Effects of prenatal nutrient supplementation and early life exposures on neurodevelopment at age 10: a randomised controlled trial - the COPSYCH study protocol

Parisa Mohammadzadeh, Julie Bøjstrup Rosenberg, Rebecca Vinding, Jens Richardt Møllegaard Jepsen, Ulrich Lindberg, Nilo Følsgaard, Mikkel Erlang Sørensen, Daban Sulaiman, Niels Bilenberg, Jayachandra Mitta Raghava, Birgitte Fagerlund, Mark Vestergaard, Christos Pantelis, Jakob Stokholm, Bo Chawes, Henrik Larsson, Birte Yding Glenthøj, Klaus Bønnelykke, Bjørn H Ebdrup, Hans Bisgaard, Parisa Mohammadzadeh, Julie Bøjstrup Rosenberg, Rebecca Vinding, Jens Richardt Møllegaard Jepsen, Ulrich Lindberg, Nilo Følsgaard, Mikkel Erlang Sørensen, Daban Sulaiman, Niels Bilenberg, Jayachandra Mitta Raghava, Birgitte Fagerlund, Mark Vestergaard, Christos Pantelis, Jakob Stokholm, Bo Chawes, Henrik Larsson, Birte Yding Glenthøj, Klaus Bønnelykke, Bjørn H Ebdrup, Hans Bisgaard

Abstract

Introduction: Nutrient deficiency and immune and inflammatory disturbances in early life may compromise neurodevelopment and be implicated in the aetiology of psychiatric disorders. However, current evidence is limited by its predominantly observational nature. COpenhagen Prospective Study on Neuro-PSYCHiatric Development (COPSYCH) is a research alliance between Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) and Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research with the overall aim to investigate effects of prenatal and early life exposures on neurodevelopment at 10 years. COPSYCH will investigate the impact of prenatal n-3 long-chain polyunsaturated fatty acids (n-3 LCPUFA) and high-dose vitamin D supplementation on neurodevelopment reflected by brain development, neurocognition and psychopathology. Moreover, the neurodevelopmental impact of early life exposures such as infections, low grade inflammation and the gut microbiome will be scrutinised.

Methods and analysis: COPSYCH is based on the prospective and ongoing COPSAC2010 birth cohort of 700 mother-child pairs. Randomised controlled trials of supplementation with n-3 LCPUFA and/or high-dose vitamin D or placebo in the third trimester were embedded in a factorial 2×2 design (ClinicalTrials.gov: NCT01233297 and NCT00856947). This unique cohort provides deep phenotyping data from 14 previous clinical follow-up visits and exposure assessments since birth. The ongoing 10-year visit is a 2-day visit. Day 1 includes a comprehensive neurocognitive examination, and assessment of psychopathological dimensions, and assessment of categorical psychopathology. Day 2 includes acquisition of brain structural, diffusion and functional sequences using 3 Tesla MRI. Study outcomes are neurocognitive, psychopathological and MRI measures.

Ethics and dissemination: This study has been approved by the Danish National Committee on Health Research Ethics and The Danish Data Protection Agency. The study is conducted in accordance with the guiding principles of the Declaration of Helsinki. Parents gave written informed consent before enrolment.

Keywords: child & adolescent psychiatry; mental health; paediatric infectious disease & immunisation; paediatric radiology.

Conflict of interest statement

Competing interests: BHE is part of the Advisory Board of Eli Lilly Denmark A/S, JanssenCilag, Lundbeck Pharma A/S and Takeda Pharmaceutical Company; and has received lecture fees from Bristol Myers Squibb, Otsuka Pharma Scandinavia AB, Eli Lilly Company, Boehringer Ingelheim Danmark A/S and Lundbeck Pharma A/S.

© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Overview of inflammation and infection markers in COPSAC2010 (mothers) - Modified from: http://copsac.com/home/copsac-cohorts/copsac2010-clinic/)
Figure 2
Figure 2
Overview of inflammation and infection markers in COPSAC2010 (children) - Modified from: http://copsac.com/home/copsac-cohorts/copsac2010-clinic/)
Figure 3
Figure 3
Neurodevelopmental outcomes in COPSAC2010. ADHD-RS, Attention Deficit/Hyperactivity Disorder-Rating Scale; ASQ, Ages and Stages Questionnaire; COPSAC2010, Copenhagen Prospective Studies on Asthma in Childhood 2010; COPSYCH, COpenhagen Prospective Study on Neuro-PSYCHiatric Development; SDQ, Strengths and Difficulties Questionnaire.

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