Neurobehavioral Development in Toddlers and Preschoolers in Relation to Prenatal Exposure of Mild Analgesics (NeuroToP - a COPANA Follow up)

NCT07316387 | Enrolling By Invitation DMC

• 1 other identifier: COPANA_NEUROTOP
• Study Type: observational
• Target: 685
• Locations: 1 country
• Sites: 1

Brief Summary

Fundamental aspects of both neurological and reproductive function are established in fetal life, and there is a present increased awareness of the potential effects of fetal exposures on neurodevelopmental and reproductive health of offspring. Experimental and epidemiological research studies strongly suggest that paracetamol and NSAID are endocrine disruptive in the fetus, which could increase the risks of some neurodevelopmental, reproductive, and urogenital disorders. In recent years, there has been an increasing rate of neurodevelopmental disorders such as ADHD and autism. The original cohort, the Copenhagen Analgesic Study (COPANA), is the first prospective human study designed primarily to assess the effect of fetal exposure to mild analgesics on male and female reproductive function. If the same children are examined with relevant neurobehavioral testing during mid-childhood, the study design allows the investigators to assess the effect of mild analgesics as well as other EDCs on neurodevelopmental health.

Conditions

Gonad Regulating Hormone Adverse Reaction; Analgesic Adverse Reaction; Adhd; Autism Spectrum Disorder; Developmental Disability; Language Development

Outcome Measures

Primary Outcomes (15)

• Behavior Rating Inventory of Executive Function-Preschool Version (BRIEF-P) (male and female children)

  Parents will complete the BRIEF-P to assess their child's executive functioning, and the Global Executive Composite score will be used in the analysis.

  2-5 years of age

• BRIEF-P Global Executive Composite (GEC) (male and female children)

  The Global Executive Composite (GEC) score is derived from the BRIEF-P questionnaire, which includes 63 items assessing executive functioning in preschool-aged children. The GEC score reflects the overall level of executive function difficulties and is calculated from the five clinical subscales: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize.

  2-5 years of age

• BRIEF-P Emergent Metacognition Index (male and female children)

  The EMI score reflects the child's ability to sustain ideas and activities in working memory and to plan and organize problem-solving approaches. It is composed of the Working Memory and Plan/Organize subscales and is critical for developing systematic metacognitive strategies.

  2-5 years

• Child Behavioral and Emotional Functioning - Child Behavior Checklist (CBCL) - (male and female children)

  Behavioral and emotional functioning will be assessed using the Child Behavior Checklist (CBCL), a validated parent-report questionnaire. The CBCL provides a Total Score as well as multiple subscale scores reflecting specific behavioral and emotional domains. The questionnaire is completed electronically by the child's mother or father when the child is between 2 and 4 years of age. Unit of Measure: CBCL standardized score (T-score)

  2-5 years of age

• CBCL Total Problem Score (TPS) (male and female children)

  The Total Problem Score (TPS) from the Child Behavior Checklist for Ages 1½-5 (CBCL/1½-5) is derived by summing responses of all items. The possible TPS ranges from 0 to 200, with higher scores representing more severe behavioral and emotional problems. According to standardized CBCL norms. Raw scores are converted to age- and sex-adjusted T-scores for interpretation.

  2-5 years of age

• CBCL Internalizing Score (male and female children)

  The Internalizing Score is based on 24 items assessing emotional symptoms such as anxiety, depression, and withdrawal. The score range is 0-48.

  2-5 years of age

• CBCL Externalizing Score (male and female children)

  The Externalizing Score is based on 36 items assessing behaviors such as aggression and rule-breaking. The score range is 0-72.

  2-5 years of age

• Danish MacArthur-Bates Communicative Development Inventories (MB-CDI) (male and female children)

  Using the validated Danish MacArthur-Bates Communicative Development Inventories (MB-CDI) "Words and Sentences", which consists of a vocabulary check list (part I) and questions regarding sentences and grammar (part II). Distributed electronically to the mother of the child at age 2-4 years.

  2-4 years

• MB-CDI Vocabulary Size (Words Understood and Produced) (male and female children)

  Assessed using Part I of the validated Danish version of the MacArthur-Bates Communicative Development Inventories (MB-CDI) "Words and Sentences". This section consists of a vocabulary checklist completed by the child's mother. Unit of Measure: Number of words understood and/or produced

  2-4 years

• MB-CDI Sentence and Grammar Use (male and female children)

  Assessed using Part II of the Danish MB-CDI "Words and Sentences", which includes questions about the child's use of sentences and grammatical structures. The questionnaire is distributed electronically to the mother. Unit of Measure: Parental report of sentence complexity and grammatical usage (qualitative and/or categorical scoring)

  2-4 years of age

• Preschool Activities Inventory - Gender-typical behavior (male and female children)

  Using the "Preschool Activities Inventory "(PSAI). This includes 24 items about the child's toy and activity preferences. The inventory holds 12 typical masculine and 12 typical feminine activities. The parents will score each activity on a likert scale which creates a composite score on the childs preferences.

