Platform for the Prospective Mother-child Study of the Determinants of Neurodevelopmental Disorders

Autism Spectrum Disorder Clinical Trial

— MARIANNE  

Official title:

Platform for the Prospective Mother-child Study of the Determinants of Autism Spectrum Disorder and Neurodevelopmental Disorders Neurodevelopmental Disorders

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05681923
• Other study ID #: RECHMPL22_0010
• Status: Recruiting
• Start date: April 19, 2023
• Est. completion date: March 2034

Study information

• Verified date: May 2023
• Source: University Hospital, Montpellier
• Contact: Amaria Baghdadli, MD PhD
• Phone: +33 4 67 33 63 83
• Email: a-baghdadli[@]chu-montpellier.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

Neurodevelopmental disorders such as attention deficit disorder with or without hyperactivity, autism spectrum disorder, language and social communication disorder, motor coordination disorder, learning disorder (dyslexia, dyscalculia, dysorthography), intellectual development disorder are frequent and long-lasting developmental difficulties that can be observed in children in various domains. They are often associated and have a significant impact on daily functioning at school and at home.

The rate of people affected by neurodevelopmental disorders including autism spectrum disorder have increased significantly over the past 20 years. Improved screening only partly explains this evolution.

A genetic predisposition plays an important role in the occurrence of these disorders, however, current scientific data suggest a multifactorial origin. Exposures such as those related to the use of pesticides, air pollution or the presence of endocrine disruptors in our diet could be involved in the genesis of neurodevelopmental disorders, particularly during intrauterine life, a period of great vulnerability.

The current diagnostic pathways for autism rarely enable the early identification of babies at risk. Without early detection and timely targeted intervention, these children have a poor health outcome and do not reach their full potential.

The general objective of the MARIANNE cohort is to constitute a French research infrastructure dedicated to research on the biological and environmental determinants of neurodevelopmental disorders including autism.

This cohort is based on the follow-up of 1200 families with already a child affected by an autism spectrum disorder, which implies a high risk of neurodevelopmental disorders including autism spectrum disorder for the siblings, and of 500 families from the general population with no excess risk of neurodevelopmental disorders. The total number of subjects to be included (mother, father, unborn child and ASD sibling for the HR group) is thus 6300.

The inclusion of these families will be at the beginning of a new pregnancy and the follow-up will be carried out from the second trimester of pregnancy until the children are 6 years old, the age at which the diagnosis of neurodevelopmental disorders is possible.

Biological, clinical, social and environmental data will be collected at different stages of the follow-up and will be included into a large database.

Description:

Context: Various forms of Autism Spectrum Disorder (ASD) affect 52 million people worldwide. ASD is an early-onset, life-long and heterogeneous condition believed to arise from combinations of genetic and environmental influences, but without specific known causes. ASD is also a pervasive syndrome that greatly impacts the functioning of the individual throughout life in multiple domains, as well as the family and the broader society. Approximately 1 to 2% of the population is affected by an autism spectrum disorder and 10% to 15% if considering all neurodevelopmental disorders (NDD). They have increased dramatically over the past 20 years, in line with improved screening and diagnostic practices. However, these factors explain only part of the observed increase, and have raised questions about the contribution of environmental changes. Research has shown that ASD overlaps or co-occurs with other clinical neurodevelopmental disorders (NDDs) such as attention-deficit/hyperactivity disorder or intellectual disabilities. This raises the question of phenotypic variations or comorbid association between the disorders. In addition, there is a familial recurrence risk of ASD, studies supporting that younger siblings of children with ASD have an 18 increased relative risk of being diagnosed with ASD themselves. The current diagnostic pathways for ASD rarely enable the early identification of babies at risk. Without early detection and timely targeted intervention, these children have a poor health outcome and do not reach their full potential.

Objectives: The MARIANNE platform is a research infrastructure aiming to allow future scientific studies on the early external (environmental, social) and internal (genetic) drivers of ASD and NDDs, as well as on the outcome of children with ASD.

The primary objective is to compare exposures and development from birth to 6 years of age in children with ASD/NDD and those with normal development in a cohort study whose data will be used to build a large research infrastructure. Specific descriptive, etiological, economic and social objectives are also included:

Descriptive Objectives:

• To identify and clinically characterize cases of ASD and NDD;

• To describe the clinical course of ASD and NDD cases from birth to age 6, in different dimensions (autistic, psychiatric and neurodevelopmental symptoms, health, and development);

• Describe access to care and the care pathway of ASD and NDD cases (use of health services, treatments and interventions) and the modalities of care (specialized interventions, schooling, childcare...).

