Micronutrients, vitamins and minerals accessible from the diet, are essential for biologic activity. Micronutrient status varies widely throughout pregnancy and across populations. Women in ...low-income countries often enter pregnancy malnourished, and the demands of gestation can exacerbate micronutrient deficiencies with health consequences for the fetus. Examples of efficacious single micronutrient interventions include folic acid to prevent neural tube defects, iodine to prevent cretinism, zinc to reduce risk of preterm birth, and iron to reduce the risk of low birth weight. Folic acid and vitamin D might also increase birth weight. While extensive mechanistic and association research links multiple antenatal micronutrients with plausible materno-fetal health advantages, hypothesized benefits have often been absent, minimal or unexpected in trials. These findings suggest a role for population context in determining health responses and filling extensive gaps in knowledge. Multiple micronutrient supplements reduce the risks of being born with low birth weight, small for gestational age or stillborn in undernourished settings, and justify micronutrient interventions with antenatal care. Measurable health effects of gestational micronutrient exposure might persist into childhood but few data exists on potential long-term benefits. In this Review, we discuss micronutrient intake recommendations, risks and consequences of deficiencies, and the effects of interventions with a particular emphasis on offspring.
Achondroplasia is the most common short stature skeletal dysplasia (1:20,000–30,000), but the risk of adverse health outcomes from cardiovascular diseases, pain, poor function, excess weight, and ...sleep apnea is unclear. A multicenter retrospective natural history study was conducted to understand medical and surgical practices in achondroplasia.
Data from patients with achondroplasia evaluated by clinical geneticists at Johns Hopkins University, A.I. duPont Hospital for Children, McGovern Medical School UTHealth, and University of Wisconsin were populated into a REDCap database. All available retrospective medical records of anthropometry (length/height, weight, occipitofrontal circumference), surgery, polysomnography (PSG), and imaging (e.g., X-ray, magnetic resonance imaging) were included.
Data from 1,374 patients (48.8% female; mean age 15.4±13.9 years) constitute the primary achondroplasia cohort (PAC) with 496 subjects remaining clinically active and eligible for prospective studies. Within the PAC, 76.0% had a de novo FGFR3 pathologic variant and 1,094 (79.6%) had one or more achondroplasia-related surgeries. There are ≥37,000 anthropometry values, 1,631 PSGs and 10,727 imaging studies.
This is the largest multicenter achondroplasia natural history study, providing a vast array of medical information for use in caring for these patients. This well-phenotyped cohort is a reference population against which future medical and surgical interventions can be compared.
Antenatal multiple micronutrient (MM) supplementation improves birth outcomes relative to iron–folic acid (IFA) in developing countries, but limited data exist on its impact on pregnancy ...micronutrient status.
We assessed the efficacy of a daily MM (15 nutrients) compared with IFA supplement, each providing approximately 1 RDA of nutrients and given beginning at pregnancy ascertainment, on late pregnancy micronutrient status of women in rural Bangladesh. Secondarily, we explored other contributors to pregnancy micronutrient status.
Within a double-masked trial (JiVitA-3) among 44,500 pregnant women, micronutrient status indicators were assessed in n = 1526 women, allocated by cluster to receive daily MM (n = 749) or IFA (n = 777), at 10 wk (baseline: before supplementation) and 32 wk (during supplementation) gestation. Efficacy of MM supplementation on micronutrient status indicators at 32 wk was assessed, controlling for baseline status and other covariates (e.g., inflammation and season), in regression models.
Baseline status was comparable by intervention. Prevalence of deficiency among all participants was as follows: anemia, 20.6%; iron by ferritin, 4.0%; iron by transferrin receptor, 4.7%; folate, 2.5%; vitamin B-12, 35.4%; vitamin A, 6.7%; vitamin E, 57.7%; vitamin D, 64.0%; zinc, 13.4%; and iodine, 2.6%. At 32 wk gestation, vitamin B-12, A, and D and zinc status indicators were 3.7–13.7% higher, and ferritin, γ-tocopherol, and thyroglobulin indicators were 8.7–16.6% lower, for the MM group compared with the IFA group, with a 15–38% lower prevalence of deficiencies of vitamins B-12, A, and D and zinc (all P < 0.05). However, indicators typically suggested worsening status during pregnancy, even with supplementation, and baseline status or other covariates were more strongly associated with late pregnancy indicators than was MM supplementation.
