STUDY QUESTION Does preconceptional exposure to oil-based iodinated contrast media during hysterosalpingography (HSG) impact children’s neurodevelopment compared with exposure to water-based alternatives? SUMMARY ANSWER Our study found no large-sized effects for neurodevelopment in children with preconceptional exposure to oil-based iodinated contrast media during HSG compared with water-based alternatives. WHAT IS KNOWN ALREADY HSG is widely used as a diagnostic tool in the female fertility work-up. Tubal flushing with oil-based iodinated contrast has been shown to enhance fertility outcomes in couples with unexplained infertility, increasing the chances of pregnancy and live birth compared with water-based alternatives. However, oil-based contrast contains higher doses of iodine and has a longer half-life, and concerns exist that iodinated contrast media can affect women’s iodine status and cause temporary (sub)clinical hypothyroidism in mothers and/or foetuses. Considering that thyroid hormones are vital to embryonal and foetal brain development, oil-based contrast media use could increase the risk of impaired neurodevelopment in children conceived shortly after HSG. Here we examine neurodevelopmental outcomes in school-aged children conceived after HSG. STUDY DESIGN, SIZE, DURATION This is a long-term follow-up of the H2Oil trial in which oil-based or water-based contrast was used during HSG (Netherlands; 2012–2014; NTR3270). Of 369 children born <6 months after HSG in the study, we contacted the mothers of 140 children who gave consent to be contacted for follow-up. The follow-up study took place from January to July 2022 (NCT05168228). PARTICIPANTS/MATERIALS, SETTINGS, METHODS The study included 69 children aged 6–9 years who were conceived after HSG with oil-based (n = 42) or water-based contrast (n = 27). The assessments targeted intelligence (Wechsler Intelligence Scale for Children), neurocognitive outcomes (computerized neurocognitive tests), behavioural functioning (parent and teacher questionnaires), and academic performance. Linear regression models, adjusted for age, sex, and parental educational attainment were employed to compare groups. MAIN RESULTS AND THE ROLE OF CHANCE School-aged children born to mothers after oil-based contrast HSG did not significantly differ from children born to mothers after water-based contrast HSG, in regards to intelligence, neurocognitive functioning, behavioural functioning, or academic performance, with the exception of better performance for visuomotor integration functions in children exposed to oil-based contrast preconception. After exploratory correction for multiple comparisons, none of the group differences was statistically significant. LIMITATIONS, REASONS FOR CAUTION The small sample size of this follow-up study limited statistical power. This study provides evidence for the absence of large-sized differences between preconceptional exposure to the two contrast media types but does not rule out more subtle effects on neurodevelopment compared to naturally conceived children without preconceptional exposure to HSG. WIDER IMPLICATIONS OF THE FINDINGS This study contributes to our knowledge about the long-term effects of different types of iodinated contrast media used in fertility work-up, indicating that choosing oil-based over water-based iodinated contrast media is unlikely to have major effect on the long-term neurodevelopmental outcomes of children conceived shortly after HSG. However, further research should focus on the overall safety of iodine exposure during HSG, comparing children conceived after HSG to those conceived naturally as both types of contrast contain high amounts of iodine. STUDY FUNDING/COMPETING INTEREST(S) The original H2Oil randomized controlled trial was an investigator-initiated study that was funded by the two academic hospitals now merged into the Amsterdam University Medical Centre. The current follow-up study (Neuro-H2Oil) is funded through a research grant awarded to the authors by the Amsterdam Reproduction & Development (AR&D) research institute. S.K. is funded by a AMC MD/PhD Scholarship from the Amsterdam UMC. S.K. reports holding voluntary roles in the civil society organizations Universities Allied for Essential Medicines and People's Health Movement. V.M. reports receiving travel and speaker fees as well as research grants from Guerbet, Merck and Ferring. K.D. reports receiving travel and speaker fees as well as research grants from Guerbet. BWM is supported by a NHMRC Investigator grant (GNT1176437) and reports consultancy, travel support and research funding from Merck, consultancy for Organon and Norgine, and holding stock from ObsEva. The other authors report no conflict of interest. TRIAL REGISTRATION NUMBER NCT05168228

