Metabolomic profiles during early childhood and risk of food allergies and asthma in multiethnic children from a prospective birth cohort.

BACKGROUND: There are increasing numbers of metabolomic studies in food allergy (FA) and asthma, which, however, are predominantly limited by cross-sectional designs, small sample size, and being conducted in European populations. OBJECTIVE: We sought to identify metabolites unique to and shared by children with FA and/or asthma in a racially diverse prospective birth cohort, the Boston Birth Cohort. METHODS: Mass spectrometry-based untargeted metabolomic profiling was performed using venous plasma collected in early childhood (n = 811). FA was diagnosed according to clinical symptoms consistent with an acute hypersensitivity reaction at food ingestion and food specific-IgE > 0.35 kU/L. Asthma was defined on the basis of physician diagnosis. Generalized estimating equations were applied to analyze metabolomic associations with FA and asthma, adjusting for potential confounders. RESULTS: During a mean ± standard deviation follow-up of 11.8 ± 5.2 years from birth, 78 children developed FA and 171 developed asthma. Androgenic and pregnenolone steroids were significantly associated with a lower risk of FA, especially for egg allergy. N,N,N-trimethyl-5-aminovalerate (odds ratio [OR] = 0.65, 95% confidence interval [CI] = 0.48-0.87), and 1-oleoyl-2-arachidonoyl-sn-glycero-3-phosphoinositol (OR = 0.77; 95% CI = 0.66-0.90) were inversely associated with FA risk. Orotidine (OR = 4.73; 95% CI = 2.2-10.2) and 4-cholesten-3-one (OR = 0.52; 95% CI = 0.35-0.77) were the top 2 metabolites associated with risk of asthma, although they had no association with FA. In comparison, children with both FA and asthma exhibited an altered metabolomic profile that aligned with that of FA, including altered levels of lipids and steroids. CONCLUSION: In this US multiethnic prospective birth cohort, unique and shared alterations in plasma metabolites during early childhood were associated with risk of developing FA and/or asthma. These findings await further validation.

Maternal Mediterranean-Style Diet Adherence during Pregnancy and Metabolomic Signature in Postpartum Plasma: Findings from the Boston Birth Cohort.

BACKGROUND: The health benefits of a Mediterranean-style diet (MSD) are well observed, but the underlying mechanisms are unclear. Metabolomic profiling offers a systematic approach for identifying which metabolic biomarkers and pathways might be affected by an MSD. OBJECTIVES: This study aimed to identify postpartum plasma metabolites that are associated with MSD adherence during pregnancy and to further test whether these identified metabolites may vary by maternal characteristics. METHODS: We analyzed data from 1410 mothers enrolled in the Boston Birth Cohort (BBC). A maternal food frequency questionnaire (FFQ) was administered and epidemiologic information was obtained via an in-person standard questionnaire interview within 24-72 h postpartum. Maternal clinical information was extracted from electronic medical records. A Mediterranean-style diet score (MSDS) was calculated using responses to the FFQ. Metabolomic profiling in postpartum plasma was conducted by liquid chromatography-MS. Linear regression models were used to assess the associations of each metabolite with an MSDS, adjusting for covariates. RESULTS: Among the 380 postpartum plasma metabolites analyzed, 24 were associated with MSDS during pregnancy (false discovery rate < 0.05). Of 24 MSDS-associated metabolites, 19 were lipids [for example, triacylglycerols, phosphatidylcholines (PCs), PC plasmalogen, phosphatidylserine, and phosphatidylethanolamine]; others were amino acids (methionine sulfoxide and threonine), tropane (nor-psi-tropine), vitamin (vitamin A), and nucleotide (adenosine). The association of adenosine and methionine sulfoxide with MSDS differed by race (P-interaction = 0.033) and maternal overweight or obesity status (P-interaction = 0.021), respectively. CONCLUSIONS: In the BBC, we identified 24 postpartum plasma metabolites associated with MSDS during pregnancy. The associations of the 2 metabolites varied by maternal race and BMI. This study provides a new insight into dietary effects on health under the skin. More studies are needed to better understand the metabolic pathways underlying the short- and long-term health benefits of an MSD during pregnancy.

The impact of COVID-19 on psychiatric clinical encounters among low-income racially-diverse children.

