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• W4283728376 abstract "In the retrospective, population-based study of the association of assisted reproductive technology (ART) with childhood morbidity, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) demonstrated that in a cohort of approximately 800,000 singleton children who were born between 2008 and 2019 in Quebec, Canada, ART exposure was associated with 1.23 times the risk of any hospitalization up to 11 years of age, with the greatest risk being in the first 5 years of life. In this work, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) used several robust methodologic approaches to tackle the difficulties in studying ART as the primary exposure. First, their population-based data source was the Study of Hospital Clientele repository, which contains 100% of inpatient hospitalizations in Quebec, and allowed for the investigation of uncommon outcomes with sufficient power. In general, children do not require frequent and/or repeated hospitalizations; thus, significant differences in outcomes can only be assessed with state/provincial/regional-level datasets. Second, the sibling discordant design attempted to disentangle the impact of ART from confounders, such as social and environmental factors and genetic makeup, that might differ between nonsibling ART-exposed and unexposed groups. Third, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) used a robust approach in which child hospitalization was categorized on the basis of diagnoses, first by pathologies and then by organ systems, to gain more granular understanding of the reasons for hospital admission and recognized that individual International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, codes cannot be meaningful reported with such a large cohort.However, several notable limitations to this work exist, some of which are highlighted by the investigators in the discussion. First, although the comparison groups are ART vs. non-ART–exposed children, it is well known that the non-ART group includes children who were born after other non-ART fertility treatments, such as pharmacologic therapy or intrauterine insemination. In addition, the non-ART group likely includes some children who were born to women with a previous history of infertility who did not require medical treatment to conceive for the index pregnancy. Thus, the underlying maternal medical conditions that are associated with infertility are likely present in both the groups, albeit to a lesser severity in the non-ART group. This has been demonstrated in a number of articles from the Massachusetts Outcome Study of ART, which created a “subfertile” comparison group of women who did not receive ART but had other indications of infertility in the dataset. These studies demonstrated that the risk of adverse infant and childhood outcomes were greater in the subfertile group than in the fertile group; however, this risk was of lower magnitude when the ART group was compared with the fertile group (2Hwang S.S. Dukhovny D. Gopal D. Cabral H. Missmer S. Diop H. et al.Health of infants after ART-treated, subfertile, and fertile deliveries.Pediatrics. 2018; 142e20174069Crossref Scopus (24) Google Scholar). Thus, one can hypothesize that the results of the study by Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) likely underestimate the difference in outcomes between the ART and non-ART groups.Second, although the discordant sibling analyses attempted to address potential confounders between the ART and non-ART populations in social and environmental factors and genetic makeup of the 2 comparison groups, the maternal medical conditions associated with infertility were likely common “exposures” to both ART and non-ART groups. Similar to the aforementioned discussion of the subfertile group, the non-ART sibling group may have been conceived by non-ART treatments. Here, again, the attenuation of risk in adverse outcomes (compared with the nonsibling analysis) may be due to unmeasured confounding, leading to underestimation of the risk of ART.Third, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) did not appear to assess preterm birth (gestational age <37 weeks) as a confounder and/or mediator in their models assessing ART with childhood hospitalization. It is widely accepted that ART increases the risk of preterm birth even among singleton gestation (3Pinborg A. Wennerholm U.B. Romundstad L.B. Loft A. Aittomaki K. Söderström-Anttila V. et al.Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis.Hum Reprod Update. 2013; 19: 87-104Crossref PubMed Scopus (464) Google Scholar). Moreover, prematurity is a significant risk factor for ongoing adverse health outcomes among children, including hospitalizations. Given the unequal distribution of prematurity between ART and non-ART groups, it would be important to consider gestational age in multivariable and/or mediation analyses.Finally, given that Quebec has universal health insurance with free coverage for 3 cycles of ART, this study cohort was likely more heterogeneous in sociodemographic composition than most US ART cohorts that have an overrepresentation of non-Hispanic White, privately insured women of higher socioeconomic status. The racial and ethnic data of the study cohort were not available and/or not reported but would be important in comparing outcomes between ART and non-ART groups. In the United States, significant racial and ethnic disparities exist in the general birthing population, with nearly all studies focusing on the general birthing population without explicitly accounting