Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study | Pediatrics | JAMA Psychiatry | JAMA Network
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Figure.  Association of Prenatal Cannabis Exposure After Maternal Knowledge of Pregnancy With Risk of Adverse Childhood Outcomes
Association of Prenatal Cannabis Exposure After Maternal Knowledge of Pregnancy With Risk of Adverse Childhood Outcomes

A, Psychotic-like experiences. B, Internalizing problems. C, Externalizing problems. D, Attention problems. E, Thought problems. F, Social problems. G, Cognition. H, Birth weight. Raw data values are plotted. As scales differ, y axes are not directly comparable across panels. Vertical lines indicate SEs. Statistics are presented in Table 2 and Table 3 and eTables 1 and 2 in the Supplement. Log-transforming data reduce differences in variability across groups and results in similar conclusions (eTable 4 in the Supplement). CBCL indicates Child Behavior Checklist.

aP < .05 only before false discovery rate correction.

bFalse discovery rate–corrected P < .05.

Table 1.  ABCD Study Sample Characteristicsa
ABCD Study Sample Characteristicsa
Table 2.  Associations With Prenatal Cannabis Exposure Without Inclusion of Potentially Confounding Covariatesa
Associations With Prenatal Cannabis Exposure Without Inclusion of Potentially Confounding Covariatesa
Table 3.  Associations With Prenatal Cannabis Exposure When Including Potentially Confounding Covariatesa
Associations With Prenatal Cannabis Exposure When Including Potentially Confounding Covariatesa
Supplement.

eMethods.

eResults.

eTable 1. Full Regression Results From Models Examining Associations Between Prenatal Cannabis Exposure and CBCL Outcomes When Including Potentially Confounding Covariates

eTable 2. Full Regression Results From Models Examining Associations Between Prenatal Cannabis Exposure and Psychotic-Like Experiences, BMI, Cognition, Sleep Problems, and Birth Weight When Including Potentially Confounding Covariates

eTable 3. Full Regression Results From Models Examining Associations Between Prenatal Cannabis Exposure and Brain Structure Metrics When Including Potentially Confounding Covariates

eTable 4. Regression Results From Models Examining Associations Between Prenatal Cannabis Exposure and Log-Transformed Outcomes When Including Potentially Confounding Covariates

eTable 5. Full Regression Results From Models Examining Associations Between Prenatal Cannabis Exposure and CBCL Outcomes When Including Potentially Confounding Covariates Associated With the Outcome Only

eTable 6. Psychotic-Like Experiences, BMI, Cognition, Sleep, and Birth Weight Models With Significant Fixed Effect Covariates Only

eTable 7. Brain Structure Models With Significant Fixed Effect Covariates Only

eTable 8. Test of Overfitting Results From 5-Fold Cross Validation

eTable 9. Regression Results When Excluding Children With Non-Prevalent Substance Use

eTable 10. Regression Results When Excluding Children Prenatally Exposed to Illicit Substances Other Than Marijuana

eTable 11. Regression Results When Excluding Children Born at Extreme Prematurity

eTable 12. Regression Results When Excluding Children Who Had a Non-Biological Mother Report as the Parent/Caregiver Respondent

eTable 13. Regression Results Restricted to the Subsample of Individuals With Genomically-Confirmed European Ancestry

eTable 14. Regression Results When Including Polygenic Risk Scores and Ancestrally-Informative Principal Components as Additional Covariates

eTable 15. Associations Between Psychotic-Like Experiences and Polygenic Scores for Schizophrenia, Educational Attainment, and Cannabis Use

eTable 16. Associations Between Social Problems and Polygenic Scores for Cannabis Use

eTable 17. Non-Mutually Exclusive Groups Regression Results Without Covariates

eTable 18. Non-Mutually Exclusive Groups Regression Results With Covariates

eTable 19. Inverse Probability Weighting Balance Analysis Results

eTable 20. Inverse Probability Weighting Regression Results

eTable 21. Regression Results When Excluding Children Whose Mother Used Cannabis Only Prior to Pregnancy Knowledge and Discovered Pregnancy After 15 Weeks

eTable 22. Regression Results When Excluding Children Whose Mother Used Cannabis Only Prior to Pregnancy Knowledge and Discovered Pregnancy After 9 Weeks

eTable 23. Psychotic-Like Experiences and Prenatal Cannabis Exposure: Regression Results When Including Maternal Psychotic-Like Experiences as a Covariate