BACKGROUND: There is a lack of longitudinal data to examine the impact of COVID-19 on all types of clinical encounters among United States, underrepresented BIPOC (Black, Indigenous, and people of color), children. This study aims to examine the changes in all the outpatient clinical encounters during the pandemic compared to the baseline, with particular attention to psychiatric encounters and diagnoses. METHOD: This study analyzed 3-year (January 2019 to December 2021) longitudinal clinical encounter data from 3,394 children in the Boston Birth Cohort, a US urban, predominantly low-income, Black and Hispanic children. Outcomes of interest were completed outpatient clinical encounters and their modalities (telemedicine vs. in person), including psychiatric care and diagnoses, primary care, emergency department (ED), and developmental and behavioral pediatrics (DBP). RESULTS: The study children's mean (SD) age is 13.9 (4.0) years. Compared to 2019, psychiatric encounters increased by 38% in 2020, most notably for diagnoses of adjustment disorders, depression, and post-traumatic stress disorders (PTSD). In contrast, primary care encounters decreased by 33%, ED encounters decreased by 55%, and DBP care decreased by 16% in 2020. Telemedicine was utilized the most for psychiatric and DBP encounters and the least for primary care encounters in 2020. A remarkable change in 2021 was the return of primary care encounters to the 2019 level, but psychiatric encounters fluctuated with spikes in COVID-19 case numbers. CONCLUSIONS: Among this sample of US BIPOC children, compared to the 2019 baseline, psychiatric encounters increased by 38% during 2020, most notably for the new diagnoses of adjustment disorder, depression, and PTSD. The 2021 data showed a full recovery of primary care encounters to the baseline level but psychiatric encounters remained sensitive to the pandemic spikes. The long-term impact of the pandemic on children's mental health warrants further investigation.

Maternal pre-pregnancy BMI, offspring epigenome-wide DNA methylation, and childhood obesity: findings from the Boston Birth Cohort.

BACKGROUND: Maternal pre-pregnancy obesity is an established risk factor for childhood obesity. Investigating epigenetic alterations induced by maternal obesity during fetal development could gain mechanistic insight into the developmental origins of childhood obesity. While obesity disproportionately affects underrepresented racial and ethnic mothers and children in the USA, few studies investigated the role of prenatal epigenetic programming in intergenerational obesity of these high-risk populations. METHODS: This study included 903 mother-child pairs from the Boston Birth Cohort, a predominantly urban, low-income minority birth cohort. Mother-infant dyads were enrolled at birth and the children were followed prospectively to age 18 years. Infinium Methylation EPIC BeadChip was used to measure epigenome-wide methylation level of cord blood. We performed an epigenome-wide association study of maternal pre-pregnancy body mass index (BMI) and cord blood DNA methylation (DNAm). To quantify the degree to which cord blood DNAm mediates the maternal BMI-childhood obesity, we further investigated whether maternal BMI-associated DNAm sites impact birthweight or childhood overweight or obesity (OWO) from age 1 to age 18 and performed corresponding mediation analyses. RESULTS: The study sample contained 52.8% maternal pre-pregnancy OWO and 63.2% offspring OWO at age 1-18 years. Maternal BMI was associated with cord blood DNAm at 8 CpG sites (genome-wide false discovery rate [FDR] < 0.05). After accounting for the possible interplay of maternal BMI and smoking, 481 CpG sites were discovered for association with maternal BMI. Among them 123 CpGs were associated with childhood OWO, ranging from 42% decrease to 87% increase in OWO risk for each SD increase in DNAm. A total of 14 identified CpG sites showed a significant mediation effect on the maternal BMI-child OWO association (FDR < 0.05), with mediating proportion ranging from 3.99% to 25.21%. Several of these 14 CpGs were mapped to genes in association with energy balance and metabolism (AKAP7) and adulthood metabolic syndrome (CAMK2B). CONCLUSIONS: This prospective birth cohort study in a high-risk yet understudied US population found that maternal pre-pregnancy OWO significantly altered DNAm in newborn cord blood and provided suggestive evidence of epigenetic involvement in the intergenerational risk of obesity.

Fetal lipidome and incident risk of food allergy: A prospective birth cohort study.

BACKGROUND: Lipids are proposed to be important in developing adaptive immunity and allergy. However, studies to date reported inconsistent findings. OBJECTIVE: To examine newborn lipidome (a comprehensive profiling of circulating lipid metabolites) on child's risk of developing food allergy (FA). The maternal-cord joint effects of lipid metabolites on FA development were also investigated. METHODS: This study included 647 mother-child pairs from the Boston Birth Cohort and analyzed 202 lipid metabolites in cord plasma profiled by liquid chromatography tandem mass spectrometry. FA was defined based on standard clinical criteria. Logistic regression was applied to examine the relationships between individual metabolites and risk of FA. RESULTS: Of the 647 children, 61 developed FA. Cord triacylglycerols of long carbon chains and multiple double bonds were significantly associated with decreased risk of FA. These associations were comparable across strata of pertinent maternal and child covariates, and were independent of maternal triacylglycerols when assessed simultaneously. Besides, cord and maternal triacylglycerols had an additive effect in association with risk of FA: Children having high (≥Median) C56:8 triacylglycerol levels in both cord and maternal plasma were at the lowest risk of developing FA (OR = 0.24, 95% CI = 0.10-0.56, p = .001), compared to those having low levels in both cord and maternal plasma. CONCLUSION: This is the first birth cohort study to link altered cord plasma lipidome with future risk of development FA during childhood. It calls for further investigation on triacylglycerols of long carbon chains and multiple double bonds as potential novel predictive biomarkers and therapeutic targets for FA.

