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.

Joint Associations of Pregnancy Complications and Postpartum Maternal Renal Biomarkers With Severe Cardiovascular Morbidities: A US Racially and Ethnically Diverse Prospective Birth Cohort Study.

Background Pregnancy complications are risk factors for cardiovascular disease (CVD). Little is known about the role of renal biomarkers measured shortly after delivery, individually or in combination with pregnancy complications, in predicting subsequent severe maternal CVD. Methods and Results This study included 566 mothers of diverse races and ethnicities from the Boston Birth cohort, enrolled at delivery and followed prospectively. Plasma creatinine and CysC (cystatin C) were measured 1 to 3 days after delivery. CVD during follow-up was defined by physician diagnoses in electronic medical records. Associations of renal biomarkers and pregnancy complications with time-to-CVD events were assessed using Cox proportional hazards models. During an average of 10.3±3.2 years of follow-up, 30 mothers developed 1 or more CVDs. Only a modest association was observed between creatinine and risk of CVD. In comparison, we found that per 0.1 mg/L increase of CysC was associated with a hazard ratio (HR) of 1.2 (95% CI, 1.1-1.4) for CVD after adjusting for covariates. Compared with those without preeclampsia and with normal CysC level (≤75th percentile), mothers with preeclampsia and elevated CysC (>75th percentile) had the highest risk of CVD (HR, 4.6 [95% CI, 1.7-17.7]), whereas mothers with preeclampsia only or with elevated CysC only did not have significantly increased CVD risk. Similar synergistic effects for CVD were observed between CysC and preterm delivery. Conclusions In this sample of US, traditionally underrepresented multiracial and multiethnic high-risk mothers, elevated maternal plasma CysC, independently and jointly with pregnancy complications, increased risk of CVD later in life. These findings warrant further investigation. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03228875.

Impact of consuming a Mediterranean-style diet during pregnancy on neurodevelopmental disabilities in offspring: results from the Boston Birth Cohort.

Background: While consuming a Mediterranean-style diet (MSD) among pregnant women is expected to affect offspring neurodevelopment, the current evidence is limited. This prospective birth cohort study aimed to explore the association of maternal MSD with neurodevelopmental disabilities (NDD) in offspring, especially among children born to mothers with overweight or obesity (OWO) and/or diabetes mellitus (DM) since they have a higher risk for oxidative stress and immune/metabolic disturbances. Methods: We analyzed data from a subgroup of mother-child dyads enrolled in the Boston Birth Cohort. Maternal dietary information (via food frequency questionnaires, Food frequency questionnaires [FFQ]) and sociodemographic information were obtained via in-person interviews within 24 to 72 hours postpartum. Maternal clinical information and child diagnosis of NDD including autism, attention-deficit/hyperactivity disorder (ADHD), and other developmental disabilities (DD) were extracted from medical records. A Mediterranean-style diet score (MSDS) was calculated using the FFQ. The association of maternal MSDS with NDD, autism, ADHD, and other DD was evaluated using multivariable logistic regression models adjusted for pertinent covariates. Results: This study included 3153 mother-child pairs, from which we identified diagnoses of 1362 (43.2%) NDD, including 123 (3.9%) case of autism, 445 (14.1%) ADHD, and 794 (25.2%) other DD. In the overall sample, women with a higher maternal MSDS (per standard deviation increase) were less likely to have offspring with NDD (adjusted odds ratio [OR]: 0.904, 95% confidence interval [CI]: 0.817-1.000; P value: 0.049). Using MSDS quintile 1 as the reference, being in the combined group of quintiles 3-5 was associated with a 26% lower likelihood of NDD (adjusted OR: 0.738, 95% CI: 0.572-0.951; P value: 0.019). When stratified by mothers with OWO/DM vs. without OWO/DM, the association between maternal MSDS and offspring NDD was greater in children born to mothers with OWO/DM. Conclusions: In this prospective birth cohort, a higher maternal MSDS was associated with a lower likelihood of NDD in the offspring. Furthermore, this association of maternal MSDS with offspring NDD was greater in children born to women with OWO/DM. More studies are needed to replicate the findings and further analyze NDD subgroups and explore underlying molecular pathways.