1.
Hasin  DS.  US epidemiology of cannabis use and associated problems.   Neuropsychopharmacology. 2018;43(1):195-212. doi:10.1038/npp.2017.198 PubMedGoogle ScholarCrossref
2.
Volkow  ND, Han  B, Compton  WM, McCance-Katz  EF.  Self-reported medical and nonmedical cannabis use among pregnant women in the United States.   JAMA. 2019;322(2):167-169. doi:10.1001/jama.2019.7982 PubMedGoogle ScholarCrossref
3.
Yao  JL, He  QZ, Liu  M,  et al.  Effects of Δ(9)-tetrahydrocannabinol (THC) on human amniotic epithelial cell proliferation and migration.   Toxicology. 2018;394:19-26. doi:10.1016/j.tox.2017.11.016 PubMedGoogle ScholarCrossref
4.
Basavarajappa  BS, Nixon  RA, Arancio  O.  Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration.   Mini Rev Med Chem. 2009;9(4):448-462. doi:10.2174/138955709787847921 PubMedGoogle ScholarCrossref
5.
Fride  E, Gobshtis  N, Dahan  H, Weller  A, Giuffrida  A, Ben-Shabat  S.  The endocannabinoid system during development: emphasis on perinatal events and delayed effects.   Vitam Horm. 2009;81:139-158. doi:10.1016/S0083-6729(09)81006-6 PubMedGoogle ScholarCrossref
6.
Young-Wolff  KC, Sarovar  V, Tucker  LY,  et al.  Self-reported daily, weekly, and monthly cannabis use among women before and during pregnancy.   JAMA Netw Open. 2019;2(7):e196471. doi:10.1001/jamanetworkopen.2019.6471 PubMedGoogle Scholar
7.
Brown  QL, Sarvet  AL, Shmulewitz  D, Martins  SS, Wall  MM, Hasin  DS.  Trends in marijuana use among pregnant and nonpregnant reproductive-aged women, 2002-2014.   JAMA. 2017;317(2):207-209. doi:10.1001/jama.2016.17383 PubMedGoogle ScholarCrossref
8.
Agrawal  A, Rogers  CE, Lessov-Schlaggar  CN, Carter  EB, Lenze  SN, Grucza  RA.  Alcohol, cigarette, and cannabis use between 2002 and 2016 in pregnant women from a nationally representative sample.   JAMA Pediatr. 2019;173(1):95-96. doi:10.1001/jamapediatrics.2018.3096 PubMedGoogle ScholarCrossref
9.
Wu  CS, Jew  CP, Lu  HC.  Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain.   Future Neurol. 2011;6(4):459-480. doi:10.2217/fnl.11.27 PubMedGoogle ScholarCrossref
10.
Scheyer  AF, Melis  M, Trezza  V, Manzoni  OJJ.  Consequences of perinatal cannabis exposure.   Trends Neurosci. 2019;42(12):871-884. doi:10.1016/j.tins.2019.08.010 PubMedGoogle ScholarCrossref
11.
Volkow  ND, Compton  WM, Wargo  EM.  The risks of marijuana use during pregnancy.   JAMA. 2017;317(2):129-130. doi:10.1001/jama.2016.18612 PubMedGoogle ScholarCrossref
12.
Jansson  LM, Jordan  CJ, Velez  ML.  Perinatal marijuana use and the developing child.   JAMA. 2018;320(6):545-546. doi:10.1001/jama.2018.8401 PubMedGoogle ScholarCrossref
13.
National Academies of Sciences, Engineering, and Medicine.  The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press; 2017.
14.
Office of the Surgeon General, US Department of Health and Human Services. U.S. Surgeon General’s advisory: marijuana use and the developing brain. Accessed October 16, 2019. https://www.hhs.gov/surgeongeneral/reports-and-publications/addiction-and-substance-misuse/advisory-on-marijuana-use-and-developing-brain/index.html#
15.
Ryan  SA, Ammerman  SD, O’Connor  ME; Committee on Substance Use and Prevention; Section on Breastfeeding.  Marijuana use during pregnancy and breastfeeding: implications for neonatal and childhood outcomes.   Pediatrics. 2018;142(3):e20181889. doi:10.1542/peds.2018-1889 PubMedGoogle Scholar
16.
Smith  AM, Mioduszewski  O, Hatchard  T, Byron-Alhassan  A, Fall  C, Fried  PA.  Prenatal marijuana exposure impacts executive functioning into young adulthood: an fMRI study.   Neurotoxicol Teratol. 2016;58:53-59. doi:10.1016/j.ntt.2016.05.010 PubMedGoogle ScholarCrossref
17.
Leech  SL, Richardson  GA, Goldschmidt  L, Day  NL.  Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds.   Neurotoxicol Teratol. 1999;21(2):109-118. doi:10.1016/S0892-0362(98)00042-7 PubMedGoogle ScholarCrossref
18.
Corsi  DJ, Walsh  L, Weiss  D,  et al.  Association between self-reported prenatal cannabis use and maternal, perinatal, and neonatal outcomes.   JAMA. 2019;322(2):145-152. doi:10.1001/jama.2019.8734 PubMedGoogle ScholarCrossref
19.
Gray  KA, Day  NL, Leech  S, Richardson  GA.  Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age.   Neurotoxicol Teratol. 2005;27(3):439-448. doi:10.1016/j.ntt.2005.03.010 PubMedGoogle ScholarCrossref
20.
Goldschmidt  L, Day  NL, Richardson  GA.  Effects of prenatal marijuana exposure on child behavior problems at age 10.   Neurotoxicol Teratol. 2000;22(3):325-336. doi:10.1016/S0892-0362(00)00066-0 PubMedGoogle ScholarCrossref
21.
Day  NL, Goldschmidt  L, Day  R, Larkby  C, Richardson  GA.  Prenatal marijuana exposure, age of marijuana initiation, and the development of psychotic symptoms in young adults.   Psychol Med. 2015;45(8):1779-1787. doi:10.1017/S0033291714002906 PubMedGoogle ScholarCrossref
22.
Dahl  RE, Scher  MS, Williamson  DE, Robles  N, Day  N.  A longitudinal study of prenatal marijuana use: effects on sleep and arousal at age 3 years.   Arch Pediatr Adolesc Med. 1995;149(2):145-150. doi:10.1001/archpedi.1995.02170140027004 PubMedGoogle ScholarCrossref
23.
Zammit  S, Thomas  K, Thompson  A,  et al.  Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring.   Br J Psychiatry. 2009;195(4):294-300. doi:10.1192/bjp.bp.108.062471 PubMedGoogle ScholarCrossref
24.
Ruisch  IH, Dietrich  A, Glennon  JC, Buitelaar  JK, Hoekstra  PJ.  Maternal substance use during pregnancy and offspring conduct problems: a meta-analysis.   Neurosci Biobehav Rev. 2018;84:325-336. doi:10.1016/j.neubiorev.2017.08.014 PubMedGoogle ScholarCrossref
25.
Huizink  AC.  Prenatal cannabis exposure and infant outcomes: overview of studies.   Prog Neuropsychopharmacol Biol Psychiatry. 2014;52:45-52. doi:10.1016/j.pnpbp.2013.09.014 PubMedGoogle ScholarCrossref
26.
Fine  JD, Moreau  AL, Karcher  NR,  et al.  Association of Prenatal cannabis exposure with psychosis proneness among children in the Adolescent Brain Cognitive Development (ABCD) Study.   JAMA Psychiatry. 2019;76(7):762-764. doi:10.1001/jamapsychiatry.2019.0076 PubMedGoogle ScholarCrossref
27.
Buckley  NE, Hansson  S, Harta  G, Mezey  E.  Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat.   Neuroscience. 1998;82(4):1131-1149. doi:10.1016/S0306-4522(97)00348-5 PubMedGoogle ScholarCrossref
28.
Zurolo  E, Iyer  AM, Spliet  WG,  et al.  CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies.   Neuroscience. 2010;170(1):28-41. doi:10.1016/j.neuroscience.2010.07.004 PubMedGoogle ScholarCrossref
29.
Volkow  ND, Koob  GF, Croyle  RT,  et al.  The conception of the ABCD Study: from substance use to a broad NIH collaboration.   Dev Cogn Neurosci. 2018;32:4-7. doi:10.1016/j.dcn.2017.10.002 PubMedGoogle ScholarCrossref
30.
Karcher  NR, Barch  DM, Avenevoli  S,  et al.  Assessment of the Prodromal Questionnaire–Brief Child Version for measurement of self-reported psychoticlike experiences in childhood.   JAMA Psychiatry. 2018;75(8):853-861. doi:10.1001/jamapsychiatry.2018.1334 PubMedGoogle ScholarCrossref
31.
Loewy  RL, Pearson  R, Vinogradov  S, Bearden  CE, Cannon  TD.  Psychosis risk screening with the Prodromal Questionnaire–Brief Version (PQ-B).   Schizophr Res. 2011;129(1):42-46. doi:10.1016/j.schres.2011.03.029 PubMedGoogle ScholarCrossref
32.
Achenbach  TM, Rescorla  LA.  Manual for the ASEBA School-Age Forms & Profiles: An Integrated System of Multi-informant Assessment. ASEBA; 2001.
33.
Akshoomoff  N, Beaumont  JL, Bauer  PJ,  et al.  VIII. NIH Toolbox Cognition Battery (CB): composite scores of crystallized, fluid, and overall cognition.   Monogr Soc Res Child Dev. 2013;78(4):119-132. doi:10.1111/mono.12038 PubMedGoogle ScholarCrossref
34.
Bruni  O, Ottaviano  S, Guidetti  V,  et al.  The Sleep Disturbance Scale for Children (SDSC): construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence.   J Sleep Res. 1996;5(4):251-261. doi:10.1111/j.1365-2869.1996.00251.x PubMedGoogle ScholarCrossref
35.
FreeSurfer. FreeSurfer software suite. Accessed August 12, 2020. http://surfer.nmr.mgh.harvard.edu/
36.
Dale  AM, Fischl  B, Sereno  MI.  Cortical surface–based analysis, I: segmentation and surface reconstruction.   Neuroimage. 1999;9(2):179-194. doi:10.1006/nimg.1998.0395 PubMedGoogle ScholarCrossref
37.
Fischl  B, van der Kouwe  A, Destrieux  C,  et al.  Automatically parcellating the human cerebral cortex.   Cereb Cortex. 2004;14(1):11-22. doi:10.1093/cercor/bhg087 PubMedGoogle ScholarCrossref
38.
Casey  BJ, Cannonier  T, Conley  MI,  et al; ABCD Imaging Acquisition Workgroup.  The Adolescent Brain Cognitive Development (ABCD) Study: imaging acquisition across 21 sites.   Dev Cogn Neurosci. 2018;32:43-54. doi:10.1016/j.dcn.2018.03.001 PubMedGoogle ScholarCrossref
39.
Hagler  DJ  Jr, Hatton  S, Cornejo  MD,  et al.  Image processing and analysis methods for the Adolescent Brain Cognitive Development Study.   Neuroimage. 2019;202:116091. doi:10.1016/j.neuroimage.2019.116091 PubMedGoogle Scholar
40.
Bates  D, Mächler  M, Bolker  B, Walker  S.  Fitting linear mixed-effects models using lme4.   J Stat Software. 2015;67(1):48. doi:10.18637/jss.v067.i01Google ScholarCrossref
41.
Bogdan  R, Baranger  DAA, Agrawal  A.  Polygenic risk scores in clinical psychology: bridging genomic risk to individual differences.   Annu Rev Clin Psychol. 2018;14:119-157. doi:10.1146/annurev-clinpsy-050817-084847 PubMedGoogle ScholarCrossref
42.
Schizophrenia Working Group of the Psychiatric Genomics Consortium.  Biological insights from 108 schizophrenia-associated genetic loci.   Nature. 2014;511(7510):421-427. doi:10.1038/nature13595 PubMedGoogle ScholarCrossref
43.
Lee  JJ, Wedow  R, Okbay  A,  et al; 23andMe Research Team; COGENT (Cognitive Genomics Consortium); Social Science Genetic Association Consortium.  Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.   Nat Genet. 2018;50(8):1112-1121. doi:10.1038/s41588-018-0147-3 PubMedGoogle ScholarCrossref
44.
Pasman  JA, Verweij  KJH, Gerring  Z,  et al; 23andMe Research Team; Substance Use Disorders Working Group of the Psychiatric Genomics Consortium; International Cannabis Consortium.  GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.   Nat Neurosci. 2018;21(9):1161-1170. doi:10.1038/s41593-018-0206-1 PubMedGoogle ScholarCrossref
45.
Carliner  H, Brown  QL, Sarvet  AL, Hasin  DS.  Cannabis use, attitudes, and legal status in the U.S.: a review.   Prev Med. 2017;104:13-23. doi:10.1016/j.ypmed.2017.07.008 PubMedGoogle ScholarCrossref
46.
Dickson  B, Mansfield  C, Guiahi  M,  et al.  Recommendations from cannabis dispensaries about first-trimester cannabis use.   Obstet Gynecol. 2018;131(6):1031-1038. doi:10.1097/AOG.0000000000002619 PubMedGoogle ScholarCrossref
47.
de Salas-Quiroga  A, Díaz-Alonso  J, García-Rincón  D,  et al.  Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.   Proc Natl Acad Sci U S A. 2015;112(44):13693-13698. doi:10.1073/pnas.1514962112 PubMedGoogle ScholarCrossref
48.
Fügedi  G, Molnár  M, Rigó  J  Jr, Schönléber  J, Kovalszky  I, Molvarec  A.  Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study.   BMC Pregnancy Childbirth. 2014;14:395. doi:10.1186/s12884-014-0395-x PubMedGoogle ScholarCrossref
49.
Baranger  DAA, Bogdan  R.  Editorial: causal, predispositional, or correlate? group differences in cognitive control–related brain function in cannabis-using youth raise new questions.   J Am Acad Child Adolesc Psychiatry. 2019;58(7):665-667. doi:10.1016/j.jaac.2019.05.018 PubMedGoogle ScholarCrossref
50.
Baranger  DAA, Demers  CH, Elsayed  NM,  et al.  Convergent evidence for predispositional effects of brain gray matter volume on alcohol consumption.   Biol Psychiatry. 2020;87(7):645-655. doi:10.1016/j.biopsych.2019.08.029PubMedGoogle ScholarCrossref
51.
Demontis  D, Rajagopal  VM, Thorgeirsson  TE,  et al.  Genome-wide association study implicates CHRNA2 in cannabis use disorder.   Nat Neurosci. 2019;22(7):1066-1074. doi:10.1038/s41593-019-0416-1 PubMedGoogle ScholarCrossref
52.
Murphy  SK, Itchon-Ramos  N, Visco  Z,  et al.  Cannabinoid exposure and altered DNA methylation in rat and human sperm.   Epigenetics. 2018;13(12):1208-1221. doi:10.1080/15592294.2018.1554521 PubMedGoogle ScholarCrossref
53.
Bishai  R, Koren  G.  Maternal and obstetric effects of prenatal drug exposure.   Clin Perinatol. 1999;26(1):75-86, vii. doi:10.1016/S0095-5108(18)30073-3 PubMedGoogle ScholarCrossref
54.
Moore  TH, Zammit  S, Lingford-Hughes  A,  et al.  Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.   Lancet. 2007;370(9584):319-328. doi:10.1016/S0140-6736(07)61162-3 PubMedGoogle ScholarCrossref
55.
Mason  O, Morgan  CJ, Dhiman  SK,  et al.  Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis.   Psychol Med. 2009;39(6):951-956. doi:10.1017/S0033291708004741 PubMedGoogle ScholarCrossref
56.
Power  RA, Verweij  KJ, Zuhair  M,  et al.  Genetic predisposition to schizophrenia associated with increased use of cannabis.   Mol Psychiatry. 2014;19(11):1201-1204. doi:10.1038/mp.2014.51 PubMedGoogle ScholarCrossref
57.
Carey  CE, Agrawal  A, Bucholz  KK,  et al.  Associations between polygenic risk for psychiatric disorders and substance involvement.   Front Genet. 2016;7:149. doi:10.3389/fgene.2016.00149 PubMedGoogle ScholarCrossref
58.
Verweij  KJ, Abdellaoui  A, Nivard  MG,  et al; International Cannabis Consortium.  Short communication: genetic association between schizophrenia and cannabis use.   Drug Alcohol Depend. 2017;171:117-121. doi:10.1016/j.drugalcdep.2016.09.022 PubMedGoogle ScholarCrossref
59.
Vaucher  J, Keating  BJ, Lasserre  AM,  et al.  Cannabis use and risk of schizophrenia: a mendelian randomization study.   Mol Psychiatry. 2018;23(5):1287-1292. doi:10.1038/mp.2016.252 PubMedGoogle ScholarCrossref
60.
Karcher  NR, Barch  DM, Demers  CH,  et al.  Genetic predisposition vs individual-specific processes in the association between psychotic-like experiences and cannabis use.   JAMA Psychiatry. 2019;76(1):87-94. doi:10.1001/jamapsychiatry.2018.2546 PubMedGoogle ScholarCrossref
61.
Gage  SH, Jones  HJ, Burgess  S,  et al.  Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample mendelian randomization study.   Psychol Med. 2017;47(5):971-980. doi:10.1017/S0033291716003172 PubMedGoogle ScholarCrossref
62.
Owen  MJ, O’Donovan  MC, Thapar  A, Craddock  N.  Neurodevelopmental hypothesis of schizophrenia.   Br J Psychiatry. 2011;198(3):173-175. doi:10.1192/bjp.bp.110.084384 PubMedGoogle ScholarCrossref
63.
Seiler  NK.  Alcohol and pregnancy: CDC’s health advice and the legal rights of pregnant women.   Public Health Rep. 2016;131(4):623-627. doi:10.1177/0033354916662222 PubMedGoogle ScholarCrossref
64.
Hopson  MB, Margolis  A, Rauh  V, Herbstman  J.  Impact of the home environment on the relationship between prenatal exposure to environmental tobacco smoke and child behavior.   Int J Child Health Hum Dev. 2016;9(4):453-464.PubMedGoogle Scholar
65.
D’Onofrio  BM, Van Hulle  CA, Waldman  ID,  et al.  Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds.   Dev Psychopathol. 2008;20(1):139-164. doi:10.1017/S0954579408000072 PubMedGoogle ScholarCrossref
66.
Skoglund  C, Chen  Q, D’Onofrio  BM, Lichtenstein  P, Larsson  H.  Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring.   J Child Psychol Psychiatry. 2014;55(1):61-68. doi:10.1111/jcpp.12124 PubMedGoogle ScholarCrossref
67.
Palmer  RH, Bidwell  LC, Heath  AC, Brick  LA, Madden  PA, Knopik  VS.  Effects of maternal smoking during pregnancy on offspring externalizing problems: contextual effects in a sample of female twins.   Behav Genet. 2016;46(3):403-415. doi:10.1007/s10519-016-9779-1 PubMedGoogle ScholarCrossref
68.
Knopik  VS, Heath  AC, Marceau  K,  et al.  Missouri mothers and their children: a family study of the effects of genetics and the prenatal environment.   Twin Res Hum Genet. 2015;18(5):485-496. doi:10.1017/thg.2015.46 PubMedGoogle ScholarCrossref
69.
Quinn  PD, Rickert  ME, Weibull  CE,  et al.  Association between maternal smoking during pregnancy and severe mental illness in offspring.   JAMA Psychiatry. 2017;74(6):589-596. doi:10.1001/jamapsychiatry.2017.0456 PubMedGoogle ScholarCrossref
70.
D’Onofrio  BM, Class  QA, Rickert  ME,  et al.  Translational epidemiologic approaches to understanding the consequences of early-life exposures.   Behav Genet. 2016;46(3):315-328. doi:10.1007/s10519-015-9769-8 PubMedGoogle ScholarCrossref
71.
Hannigan  JH, Chiodo  LM, Sokol  RJ,  et al.  A 14-year retrospective maternal report of alcohol consumption in pregnancy predicts pregnancy and teen outcomes.   Alcohol. 2010;44(7-8):583-594. doi:10.1016/j.alcohol.2009.03.003 PubMedGoogle ScholarCrossref
72.
Garg  M, Garrison  L, Leeman  L,  et al.  Validity of self-reported drug use information among pregnant women.   Matern Child Health J. 2016;20(1):41-47. doi:10.1007/s10995-015-1799-6PubMedGoogle ScholarCrossref
73.
Di Forti  M, Quattrone  D, Freeman  TP,  et al; EU-GEI WP2 Group.  The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study.   Lancet Psychiatry. 2019;6(5):427-436. doi:10.1016/S2215-0366(19)30048-3 PubMedGoogle ScholarCrossref
74.
Frau  R, Miczán  V, Traccis  F,  et al.  Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone.   Nat Neurosci. 2019;22(12):1975-1985. doi:10.1038/s41593-019-0512-2 PubMedGoogle ScholarCrossref
75.
Dong  C, Chen  J, Harrington  A, Vinod  KY, Hegde  ML, Hegde  VL.  Cannabinoid exposure during pregnancy and its impact on immune function.   Cell Mol Life Sci. 2019;76(4):729-743. doi:10.1007/s00018-018-2955-0 PubMedGoogle ScholarCrossref
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    2 Comments for this article
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    Perception of Risk in Study Objects
    pamela mccoll, BA | Clear the Air
    Studying pregnant women who are cannabis users calls into question serious issues over human rights and raises ethical questions, including mandatory reporting pertaining to substance abuse in pregnancy. As the September 23/2020 calls for further research on the impact of prenatal cannabis exposure and childhood outcomes the following is relevant to the discussion.