A prospective cohort study on the intersectionality of obesity, chronic disease, social factors, and incident risk of COVID-19 in US low-income minority middle-age mothers.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) has disproportionally affected communities of color. We aimed to determine what factors are associated with COVID-19 testing and test positivity in an underrepresented, understudied, and underreported (U3) population of mothers. METHODS: This study included 2996 middle-aged mothers of the Boston Birth Cohort (a sample of predominantly urban, low-income, Black and Hispanic mothers) who were enrolled shortly after they gave birth and followed onward at the Boston Medical Center. COVID-19 testing and test positivity were defined by the SARS-CoV-2 nucleic acid test. Two-probit Heckman selection models were performed to identify factors associated with test positivity while accounting for potential selection associated with COVID testing. RESULTS: The mean (SD) age of study mothers was 41.9 (±7.7) years. In the sample, 1741 (58.1%) and 667 (22.3%) mothers were self-identified as Black and Hispanic, respectively. A total of 396 mothers had COVID-19 testing and of those, 95 mothers tested positive from March 2020 to February 2021. Among a multitude of factors examined, factors associated with the probability of being tested were obesity (RR = 1.27; 95% confidence interval (CI): 1.08-1.49); and presence of preexisting chronic medical conditions including hypertension, asthma, stroke, and other comorbidities (coronary heart disease, chronic kidney disease, and sickle cell disease) with a corresponding RR = 1.40 (95% CI: 1.23-1.60); 1.29 (95% CI: 1.11-1.50); 1.44 (95% CI: 1.23-1.68); and 1.37 (95% CI: 1.12-1.67), respectively. Factors associated with higher incident risk of a positive COVID-19 test were body mass index, birthplace outside of the USA, and being without a college-level education. CONCLUSIONS: This study demonstrated the intersectionality of obesity and social factors in modulating incident risk of COVID-19 in this sample of US Black and Hispanic middle-aged mothers. Methodologically, our findings underscore the importance of accounting for potential selection bias in COVID-19 testing in order to obtain unbiased estimates of COVID-19 infection.

Trajectory of Body Mass Index from Ages 2 to 7 Years and Age at Peak Height Velocity in Boys and Girls.

OBJECTIVE: To examine the associations between body mass index (BMI) at 2-4 years and 5-7 years and age at peak height velocity (APHV), an objective measure of pubertal timing, among boys and girls from predominantly racial minorities in the US that have been historically underrepresented in this research topic. STUDY DESIGN: This study included 1296 mother-child dyads from the Boston Birth Cohort, a predominantly Black and low-income cohort enrolled at birth and followed prospectively during 1998-2018. The exposure was overweight or obesity, based on Centers for Disease Control and Prevention reference standards. The outcome was APHV, derived using a mixed effects growth curve model. Multiple regression was used to estimate the overweight or obesity-APHV association and control for confounders. RESULTS: Obesity at 2-4 years was associated with earlier APHV in boys (B in years, -0.19; 95% CI, -0.35 to -0.03) and girls (B, -0.22; 95% CI, -0.37 to -0.07). Obesity at 5-7 years was associated with earlier APHV in boys (B, -0.18; 95% CI, -0.32 to -0.03), whereas overweight and obesity at 5-7 years were both associated with earlier APHV in girls (overweight: B, -0.24; 95% CI, -0.40 to -0.08; obesity: B, -0.27; 95% CI, -0.40 to -0.13). With BMI trajectory, boys with persistent overweight or obesity and girls with overweight or obesity at 5-7 years, irrespective of overweight or obesity status at 2-4 years, had earlier APHV. CONCLUSIONS: This prospective birth cohort study found that overweight or obesity during 2-7 years was associated with earlier pubertal onset in both boys and girls. The BMI trajectory analyses further suggest that reversal of overweight or obesity may halt the progression toward early puberty.

A Nonlinear Relation Between Maternal Red Blood Cell Manganese Concentrations and Child Blood Pressure at Age 6-12 y: A Prospective Birth Cohort Study.

