Maternal low and high hemoglobin concentrations and associations with adverse maternal and infant health outcomes: an updated global systematic review and meta-analysis.

BACKGROUND: Growing evidence suggests low and high maternal hemoglobin (Hb) concentrations may have adverse consequences for maternal and child health. There remain questions on specific Hb thresholds to define anemia and high Hb as well as how cutoffs may vary by anemia etiology and timing of assessment. METHODS: We conducted an updated systematic review (using PubMed and Cochrane Review) on low (< 110 g/L) and high (≥ 130 g/L) maternal Hb concentrations and associations with a range of maternal and infant health outcomes. We examined associations by timing of Hb assessment (preconception; first, second, and third trimesters, as well as at any time point in pregnancy), varying cutoffs used for defining low and high hemoglobin concentrations and performed stratified analyses by iron-deficiency anemia. We conducted meta-analyses to obtain odds ratios (OR) and 95% confidence intervals. RESULTS: The updated systematic review included 148 studies. Low maternal Hb at any time point in pregnancy was associated with: low birthweight, LBW (OR (95% CI) 1.28 (1.22-1.35)), very low birthweight, VLBW (2.15 (1.47-3.13)), preterm birth, PTB (1.35 (1.29-1.42)), small-for-gestational age, SGA (1.11 (1.02-1.19)), stillbirth 1.43 (1.24-1.65)), perinatal mortality (1.75 (1.28-2.39)), neonatal mortality (1.25 (1.16-1.34), postpartum hemorrhage (1.69 (1.45-1.97)), transfusion (3.68 (2.58-5.26)), pre-eclampsia (1.57 (1.23-2.01)), and prenatal depression (1.44 (1.24-1.68)). For maternal mortality, the OR was higher for Hb < 90 (4.83 (2.17-10.74)) than for Hb < 100 (2.87 (1.08-7.67)). High maternal Hb was associated with: VLBW (1.35 (1.16-1.57)), PTB (1.12 (1.00-1.25)), SGA (1.17 (1.09-1.25)), stillbirth (1.32 (1.09-1.60)), maternal mortality (2.01 (1.12-3.61)), gestational diabetes (1.71 (1.19-2.46)), and pre-eclampsia (1.34 (1.16-1.56)). Stronger associations were noted earlier in pregnancy for low Hb and adverse birth outcomes while the role of timing of high Hb was inconsistent. Lower Hb cutoffs were associated with greater odds of poor outcomes; for high Hb, data were too limited to identify patterns. Information on anemia etiology was limited; relationships did not vary by iron-deficiency anemia. CONCLUSION: Both low and high maternal Hb concentrations during pregnancy are strong predictors of adverse maternal and infant health outcomes. Additional research is needed to establish healthy reference ranges and design effective interventions to optimize maternal Hb during pregnancy.

Maternal hemoglobin concentrations across pregnancy and child health and development from birth through 6-7 years.

Background: The role of changes in maternal hemoglobin (Hb) across pregnancy on child health and development (CHD) remains unclear. Objective: We examined the association between maternal Hb trajectories and CHD outcomes: (a) birth outcomes (birth weight, length, gestational age, preterm, and small for gestational age); (b) child Hb at 3, 6, 12, and 24 months; and (c) motor and mental development at 12 and 24 months and cognitive functioning at age 6-7 years. Methods: We used data from a randomized controlled trial (PRECONCEPT) conducted in Vietnam (N = 1,175 women enrolled during preconception with offspring follow-up through 6-7 years). Maternal Hb trajectories were developed using latent class analysis with Hb data at preconception, early (≤20 weeks), mid (21-29 weeks), and late (≥30 weeks) pregnancy. Multivariable linear and logistic regression models were used to assess the association between maternal Hb trajectories on CHD outcomes, adjusting for confounding variables at the maternal, child and household levels. Results: Four distinct maternal Hb trajectories were identified. Track 1 (low initial Hb-decline) was associated with lower child Hb at 3 months (ß [95% CI] -0.52 [-0.87, -0.16]), 6 months (-0.36 [-0.68, -0.05]), 12 months (-0.46 [-0.79, -0.13]), and 24 months (-0.44 [-0.72, -0.15]) and motor development at 12 months (-3.58 [-6.76, -0.40]) compared to track 4 (high initial Hb-decline). After adjustment for multiple testing, relationships remained robust with the exception of associations with child Hb at 6 months and motor development at 12 months. Track 2 (low initial Hb-improve) was the only Hb trajectory to increase across pregnancy; however, it was insufficiently powered. Track 3 (mid Hb-decline) was associated with lower child Hb at 12 months (-0.27 [-0.44, -0.10]) and 24 months (-0.20 [-0.34, -0.05]) compared to track 4 (high initial Hb-decline). Maternal Hb trajectories were not associated with birth outcomes or child development at 24 months or 6-7 years. Conclusion: Maternal Hb trajectories during pregnancy are associated with child Hb concentrations across the first 1,000 days, but not with birth outcomes or later cognitive functioning. More work is needed to better understand and interpret changes in Hb levels during pregnancy especially in resource poor settings.

