Safety and Risks · Long Term Child Outcomes
Ban M et al., 2024 · Reproductive biomedicine online
What is the potential transmission of metabolic phenotype from IVF offspring to the subsequent generation? An IVF mouse model was established. The F1 generation mice were produced though IVF or natural mating and the F2 generation was obtained through the mating of F1 generation males with normal females. Their metabolic phenotype, including systemic and hepatic glucolipid metabolism, was examined. It was found that IVF F1 males exhibited metabolic changes. Compared with the control group, the IVF F1 generation showed increased body weight, elevated fasting glucose and insulin, and increased serum triglyceride concentrations. IVF F1 mice also showed an increased expression of hepatic lipogenesis and autophagy genes. Moreover, IVF F1 males transmitted some metabolic changes to their own male progeny (IVF F2) in the absence of a dietary challenge. IVF F2 mice had increased peri-epididymal and subcutaneous fat and decreased insulin sensitivity. Under the 'second hit' of a high-fat diet, IVF F2 mice further showed increased hepatic lipid deposition with unaltered autophagy levels. This research demonstrates the impact of IVF on hepatic glucose-lipid metabolism in two successive generations of offspring, highlighting the need for additional investigation. Enhanced understanding of the mechanisms underlying the transmission of multigenerational effects induced by IVF could potentially lead to the advancement of therapeutic interventions for individuals experiencing infertility.
Safety and Risks · Long Term Child Outcomes
Fauser BC et al., 2014 · Reproductive biomedicine online
The Sixth Evian Annual Reproduction (EVAR) Workshop Group Meeting was held to evaluate the impact of IVF/intracytoplasmic sperm injection on the health of assisted-conception children. Epidemiologists, reproductive endocrinologists, embryologists and geneticists presented data from published literature and ongoing research on the incidence of genetic and epigenetic abnormalities and congenital malformations in assisted-conception versus naturally conceived children to reach a consensus on the reasons for potential differences in outcomes between these two groups. IVF-conceived children have lower birthweights and higher peripheral fat, blood pressure and fasting glucose concentrations than controls. Growth, development and cognitive function in assisted-conception children are similar to controls. The absolute risk of imprinting disorders after assisted reproduction is less than 1%. A direct link between assisted reproduction and health-related outcomes in assisted-conception children could not be established. Women undergoing assisted reproduction are often older, increasing the chances of obtaining abnormal gametes that may cause deviations in outcomes between assisted-conception and naturally conceived children. However, after taking into account these factors, it is not clear to what extent poorer outcomes are due to the assisted reproduction procedures themselves. Large-scale, multicentre, prospective epidemiological studies are needed to investigate this further and to confirm long-term health consequences in assisted-conception children. Assisted reproduction treatment is a general term used to describe methods of achieving pregnancy by artificial means and includes IVF and sperm implantation. The effect of assisted reproduction treatment on the health of children born using these artificial methods is not fully understood. In April 2011, fertility research experts met to give presentations based on research in this area and to look carefully at the evidence for the effects of assisted reproduction treatment on children's health. The purpose of this review was to reach an agreement on whether there are differences in the health of assisted-conception children with naturally conceived children. The researchers discovered no increased risk in birth defects in assisted-conception children compared with naturally conceived children. They found that IVF-conceived children have lower birth weights and higher fat under the skin, higher blood pressure and higher fasting glucose concentrations than naturally conceived children; however, growth, development and cognitive function are similar between groups. A very low risk of disorders of genetic control was observed in assisted-conception children. Overall, there did not appear to be a direct link between assisted reproduction treatment and children's health. The researchers concluded that the cause of some differences in the health of children conceived using assisted reproduction treatment may be due to the age of the woman receiving treatment. Large-scale, research studies are needed to study the long-term health of children conceived using assisted reproduction treatment.
