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STUDY QUESTION Does exposure to preconceptional hysterosalpingography (HSG) with iodinated oil-based contrast affect neonatal thyroid function as compared to iodinated water-based contrast? SUMMARY ANSWER Preconceptional HSG with iodinated contrast did not influence the neonatal thyroid function. WHAT IS KNOWN ALREADY HSG is a commonly applied tubal patency test during fertility work-up in which either oil- or water-based contrast is used. Oil-based contrast contains more iodine compared to water-based contrast. A previous study in an East Asian population found an increased risk of congenital hypothyroidism (CH) in neonates whose mothers were exposed to high amounts of oil-based contrast during HSG. STUDY DESIGN, SIZE, DURATION This is a retrospective data analysis of the H2Oil study, a randomized controlled trial (RCT) comparing HSG with the use of oil- versus water-based contrast during fertility work-up. After an HSG with oil-based contrast, 214 women had an ongoing pregnancy within 6 months leading to a live birth compared to 155 women after HSG with water-based contrast. PARTICIPANTS/MATERIALS, SETTING, METHODS Of the 369 women who had a live born infant, 208 consented to be approached for future research and 138 provided informed consent to collect data on the thyroid function tests of their offspring (n = 140). Thyroid function tests of these children were retrieved from the Dutch neonatal screening program, which includes the assessment of total thyroxine (T4) in all newborns, followed by thyroid-stimulating hormone only in those with a T4 level of ≤ −0.8 SD score. Furthermore, amount of contrast medium used and time between HSG and conception were compared between the two study groups. MAIN RESULTS AND THE ROLE OF CHANCE Data were collected from 140 neonates conceived after HSG with oil-based (n = 76) or water-based (n = 64) contrast. The median T4 concentration was 87.0 nmol/l [76.0–96.0] in the oil group and 90.0 nmol/l [78.0–106.0] in the water group (P = 0.13). None of the neonates had a positive screening result for CH. The median amount of contrast medium used was 9.0 ml [interquartile range (IQR), 6.0–11.8] in the oil-group and 10.0 ml [IQR, 7.5–14.0] in the water group (P = 0.43). No influence of the amount of contrast on the effect of contrast group on T4 concentrations was found (P-value for interaction, 0.37). LIMITATIONS, REASONS FOR CAUTION A relatively small sample size and possible attrition at follow-up are limitations of this study. Although our results suggest that the use of iodinated contrast media for HSG is safe for the offspring, the impact of a decrease in maternal thyroid function on offspring neurodevelopment could not be excluded, as data on maternal thyroid function after HSG and during conception were lacking. WIDER IMPLICATIONS OF THE FINDINGS As HSG with oil-based contrast does not affect thyroid function of the offspring, there is no reason to withhold this contrast to infertile women undergoing HSG. Future studies should investigate whether HSG with iodinated contrast influences the periconceptional maternal thyroid function and, consequently, offspring neurodevelopment. STUDY FUNDING/COMPETING INTEREST(S) This study received no funding. The original H2Oil RCT was an investigator-initiated study that was funded by the two academic institutions (Academic Medical Center and VU University Medical Center) of the Amsterdam UMC. The funders had no role in study design, collection, analysis and intrepretation of the data. I.R. reports receiving travel fee from Guerbet. C.B.L. reports speakers fee from Ferring in the past and research grants from Ferring, Merck and Guerbet. K.D. reports receiving travel fee and speakers fee from Guerbet. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548). B.W.M. reports consultancy for ObsEva, Merck KGaA and Guerbet and travel and research grants from Merck KGaA and Guerbet. V.M. reports receiving travel fee and speakers fee as well as research grants from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER Netherlands Trial Register NTR 7526 (Neonates born after the H2Oil study), NTR 3270 (original H2Oil study), www.trialregister.nl