Enteral Multiple Micronutrient Supplementation in Preterm and Low Birth Weight Infants: A Systematic Review and Meta-analysis.

OBJECTIVES: To assess effects of supplementation with 3 or more micronutrients (multiple micronutrients; MMN) compared to no MMN in human milk-fed preterm and low birth weight (LBW) infants. RESULTS: Data on a subgroup of 414 preterm or LBW infants from 2 randomized controlled trials (4 reports) were included. The certainty of evidence ranged from low to very low. For growth outcomes in the MMN compared to the non-MMN group, there was a small increase in weight-for-age (2 trials, 383 participants) and height-for-age z-scores (2 trials, 372 participants); a small decrease in wasting (2 trials, 398 participants); small increases in stunting (2 trials, 399 participants); and an increase in underweight (2 trials, 396 participants). For neurodevelopment outcomes at 78 weeks, we found small increases in Bayley Scales of Infant Development, Version III (BISD-III), scores (cognition, receptive language, expressive language, fine motor, gross motor) in the MMN compared to the non-MMN group (1 trial, 27 participants). There were no studies examining dose or timing of supplementation. CONCLUSIONS: Evidence is insufficient to determine whether enteral MMN supplementation to preterm or LBW infants who are fed mother's own milk is associated with benefit or harm. More trials are needed to generate evidence on mortality, morbidity, growth, and neurodevelopment.

Maternal FADS2 single nucleotide polymorphism modified the impact of prenatal docosahexaenoic acid (DHA) supplementation on child neurodevelopment at 5 years: Follow-up of a randomized clinical trial.

BACKGROUND: Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 docosahexaenoic acid (DHA) on neurodevelopment. OBJECTIVE: To assess if maternal FADS2 single nucleotide polymorphisms (SNPs) modified the effect of prenatal DHA on offspring development at 5 years. DESIGN: We conducted a post-hoc interaction analysis of the POSGRAD randomized controlled trial (NCT00646360) of prenatal supplementation with algal-DHA where 1094 pregnant women originally randomized to 400 mg/day of preformed algal DHA or a placebo from gestation week 18-22 through delivery. In this analysis, we included offspring with information on maternal genotype and neurodevelopment at 5 years (DHA = 316; Control = 306) and used generalized linear models to assess interactions between FADS2 SNPs rs174602 or rs174575 and prenatal DHA on neurodevelopment at 5 years measured with McCarthy Scales of Children's Abilities (MSCA). RESULTS: Maternal and offspring characteristics were similar between groups. At baseline, mean (±standard deviation) maternal age was 26 ± 5 years and schooling was 12 ± 4 years. Forty-six percent (46%) of the children were female. Maternal minor allele frequencies were 0.37 and 0.33 for SNPs rs174602 and rs174575, respectively. There were significant variations by SNP rs174602 and intervention group (p for interactions <0.05) where children in the intervention group had higher MSCA scores on the quantitative (DHA: mean ± SEM = 22.6 ± 0.9 vs. Control = 19.1 ± 0.9, mean difference (Δ) = 3.45; p = 0.01) and memory (DHA = 27.9 ± 1.1 vs. Control = 23.7 ± 1.1, Δ = 4.26; p = 0.02) scales only among offspring of TT (minor allele homozygotes). CONCLUSIONS: Maternal FADS2 SNP rs174602 modified the effect of prenatal DHA on cognitive development at 5 years. Variations in the genetic make-up of target populations could be an important factor to consider for prenatal DHA supplementation interventions.

