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  5. Early life origins of ASD: Role of maternal and cord blood metabolome, placental histology and fetal growth trajectory

Early life origins of ASD: Role of maternal and cord blood metabolome,
placental histology and fetal growth trajectory

Project profile

Institution: Johns Hopkins University
Principal Investigator: Xiaobin Wang
Project Number: UJ2MC31074
Project Date: 09-01-2017

Age Group(s)

  • Women/Maternal
  • Perinatal/Infancy (0-12 months)
  • Toddlerhood (13-35 months)
  • Early Childhood (3-5 years)
  • Middle Childhood (6-11 years)
  • Adolescence (12-18 years)
  • Young Adulthood (19-25 years)

Targeted/Underserved Population

  • Low-income
  • African American
  • Hispanic/Latino
  • Asian/Pacific Islander
  • Immigrant
  • Special Health Care Needs


Autism Spectrum Disorder (ASD) affects 1 in 68 U.S. children. Early identification and prevention are key to reducing the population burden of ASD. Growing evidence supports fetal or even preconception origins of ASD yet existing findings are mostly derived from case-control or retrospective studies. No adequately powered birth cohort studies have prospectively ascertained early life risk factors and biomarkers for ASD in US minorities.

Goals and objectives:

This proposal aims to address the areas of interest outlined by HRSA- 17- 014 (Autism Longitudinal Data Project): 'Genomic metabolic and inflammatory markers for screening'; 'minority population'; and 'maternal and perinatal origins'. We will leverage the exceptional resources of the Boston Birth Cohort (BBC) to accomplish the following aims in a time and cost-efficient fashion: Aim 1. Examine the role of maternal and cord blood metabolomes in ASD; Aim 2. Examine placental histological findings in relation to the risk of ASD; Aim 3. Examine in utero fetal growth patterns in relation to the risk of ASD; Aim 4. Integrate multi-dimensional data to develop early prediction models and test interventions; and Aim 5. Provide leadership in education training and dissemination. Methods: We will apply cutting-edge metabolomic technologies which allow for a highthroughput and comprehensive characterization of all major circulating metabolites reflecting the biological state of genetic and environmental interactions. In addition we will examine placental histological findings as assessed by highly experienced placental pathologists and fetal longitudinal growth patterns as assessed by a series of prenatal ultrasound exams. We will also use a novel approach that combines computational systems modeling with empirical data from the BBC to understand the complex interplay of pre- peri- and post-natal factors in ASD; determine key modifiable factors that most impact the subsequent development of ASD; and test the intervention effects by modifying these factors to different degrees under a variety of scenarios in a computer environment. Healthy People 2020 Objective(s): To our knowledge this will be by far the largest prospective birth cohort study on ASD and associated developmental disabilities in a U.S. urban predominantly low-income minority population. This study is unprecedented due to the integration of maternal and cord blood metabolome with a prospective birth cohort and has a high likelihood to discover novel maternal and cord blood biomarkers which in turn will be much useful to develop screening algorithms to identify newborns at higher risk for ASD. By integrating a myriad of multi-level longitudinal data and dissecting the complex causal pathways that contribute to ASD at critical early developmental windows this study may lead to a transformation in the way in which clinical and public health services are organized and delivered. This will ultimately lead to the development of cost-effective interventions to halt or reverse the ASD risk trajectory during early developmental periods when interventions may have the greatest life-long impact. The establishment of these novel approaches amongst high-risk urban U.S. populations will be of key importance for lowering the population burden of ASD.


Li M, Fallin MD, Riley A, Landa R, Walker SO, Silverstein M, Caruso D, Pearson C, Kiang S, Dahm JL, Hong X, Wang G, Wang MC, Zuckerman B, Wang X. The Association of maternal obesity and diabetes with autism and other developmental disabilities. Pediatrics. 2016 Feb;137(2):e20152206. doi: 10.1542/peds.2015-2206. Epub 2016 Jan 29 DOI:10.1542/peds.2015-2206 February 2016 Pediatrics