Independent and joint association of cord plasma pantothenate and cysteine levels with autism spectrum disorders and other neurodevelopmental disabilities in children born term and preterm.

Background: Pantothenate (vitamin B5) is a precursor for coenzyme A (CoA) synthesis, which serves as a cofactor for hundreds of metabolic reactions. Cysteine is an amino acid in the CoA synthesis pathway. To date, research on the combined role of early life pantothenate and cysteine levels in childhood neurodevelopmental disabilities is scarce. Objective: To study the association between cord pantothenate and cysteine levels and risk of autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and other developmental disabilities (DD) in children born term and preterm. Methods: The study sample (n = 996, 177 born preterm) derived from the Boston Birth Cohort included 416 neurotypical children, 87 ASD, 269 ADHD, and 224 other DD children, who were mutually exclusive. Participants were enrolled at birth and were followed up prospectively (from October 1, 1998, to June 30, 2018) at the Boston Medical Center. Cord blood sample was collected at birth. Plasma pantothenate and cysteine levels were measured using liquid chromatography-tandem mass spectrometry. Results: Higher cord pantothenate (≥50th percentile vs. <50th percentile) was associated with a greater risk of ASD (adjusted odds ratio [aOR]: 1.94, 95% confidence interval [CI]: 1.06, 3.55) and ADHD (aOR: 1.66, 95% CI: 1.14, 2.40), after adjusting for potential confounders. However, cord cysteine alone was not associated with risk of ASD, ADHD, or other DD. When considering the joint association, greater ASD risk was noted when both cord pantothenate and cysteine levels were elevated (≥50th percentile) (aOR: 3.11, 95% CI: 1.24, 7.79), when compared to children with low cord pantothenate (<50th percentile) and high cysteine. Even though preterm and higher pantothenate independently increased the ASD risk, the greatest risk was found in preterm children who also had elevated pantothenate (≥50th percentile), which was true for all three outcomes: ASD (aOR: 5.36, 95% CI: 2.09, 13.75), ADHD (aOR: 3.31, 95% CI: 1.78, 6.16), and other DD (aOR: 3.39, 95% CI: 1.85, 6.24). Conclusions: In this prospective birth cohort, we showed that higher cord pantothenate individually and in combination with higher cysteine or preterm birth were associated with increased risk of ASD and ADHD. More study is needed to explore this biologically plausible pathway.

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.

Umbilical cord DNA methylation is associated with body mass index trajectories from birth to adolescence.

BACKGROUND: DNA methylation (DNAm) in cord blood has been associated with various prenatal factors and birth outcomes. This study sought to fill an important knowledge gap: the link of cord DNAm with child postnatal growth trajectories from birth to age 18 years (y). METHODS: Using data from a US predominantly urban, low-income, multi-ethnic birth cohort (N = 831), we first applied non-parametric methods to identify body-mass-index percentile (BMIPCT) trajectories from birth to age 18 y (the outcome); then, conducted epigenome-wide association study (EWAS) of the outcome, interrogating over 700,000 CpG sites profiled by the Illumina Infinium MethylationEPIC BeadChip. Multivariate linear regression models and likelihood ratio tests (LRT) were applied to examine the DNAm-outcome association in the overall sample and sex strata. FINDINGS: We identified four distinct patterns of BMIPCT trajectories: normal weight (NW), Early overweight or obesity (OWO), Late OWO, and normal to very late OWO. DNAm at CpG18582997 annotated to TPGS1, CpG15241084 of TLR7, and cg24350936 of RAB31 were associated with BMIPCT at birth-to-3 y, 10 y, and 14 y, respectively (LRT FDR < 0.05 for all). INTERPRETATION: In this prospective birth cohort study, we identified 4 distinct and robust patterns of growth trajectories from birth to 18 y, which were associated with variations in cord blood DNAm at genes implicated in inflammation induction pathways. These findings, if further replicated, raise the possibility that these DNAm markers along with early assessment of BMIPCT trajectories may help identify young children at high-risk for obesity later in life. FUNDING: Detailed in the Acknowledgements section.