Safety and Risks · Long Term Child Outcomes
Kahn LG et al., 2026 · JAMA Network Open
Increasing numbers of children are conceived using infertility treatment; concerns remain about potential effects on child neurodevelopment. To evaluate whether infertility treatment is associated with child neurodevelopment and whether such an association may be attributable to underlying subfecundity. DESIGN, SETTING, This cohort study was conducted among mother-child dyads in the National Institutes of Health Environmental Influences on Child Health Outcomes (ECHO) Cohort, with infants conceived between 1998 and 2022. Associations of subfecundity and infertility treatment with neurodevelopmental outcomes were assessed among children ages 2 to 10 years. Data were analyzed from May 14, 2025, to March 31, 2026. Subfecundity was defined as prior consultation for, treatment of, or diagnosis of infertility for either partner; at least 2 prior miscarriages; or ever having had unprotected heterosexual intercourse for 12 months without conceiving. Infertility treatment was categorized as in vitro fertilization (IVF) or non-IVF treatment. Harmonized caregiver responses to the Strengths and Difficulties Questionnaire and the Child Behavior Checklist yielded continuous raw scores for externalizing and internalizing problems. The total raw Social Responsiveness Scale (SRS) score quantified autism-like symptoms. Caregivers reported physician diagnosis of autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Among 15 382 mother-infant dyads, there were 14 191 unique maternal participants (mean [SD] age at delivery, 30.9 [5.33] years; 8780 parous participants [57.1%]). ASD and ADHD were diagnosed in 876 offspring (7.6%) and 819 offspring (7.1%), respectively. In generalized linear models, subfecundity was associated with higher externalizing problem and SRS scores among all pregnancies (externalizing problems: b = 0.47 [95% CI, 0.14-0.81]; SRS score: b = 1.08 [95% CI, 0.01-2.14]) and when restricted to natural conceptions (externalizing problems: b = 0.45 [95% CI, 0.07-0.83]; SRS score: b = 1.12 [95% CI, -0.09 to 2.34]). Offspring of parents with subfecundity had higher odds of ASD (overall: odds ratio [OR], 1.27 [95% CI, 1.03-1.57]; natural conceptions: OR, 1.31 [95% CI, 1.04-1.64]). Children conceived via non-IVF treatment had higher odds of ADHD compared with those conceived via natural conception with subfecundity (OR, 1.77 [95% CI, 1.16-2.68]) or without subfecundity (OR, 1.54 [95% CI, 1.05-2.25]). There were no significant associations for IVF treatment. In this large US cohort study, subfecundity was associated with elevated scores for caregiver-reported symptoms of behavioral problems and higher odds of ASD diagnosis, independent of infertility treatment. Non-IVF treatment was associated with ADHD, warranting further research into specific indications for treatment that may increase risk of offspring neurodevelopmental problems.
Safety and Risks · Long Term Child Outcomes
Oakley LL et al., 2025 · Human reproduction (Oxford, England)
Does the risk of childhood cancer following ARTs vary by sex? In this registry-based study, some childhood cancers showed positive sex- and age-specific associations in children conceived using certain ART modalities, which were not evident in overall combined analyses. The relationship between ART and risk of childhood cancer has shown diverse outcomes in prior research. Studies examining whether there are sex differences in childhood cancer risk after ART conception are lacking. This registry-based cohort study included all children born in Norway between 1984 and 2022 (n = 2 255 025), followed until 31 December 2023. Children were identified via the Medical Birth Registry of Norway, and information was extracted on whether they were conceived via ART (defined as IVF/ICSI). Of the 2 255 025 children included in the study, 53 694 were ART-conceived. Birth records were linked to the Cancer Registry of Norway. Childhood cancer was defined as a cancer diagnosis according to the International Classification of Childhood Cancer Third Edition (ICCC-3) before the age of 18 years. Cox regression models were used to estimate the age- and sex-specific risk of cancer for ART-conceived children compared to children not conceived via ART. Among all children, 0.25% had a cancer diagnosis before the age of 18 years. The cumulative incidence of cancer was higher in children conceived by ART (IVF/ICSI) than in those not conceived via ART (21.5 vs 17.5 per 100 000 person-years, P = 0.04), and especially higher in boys conceived with ICSI or after cryopreserved embryo transfer. When combining all age groups, both sexes and all cancer types, there was little evidence of increased cancer risk with ART (adjusted hazard ratio (aHR) 1.13, 95% CI 0.94-1.36). However, differences were found when stratifying by age and sex. From age 5-9 years, ART-conceived children had a higher overall risk of cancer (aHR 1.53, 95% CI 1.06-2.20), with a slightly higher estimate in boys (aHR 1.73, 95% CI 1.09-2.74), than in girls (aHR 1.28, 95% CI 0.70-2.33). The risk was not higher up to age 5 years, or after age 10 years. In combined analyses, there was no overall increased risk after ICSI. When stratifying by sex, a higher risk was seen after ICSI for boys (aHR 1.69, 95% CI 1.18-2.42), but not for girls (aHR 0.65, 95% CI 0.37-1.16). The combined risk after cryopreservation (aHR 1.42, 95% CI 0.95-2.13) was driven by a higher risk in boys (aHR 1.79, 95% CI 1.09-2.94), while no evidence of an association was found in girls (aHR 1.01, 95% CI 0.50-2.03). No increased risk was seen with IVF or after fresh transfer for either boys or girls. Childhood cancer is a rare outcome, and some analyses of cancer subtypes were likely underpowered. Results from this large registry-based study suggest that addressing age- and sex-specific differences in the risk of childhood cancer following ART conception reveals increased risks for certain groups. Our findings require further study with consideration of possible underlying sex-specific mechanisms related to ART and different childhood cancers. This work was funded by: the Research Council of Norway through its Centres of Excellence Funding Scheme (project number 262700); the Norwegian Cancer Association (project number 244291); and the Norwegian Institute of Public Health. The funding agencies had no role in the conceptualization, design, data collection, analysis, decision to publish, or preparation of the manuscript. The authors declare no conflict of interests. N/A.