Multiple Infections, Nutrient Deficiencies, and Inflammation as Determinants of Anemia and Iron Status during Pregnancy: The MINDI Cohort.

In pregnant women with multiple infections, nutrient deficiencies, and inflammation (MINDI), the study of anemia and iron status is limited. For this cross-sectional study (n = 213 Panamanian indigenous women), we investigated if hemoglobin, anemia (Hb < 110 g/L), ferritin, serum iron, serum transferrin receptor, and hepcidin were associated with (1) maternal nutritional status and supplementation practices, (2) biomarkers of inflammation, and (3) presence/absence of infections. Hierarchical generalized linear and logistic regression models and dominance analyses identified the relative importance of these predictors. Anemia (38%), which was likely underestimated due to low plasma volume (95%), was associated with lower ferritin, vitamin A, and weight-for-height, suggesting anemia of undernutrition. Inflammation was not associated with Hb or anemia; nevertheless, higher CRP was associated with increased odds of low serum iron and higher ferritin and hepcidin, indicating iron restriction due to inflammation. The length of iron supplementation did not enter models for anemia or iron indicators, but a multiple nutrient supplement was associated with higher ferritin and hepcidin. Moreover, iron supplementation was associated with higher odds of vaginal trichomoniasis but lower odds of caries and bacterial vaginosis. The complex pathogenesis of anemia and iron deficiency in MINDI settings may require other interventions beyond iron supplementation.

Multiple Indicators of Undernutrition, Infection, and Inflammation in Lactating Women Are Associated with Maternal Iron Status and Infant Anthropometry in Panama: The MINDI Cohort.

Maternal infections, nutrient deficiencies, and inflammation (MINDI) co-exist in lactating indigenous women in Panama, but their impact on maternal iron status and infant growth is unknown. For this secondary analysis of cross-sectional data of lactating mothers from our MINDI cohort, we investigated associations of MINDI variables with maternal anemia, elevated serum transferrin receptor (sTfR), low serum iron, hepcidin, ferritin, and infant weight-for-age (WAZ), length-for-age (LAZ), and head-circumference-for-age (HCAZ) Z-scores in 99 mother-infant dyads. A bootstrapping resampling procedure preselected covariates for inclusion in multivariable regressions models from chronic maternal infections and nutritional status [folate, vitamins A, D, retinol-binding protein (RBP), insulin-growth factor-1 (IGF-1)] and inflammation [C-reactive protein (CRP), cytokines, platelet indices] indicators. Anemia was prevalent (53.5%) but underestimated due to widespread low plasma volume (<2.2 L, 79.9%) and was associated with indicators of malnutrition [lower IGF-1, body mass index (BMI), vitamin D, and intake of green/leafy vegetables], but not inflammation. Higher CRP was associated with lower serum iron, and higher hepcidin and ferritin, whereas maternal platelets were associated with lower HCAZ (ß = −0.22), WAZ (ß = −0.17), and LAZ (ß = −0.17). Higher LAZ was also associated with maternal serum vitamin D (ß = 0.23), whereas maternal iron supplementation lowered LAZ (ß = −0.22). Assessment of iron status in this MINDI cohort is complex and supplementation strategies must consider consequences for both the mother and the infant.

Maternal and cord blood parameters are associated with placental and newborn outcomes in indigenous mothers: A case study in the MINDI cohort / Parámetros maternos y de sangre de cordón asociados con medidas placentarias y del recién nacido: Un estudio de casos en madres indígenas de la cohorte MINDI

Abstract Background: Multiple infections, nutrient deficiencies and inflammation (MINDI) occur in indigenous communities, but their associations with perinatal outcomes have not been described. Objective: To assess maternal and cord blood micronutrient and inflammation status in peripartum mothers from the Ngäbe-Buglé comarca in Panama, and their associations with placental and infant outcomes. Methods: In 34 mother-newborn dyads, placental weight and diameter were measured, and maternal and cord blood were processed for complete cell counts, serum C-reactive protein, ferritin, serum transferrin receptor (sTfR), vitamins A and D. Blood volumes were calculated using Nadler's formula. Results: Mothers had low plasma volume (<2.8 L, 96%), vitamin A (52.9%), vitamin D (29.4%), iron (58.8%) and hemoglobin (23.5%), but high hematocrit (>40%, 17.6%) and inflammation (C-reactive protein >8.1 mg/L, 85.3%). Birthweights were normal, but low placental weight (35.3%), low head circumference Z-scores (17.6%), and low cord hemoglobin (5.9%), iron (79.4%), vitamin A (14.7%) and vitamin D (82.3%) were identified. Maternal and cord vitamin D were highly correlated. Higher maternal plasma volume was associated with heavier placentae (β= 0.57), and higher cord D (β= 0.43) and eosinophils (β= 0.43) with larger placentae. Hemoconcentration (higher cord hematocrit) was associated with lower newborn weight (β= -0.48) and head circumference (β= -0.56). Inflammation [higher maternal neutrophils (β= -0.50), and cord platelets (β= -0.32)] was associated with lower newborn length and head circumference. Conclusion: Maternal-newborn hemoconcentration, subclinical inflammation and multiple nutrient deficiencies, particularly neonatal vitamin D deficiency, were identified as potential targets for interventions to improve pregnancy outcomes in vulnerable communities.

