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.
Safety and Risks · Long Term Child Outcomes
Terho AM et al., 2022 · Human reproduction (Oxford, England)
Is the health of singletons born after frozen embryo transfer (FET) comparable to that of singletons born after fresh embryo transfer (ET) until early adulthood? The health of singletons born after FET does not differ from that of singletons born after fresh ET. The differences in perinatal outcomes of children born after FET and fresh ET are well known. FET is associated with an increased risk of large-for-gestational-age but diminished risks of preterm birth (PTB), small-for-gestational-age and decreased perinatal mortality compared to fresh ET. However, knowledge on the long-term health after FET is scarce. This retrospective register-based cohort study compares singletons born after FET (n = 1825) between the years 1995 and 2006 to those born after fresh ET (n = 2933) and natural conception (NC, n = 31 136) with a mean follow-up time of 18-20 years. Singletons born after FET were compared to those born after fresh ET and NC regarding the frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision), the number of outpatient visits and hospital admissions, and mortality. Adjustments were made for PTB, maternal age, parity, socioeconomic status based on mother's occupation and offspring sex. The study combines data from the Finnish Medical Birth Register, the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland. The Student's T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate crude and adjusted hazard ratios (HRs and aHRs, respectively). A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person. No significant differences between the FET and fresh ET groups were found in the frequency of diagnoses in any of the ICD-10 chapters or in the parameters describing the need for hospital care. However, compared to the NC group, higher proportions in the FET group had outpatient visits in the hospital (93.5% vs 92.2%, aHR 1.23, 95% CI 1.17, 1.30) or hospital admissions (48% vs 46.5%, aHR 1.28, 95% CI 1.19, 1.37). Compared to the NC group, the FET group had elevated adjusted risks of diagnoses of infectious and parasitic diseases (aHR 1.24; 95% CI 1.11, 1.38), neoplasms (aHR 1.68; 95% CI 1.48, 1.91), diseases of the eye and adnexa, the ear or mastoid process (aHR 1.11; 95% CI 1.01, 1.21), the respiratory system (aHR 1.15; 95% CI 1.06, 1.23), the digestive system (aHR 1.17; 95% CI 1.05, 1.32), the skin or subcutaneous tissue (aHR 1.28; 95% CI 1.14, 1.43) and the genitourinary system (aHR 1.27; 95% CI 1.11, 1.45), as well as congenital malformations or chromosomal abnormalities (aHR 1.31; 95% CI 1.14, 1.50) and symptoms, signs or abnormal clinical or laboratory findings (aHR 1.25, 95% CI 1.16, 1.34). Only hospital-based inpatient and outpatient care is covered by the CRHC register, excluding milder cases diagnosed elsewhere. We were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study rare outcomes, such as cancer. For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET. The results on FET versus fresh ET are reassuring, whereas the results on FET versus NC warrant further investigation. Finnish government research funding was obtained for this study. Funding was also obtained from the Finnish Medical Society Duodecim, the Päivikki and Sakari Sohlberg Foundation, Orion Research Foundation, Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.) and Finnish government research funding. The funding sources were not involved in the planning or execution of the study. The authors have no competing interests to declare. N/A.