BACKGROUND: Although manganese (Mn) is an essential trace element and a common component of most multivitamins on the market, an adverse effect on blood pressure (BP) has been reported in adults. In addition, the longitudinal relation between prenatal Mn status and childhood BP is still unknown. OBJECTIVE: This study investigated the association between prenatal Mn concentrations and risk of elevated BP at ages 3-12 y. METHOD: The analyses included 1268 mother-child dyads who were enrolled at birth and followed prospectively at the Boston Medical Center. Maternal RBC Mn concentrations were measured by inductively coupled plasma mass spectrometry, using RBCs collected within 1-3 d after delivery (reflecting late-pregnancy Mn exposure). Child elevated BP was defined as systolic or diastolic BP ≥90th percentile for a given age, sex and height. Multivariate logistic regression models were conducted. Path analysis was applied to mediation estimation. RESULTS: The median (IQR) maternal RBC Mn concentration was 37.5 (29.2-48.5) µg/L. The rate of child elevated BP at ages 3-12 y was 25%. Both the lowest and highest quartiles of maternal RBC Mn concentrations were associated with higher risk of elevated BP among children aged 6-12 y (OR: 1.52; 95% CI: 1.04, 2.21 and OR: 1.65; 95% CI: 1.13, 2.40, respectively) compared with those in the second and third quartiles. Gestational age and fetal growth mediated the association between low maternal RBC Mn (first quartile) and child elevated BP, explaining 25% of the association, but not for high (fourth quartile) maternal RBC Mn concentrations. No association was found between maternal RBC Mn concentrations and BP among children aged 3-5 y. CONCLUSION: We found a nonlinear association between maternal RBC Mn concentrations and elevated BP among children aged 6-12 y from a high-risk, predominantly minority population. Our findings warrant further investigation.

Genome-wide association study identifies a novel maternal gene × stress interaction associated with spontaneous preterm birth.

BACKGROUND: Maternal stress is potentially a modifiable risk factor for spontaneous preterm birth (sPTB). However, epidemiologic findings on the maternal stress-sPTB relationship have been inconsistent. METHODS: To investigate whether the maternal stress-sPTB associations may be modified by genetic susceptibility, we performed genome-wide gene × stress interaction analyses in 1490 African-American women from the Boston Birth cohort who delivered term (n = 1033) or preterm (n = 457) infants. Genotyping was performed using Illumina HumanOmni 2.5 array. Replication was performed using data from the NICHD genomic and Proteomic Network (GPN) for PTB research. RESULTS: rs35331017, a T-allele insertion/deletion polymorphism in the protein-tyrosine phosphatase receptor Type D (PTPRD) gene, was the top hit that interacted significantly with maternal lifetime stress on risk of sPTB (PG × E = 4.7 × 10-8). We revealed a dose-responsive association between degree of stress and risk of sPTB in mothers carrying the insertion/insertion genotype, but an inverse association was observed in mothers carrying the heterozygous or deletion/deletion genotypes. This interaction was replicated in African-American (PG × E = 0.088) and Caucasian mothers (PG × E = 0.023) from the GPN study. CONCLUSION: We demonstrated a significant maternal PTPRD × stress interaction on sPTB risk. This finding, if further confirmed, may provide new insight into individual susceptibility to stress-induced sPTB. IMPACT: This was the first preterm study to demonstrate a significant genome-wide gene-stress interaction in African Americans, specifically, PTPRD gene variants can interact with maternal perceived stress to affect risk of spontaneous preterm birth. The PTPRD × maternal stress interaction was demonstrated in African Americans and replicated in both African Americans and Caucasians from the GPN study. Our findings highlight the importance of considering genetic susceptibility in assessing the role of maternal stress on spontaneous preterm birth.

Maternal and cord plasma branched-chain amino acids and child risk of attention-deficit hyperactivity disorder: a prospective birth cohort study.

BACKGROUND: Branched-chain amino acids (BCAA: leucine, isoleucine, and valine) are essential amino acids involved in biological functions of brain development and recently linked with autism. However, their role in attention-deficit hyperactivity disorder (ADHD) is not well-studied. We investigated individual and combined relationships of maternal plasma and newborn cord plasma BCAAs with childhood development of ADHD. METHODS: We utilized the Boston Birth Cohort, a predominantly urban, low-income, US minority population. Child developmental outcomes were defined in three mutually exclusive groups - ADHD, neurotypical (NT), or other developmental disabilities based on physician diagnoses per ICD-9 or 10 in medical records. The final sample included 626 children (299 ADHD, 327 NT) excluding other developmental disabilities. BCAAs were measured by liquid chromatography-tandem mass spectrometry. We used factor analysis to create composite scores of maternal and cord BCAA, which we divided into tertiles. Logistic regressions analyzed relationships between maternal or cord BCAA tertiles with child ADHD risk, controlling for maternal race, age, parity, smoking, education, low birth weight, preterm birth, and child sex. Additionally, we analyzed maternal and cord plasma BCAAs jointly on child ADHD risk. RESULTS: Adjusted logistic regression found significantly increased odds of child ADHD diagnosis for the second (OR 1.63, 95% CI: 1.04, 2.54, p = .032) and third tertiles (OR 2.01, 95% CI: 1.28, 3.15, p = .002) of cord BCAA scores compared to the first tertile. This finding held for the third tertile when further adjusting for maternal BCAA score. There was no significant association between maternal BCAA score and child ADHD risk, nor a significant interaction between maternal and cord BCAA scores. CONCLUSIONS: In this prospective US birth cohort, higher cord BCAA levels were associated with a greater risk of developing ADHD in childhood. These results have implications for further research into mechanisms of ADHD development and possible early life screening and interventions.