for racial and ethnic disparities in women and infant outcomes among infertile populations (4Centers for Disease Control and PreventionPregnancy mortality surveillance system. Maternal and infant health.https://www.cdc.gov/reproductivehealth/maternal-mortality/pregnancy-mortality-surveillance-system.htmDate accessed: June 3, 2022Google Scholar). In the United States, more than 330,000 cycles of ART were performed in 2019, and ART accounted for nearly 2% of all infants born in the United States (5CDC2019 Assisted reproductive technology (ART) fertility clinic and national summary report.https://www.cdc.gov/art/reports/2019/fertility-clinic.htmlDate accessed: June 3, 2022Google Scholar). Given the continuingly increasing rates of ART use and persistent racial and ethnic disparities in perinatal health, the impact of ART on infant and child health outcomes should be stratified and analyzed by race and ethnicity to identify, measure, and compare the magnitude of ART risk within and across subpopulations.Given the results of this study, how should we consider this 1.23 times adjusted risk for childhood morbidity after ART? When we consider the perspective of birthing individuals, families, and children, the differentiation between the absolute risk and relative risk is critical. At the population level, small differences in relative risk for adverse outcomes can impact a large number of individuals. Indeed, in this study, 2.1% or 4,210 children conceived after ART required hospitalization during the study period, and ART-exposed children were at an approximately 25% greater risk of hospitalization than the non-ART group.However, if one compares the absolute risks between groups, the magnitude of the risk through an individual patient’s perspective may seem less severe. In this study, the absolute incidence rate difference between the ART and non-ART groups was 5.9 hospitalizations per 1000 person-years. Individual patients will have differing opinions on how much risk is too much risk in their decision making related to ART as well as whether they want to consider absolute risk vs. relative risk or both in their decision-making process. Therefore, it is critical for providers to engage with patients in shared decision making about how to interpret data and consider what magnitude of risk for adverse outcomes is meaningful for birthing individuals and their children and families. In the retrospective, population-based study of the association of assisted reproductive technology (ART) with childhood morbidity, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) demonstrated that in a cohort of approximately 800,000 singleton children who were born between 2008 and 2019 in Quebec, Canada, ART exposure was associated with 1.23 times the risk of any hospitalization up to 11 years of age, with the greatest risk being in the first 5 years of life. In this work, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) used several robust methodologic approaches to tackle the difficulties in studying ART as the primary exposure. First, their population-based data source was the Study of Hospital Clientele repository, which contains 100% of inpatient hospitalizations in Quebec, and allowed for the investigation of uncommon outcomes with sufficient power. In general, children do not require frequent and/or repeated hospitalizations; thus, significant differences in outcomes can only be assessed with state/provincial/regional-level datasets. Second, the sibling discordant design attempted to disentangle the impact of ART from confounders, such as social and environmental factors and genetic makeup, that might differ between nonsibling ART-exposed and unexposed groups. Third, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) used a robust approach in which child hospitalization was categorized on the basis of diagnoses, first by pathologies and then by organ systems, to gain more granular understanding of the reasons for hospital admission and recognized that individual International Classification of Diseases, Ninth Revision, and International Classification of Diseases, Tenth Revision, codes cannot be meaningful reported with such a large cohort. However, several notable limitations to this work exist, some of which are highlighted by the investigators in the discussion. First, although the comparison groups are ART vs. non-ART–exposed children, it is well known that the non-ART group includes children who were born after other non-ART fertility treatments, such as pharmacologic therapy or intrauterine insemination. In addition, the non-ART group likely includes some children who were born to women with a previous history of infertility who did not require medical treatment to conceive for the index pregnancy. Thus, the underlying maternal medical conditions that are associated with infertility are likely present in both the groups, albeit to a lesser severity in the non-ART group. This has been demonstrated in a number of articles from the Massachusetts Outcome Study of ART, which created a “subfertile” comparison group of women who did not receive ART but had other indications of infertility in the dataset. These studies demonstrated that the risk of adverse infant and childhood outcomes were greater in the subfertile group than in the fertile group; however, this risk was of lower magnitude when the ART group was compared with the fertile group (2Hwang S.S. Dukhovny D. Gopal D. Cabral H. Missmer S. Diop H. et al.Health of infants after ART-treated, subfertile, and fertile deliveries.Pediatrics. 