Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study

Paul C Madley-Dowd; Christina Dardani; Robyn E Wootton; Kyle A W Dack; Tom M Palmer; Rupert Thurston; Karoline Alexandra Havdahl; Jean Golding; Debbie A Lawlor; Dheeraj Rai

doi:10.1186/s13229-022-00523-4

Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study

Paul C Madley-Dowd^*, Christina Dardani, Robyn E Wootton, Kyle A W Dack, Tom M Palmer, Rupert Thurston, Karoline Alexandra Havdahl, Jean Golding, Debbie A Lawlor, Dheeraj Rai

^*Corresponding author for this work

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Abstract

Background: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive.
Methods: We used data from a UK based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising of 7,689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder adjusted regression models. Multiple imputation was used to account for missing data and restricted cubic splines were used to investigate non-linear associations. Mendelian randomization was used to strengthen causal inference.
Results: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR=0.98, 95%CI= 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR=0.99, 95%CI=0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR=1.08, 95%CI=0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis.
Limitations: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data.
Conclusions: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

Original language	English
Article number	44
Number of pages	14
Journal	Molecular Autism
Volume	13
Issue number	1
DOIs	https://doi.org/10.1186/s13229-022-00523-4
Publication status	Published - 12 Nov 2022

Bibliographical note

Funding Information:
The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and PMD will serve as guarantor for the contents of this paper. This research was funded by the Wellcome Trust [Grant ref: 203776/Z/16/A]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The MRC funded collection of vitamin D data in ALSPAC (G0701603) and Wellcome funded maternal GWAS data (WT088806). Child GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. PMD, TP and DAL work in or are affiliated to a unit that receives support from the University of Bristol (MC_UU_00011/3 and MC_UU_00011/1), and DAL is an NIHR Senior investigatory (NF-0616-10102). REW is supported by a postdoctoral fellowship from the South-Eastern Norway Regional Health Authority (2020024). KD is supported by a Ph.D. studentship from the MRC Integrative Epidemiology Unit at the University of Bristol (faculty matched place for MRC and Peter and Jean James Scholarship). CD is supported by the Wellcome Trust [215379/Z/19/Z]. DR is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (Grant ref: BRC-1215-2011). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care or any other funder. The funders had no role in the study design, analyses or interpretation of results.

Publisher Copyright:
© 2022, The Author(s).

Research Groups and Themes

ALSPAC

Keywords

Autism
Mendelian randomization
Pregnancy
Vitamin D

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THE PUBLIC HEALTH IMPORTANCE OF VITAMIN D: DETERMINING CAUSAL EFFECTS OF INTRAUTERINE AND LIFETIME EXPOSURE TO VITAMIN D
Lawlor, D. A. (Principal Investigator)
1/10/08 → 1/12/13
Project: Research

Cite this

@article{b28ceacb0839419b84c8eb3b1e84c492,

title = "Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study",

abstract = "Background: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. Methods: We used data from a UK based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising of 7,689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder adjusted regression models. Multiple imputation was used to account for missing data and restricted cubic splines were used to investigate non-linear associations. Mendelian randomization was used to strengthen causal inference. Results: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR=0.98, 95\%CI= 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR=0.99, 95\%CI=0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR=1.08, 95\%CI=0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. Limitations: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. Conclusions: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism. ",

keywords = "Autism, Mendelian randomization, Pregnancy, Vitamin D",

author = "Madley-Dowd, \{Paul C\} and Christina Dardani and Wootton, \{Robyn E\} and Dack, \{Kyle A W\} and Palmer, \{Tom M\} and Rupert Thurston and Havdahl, \{Karoline Alexandra\} and Jean Golding and Lawlor, \{Debbie A\} and Dheeraj Rai",

note = "Funding Information: The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and PMD will serve as guarantor for the contents of this paper. This research was funded by the Wellcome Trust [Grant ref: 203776/Z/16/A]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The MRC funded collection of vitamin D data in ALSPAC (G0701603) and Wellcome funded maternal GWAS data (WT088806). Child GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. PMD, TP and DAL work in or are affiliated to a unit that receives support from the University of Bristol (MC\_UU\_00011/3 and MC\_UU\_00011/1), and DAL is an NIHR Senior investigatory (NF-0616-10102). REW is supported by a postdoctoral fellowship from the South-Eastern Norway Regional Health Authority (2020024). KD is supported by a Ph.D. studentship from the MRC Integrative Epidemiology Unit at the University of Bristol (faculty matched place for MRC and Peter and Jean James Scholarship). CD is supported by the Wellcome Trust [215379/Z/19/Z]. DR is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (Grant ref: BRC-1215-2011). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care or any other funder. The funders had no role in the study design, analyses or interpretation of results. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = nov,

day = "12",

doi = "10.1186/s13229-022-00523-4",

language = "English",

volume = "13",

journal = "Molecular Autism",

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TY - JOUR

T1 - Maternal vitamin D during pregnancy and offspring autism and autism-associated traits