Brucato M, Ladd-Acosta C, Li M, Caruso D, Hong X, Kaczaniuk J, Stuart EA, Fallin MD, Wang X. Prenatal exposure to fever is associated with Autism Spectrum Disorder in the Boston Birth Cohort. Autism Research. First published: 11 August 2017. DOI: 10.1002/aur.1841 DOI:10.1002/aur.1841 August 2017 Autism Research

Raghavan R, Riley AW, Volk H, Caruso D, Hironaka L, Sices L, Hong X, Wang G, Ji Y, Brucato M, Wahl A; Stivers T, Pearson C, Zuckerman B, Stuart EA, Landa R, Fallin DM, Wang X. Maternal multivitamin intake, plasma folate and vitamin B12 levels and ASD risk in offspring. Pediatrics and Perinatal Epidemiology. 2017 Oct 6. doi: 10.1111/ppe.12414. [Epub ahead of print] DOI:10.1111/ppe.12414 October 2017 Pediatrics and Perinatal Epidemiology

Lauren O, Ji Y, Riley AW, Wang X. Maternal psychosocial stress and children�s ADHD diagnosis: a prospective birth cohort study. J Psychosom Obs Gyn 2018 May 23:1-9. doi: 10.1080/0167482X.2018.1468434. [Epub ahead of print] DOI:10.1080/0167482X.2018.1468434 May 2018 J Psychosom Obs Gyn

Ji Y, Riley AW, Lee LC, Volk H, Hong X, Wang G, Angomas R, Stivers T, Wahl A, Ji H, Bartell TR, Burd I, Paige D, Fallin MD, Zuckerman B, Wang X. A prospective birth cohort study on maternal cholesterol levels and offspring attention deficit hyperactivity disorder: new insight on sex differences. Brain Sci. 2017 Dec 23;8(1). pii: E3. doi: 10.3390/brainsci8010003. DOI:10.3390/brainsci8010003 November 2017 Brain Sci

Ji Y, Hong X, Wang G, Chatterjee N, Riley AW, Lee LC, Surkan P, Bartell TR, Zuckerman B, Wang X. A prospective birth cohort study on early childhood lead levels and attention deficit hyperactivity disorder: new insight on sex differences. J of Pediatrics. 2018. Aug. 199;124-34.e8. DOI: August 2018 J of Pediatrics

Zhang M, Mueller NT, Wang H, Hong X, Appel LJ, Wang X. Maternal exposure to ambient pm2.5 during pregnancy and the risk for high blood pressure in childhood: findings from the Boston Birth Cohort. Hypertension. May 2018. DOI: 10.1161/HYPERTENSIONAHA.117.10944. DOI:10.1161/HYPERTENSIONAHA.117.10944. May 2018 Hypertension

Surkan PJ, Dong L, Ji Y, Hong X, Ji H, Wang X. Paternal involvement and support and risk of preterm birth: Findings from the Boston Birth Cohort. J Psychosom Obs Gyn, 2017 Nov 16:1-9. doi: 10.1080/0167482X.2017.1398725. PMID:29144191 DOI:10.1080/0167482X.2017.1398725 November 2017 29144191 J Psychosom Obs Gyn

Bustamante-helfrich B, Chilukuri N, He H, Cerda SR, Hong X, Wang G, Pearson C, Burd I, Wang X. Maternal vascular malperfusion of the placental bed associated with hypertensive disorders in the boston birth cohort. Placenta 2017 Apr;52:106-113 doi: 10.1016/j.placenta.2017.02.016 PMID: 28454692 DOI:10.1016/j.placenta.2017.02.016 April 2017 Placenta

Cheng TL, Mistry KB, Wang G, Zuckerman B, Wang X. Folate Nutrition Status in Mothers of the Boston Birth Cohort, Sample of a US Urban Low-Income Population. Am J Public Health. 2018 Apr 19:e1-e9. doi: 10.2105/AJPH.2018.304355. PMID: 29672150 DOI:10.2105/AJPH.2018.304355 April 2018 29672150 Am J Public Health

Panjwani A, Ji Y, Fahey J, et al. Maternal obesity/diabetes, plasma branched-chain amino acids (BCAASs), and offspring ASD: evidence of sex difference. Curr Dev Nutr. 2019; 3(suppl 1):11-141-19. DOI:10.1093/cdn/nzz048.P11-141-19 June 2019 PMC6578492 Curr Dev Nutr

