Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden
Rodriguez-Wallberg KA,Lundberg FE,Ekberg S,Johansson ALV,Ludvigsson JF,Almqvist C,Cnattingius S,Iliadou AN
Published February 23, 2020Fertility and Sterility, 113(3), 524-532
Rodriguez-Wallberg, K. A., Lundberg, F. E., Ekberg, S., Johansson, A. L. V., Ludvigsson, J. F., Almqvist, C., Cnattingius, S., & Iliadou, A. N. (2020). Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden. Fertility and sterility, 113(3), 524-532. https://doi.org/10.1016/j.fertnstert.2019.10.018
Rodriguez-Wallberg KA, Lundberg FE, Ekberg S, Johansson ALV, Ludvigsson JF, Almqvist C, et al. Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden. Fertil Steril. 2020;113(3):524-532. doi:10.1016/j.fertnstert.2019.10.018
Rodriguez-Wallberg, Kenny A., et al. "Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden." Fertility and sterility, vol. 113, no. 3, 2020, pp. 524-532.
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Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
Linked to ROR, the Research Organization Registry
RRM Academy Synopsis
Singletons conceived through ART had higher infant mortality in Sweden
Singletons conceived through ART had a higher risk of dying before age one, in a Swedish registry cohort of 2,847,108 single-born children followed from 1983 to 2012. The higher infant risk compared with naturally conceived singletons was most marked after frozen embryo transfer. No higher risk of death appeared between ages 1 and 18.
Key Findings
Before age 1, 114 ART-conceived singletons (0.26%) and 7,236 naturally conceived singletons (0.26%) died. The adjusted hazard ratio was 1.45 (95% CI, 1.19–1.77).
Infant mortality after frozen-thawed embryo transfer had an adjusted hazard ratio of 2.30 (95% CI, 1.46–3.64), based on 19 deaths (0.41%). After fresh embryo transfer it was 1.31 (95% CI, 1.03–1.67).
For deaths in the first week of life after blastocyst transfer, the adjusted hazard ratio was 2.40 (95% CI, 1.05–5.48) among births from 2002 to 2012.
Between ages 1 and 18, 35 ART-conceived children died (0.08%). The adjusted hazard ratio was 0.99 (95% CI, 0.70–1.39).
Interpretation
The study is a nationwide registry cohort of ART (IVF with or without ICSI), so it shows association. Children were followed for a median of 15.9 years. The analysis adjusted for maternal age, infertility and other factors, but the authors could not account for how long couples had been infertile. The frozen embryo and blastocyst results rest on small numbers, and most children who died in those groups were born preterm. The authors advise caution in reading them. Deaths after age 1 were rare, so small differences could go undetected. The analyses excluded children with congenital malformations, so the results cover singletons without them.
RRM Context
Earlier work the authors cite found a threefold higher risk of perinatal death for infertile women who conceived naturally without treatment. Underlying infertility is part of the picture. ART does not address why conception fails. Restorative reproductive medicine works to find and treat that cause. The Swedish registry has no restorative-care group.
Our editorial summary of this paper, not the article's abstract.
Abstract
Objective
To assess infant (<1 year) and childhood (1-18 years) mortality in singletons conceived through assisted reproductive techniques (ART) versus naturally conceived singletons.
Design
Nationwide prospective study.
Setting
Sweden.
Patients
All singleton liveborn infants born from 1983 to 2012 in Sweden identified using the Medical Birth Register (N = 2,847,108), of whom 43,506 were conceived through ART treatments including in vitro fertilization with and without intracytoplasmic sperm injection.
Interventions
None.
Main Outcome Measures
Infant (<1 year) and childhood (1-18 years) mortality.
Results
Data on ART treatment and covariates were retrieved from population-based registers using the unique personal identity number assigned to all permanent residents in Sweden. Cox proportional hazards models estimated the hazard ratios (HRs) with 95% confidence intervals (CIs) as measures of association between ART treatments and death. The analyses were adjusted for maternal characteristics, infertility, child sex, and birth cohort and were restricted to individuals with complete information on covariates for fully adjusted analysis. Compared with naturally conceived singletons, higher infant mortality risks were seen in infants conceived through ART (adjusted HR 1.45; 95% CI, 1.19-1.77), especially after transfer of cryopreserved embryos (adjusted HR 2.30; 95% CI, 1.46-3.64). Early neonatal mortality risk (deaths during the first week) was increased in children born after transfer of blastocysts (HR 2.40; 95% CI, 1.05-5.48). No increased mortality risk was observed between the ages of 1 and 18 years.