Resumen Antecedentes: Las Múltiples Infecciones, Nutrición Deficiente e Inflamación (MINDI), son frecuentes en comunidades indígenas, sin embargo, sus asociaciones con resultados de salud perinatales no han sido descritos. Objetivo: Evaluar la inflamación y los micronutrientes en sangre materna y de cordón de madres en trabajo de parto en la comarca Ngäbe-Buglé en Panamá, así como sus asociaciones con medidas placentarias y del recién nacido. Métodos: En 34 pares madre-recién nacido, se midieron peso y diámetro placentario, y se analizaron muestras de sangre materna y de cordón umbilical para hemograma completo, proteína-C reactiva (PCR), ferritina, receptor sérico de transferrina (RsTf), vitaminas A y D. Se usó la fórmula de Nadler para calcular volúmenes sanguíneos. Resultados: Las madres presentaron volumen plasmático (<2.8 L, 96%), vitamina A (52.9%), vitamina D (29.4%), hierro (58.8%) y hemoglobina (23.5%) bajos, pero el 17.6% presentaron hematocrito >40% y 85.3% presentaron inflamación (PCR >8.1 mg/L). Los pesos al nacer fueron normales, pero se identificó bajo peso placentario (35.3%), bajo puntaje-z de circunferencia cefálica neonatal, y en sangre de cordón, bajos hemoglobina (5.9%), hierro (79.4%), vitamina A (14.7%) y vitamina D (82.3%). Se encontró una fuerte correlación positiva entre la vitamina D materna y de sangre de cordón. Un mayor volumen plasmático materno se asoció con placentas de mayor peso (β= 0.57), en tanto que concentraciones más altas de vitamina D (β= 0.43) y mayor número de eosinófilos (β= 0.43) se asociaron con mayor diámetro placentario. Una mayor hemoconcentración (hematocrito en cordón más alto) se asoció con menores peso al nacer (β= -0.48) y circunferencia cefálica (β= -0.56). La inflamación [mayor número de neutrófilos maternos (β= -0.50) y plaquetas en sangre de cordón (β= -0.32)] se asoció con menor talla y circunferencia cefálica neonatales. Conclusión: La hemoconcentración materna y del recién nacido, la inflamación subclínica y las múltiples deficiencias en micronutrientes, particularmente la deficiencia de vitamina D neonatal, se identificaron como potenciales áreas de intervención para mejorar los resultados de salud del embarazo en comunidades vulnerables.

Differential expression of genes in fetal brain as a consequence of maternal protein deficiency and nematode infection.

Maternal dietary protein deficiency and gastrointestinal nematode infection during early pregnancy have negative impacts on both maternal placental gene expression and fetal growth in the mouse. Here we used next-generation RNA sequencing to test our hypothesis that maternal protein deficiency and/or nematode infection also alter the expression of genes in the developing fetal brain. Outbred pregnant CD1 mice were used in a 2×2 design with two levels of dietary protein (24% versus 6%) and two levels of infection (repeated sham versus Heligmosomoides bakeri beginning at gestation day 5). Pregnant dams were euthanized on gestation day 18 to harvest the whole fetal brain. Four fetal brains from each treatment group were analyzed using RNA Hi-Seq sequencing and the differential expression of genes was determined by the edgeR package using NetworkAnalyst. In response to maternal H. bakeri infection, 96 genes (88 up-regulated and eight down-regulated) were differentially expressed in the fetal brain. Differentially expressed genes were involved in metabolic processes, developmental processes and the immune system according to the PANTHER classification system. Among the important biological functions identified, several up-regulated genes have known neurological functions including neuro-development (Gdf15, Ing4), neural differentiation (miRNA let-7), synaptic plasticity (via suppression of NF-κß), neuro-inflammation (S100A8, S100A9) and glucose metabolism (Tnnt1, Atf3). However, in response to maternal protein deficiency, brain-specific serine protease (Prss22) was the only up-regulated gene and only one gene (Dynlt1a) responded to the interaction of maternal nematode infection and protein deficiency. In conclusion, maternal exposure to GI nematode infection from day 5 to 18 of pregnancy may influence developmental programming of the fetal brain.