    The Office of Human Research Protection regulations read as follows (https://www.hhs.gov/ohrp/regulations-and-policy/regulations/45-cfr-46/ ): "Subpart B presumption that pregnant women may be included in research, provided certain conditions are met. According to Subpart B, the permissibility of research with pregnant women hinges on a judgment of the
    potential benefits and risks of the research. Approval of proposed research carrying no “prospect of direct benefit” to the woman or fetus requires that the risk to the fetus be judged “not greater than minimal”. Fetal risk that exceeds that standard is permissible only when the proposed research offers a prospect of direct benefit to the pregnant woman, the fetus, or both. Notably, if the proposed research does not fit within either of those two parameters, Subpart B offers an additional mechanism at the national level for approval by the Secretary of Health and Human Services."
    The federal definition of minimum risk reads: “That the magnitude and probability of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests.”

    In principle, any study that tracks the consequences of administering a drug to a developing fetus should be carried out in animal models first, and not in humans until the animal results point towards safety. The evidence of decades of research on marijuana in pregnancy does not point to safety but rather to risk and harm.

    Two basic principles in bioethics are relied upon to determine the merit of research that involves human subjects: Is the study necessary and can the research be done without the use of human subjects? There now exists a significant body of scientific evidence that warrants and justifies warning women not to use marijuana products at pre-conception, while pregnant, or breast-feeding. Is further study necessary to conclude that marijuana use is associated with risk to the child (and also the mother). I would argue it is not, especially if it allows in any measure a diminishment of the perception of risk associated with prenatal cannabis use.
    CONFLICT OF INTEREST: None Reported
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    Research into cannabis and mental health must adjust for diet type and B12 transport status
    George Henderson |
    Epidemiological research into cannabis use and mental health outcomes will be more robust if it is adjusted for diet type and genetic determinants of nutritional status. Methods, including adjustments, should be described in the abstract of such a paper; I note they are not mentioned in publicity materials for this study either.

    Cannabis users may be more likely to be vegan or vegetarian because cannabis has long been seen as a "clean" and "plant-based" intoxicant, and because hemp use is seem as environmentally friendly.

    Hibbeln et al. found that both maternal meat avoidance, and maternal soy exposure, were
    associated with an increased risk of cannabis use in offspring, OR = 2.70, 95% CI = (1.89, 4.00), p < 0.001 for vegetarian diet.[1] This study also showed an effect of a TCN2 mutation impairing vitamin B12 transport.

    After controlling for potential confounders, researchers looking at Stockholm Youth Cohort data (n=532,232) observed that anemia diagnosed during the first 30 weeks of pregnancy but not later was associated with increased risk of neurodevelopmental disorders - ASD (odds ratio [OR], 1.44; 95% CI, 1.13-1.84), ADHD (OR, 1.37; 95% CI, 1.14-1.64), and ID (OR, 2.20; 95% CI, 1.61-3.01).[2]

    The Stockholm researchers, who attempted to control for malnutrition, inadequate prenatal care, poor adherence to prenatal vitamins, hypothesized that iron deficiency anemia disrupts fetal brain development, noting that iron is essential for processes including myelination, dendrite arborization, and synthesis of monoamine neurotransmitters. To this I would add, iron is also required for brain l-carnitine synthesis, allowing normal brain energy use.

    Parents who are vegetarian or vegan may also feed such diets to children, so that maternal exposure may be compounded by post-natal exposures. In a recent systematic review, 11 of 18 studies demonstrated that meat-abstention was associated with poorer psychological health, 4 studies were equivocal, and 3 showed that meat-abstainers had better outcomes. The most rigorous studies demonstrated that the prevalence or risk of depression and/or anxiety were significantly greater in participants who avoided meat consumption. [3]

    This is not only a major confounder in cannabis research, one that is crying out for adjustment, it may well be the more valuable area of research for those seeking to improve community mental health.




    [1] Hibbeln, J.R., SanGiovanni, J.P., Golding, J., Emmett, P.M., Northstone, K., Davis, J.M., Schuckit, M. and Heron, J. (2017), Meat Consumption During Pregnancy and Substance Misuse Among Adolescent Offspring: Stratification of TCN2 Genetic Variants. Alcohol Clin Exp Res, 41: 1928-1937. doi:10.1111/acer.13494

    [2] Wiegersma AM, Dalman C, Lee BK, Karlsson H, Gardner RM. Association of Prenatal Maternal Anemia With Neurodevelopmental Disorders [published online ahead of print, 2019 Sep 18]. JAMA Psychiatry. 2019;76(12):1-12. doi:10.1001/jamapsychiatry.2019.2309

    [3] Urska Dobersek, Gabrielle Wy, Joshua Adkins, Sydney Altmeyer, Kaitlin Krout, Carl J. Lavie & Edward Archer (2020) Meat and mental health: a systematic review of meat abstention and depression, anxiety, and related phenomena, Critical Reviews in Food Science and Nutrition, DOI: 10.1080/10408398.2020.1741505
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    September 23, 2020

    Associations Between Prenatal Cannabis Exposure and Childhood Outcomes: Results From the ABCD Study

    Author Affiliations
    • 1Department of Psychological and Brain Sciences, Washington University in St Louis, St Louis, Missouri
    • 2Department of Psychiatry, Washington University in St Louis School of Medicine, St Louis, Missouri
    • 3Department of Obstetrics and Gynecology, Washington University School of Medicine in St Louis, St Louis, Missouri
    JAMA Psychiatry. 2021;78(1):64-76. doi:10.1001/jamapsychiatry.2020.2902
    Key Points

    Question  Is prenatal exposure to cannabis associated with child outcomes?