Postpartum plasma metabolomic profile among women with preeclampsia and preterm delivery: implications for long-term health.

BACKGROUND: Preeclampsia and preterm delivery (PTD) are believed to affect women's long-term health including cardiovascular disease (CVD), but the biological underpinnings are largely unknown. We aimed to test whether maternal postpartum metabolomic profiles, especially CVD-related metabolites, varied according to PTD subtypes with and without preeclampsia, in a US urban, low-income multi-ethnic population. METHODS: This study, from the Boston Birth Cohort, included 980 women with term delivery, 79 with medically indicated PTD (mPTD) and preeclampsia, 52 with mPTD only, and 219 with spontaneous PTD (sPTD). Metabolomic profiling in postpartum plasma was conducted by liquid chromatography-mass spectrometry. Linear regression models were used to assess the associations of each metabolite with mPTD with preeclampsia, mPTD only, and sPTD, respectively, adjusting for pertinent covariates. Weighted gene coexpression network analysis was applied to investigate interconnected metabolites associated with the PTD/preeclampsia subgroups. Bonferroni correction was applied to account for multiple testing. RESULTS: A total of 380 known metabolites were analyzed. Compared to term controls, women with mPTD and preeclampsia showed a significant increase in 36 metabolites, mainly representing acylcarnitines and multiple classes of lipids (diacylglycerols, triacylglycerols, phosphocholines, and lysophosphocholines), as well as a decrease in 11 metabolites including nucleotides, steroids, and cholesteryl esters (CEs) (P < 1.3 × 10-4). Alterations of diacylglycerols, triacylglycerols, and CEs in women with mPTD and preeclampsia remained significant when compared to women with mPTD only. In contrast, the metabolite differences between women with mPTD only and term controls were only seen in phosphatidylethanolamine class. Women with sPTD had significantly different levels of 16 metabolites mainly in amino acid, nucleotide, and steroid classes compared to term controls, of which, anthranilic acid, bilirubin, and steroids also had shared associations in women with mPTD and preeclampsia. CONCLUSION: In this sample of US high-risk women, PTD/preeclampsia subgroups each showed some unique and shared associations with maternal postpartum plasma metabolites, including those known to be predictors of future CVD. These findings, if validated, may provide new insight into metabolomic alterations underlying clinically observed PTD/preeclampsia subgroups and implications for women's future cardiometabolic health.

Can social support during pregnancy affect maternal DNA methylation? Findings from a cohort of African-Americans.

BACKGROUND: While stress and the absence of social support during pregnancy have been linked to poor health outcomes, the underlying biological mechanisms are unclear. METHODS: We examined whether adverse experiences during pregnancy alter DNA methylation (DNAm) in maternal epigenomes. Analyses included 250 African-American mothers from the Boston Birth Cohort. Genome-wide DNAm profiling was performed in maternal blood collected after delivery, using the Infinium HumanMethylation450 Beadchip. Linear regression models, with adjustment of pertinent covariates, were applied. RESULTS: While self-reported maternal psychosocial lifetime stress and stress during pregnancy was not associated with DNAm alterations, we found that absence of support from the baby's father was significantly associated with maternal DNAm changes in TOR3A, IQCB1, C7orf36, and MYH7B and that lack of support from family and friends was associated with maternal DNA hypermethylation on multiple genes, including PRDM16 and BANKL. CONCLUSIONS: This study provides intriguing results suggesting biological embedding of social support during pregnancy on maternal DNAm, warranting additional investigation, and replication.

Maternal persistent marijuana use and cigarette smoking are independently associated with shorter gestational age.