Interactions among urogenital, intestinal, skin, and oral infections in pregnant and lactating Panamanian Ngäbe women: a neglected public health challenge.

Interrelationships among bacteria, protozoa, helminths, and ectoparasites were explored in a cross-sectional survey of 213 pregnant and 99 lactating indigenous women. Prevalences in pregnancy and lactation, respectively, were: vaginitis (89.2%; 46.8%), vaginal trichomoniasis (75.3%; 91.1%), bacterial vaginosis (BV; 60.6%; 63.3%), hookworm (56.6%; 47.8%), asymptomatic bacteriuria/urinary tract infection (AB/UTI; 56.2%; 36.2%), cervicitis (33.3%; 6.3%), vaginal yeast (24.9%; 11.4%), Ascaris (32.5%; 17.4%), vaginal diplococci (20.4%; 31.6%), caries (19.7%; 18.2%), scabies (17.4%; 8.1%), and Trichuris (12.5%; 8.7%). Multiple regressions revealed positive associations during pregnancy (trichomoniasis and AB/UTI; diplococci and Ascaris) and lactation (yeast and scabies). Negative associations were detected in pregnancy (BV and trichomoniasis; hookworm and diplococci) and lactation (BV and yeast). Vaginal Lactobacillus reduced odds of diplococci in pregnancy and lactation, but increased Ascaris eggs per gram (epg) and odds of trichomoniasis in pregnancy and yeast in lactation. These associations raised a concern that treatment of one condition may increase the risk of another.

Protein deficiency and intestinal nematode infection in pregnant mice differentially impact fetal growth through specific stress hormones, growth factors, and cytokines.

BACKGROUND: Protein deficiency (PD) and intestinal nematode infections commonly co-occur during pregnancy and impair fetal growth, but the complex network of signals has not been explored. OBJECTIVE: Our objective was to assess those stress hormones, growth factors, and cytokines affected by maternal PD and nematode infection and associated with fetal growth. METHODS: Using a 2 × 2 factorial design, CD-1 mice, fed protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isoenergetic diets, were either uninfected or infected every 5 d with Heligmosomoides bakeri, beginning on gestational day (GD) 5. Biomarker concentrations were measured on GD 18 in maternal serum (m), fetal serum (f), and amniotic fluid (af) by using Luminex. RESULTS: Maternal PD lowered fetal body mass (PS/uninfected 1.25 ± 0.02 g, PS/infected 1.19 ± 0.02 g vs. PD/uninfected 1.11 ± 0.02 g, PD/infected 0.97 ± 0.02 g; P = 0.02), fetal lung (P = 0.005), and liver (P = 0.003) but not brain mass, whereas maternal infection lowered fetal length (PS/uninfected 2.28 ± 0.02 cm, PD/uninfected 2.27 ± 0.03 cm vs. PS/infected 2.21 ± 0.03 cm, PD/infected 2.11 ± 0.02 cm; P = 0.05) and kidney mass (P = 0.04). PD elevated stress hormones (m-adrenocortiotropic hormone, f-corticosterone, af-corticosterone) and reduced insulin-like growth factor 1 in all compartments (P ≤ 0.01), but these were unassociated with fetal mass or length. Fetal mass was positively associated with f-leptin (R(2) = 0.71, P = 0.0001) and negatively with fetal cytokines [tumor necrosis factor-α: R(2) = 0.62, P = 0.001; interleukin-4 (IL-4): R(2) = 0.63, P = 0.0004]. In contrast, maternal infection lowered f-prolactin (P = 0.02) that was positively associated with fetal length (R(2) = 0.43; P = 0.03); no other biomarker was affected by infection. Regression analyses showed associations between organ growth, cytokines, and growth factors: 1) thymus, spleen, heart, and brain with m-IL-10; 2) brain and kidney with f-vascular endothelial growth factor, af-monocyte chemotactic protein 1, af-interferon-γ, and af-eotaxin; and 3) liver and lung with f-leptin and af-corticosterone (all P ≤ 0.02). CONCLUSIONS: PD and nematode infection impaired fetal mass and linear growth, respectively. Fetal mass, length, and individual organ masses were regulated by different hormones, growth factors, and cytokines.