    Findings  This cross-sectional analysis of 11 489 children (655 exposed to cannabis prenatally) found that prenatal cannabis exposure after maternal knowledge of pregnancy was associated with greater psychopathology during middle childhood, even after accounting for potentially confounding variables.

    Meaning  Prenatal cannabis exposure may increase risk for psychopathology; consistent with recent recommendations by the Surgeon General of the United States, these data suggest that cannabis use during pregnancy should be discouraged by clinicians and dispensaries.

    Abstract

    Importance  In light of increasing cannabis use among pregnant women, the US Surgeon General recently issued an advisory against the use of marijuana during pregnancy.

    Objective  To evaluate whether cannabis use during pregnancy is associated with adverse outcomes among offspring.

    Design, Setting, and Participants  In this cross-sectional study, data were obtained from the baseline session of the ongoing longitudinal Adolescent Brain and Cognitive Development Study, which recruited 11 875 children aged 9 to 11 years, as well as a parent or caregiver, from 22 sites across the United States between June 1, 2016, and October 15, 2018.

    Exposure  Prenatal cannabis exposure prior to and after maternal knowledge of pregnancy.

    Main Outcomes and Measures  Symptoms of psychopathology in children (ie, psychotic-like experiences [PLEs] and internalizing, externalizing, attention, thought, and social problems), cognition, sleep, birth weight, gestational age at birth, body mass index, and brain structure (ie, total intracranial volume, white matter volume, and gray matter volume). Covariates included familial (eg, income and familial psychopathology), pregnancy (eg, prenatal exposure to alcohol and tobacco), and child (eg, substance use) variables.

    Results  Among 11 489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years) with nonmissing prenatal cannabis exposure data, 655 (5.7%) were exposed to cannabis prenatally. Relative to no exposure, cannabis exposure only before (413 [3.6%]) and after (242 [2.1%]) maternal knowledge of pregnancy were associated with greater offspring psychopathology characteristics (ie, PLEs and internalizing, externalizing, attention, thought and, social problems), sleep problems, and body mass index, as well as lower cognition and gray matter volume (all |β| > 0.02; all false discovery rate [FDR]–corrected P < .03). Only exposure after knowledge of pregnancy was associated with lower birth weight as well as total intracranial volume and white matter volumes relative to no exposure and exposure only before knowledge (all |β| > 0.02; all FDR-corrected P < .04). When including potentially confounding covariates, exposure after maternal knowledge of pregnancy remained associated with greater PLEs and externalizing, attention, thought, and social problems (all β > 0.02; FDR-corrected P < .02). Exposure only prior to maternal knowledge of pregnancy did not differ from no exposure on any outcomes when considering potentially confounding variables (all |β| < 0.02; FDR-corrected P > .70).

    Conclusions and Relevance  This study suggests that prenatal cannabis exposure and its correlated factors are associated with greater risk for psychopathology during middle childhood. Cannabis use during pregnancy should be discouraged.

    Introduction

    Alongside increasingly permissive sociocultural attitudes and laws surrounding cannabis,1 past-month cannabis use among pregnant US women increased by 106% from 2002 (3.4%) to 2017 (7.0%).2 Tetrahydrocannabinol (THC), the psychoactive component of cannabis, crosses the placenta and interfaces with the endocannabinoid system, which is associated with neural development.3-5 Thus, it is plausible that cannabis use during pregnancy may relate to outcomes in offspring. The increase of cannabis use among pregnant mothers,2,6-8 as well as evidence linking prenatal exposure to adverse outcomes,9-13 prompted the US Surgeon General to release an advisory against cannabis use during pregnancy and breastfeeding on August 29, 2019.14

    To our knowledge, there have been relatively few investigations of prenatal cannabis exposure and child outcomes. Available evidence has linked exposure to reduced birth weight15 and cognition,16,17 as well as heightened risk for premature birth,18 psychopathology (ie, psychosis, internalizing, and externalizing),19-21 and sleep problems.22 However, limited cross-study replication23-25 and an inability to account for potential confounders (eg, child substance use and familial risk) in most studies has left these associations tenuous. Indeed, the National Academies of Sciences, Engineering, and Medicine recently concluded that only reduced birth weight has been robustly linked to prenatal cannabis exposure.13

    Using data from the Adolescent Brain Cognitive Development (ABCD) Study (data release 2.0.1) of 11 875 children, we test whether prenatal cannabis exposure before and after maternal knowledge of pregnancy is associated with psychopathology (ie, internalizing, externalizing, attention, thought, and social problems, as well as psychotic-like experiences [PLEs]), sleep, cognition, birth weight, premature birth, body mass index (BMI), and gross brain structure (ie, white matter volume [WMV], gray matter volume [GMV], and intracranial volume [ICV]). This study represents a comprehensive extension of a prior investigation of prenatal cannabis exposure and PLEs among the initial ABCD Study data release (N = 4361).26 Cannabis use during the lifetime is associated with various psychosocial and familial correlates.1 In addition, from a neurodevelopmental perspective, endocannabinoid receptors are not expressed in the fetus until 5 to 6 weeks’ gestation,9,27,28 which approximately corresponds to when, in this study, mothers learned they were pregnant (mean [SD], 6.9 [6.8] weeks). Thus, we hypothesized that any observed associations with cannabis exposure only before maternal knowledge of pregnancy would be dependent on potential confounders (eg, socioeconomic status and familial history of psychopathology). However, we expected that associations with maternal use of cannabis after knowledge of pregnancy would partially capture cannabis-specific associations and therefore persist even on inclusion of potentially confounding covariates.

    Methods
    Participants

    Data for this cross-sectional study were collected between June 1, 2016, and October 15, 2018, from children born between 2005 and 2009 to 9987 mothers through 10 801 pregnancies, who completed the baseline session of the ongoing longitudinal ABCD Study (release 2.0.1; https://abcdstudy.org/).29 The study includes a family-based design in which twin (n = 2108), triplet (n = 30), nontwin siblings (n = 1589), and singletons (n = 8148) were recruited. All parents or caregivers (10 131 of 11 875 biological mothers [85.3%]) provided written informed consent and children provided verbal assent to a research protocol approved by the institutional review board at each data collection site (n = 22) throughout the United States (https://abcdstudy.org/sites/abcd-sites.html). All analyses were rerun excluding parent or caregiver respondents who were not the mother; all results and conclusions remained the same; eTable 12 in the Supplement. For our analyses, participants with nonmissing prenatal cannabis exposure data were included (n = 11 489; Table 1). This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Measures

    All measures are described in the eMethods in the Supplement and Table 1. Child prenatal cannabis exposure was based on parent or caregiver retrospective report. Three mutually exclusive groups were formed: no exposure (n = 10 834), exposure prior to maternal knowledge of pregnancy only (n = 413), and exposure after maternal knowledge of pregnancy (n = 242, with or without exposure prior to maternal knowledge).

    The Prodromal Questionnaire–Brief Child Version30,31 total score was used to assess child-reported PLEs. Higher scores indicate more PLEs.

    The Child Behavior Checklist32 was used to assess broad-spectrum internalizing and externalizing problems as well as attention, thought, and social problems in children according to parent or caregiver report. Higher scores are reflective of more problems.

    The National Institutes of Health Toolbox Cognition Battery–Total Cognition Composite33 indexed child cognitive ability. Higher scores indicate greater cognitive performance.

    The Sleep Disturbance Scale for Children34 total score was used to assess sleep problems in children according to parent or caregiver report. Higher scores reflect more sleep problems.

    A parent or caregiver retrospectively reported their child’s gestational age at birth and birth weight. Child BMI was calculated using measured height and weight.

    FreeSurfer, version 5.335 was used to estimate total ICV, GMV, and WMV. See the eMethods in the Supplement for imaging acquisition and processing.36-39

    Covariates

    The following fixed-effect covariates were dummy coded: race/ethnicity (White, Black, Asian, Native American, Pacific Islander, Hispanic, and other), first-degree familial history of psychopathology (depression, psychosis, anxiety, mania, and antisocial behavior), prenatal exposure to tobacco or alcohol before or after maternal knowledge of pregnancy, unplanned pregnancy, prenatal vitamin use, child had tried alcohol, child had tried tobacco, child sex, and twin or triplet status. Annual household income was treated as a 5-level categorical variable. The following continuous covariates were included: birth weight, maternal age at birth, gestational age when pregnancy was discovered (weeks), child age, and maternal educational level. These variables were reported by caregivers. Intracranial volume was further included as a covariate in models with GMV and WMV as outcomes. Polygenic scores (PGS) for schizophrenia, educational attainment, and cannabis use as well as ancestrally informative principal components (n = 10) were included as covariates in post hoc analyses within the genomically confirmed European ancestry subsample (eMethods in the Supplement). Owing to limited endorsement of ever having a marijuana puff among children (n = 14), we did not include this variable as a covariate.

    Uncommon substance use among children (ie, use other than trying alcohol or tobacco [eg, having a marijuana puff or a full alcoholic drink]) or by women while they were pregnant as well as extreme premature birth (ie, <32 weeks) and nonbiological mother caregiver report were not included as covariates. Post hoc analyses excluded individuals based on these variables (eMethods in the Supplement).

    Statistical Analysis

    Individual values on continuous predictor and outcome variables were winsorized (to 3 SD) to minimize the influence of extreme values. We used linear mixed-effects models with random intercept parameters to account for site and family membership for all analyses with the lme4 package in R, version 3.6.0 (R Project for Statistical Computing).40 We examined the association between prenatal cannabis exposure and outcomes using 3 analytic approaches.

    First, we tested whether mutually exclusive prenatal cannabis exposure groups were associated with outcomes of interest in nested mixed models with no fixed-effect covariates with the following orthogonal contrasts: (1) exposure after maternal knowledge of pregnancy vs no exposure, (2) exposure only before maternal knowledge of pregnancy vs no exposure, and (3) exposure after vs only before maternal knowledge of pregnancy. Benjamini-Hochberg false discovery rate (FDR) correction was used to adjust for testing multiple phenotypes within each group contrast (14 tests). Second, we examined whether any associations that were significant after multiple testing correction were robust to the inclusion of potentially confounding covariates (equations are illustrated in the eMethods in the Supplement), using FDR correction to adjust for multiple testing within each group contrast (13 tests). Third, to account for possible confounding associations of genomic liability with offspring outcomes not accounted for by familial history, we examined associations when accounting for child PGS for related outcomes (eMethods in the Supplement).41 To ensure that effect-size changes could not be attributed to reduced sample size alone, we first recomputed covariate-adjusted associations in the genomically confirmed European ancestry subsample (n = 4591). We then tested whether any significant estimates (P < .05 for any contrast) were altered by inclusion of PGS (ie, schizophrenia,42 educational level,43 and cannabis use44 for PLEs; and cannabis use for social problems; eMethods in the Supplement). Post hoc sensitivity analyses of nonmutually exclusive dummy variables entered into regressions simultaneously and inverse probability propensity score weighting were used to test whether observed associations were robust to analytic alternatives to our mutually exclusive group approach and use of covariates, respectively (eMethods in the Supplement). All P values were from 2-sided tests and results were deemed statistically significant at FDR-corrected P < .05.