2018; 142e20174069Crossref Scopus (24) Google Scholar). Thus, one can hypothesize that the results of the study by Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) likely underestimate the difference in outcomes between the ART and non-ART groups. Second, although the discordant sibling analyses attempted to address potential confounders between the ART and non-ART populations in social and environmental factors and genetic makeup of the 2 comparison groups, the maternal medical conditions associated with infertility were likely common “exposures” to both ART and non-ART groups. Similar to the aforementioned discussion of the subfertile group, the non-ART sibling group may have been conceived by non-ART treatments. Here, again, the attenuation of risk in adverse outcomes (compared with the nonsibling analysis) may be due to unmeasured confounding, leading to underestimation of the risk of ART. Third, Wei et al. (1Wei S.Q. Luu T.M. Bilodeau-Bertrand M. Auger N. Assisted reproductive technology and childhood morbidity: a longitudinal cohort study.Fertil Steril. 2022; 118: 360-368Abstract Full Text Full Text PDF Scopus (2) Google Scholar) did not appear to assess preterm birth (gestational age <37 weeks) as a confounder and/or mediator in their models assessing ART with childhood hospitalization. It is widely accepted that ART increases the risk of preterm birth even among singleton gestation (3Pinborg A. Wennerholm U.B. Romundstad L.B. Loft A. Aittomaki K. Söderström-Anttila V. et al.Why do singletons conceived after assisted reproduction technology have adverse perinatal outcome? Systematic review and meta-analysis.Hum Reprod Update. 2013; 19: 87-104Crossref PubMed Scopus (464) Google Scholar). Moreover, prematurity is a significant risk factor for ongoing adverse health outcomes among children, including hospitalizations. Given the unequal distribution of prematurity between ART and non-ART groups, it would be important to consider gestational age in multivariable and/or mediation analyses. Finally, given that Quebec has universal health insurance with free coverage for 3 cycles of ART, this study cohort was likely more heterogeneous in sociodemographic composition than most US ART cohorts that have an overrepresentation of non-Hispanic White, privately insured women of higher socioeconomic status. The racial and ethnic data of the study cohort were not available and/or not reported but would be important in comparing outcomes between ART and non-ART groups. In the United States, significant racial and ethnic disparities exist in the general birthing population, with nearly all studies focusing on the general birthing population without explicitly accounting for racial and ethnic disparities in women and infant outcomes among infertile populations (4Centers for Disease Control and PreventionPregnancy mortality surveillance system. Maternal and infant health.https://www.cdc.gov/reproductivehealth/maternal-mortality/pregnancy-mortality-surveillance-system.htmDate accessed: June 3, 2022Google Scholar). In the United States, more than 330,000 cycles of ART were performed in 2019, and ART accounted for nearly 2% of all infants born in the United States (5CDC2019 Assisted reproductive technology (ART) fertility clinic and national summary report.https://www.cdc.gov/art/reports/2019/fertility-clinic.htmlDate accessed: June 3, 2022Google Scholar). Given the continuingly increasing rates of ART use and persistent racial and ethnic disparities in perinatal health, the impact of ART on infant and child health outcomes should be stratified and analyzed by race and ethnicity to identify, measure, and compare the magnitude of ART risk within and across subpopulations. Given the results of this study, how should we consider this 1.23 times adjusted risk for childhood morbidity after ART? When we consider the perspective of birthing individuals, families, and children, the differentiation between the absolute risk and relative risk is critical. At the population level, small differences in relative risk for adverse outcomes can impact a large number of individuals. Indeed, in this study, 2.1% or 4,210 children conceived after ART required hospitalization during the study period, and ART-exposed children were at an approximately 25% greater risk of hospitalization than the non-ART group. However, if one compares the absolute risks between groups, the magnitude of the risk through an individual patient’s perspective may seem less severe. In this study, the absolute incidence rate difference between the ART and non-ART groups was 5.9 hospitalizations per 1000 person-years. Individual patients will have differing opinions on how much risk is too much risk in their decision making related to ART as well as whether they want to consider absolute risk vs. relative risk or both in their decision-making process. Therefore, it is critical for providers to engage with patients in shared decision making about how to interpret data and consider what magnitude of risk for adverse outcomes is meaningful for birthing individuals and their children and families. Assisted reproductive technology and childhood morbidity: a longitudinal cohort studyFertility and SterilityVol. 118Issue 2PreviewTo evaluate the association between assisted reproductive technology (ART) and offspring morbidity in the first decade of life. Full-Text PDF" @default.
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• W4283728376 title "Assisted reproductive technology and childhood morbidity: How should we measure the risk and what amount of risk is meaningful?" @default.
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