Etiological Objectives:

• To identify prenatal and perinatal risk factors for ASD and NDD related to the external exposome, such as parental health and lifestyle, socioeconomic characteristics, maternal diet during pregnancy, maternal medication use during pregnancy, pregnancy and delivery complications (clinical, social, health, behaviors, and interventions), and environmental chemical exposures (indoor, outdoor, and occupational);

• To study the interactions between exposome and genome risk factors in ASD or NDD;

Economic and Social Objectives:

• Assess the medico-economic impact of ASD and NDD;

• To study the impact on child health and outcomes of parental mental health, access to care and specialized interventions, socioeconomic status, and education.

Methods:

Cohort study including two groups of families recruited over the same period in the same maternity hospitals, without any other matching criteria.

• At-risk families: 1,200 pregnant women over 18 years of age at increased risk of having a child with TSA or NDDs (e.g. because they already have biological child and/or a partner's biological child with a confirmed ASD), (ii) their partner, and (iii) the future child. The women should be able to read and respond to the questionnaires. Both parents will agree to their child being monitored and to at least the mother being monitored as well.

• Control or Low-risk families: 500 pregnant women, not primiparius (single or multiple pregnancies included from the 2nd trimester of pregnancy), over the age of 18 years, with no biological child over the age of 2 years with a known or suspected diagnosis of ASD or NDD. If there are non-biological children in the family, such as the father's children, the pregnant women may be included in the study if these children have never been suspected of or had a confirmed ASD or NDD. These women should be able to read and respond to the questionnaires. Both parents will agree to their child being monitored and to at least the mother being monitored as well.

The follow-up will start during the second or third trimesters of pregnancy. It will continue at birth and into childhood up until the age of 3 and 6 years, when the diagnoses of ASD and other NDDs can be confirmed by clinical multidisciplinary assessment. Biospecimens (blood, urine…) will be collected from the parents and children and stored in a biobank to allow future assays of exposure and effect biomarkers as well as genotyping. The multidimensional questionnaires and examinations will provide a clinical, biological and social assessment of the child, his/her parents and his/her autistic elder sibling.

Based on the estimated number of subjects needed, 1200 families will be included in the high-risk cohort, which, after a 6-year follow-up, is expected to identify approximately 200 children with ASD, 340 with other ASD, and 660 children with normal development.

The control cohort will consist of 500 families, of which approximately 445 children with normal development, 5 with ASD, and 50 with other NDD are expected. The total number of subjects to be included (mother, father, unborn child and ASD sibling for the HR group) is thus 6300.

Expected benefits: With the recruitment of 1,200 families, MARIANNE cohort is expected to be one of the largest studies on ASD and NDDs with prenatal recruitment. At a societal level, the identification of biomarkers will facilitate the diagnosis and medical management of ASD and NDDs. Another impact covers scientific advances fostered by a better understanding of the underlying etiopathogenic mechanisms. Finally, by proposing an evaluation of the care pathways of a large sample of children, the MARIANNE platform will contribute to providing useful indicators for the piloting of national policies on access to care and management of ASD and NDDs in France.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 6300
• Est. completion date: March 2034
• Est. primary completion date: March 2034
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: N/A and older

Eligibility

INCLUSION CRITERIA:

General inclusion criteria (High risk and Low risk cohorts)

Mother:

• Be pregnant (single or multiple pregnancy), at least 16 weeks of amenorrhea,

• Have at least one biological child of 24 months or older,

• At least 18 years of age

Father:

• Be the biological father of the unborn child,

• At least 18 years of age

Unborn Child:

• Have a woman study participant as mother.

Specific inclusion criteria for the High risk cohort:

• Autistic sibling: refers to the biological child(ren) of the mother and/or father participating in the study and being the parent(s) of the unborn child

• Be at least 24 months old and less than 18 years old,

• Have a confirmed diagnosis of Autism Spectrum Disorder based on medical records. If in doubt, the SRS-2 (Social Responsiveness Scale for Adults) and PEDS-DM (Parents' Evaluation of developmental status) questionnaires will be completed. Only children with positive scores on one of these questionnaires will be included after validation of the diagnosis by an expert committee,

• In case of several children with Autism Spectrum Disorder based in the siblings, only the last born will be included.

Remarks:

• Autism Spectrum Disorder siblings resulting from a medically assisted procreation are eligible provided that part of the genetic heritage is common to that of the mother or father of the unborn child participating in the study.

• If the father does not live with the mother of the unborn child, his participation is not required and does not preclude the participation of other family members.

