Iron from nanostructured ferric phosphate: absorption and biodistribution in mice and bioavailability in iron deficient anemic women.

Food fortification with iron nanoparticles (NPs) could help prevent iron deficiency anemia, but the absorption pathway and biodistribution of iron-NPs and their bioavailability in humans is unclear. Dietary non-heme iron is physiologically absorbed via the divalent metal transporter-1 (DMT1) pathway. Using radio- iron isotope labelling in mice with a partial knockdown of intestine-specific DMT1, we assessed oral absorption and tissue biodistribution of nanostructured ferric phosphate (FePO4-NP; specific surface area [SSA] 98 m2g-1) compared to to ferrous sulfate (FeSO4), the reference compound. We show that absorption of iron from FePO4-NP appears to be largely DMT1 dependent and that its biodistribution after absorption is similar to that from FeSO4, without abnormal deposition of iron in the reticuloendothelial system. Furthermore, we demonstrate high bioavailability from iron NPs in iron deficient anemic women in a randomized, cross-over study using stable-isotope labelling: absorption and subsequent erythrocyte iron utilization from two 57Fe-labeled FePO4-NP with SSAs of 98 m2g-1 and 188 m2g-1 was 2.8-fold and 5.4-fold higher than from bulk FePO4 with an SSA of 25 m2g-1 (P < 0.001) when added to a rice and vegetable meal consumed by iron deficient anemic women. The FePO4-NP 188 m2g-1 achieved 72% relative bioavailability compared to FeSO4. These data suggest FePO4-NPs may be useful for nutritional applications.

Maternal iron kinetics and maternal-fetal iron transfer in normal-weight and overweight pregnancy.

BACKGROUND: Inflammation during pregnancy may aggravate iron deficiency (ID) by increasing serum hepcidin and reducing iron absorption. This could restrict iron transfer to the fetus, increasing risk of infant ID and its adverse effects. OBJECTIVES: We aimed to assess whether iron bioavailability and/or iron transfer to the fetus is impaired in overweight/obese (OW) pregnant women with adiposity-related inflammation, compared with normal-weight (NW) pregnant women. METHODS: In this prospective study, we followed NW (n = 43) and OW (n = 40) pregnant women who were receiving iron supplements from the 14th week of gestation to term and followed their infants to age 6 mo. We administered 57Fe and 58Fe in test meals mid-second and mid-third trimester, and measured tracer kinetics throughout pregnancy and infancy. RESULTS: In total, 38 NW and 36 OW women completed the study to pregnancy week 36, whereas 30 NW and 27 OW mother-infant pairs completed the study to 6 mo postpartum. Both groups had comparable iron status, hemoglobin, and serum hepcidin throughout pregnancy. Compared with the NW, the OW pregnant women had 1) 43% lower fractional iron absorption (FIA) in the third trimester (P = 0.033) with median [IQR] FIA of 23.9% [11.4%-35.7%] and 13.5% [10.8%-19.5%], respectively; and 2) 17% lower maternal-fetal iron transfer from the first tracer (P = 0.051) with median [IQR] maternal-fetal iron transfer of 4.8% [4.2%-5.4%] and 4.0% [3.6%-4.6%], respectively. Compared with the infants born to NW women, infants born to OW women had lower body iron stores (BIS) with median [IQR] 7.7 [6.3-8.8] and 6.6 [4.6-9.2] mg/kg body weight at age 6 mo, respectively (P = 0.024). Prepregnancy BMI was a negative predictor of maternal-fetal iron transfer (ß = -0.339, SE = 0.144, P = 0.025) and infant BIS (ß = -0.237, SE = 0.026, P = 0.001). CONCLUSIONS: Compared with NW, OW pregnant women failed to upregulate iron absorption in late pregnancy, transferred less iron to their fetus, and their infants had lower BIS. These impairments were associated with inflammation independently of serum hepcidin.This trial was registered at clinicaltrials.gov as NCT02747316.

Iodine Supplementation in Mildly Iodine-Deficient Pregnant Women Does Not Improve Maternal Thyroid Function or Child Development: A Secondary Analysis of a Randomized Controlled Trial.