  3-5 years

• Attention deficit hyperactivity disorder (ADHD) symptom load - Measured by the ADHD Rating Scale (male and female children)

  The ADHD Rating Scale (ADHD-RS) assesses ADHD symptom severity based on 26 items rated on a 4-point scale (0 = never, 3 = very often). The total score ranges from 0 to 78, with higher scores indicating greater symptom severity. The total score is calculated by summing all item scores.

  At 5 years of age

• Inattention symptom load - Measured by the ADHD Rating Scale (male and female children)

  The ADHD Rating Scale Inattention Subscore is based on 9 items rated on a 4-point scale (0 = never, 3 = very often). Scores range from 0 to 27, with higher scores indicating greater severity of inattention symptoms.

  5 years of age

• Hyperactivity/Impulsivity symptom load - Measured by the ADHD Rating Scale (male and female children)

  The ADHD Rating Scale Inattention Subscore is based on 9 items rated on a 4-point scale (0 = never, 3 = very often). Scores range from 0 to 27, with higher scores indicating greater severity of inattention symptoms.

  5 years of age

• Total Difficulties Score derived from the "Strengths and Difficulties Questionnaire" (SDQ) (male and female children)

  The Strengths and Difficulties Questionnaire (SDQ) is a 25-item behavioral screening tool that assesses emotional and behavioral problems in children. The Total Difficulties Score is calculated by summing four subscales: Emotional Symptoms, Conduct Problems, Hyperactivity-Inattention, and Peer Problems (20 items in total). The Total Difficulties Score ranges from 0 to 40, with higher scores indicating greater emotional and behavioral difficulties. According to standardized norms, scores can be interpreted depending on age- and sex-specific cutoffs. The SDQ also includes a separate Prosocial Behavior subscale, which is not included in the Total Difficulties Score.

  2-5 years

Secondary Outcomes (54)

• Gross motor development (Parent reported)

  1-2 year

• Childhood Infections (Parent-Reported and Registry-Based Assessment)

  1-6 years old

• Length (male and female children)

  2-4 years

• Weight (male and female children)

  2-4 years

• Head circumference (male and female children)

  2-4 years

Study Arms (2)

Children

Healthy children originally recruited specifically for COPANA will be reinvited for follow up, including a child examination.

The mothers and fathers of the children

The parents, i.e., the mother and father, of the healthy children. The parents will answer the inventories regarding the neurobehavioral development of the child and the general health questionnaire including parental educational level etc.

Eligibility Criteria

• Age: 2 Years - 6 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17)
• Sampling Method: Non-Probability Sample

Study Population

This study is a population based prospective cohort study of 685 families (healthy pregnant mothers, biological fathers and their healthy male/female offspring.)There are two groups of participants in this study: 1. Healthy children recruited in 2020-2022 in the COPANA study and the parents, i.e. the mother and father, of the healthy children.

You may qualify if:

• \- Participant in the COPANA project

You may not qualify if:

• Premature birth
• Postterm birth
• Twin birth (gemelli)
• Severe disease in the child
• Stillbirth
• Late abortion

Sponsors & Collaborators

• Rigshospitalet, Denmark: lead

Study Sites (1)

Department of Growth and Reproduction, Rigshospitalet

Copenhagen, 2100, Denmark

Location

Related Publications (32)

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Biospecimen

Retention: SAMPLES WITH DNA

Bloodsamples Urine samples

MeSH Terms

Conditions

Developmental Disabilities; Attention Deficit Disorder with Hyperactivity; Autism Spectrum Disorder

Condition Hierarchy (Ancestors)

Neurodevelopmental Disorders; Mental Disorders; Attention Deficit and Disruptive Behavior Disorders; Child Development Disorders, Pervasive

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor

Study Record Dates

• First Submitted: March 17, 2025
• First Posted: January 5, 2026
• Study Start: May 27, 2024
• Primary Completion (Estimated): May 27, 2028
• Study Completion (Estimated): May 27, 2028
• Last Updated: January 5, 2026

Record last verified: 2025-12

Locations

DK (1)