BACKGROUND: Research assessing the effects of marijuana use on preterm birth has found mixed results, in part, due to lack of attention to the role of maternal tobacco smoking during pregnancy. OBJECTIVES: The study objective was to investigate whether maternal marijuana use was independently associated with gestational age, preterm birth, and two preterm birth subtypes (spontaneous vs clinician-initiated). METHODS: Participants included 8261 mother-newborn pairs from the Boston Birth Cohort. Information on gestational age was collected from electronic medical records. Marijuana use and tobacco smoking during pregnancy were assessed through a standard questionnaire after birth. Linear and log-linear regression models were used to assess associations between marijuana use with and without tobacco smoking during pregnancy and the outcomes of interest. RESULTS: Of the 8261 mothers, 27.5% had preterm births. About 3.5% of mothers with term deliveries and 5.2% of mothers with preterm births used marijuana during pregnancy. Marijuana use and cigarette smoking were independently associated with a decrease in gestational age by 0.50 weeks (95% confidence interval [CI] -0.87, -0.13) and 0.52 weeks (95% CI -0.76, -0.28), respectively. Marijuana use during early or late pregnancy was associated with a similar decrease in gestational age by 0.50 weeks. When we examined the effects on the preterm birth subtypes, simultaneous marijuana use and tobacco smoking were associated with higher risk of spontaneous preterm birth (RR 1.64, 95% CI 1.23, 2.18). The elevated risk was not observed with clinician-initiated preterm birth. CONCLUSIONS: In this high-risk US population, maternal marijuana use and cigarette smoking during pregnancy were independently associated with shorter gestational age. When we examined the effects on preterm birth subtypes, the elevated risk was only observed with spontaneous preterm birth.

Maternal triacylglycerol signature and risk of food allergy in offspring.

BACKGROUND: The prevalence of IgE-mediated food allergy (FA) is increasing worldwide, but the underlying mechanisms are poorly understood. OBJECTIVE: We sought to examine the role of maternal lipidomic profiles in risk of FA development in offspring and to investigate the potential modification effects by timing of first solid-food introduction. METHODS: This report included 1068 mother-child dyads from the Boston Birth Cohort. Maternal lipid metabolites in plasma were assessed by using liquid chromatography tandem mass spectrometry. Food sensitization (FS) was defined as a specific IgE level of 0.35 kU/L or greater to any of the 8 common food allergens determined by using ImmunoCAP. FA was defined based on FS, clinical symptoms, and food avoidance. Logistic regression was applied to analyze associations between maternal metabolites and risk of FS and FA in offspring and to explore potential effect modifications. RESULTS: Of the 1068 children, 411 had FS, and 132 had FA. Among the 209 metabolites, maternal triacylglycerols (TAGs) of shorter carbon chains and fewer double bonds were associated with greater risk of FA, whereas TAGs of longer carbon chains and more double bonds were significantly associated with lower risk of FA in offspring. These associations were stronger in children with delayed solid-food introduction (≥7 months of age) than those with earlier solid-food introduction (P = .010 for interaction between the maternal TAG score and timing of solid-food introduction). No significant association was found for FS. CONCLUSION: This is the first study to demonstrate a link between maternal TAGs and risk of FA in offspring and potential risk modification by timing of solid-food introduction.

Inter-generational link of obesity in term and preterm births: role of maternal plasma acylcarnitines.

BACKGROUND/OBJECTIVES: Acylcarnitines, intermediates of fatty acid oxidation, are known to be involved in obesity and insulin resistance. Since maternal prepregnancy overweight or obesity (OWO) is a recognized major risk factor for offspring OWO, we hypothesized that maternal plasma acylcarnitines may play a role in inter-generational OWO. SUBJECTS/METHODS: This study included 1402 mother-child pairs (1043 term, 359 preterm) recruited at birth from 1998-2013 and followed prospectively up to age 18 years at the Boston Medical Center. The primary outcomes were child OWO defined as BMI ≥ 85th percentile for age and sex. The primary exposures were maternal prepregnancy OWO defined as BMI ≥ 25 kg/m2 and maternal acylcarnitine levels measured in plasma samples collected soon after delivery using liquid chromatography-tandem mass spectrometry (LC-MS) in a targeted manner. RESULTS: Approximately 40% of the children in this study were OWO by age 5. Maternal OWO had a significant association with childhood OWO, both in term and preterm births. ß-hydroxybutyryl-carnitine (C4-OH) levels were significantly and positively associated with child OWO among term births after adjustment for potential confounders and multiple-comparisons. Children born to OWO mothers in the top tertile C4-OH levels were at the highest risk of OWO: OR = 3.78 (95%CI: 2.47, 5.79) as compared with those born to non-OWO mothers in the lowest tertile (P for interaction of maternal OWO and C4-OH = 0.035). In a four-way decomposition of mediation/interaction analysis, we estimated that C4-OH levels explained about 27% (se = 0.08) of inter-generational OWO risk (P = 0.001). In contrast, these associations were not observed in preterm births. CONCLUSIONS: In this U.S. urban low-income birth cohort, we provide further evidence of the inter-generational link of OWO and reveal the differential role of C4-OH in explaining the inter-generational obesity between term and preterm births. Further investigations are warranted to better understand and prevent the inter-generational transmission of OWO.

Prenatal, Perinatal, and Early Childhood Factors Associated with Childhood Obstructive Sleep Apnea.