Conclusions
Singletons conceived through ART had an increased risk of infant mortality from birth up to 1 year of life, predominantly in the early neonatal period and in pregnancies after transfer of frozen and thawed embryos.
Weibring K et al., 2024·Frontiers in endocrinology·Free full text on PubMed Central
The possibility of future parenthood is a highly relevant issue for patients of reproductive age facing oncologic treatment. This study aimed to investigate how fatherhood was achieved in a patient cohort of adolescents and young adults (AYAs) banking semen at time of cancer diagnosis and to determine the effectiveness of cryopreservation aimed at fertility preservation in the cohort. Observational cohort study examining AYAs with a cancer diagnosis who underwent semen banking for fertility preservation at Karolinska University Hospital 1988-2020, as part of the Stockholm regional fertility preservation program. This cohort is being prospectively followed since time of referral to the program, with most individuals included when presenting with primary cancers (Study Registration: ClinicalTrials.gov NTC04602962). Individuals achieving adulthood in the cohort were followed-up regarding their reproductive outcomes by linking to the Swedish Multi-generation Register, to identify fatherhood through natural conception or adoption, and to the Swedish National Quality Registry for Assisted Reproduction to identify parenthood through medical assistance, including the use of own sperm either cryopreserved or fresh, or donor sperm. Of the 1,378 patients referred during the study period, 1,357 were eligible for fatherhood analysis (aged >20 years at the end of follow-up, December 31, 2021). In total, 493 men became fathers following cancer treatment: 399 (81%) did so naturally, 87 (18%) via assisted reproductive techniques (including two using donor sperm), and 7 (1%) through adoption. Of the 92 patients who used their cryopreserved sperm for assisted reproductive techniques, 34 (37%) successfully fathered a child. The patients may have had children prior to cryopreservation. A large proportion of AYA cancer survivors achieved fatherhood through natural conception in this cohort, whereas less than 1 in 5 survivors needed medical assistance to conceive. Although a low utilization rate of cryopreserved sperm was found in this cohort, its use was highly effective in the group that developed infertility. At present there are no standardized predictors of testicular toxicity after cancer treatment, and inter-individual variability is high. Further research is needed to identify patients at risk of infertility who would benefit from fertility preservation.
Abstract Do children conceived by assisted reproductive technology (ART) have increased overall or cause-specific mortality risk through adolescence, compared with children not conceived by ART? Reassuringly, after median follow-up of 17 years, overall and cause-specific mortality risk was not increased in ART-conceived children compared with non-ART-conceived children. More than 10 million children worldwide have been born as a result of ART. While there is evidence of increased risk of perinatal mortality and perinatal complications among babies born after ART, little is known about overall and cause-specific mortality risk in children and adolescents. Since the proportion of children born after ART has increased dramatically in recent decades, it is important from a public health perspective to investigate overall and cause-specific mortality in ART-offspring, particularly up to adolescence and young adulthood. Study design, size, duration
Data were used from the OMEGA cohort, a historical nationwide cohort with prospective follow-up in The Netherlands. Children of women who were treated in one of the 13 IVF clinics or 2 regional fertility centers during 1983-2011 were included. Of 83,413 live-born children, 47,870 were ART-conceived and 35,543 were not ART-conceived (conceived naturally with or without ovarian stimulation among subfertile couples). Participants/materials, setting, Data on type of fertility treatment and maternal risk factors were available from maternal medical records and the Dutch Perinatal Registry. Complete information on date and cause of death was ascertained through Statistics Netherlands through 2019. The mortality risk in ART children was compared with the mortality risk in non-ART children, using Cox regression analysis (adjusted hazard ratios [HRs]) and with mortality risk in children from the general Dutch population, calculating standardized mortality ratios (SMRs). Main Median age at end of follow-up was 17.5 years (IQR=12.1-24.3) and was shorter in ART-conceived children (16.0 years) than in non-ART children (19.8 years). In total, 718 children died, 399 in the ART group and 319 in the non-ART group, median age of death was 0.02 (IQR=0.00-0.40) and 0.14 years (IQR=0.00-15.93), respectively. Overall mortality risk was not increased in ART-conceived children compared with children of subfertile couples not conceived by ART (HR = 1.02, 95%CI=0.87-1.20), also not for IVF and ICSI specifically (HR = 1.08, 95%CI=0.91-1.28; HR = 0.90, 95%CI=0.71-1.12, respectively). However, for IVF-conceived children, mortality risk was increased in the first 6 months of life (<6 months: HR = 1.23, 95%CI=1.00-1.51) compared with children not conceived by ART. IVF-conceived children were at increased