Rural Bangladeshi women commonly entered pregnancy deficient in micronutrients other than iron and folic acid. Supplementation with MM improved micronutrient status, although deficiencies persisted. Preconception supplementation or higher nutrient doses may be warranted to support nutritional demands of pregnancy in undernourished populations. This trial was registered at clinicaltrials.gov as NCT00860470.
ABSTRACT
Objectives:
Environmental enteric dysfunction (EED) may inhibit growth and development in low‐ and middle‐income countries, but available assessment methodologies limit its study. In rural ...Bangladesh, we measured EED using the widely used lactulose mannitol ratio (L:M) test and a panel of intestinal and systemic health biomarkers to evaluate convergence among biomarkers and describe risk factors for EED.
Methods:
In 539 18‐month‐old children finishing participation in a randomized food supplementation trial, serum, stool, and urine collected after lactulose and mannitol dosing were analyzed for biomarkers of intestinal absorption, inflammation, permeability and repair, and systemic inflammation. EED scores for each participant were developed using principal component analysis and partial least squares regression. Associations between scores and L:M and with child sociodemographic and health characteristics were evaluated using regression analysis.
Results:
EED prevalence (L:M > 0.07) was 39.0%; 60% had elevated acute phase proteins (C‐reactive protein >5 mg/L or α‐1 acid glycoprotein >100 mg/dL). Correlations between intestinal biomarkers were low, with the highest between myeloperoxidase and α‐1 antitrypsin (r = 0.33, P < 0.01), and biomarker values did not differ by supplementation history. A 1‐factor partial least squares model with L:M as the dependent variable explained only 8.6% of L:M variability. In adjusted models, L:M was associated with child sex and socioeconomic status index, whereas systemic inflammation was predicted mainly by recent illness, not EED.
Conclusions:
Impaired intestinal health is widespread in this setting of prevalent stunting, but a panel of serum and stool biomarkers demonstrated poor agreement with L:M. Etiologies of intestinal and systemic inflammation are likely numerous and complex in resource‐poor settings, underscoring the need for a better case definition with corresponding diagnostic methods to further the study of EED.
•Aflatoxin B1-lysine albumin biomarkers were measured in rural South Asian women during pregnancy and across the first 1000 days of life.
Aflatoxin B1 is a potent carcinogen, occurring from mold ...growth that contaminates staple grains in hot, humid environments. In this investigation, aflatoxin B1-lysine albumin biomarkers were measured by mass spectrometry in rural South Asian women, during the first and third trimester of pregnancy, and their children at birth and at two years of age. These subjects participated in randomized community trials of antenatal micronutrient supplementation in Sarlahi District, southern Nepal and Gaibandha District in northwestern Bangladesh. Findings from the Nepal samples demonstrated exposure to aflatoxin, with 94% detectable samples ranging from 0.45 to 2939.30 pg aflatoxin B1-lysine/mg albumin during pregnancy. In the Bangladesh samples the range was 1.56 to 63.22 pg aflatoxin B1-lysine/mg albumin in the first trimester, 3.37 to 72.8 pg aflatoxin B1-lysine/mg albumin in the third trimester, 4.62 to 76.69 pg aflatoxin B1-lysine/mg albumin at birth and 3.88 to 81.44 pg aflatoxin B1-lysine/mg albumin at age two years. Aflatoxin B1-lysine adducts in cord blood samples demonstrated that the fetus had the capacity to convert aflatoxin into toxicologically active compounds and the detection in the same 2-year-old children illustrates exposure over the first 1000 days of life.
