Evaluating the Long-term Neurocognitive Effects of Preconceptional Exposure to Iodinated Contrast on the Offspring (Neuro-H2Oil)

Evaluating the Long-term Neurocognitive Effects of Preconceptional Exposure to Iodinated Contrast During Hysterosalpingography (HSG) on the Offspring of the H2Oil Trial

Iodinated contrast is commonly used in hysterosalpingography (HSG), a diagnostic tool in fertility work-up. This study aims to investigate the safety of contrast media used during HSG by evaluating the long-term effects on the neurodevelopment of offspring 6-8 years after exposure to iodinated contrast media.

Study Overview

• Status: Active, not recruiting
• Conditions: Neurocognitive Disorders
• Intervention / Treatment: Procedure: Oil- versus waterbased contrast in hysterosalpingography (HSG)

Detailed Description

Background: Iodinated contrast is commonly used in hysterosalpingography (HSG), a diagnostic tool in fertility work-up. Yet excessive iodine may pool for a long time in the body, crosses the placenta easily, and can induce hypothyroidism in both mothers and foetuses. Inadequate supplies of thyroid hormones have previously been associated with neurocognitive impairments in offspring. Considering the widespread use of iodinated contrast during fertility work-up, the potential iatrogenic effect of preconceptional iodine exposure on the brain development of the offspring needs to be addressed urgently.

Objectives: This project aims to investigate the safety of contrast media used during HSG by evaluating the long-term effects on the neurodevelopment of offspring 6-8 years after exposure to iodinated contrast media. To do this, the investigators will follow up on a cohort of offspring conceived during the H2Oil randomised controlled trial (NTR 3270), which was set up to evaluate the effect of using water- or oil-based media during HSG on pregnancy rates.

Methods: The study team have previously obtained parental permission for follow-up research in 140 children conceived during the H2Oil study <6 months after exposure to iodine during the HSG. The investigators will conduct comprehensive an in-depth outcome assessment of intelligence, neurocognitive development, school performance, and behavioural functioning.

Relevance: Using this diverse range of methods, the investigators expect to be the first to shed light on the long-term iatrogenic consequences of using iodinated contrast just before conception on the neurodevelopment of their offspring. The findings of this study will have implications for current clinical practice, where HSG is readily used in subfertile women, and will be used to inform the Dutch guidelines for fertility work-up.

• Study Type: Observational
• Enrollment (Anticipated): 64

Contacts and Locations

Study Locations

• Netherlands
  • Noord-Holland
    • Amsterdam, Noord-Holland, Netherlands
      • Emma Kinderziekenhuis

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 5 years to 10 years (CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Children born to mothers who participated in the original H2Oil study (NTR3270), a multicentre randomised controlled trial on oil- versus water-based HSG in 2012-2014 whose parents gave consent to be contacted for follow up studies (n=140).

Description

Inclusion Criteria:

• Children conceived after the mother underwent HSG procedure in the context of the H2Oil trial (2012-2014)
• Children must be conceived <6 months after the HSG procedure
• Parents must have given consent for recontacting for follow up research

Exclusion Criteria:

• Children conceived after the mother underwent HSG procedure that was not part of the H2Oil trial
• Children conceived >6 months after the HSG procedure
• Children whose parents did not give permission to be recontacted for follow up research
• Children that are not able to comprehend the instructions at the time of assessment
• Absence or withdrawal of written informed consent
• Inability to comprehend testing instructions at time of assessment
• Severe motor disability that interferes with outcome assessment at time of assessment
• Documented and/or parent-reported diagnosis of a neurological disorder
• Somatic disorders known to affect the outcome assessments at time of assessment

