The effects of intrauterine insemination and single embryo transfer or modified natural cycle in vitro fertilization on offspring's health—Follow-up of a randomized clinical trial

S. Mintjens*, M. D. Menting, R. J.B.J. Gemke, M. N.M. van Poppel, M. van Wely, A. J. Bensdorp, R. I. Tjon Kon Fat, B. W.J. Mol, R. C. Painter, C. van de Beek, T. J. Roseboom

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)


Objective: Does ovarian hyperstimulation and/or the in vitro procedure of assisted reproduction affect neurodevelopmental and physical health of the offspring? Study design: Infertile couples were randomly allocated to intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH), modified natural cycle in vitro fertilization (IVF-MNC) or single embryo transfer IVF (IVF-SET). We compared neurodevelopmental and physical health in childhood (4–7 years). We used age-appropriate questionnaires to assess behavioral problems (Child Behavior Check List (CBCL)) and executive functioning (Behavior Rating Inventory of Executive Function (BRIEF)). We measured body mass index Z-score, waist- and hip-circumference, body fat percentage, blood pressure Z-scores, pulse wave velocity, glucose, insulin, insulin resistance, total cholesterol, high- and low-density lipoprotein cholesterol, triglycerides, and high sensitivity c-reactive protein. We compared groups by analysis of variance. Results: We examined 191 (57%) of the 333 children born in the study at a mean age of 5.5 years (range 4.0–7.6 years). We found no statistically significant differences between randomization groups in children's neurodevelopmental or physical health indices (all p-values > 0.05). Comparing the outcomes between actual method of conception, including a naturally conceived group, also did not show statistically significant differences. Conclusions: Although this follow-up study was not powered on childhood outcomes and limited power due to attrition may have hampered detection of subtle effects, we found no indications of differences in neurodevelopmental and physical health between ovarian hyperstimulation and/or the in vitro procedure of assisted reproduction. Future trials should be powered on child outcomes, and aim to optimize follow-up rates to provide answers that are more definitive.

Original languageEnglish
Pages (from-to)131-138
Number of pages8
JournalEuropean Journal of Obstetrics and Gynecology and Reproductive Biology
Early online date26 Sept 2019
Publication statusPublished - Nov 2019

Bibliographical note

This work was supported by a grant of the Dutch Heart Foundation (2013T085). The initial trial was supported by a grant from ZonMW, the Dutch Organization for Health Research and Development (120620027) and a grant from Zorgverzekeraars Nederland, the Dutch association of healthcare insurers (09-003). The funders had no role in the design, conduct and interpretation of the study. The authors declare no conflict of interest.

Stijn Mintjens, Malou Menting, Reinoud Gemke, Mireille van Poppel, Madelon van Wely, Alexandra Bensdorp, Raïssa Tjon Kon Fat, Ben Willem Mol, Rebecca Painter, Cornelieke van de Beek and Tessa Roseboom declare no conflicts of interest relevant to this study. Outside the work submitted, Ben Willem Mol is supported by a NHMRC practitioner Fellowship and reports consultancy for ObsEva, Merck, Merck KGaA and Guerbet. Rebecca Painter reports board membership for the Dutch Gezondheidsraad and NVVH guideline committees, and travel expenses reimbursement for ESHRE meeting Barcelona 2018 (June).

We thank all the women and children who participated in this study. We are grateful to all who contributed to the follow-up study; with special thanks to our colleague PhD students, post-docs, research assistants and students. This follow-up study would not have been possible without the original INeS trial; therefore, we thank all participating hospitals for their contribution to this study, and the gynecologists, research nurses, research midwives and office members of the Dutch Consortium ( for their hard work and dedication.


  • Assisted reproductive techniques
  • Cardiometabolic health
  • Follow-up
  • Hormone stimulation
  • In vitro fertilization
  • Neurodevelopment


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