Background: Iodine deficiency during pregnancy may be associated with lower offspring IQ, but there are few data on the safety and efficacy of maternal iodine supplementation on child development. In a previously reported multi-center randomized trial conducted in Thailand and India, we assessed the effect of iodine supplementation in mildly iodine-deficient pregnant women on offspring development. In this secondary analysis of that trial, we report data only from the Thai pregnant women in the study, who were more iodine deficient at entry. Methods: Pregnant women in Bangkok, Thailand, were randomized to receive daily 200 µg oral iodine or placebo until delivery. We assessed thyroid size and thyroid function during pregnancy and cognitive and motor development at ages 1, 2, and 5.7 years. The trial was registered at www.clinicaltrials.gov/NCT00791466. Findings: Women (n = 514) entered the trial between November 2008 and March 2011 at a mean ± SD gestational age of 11 ± 2.8 weeks; their median (IQR) UIC was 112 (75, 170) µg/L. Mean compliance with supplementation was 88%. We assessed 397 mothers in the 3rd trimester, 231 infants at age 2 y, and 157 children at mean age 5.7 y. During pregnancy, there was a slightly greater decrease in free and total thyroxine concentrations in the iodine group (p < 0.05). At age 2 years, the iodine group had borderline lower scores for combined fine and gross motor function (p = 0.05), but there were no other significant differences in development. At 5.7 years, there were no significant group differences in child development. Conclusion: Daily iodine supplementation in mildly iodine deficient pregnant women was associated with small negative effects on maternal thyroxine concentrations, but did not affect child development. The safety and efficacy of iodine supplementation in mildly-iodine deficient pregnant women needs to be evaluated further in large randomized controlled trials.

Effect of iodine supplementation in pregnant women on child neurodevelopment: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Iodine deficiency during pregnancy might be associated with reduced intelligence quotient (IQ) score in offspring. We assessed the effect of iodine supplementation in mildly iodine-deficient pregnant women on neurodevelopment of their offspring in areas where schoolchildren were iodine sufficient. METHODS: In this randomised, placebo-controlled trial, pregnant women in Bangalore, India, and Bangkok, Thailand, were randomly assigned (1:1) to receive 200 µg iodine orally once a day or placebo until delivery. Randomisation was done with a computer-generated sequence and stratified by site. Co-primary outcomes were verbal and performance IQ scores on the Wechsler Preschool and Primary Scale of Intelligence Third Edition (WPPSI-III) and the global executive composite score from the Behaviour Rating Inventory of Executive Function-Preschool Version (BRIEF-P) in the children at age 5-6 years. The trial was double-blinded; some unmasking took place at age 2 years for an interim analysis, but participants and nearly all investigators remained masked to group assignment until age 5-6 years. Analysis was by intention to treat using mixed-effects models. This trial is registered with ClinicalTrials.gov, number NCT00791466. FINDINGS: Between Nov 18, 2008, and March 12, 2011, 832 women entered the trial at a mean gestational age of 10·7 weeks (SD 2·7); median urinary iodine concentration was 131 µg/L (IQR 81-213). Mean compliance with supplementation was 87%, assessed by monthly tablet counts. 313 children (iodine group, n=159; placebo group, n=154) were analysed for verbal and performance IQ with WPPSI-III and 315 (iodine group, n=159; placebo group, n=156) for overall executive function with BRIEF-P. Mean WPPSI-III scores for verbal IQ were 89·5 (SD 9·8) in the iodine group and 90·2 (9·8) in the placebo group (difference -0·7, 95% CI -2·9 to 1·5; p=0·77), and for performance IQ were 97·5 (12·5) in the iodine group and 99·1 (13·4) in the placebo group (difference -1·6, -4·5 to 1·3; p=0·44). The mean BRIEF-P global executive composite score was 90·6 (26·2) in the iodine group and 91·5 (27·0) in the placebo group (difference -0·9, -6·8 to 5·0; p=0·74). The frequency of adverse events did not differ between groups during gestation or at delivery: 24 women in the iodine group and 28 in the placebo group reported adverse events (iodine group: abortion, n=20; blighted ovum, and n=2; intrauterine death, n=2; placebo group: abortion, n=22; blighted ovum, n=1; intrauterine death, n=2; early neonatal death, n=1; and neonatal death, n=2). INTERPRETATION: Daily iodine supplementation in mildly iodine-deficient pregnant women had no effect on child neurodevelopment at age 5-6 years. FUNDING: Swiss National Science Foundation, Nestlé Foundation, Wageningen University and Research, and ETH Zurich.