Hong X, Liang L, Sun Q, et al. Maternal triacylglycerol signature and risk of food allergy in offspring. J Allergy Clin Immunol. 2019 Apr 18 DOI:10.1016/j.jaci.2019.03.033 April 2019 31004614 J Allergy Clin Immunol

Wang T, Sun Q, Liang L, et al. Inter-generational link of obesity in term and preterm births: role of maternal plasma acylcarnitines. Int J Obes (Lond) DOI:10.1038/s41366-019-0417-x April 2019 31332276 Int J Obes

Raghavan R, Helfrich B, Cerda SR, et al. Preterm birth subtypes, placental pathology findings, and risk of neurodevelopmental disabilities during childhood. Placenta. 2019;83,17-25. DOI:10.1016/j.placenta.2019.06.374 August 2019

Olapeju B, Saifuddin A, Wang G, et al. Maternal postpartum plasma folate status and preterm birth in a high-risk US population. Public Health Nutr. 2019;22(7):1281-1291. DOI:10.1017/S1368980018003221 May 2019 30486913 Public Health Nutr

Wang G, Liu X, Bartell TR, Pearson C, Cheng TL, Wang X. Vitamin D trajectories from birth to early childhood and elevated systolic blood pressure during childhood and adolescence. Hypertension. 2019;74(2):421-430. DOI:10.1161/HYPERTENSIONAHA.119.13120 July 2019 31256718

Azuine RE, Ji Y, Chang HY, Kim Y, Ji H, DiBari J, Hong X, Wang G, Singh GK, Pearson C, Zuckerman B, Surkan PJ, Wang X. Prenatal risk factors and perinatal and postnatal outcomes associated with maternal opioid exposure in an urban, low-income, multiethnic US population. JAMA Netw Open. 2019 Jun 5;2(6):e196405. DOI:10.1001/jamanetworkopen.2019.6405 June 2019 JAMA Netw Open

Wang G, DiBari J, Bind E, Steffens AM, Mukherjee J, Azuine RE, Singh GK, Hong X, Ji Y, Ji H, Pearson C, Zuckerman BS, Cheng TL, Wang X. Association between maternal exposure to lead, maternal folate status, and intergenerational risk of childhood overweight and obesity. JAMA Netw Open. 2019 Oct 2;2(10):e1912343. DOI:10.1001/jamanetworkopen.2019.12343 October 2019 JAMA Netw Open

Wang G, DiBari J, Bind E, Steffens AW, Mukherjee J, Azuine RE, Singh GK, Hong X, Ji Y, Ji H, Pearson C, Zuckerman B, Cheng TL, Wang X. In utero exposure to lead, folate status, and inter-generational link of obesity. JAMA Network Open 2019 Oct 2;2(10):e1912343. DOI:10.1001/jamanetworkopen.2019.12343 October 2019 31577354 JAMA Netw Open

Panjwani, A.A., Ji, Y., Fahey, J.W., Palmer, A., Wang G., Hong, X., Zuckerman, B., Wang, X. Maternal dyslipidemia, plasma branched-chain amino acids levels, and the risk of offspring Autism Spectrum Disorder: evidence of sex difference. Journal of Autism and Developmental Disorders 50(5) � February 2020. DOI:10.1007/s10803-019-04264-x February 2020 31686281 J Autism Dev Disord

Ji Y, Azuine RE, Zhang Yan, Hou W, Hong X, Wang G, Riley A, Pearson C, Zuckerman B, Wang X. Cord plasma biomarker of in utero acetaminophen exposure and risk of ADHD and ASD in childhood. JAMA Psychiatry 2019 Oct 30:1-11. doi: 10.1001/jamapsychiatry.2019.3259. DOI:10.1001/jamapsychiatry.2019.3259 October 2019 31664451

Raghavan, R., Selhub J, Paul L, Ji Y, Wang G, Hong X, Zuckerman B., Fallin D.M., Wang X. A prospective birth cohort study on cord blood folate sub-types and risk of autism spectrum disorder. AJCN (in press) 2020