Gestational Diabetes Mellitus, Postpartum Lipidomic Signatures, and Subsequent Risk of Type 2 Diabetes: A Lipidome-Wide Association Study.

OBJECTIVE: To identify a postpartum lipidomic signature associated with gestational diabetes mellitus (GDM) and investigate the role of the identified lipids in the progression to type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: This prospective cohort study enrolled 1,409 women at 24-72 h after delivery of a singleton baby and followed them prospectively at the Boston Medical Center. The lipidome was profiled by liquid chromatography-tandem mass spectrometry. Diagnoses of GDM and incident T2D were extracted from medical records and verified using plasma glucose levels. RESULTS: Mean (SD) age of study women at baseline was 28.5 (6.6) years. A total of 219 (16.4%) women developed incident diabetes over a median follow-up of 11.8 (interquartile range 8.2-14.8) years. We identified 33 postpartum lipid species associated with GDM, including 16 inverse associations (primarily cholesterol esters and phosphatidylcholine plasmalogens), and 17 positive associations (primarily diacyglycerols and triacyglycerols). Of these, four were associated with risk of incident T2D and mediated ∼12% of the progression from GDM to T2D. The identified lipid species modestly improved the predictive performance for incident T2D above classical risk factors when the entire follow-up period was considered. CONCLUSIONS: GDM was associated with a wide range of lipid metabolic alterations at early postpartum, among which some lipid species were also associated with incident T2D and mediated the progression from GDM to T2D. The improvements attained by including lipid species in the prediction of T2D provides new insights regarding the early detection and prevention of progression to T2D.

Plasma Insulin Concentration in Newborns and Children and Age at Menarche.

OBJECTIVE: To investigate the association of plasma insulin levels and their trajectories from birth to childhood with the timing of menarche. RESEARCH DESIGN AND METHODS: This prospective study included 458 girls recruited at birth between 1998 and 2011 and followed prospectively at the Boston Medical Center. Plasma nonfasting insulin concentrations were measured at two time points: at birth (cord blood) and in childhood (age 0.5-5 years). Age at menarche was obtained from a pubertal developmental questionnaire or abstracted from electronic medical records. RESULTS: Three hundred six (67%) of the girls had reached menarche. The median (range) age at menarche was 12.4 (9-15) years. Elevated plasma insulin concentrations at birth (n = 391) and in childhood (n = 335) were each associated with an earlier mean age at menarche: approximately 2 months earlier per doubling of insulin concentration (mean shift, -1.95 months, 95% CI, -0.33 to -3.53, and -2.07 months, 95% CI, -0.48 to -3.65, respectively). Girls with overweight or obesity in addition to elevated insulin attained menarche about 11-17 months earlier, on average, than those with normal weight and low insulin. Considering longitudinal trajectories (n = 268), having high insulin levels both at birth and in childhood was associated with a roughly 6 months earlier mean age at menarche (mean shift, -6.25 months, 95% CI, -0.38 to -11.88), compared with having consistently low insulin levels at both time points. CONCLUSIONS: Our data showed that elevated insulin concentrations in early life, especially in conjunction with overweight or obesity, contribute to the earlier onset of menarche, suggesting the need for early screening and intervention.

Impact of intrauterine exposure to maternal diabetes on preterm birth: fetal DNA methylation alteration is an important mediator.