T2 - a prospective cohort study

AU - Madley-Dowd, Paul C

AU - Dardani, Christina

AU - Wootton, Robyn E

AU - Dack, Kyle A W

AU - Palmer, Tom M

AU - Thurston, Rupert

AU - Havdahl, Karoline Alexandra

AU - Golding, Jean

AU - Lawlor, Debbie A

AU - Rai, Dheeraj

N1 - Funding Information: The UK Medical Research Council and Wellcome (Grant Ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors, and PMD will serve as guarantor for the contents of this paper. This research was funded by the Wellcome Trust [Grant ref: 203776/Z/16/A]. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. A comprehensive list of grants funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf ). The MRC funded collection of vitamin D data in ALSPAC (G0701603) and Wellcome funded maternal GWAS data (WT088806). Child GWAS data were generated by Sample Logistics and Genotyping Facilities at Wellcome Sanger Institute and LabCorp (Laboratory Corporation of America) using support from 23andMe. PMD, TP and DAL work in or are affiliated to a unit that receives support from the University of Bristol (MC_UU_00011/3 and MC_UU_00011/1), and DAL is an NIHR Senior investigatory (NF-0616-10102). REW is supported by a postdoctoral fellowship from the South-Eastern Norway Regional Health Authority (2020024). KD is supported by a Ph.D. studentship from the MRC Integrative Epidemiology Unit at the University of Bristol (faculty matched place for MRC and Peter and Jean James Scholarship). CD is supported by the Wellcome Trust [215379/Z/19/Z]. DR is supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol (Grant ref: BRC-1215-2011). The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health and Social Care or any other funder. The funders had no role in the study design, analyses or interpretation of results. Publisher Copyright: © 2022, The Author(s).

PY - 2022/11/12

Y1 - 2022/11/12

N2 - Background: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. Methods: We used data from a UK based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising of 7,689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder adjusted regression models. Multiple imputation was used to account for missing data and restricted cubic splines were used to investigate non-linear associations. Mendelian randomization was used to strengthen causal inference. Results: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR=0.98, 95%CI= 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR=0.99, 95%CI=0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR=1.08, 95%CI=0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. Limitations: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. Conclusions: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

AB - Background: There has been a growing interest in the association between maternal levels of vitamin D during pregnancy and offspring autism. However, whether any associations reflect causal effects is still inconclusive. Methods: We used data from a UK based pregnancy cohort study (Avon Longitudinal Study of Parents and Children) comprising of 7,689 births between 1991 and 1992 with maternal blood vitamin D levels recorded during pregnancy and at least one recorded outcome measure, including autism diagnosis and autism-associated traits. The association between each outcome with seasonal and gestational age adjusted maternal serum 25-hydroxyvitamin D during pregnancy was estimated using confounder adjusted regression models. Multiple imputation was used to account for missing data and restricted cubic splines were used to investigate non-linear associations. Mendelian randomization was used to strengthen causal inference. Results: No strong evidence of an association between maternal serum 25-hydroxyvitamin D during pregnancy and any offspring autism-associated outcome was found using multivariable regression analysis (autism diagnosis: adjusted OR=0.98, 95%CI= 0.90-1.06), including with multiple imputation (autism diagnosis: adjusted OR=0.99, 95%CI=0.93-1.06), and no evidence of a causal effect was suggested by Mendelian randomization (autism diagnosis: causal OR=1.08, 95%CI=0.46-2.55). Some evidence of increased odds of autism-associated traits at lower levels of maternal serum 25-hydroxyvitamin D was found using spline analysis. Limitations: Our study was potentially limited by low power, particularly for diagnosed autism cases as an outcome. The cohort may not have captured the extreme lows of the distribution of serum 25-hydroxyvitamin D, and our analyses may have been biased by residual confounding and missing data. Conclusions: The present study found no strong evidence of a causal link between maternal vitamin D levels in pregnancy and offspring diagnosis or traits of autism.

KW - Autism

KW - Mendelian randomization

KW - Pregnancy

KW - Vitamin D

U2 - 10.1186/s13229-022-00523-4

DO - 10.1186/s13229-022-00523-4

M3 - Article (Academic Journal)

C2 - 36371219

SN - 2040-2392

VL - 13

JO - Molecular Autism

JF - Molecular Autism

IS - 1

M1 - 44

ER -

Maternal vitamin D during pregnancy and offspring autism and autism-associated traits: a prospective cohort study

Abstract

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THE PUBLIC HEALTH IMPORTANCE OF VITAMIN D: DETERMINING CAUSAL EFFECTS OF INTRAUTERINE AND LIFETIME EXPOSURE TO VITAMIN D

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