Pre-pregnancy body mass index and gestational weight gain in Thai pregnant women as risks for low birth weight and macrosomia.

BACKGROUND AND OBJECTIVES: Maternal pre-pregnancy body mass index (BMI) and gestational weight gain (GWG) have been reported to be associated with pregnancy outcomes. Due to the nutrition transition in Thailand, the double burden of malnutrition is increasing and this may have negative consequences on birth outcomes. This study aimed to investigate the relationship between pre-pregnancy BMI and GWG with the risks of low birth weight and macrosomia. METHODS AND STUDY DESIGN: We performed a secondary analysis of data obtained from an iodine supplementation trial in mildly iodine-deficient Thai pregnant women. Pre-pregnancy BMI was classified using the WHO classification. GWG was categorized using the IOM recommendation. Binary and multinomial logistic regressions were performed. RESULTS: Among 378 pregnant women, the prevalence of pre-pregnancy underweight (BMI<18.5 kg/m2) and overweight (BMI>=25 kg/m2) were 17.2% and 14.3%, respectively. Normal weight women had the highest median GWG [15.0 (12.0, 19.0) kg] when compared to overweight women [13.2 (9.0, 16.3) kg]. Forty-one percent of women had excessive GWG, while 23% of women gained weight inadequately. Women with a high pre-pregnancy BMI had a 7-fold higher risk of having a macrosomic infant. Women who had excessive GWG were 8 times more likely to deliver a newborn with macrosomia. CONCLUSIONS: Both high pre-pregnancy maternal weight and excessive weight gain during pregnancy increase risk of infant macrosomia. Therefore, maintaining normal body weight before and throughout pregnancy should be recommended in order to reduce the risk of excessive infant birth weight and its associated complications.

Iodine supplementation in pregnancy and its effect on child cognition.

Maternal hypothyroidism and hypothyroxenemia due to iodine deficiency have been shown to affect development of the newborn negatively. Maternal iodine supplementation may therefore improve cognitive performance of the offspring, even in areas of mild-to-moderate iodine deficiency (ID). Several iodine supplementation studies have been performed in mildly ID pregnant women in Europe. These studies have shown that iodine supplementation increases maternal urinary iodine (UI) excretion and reduces thyroid volume, as well as prevents increases in infant thyroid volume and thyroglobuline. However, randomized controlled studies with long-term outcomes are lacking. Therefore, two trials were started in 2008 in areas of low iodine status; one in Bangalore, India (n=325), and another in Bangkok, Thailand (n=514). Pregnant women were recruited <14 weeks gestational age and randomized to either receive a daily dose of 200 µg I (as KI) or an identical placebo throughout pregnancy. Both trials are ongoing, and women are followed up during pregnancy and at delivery. UI, thyroid hormones, and thyroid size are measured. Birth outcomes are recorded, such as gestational age at delivery, height, weight, and APGAR scores, and cord blood and heel stick blood (<72 h) is collected from the child. Child development is assessed at 6 weeks of age using the Neonatal Behavioral Assessment Scale (NBAS), and at 12 and 24 months of age using the Bayley Scales of Infant Development. The outcomes of these trials will contribute importantly to the evidence base for iodine supplementation of pregnant women living in areas of mild iodine deficiency.

Iron metabolism in heterozygotes for hemoglobin E (HbE), alpha-thalassemia 1, or beta-thalassemia and in compound heterozygotes for HbE/beta-thalassemia.

BACKGROUND: Despite large populations carrying traits for thalassemia in countries implementing universal iron fortification, there are few data on the absorption and utilization of iron in these persons. OBJECTIVE: We aimed to determine whether iron absorption or utilization (or both) in women heterozygous for beta-thalassemia, alpha-thalassemia 1, or hemoglobin E (HbE) differed from that in control subjects and compound HbE/beta-thalassemia heterozygotes. DESIGN: In Thai women (n = 103), red blood cell indexes, iron status, non-transferrin-bound iron, and growth differentiation factor 15 were measured, and body iron was calculated. Fractional iron absorption was measured from meals fortified with isotopically labeled ((57)Fe) Fe sulfate, and iron utilization was measured by the infusion of ((58)Fe) Fe citrate. RESULTS: Iron utilization was approximately 15% lower in alpha-thalassemia 1 or beta-thalassemia heterozygotes than in controls. When corrected for differences in serum ferritin, absorption was significantly higher in the alpha- and beta-thalassemia groups, but not the HbE heterozygotes, than in controls. HbE/beta-thalassemia compound heterozygotes had lower iron utilization and higher iron absorption and body iron than did controls. Nontransferrin-bound iron and growth differentiation factor 15 were higher in the compound heterozygotes, but not in the other groups, than in the controls. CONCLUSIONS: In alpha-thalassemia 1 and beta-thalassemia heterozygotes with ineffective erythropoesis, dietary iron absorption is not adequately down-regulated, despite a modest increase in body iron stores. In populations with a high prevalence of these traits, a program of iron fortification could include monitoring for possible iron excess and for iron deficiency.