BACKGROUND: In utero exposure to diabetes has been shown to contribute to preterm birth, though the underlying biological mechanisms are yet to be fully elucidated. Fetal epigenetic variations established in utero may be a possible pathway. This study aimed to investigate whether in utero exposure to diabetes was associated with a change in newborn DNA methylation, and whether the identified CpG sites mediate the association between diabetes and preterm birth in a racially diverse birth cohort population. METHODS: This study included 954 mother-newborn pairs. Methylation levels in the cord blood were determined using the Illumina Infinium MethylationEPIC BeadChip 850 K array platform. In utero exposure to diabetes was defined by the presence of maternal pregestational or gestational diabetes. Preterm birth was defined as gestational age at birth less than 37 weeks. Linear regression analysis was employed to identify differentially methylated CpG sites. Differentially methylated regions were identified using the DMRcate Package. RESULTS: 126 (13%) newborns were born to mothers with diabetes in pregnancy and 173 (18%) newborns were born preterm, while 41 newborns were born both preterm and to mothers with diabetes in pregnancy. Genomic-wide CpG analysis found that eighteen CpG sites in cord blood were differentially methylated by maternal diabetes status at an FDR threshold of 5%. These significant CpG sites were mapped to 12 known genes, one of which was annotated to gene Major Histocompatibility Complex, Class II, DM Beta (HLA-DMB). Consistently, one of the two identified significant methylated regions overlapped with HLA-DMB. The identified differentially methylated CpG sites mediated the association between diabetes in pregnancy and preterm birth by 61%. CONCLUSIONS: In this US birth cohort, we found that maternal diabetes was associated with altered fetal DNA methylation patterns, which substantially explained the link between diabetes and preterm birth.

Cord Blood Insulin Concentration and Hypertension Among Children and Adolescents Enrolled in a US Racially Diverse Birth Cohort.

BACKGROUND: Although insulin resistance is closely related to hypertension, the debate continues as to whether insulin resistance is a cause or a consequence of hypertension. This study investigated the associations of cord blood insulin concentration with blood pressure (BP) and hypertension in childhood and adolescence. METHODS: This study included 951 children enrolled from 1998 to 2012 and followed from birth onwards at the Boston Medical Center, Boston, MA. Cord blood insulin concentration was measured using a sandwich immunoassay. Hypertension in childhood and adolescence was defined based on the 2017 American Academy of Pediatrics Clinical Practice Guidelines. RESULTS: The median (interquartile range) for cord blood insulin concentration was 12.1 (7.2-19.0) µIU/mL. The age range of BP measurements was 3 to 18 years (median, 10.6 years). Cord blood insulin concentration was positively associated with systolic and diastolic BP as well as the risk of hypertension at age 3 to 18 years. Compared with the lowest tertile of cord blood insulin concentration, the top tertile insulin concentration was associated with a 5.18 (95% CI, 1.97-8.39) percentile increase in systolic BP, 4.29 (95% CI, 1.74-6.84) percentile increase in diastolic BP, and 1.62-fold (95% CI, 1.27-2.08) higher risk of hypertension. The association between insulin and hypertension was stronger among children born preterm (P for interaction=0.048). Furthermore, preterm birth and childhood overweight or obesity enhanced the associations. CONCLUSIONS: Our results suggest that elevated insulin concentration at birth plays a critical role in the early life origins of hypertension and support the hypothesis implicating insulin resistance in the etiology of hypertension.

Joint associations of pregnancy complications and postpartum maternal renal biomarkers with severe cardiovascular morbidities: A US racially diverse prospective birth cohort study.