EXCLUSION CRITERIA:

General non-inclusion criteria (High risk and Low risk cohorts):

Father and mother:

• Unable to understand French or the study questionnaires

• Participant on protective measures (guardianship or curatorship) or deprived of liberty by judicial or administrative decision, or subject to a legal protection measure

• Not affiliated to a social security system

• Refusal to participate. In the case of consent given for the born and unborn child, the consent must be given by the person(s) with parental authority.

• Live at a distance from the recruitment center incompatible with follow-up.

Specific non-inclusion criteria for the Low risk cohort:

Mother and/or father of unborn child:

• Have a biological child with a diagnosis of Autism Spectrum Disorder or other neuro developmental disorder

Related Conditions & MeSH terms

• Autism Spectrum Disorder
• Disease
• Neurodevelopmental Disorders

Intervention

Other:
• Questionnaires
Parents will be asked to complete online self-questionnaires. These questionnaires will provide essential information on medical data, child development, lifestyle habits, nutritional habits, environmental exposures, and family social characteristics.
• Biospecimen collection
urine, hair, nails, baby tooth, stool, blood, umbilical cord blood, placenta
• Neurodevelopmental assessment visit
Clinical observations of the unborn child will be performed at 3 months, 6 months, 12 months, between 24 and 30 months, 36 months, between 60 and 66 months, and 72 months by psychologists or child psychiatrists in the participating hospitals. They will allow to evaluate the child's behaviors in the areas of communication and social interaction. A video recording of the baby at 3 months of age will allow the analysis of the General Movements Assessment.
• DNA collection
If genetic consultation is provided to the family as part of the routine care, the results will be collected and additional blood samples may be taken.

Locations

Country	Name	City	State
France	CHU Montpellier	Montpellier

Sponsors (7)

Lead Sponsor	Collaborator
University Hospital, Montpellier	Hôpital le Vinatier, Hospices Civils de Lyon, University Hospital of Saint-Etienne, University Hospital, Lille, University Hospital, Rouen, University Hospital, Toulouse

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Autism Spectrum Disorder diagnosis	ASD diagnosis will be determined by the ADOS-2 (Autism Diagnostic Observation Schedule)	between 60 and 66 months
Primary	Autism Spectrum Disorder diagnosis	ASD diagnosis will be determined by the ADOS-2 (Autism Diagnostic Observation	between 24 and 30 months
Primary	Developmental Intelligence Disorder diagnosis	Measure of intelligence quotient by scales adapted to the child's age and level of development and developmental level: Weschler, or Mullen scales	at 72 months
Primary	Developmental Coordination Disorder diagnosis	Description: the diagnosis will be determined by the DCDQ-FE (Developmental Coordination Disorder Parent Questionnaire Coordination), a 15 items scale, which is the French-European version of the DCDQ-0, Developmental Coordination Disorder Parent Questionnaire Coordination to help identify Developmental Coordination Disorder in children aged 5 to 15 years. The items are grouped into three subdomains: 1) control during movement, 2) fine motor/writing, and 3) global coordination. Each item is rated on a 5-point scale, from 1 ("does not match my child at all") to 5 ("matches my child perfectly")."	at 72 months
Primary	Attention Deficit Hyperactivity Disorder diagnosis	The diagnosis will be determined by ADHD-RS, which is a parent questionnaire for the assessment of Attention Deficit Hyperactivity Disorder (ADHD). The items are rated on a 4-point scale (from 0= rarely or never, to 3= very often). A score greater than or equal to 28 is required to qualify as significant ADHD with this scale.	at 72 months
Primary	Diagnosis of Language and Learning Disorder	the diagnosis will be determined with the Parents' Evaluation of developmental status (PEDS: DM), which targets the concerns of parents of children aged 0 to 8 years in 8 domains (gross and fine motor skills and writing and mathematics; social/emotional; oral/written language and reading; adaptive behavior).; This questionnaire has been validated in several countries and covers several domains, each with 6 to 8 questions and 3 answer choices. The results are evaluated as normal/delayed "Are you worried about your child's development? Yes/No" with details of the reasons, the age of onset and a question on the wish to have an interview with a psychologist or a child psychiatrist.	at 72 months
Primary	Socioeconomic and lifestyle risk factors for neurodevelopmental disorders including autism spectrum disorder	Parental self-questionnaire	at inclusion
Primary	Maternal diet and medication use during pregnancy	Parental self-questionnaire	at inclusion
Primary	Environmental exposition	Parental self-questionnaire. A biological collection is realized for the realization of future assays	at inclusion