This study aimed to describe the timing and patterns of pubertal maturation of girls living in rural Bangladesh. Starting in September 2015, a total of 15,320 girls from a birth cohort, aged 9 to 15 ...years at initial encounter, were visited twice at about a one year interval, typically in their birth month. Participants were asked to self-report extent of pubertal maturation, including breast development, pubic hair growth and age at menarche, if applicable. Pubertal stage (abbreviated as B2 and B3-4 for breast development and PH2 and PH3-4 for pubic hair growth) was assigned. Data from both visits were pooled, yielding a total of 29,377 age-related observations per pubertal characteristic. Probit regression models were used to estimate distributions of age at which each stage of pubertal development was attained. Before age 8, <3% of the study population initiated pubertal maturation as indicated by onset of breast development (B2). The median (95% confidence interval) age of B2 and B3-4 was 11.02 (11.00-11.04) and 12.82 (12.80-12.83) years, respectively; and 12.93 (12.91-12.94) and 14.29 (14.27-14.31) years for the onset (PH2) and advanced stage (PH3-4) of pubic hair growth, respectively. Median age at menarche was 13.17 (13.15-13.19) years, with 2.15 years of timespan from B2 to menarche. Girls in rural Bangladesh progressed through puberty following a well-documented sequence of sexual maturation stages. The age at which each pubertal milestone took place was somewhat later, but the tempo from breast development to menarche was comparable to that observed elsewhere. Our findings present a current norm of pubertal maturation in a typical, rural adolescent population in South Asia, which could help inform future studies and interventions to preserve or improve early adolescent health and development.
Environmental enteric dysfunction increases the likelihood of micronutrient deficiencies among infants, but few studies have assessed the potential impact of gut health on urinary iodine ...concentration (UIC) among this vulnerable group.
We describe the trends of iodine status among infants from 6 to 24 mo old and examine the associations between intestinal permeability, inflammation, and UIC from 6 to 15 mo of age.
Data from 1557 children enrolled in this birth cohort study conducted in 8 sites were included in these analyses. UIC was measured at 6, 15, and 24 mo of age by using the Sandell-Kolthoff technique. Gut inflammation and permeability were assessed using the concentrations of fecal neopterin (NEO), myeloperoxidase (MPO) and alpha-1–antitrypsin (AAT), and lactulose–mannitol ratio (LM). A multinomial regression analysis was used to assess the classified UIC (deficiency or excess). Linear mixed regression was used to test the effect of interactions among biomarkers on logUIC.
All studied populations had adequate (≥100 μg/L) to excess (≥371 μg/L) median UIC at 6 mo. Between 6 and 24 mo, 5 sites displayed a significant decline in the infant’s median UIC. However, median UIC remained within the optimal range. An increase of NEO and MPO concentrations by +1 unit in ln scale reduced the risk of low UIC by 0.87 (95% CI: 0.78–0.97) and 0.86 (95% CI: 0.77–0.95), respectively. AAT moderated the association between NEO and UIC (P < 0.0001). The shape of this association appears to be asymmetric and in a reverse J-shape, with a higher UIC observed at both lower NEO and AAT concentrations.
Excess UIC was frequent at 6 mo and tended to normalize at 24 mo. Aspects of gut inflammation and increased permeability appear to reduce the prevalence of low UIC in children aged 6 to 15 mo. Programs addressing iodine-related health should consider the role of gut permeability in vulnerable individuals.
Inflammation is a condition stemming from complex host defense and tissue repair mechanisms, often simply characterized by plasma levels of a single acute reactant. We attempted to identify candidate ...biomarkers of systemic inflammation within the plasma proteome. We applied quantitative proteomics using isobaric mass tags (iTRAQ) tandem mass spectrometry to quantify proteins in plasma of 500 Nepalese children 6-8 years of age. We evaluated those that co-vary with inflammation, indexed by α-1-acid glycoprotein (AGP), a conventional biomarker of inflammation in population studies. Among 982 proteins quantified in >10% of samples, 99 were strongly associated with AGP at a family-wise error rate of 0.1%. Magnitude and significance of association varied more among proteins positively (n = 41) than negatively associated (n = 58) with AGP. The former included known positive acute phase proteins including C-reactive protein, serum amyloid A, complement components, protease inhibitors, transport proteins with anti-oxidative activity, and numerous unexpected intracellular signaling molecules. Negatively associated proteins exhibited distinct differences in abundance between secretory hepatic proteins involved in transporting or binding lipids, micronutrients (vitamin A and calcium), growth factors and sex hormones, and proteins of largely extra-hepatic origin involved in the formation and metabolic regulation of extracellular matrix. With the same analytical approach and the significance threshold, seventy-two out of the 99 proteins were commonly associated with CRP, an established biomarker of inflammation, suggesting the validity of the identified proteins. Our findings have revealed a vast plasma proteome within a free-living population of children that comprise functional biomarkers of homeostatic and induced host defense, nutrient metabolism and tissue repair, representing a set of plasma proteins that may be used to assess dynamics and extent of inflammation for future clinical and public health application.