Rationale & Objective: Pregnancy complications are risk factors for cardiovascular diseases (CVD). Little is known about the role of renal biomarkers measured shortly after delivery, individually or in combination with pregnancy complications, in predicting subsequent severe maternal CVD. Methods: This study included 576 mothers of diverse ethnicities from the Boston Birth cohort, enrolled at delivery and followed prospectively. Plasma creatinine and cystatin C were measured 1-3 days after delivery. CVD during follow-up was defined by physician diagnoses in electronic medical records. Associations of renal biomarkers and pregnancy complications with time-to-CVD events were assessed using Cox proportional hazards models. Results: During an average of 10.3±3.2 years of follow-up, 34 mothers developed one or more CVD events. Although no significant associations were found between creatinine and risk of CVD, per unit increase of cystatin C (CysC) was associated with a hazard ratio (HR) of 5.21 (95%CI = 1.49-18.2) for CVD. A borderline significant interactive effect was observed between elevated CysC (≥75th percentile) and preeclampsia. Compared to those without preeclampsia and with normal CysC level (<75 th percentile), mothers with preeclampsia and elevated CysC had the highest risk of CVD (HR=3.8, 95%CI = 1.4-10.2), while mothers with preeclampsia only or with elevated CysC only did not have significantly increased CVD risk. Similar synergistic effects for CVD were observed between CysC and preterm delivery. Conclusions: In this sample of US, traditionally under-represented multi-ethnic high-risk mothers, elevated maternal plasma cystatin C and pregnancy complications synergistically increased risk of CVD later in life. These findings warrant further investigation. Clinical Perspectives: What is new?Maternal postpartum elevated levels of cystatin C are independently associated with higher risk of cardiovascular diseases (CVD) later in life.Maternal pregnancy complications coupled with postpartum elevated levels of cystatin C synergistically increased future risk of CVD.What are the clinical implications?These findings, if further confirmed, suggest that women with pregnancy complications and elevated postpartum cystatin C may be at particular high risk for CVD later in life compared to women without these risk factors.

Cord Blood Plasma Metabolome-wide Associations With Height From Birth to Adolescence.

Although the maternal intrauterine metabolic environment has been recognized to have a profound impact on fetal growth and development with lifelong health implications, to our knowledge, there have been few large-scale birth cohort studies linking the cord metabolome (reflecting both the maternal and fetal metabolic state) with postnatal height measurements across the pediatric age range. Using data from the Boston Birth Cohort, an ongoing prospective birth cohort, this study investigated the association of cord plasma metabolites with children's height from birth to adolescence. Height was analyzed as attained height and longitudinal trajectories. Distinctive cord metabolite types were associated with attained height at different developmental windows: triacylglycerols [TAGs], diacylglycerols [DAGs], cholesterol ester [CEs], phospholipids, amino acids [AAs], acylcarnitines [ACs], and nucleotides in early (age 0-4 years) and middle (age 6-12 years) childhood; various metabolite types other than TAGs in later childhood (after age 14 years). Functional principal component analysis on children's repeated height measurements summarized two typical height trajectory components: loadings on first eigenfunction [FPC1] representing overall height by age, and loadings on second eigenfunction [FPC2] representing speed of pubertal height growth. Although only one cord metabolite was correlated with FPC1 after accounting for multiple testing, the study found 27 metabolites with significant overall effect on FPC2 among females and 18 among males. These metabolites were mostly phospholipids (including phosphatidylethanolamines [PEs], phosphatidylethanolamine plasmalogens [PE_Ps], phosphatidylcholines [PCs], lysophosphatidylethanolamines [LPEs], and lysophosphatidylcholines [LPCs]), AAs, and nucleotides. Their associations with height differed between overweight/obesity (OWO) and non-OWO children, especially among females. In this prospective study of US understudied urban, low-income, racially diverse children, we demonstrated that cord plasma metabolites were significantly associated with postnatal attained height at different age windows as well as height trajectories from birth to adolescence. We also revealed how these associations differed by children's sex and OWO status. Our findings help elucidate metabolic pathways underlying fetal origins of height growth across developmental stages. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Prospective Cohort Study of Emergency Department Visit Frequency and Diagnoses Before and During COVID-19 Pandemic in Urban, Low-Income, US- and Foreign-Born Mothers in Boston, MA.

