigravidae. Mean haemoglobin concentrations were significantly lower in the infant who had been LBW babies than in the others, and significantly associated with parity, peripheral parasitaemia at delivery and placental malaria. At 1 year post-delivery, life status was known for 364 (80.7%) of the 451 infants enrolled in the follow-up study. Independent risk factors for post-neonatal mortality were maternal HIV infection, LBW, and iron deficiency at delivery. This study identifies priorities for improving the health of pregnant women and their babies in this rural area of Malawi.

Anaemia in pregnant women in eastern Caprivi, Namibia.

OBJECTIVE: To describe the prevalence, character and possible aetiology of anaemia in the study region. DESIGN: A cross-sectional study involving a lifestyle and dietary questionnaire, a clinical examination and an analysis of blood and stool samples. SETTING: Katima Mulilo antenatal clinic, East Caprivi, Namibia. SUBJECTS: 171 pregnant women attending the clinic in September 1995. MAIN OUTCOME MEASURES: Effects on haemoglobin concentration of age, trimester, parity, residential area, sociodemographic factors, malaria, parasites, geophagy, diet, cooking pot used, vitamin and mineral supplementation and malaria prophylaxis. RESULTS: 41.5% of the women were found to be anaemic (haemoglobin < 11 g/dl) and there was a significant risk of their being iron-deficient (P = 0.01). Three maternal characteristics were found to have a significant effect on a woman's risk of anaemia: urban residence (P < 0.05), geophagy (P < 0.01) and the taking of prophylactic chloroquine (P < 0.05). CONCLUSION: Mild anaemia affects a large proportion of the pregnant women in East Caprivi; severe anaemia (< 7 g/dl) is not common. The picture is predominantly one of iron deficiency, possibly complicated by concomitant folate deficiency. There is no single easily identifiable cause of this anaemia; it appears to have a multifactorial aetiology. Further studies on the effect of the current malaria prophylaxis programme are warranted.

Effects of weekly iron supplementation on pregnant Indonesian women are similar to those of daily supplementation.

The effect of daily rather than weekly iron supplementation was compared in women who were 8-24 wk pregnant. One group (n = 68) received 60 mg Fe/d, the second group (n = 71) received 120 mg Fe/wk, given at once. Supplementation lasted 11.3 wk on average, depending on gestational date at entry, and was not supervised. Hemoglobin increased in both groups (P < 0.001); serum ferritin did not change significantly. There was no significant difference between groups for changes in hemoglobin and serum ferritin. In a subgroup of women with a hemoglobin concentration < 110 g/L at baseline (n = 45 daily; n = 54 weekly) no significant within-group changes occurred in serum ferritin, but the change in the daily group was 4.1 micrograms/L higher than in the weekly group (P = 0.049). Compliance, as indicated by two positive stool tests, was approximately equal to 54.3% in the daily group and 62.2% in the weekly group. We conclude that for the complete sample of subjects, the treatment effect of daily compared with weekly supplementation was similar under conditions resembling a normal antenatal care program.

The response to iron supplementation of pregnant women with the haemoglobin genotype AA or AS.

The influence of haemoglobin genotype on the response to iron supplementation was studied in a randomized, double blind, placebo-controlled trial involving 497 multigravid pregnant women from a rural area of The Gambia. Women were randomly allocated to receive either oral iron (60mg elemental iron per day) or placebo. At 36 weeks of pregnancy, women who had received oral iron during pregnancy had higher mean haemoglobin, packed cell volume, plasma iron and ferritin levels than did women who received placebo. Iron supplementation of pregnant women with the AA haemoglobin genotype also resulted in increases in the packed cell volume (PCV) and haemoglobin level measured after delivery, and in the birth weight of the infant. However, in AS women PCV and haemoglobin level at delivery were lower in the supplemented group and supplementation was also associated with reduced birth weights. In malaria endemic areas, pregnant women with the haemoglobin genotype AS may not benefit from iron supplementation during pregnancy.

The effects of iron supplementation during pregnancy, given by traditional birth attendants, on the prevalence of anaemia and malaria.

A randomized, double-blind, placebo-controlled community-based trial of oral iron supplementation (200 mg ferrous sulphate daily) administered to multigravid pregnant women by traditional birth attendants (TBAs) was carried out in a rural area of The Gambia. Iron supplementation led to a significant reduction in the prevalence of anaemia and of iron deficiency. Iron supplementation was not accompanied by increased susceptibility to malaria infection; there was no difference in the prevalence and severity of peripheral blood or placental malaria infection between the 2 groups of women. The birth weight of children born to women who received iron prophylaxis was increased by an average of 56 g. It is concluded that oral iron prophylaxis can be successfully delivered through TBAs integrated into a primary health care programme. This simple intervention can produce significant beneficial effects on the health of the mother without inducing increased susceptibility to malaria and has the potential for reducing perinatal mortality by increasing birth weight.

The contribution of Gambian traditional birth attendants to field research.

One thousand, one hundred and forty-seven pregnant women from a rural area of The Gambia were followed throughout pregnancy. In order to determine the incidence of malaria infection of the placenta, traditional birth attendants (TBAs) from 18 villages were trained to collect placental biopsies and to prepare thick smears of placental blood at delivery. Nine hundred and eighty-eight of 1112 term deliveries (89%) occurred at home. Eight hundred and fifty-nine (87%) of these home deliveries were assisted by a TBA. TBAs collected 829 placental biopsies and 800 thick blood smears from the 859 women whom they assisted. Seven hundred and forty-seven thick blood films (93%) and 807 placental samples (97%) were satisfactory. TBAs are an important resource for clinical research; in this case they made a major contribution to a community study of the impact of malaria on pregnancy.