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STUDY QUESTION Does assisted reproduction, such as ovarian stimulation and/or laboratory procedures, have impact on perinatal outcomes of singleton live births compared to natural conception in couples with unexplained subfertility? SUMMARY ANSWER Compared to natural conception, singletons born after intrauterine insemination with ovarian stimulation (IUI-OS) had a lower birthweight, while singletons born after IVF had comparable birthweights, in couples with unexplained subfertility. WHAT IS KNOWN ALREADY Singletons conceived by assisted reproduction have different perinatal outcomes such as low birthweight and a higher risk of premature birth than naturally conceived singletons. This might be due to the assisted reproduction, such as laboratory procedures or the ovarian stimulation, or to an intrinsic factor in couples with subfertility. STUDY DESIGN, SIZE, DURATION We performed a prospective cohort study using the follow-up data of two randomized clinical trials performed in couples with unexplained subfertility. We evaluated perinatal outcomes of 472 live birth singletons conceived after assisted reproduction or after natural conception within the time horizon of the studies. PARTICIPANTS/MATERIALS, SETTING, METHODS To assess the possible impact of ovarian stimulation we compared the singletons conceived after IUI with FSH or clomiphene citrate (CC) and IVF in a modified natural cycle (IVF-MNC) or standard IVF with single embryo transfer (IVF-SET) to naturally conceived singletons in the same cohorts. To further look into the possible effect of the laboratory procedures, we put both IUI and IVF groups together into IUI-OS and IVF and compared both to singletons born after natural conception. We only included singletons conceived after fresh embryo transfers. The main outcome was birthweight presented as absolute weight in grams and gestational age- and gender-adjusted percentiles. We calculated differences in birthweight using regression analyses adjusted for maternal age, BMI, smoking, parity, duration of subfertility and child gender. MAIN RESULTS AND THE ROLE OF CHANCE In total, there were 472 live birth singletons. Of the 472 singleton pregnancies, 209 were conceived after IUI-OS (136 with FSH and 73 with CC as ovarian stimulation), 138 after IVF (50 after IVF-MNC and 88 after IVF-SET) and 125 were conceived naturally. Singletons conceived following IUI-FSH and IUI-CC both had lower birthweights compared to naturally conceived singletons (adjusted difference IUI-FSH −156.3 g, 95% CI −287.9 to −24.7; IUI-CC −160.3 g, 95% CI −316.7 to −3.8). When we compared IVF-MNC and IVF-SET to naturally conceived singletons, no significant difference was found (adjusted difference IVF-MNC 75.8 g, 95% CI −102.0 to 253.7; IVF-SET −10.6 g, 95% CI −159.2 to 138.1). The mean birthweight percentile was only significantly lower in the IUI-FSH group (−7.0 percentile, 95% CI −13.9 to −0.2). The IUI-CC and IVF-SET group had a lower mean percentile and the IVF-MNC group a higher mean percentile, but these groups were not significant different compared to the naturally conceived group (IUI-CC −5.1 percentile, 95% CI −13.3 to 3.0; IVF-MNC 4.4 percentile, 95% CI −4.9 to 13.6; IVF-SET −1.3 percentile, 95% CI −9.1 to 6.4). Looking at the laboratory process that took place, singletons conceived following IUI-OS had lower birthweights than naturally conceived singletons (adjusted difference −157.7 g, 95% CI −277.4 to −38.0). The IVF group had comparable birthweights with the naturally conceived group (adjusted difference 20.9 g, 95% CI −110.8 to 152.6). The mean birthweight percentile was significantly lower in the IUI-OS group compared to the natural group (−6.4 percentile, 95% CI −12.6 to −0.1). The IVF group was comparable (0.7 percentile, 95% CI −6.1 to 7.6). LIMITATIONS, REASONS FOR CAUTION The results are limited by the number of cases. The data were collected prospectively alongside the randomized controlled trials, but analyzed as treated. WIDER IMPLICATIONS OF THE FINDINGS Our data suggest IUI in a stimulated cycle may have a negative impact on the birthweight of the child and possibly on pre-eclampsia. Further research should look into the effect of different methods of ovarian stimulation on placenta pathology and pre-eclampsia in couples with unexplained subfertility using naturally conceived singletons in the unexplained population as a reference. STUDY FUNDING/COMPETING INTEREST(S) Both initial trials were supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (INeS 120620027, SUPER 80-83600-98-10192). The INeS study also had a grant from Zorgverzekeraars Nederland, the Dutch association of healthcare insurers (09-003). B.W.J.M. is supported by an NHMRC investigator Grant (GNT1176437) and reports consultancy for ObsEva, Merck Merck KGaA, Guerbet and iGenomix, outside the submitted work. A.H. reports grants from Ferring Pharmaceutical company (the Netherlands), outside the submitted work. F.J.M.B. receives monetary compensation as a member of the external advisory board for Merck Serono (the Netherlands), Ferring Pharmaceutics BV (the Netherlands) and Gedeon Richter (Belgium), he receives personal fees from educational activities for Ferring BV (the Netherlands) and for advisory and consultancy work for Roche and he receives research support grants from Merck Serono and Ferring Pharmaceutics BV, outside the submitted work. The remaining authors have nothing to disclose. TRIAL REGISTRATION NUMBER INeS study Trial NL915 (NTR939); SUPER Trial NL3895 (NTR4057)