Individual, social and environmental factors influencing physical activity levels and behaviours of multiethnic socio-economically disadvantaged urban mothers in Canada: a mixed methods approach.

BACKGROUND: Existing data provide little insight into the physical activity context of multiethnic socio-economically disadvantaged mothers in Canada. Our primary objectives were: (1) to use focus group methodology to develop tools to identify the individual, social, and environmental factors influencing utilitarian and leisure time physical activities (LTPA) of multiethnic SED mothers; and (2) to use a women specific physical activity survey tool to assess psychosocial barriers and supports and to quantify individual physical activity (PA) levels of multi-ethnic SED mothers in Canada. METHODS: Qualitative focus group sessions were conducted in West, Central and Eastern Canada with multiethnic SED mothers (n = 6 focus groups; n = 42 SED mothers) and with health and recreation professionals (HRPs) (n = 5 focus groups; n = 25 HRPs) involved in community PA programming for multiethnic SED mothers. Administration of the women specific Kaiser Physical Activity Survey (KPAS) tool was completed by consenting SED mothers (n = 59). RESULTS: More than half of SED mothers were employed and had higher total PA scores with occupation included than unemployed mothers. However, nearly 60% of both groups were overweight or obese. Barriers to LTPA included the lack of available, affordable and accessible LTPA programs that responded to cultural and social needs. Concerns for safety, nonsupportive cultural and social norms and the winter climate were identified as key barriers to both utilitarian and LTPA. CONCLUSIONS: Findings show that multiethnic SED mothers experience many barriers to utilitarian and LTPA opportunities within their communities. The varying LTPA levels among these multi-ethnic SED mothers and the occurrence of overweight and obesity suggests that current LTPA programs are likely insufficient to maintain healthy body weights.

Protein deficiency and nematode infection during pregnancy and lactation reduce maternal bone mineralization and neonatal linear growth in mice.

Using a 2 x 2 factorial design, we investigated the combined impact of protein deficiency (PD) and gastrointestinal nematode infection during late pregnancy and lactation on resting metabolic rate (RMR), body composition and bone mineralization, neonatal growth, and the regulatory hormones [corticosterone, leptin, and insulin-like growth factor-1 (IGF-1)] and proinflammatory cytokines [interleukin (IL)-1 beta and IL-6] that may drive these processes. Pregnant CD1 mice, fed either a protein-sufficient (PS; 24%) or protein-deficient (PD; 6%) isocaloric diet, were infected 4 times with either 0 (sham) or 100 Heligmosomoides bakeri larvae beginning on d 14 of pregnancy. Dams were killed on d 20 postpartum and pups on d 2, 7, 14, and 21. Diet and infection had largely independent effects. The PD diet elevated corticosterone and upregulated leptin concentration in maternal serum, which was associated with reduced food intake leading to lower body mass, RMR, and body temperature. Infection reduced food intake but elevated maternal serum IL-1 beta and IL-6 and did not affect corticosterone, leptin, RMR, or body temperature. The PD diet decreased maternal bone area and bone mineral content. Infection lowered maternal bone mineral density, consistent with elevated IL-1 beta and IL-6. The elevated serum IL-1 beta and lower IGF-1 in pups of PD dams and lower serum leptin and IGF-1 in pups of infected dams were both consistent with the lower pup body mass and shorter crown-rump length. This mouse model provides a novel framework to study the impact of diet and nematode infection on bone.

Increased oxidative modifications of amniotic fluid albumin in pregnancies associated with gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a state of hyperglycaemia and increased oxidative stress with onset during pregnancy. Human serum albumin (HSA) was extracted from 26 GDM and 26 nonGDM amniotic fluid samples collected at 15 weeks gestation and analyzed by mass spectrometry. The majority of all albumin isoforms were oxidized with the cysteinylated HSA as the base peak in the deconvoluted spectrum. The HSA peak areas, from a control sample, had 36% relative standard deviation (RSD) across the six experimental days but using the relative isoform distribution improved the precision to 3-6%. The results show that the relative contribution of permanently oxidized HSA was greater (P = 0.002) and reversibly oxidized HSA was lower (P = 0.006) for GDM compared to nonGDM in the samples measured. This implies that the path toward GDM has been set prior to 15 weeks gestation and results in increased protein oxidation.