Hong X, Surkan PJ, Zhang B, Keiser A, Ji Y, Ji H, Burd I, Ogunwole SM, Tang WY, Liu L, Pearson C, Cerda S, Zuckerman B, Hao L, Wang X. Genome-wide association study identifies a novel maternal gene � stress interaction associated with spontaneous preterm birth. Pediatr Res.2020 Jul 29 . Online ahead of print. DOI:10.1038/s41390-020-1093-1 July 2020 Pediatr Res

Hong X, Zhang B, Liang L, Zhang Y, Ji Y, Wang G, Ji H, Clish C, Burd I, Pearson C, Zuckerman B, Hu FB, Wang X. Postpartum plasma metabolomic profile among women with preeclampsia and preterm delivery: implications for long-term health. 2020 BMC Medicine. 18:255 DOI: October 2020

Nawa N, Garrison-Desany HM, Kim Y, Ji Y, Hong X, Wang G, Pearson C, Zuckerman BS, Wang X, Surkan PJ. Maternal persistent marijuana use and cigarette smoking are independently associated with shorter gestational age. Paediatr Perinat Epidemiol. 2020 Jun 30. Online ahead of print. DOI:10.1111/ppe.12686 June 2020 32602574 Paediatr Perinat Epidemiol

Garrison-Desany H, Nawa N, Kim Y, Ji Y, Chang HY, Hong X, Wang G, Pearson C, Zuckerman BS, Wang X, Surkan PJ. (2020). Associations between depressant and stimulant drug use in pregnancy and preterm birth in a sample of US urban low-income multiethnic population. Public Health Reports. 2020 In Press. 2020

Wang G, DiBari J, Bind E, Steffens AM, Mukherjee J, Bartell TR, Bellinger DC, Hong X, Ji Y, Wang MC, Wills-Karp M, Cheng TL, Wang X. In utero exposure to mercury and childhood overweight or obesity: counteracting effect of maternal folate status. BMC Med. 2019 Nov 28;17(1):216. PubMed Central PMCID: PMC6882077. DOI:10.1186/s12916-019-1442-2 November 2019 31775748 BMC Med

Lee ASE, Ji Y, Raghavan R, Wang G, Hong X, Pearson C, Mirolli G, Bind E, Steffens A, Mukherjee J, Haltmeier D, Fan ZT, Wang X. Maternal prenatal selenium levels and child risk of neurodevelopmental disorders: A prospective birth cohort study. Autism Res. 2021 Dec;14(12):2533-2543. doi: 10.1002/aur.2617. Epub 2021 Sep 24. PMID: 34558795; PMCID: PMC8665097. December 2021

Ji Y, Raghavan R, Wang X. Early Life Origins of ASD and ADHD. Oxford Research Encyclopedia of Global Public Health, May 2021 May 2021

Anand NS, Raghavan R, Wang G, Hong X, Azuine RE, Pearson C, Zuckerman B, Xie H, Wang X. Perinatal Acetaminophen Exposure and Childhood Attention-Deficit/Hyperactivity Disorder (ADHD): Exploring the Role of Umbilical Cord Plasma Metabolites in Oxidative Stress Pathways. Brain Sciences. 2021; 11(10):1302. PMID: 34679367 PMCID: PMC8533963 October 2021

"Rhee DK, Ji Y, Hong X, Pearson C, Wang X, Caulfield LE. Mediterranean-Style Diet and Birth Outcomes in an Urban, Multiethnic, and Low-Income US Population. Nutrients. 2021 Apr 3;13(4):1188. doi: 10.3390/nu13041188. PMID: 33916686; PMCID: PMC8066173." May 2021

"Makker K, Ji Y, Hong X, Wang X. Antenatal and neonatal factors contributing to extra uterine growth failure (EUGR) among preterm infants in Boston Birth Cohort (BBC). J Perinatol. 2021 May;41(5):1025-1032. doi: 10.1038/s41372-021-00948-4. Epub 2021 Feb 15. PMID: 33589730; PMCID: PMC7883994." May 2021