OBJECTIVES: To investigate prenatal, perinatal, and early childhood factors, including cord and early childhood plasma leptin, on a clinical diagnosis of obstructive sleep apnea (OSA) among children in the Boston Birth Cohort. STUDY DESIGN: We conducted a secondary analysis of 2867 mother-child pairs from the Boston Birth Cohort who were enrolled between 1998 and 2014 at Boston Medical Center and followed from birth to age 16 years. Child's OSA was defined based on clinical diagnoses documented in the medical record. Plasma leptin was measured in cord and early childhood blood samples. Logistic regression was used to examine individual and combined effects of early life factors on the risk of OSA, adjusting for potential confounders. RESULTS: The mean age of the study children was 6.39 years (SD = 3.77); 49.3% were girls, and 209 (7.3%) had ever been diagnosed with OSA. Four significant risk factors for OSA were identified: maternal obesity/diabetes during pregnancy (OR, 1.63; 95% CI, 1.21-2.21; P = .001), preterm/low birth weight (OR, 1.74; 95% CI, 1.30-2.32; P < .001), early childhood obesity (OR, 1.89; 95% CI, 1.37-2.62; P < .001), and high leptin levels in early childhood (OR, 1.94; 95% CI, 1.22-3.09; P = .005). The presence of all these 4 risk factors significantly amplified the odds of OSA by about 10 times (OR, 9.95; 95% CI, 3.42-28.93; P < .001) compared with those lacking these factors. CONCLUSIONS: Our findings, if further confirmed, provide new insight into the early life risk factors of pediatric OSA and underscore the need for early screening and prevention of OSA among children with those risk factors.

Maternal Multivitamin Intake, Plasma Folate and Vitamin B12 Levels and Autism Spectrum Disorder Risk in Offspring.

BACKGROUND: To examine the prospective association between multivitamin supplementation during pregnancy and biomarker measures of maternal plasma folate and vitamin B12 levels at birth and child's Autism Spectrum Disorder (ASD) risk. METHODS: This report included 1257 mother-child pairs, who were recruited at birth and prospectively followed through childhood at the Boston Medical Center. ASD was defined from diagnostic codes in electronic medical records. Maternal multivitamin supplementation was assessed via questionnaire interview; maternal plasma folate and B12 were measured from samples taken 2-3 days after birth. RESULTS: Moderate (3-5 times/week) self-reported supplementation during pregnancy was associated with decreased risk of ASD, consistent with previous findings. Using this as the reference group, low (≤2 times/week) and high (>5 times/week) supplementation was associated with increased risk of ASD. Very high levels of maternal plasma folate at birth (≥60.3 nmol/L) had 2.5 times increased risk of ASD [95% confidence interval (CI) 1.3, 4.6] compared to folate levels in the middle 80th percentile, after adjusting for covariates including MTHFR genotype. Similarly, very high B12 (≥536.8 pmol/L) showed 2.5 times increased risk (95% CI 1.4, 4.5). CONCLUSION: There was a 'U shaped' relationship between maternal multivitamin supplementation frequency and ASD risk. Extremely high maternal plasma folate and B12 levels at birth were associated with ASD risk. This hypothesis-generating study does not question the importance of consuming adequate folic acid and vitamin B12 during pregnancy; rather, raises new questions about the impact of extremely elevated levels of plasma folate and B12 exposure in-utero on early brain development.

Prepregnancy body mass index and risk of preterm birth: association heterogeneity by preterm subgroups.

BACKGROUND: To evaluate the association between prepregnancy body mass index (BMI) is associated with early vs. late and medically-induced vs. spontaneous preterm birth (PTB) subtypes. METHODS: Using data from the Boston Birth Cohort, we examined associations of prepregnancy BMI with 189 early (<34 completed weeks) and 277 late (34-36 completed weeks) medically-induced PTBs and 320 early and 610 late spontaneous PTBs vs. 3281 term births (37-44 weeks) in multinomial regression. To assess for mediation by important pregnancy complications, we performed sequential models with and without hypertensive disorders of pregnancy, chorioamnionitis, and gestational diabetes. RESULTS: Prevalence of prepregnancy obesity (BMI ≥ 30.0 kg/m2) was 28% among mothers with medically-induced PTBs, 18% among mothers with spontaneous PTBs, and 18% among mothers with term births (p = <0.001). After adjustment for demographic and known risk factors for PTB, prepregnancy obesity was associated with higher odds of both early [OR 1.78 (1.19, 2.66)] and late [OR 1.49 (1.09, 2.04)] medically-induced PTB. These effect estimates were attenuated with inclusion of hypertensive disorders of pregnancy and gestational diabetes. For spontaneous deliveries, prepregnancy obesity was associated with decreased odds of PTB (0.76 [0.58, 0.98]) and underweight was nearly associated with increased odds of PTB (1.46 [0.99, 2.16]). CONCLUSION: Prepregnancy obesity is associated with higher risk of medically-induced, but not spontaneous PTB. Hypertensive disorders of pregnancy and gestational diabetes appear to partially explain the association between prepregnancy obesity and early and late medically-induced PTB.