Background: The coronavirus 2019 (COVID-19) pandemic fundamentally changed how populations interface with the healthcare system. Despite historical spikes in US mortality during the pandemic, emergency department (ED) visits were paradoxically low. This is a concerning phenomenon that raises a red flag regarding access to care, especially among vulnerable populations. In this study we sought to understand how ED utilization evolved during the COVID-19 pandemic among traditionally understudied, low-income, racially diverse US- and foreign-born mothers. Methods: This is a secondary analysis of a pre-existing dataset of 3,073 participants enrolled in the Boston Birth Cohort at birth and followed prospectively. We obtained ED visit diagnoses from 2019 and 2020 via electronic health records, categorized according to the International Classification of Diseases, 10th Revision, and compared them using graph plots, chi-square, and negative binomial regression. Results: The number of ED visits decreased by 29.1% (P < 0.001) from 2019 (1,376) to 2020 (976). However, visits for infectious and parasitic diseases, including COVID-19, increased by 90.6% (32:61) with COVID-19 accounting for 77% of those visits in 2020 (47/61). Mental health-related visits increased by 40.9% (44:62), with diagnoses of alcohol use disorder increasing by 183% (6:17). Regression analysis showed 50% less ED utilization among foreign- vs US-born participants; however, the increase in infectious diseases visits was greater among foreign-born compared to US-born mothers (185% vs 26%, P = 0.01), while the increase in mental health diagnoses was greater among US-born mothers (69% vs -33%, P = 0.10). Conclusion: Despite a decrease in total ED visits during the pandemic, there was an increase in COVID-19- (immigrant > US born) and mental health- (US-born only) related visits. Our findings demonstrate that EDs remain a critical access point for care for minority populations and have implications for preparedness, resources, and services of EDs in urban settings to better address the needs of communities. However, alternative avenues for healthcare services for these populations, particularly during health crises, warrant further investigation.

Association of mitochondrial DNA content, heteroplasmies and inter-generational transmission with autism.

Mitochondria are essential for brain development. While previous studies linked dysfunctional mitochondria with autism spectrum disorder (ASD), the role of the mitochondrial genome (mtDNA) in ASD risk is largely unexplored. This study investigates the association of mtDNA heteroplasmies (co-existence of mutated and unmutated mtDNA) and content with ASD, as well as its inter-generational transmission and sex differences among two independent samples: a family-based study (n = 1,938 families with parents, probands and sibling controls) and a prospective birth cohort (n = 997 mother-child pairs). In both samples, predicted pathogenic (PP) heteroplasmies in children are associated with ASD risk (Meta-OR = 1.56, P = 0.00068). Inter-generational transmission of mtDNA reveals attenuated effects of purifying selection on maternal heteroplasmies in children with ASD relative to controls, particularly among males. Among children with ASD and PP heteroplasmies, increased mtDNA content shows benefits for cognition, communication, and behaviors (P ≤ 0.02). These results underscore the value of exploring maternal and newborn mtDNA in ASD.

Association between cord blood metabolites in tryptophan pathway and childhood risk of autism spectrum disorder and attention-deficit hyperactivity disorder.

Alterations in tryptophan and serotonin have been implicated in various mental disorders; but studies are limited on child neurodevelopmental disabilities such as autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). This prospective cohort study examined the associations between levels of tryptophan and select metabolites (5-methoxytryptophol (5-MTX), 5-hydroxytryptophan (5-HTP), serotonin, N-acetyltrytophan) in cord plasma (collected at birth) and physician-diagnosed ASD, ADHD and other developmental disabilities (DD) in childhood. The study sample (n = 996) derived from the Boston Birth Cohort, which included 326 neurotypical children, 87 ASD, 269 ADHD, and 314 other DD children (mutually exclusive). These participants were enrolled at birth and followed-up prospectively (from October 1, 1998 to June 30, 2018) at the Boston Medical Center. Higher levels of cord 5-MTX was associated with a lower risk of ASD (aOR: 0.56, 95% CI: 0.41, 0.77) and ADHD (aOR: 0.79, 95% CI: 0.65, 0.96) per Z-score increase, after adjusting for potential confounders. Similarly, children with cord 5-MTX ≥ 25th percentile (vs. <25th percentile) had a reduction in ASD (aOR: 0.27, 95% CI: 0.14, 0.49) and ADHD risks (aOR: 0.45, 95% CI: 0.29, 0.70). In contrast, higher levels of cord tryptophan, 5-HTP and N-acetyltryptophan were associated with higher risk of ADHD, with aOR: 1.25, 95% CI: 1.03, 1.51; aOR: 1.32, 95% CI: 1.08, 1.61; and aOR: 1.27, 95% CI: 1.05, 1.53, respectively, but not with ASD and other DD. Cord serotonin was not associated with ASD, ADHD, and other DD. Most findings remained statistically significant in the sensitivity and subgroup analyses.