Infant Metabolome in Relation to Prenatal DHA Supplementation and Maternal Single-Nucleotide Polymorphism rs174602: Secondary Analysis of a Randomized Controlled Trial in Mexico.

BACKGROUND: Although DHA (22:6n-3) is critical for fetal development, results from randomized controlled trials (RCTs) of prenatal DHA supplementation report inconsistent effects on offspring health. Variants in fatty acid desaturase (FADS) genes that regulate the conversion of n-3 and n-6 essential fatty acids into their biologically active derivatives may explain this heterogeneity. OBJECTIVES: We investigated the effect of prenatal DHA supplementation on the offspring metabolome at age 3 mo and explored differences by maternal FADS single-nucleotide polymorphism (SNP) rs174602. METHODS: Data were obtained from a double-blind RCT in Mexico [POSGRAD (Prenatal Omega-3 Fatty Acid Supplementation and Child Growth and Development)] in which women (18-35 y old) received DHA (400 mg/d) or placebo from mid-gestation until delivery. Using high-resolution MS with LC, untargeted metabolomics was performed on 112 offspring plasma samples. Discriminatory metabolic features were selected via linear regression (P < 0.05) with false discovery rate (FDR) correction (q = 0.2). Interaction by SNP rs174602 was assessed using 2-factor ANOVA. Stratified analyses were performed, where the study population was grouped into carriers (TT, TC; n = 70) and noncarriers (CC; n = 42) of the minor allele. Pathway enrichment analysis was performed with Mummichog (P < 0.05). RESULTS: After FDR correction, there were no differences in metabolic features between infants whose mothers received prenatal DHA (n = 58) and those whose mothers received placebo (n = 54). However, we identified 343 differentially expressed features in the interaction analysis after FDR correction. DHA supplementation positively enriched amino acid and aminosugars metabolism pathways and decreased fatty acid metabolism pathways among offspring of minor allele carriers and decreased metabolites within the tricarboxylic acid cycle and galactose metabolism pathways among offspring of noncarriers. CONCLUSIONS: Our findings demonstrate differences in infant metabolism in response to prenatal DHA supplementation by maternal SNP rs174602 and further support the need to incorporate genetic analysis of FADS polymorphisms into DHA supplementation trials.This trial was registered at clinicaltrials.gov as NCT00646360.

Immunologic mechanisms of seasonal influenza vaccination administered by microneedle patch from a randomized phase I trial.

In a phase 1 randomized, single-center clinical trial, inactivated influenza virus vaccine delivered through dissolvable microneedle patches (MNPs) was found to be safe and immunogenic. Here, we compare the humoral and cellular immunologic responses in a subset of participants receiving influenza vaccination by MNP to the intramuscular (IM) route of administration. We collected serum, plasma, and peripheral blood mononuclear cells in 22 participants up to 180 days post-vaccination. Hemagglutination inhibition (HAI) titers and antibody avidity were similar after MNP and IM vaccination, even though MNP vaccination used a lower antigen dose. MNPs generated higher neuraminidase inhibition (NAI) titers for all three influenza virus vaccine strains tested and triggered a larger percentage of circulating T follicular helper cells (CD4 + CXCR5 + CXCR3 + ICOS + PD-1+) compared to the IM route. Our study indicates that inactivated influenza virus vaccination by MNP produces humoral and cellular immune response that are similar or greater than IM vaccination.

A Retrospective Chart Review on the Role of Suppressive Therapy in the Management of Spinal Infections Involving Hardware.