Preterm birth and random plasma insulin levels at birth and in early childhood.

IMPORTANCE: Although previous reports have linked preterm birth with insulin resistance in children and adults, it is not known whether altered insulin homeostasis is detectable at birth and tracks from birth through childhood. OBJECTIVE: To investigate whether preterm birth is associated with elevated plasma insulin levels at birth and whether this association persists into early childhood. DESIGN, SETTING, AND PARTICIPANTS: A prospective birth cohort of 1358 children recruited at birth from 1998 to 2010 and followed-up with prospectively from 2005 to 2012 at the Boston Medical Center in Massachusetts. MAIN OUTCOMES AND MEASURES: Random plasma insulin levels were measured at 2 time points: at birth (cord blood) and in early childhood (venous blood). The median age was 1.4 years (interquartile range [IQR], 0.8-3.3) among 4 gestational age groups: full term (≥39 wk), early term (37-38 wk), late preterm (34-36 wk), and early preterm (<34 wk). RESULTS: The geometric mean of insulin levels at birth were 9.2 µIU/mL (95% CI, 8.4-10.0) for full term; 10.3 µIU/mL (95% CI, 9.3-11.5) for early term; 13.2 µIU/mL (95% CI, 11.8-14.8) for late preterm; and 18.9 µIU/mL (95% CI, 16.6-21.4) for early preterm. In early childhood, these levels were 11.2 µIU/mL (95% CI, 10.3-12.0) for full term; 12.4 µIU/mL (95% CI, 11.3-13.6) for early term; 13.3 µIU/mL (95% CI, 11.9-14.8) for late preterm; and 14.6 µIU/mL (95% CI, 12.6-16.9) for early preterm. Insulin levels at birth were higher by 1.13-fold (95% CI, 0.97-1.28) for early term, 1.45-fold (95% CI, 1.25-1.65) for late preterm, and 2.05-fold (95% CI, 1.69-2.42) for early preterm than for those born full term. In early childhood, random plasma insulin levels were 1.12-fold (95% CI, 0.99-1.25) higher for early term, 1.19-fold (95% CI, 1.02-1.35) for late preterm, and 1.31-fold (95% CI, 1.10-1.52) for early preterm than those born full term. The association was attenuated after adjustment for postnatal weight gain and was not significant after adjustment for insulin levels at birth. Infants ranked in the top insulin tertile at birth were more likely to remain in the top tertile (41.2%) compared with children ranked in the lowest tertile (28.6%) in early childhood. CONCLUSIONS AND RELEVANCE: There was an inverse association between gestational age and elevated plasma insulin levels at birth and in early childhood. The implications for future development of insulin resistance and type 2 diabetes warrant further investigation.

The combined association of psychosocial stress and chronic hypertension with preeclampsia.

OBJECTIVE: This study aims to evaluate perceived lifetime stress, perceived stress during pregnancy, chronic hypertension, and their joint association with preeclampsia risk. STUDY DESIGN: This study includes 4314 women who delivered a singleton live birth at the Boston Medical Center from October 1998 through February 2008. Chronic hypertension was defined as hypertension diagnosed before pregnancy. Information regarding lifetime stress and perceived stress during pregnancy was collected by questionnaire. Preeclampsia was diagnosed by clinical criteria. RESULTS: Lifetime stress (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.6-2.9), perceived stress during pregnancy (OR, 1.7; 95% CI, 1.3-2.2), and chronic hypertension (OR, 10.4; 95% CI, 7.5-14.4) were each associated with an increased risk of preeclampsia. Compared to normotensive pregnancy with low lifetime stress, both normotensive pregnancy with high lifetime stress (OR, 2.1; 95% CI, 1.6-2.9) and pregnancy with chronic hypertension and low lifetime stress (OR, 10.2; 95% CI, 7.0-14.9) showed an increased risk of preeclampsia, while pregnancy with high lifetime stress and chronic hypertension yielded the highest risk of preeclampsia (OR, 21.3; 95% CI, 10.2-44.3). The joint association of perceived stress during pregnancy and chronic hypertension with preeclampsia was very similar to that of the joint association of lifetime stress and chronic hypertension with preeclampsia. CONCLUSION: This finding indicates that high psychosocial stress and chronic hypertension can act in combination to increase the risk of preeclampsia up to 20-fold. This finding underscores the importance of efforts to prevent, screen, and manage chronic hypertension, along with those to reduce psychosocial stress, particularly among women with chronic hypertension.