Individual and Combined Association Between Prenatal Polysubstance Exposure and Childhood Risk of Attention-Deficit/Hyperactivity Disorder.

Importance: Polysubstance use among pregnant women has increased because of the opioid epidemic and the increasing legalization of cannabis along with persistent tobacco and alcohol consumption. Previous research on prenatal substance use and the child's risk of attention-deficit/hyperactivity disorder (ADHD) has mostly focused on single-substance exposures; simultaneous examination of multiple substance use and assessment of their synergistic health consequences is needed. Objectives: To assess the consequences of the use of specific substances during pregnancy, investigate whether the interaction of multiple prenatal substance exposures is associated with increases in the risk of childhood ADHD, and estimate the aggregate burden of polysubstance exposure during gestation. Design, Setting, and Participants: This cohort study analyzed data from the Boston Birth Cohort from 1998 to 2019. The sample of the present study comprised a multiethnic urban cohort of mother-child pairs who were predominantly low income. A total of 3138 children who were enrolled shortly after birth at Boston Medical Center were included and followed up from age 6 months to 21 years. Exposures: Substance use during pregnancy was identified based on self-reported tobacco smoking, alcohol consumption, and use of cannabis, cocaine, or opioids in any trimester of pregnancy. Diagnostic codes for neonatal opioid withdrawal syndrome or neonatal abstinence syndrome from the International Classification of Diseases, Ninth Revision, and the International Classification of Diseases, Tenth Revision, were also used to identify opioid exposure during gestation. Main Outcomes and Measures: ADHD diagnosis in the child's electronic medical record. Results: Among 3138 children (1583 boys [50.4%]; median age, 12 years [IQR, 9-14 years]; median follow-up, 10 years [IQR, 7-12 years]) in the final analytic sample, 486 (15.5%) had an ADHD diagnosis and 2652 (84.5%) were neurotypical. The median postnatal follow-up duration was 12 years (IQR, 9-14 years). Among mothers, 46 women (1.5%) self-identified as Asian (non-Pacific Islander), 701 (22.3%) as Hispanic, 1838 (58.6%) as non-Hispanic Black, 227 (7.2%) as non-Hispanic White, and 326 (10.4%) as other races and/or ethnicities (including American Indian or Indigenous, Cape Verdean, Pacific Islander, multiracial, other, or unknown). A total of 759 women (24.2%) reported the use of at least 1 substance during pregnancy, with tobacco being the most frequently reported (580 women [18.5%]). Cox proportional hazards models revealed that opioid exposure (60 children) had the highest adjusted hazard ratio (HR) for ADHD (2.19; 95% CI, 1.10-4.37). After including main statistical effects of all individual substances in an elastic net regression model, the HR of opioids was reduced to 1.60, and evidence of a statistical interaction between opioids and both cannabis and alcohol was found, producing 1.42 and 1.15 times higher risk of ADHD, respectively. The interaction between opioids and smoking was also associated with a higher risk of ADHD (HR, 1.17). Conclusions and Relevance: The findings of this study suggest that it is important to consider prenatal concurrent exposure to multiple substances and their possible interactions when counseling women regarding substance use during pregnancy, the future risk of ADHD for their children, and strategies for cessation and treatment programs.

Longitudinal trajectories and determinants of plasma per- and polyfluoroalkyl substance (PFAS) levels from birth to early childhood and metabolomic associations: A pilot study in the Boston Birth Cohort.