Second trimester amniotic fluid transferrin and uric acid predict infant birth outcomes.

OBJECTIVE: To establish whether second trimester amniotic fluid protein and/or uric acid concentrations were associated with and predictive of infant birth weight and/or gestational age. METHODS: Second trimester amniotic fluid samples (n = 230) in mothers undergoing age-related amniocentesis for genetic testing were collected and quantified using capillary zone electrophoresis (CZE) for albumin, IgG, transferrin and uric acid. Maternal characteristics (prepregnancy weight and height, parity, ethnicity, smoking status) and infant birth weight, gestational age and gender were obtained from questionnaires and maternal obstetrical chart review. RESULTS: Preterm infants had higher concentrations of second trimester amniotic fluid transferrin than term infants (P = 0.0215). Transferrin was negatively associated with length of gestation, whereas uric acid was positively associated with the gestational age in spontaneous vaginal delivery (SVD) infants. Uric acid was also a significant predictor of the infant birth weight in grams. CONCLUSION: Second trimester amniotic fluid transferrin and uric acid concentrations are related to subsequent birth outcomes and might emerge as biomarkers of early fetal development.

Amniotic fluid amino acid concentrations are modified by maternal dietary glucose, gestational age, and fetal growth in rats.

Amniotic fluid (AF) contains free amino acids that enter via transplacental and transmembranous routes from maternal sources; subsequently, the developing fetus "ingests" these amino acids early in gestation through unkeratinized skin and later through continuous AF swallowing. Our objectives were as follows: 1) to determine whether a restriction of maternal dietary glucose modulates the free AF amino acid pool, and 2) to establish whether any diet-induced changes were predictive of fetal weight near term (d 21.5). To produce varying in utero growth rates, pregnant rat dams were fed varying levels of glucose (0, 12, 24, 60%) throughout pregnancy. AF samples, collected on gestational days 18-21, were precolumn derivatized by 9-fluorenylmethyloxychloroformate to produce stable primary and secondary amino acid derivatives required for HPLC detection at low amino acid concentrations. Eighteen amino acids were identified. A 2-way ANOVA with main effects of diet (< or =12% and > or =24% glucose) and gestational age (d 18/19 and 20/21) showed that 2 AF amino acids, methionine and phenylalanine, and 12 AF amino acids were independently modified by diet and gestational age, respectively. Of note were the 364% increase in AF methionine and the constant decline in AF taurine as both gestational age lengthened and fetal weight increased. Multiple regression demonstrated that in addition to methionine, 3 specific AF amino acids, cysteine, lysine, and tyrosine, predicted fetal weight. These results demonstrate that the AF amino acid pool can be modified by the glucose content of the maternal diet and that specific AF amino acids are associated with gestational age and fetal growth.

Insulin-like growth factor II and binding proteins 1 and 3 from second trimester human amniotic fluid are associated with infant birth weight.

The developing fetus begins to swallow amniotic fluid (AF) early in gestation, a process that results in ingestion of numerous growth factors. Our objectives were 2-fold: 1) to assess the concentration and distribution of insulin-like growth factor II (IGF II) and its binding proteins (BP) 1 and 3 in 2nd trimester amniotic fluid using ELISA, and 2) to establish whether concentrations of AF IGF II and its binding proteins IGF BP1 and 3, measured early in pregnancy, were associated with and predictive of infant birth weight. Birth weights were categorized using recently developed birth-weight-for-gestational-age percentiles for fetal growth in which infants < 10% were classified as SGA (small-for-gestational-age) and those > 90% as LGA (large-for-gestational-age). AF samples were collected after routine genetic testing (15.1 +/- 0.04 wk, range 12-20 wk) from 543 mother-infant pairs in Montreal, QC, Canada. Maternal and fetal characteristics were obtained from questionnaires and medical chart review. Multivariate regression analysis that controlled for maternal height, prepregnancy weight, smoking behavior, infant gender, gestational age, parity, as well as amniocentesis week showed that higher AF IGF BP1 was associated with lower birth weight (partial r2 = 0.0062). Regression analyses revealed that AF IGF BP3 was positively associated with birth weight within LGA and macrosomia subpopulations (partial r2 = 0.0283 and 0.0404, respectively). These results show that 2nd trimester AF IGF BP1, BP3, and IGF II may emerge as early indicators of fetal growth.