中文翻译：

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使用油基或水基碘造影剂进行子宫输卵管造影后受孕的学龄儿童的神经发育结局：一项全国随机对照试验的长期随访


研究问题 与水基替代品相比，子宫输卵管造影 （HSG） 期间孕前暴露于油基碘造影剂是否会影响儿童的神经发育？摘要答案 我们的研究发现，与水基替代品相比，HSG 期间孕前暴露于油基碘造影剂的儿童的神经发育没有大面积影响。众所周知，HSG 被广泛用作女性生育检查的诊断工具。油基碘造影剂冲洗输卵管已被证明可以提高不明原因不孕症夫妇的生育结果，与水基替代方案相比，增加怀孕和活产的机会。然而，油基造影剂含有更高剂量的碘，半衰期更长，并且人们担心碘造影剂会影响女性的碘状态并导致母亲和/或胎儿出现暂时性（亚）临床甲状腺功能减退症。考虑到甲状腺激素对胚胎和胎儿大脑发育至关重要，使用油基造影剂可能会增加 HSG 后不久受孕儿童神经发育受损的风险。在这里，我们检查了 HSG 后受孕的学龄儿童的神经发育结果。研究设计、规模、持续时间 这是对 H2Oil 试验的长期随访，在该试验中，在 HSG 期间使用油基或水基造影剂（荷兰;2012-2014 年;NTR3270）。在研究中 HSG 后 6 个月出生的 369 名儿童中，我们联系了 140 名同意联系进行随访的儿童的母亲。后续研究于 2022 年 1 月至 7 月（NCT05168228 年）进行。 参与者/材料、设置、方法 该研究包括 69 名 6-9 岁的儿童，他们在 HSG 后使用油性造影剂 （n = 42） 或水基造影剂 （n = 27） 受孕。评估针对智力（韦氏儿童智力量表）、神经认知结果（计算机化神经认知测试）、行为功能（家长和教师问卷）和学习成绩。采用针对年龄、性别和父母受教育程度进行调整的线性回归模型来比较各组。主要结果和机会的作用 油基造影剂后母亲所生的学龄儿童与水基造影剂后所生的学龄儿童在智力、神经认知功能、行为功能或学习成绩方面没有显著差异，除了暴露于油基造影剂前的儿童的视觉运动统合功能表现更好。在对多重比较进行探索性校正后，所有组间差异均无统计学意义。局限性，谨慎的原因 这项后续研究的小样本量限制了统计功效。这项研究提供了证据，证明孕前暴露于两种造影剂类型之间不存在大的差异，但不排除与没有孕前暴露于 HSG 的自然受孕儿童相比，对神经发育有更微妙的影响。 研究结果的更广泛意义 本研究有助于我们了解生育检查中使用的不同类型碘造影剂的长期影响，表明选择油基而不是水基碘造影剂不太可能对 HSG 后不久受孕儿童的长期神经发育结果产生重大影响。然而，进一步的研究应侧重于 HSG 期间碘暴露的总体安全性，将 HSG 后受孕的儿童与自然受孕的儿童进行比较，因为两种类型的造影剂都含有大量碘。研究资金/利益争夺 最初的 H2Oil 随机对照试验是一项由研究者发起的研究，由两家现已并入阿姆斯特丹大学医学中心的学术医院资助。当前的后续研究（Neuro-H2Oil）是由阿姆斯特丹生殖与发展（AR&D）研究所授予作者的研究资助的。SK 由阿姆斯特丹 UMC 的 AMC MD/PhD 奖学金资助。S.K. 报告称，他在民间社会组织 Universities Allied for Essential Medicines 和 People's Health Movement 中担任志愿者角色。V.M. 报告说，他收到了 Guerbet、Merck 和 Ferring 的差旅费和演讲费以及研究资助。K.D. 报告说，他收到了 Guerbet 的差旅费和演讲费以及研究资助。BWM 得到了 NHMRC 研究者资助 （GNT1176437） 的支持，并报告了默克的咨询、差旅支持和研究资金，Organon 和 Norgine 的咨询，以及 ObsEva 的股票。其他作者报告没有利益冲突。试验注册号 NCT05168228