Background: Per- and polyfluoroalkyl substances (PFAS) are a major public health concern worldwide due to their ubiquitous exposures, environmental persistence, maternal-to-fetal transfer, and multi-organ toxicity. This pilot study aimed to generate preliminary data to inform future studies to address data gaps in the field, including early life PFAS exposure levels, longitudinal changes, determinants, and associated metabolomic alterations in understudied Black and Hispanic children in the United States (U.S.). Methods: This study leveraged existing biosamples and data in the Boston Birth Cohort and measured 12 legacy and emerging PFAS, including Me-PFOSA-AcOH, PFDA, PFDoA, PFHxS, PFNA, PFOA, PFOS, PFUnA, GenX, ADONA, 9Cl-PF3ONS, and PFHpS, in paired cord and early childhood plasma samples. Summary statistics and graphic plots were used to depict PFAS levels at the two time points and their longitudinal changes. Linear regression models were used to identify the early-life factors associated with cord and early childhood PFAS levels. Associations of cord PFAS with cord metabolites were explored using a metabolome-wide association approach and a targeted approach. Results: This study included 39 children, of whom 25 (64%) were Black, 14 (36%) were Hispanic, and 15 (38%) were female. PFOA, PFOS, PFNA, and PFHpS were detectable in all cord and early childhood plasma samples, while GenX and ADONA were not detectable in any sample. Cord PFAS levels were weakly-to-moderately correlated with early childhood PFAS levels (r = -0.03 to 0.40). Several maternal and child factors, including gestational age, year at blood collection, and race/ethnicity, were associated with cord and early childhood PFAS levels. The metabolome-wide association study and the targeted study identified several cord metabolites that may have been affected by in utero PFAS exposure. Conclusions: This pilot study found ubiquitous exposure to multiple PFAS in cord plasma (reflects in utero exposure) and in early childhood plasma (reflects both prenatal and postnatal exposure) among U.S. Black and Hispanic children. Metabolomic analysis suggests that in utero PFAS exposures may alter fetal metabolism. Future large-scale studies are needed to replicate the findings and further examine the associations of fetal PFAS exposure with long-term health outcomes and underlying metabolic pathways.

Boston Birth Cohort profile: rationale and study design.

In1998, the Boston Birth Cohort (BBC) was initiated at Boston Medical Center (BMC) in response to persistently high rates of preterm birth (PTB, defined as birth before 37 weeks of gestation) in the US population and the longstanding profound PTB disparity among Black, Indigenous, and people of color (BIPOC). The BBC encompasses two linked study protocols: The PTB Study serves as the baseline recruitment in the BBC. It aims to address fundamental questions about the causes and consequences of PTB. The study oversamples preterm babies using a case/control study design, in which cases are defined as mothers who deliver a preterm and/or low birthweight baby (<2500 grams regardless of gestational age). Controls are enrolled at a 2:1 control/case ratio and matched by maternal age (±5 years), self-reported race and ethnicity, and date of delivery (± 7 days for case delivery). From inception, it was designed as a comprehensive gene-environmental study of PTB. As a natural extension, the Children's Health Study, under a separate but linked Institutional Review Board protocol, is a longitudinal follow-up study of the participants who were recruited at birth in the PTB Study and who continue pediatric care at BMC. This linked model allows for investigation of early life origins of pediatric and chronic disease in a prospective cohort design. The BBC is one of the largest and longest National Institutes of Health-funded prospective birth cohort studies in the United States, consisting of 8733 mother-child dyads enrolled in the PTB Study at birth, and of those, 3592 children have been enrolled in the Children's Health Study, with a median follow-up of 14.5 years. The BBC mirrors the urban, underresourced, and underrepresented BIPOC population served by BMC. A high proportion of BBC children were born prematurely and had chronic health conditions (e.g., asthma, obesity, and elevated blood pressure) in childhood. The BBC's long-term goal has been to build a large, comprehensive database (epidemiological, clinical, and multiomics) and biospecimen repository to elucidate early life origins of pediatric and chronic diseases and identify modifiable upstream factors (e.g., psychosocial, environmental, and nutritional) to improve health across the life course for BIPOC mothers and children.