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
School performance	Longitudinal data on school performance will be collected using standardised tests from the pupil monitoring system developed by the Dutch National Institute for Educational Measurement (CITO-test). CITO-tests are used to assess children's academic performance (reading comprehension, spelling, and arithmetic performance) in primary schools in the Netherlands.	Between the ages of 4-12, up to 12 years
Intelligence	General intelligence will be assessed using a shortened Fifth version of the Wechsler Intelligence Scale for Children. Full-scale IQ (FSIQ) will be estimated using the subtests Vocabulary, Similarities, Matrix Reasoning, and Block Design.	1 Day
Behavioural functioning evaluated through the Strengths and Difficulties Questionnaire (SDQ).	Behavioural functioning will be evaluated through the Strengths and Difficulties Questionnaire (SDQ). Both parents and teachers will fill in the SDQ.	1 Day
Behavioural functioning evaluated through the Strengths and Weaknesses of ADHD Symptoms And Normal behaviour (SWAN) scale.	Behavioural functioning will be evaluated will be evaluated using the Strengths and Weaknesses of ADHD Symptoms And Normal behaviour (SWAN) scale. Both parents and teachers will fill in the SWAN scale.	1 Day

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visuomotor integration	Visuomotor integration will be assessed using a Track & Trace task of the Emma Toolbox for Neurocognitive Functioning, which is an in-house designed battery of computerised tests for assessing different neurocognitive domains.	1 Day
Processing & Control	Processing & Control will be assessed using an Attention Network Test of the Emma Toolbox for Neurocognitive Functioning, which is an in-house designed battery of computerised tests for assessing different neurocognitive domains.	1 Day
Visual Memory	Visual Memory will be assessed using an Location Learning Test of the Emma Toolbox for Neurocognitive Functioning, which is an in-house designed battery of computerised tests for assessing different neurocognitive domains.	1 Day
Verbal Memory	Verbal Memory will be assessed using a Rey Auditory Verbal Learning Test (Dutch Version) of the Emma Toolbox for Neurocognitive Functioning, which is an in-house designed battery of computerised tests for assessing different neurocognitive domains.	1 Day
Visual Working Memory	Visual Working Memory will be assessed using a Klinberg task of the Emma Toolbox for Neurocognitive Functioning, which is an in-house designed battery of computerised tests for assessing different neurocognitive domains.	1 Day
Verbal Working Memory	Verbal Working Memory will be assessed using a Digit Span task of the Emma Toolbox for Neurocognitive Functioning, which is an in-house designed battery of computerised tests for assessing different neurocognitive domains.	1 Day

Collaborators and Investigators

• Sponsor: Amsterdam UMC, location VUmc
• Collaborators: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Marsh Königs, PhD, Emma Children's Hospital, Amsterdam UMC

Publications and helpful links

General Publications

• Konigs M, Verhoog EM, Oosterlaan J. Exploring the neurocognome: Neurocognitive network organization in healthy young adults. Cortex. 2021 Oct;143:12-28. doi: 10.1016/j.cortex.2021.06.011. Epub 2021 Jul 14.
• Dreyer K, van Rijswijk J, Mijatovic V, Goddijn M, Verhoeve HR, van Rooij IAJ, Hoek A, Bourdrez P, Nap AW, Rijnsaardt-Lukassen HGM, Timmerman CCM, Kaplan M, Hooker AB, Gijsen AP, van Golde R, van Heteren CF, Sluijmer AV, de Bruin JP, Smeenk JMJ, de Boer JAM, Scheenjes E, Duijn AEJ, Mozes A, Pelinck MJ, Traas MAF, van Hooff MHA, van Unnik GA, de Koning CH, van Geloven N, Twisk JWR, Hompes PGA, Mol BWJ. Oil-Based or Water-Based Contrast for Hysterosalpingography in Infertile Women. N Engl J Med. 2017 May 25;376(21):2043-2052. doi: 10.1056/NEJMoa1612337. Epub 2017 May 18.

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 26, 2022
• Primary Completion (ANTICIPATED): July 1, 2022
• Study Completion (ANTICIPATED): August 1, 2022

Study Registration Dates

• First Submitted: November 25, 2021
• First Submitted That Met QC Criteria: December 22, 2021
• First Posted (ACTUAL): December 23, 2021

Study Record Updates

• Last Update Posted (ACTUAL): January 27, 2022
• Last Update Submitted That Met QC Criteria: January 26, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Keywords: Iodine; Intelligence; Hysterosalpingography; Iodinated contrast media; Neurocognitive development
• Additional Relevant MeSH Terms: Mental Disorders; Neurocognitive Disorders
• Other Study ID Numbers: 2021.0448

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No