BACKGROUND: One percent to 8% of patients undergoing spinal instrumentation surgeries develop infections. There is no consensus on the medical and surgical management of these infections. METHODS: We conducted a retrospective chart review based on International Classification of Diseases, Ninth Revision, and Common Procedural Terminology codes relevant to spinal infections with hardware within Emory Healthcare over a 10-year period. Extracted data included patient demographics, clinical presentation, laboratory and microbiologic results, and surgical and medical management including choice and duration of suppressive therapy. Multivariable logistic regression was used to assess the association of length of use of suppressive antibiotics with treatment success and to identify predictors of use of suppressive antibiotics. RESULTS: Of 869 records, 124 met inclusion criteria. Fifty patients (40.3%) had an infection that occurred after hardware placement, mostly within 3 months postsurgery, while the remainder had vertebral osteomyelitis that required hardware placement. After initial intravenous antibiotic treatment for ≥4 weeks, 72 patients (64.5%) were given suppressive antibiotics. The overall treatment success rate was 78.2%. In spinal infections involving hardware with gram-negative rods, patients were less likely to receive suppressive antibiotics, less likely to have hardware removed, and less likely to have treatment success compared with patients with infections with Staphylococcus species. CONCLUSIONS: Management of spinal infections involving hardware should be tailored to the timing of onset of infection and causative organism. Further studies are needed to determine best management practices, particularly for gram-negative rod infections where the role of further suppressive antibiotics and hardware removal may be warranted.

Maternal hemoglobin concentrations across pregnancy and maternal and child health: a systematic review and meta-analysis.

Maternal anemia is a well-recognized global health problem; however, there remain questions on specific hemoglobin (Hb) thresholds that predict health risk or protection for mother and child. We conducted a systematic review and meta-analysis to examine the associations of maternal Hb concentrations with a range of maternal and infant health outcomes, accounting for the timing of measurement (preconception, and first, second, and third trimesters), etiology of anemia, and cutoff category. The systematic review included 272 studies and the meta-analysis included 95 studies. Low maternal Hb (<110 g/L) was associated with poor birth outcomes (low birth weight, preterm birth, small-for-gestational-age (SGA), stillbirth, and perinatal and neonatal mortality) and adverse maternal outcomes (postpartum hemorrhage, preeclampsia, and blood transfusion). High maternal Hb (>130 g/L) was associated with increased odds of SGA, stillbirth, preeclampsia, and gestational diabetes. Relationships varied by the timing of measurement and cutoff category (stronger associations with lower cutoffs); limited data were available on anemia etiology. There were insufficient data for other maternal outcomes and long-term child health outcomes. Current data are insufficient for determining if revisions to current Hb cutoffs are required. Pooled high-quality individual-level data analyses, as well as prospective cohort studies, would be valuable to inform the reevaluation of Hb cutoffs.

Effects of Supplemental Calcium and Vitamin D on Expression of Toll-Like Receptors and Phospho-IKKα/ß in the Normal Rectal Mucosa of Colorectal Adenoma Patients.

Chronic inflammation in the colorectum, a significant contributor to colorectal carcinogenesis, can be triggered by the activation of proinflammatory signaling pathways such as those initiated by Toll-like receptors (TLR) and nuclear factor κB (NF-κB). Although experimental evidence supports calcium and vitamin D potentially modifying these proinflammatory pathways in the colorectum, human data in these regards are scarce. We investigated supplemental calcium (1,200 mg daily) and/or vitamin D3 (1,000 IU daily) effects on inflammatory signaling pathway-related biomarkers in a subset of 105 participants from a colorectal adenoma recurrence chemoprevention clinical trial. We assessed expression of TLR4 and TLR5, which recognize the bacterial components lipopolysaccharides and flagellin, respectively, and phospho-IKKα/ß (pIKKα/ß), a biomarker of inflammation, in the normal-appearing rectal crypt epithelium and stroma using standardized, automated immunohistochemistry and quantitative image analysis. Following 1 year of treatment, TLR4, TLR5, and pIKKα/ß expression in the rectal mucosa did not statistically significantly change with vitamin D or calcium supplementation, taken alone or in combination. Several baseline participant characteristics, including body mass index, history of sessile serrated adenomas, high red/processed meat intake, and high levels of rectal epithelial cell proliferation (as measured by MIB-1/Ki-67), were associated with higher baseline expression of TLRs or pIKKα/ß. Our findings suggest that vitamin D and calcium may have no substantial effect on the investigated biomarkers. However, several modifiable lifestyle factors may be associated with TLRs and pIKKα/ß expression in the normal rectal mucosa, supporting their future investigation as potentially treatable, preneoplastic risk factors for colorectal neoplasms. Cancer Prev Res; 11(11); 707-16. ©2018 AACR.