    Results

    Among 11 489 children (5997 boys [52.2%]; mean [SD] age, 9.9 [0.6] years; 8589 of 11 489 White [74.8%]), 655 (5.7%) were prenatally exposed to cannabis (Table 1). Of these, 413 were exposed only before maternal knowledge of pregnancy, 235 were exposed both before and after maternal knowledge, and 7 were exposed only after maternal knowledge. Mothers learned of their pregnancy at a mean (SD) of 6.9 (6.8) weeks. Rates of tobacco and alcohol use during pregnancy were higher than cannabis use and were modestly correlated with prenatal cannabis exposure (tobacco, 1519 of 11 489 [13.2%]; r = 0.34; and alcohol, 2820 of 11 489 [24.5%]; r = 0.20). Data on frequency of cannabis use during pregnancy were collected; however, high rates of missingness (eg, 20%-38%) and nonspecific item wording (“how many times per day”) preclude meaningful analyses. Of those with reported data, 87.0% of those in the exposure only before maternal knowledge group (287 of 330) and 92.7% of those in the exposure after maternal knowledge group (140 of 151) reported using cannabis at least once per day; groups did not differ in reported frequency of use during pregnancy (t = 0.43; P = .67).

    Prenatal Cannabis Exposure and Outcomes Without Covariates

    Before covariate adjustment, prenatal cannabis exposure only before and after maternal knowledge of pregnancy were associated with higher PLEs, BMI, and internalizing, externalizing, attention, thought, social, and sleep problems, as well as lower cognition and GMV, relative to no prenatal exposure (all |β| > 0.02; all FDR-corrected P < .03; Table 2). Prenatal exposure after, but not before, maternal knowledge of pregnancy was also associated with lower birth weight, ICV, and WMV when compared with those with no prenatal exposure (all |β| > 0.07; all FDR-corrected P < .002; Table 2). Comparing groups with prenatal exposure revealed that exposure after maternal knowledge of pregnancy was associated with relatively higher psychopathology across all measures, BMI, sleep problems, lower cognition, birth weight, ICV, GMV, and WMV (all |β| > 0.02; all FDR-corrected P < .05; Table 2). Prenatal cannabis exposure explained less than 1.9% of variance in outcomes.

    Association of Prenatal Cannabis Exposure and Outcomes With Covariates

    When including covariates, exposure after knowledge of pregnancy remained associated with higher PLEs as well as externalizing, attention, thought, and social problems relative to those with no reported prenatal exposure and those with exposure only before maternal knowledge of pregnancy (all |β| > 0.02; all FDR-corrected P < .02; Figure and Table 3; eTables 1-7 in the Supplement). These associations explained less than 0.4% of variance in outcomes. Full regression results are provided in eTables 1, 2, and 3 in the Supplement. While they did not survive FDR correction, exposure after maternal knowledge was also associated with greater internalizing problems and reduced birth weight relative to both other groups at nominal/marginal levels of significance (all |β| > 0.02; all P < .064; all FDR-corrected P < .12) as well as reduced cognition relative to exposure only before maternal knowledge (β = −0.023; P = .043; FDR-corrected P = .07; Figure and Table 3). Of note, effect sizes (ie, β coefficients) for group differences when comparing prenatal cannabis exposure after knowledge with either no exposure or exposure only before knowledge of pregnancy were roughly equivalent (Table 3). No group differences were found when comparing prenatal cannabis exposure before maternal knowledge of pregnancy with no exposure. Generally, no small group of covariates was responsible for attenuating these associations (eResults in the Supplement).

    Post hoc analyses excluding children who engaged in uncommon substance use, who were exposed to other illicit substances prenatally, who were born at extreme levels of prematurity (eMethods in the Supplement), or whose biological mothers were not the parent or caregiver respondent revealed consistent findings (eTables 9-12 in the Supplement). Log-transforming outcomes or including only covariates significantly associated with outcomes in the full regression models did not meaningfully alter any observed associations (eTables 4-7 and 12 in the Supplement). Five-fold cross-validation suggests that inclusion of all covariates did not appreciably alter the stability of β coefficient estimates. This finding suggests that our primary analytic approach did not alter β estimates by overfitting these data (eMethods and eTable 8 in the Supplement). Finally, in the subsample of children with genomically confirmed European ancestry (181 of 4591 [3.9%] reporting any prenatal exposure), PLEs and social problems remained more associated with exposure after maternal knowledge of pregnancy. Further accounting for child PGS for schizophrenia, educational level, and/or cannabis use did not substantively alter the findings (eTables 13-16 in the Supplement).

    Sensitivity Analyses

    As prenatal exposure after maternal knowledge, regardless of contrast group (ie, no exposure or exposure only before maternal knowledge), was associated with outcomes (Table 3), we conducted regression analyses with prenatal exposure coded as 2 nonmutually exclusive exposure variables (ie, any exposure before or after knowledge) and the results remained unchanged. To account for possible imbalance in covariate distributions across exposed and unexposed individuals, we also conducted inverse probability propensity score–weighted analyses, which also broadly recapitulated the conclusions reported above (eTables 17-20 in the Supplement).

    Discussion

    This study suggests that prenatal cannabis exposure after maternal knowledge of pregnancy is associated with a small elevation in risk for psychopathology during childhood (Table 2 and Table 3). That these associations were robust to the inclusion of potentially confounding variables increases the plausibility that prenatal cannabis exposure may be independently associated with psychopathology risk in children. In contrast to increasingly permissive attitudes surrounding cannabis use among pregnant mothers45 and suggestions by dispensaries to use cannabis to combat pregnancy-related nausea,46 our findings align with recent recommendations by the US Surgeon General14 regarding the potential association of in utero cannabis exposure with outcomes in children.

    All studied outcomes except gestational age at birth were associated with prenatal exposure before and after maternal knowledge of pregnancy relative to no exposure; however, only associations between prenatal exposure after maternal knowledge of pregnancy and child psychopathology were robust to covariate inclusion, with birth weight and sleep problems showing nonsignificant nominal trends (Table 3). Effect size estimates were largely overlapping when contrasting prenatal exposure after maternal knowledge of pregnancy vs no prenatal exposure and vs prenatal exposure before maternal knowledge of pregnancy (Table 3); regression analyses of prenatal exposure after knowledge of pregnancy vs no exposure after knowledge (ie, no exposure and exposure only before maternal knowledge of pregnancy) produced equivalent findings (eTable 18 in the Supplement). Collectively, these findings suggest that prenatal exposure after maternal knowledge of pregnancy may plausibly be independently associated with child outcomes, while associations with exposure only before maternal knowledge of pregnancy may be attributable to confounding variables, such as familial and pregnancy-related factors correlated with cannabis use and/or offspring outcomes.

    There are several potential explanations for the overall pattern of findings. First, endocannabinoid system ontogeny may play a role. Animal models suggest that endocannabinoid type 1 receptors (CB1Rs) are critical for THC’s impact on the developing brain47 and are not expressed before the equivalent of 5 to 6 weeks’ gestation in humans.9 Independent associations of cannabis with child behavioral outcomes may arise only when sufficient CB1Rs are present in the fetus, which may not occur until many women learn they are pregnant. It is possible that exposure before this time might not have a direct association with fetal brain development, although it remains possible that there may be indirect associations through endocannabinoid receptor expression in the placenta.48 Excluding women who reported only using cannabis prior to knowledge of pregnancy but learning of their pregnancy at more than 14 weeks’ or more than 9 weeks’ gestation produced consistent results (eTables 21 and 22 in the Supplement). Second, use of cannabis despite knowledge of pregnancy might represent a preexisting and more severe form of cannabis use (eg, cannabis use disorder), indicative of greater prenatal and potential postnatal exposure (eg, through breastfeeding).49 Third, sustained cannabis use during pregnancy may reflect a predisposition to the observed negative outcomes (eg, socioeconomic status and genetic susceptibility).50,51 However, controlling for such factors did not eliminate associations (eTables 2, 3, 13, and 14 in the Supplement). Fourth, associations may be attributable to an unmeasured common variable (eg, paternal germline exposure to cannabis, health care access, or postpartum maternal behavior)52,53 or an alternative derivation of an included confounder. Accounting for scores from a 4-item assessment of PLEs in mothers (eMethods in the Supplement) as opposed to familial history of psychosis, which has a low rate of report, does not alter the significance of the association between prenatal cannabis exposure and PLEs in offspring (eTable 23 in the Supplement).

    Chronic self-administration of cannabis during adolescence has been linked to increased psychopathology, particularly psychosis.54 In contrast to acute THC psychotomimetic effects,55 mounting evidence supports common genetic liability as a major factor in this association,44,51,56-58 although potential bidirectional44,51,59-61 causal effects cannot be ruled out. Consistent with prior work,21 we find that child psychosis liability (ie, PLEs and thought problems) is modestly higher among children prenatally exposed to cannabis after maternal knowledge of pregnancy. That the association with PLEs remained after accounting for family history of psychosis as well as child PGS suggests that this association may not be entirely attributable to common genomic liability, as indexed by PGS and family history. Putative mechanisms underlying psychosis liability in children prenatally exposed to cannabis may be distinct from those associated with self-administered cannabis use. For instance, CB1Rs have neuromodulatory functions throughout life, but during the prenatal period they are ubiquitously expressed in neural progenitors and contribute to neural migration, axonal elongation, and synaptic formation.9 Although abnormalities in these neural processes are consistent with neurodevelopmental theories of psychosis,62 the associations we observed with metrics of gross brain morphologic characteristics were not robust to covariate inclusion. It is possible that neurodevelopmental differences (eg, synaptic formation) are not detectable using magnetic resonance imaging, are regionally specific, or emerge at different developmental stages.