risk of death due to perinatal complications compared with non-ART children (HR = 1.29, 95%CI=1.02-1.65). For ICSI-conceived children, no increased risks were observed. Risks of overall mortality in children aged ≥6 months were non-significantly decreased (>6 months: HR = 0.81, 95%CI=0.61-1.08; HR = 0.81, 95%CI=0.59-1.10; HR = 0.83, 95%CI=0.50-1.36). Overall mortality risk among ART-children was increased compared with mortality incidence in the general population (SMR=1.19, 95%CI=1.08-1.32), mainly driven by excess deaths due to conditions originating in the perinatal period (SMR=2.01, 95%CI=1.76-2.30). No other increased cause-specific mortality risks were observed. Limitations, Despite the large cohort and long-term follow-up, the absolute number of deaths was small, which limited the power to detect differences in some subgroups. In addition, results are largely based on ART treatment protocols used until 2011, consequently, it is uncertain how study results generalize to more contemporary ART treatment. These results contribute to knowledge about long-term health risks in ART-offspring. Reassuringly, long-term mortality up to the age of 24 years among ART-conceived children was similar to mortality in non-ART children and the general population. This knowledge is important for ART children, future parents considering ART, and physicians. No
Assisted reproduction technology (ART) is used worldwide, at increasing rates, and data show that some adverse outcomes occur more frequently than following spontaneous conception (SC). Possible explanatory factors for the well-known adverse perinatal outcome in ART singletons were evaluated. PubMed and Cochrane databases from 1982 to 2012 were searched. Studies using donor or frozen oocytes were excluded, as well as those with no control group or including <100 children. The main outcome measure was preterm birth (PTB defined as delivery <37 weeks of gestation), and a random effects model was used for meta-analyses of PTB. Other outcomes were very PTB, low-birthweight (LBW), very LBW, small for gestational age and perinatal mortality. The search returned 1255 articles and 65 of these met the inclusion criteria. The following were identified as predictors for PTB in singletons: SC in couples with time to pregnancy (TTP) > 1 year versus SC singletons in couples with TTP ≤ 1 year [adjusted odds ratio (AOR) 1.35, 95% confidence interval (CI) 1.22, 1.50]; IVF/ICSI versus SC singletons from subfertile couples (TTP > 1 year; AOR 1.55, 95% CI 1.30, 1.85); conception after ovulation induction and/or intrauterine insemination versus SC singletons where TTP ≤ 1 year (AOR 1.45, 95% CI 1.21, 1.74); IVF/ICSI singletons versus their non-ART singleton siblings (AOR 1.27, 95% CI 1.08, 1.49). The risk of PTB in singletons with a 'vanishing co-twin' versus from a single gestation was AOR of 1.73 (95% CI 1.54, 1.94) in the narrative data. ICSI versus IVF (AOR 0.80, 95% CI 0.69-0.93), and frozen embryo transfer versus fresh embryo transfer (AOR 0.85, 95% CI 0.76, 0.94) were associated with a lower risk of PTB. Subfertility is a major risk factor for adverse perinatal outcome in ART singletons, however, even in the same mother an ART singleton has a poorer outcome than the non-ART sibling; hence, factors related to the hormone stimulation and/or IVF methods per se also may play a part. Further research is required into mechanisms of epigenetic modification in human embryos and the effects of cryopreservation on this, whether milder ovarian stimulation regimens can improve embryo quality and endometrial conditions, and whether longer culture times for embryos has a negative influence on the perinatal outcome.
Sargisian N et al., 2024·European heart journal·Free full text on PubMed Central
Children born after assisted reproductive technology (ART) have worse perinatal outcomes compared with spontaneously conceived children. This study investigates whether children conceived after ART have a higher risk of congenital heart defects (CHDs) compared with children born after spontaneous conception (SC). All 7 747 637 liveborn children in Denmark (1994-2014), Finland (1990-2014), Norway (1984-2015), and Sweden (1987-2015), where 171 735 children were conceived after ART, were included. National ART and medical birth registry data were cross-linked with data from other health and population registries. Outcomes were major CHDs, severe CHDs, 6 hierarchical CHD lesion groups, and 10 selected major CHDs, diagnosed prenatally or up to 1 year of age (Denmark, Finland, and Sweden) and prenatally or at birth (Norway). The association between ART and CHDs was assessed with multivariable logistic regression analysis, with adjustment for available confounders. Major CHDs were detected in 3159 children born after ART (1.84%) and in 86 824 children born after SC [1.15%; adjusted odds ratio (AOR) 1.36; 95% confidence interval (CI) 1.31-1.41]. Risk was highest in multiples, regardless of conception method. Severe CHDs were detected in 594 children born after ART (0.35%) and in 19 375 children born after SC (0.26%; AOR 1.30; 95% CI 1.20-1.42). Risk was similar between ICSI and IVF and between frozen and fresh embryo transfer. Assisted reproductive technology-conceived children have a higher prevalence of major CHDs, being rare, but severe conditions. The absolute risks are, however, modest and partly associated with multiple pregnancies, more prevalent in ART.