Wang X. Healthy diet during pregnancy-navigating the double-edged sword. Am J Clin Nutr. 2021 May 26:nqab168. doi: 10.1093/ajcn/nqab168. Epub ahead of print. PMID: 34038942. September 2021

Olapeju B, Hong X, Wang G, Summers A, Burd I, Cheng TL, Wang X. Birth outcomes across the spectrum of maternal age: Dissecting aging effect versus confounding by social and medical determinants. BMC Pregnancy Childbirth 21, 594 (2021). December 2021

Park S, Ji Y, Hong X, Zuckerman B, Wang X, Surkan PJ. Effects of Stress and Nativity on Maternal Antenatal Substance Use and Postnatal Mental Disorders. J Womens Health (Larchmt). 2021 Dec 17. doi: 10.1089/jwh.2021.0016. Epub ahead of print. PMID: 34935494. December 2021

Boakye E, Kwapong YA, Obisesan F, Ogunwole SM, Hays AG, Nasir K, Blumenthal RS, Douglas PS, Blaha MJ, Creanga AA, Wang X, Sharma G. Nativity-related Disparities in Preeclampsia and Cardiovascular Disease Risk Profile among Racially Diverse Women in the United States. JAMA Network Open. 2021 Dec 1;4(12):e2139564. doi: 10.1001/jamanetworkopen.2021.39564. PMID: 34928357. November 2021

Zhang M, Buckley JP, Liang L, Hong X, Wang G, Guallar E, Wang MC, Wills-Karp M, Wang X, Mueller N. A metabolome-wide association study of in utero metal and trace element exposures with cord blood metabolome profile: findings from the Boston Birth Cohort. Environmental International 2021, Volume158. PMCID in progress November 2021

Long J, Zhang M, Wang G, Hong X, Ji Y, Bustamante-Helfrich B, Wang X, Mueller NT. Association of Placental Pathology with Childhood Blood Pressure Among Children Born Preterm. American Journal of Hypertension, Volume 34, Issue 11, November 2021, Pages 1154�1162, October 2021

Cao T, Zhao J, Hong X, Wang G, Hu F, Wang X, Liang L. Associations of cord blood plasma lipid metabolites with longitudinal BMI trajectory from birth to adolescence in US multi-ethnic birth cohort. Metabolites 2021, 11, 739. January 2021

Zhang M, Liu T, Wang G, Buckley JP, Guallar E, Hong X, Wang MC, Wills-Karp M, Wang X, Mueller NT. In-Utero Exposure to Heavy Metals and Trace Elements and Childhood Blood Pressure in a U.S. Urban, Low-Income, Minority Birth Cohort. Environ Health Perspect. 2021 Jun;129(6):67005. doi: 10.1289/EHP8325. Epub 2021 Jun 23. PMID: 34160246; PMCID: PMC8221032. November 2021

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Wang G, Tang WY, Ji H, Wang X. Prenatal exposure to mercury and precocious puberty: a prospective birth cohort study. Hum Reprod. 2021 Feb 18;36(3):712-720. doi: 10.1093/humrep/deaa315. PMID: 33367618; PMCID: PMC7891807. August 2021

Wang G, Foney DM, DiBari J, Hong X, Showell N, Kim KS, Ji H, Pearson C, Mirolli G, Rusk S, Sharfstein J, Cheng TL, Zuckerman B, Wang X. 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. 2021 International Journal of Obesity (Lond). 2021 Aug 19:1�8. doi: 10.1038/s41366-021-00943-x. Epub ahead of print. PMID: 34413468; PMCID: PMC8374030. August 2021

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Huang W, Igusa T, Wang G, et al. In-utero co-exposure to toxic metals and micronutrients on childhood risk of overweight or obesity: new insight on micronutrients counteracting toxic metals. Int J Obes (Lond). 2022;46(8):1435-1445. doi:10.1038/s41366-022-01127-x DOI:10.1038/s41366-022-01127-x August 2022 35589962

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Brucato M, Lance E, Lanzkron S, Wang X, Pecker LH. Developmental disorders in children born to women with sickle cell disease: A report from the Boston Birth Cohort. EJHaem. 2022;3(3):894-898. doi:10.1002/jha2.478 DOI:10.1002/jha2.478 June 2022 36051016

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