    In addition to associations with PLEs and thought problems, children prenatally exposed to cannabis after maternal knowledge of pregnancy had elevated externalizing, attention, and social problems. Prenatal exposure to alcohol and tobacco were also associated with psychopathology in offspring, but these associations were predominantly with exposure prior to, as opposed to after, maternal knowledge of pregnancy and were observed inconsistently relative to associations with cannabis exposure (eTables 1 and 2 in the Supplement). The lack of association with alcohol or tobacco use subsequent to knowledge of pregnancy may indicate the more pronounced public awareness of fetal risks and obstetric oversight of the use of these substances that is associated with greater reductions in use after knowledge of pregnancy, relative to cannabis,8,63 as well as phenotypic heterogeneity encompassed by our dichotomous phenotypes. Alternatively, prenatal cannabis exposure may serve as a proxy for exposure to a permissive home environment that promotes externalizing behaviors and related cognitive disengagement.64 As has been shown for the increased likelihood of tobacco smoking during pregnancy in women with attention-deficit/hyperactivity disorder and the confounding of consequent associations with attention-deficit/hyperactivity disorder in offspring,65-67 women with externalizing features might be more likely to continue using cannabis during their pregnancy. Although our consideration of covariates suggests potential independent associations of cannabis with these outcomes, genetically informed designs (eg, sibling crossover design where nontwin siblings are discordant for prenatal exposure)68,69 would be a useful approach to consider familial sources of confounding.70

    Limitations

    Some limitations of this study are noteworthy. First, parents or caregivers retrospectively reported on cannabis use during pregnancy that occurred approximately 10 years earlier, which may have resulted in biased reporting and misclassification.71 For example, retrospective report of substance use during pregnancy 14 years earlier has been found to be more common than antenatal report and more strongly correlated with child outcomes (eg, measured birth weight and behavioral problems).71 Although these findings may indicate greater accuracy during retrospective recall, they could also reflect recall bias related to children contemporaneously experiencing problems. However, ABCD Study prevalence estimates of self-reported prenatal cannabis use align with toxicology-based prevalence estimates from national data sets collected during the years these children were born.72

    Second, although the ABCD Study is, to our knowledge, the largest integrative study of child health and substance use and among the largest studies of prenatal exposure and child outcomes (the number of exposed children exceeded entire samples from other studies),21 there was a proportionally small number of participants who were exposed to cannabis prenatally, thereby reducing power. Third, THC concentration differs between fetuses whose mothers use cannabis once per month compared with once per day.15 There are limited or no data on potency, frequency (see Results), timing, or quantity of cannabis exposure in this data set. It will be important for future efforts to better understand the impact of dosage, strain, and method of ingestion.73 Fourth, while we were able to account for many known familial, pregnancy-related, and child-related confounding variables, the role of unmeasured confounders cannot be discounted. Relatedly, while we account for underlying genetic vulnerability using both familial history and PGS, it is possible that the current genome-wide association studies from which PGS weighting was estimated do not adequately represent genetic risk for the specific child outcomes under study (eTables 15 and 16 in the Supplement).

    Conclusions

    Despite increasingly permissive social attitudes and the marked relaxation of legal restrictions on cannabis use,1 prenatal cannabis exposure and the correlated risks that it indexes may place offspring at increased risk for psychopathology in middle childhood. In the context of increasing cannabis use among pregnant women,2,6 it is clear that more studies on the association between prenatal cannabis exposure and offspring developmental outcomes are needed to examine potential causal effects, moderating or protective factors, and biological mechanisms.74,75 Similar to the effective messaging surrounding the adverse consequences of alcohol and tobacco exposure during pregnancy, education regarding the potential harms associated with prenatal cannabis use is necessary. Currently, pregnant women, and even those contemplating pregnancy, should be discouraged from using any cannabis by health care professionals, dispensaries, and others; women refraining from cannabis use during pregnancy may benefit offspring.11,14

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    Article Information

    Accepted for Publication: July 21, 2020.

    Corresponding Authors: Sarah E. Paul, BA (spaul24@wustl.edu), and Ryan Bogdan, PhD (rbogdan@wustl.edu), Department of Psychological and Brain Sciences, Washington University in St Louis, One Brookings Drive, CB 1125 Psychological and Brain Sciences Bldg, Room 453, St Louis, MO 63130.

    Published Online: September 23, 2020. doi:10.1001/jamapsychiatry.2020.2902

    Author Contributions: Ms Paul and Dr Hatoum had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Ms Paul and Dr Hatoum contributed equally to the work.

    Concept and design: Paul, Hatoum, Fine, Hansen, Moreau, Bondy, Agrawal, Barch, Bogdan.

    Acquisition, analysis, or interpretation of data: Paul, Hatoum, Fine, Johnson, Hansen, Karcher, Qu, Carter, Rogers, Agrawal, Barch, Bogdan.

    Drafting of the manuscript: Paul, Fine, Bogdan.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Paul, Hatoum, Fine, Johnson, Hansen, Qu, Agrawal, Bogdan.

    Obtained funding: Barch, Bogdan.

    Administrative, technical, or material support: Hansen, Moreau, Bondy, Qu, Carter, Barch, Bogdan.

    Supervision: Hatoum, Barch, Bogdan.

    Conflict of Interest Disclosures: Dr Hatoum reported receiving grants from the National Institute for Drug Abuse. Ms Hansen reported receiving grants from the Missouri Louis Stokes Alliance for Minority Participation during the conduct of the study. Dr Rogers reported receiving grants from the National Institutes of Health during the conduct of the study. Dr Agrawal reported receiving grants from the National Institute on Drug Abuse during the conduct of the study; and grants from the National Institute on Drug Abuse, National Institutes on Alcohol Abuse and Alcoholism, and National Institute on Mental Health outside the submitted work. Dr Barch reported receiving grants from the National Institute of Mental Health and the National Institute on Drug Abuse during the conduct of the study. Dr Bogdan reported receiving grants from the National Institute of Aging and the National Institute of Alcohol Abuse and Alcoholism during the course of the study. No other disclosures were reported.

    Funding/Support: Data used in the preparation of this article were obtained from the Adolescent Brain Cognitive Development (ABCD) Study (https://abcdstudy.org), held in the NIMH Data Archive (NDA). This is a multisite, longitudinal study designed to recruit more than 10 000 children aged 9 to 10 years and follow them over 10 years into early adulthood. The ABCD Study is supported by the National Institutes of Health and additional federal partners under award numbers U01DA041048, U01DA050989, U01DA051016, U01DA041022, U01DA051018, U01DA051037, U01DA050987, U01DA041174, U01DA041106, U01DA041117, U01DA041028, U01DA041134, U01DA050988, U01DA051039, U01DA041156, U01DA041025, U01DA041120, U01DA051038, U01DA041148, U01DA041093, U01DA041089, U24DA041123, and U24DA041147. A full list of supporters is available at https://abcdstudy.org/federal-partners.html. A listing of participating sites and a complete listing of the study investigators can be found at https://abcdstudy.org/consortium_members/. ABCD consortium investigators designed and implemented the study and/or provided data but did not necessarily participate in analysis or writing of this report. The ABCD data repository grows and changes over time. The ABCD data used in this report came from 10.15154/1519186. The DOIs can be found at https://dx.doi.org/10.15154/1519186. Authors received funding support from the National Institutes of Health: Dr Hatoum (grant T32-DA007261), Dr Johnson (grant F32 AA027435), Dr Karcher (grant MH014677), Dr Carter (grant R01-DA046224), Dr Rogers (grant R01-DA046224), Dr Agrawal (grants 5K02DA32573 and R01-DA046224), Dr Barch (grants R01-MH113883, R01-MH066031, U01-MH109589, U01-A005020803, and R01-MH090786), and Dr Bogdan (grants R01-AG045231, R01-HD083614, R01-AG052564, R21-AA027827, and R01-DA046224). Ms Hansen received support to work on this project from the Missouri Louis Stokes Alliance for Minority Participation.

    Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: This manuscript reflects the views of the authors and may not reflect the opinions or views of the NIH or ABCD consortium investigators.

    Additional Contributions: We would like to acknowledge all participating groups of the International Cannabis Consortium, in particular the members of the working group including Sven Stringer, PhD, VU University Center for Neurogenomics and Cognitive Research (CNCR), Camelia Minica, PhD, VU University Amsterdam, Karin Verweij, PhD, VU University Amsterdam, Hamdi Mbarek, PhD, VU University Amsterdam, Eske Derks, PhD, Queensland Institute of Medical Research, Nathan Gillespie, PhD, Virginia Commonwealth University, and Jacqueline Vink, PhD, Radboud University, all of whom did not receive financial compensation.