Worldwide, more than 7 million children have now been born after these delivery rates are steadily rising and now comprise 2-6% of births in the European countries. To achieve higher pregnancy rates, the transfer of two or more embryos was previously the gold standard in ART. However, recently the practise has moved towards a single embryo transfer policy to avoid multiple births. The positive consequences of the declining multiple birth rates after ART are decreasing perinatal risks and overall improved health for the ART progeny. In this review we summarize the risks for short- and long-term health in ART singletons and discuss if the increased health risks are associated with intrinsic maternal or paternal factors related to subfertility or to the ART treatments per se. Although the risks are modest, singletons born after ART are more likely to have adverse perinatal outcomes compared to spontaneously conceived (SC) singletons dependent on the ART method. Fresh embryo transfer is associated with a higher risk of small for gestational age babies (SGA), low birthweight and preterm birth (PTB), while frozen embryo transfer is associated with large-for-gestational age babies and pre-eclampsia. ICSI may be associated with a higher risk of birth defects and transferral of the poor semen quality to male progeny, while oocyte donation is associated with increased risk of SGA and pre-eclampsia. Concerning long-term health risks, the current evidence is limited but suggests an increased risk of altered blood pressure and cardiovascular function in ART children. The data that are available for malignancies seem reassuring, while results on neurodevelopmental health are more equivocal with a possible association between ART and cerebral palsy. The laboratory techniques used in ART may also play a role, as different embryo culture media give rise to different birthweights and growth patterns in children, while culture to blastocyst stage is associated with PTB. In addition, children born after ART have altered epigenetic profiles, and these alterations may be one of the key areas to explore to improve our understanding of adverse child outcomes after ART. A major challenge for research into adverse perinatal outcomes is the difficulty in separating the contribution of infertility per se from the ART treatment (i.e. 'the chicken or the egg'?). Choosing and having access to the appropriate control groups for the ART children in order to eliminate the influence of subfertility per se (thereby exploring the pure association between ART and child outcomes) is in itself challenging. However, studies including children of subfertile couples or of couples treated with milder fertility treatments, such as IUI, as controls show that perinatal risks in these cohorts are lower than for ART children but still higher than for SC indicating that both subfertility and ART influence the future outcome. Sibling studies, where a mother gave birth to both an ART and a SC child, support this theory as ART singletons had slightly poorer outcomes. The conclusion we can reach from the well designed studies aimed at disentangling the influence on child health of parental and ART factors is that both the chicken and the egg matter.
Assisted Reproduction › Safety and Risks › Long Term Child Outcomes
Sara Ekberg, Anna L V Johansson, Jonas F Ludvigsson, Catarina Almqvist, Sven Cnattingius, Frida E Lundberg
S Ekberg, A Johansson, J Ludvigsson, C Almqvist, S Cnattingius, F Lundberg
PMID 32081362 32081362 DOI 10.1016/j.fertnstert.2019.10.018 10.1016/j.fertnstert.2019.10.018 Rodriguez-Wallberg et al. 2020, Rodriguez-Wallberg 2020
Cite this article
Rodriguez-Wallberg, K. A., Lundberg, F. E., Ekberg, S., Johansson, A. L. V., Ludvigsson, J. F., Almqvist, C., Cnattingius, S., & Iliadou, A. N. (2020). Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden. Fertility and sterility, 113(3), 524-532. https://doi.org/10.1016/j.fertnstert.2019.10.018
Rodriguez-Wallberg KA, Lundberg FE, Ekberg S, Johansson ALV, Ludvigsson JF, Almqvist C, et al. Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden. Fertil Steril. 2020;113(3):524-532. doi:10.1016/j.fertnstert.2019.10.018
Rodriguez-Wallberg, Kenny A., et al. "Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques versus naturally conceived singletons in Sweden." Fertility and sterility, vol. 113, no. 3, 2020, pp. 524-532.