A multimicronutrient-fortified seasoning powder enhances the hemoglobin, zinc, and iodine status of primary school children in North East Thailand: a randomized controlled trial of efficacy.

Anemia and co-existing deficiencies of zinc, iron, iodine, and vitamin A occur among children in many developing countries including NE Thailand, probably contributing to impairments in growth, immune competence, and cognition. Sustainable strategies are urgently required to combat these deficiencies. We assessed the efficacy of a micronutrient-fortified seasoning powder served with a school lunch on reducing anemia and improving the micronutrient status of rural NE Thai children. Children (n = 569) aged 5.5-13.4y from 10 schools were randomly assigned to receive a seasoning powder either unfortified or fortified with zinc (5 mg), iron (5 mg), vitamin A (270 microg), and iodine (50 microg) (per serving) and incorporated into a school lunch prepared centrally and delivered 5 d/wk for 31 wk. Teachers monitored school lunch consumption. Baseline and final micronutrient status, hemoglobinopathies, and infection or inflammation were assessed from blood and urine samples. For the primary outcome, anemia (based on hemoglobin), no intervention effect was apparent (odds ratio: 1.02 95% CI: 0.69, 1.51) after adjustment for design strata. The odds of zinc (based on serum zinc) and urinary iodine deficiency in the fortified group were 0.63 (0.42, 0.94) and 0.52 (0.38, 0.71) times those in the unfortified group, respectively. Fortification had no effect on serum retinol (0.61: 0.25,1.51), ferritin (1.12: 0.43, 2.96), or mean red cell volume (1.16: 0.82, 1.64). Therefore, a micronutrient-fortified seasoning powder is a promising vehicle for improving zinc, iodine, and hemoglobin status, and its potential for incorporation into lunch programs in day care centers and schools in NE Thailand warrants investigation.

Comparison of the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced elemental iron: randomized, double-blind, controlled trial in Thai women.

BACKGROUND: Although elemental iron powders are widely used to fortify cereal products, little data exist on their efficacy in humans. OBJECTIVE: We compared the efficacy of wheat-based snacks fortified with ferrous sulfate, electrolytic iron, or hydrogen-reduced iron in Thai women with low iron stores. DESIGN: A double-blind intervention was conducted in 18-50-y-old women (n = 330) randomly assigned into 4 groups to receive either no fortification iron or 12 mg Fe/d for 6 d/wk for 35 wk as ferrous sulfate, electrolytic iron, or hydrogen-reduced iron in a baked, wheat-flour-based snack. Snacks were not consumed with meals, and consumption was monitored. At baseline, 20 wk, and 35 wk, hemoglobin status and iron were measured and the groups were compared. RESULTS: Between baseline and 35 wk, geometric mean serum ferritin (SF) increased significantly in all 3 groups receiving iron (P < 0.01), and geometric mean serum transferrin receptor (TfR) decreased significantly in the groups receiving ferrous sulfate and electrolytic iron (P < 0.05). Calculated mean (+/-SD) body iron stores increased from 1.5 +/- 2.8 to 5.4 +/- 2.9 mg/kg in the ferrous sulfate group, from 1.5 +/- 3.5 to 4.4 +/- 3.6 mg/kg in the electrolytic iron group, and from 1.3 +/- 3.2 to 3.2 +/- 4.3 mg/kg in the hydrogen-reduced iron group (P < 0.01 for all 3 groups) but did not change significantly in the control group. CONCLUSIONS: Ferrous sulfate, electrolytic iron, and hydrogen-reduced iron, fortified into wheat-based snacks, significantly improved iron status. On the basis of the change in body iron stores during the 35-wk study, the relative efficacy of the electrolytic and hydrogen-reduced iron compared with ferrous sulfate was 77% and 49%, respectively.