Achondroplasia is the most common genetic skeletal disorder causing disproportionate short stature/dwarfism. Common additional features include spinal stenosis, midface retrusion, macrocephaly and a ...generalized spondylometaphyseal dysplasia which manifest as spinal cord compression, sleep disordered breathing, delayed motor skill acquisition and genu varus with musculoskeletal pain. To better understand the interactions and health outcomes of these potential complications, we embarked on a multi-center, natural history study entitled CLARITY (achondroplasia natural history study). One of the CLARITY objectives was to develop growth curves (length/height, weight, head circumference, weight-for-height) and corresponding reference tables of mean and standard deviations at 1 month increments from birth through 18 years for clinical use and research for achondroplasia patients.
All available retrospective anthropometry data including length/height, weight and head circumference from achondroplasia patients were collected at 4 US skeletal dysplasia centers (Johns Hopkins University, AI DuPont Hospital for Children, McGovern Medical School University of Texas Health, University of Wisconsin School of Medicine and Public Health). Weight-for-age values beyond 3 SD above the mean were excluded from the weight-for-height and weight-for-age curves to create a stricter tool for weight assessment in this population.
Over 37,000 length/height, weight and head circumference measures from 1374 patients with achondroplasia from birth through 75 years of age were compiled in a REDCap database. Stature and weight data from birth through 18 years of age and head circumference from birth through 5 years of age were utilized to construct new length/height-for-age, weight-for-age, head circumference-for-age and weight-for-height curves.
Achondroplasia-specific growth curves are essential for clinical care of growing infants and children with this condition. In an effort to provide prescriptive, rather than purely descriptive, references for weight in this population, extreme weight values were omitted from the weight-for-age and weight-for-height curves. This well-phenotyped cohort may be studied with other global achondroplasia populations (e.g. Europe, Argentina, Australia, Japan) to gain further insight into environmental or ethnic influences on growth.
Impaired dark adaptation is an early functional indicator of vitamin A deficiency that may be prevented by regular dietary intake of foods containing provitamin A carotenoids.
We tested the impact of ...provitamin A carotenoid-biofortified maize consumption (∼15 μg β-carotene/g) on dark adaptation in Zambian children.
We used a cluster-randomized trial of children aged 4-8 y (n = 1024) in Mkushi District, Zambia, and compared the regular consumption (2 meals/d, 6 d/wk for 6 mo) of biofortified orange maize (OM) to white maize (WM). The primary outcome was the serum retinol response. In a random sample (n = 542), we used a digital pupillometer to test pre- and postintervention responses to graded light stimuli (-2.9 to 0.1 log cd/m
) in a dark-adapted state.
At baseline, 11.7% of the children had serum retinol <0.7 μmol/L, 14.4% had impaired dark adaptation (pupillary threshold ≥ -1.11 log cd/m
), and 2.3% had night blindness. The mean ± SD pupillary responsiveness to light stimuli was poorer at baseline in the OM group (16.1% ± 6.6%) than the WM group (18.1% ± 6.4%) (P = 0.02) but did not differ at follow-up (OM: 17.6% ± 6.5%; WM: 18.3% ± 6.5%). Among children with serum retinol <1.05 μmol/L at baseline, there was greater improvement in pupillary responsiveness in the OM group (2.2%; 95% CI: 0.1%, 4.3%) than the WM group (0.2%; 95% CI: -1.1%, 1.5%; P = 0.01), but there were no differences in children with adequate baseline status. We found no effect of treatment on pupillary threshold or night blindness.
The regular consumption of provitamin A carotenoid-biofortified maize increased pupillary responsiveness among children with marginal or deficient vitamin A status, providing evidence of a functional benefit to consuming this biofortified crop. This trial was registered at clinicaltrials.gov as NCT01695148.
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