Highlight
This study from the H2Oil randomized clinical trial reveals that children conceived within six months following hysterosalpingography (HSG) using iodinated contrast exhibit statistically significant lower intelligence quotient (IQ) and deficits in information processing and attention control at school age, compared with age-matched controls conceived without fertility treatments. Notably, these adverse neurodevelopmental effects were most evident when conception occurred within 12 weeks post-HSG, with no differences observed in behavioral or academic performance. Confounding factors such as prematurity, low birth weight, maternal smoking, and use of assisted reproductive technologies were ruled out, emphasizing a potential direct impact of the iodinated contrast medium on early neurodevelopment.
Study Background
Hysterosalpingography (HSG) is a diagnostic procedure routinely employed during fertility work-ups to evaluate tubal patency, commonly utilizing iodinated contrast agents. The oil-based (480 mg/ml iodine) or water-based (250 mg/ml iodine) contrasts used can transiently affect thyroid function through the Wolff-Chaikoff effect, characterized by temporary thyroid hormone suppression due to excess iodine exposure. Given thyroid hormones’ essential role in early brain development, there is concern that HSG with iodinated contrast could adversely influence offspring neurodevelopment if conception occurs shortly after the procedure. However, robust longitudinal human data linking HSG contrast use with long-term cognitive outcomes in children have been scarce.
Study Design
This observational cohort study evaluated 69 children conceived within six months after undergoing HSG with either oil-based or water-based iodinated contrast within the H2Oil randomized clinical trial (NCT05168228). These children were compared to 44 age-, sex-, and parental education-matched control children conceived without fertility treatments from the Netherlands Twin Register (NTR9574). Primary neurodevelopmental outcomes assessed at school age included intelligence quotient (IQ), behavioral metrics, and academic performance. Secondary outcomes encompassed domain-specific neurocognitive measures, such as information processing speed and attentional control.
Linear regression models adjusted for child age, sex, and parental education were applied, with false discovery rate correction for multiple comparisons. Subgroup analyses stratified children based on time intervals from HSG to conception (12 weeks) using polynomial contrast approaches. Sensitivity analyses excluded confounding by prematurity, low birth weight, maternal smoking during pregnancy, or assisted reproductive technique conception.
Key Findings
The study found a statistically significant reduction in mean IQ scores in children conceived within six months post-HSG compared to controls (104.3 versus 113.1; adjusted difference: -6.81; 95% confidence interval -10.97 to -2.65; p=0.02). More specifically, the IQ decrement was most pronounced in children conceived less than 12 weeks following HSG, suggesting a temporal association between iodinated contrast exposure and neurodevelopmental impact. Children conceived more than 12 weeks post-HSG did not differ significantly from controls.
In addition to IQ, selected neurocognitive domains, specifically information processing speed and attention control, were also significantly impaired (mean difference approximately -0.52 standard deviations; 95% CI -0.84 to -0.19; p=0.02). However, no significant differences were seen in behavioral assessments or academic performance metrics, implying that the cognitive deficits observed do not necessarily translate into overt behavioral or scholastic difficulties at school age.
Importantly, the sensitivity analyses demonstrated robustness of findings against common perinatal and conception variables, supporting the hypothesis that the effects are linked to transient thyroid disruption through iodinated contrast rather than confounding conditions.
Expert Commentary
This work addresses an important clinical question at the intersection of reproductive medicine and pediatric neurodevelopment. The Wolff-Chaikoff phenomenon offers a biologically plausible mechanism by which excess maternal iodine administration during early pregnancy or immediately before conception could transiently reduce thyroid hormone synthesis, potentially impairing fetal brain development when thyroid hormone demand is critical.
Although the observed IQ reduction was modest, a mean decrement of nearly seven points could have population-level implications, especially if the effect size is confirmed in larger studies. The lack of behavioral or academic impact might reflect the age at assessment or compensatory mechanisms. It remains uncertain whether these cognitive differences persist into adolescence or adulthood or have functional consequences.
Limitations of this study include the modest sample size and potential residual confounding despite rigorous adjustments. Additionally, differential iodine content between oil- and water-based contrast agents could not be fully evaluated given sample constraints. Further large prospective cohorts or meta-analyses are needed to confirm these findings and investigate long-term neurodevelopmental trajectories.
Conclusion
Children conceived shortly after hysterosalpingography with iodinated contrast exhibit subtle but statistically significant impairments in IQ and specific neurocognitive functions at school age. These findings advocate caution regarding the timing of conception after HSG procedures and underscore the need for replication in larger, adequately powered cohorts. The long-term clinical significance and potential mechanisms of these associations warrant further study to optimize fertility work-up protocols and ensure offspring neurodevelopmental safety.
Funding and Clinical Trials Registration
This research was conducted within the framework of the H2Oil randomized clinical trial (NCT05168228). Funding sources and ethical approvals were as detailed in the original publication.
References
- Keestra SM, Kooper CC, van Welie N, et al. Children’s neurodevelopment at school age after hysterosalpingography with iodinated contrast: a cohort study. J Clin Endocrinol Metab. 2026 Jul 6; PMID: 42405620.
- Zimmermann MB. Iodine deficiency. Endocr Rev. 2009;30(4):376-408.
- Schwartz D, et al. The Wolff-Chaikoff effect and thyroid hormone physiology. Thyroid. 2015;25(4):433-40.
