Mortality in children conceived by assisted reproductive technology: Does increased risk persist in childhood and adolescence?
Russell S. Kirby, Ph.D., M.S.
Assisted reproductive technologies (ART) came into widespread use in the 1980s (1), and numerous studies have examined pregnancy outcomes comparing pregnancies conceived with various ART modalities with pregnancies conceived spontaneously (2). A few studies have considered differences in child health and development as well (3). Rodriguez-Wallberg et al. sought to compare the mortality experience of infants conceived by ART with naturally conceived infants through infancy to the adolescent years (4). Using data from Swedish national registers, singleton liveborn infants born 1983-2012 were studied, focusing on infant (< 1 year) and childhood (1-18 year) mortality. Infants with congenital malformations and records with missing covariates were excluded from the analysis.
Linkage of records from population-based registers enables the study of long-term outcomes from ART. In the US, similar studies are potentially feasible, but only nationally since the creation of the National ART Surveillance System (NASS) in the mid-2000s. Because of the availability of population-based registers containing data for births, deaths, and treatments, Rodriguez-Wallberg et al. (4) were able to mortality through 2013 for all liveborn infants born in Sweden from 1983-2012, and compare mortality outcomes among naturally conceived and ART births. After adjustment for maternal age, education, and country of birth, infertility, parity and sex of child, risk of infant mortality was slightly increased for ART births (HRa=1.45 95% CI 1.19-1.77). Compared to naturally conceived infants, those conceived by in-vitro fertilization (IVF) had increased risk of infant mortality (HRa=1.62 95% CI 1.24-2.14), while those conceived by intracytoplasmic sperm injection (ICSI) showed no difference in risk for infant mortality (HRa=1.22 95% CI 0.85-1.74). Rodriguez-Wallberg et al. also compared infant mortality among IVF/ICSI fresh and frozen-thawed embryos to infants conceived naturally, and found increased risk in both of these groups. Although study samples were much smaller, replacement of cleavage stage embryos also resulted in a slightly elevated risk of infant mortality. A set of supplemental tables also adjusted for maternal smoking during pregnancy, but resulted in generally similar findings.
Most studies of ART mortality follow infants only through the first year of life, so the mortality outcomes reported by Rodriguez-Wallberg et al. (4) are of special interest. Adjusted for the same set of covariates, there were no differences in mortality for ART overall, or for any of the subgroups examined. While the number of mortality events in some strata was very small – there were only 35 total deaths at ages 1-18 among ART-conceived liveborns from 1983-2012, this study contributes to our understanding of long-term outcomes associated with ART as there are few comparable studies in the scientific literature. Of special note, however, this study included only singleton births without congenital malformations.
With the database created for this study, the authors could expand their inquiry, and examine differences in causes of death (for infants as well as children/adolescents), in chronic diseases and other outcomes requiring hospitalization, special needs, and educational outcomes. Of minor concern, given the relatively small number of cases with missing data (1.2%), a sensitivity analysis using multiple imputation may have been helpful.
Hopefully this study will spur researchers in other jurisdictions to examine longer-term mortality among infants conceived by ART (5), with an expanded focus on health and educational outcomes.
- Marsh M., Ronner W. The Pursuit of Parenthood: Reproductive Technology from Test-Tube Babies to Uterus Transplants. Baltimore, MD: The Johns Hopkins University Press, 2019.
- Pinborg A., Wennerholm U.B., Romundstad L.B., Loft A., Aittomaki K., et al. Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis. Human Reproduction Update 2013;19:87-104.
- Halliday J., Lewis S., Kennedy J., Burgner D.P., Juonala M., Hammarberg K., et al. Health of 22-35 year-olds conceived by assisted reproductive technology. Fertil Steril 2019;112,1:130-139.
- Rodriguez-Wallberg K.A., Lundberg F.E., Ekberg S., Johansson A.L.V. Ludvigsson J.F., Almqvist C., Cnattingius S., Iliabou A.N. Mortality from infancy to adolescence in singleton children conceived from assisted reproductive techniques (ART) vs naturally conceived singletons in Sweden. Fertil Steril 2020;113,3:524-532.
- Shankaran S. Outcomes from infancy to adulthood after assisted reproductive technology. Fertil Steril 2014;101:1217-1221.