Safety and Risks · Long Term Child Outcomes
Norrman E et al., 2020 · Human reproduction (Oxford, England)
Do children born after assisted reproductive technology (ART) have an increased risk of developing type 1 diabetes? Children born after ART were found to have an increased risk of type 1 diabetes in the unadjusted analysis, while after adjustment this association was only significant in children born after frozen embryo transfer. Some studies raise concerns as to whether fertility treatments may influence long-term morbidity in children born after ART. Elevated blood pressure and altered glucose metabolism have been found after ART in a few studies. A register-based national cohort study that included all children born in Sweden between 1985 and 2015-in total, 3 138 540 children-was carried out. The study was population-based and all live-born singleton children born after ART (n = 47 938) or spontaneous conception (SC) (n = 3 090 602) were included. The ART cohort comprised 36 727 children born after fresh embryo transfer and 11 211 children born after frozen embryo transfer. Several national registries were used together with data from Statistics Sweden. In total, 202 children born after ART and 17 916 children born after SC developed type 1 diabetes, corresponding to 43.4 and 35.5 per 100 000 person-years at risk (hazard ratio [HR] 1.23; 95% confidence interval [CI], 1.07 to 1.42). Mean follow-up was 9.7 (SD 6.4) years for ART children and 16.3 (SD 9.2) years for SC children. After adjustment for calendar year of birth, HR for type 1 diabetes was 1.13; 95% CI, 0.98-1.30. After further adjustment for sex, maternal age, country of birth, educational level, smoking and parental diabetes, HR was 1.07; 95% CI, 0.93-1.23. In subgroup analyses, an association was found between frozen embryo transfer and type 1 diabetes (adjusted HR 1.52; 95% CI, 1.08-2.14 and 1.41; 95% CI, 1.05-1.89 for frozen versus fresh and frozen versus SC, respectively). When comparing intracytoplasmic sperm injection to in vitro fertilization, no difference was found (adjusted HR 1.08; 95% CI, 0.77-1.51). Limitations were the missing data and residual confounding caused by unknown confounders. Furthermore, the control group consisted of all children not conceived by ART and not non-ART children from subfertile mothers. The study was also performed in only singletons and not in the total ART population. Type 1 diabetes is a serious disease, affecting human life in several ways, including risk of serious complications, reduced life span and a life-long treatment. Our results are generally reassuring, showing no increase in diabetes in ART children compared to children born after SC after adjustment for relevant confounders. The observation of an association between children born after frozen embryo transfer and type 1 diabetes, although based on subgroup analyses with a limited number of children and modest in size, is however a reason for concern. This study was funded by Nordforsk 71450, the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement 70940, and the Hjalmar Svensson Foundation. The authors have no competing interests. ISRCTN 11780826.
Safety and Risks · Long Term Child Outcomes
Kissin DM et al., 2015 · Human reproduction (Oxford, England)
Are assisted reproductive technology (ART) treatment factors or infertility diagnoses associated with autism among ART-conceived children? Our study suggests that the incidence of autism diagnosis in ART-conceived children during the first 5 years of life was higher when intracytoplasmic sperm injection (ICSI) was used compared with conventional IVF, and lower when parents had unexplained infertility (among singletons) or tubal factor infertility (among multiples) compared with other types of infertility. Some studies found an increased risk of autism among ART-conceived infants compared with spontaneously-conceived infants. However, few studies, and none in the USA, have examined the associations between types of ART procedures and parental infertility diagnoses with autism among ART-conceived children. Population-based retrospective cohort study using linkages between National ART Surveillance System (NASS) data for 1996-2006, California Birth Certificate data for 1997-2006, and California Department of Developmental Services (DDS) Autism Caseload data for 1997-2011. All live born ART-conceived infants born in California in 1997-2006 (n = 42 383) with 5-year observation period were included in the study. We assessed the annual incidence of autism diagnosis documented in DDS, which includes information on the vast majority of persons with autism in California, and the association of autism diagnosis with ART treatment factors and infertility diagnoses. Among ART-conceived singletons born in California between 1997 and 2006, the incidence of autism diagnosis remained at ∼0.8% (P for trend 0.19) and was lower with parental diagnosis of unexplained infertility (adjusted hazard risk ratio [aHRR]; 95% confidence interval: 0.38; 0.15-0.94) and higher when ICSI was used (aHRR 1.65; 1.08-2.52), when compared with cases without these patient and treatment characteristics. Among ART-conceived multiples, the incidence of autism diagnosis between 1997 and 2006 remained at ∼1.2% (P for trend 0.93) and was lower with parental diagnosis of tubal factor infertility (aHRR 0.56; 0.35-0.90) and higher when ICSI was used (aHRR 1.71; 1.10-2.66). Study limitations include imperfect data linkages, lack of data on embryo quality and possible underestimation of autism diagnosis cases. Limitations of the observational study design could affect the analysis by the possibility of residual confounders. Since information about ICSI use was missing for most frozen/thawed embryo transfer cycles, our findings of association of ICSI use and autism diagnosis can only be generalizable to fresh embryo transfer cycles. Our study provides additional evidence of the association between some types of ART procedures with autism diagnosis. Additional research is required to explain the increased risk of autism diagnosis with ICSI use, as well as studies on the effectiveness and safety of ICSI.