    References
    1.
    Hasin  DS.  US epidemiology of cannabis use and associated problems.   Neuropsychopharmacology. 2018;43(1):195-212. doi:10.1038/npp.2017.198 PubMedGoogle ScholarCrossref
    2.
    Volkow  ND, Han  B, Compton  WM, McCance-Katz  EF.  Self-reported medical and nonmedical cannabis use among pregnant women in the United States.   JAMA. 2019;322(2):167-169. doi:10.1001/jama.2019.7982 PubMedGoogle ScholarCrossref
    3.
    Yao  JL, He  QZ, Liu  M,  et al.  Effects of Δ(9)-tetrahydrocannabinol (THC) on human amniotic epithelial cell proliferation and migration.   Toxicology. 2018;394:19-26. doi:10.1016/j.tox.2017.11.016 PubMedGoogle ScholarCrossref
    4.
    Basavarajappa  BS, Nixon  RA, Arancio  O.  Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration.   Mini Rev Med Chem. 2009;9(4):448-462. doi:10.2174/138955709787847921 PubMedGoogle ScholarCrossref
    5.
    Fride  E, Gobshtis  N, Dahan  H, Weller  A, Giuffrida  A, Ben-Shabat  S.  The endocannabinoid system during development: emphasis on perinatal events and delayed effects.   Vitam Horm. 2009;81:139-158. doi:10.1016/S0083-6729(09)81006-6 PubMedGoogle ScholarCrossref
    6.
    Young-Wolff  KC, Sarovar  V, Tucker  LY,  et al.  Self-reported daily, weekly, and monthly cannabis use among women before and during pregnancy.   JAMA Netw Open. 2019;2(7):e196471. doi:10.1001/jamanetworkopen.2019.6471 PubMedGoogle Scholar
    7.
    Brown  QL, Sarvet  AL, Shmulewitz  D, Martins  SS, Wall  MM, Hasin  DS.  Trends in marijuana use among pregnant and nonpregnant reproductive-aged women, 2002-2014.   JAMA. 2017;317(2):207-209. doi:10.1001/jama.2016.17383 PubMedGoogle ScholarCrossref
    8.
    Agrawal  A, Rogers  CE, Lessov-Schlaggar  CN, Carter  EB, Lenze  SN, Grucza  RA.  Alcohol, cigarette, and cannabis use between 2002 and 2016 in pregnant women from a nationally representative sample.   JAMA Pediatr. 2019;173(1):95-96. doi:10.1001/jamapediatrics.2018.3096 PubMedGoogle ScholarCrossref
    9.
    Wu  CS, Jew  CP, Lu  HC.  Lasting impacts of prenatal cannabis exposure and the role of endogenous cannabinoids in the developing brain.   Future Neurol. 2011;6(4):459-480. doi:10.2217/fnl.11.27 PubMedGoogle ScholarCrossref
    10.
    Scheyer  AF, Melis  M, Trezza  V, Manzoni  OJJ.  Consequences of perinatal cannabis exposure.   Trends Neurosci. 2019;42(12):871-884. doi:10.1016/j.tins.2019.08.010 PubMedGoogle ScholarCrossref
    11.
    Volkow  ND, Compton  WM, Wargo  EM.  The risks of marijuana use during pregnancy.   JAMA. 2017;317(2):129-130. doi:10.1001/jama.2016.18612 PubMedGoogle ScholarCrossref
    12.
    Jansson  LM, Jordan  CJ, Velez  ML.  Perinatal marijuana use and the developing child.   JAMA. 2018;320(6):545-546. doi:10.1001/jama.2018.8401 PubMedGoogle ScholarCrossref
    13.
    National Academies of Sciences, Engineering, and Medicine.  The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press; 2017.
    14.
    Office of the Surgeon General, US Department of Health and Human Services. U.S. Surgeon General’s advisory: marijuana use and the developing brain. Accessed October 16, 2019. https://www.hhs.gov/surgeongeneral/reports-and-publications/addiction-and-substance-misuse/advisory-on-marijuana-use-and-developing-brain/index.html#
    15.
    Ryan  SA, Ammerman  SD, O’Connor  ME; Committee on Substance Use and Prevention; Section on Breastfeeding.  Marijuana use during pregnancy and breastfeeding: implications for neonatal and childhood outcomes.   Pediatrics. 2018;142(3):e20181889. doi:10.1542/peds.2018-1889 PubMedGoogle Scholar
    16.
    Smith  AM, Mioduszewski  O, Hatchard  T, Byron-Alhassan  A, Fall  C, Fried  PA.  Prenatal marijuana exposure impacts executive functioning into young adulthood: an fMRI study.   Neurotoxicol Teratol. 2016;58:53-59. doi:10.1016/j.ntt.2016.05.010 PubMedGoogle ScholarCrossref
    17.
    Leech  SL, Richardson  GA, Goldschmidt  L, Day  NL.  Prenatal substance exposure: effects on attention and impulsivity of 6-year-olds.   Neurotoxicol Teratol. 1999;21(2):109-118. doi:10.1016/S0892-0362(98)00042-7 PubMedGoogle ScholarCrossref
    18.
    Corsi  DJ, Walsh  L, Weiss  D,  et al.  Association between self-reported prenatal cannabis use and maternal, perinatal, and neonatal outcomes.   JAMA. 2019;322(2):145-152. doi:10.1001/jama.2019.8734 PubMedGoogle ScholarCrossref
    19.
    Gray  KA, Day  NL, Leech  S, Richardson  GA.  Prenatal marijuana exposure: effect on child depressive symptoms at ten years of age.   Neurotoxicol Teratol. 2005;27(3):439-448. doi:10.1016/j.ntt.2005.03.010 PubMedGoogle ScholarCrossref
    20.
    Goldschmidt  L, Day  NL, Richardson  GA.  Effects of prenatal marijuana exposure on child behavior problems at age 10.   Neurotoxicol Teratol. 2000;22(3):325-336. doi:10.1016/S0892-0362(00)00066-0 PubMedGoogle ScholarCrossref
    21.
    Day  NL, Goldschmidt  L, Day  R, Larkby  C, Richardson  GA.  Prenatal marijuana exposure, age of marijuana initiation, and the development of psychotic symptoms in young adults.   Psychol Med. 2015;45(8):1779-1787. doi:10.1017/S0033291714002906 PubMedGoogle ScholarCrossref
    22.
    Dahl  RE, Scher  MS, Williamson  DE, Robles  N, Day  N.  A longitudinal study of prenatal marijuana use: effects on sleep and arousal at age 3 years.   Arch Pediatr Adolesc Med. 1995;149(2):145-150. doi:10.1001/archpedi.1995.02170140027004 PubMedGoogle ScholarCrossref
    23.
    Zammit  S, Thomas  K, Thompson  A,  et al.  Maternal tobacco, cannabis and alcohol use during pregnancy and risk of adolescent psychotic symptoms in offspring.   Br J Psychiatry. 2009;195(4):294-300. doi:10.1192/bjp.bp.108.062471 PubMedGoogle ScholarCrossref
    24.
    Ruisch  IH, Dietrich  A, Glennon  JC, Buitelaar  JK, Hoekstra  PJ.  Maternal substance use during pregnancy and offspring conduct problems: a meta-analysis.   Neurosci Biobehav Rev. 2018;84:325-336. doi:10.1016/j.neubiorev.2017.08.014 PubMedGoogle ScholarCrossref
    25.
    Huizink  AC.  Prenatal cannabis exposure and infant outcomes: overview of studies.   Prog Neuropsychopharmacol Biol Psychiatry. 2014;52:45-52. doi:10.1016/j.pnpbp.2013.09.014 PubMedGoogle ScholarCrossref
    26.
    Fine  JD, Moreau  AL, Karcher  NR,  et al.  Association of Prenatal cannabis exposure with psychosis proneness among children in the Adolescent Brain Cognitive Development (ABCD) Study.   JAMA Psychiatry. 2019;76(7):762-764. doi:10.1001/jamapsychiatry.2019.0076 PubMedGoogle ScholarCrossref
    27.
    Buckley  NE, Hansson  S, Harta  G, Mezey  E.  Expression of the CB1 and CB2 receptor messenger RNAs during embryonic development in the rat.   Neuroscience. 1998;82(4):1131-1149. doi:10.1016/S0306-4522(97)00348-5 PubMedGoogle ScholarCrossref
    28.
    Zurolo  E, Iyer  AM, Spliet  WG,  et al.  CB1 and CB2 cannabinoid receptor expression during development and in epileptogenic developmental pathologies.   Neuroscience. 2010;170(1):28-41. doi:10.1016/j.neuroscience.2010.07.004 PubMedGoogle ScholarCrossref
    29.
    Volkow  ND, Koob  GF, Croyle  RT,  et al.  The conception of the ABCD Study: from substance use to a broad NIH collaboration.   Dev Cogn Neurosci. 2018;32:4-7. doi:10.1016/j.dcn.2017.10.002 PubMedGoogle ScholarCrossref
    30.
    Karcher  NR, Barch  DM, Avenevoli  S,  et al.  Assessment of the Prodromal Questionnaire–Brief Child Version for measurement of self-reported psychoticlike experiences in childhood.   JAMA Psychiatry. 2018;75(8):853-861. doi:10.1001/jamapsychiatry.2018.1334 PubMedGoogle ScholarCrossref
    31.
    Loewy  RL, Pearson  R, Vinogradov  S, Bearden  CE, Cannon  TD.  Psychosis risk screening with the Prodromal Questionnaire–Brief Version (PQ-B).   Schizophr Res. 2011;129(1):42-46. doi:10.1016/j.schres.2011.03.029 PubMedGoogle ScholarCrossref
    32.
    Achenbach  TM, Rescorla  LA.  Manual for the ASEBA School-Age Forms & Profiles: An Integrated System of Multi-informant Assessment. ASEBA; 2001.
    33.
    Akshoomoff  N, Beaumont  JL, Bauer  PJ,  et al.  VIII. NIH Toolbox Cognition Battery (CB): composite scores of crystallized, fluid, and overall cognition.   Monogr Soc Res Child Dev. 2013;78(4):119-132. doi:10.1111/mono.12038 PubMedGoogle ScholarCrossref
    34.
    Bruni  O, Ottaviano  S, Guidetti  V,  et al.  The Sleep Disturbance Scale for Children (SDSC): construction and validation of an instrument to evaluate sleep disturbances in childhood and adolescence.   J Sleep Res. 1996;5(4):251-261. doi:10.1111/j.1365-2869.1996.00251.x PubMedGoogle ScholarCrossref
    35.
    FreeSurfer. FreeSurfer software suite. Accessed August 12, 2020. http://surfer.nmr.mgh.harvard.edu/
    36.
    Dale  AM, Fischl  B, Sereno  MI.  Cortical surface–based analysis, I: segmentation and surface reconstruction.   Neuroimage. 1999;9(2):179-194. doi:10.1006/nimg.1998.0395 PubMedGoogle ScholarCrossref
    37.
    Fischl  B, van der Kouwe  A, Destrieux  C,  et al.  Automatically parcellating the human cerebral cortex.   Cereb Cortex. 2004;14(1):11-22. doi:10.1093/cercor/bhg087 PubMedGoogle ScholarCrossref
    38.
    Casey  BJ, Cannonier  T, Conley  MI,  et al; ABCD Imaging Acquisition Workgroup.  The Adolescent Brain Cognitive Development (ABCD) Study: imaging acquisition across 21 sites.   Dev Cogn Neurosci. 2018;32:43-54. doi:10.1016/j.dcn.2018.03.001 PubMedGoogle ScholarCrossref
    39.
    Hagler  DJ  Jr, Hatton  S, Cornejo  MD,  et al.  Image processing and analysis methods for the Adolescent Brain Cognitive Development Study.   Neuroimage. 2019;202:116091. doi:10.1016/j.neuroimage.2019.116091 PubMedGoogle Scholar
    40.
    Bates  D, Mächler  M, Bolker  B, Walker  S.  Fitting linear mixed-effects models using lme4.   J Stat Software. 2015;67(1):48. doi:10.18637/jss.v067.i01Google ScholarCrossref
    41.
    Bogdan  R, Baranger  DAA, Agrawal  A.  Polygenic risk scores in clinical psychology: bridging genomic risk to individual differences.   Annu Rev Clin Psychol. 2018;14:119-157. doi:10.1146/annurev-clinpsy-050817-084847 PubMedGoogle ScholarCrossref
    42.
    Schizophrenia Working Group of the Psychiatric Genomics Consortium.  Biological insights from 108 schizophrenia-associated genetic loci.   Nature. 2014;511(7510):421-427. doi:10.1038/nature13595 PubMedGoogle ScholarCrossref
    43.
    Lee  JJ, Wedow  R, Okbay  A,  et al; 23andMe Research Team; COGENT (Cognitive Genomics Consortium); Social Science Genetic Association Consortium.  Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals.   Nat Genet. 2018;50(8):1112-1121. doi:10.1038/s41588-018-0147-3 PubMedGoogle ScholarCrossref
    44.
    Pasman  JA, Verweij  KJH, Gerring  Z,  et al; 23andMe Research Team; Substance Use Disorders Working Group of the Psychiatric Genomics Consortium; International Cannabis Consortium.  GWAS of lifetime cannabis use reveals new risk loci, genetic overlap with psychiatric traits, and a causal influence of schizophrenia.   Nat Neurosci. 2018;21(9):1161-1170. doi:10.1038/s41593-018-0206-1 PubMedGoogle ScholarCrossref
    45.
    Carliner  H, Brown  QL, Sarvet  AL, Hasin  DS.  Cannabis use, attitudes, and legal status in the U.S.: a review.   Prev Med. 2017;104:13-23. doi:10.1016/j.ypmed.2017.07.008 PubMedGoogle ScholarCrossref
    46.
    Dickson  B, Mansfield  C, Guiahi  M,  et al.  Recommendations from cannabis dispensaries about first-trimester cannabis use.   Obstet Gynecol. 2018;131(6):1031-1038. doi:10.1097/AOG.0000000000002619 PubMedGoogle ScholarCrossref
    47.
    de Salas-Quiroga  A, Díaz-Alonso  J, García-Rincón  D,  et al.  Prenatal exposure to cannabinoids evokes long-lasting functional alterations by targeting CB1 receptors on developing cortical neurons.   Proc Natl Acad Sci U S A. 2015;112(44):13693-13698. doi:10.1073/pnas.1514962112 PubMedGoogle ScholarCrossref
    48.
    Fügedi  G, Molnár  M, Rigó  J  Jr, Schönléber  J, Kovalszky  I, Molvarec  A.  Increased placental expression of cannabinoid receptor 1 in preeclampsia: an observational study.   BMC Pregnancy Childbirth. 2014;14:395. doi:10.1186/s12884-014-0395-x PubMedGoogle ScholarCrossref
    49.
    Baranger  DAA, Bogdan  R.  Editorial: causal, predispositional, or correlate? group differences in cognitive control–related brain function in cannabis-using youth raise new questions.   J Am Acad Child Adolesc Psychiatry. 2019;58(7):665-667. doi:10.1016/j.jaac.2019.05.018 PubMedGoogle ScholarCrossref
    50.
    Baranger  DAA, Demers  CH, Elsayed  NM,  et al.  Convergent evidence for predispositional effects of brain gray matter volume on alcohol consumption.   Biol Psychiatry. 2020;87(7):645-655. doi:10.1016/j.biopsych.2019.08.029PubMedGoogle ScholarCrossref
    51.
    Demontis  D, Rajagopal  VM, Thorgeirsson  TE,  et al.  Genome-wide association study implicates CHRNA2 in cannabis use disorder.   Nat Neurosci. 2019;22(7):1066-1074. doi:10.1038/s41593-019-0416-1 PubMedGoogle ScholarCrossref
    52.
    Murphy  SK, Itchon-Ramos  N, Visco  Z,  et al.  Cannabinoid exposure and altered DNA methylation in rat and human sperm.   Epigenetics. 2018;13(12):1208-1221. doi:10.1080/15592294.2018.1554521 PubMedGoogle ScholarCrossref
    53.
    Bishai  R, Koren  G.  Maternal and obstetric effects of prenatal drug exposure.   Clin Perinatol. 1999;26(1):75-86, vii. doi:10.1016/S0095-5108(18)30073-3 PubMedGoogle ScholarCrossref
    54.
    Moore  TH, Zammit  S, Lingford-Hughes  A,  et al.  Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review.   Lancet. 2007;370(9584):319-328. doi:10.1016/S0140-6736(07)61162-3 PubMedGoogle ScholarCrossref
    55.
    Mason  O, Morgan  CJ, Dhiman  SK,  et al.  Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis.   Psychol Med. 2009;39(6):951-956. doi:10.1017/S0033291708004741 PubMedGoogle ScholarCrossref
    56.
    Power  RA, Verweij  KJ, Zuhair  M,  et al.  Genetic predisposition to schizophrenia associated with increased use of cannabis.   Mol Psychiatry. 2014;19(11):1201-1204. doi:10.1038/mp.2014.51 PubMedGoogle ScholarCrossref
    57.
    Carey  CE, Agrawal  A, Bucholz  KK,  et al.  Associations between polygenic risk for psychiatric disorders and substance involvement.   Front Genet. 2016;7:149. doi:10.3389/fgene.2016.00149 PubMedGoogle ScholarCrossref
    58.
    Verweij  KJ, Abdellaoui  A, Nivard  MG,  et al; International Cannabis Consortium.  Short communication: genetic association between schizophrenia and cannabis use.   Drug Alcohol Depend. 2017;171:117-121. doi:10.1016/j.drugalcdep.2016.09.022 PubMedGoogle ScholarCrossref
    59.
    Vaucher  J, Keating  BJ, Lasserre  AM,  et al.  Cannabis use and risk of schizophrenia: a mendelian randomization study.   Mol Psychiatry. 2018;23(5):1287-1292. doi:10.1038/mp.2016.252 PubMedGoogle ScholarCrossref
    60.
    Karcher  NR, Barch  DM, Demers  CH,  et al.  Genetic predisposition vs individual-specific processes in the association between psychotic-like experiences and cannabis use.   JAMA Psychiatry. 2019;76(1):87-94. doi:10.1001/jamapsychiatry.2018.2546 PubMedGoogle ScholarCrossref
    61.
    Gage  SH, Jones  HJ, Burgess  S,  et al.  Assessing causality in associations between cannabis use and schizophrenia risk: a two-sample mendelian randomization study.   Psychol Med. 2017;47(5):971-980. doi:10.1017/S0033291716003172 PubMedGoogle ScholarCrossref
    62.
    Owen  MJ, O’Donovan  MC, Thapar  A, Craddock  N.  Neurodevelopmental hypothesis of schizophrenia.   Br J Psychiatry. 2011;198(3):173-175. doi:10.1192/bjp.bp.110.084384 PubMedGoogle ScholarCrossref
    63.
    Seiler  NK.  Alcohol and pregnancy: CDC’s health advice and the legal rights of pregnant women.   Public Health Rep. 2016;131(4):623-627. doi:10.1177/0033354916662222 PubMedGoogle ScholarCrossref
    64.
    Hopson  MB, Margolis  A, Rauh  V, Herbstman  J.  Impact of the home environment on the relationship between prenatal exposure to environmental tobacco smoke and child behavior.   Int J Child Health Hum Dev. 2016;9(4):453-464.PubMedGoogle Scholar
    65.
    D’Onofrio  BM, Van Hulle  CA, Waldman  ID,  et al.  Smoking during pregnancy and offspring externalizing problems: an exploration of genetic and environmental confounds.   Dev Psychopathol. 2008;20(1):139-164. doi:10.1017/S0954579408000072 PubMedGoogle ScholarCrossref
    66.
    Skoglund  C, Chen  Q, D’Onofrio  BM, Lichtenstein  P, Larsson  H.  Familial confounding of the association between maternal smoking during pregnancy and ADHD in offspring.   J Child Psychol Psychiatry. 2014;55(1):61-68. doi:10.1111/jcpp.12124 PubMedGoogle ScholarCrossref
    67.
    Palmer  RH, Bidwell  LC, Heath  AC, Brick  LA, Madden  PA, Knopik  VS.  Effects of maternal smoking during pregnancy on offspring externalizing problems: contextual effects in a sample of female twins.   Behav Genet. 2016;46(3):403-415. doi:10.1007/s10519-016-9779-1 PubMedGoogle ScholarCrossref
    68.
    Knopik  VS, Heath  AC, Marceau  K,  et al.  Missouri mothers and their children: a family study of the effects of genetics and the prenatal environment.   Twin Res Hum Genet. 2015;18(5):485-496. doi:10.1017/thg.2015.46 PubMedGoogle ScholarCrossref
    69.
    Quinn  PD, Rickert  ME, Weibull  CE,  et al.  Association between maternal smoking during pregnancy and severe mental illness in offspring.   JAMA Psychiatry. 2017;74(6):589-596. doi:10.1001/jamapsychiatry.2017.0456 PubMedGoogle ScholarCrossref
    70.
    D’Onofrio  BM, Class  QA, Rickert  ME,  et al.  Translational epidemiologic approaches to understanding the consequences of early-life exposures.   Behav Genet. 2016;46(3):315-328. doi:10.1007/s10519-015-9769-8 PubMedGoogle ScholarCrossref
    71.
    Hannigan  JH, Chiodo  LM, Sokol  RJ,  et al.  A 14-year retrospective maternal report of alcohol consumption in pregnancy predicts pregnancy and teen outcomes.   Alcohol. 2010;44(7-8):583-594. doi:10.1016/j.alcohol.2009.03.003 PubMedGoogle ScholarCrossref
    72.
    Garg  M, Garrison  L, Leeman  L,  et al.  Validity of self-reported drug use information among pregnant women.   Matern Child Health J. 2016;20(1):41-47. doi:10.1007/s10995-015-1799-6PubMedGoogle ScholarCrossref
    73.
    Di Forti  M, Quattrone  D, Freeman  TP,  et al; EU-GEI WP2 Group.  The contribution of cannabis use to variation in the incidence of psychotic disorder across Europe (EU-GEI): a multicentre case-control study.   Lancet Psychiatry. 2019;6(5):427-436. doi:10.1016/S2215-0366(19)30048-3 PubMedGoogle ScholarCrossref
    74.
    Frau  R, Miczán  V, Traccis  F,  et al.  Prenatal THC exposure produces a hyperdopaminergic phenotype rescued by pregnenolone.   Nat Neurosci. 2019;22(12):1975-1985. doi:10.1038/s41593-019-0512-2 PubMedGoogle ScholarCrossref
    75.
    Dong  C, Chen  J, Harrington  A, Vinod  KY, Hegde  ML, Hegde  VL.  Cannabinoid exposure during pregnancy and its impact on immune function.   Cell Mol Life Sci. 2019;76(4):729-743. doi:10.1007/s00018-018-2955-0 PubMedGoogle ScholarCrossref
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