Catherine M Castillo1,2, Gregory Horne3, Cheryl T Fitzgerald1,3, Edward D Johnstone1,2, Daniel R Brison1,2,3, Stephen A Roberts4. 1. Maternal & Fetal Health Research Centre, Division of Developmental Biology and Medicine, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Sciences Centre, Oxford Rd., Manchester, UK. 2. Maternal & Fetal Health Research Centre, St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Oxford Rd., Manchester, UK. 3. Department of Reproductive Medicine, Old St. Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Sciences Centre, Oxford Rd., Manchester, UK. 4. Centre for Biostatistics, Division of Population Health, Health Services Research & Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Oxford Rd., Manchester, UK.
Abstract
STUDY QUESTION: Has birthweight (BW) changed over time among IVF-conceived singletons? SUMMARY ANSWER: Singleton BW has increased markedly over the past 25 years. WHAT IS KNOWN ALREADY: IVF conceived singletons have had a higher incidence of low BW compared to spontaneously conceived singletons, and this has raised concerns over long-term increased risks of cardio-metabolic disease. However, few causal links between IVF procedures and BW have been robustly established, and few studies have examined whether BW has changed over time as IVF techniques have developed. STUDY DESIGN, SIZE, DURATION: A total of 2780 live born singletons conceived via IVF or ICSI treated in the reproductive medicine department of a single publicly funded tertiary care centre between 1991 and 2015 were included in this retrospective study. The primary outcome measure was singleton BW adjusted for gestational age, maternal parity and child gender. Multivariable linear regression models were used to estimate the associations between patient prognostic factors and IVF treatment procedures with adjusted BW. PARTICIPANTS/MATERIALS, SETTING, METHODS: All singletons conceived at the centre following IVF/ICSI using the mother's own oocytes, and non-donated fresh or frozen/thawed embryos with complete electronic data records, were investigated. Available electronic records were retrieved from the Human Fertilization and Embryology Authority for dataset collation. Multiple linear regression analysis was used to evaluate associations between IVF treatment parameters and BW, after adjusting for the year of treatment and patient characteristics and pregnancy factors. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary multivariable model, singleton BW increased by 7.4 g per year (95% CI: 3.2-11.6 g, P = 0.001), an increase of close to 180 g throughout the 25-year period after accounting for gestational age, maternal parity, child gender, IVF treatment parameters, patient prognostic characteristics and pregnancy factors. Fresh and frozen embryo transfer-conceived singletons showed a similar increase in BW. Frozen/thawed embryo transfer conceived singletons were on average 53 g heavier than their fresh embryo conceived counterparts (95% CI: 3.7-103.3 g, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: The independent variables included in the study were limited to those that have been consistently recorded and stored electronically over the past two decades. WIDER IMPLICATIONS OF THE FINDINGS: There has been a progressive BW increase in IVF singletons over time in one large centre with consistent treatment eligibility criteria. Such a change is not seen in the general population of live born singletons in the UK or other developed countries, and seems to be specific to this IVF population. This may be a reflection of changes in practice such as undisturbed extended embryo culture to the blastocyst stage, optimized commercial culture media composition, single embryo transfer and ICSI. Moreover, singletons conceived from frozen/thawed embryos had higher birth weights when compared to their fresh embryo transfer counterparts. The causal pathway is unknown; however, it could be due to the impact on embryos of the freeze/thaw process, self-selection of embryos from couples who produce a surplus of embryos, and/or embryo replacement into a more receptive maternal environment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the EU FP7 project grant, EpiHealthNet (FP7-PEOPLE-2012-ITN-317146). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.
STUDY QUESTION: Has birthweight (BW) changed over time among IVF-conceived singletons? SUMMARY ANSWER: Singleton BW has increased markedly over the past 25 years. WHAT IS KNOWN ALREADY: IVF conceived singletons have had a higher incidence of low BW compared to spontaneously conceived singletons, and this has raised concerns over long-term increased risks of cardio-metabolic disease. However, few causal links between IVF procedures and BW have been robustly established, and few studies have examined whether BW has changed over time as IVF techniques have developed. STUDY DESIGN, SIZE, DURATION: A total of 2780 live born singletons conceived via IVF or ICSI treated in the reproductive medicine department of a single publicly funded tertiary care centre between 1991 and 2015 were included in this retrospective study. The primary outcome measure was singleton BW adjusted for gestational age, maternal parity and child gender. Multivariable linear regression models were used to estimate the associations between patient prognostic factors and IVF treatment procedures with adjusted BW. PARTICIPANTS/MATERIALS, SETTING, METHODS: All singletons conceived at the centre following IVF/ICSI using the mother's own oocytes, and non-donated fresh or frozen/thawed embryos with complete electronic data records, were investigated. Available electronic records were retrieved from the Human Fertilization and Embryology Authority for dataset collation. Multiple linear regression analysis was used to evaluate associations between IVF treatment parameters and BW, after adjusting for the year of treatment and patient characteristics and pregnancy factors. MAIN RESULTS AND THE ROLE OF CHANCE: In the primary multivariable model, singleton BW increased by 7.4 g per year (95% CI: 3.2-11.6 g, P = 0.001), an increase of close to 180 g throughout the 25-year period after accounting for gestational age, maternal parity, child gender, IVF treatment parameters, patient prognostic characteristics and pregnancy factors. Fresh and frozen embryo transfer-conceived singletons showed a similar increase in BW. Frozen/thawed embryo transfer conceived singletons were on average 53 g heavier than their fresh embryo conceived counterparts (95% CI: 3.7-103.3 g, P = 0.035). LIMITATIONS, REASONS FOR CAUTION: The independent variables included in the study were limited to those that have been consistently recorded and stored electronically over the past two decades. WIDER IMPLICATIONS OF THE FINDINGS: There has been a progressive BW increase in IVF singletons over time in one large centre with consistent treatment eligibility criteria. Such a change is not seen in the general population of live born singletons in the UK or other developed countries, and seems to be specific to this IVF population. This may be a reflection of changes in practice such as undisturbed extended embryo culture to the blastocyst stage, optimized commercial culture media composition, single embryo transfer and ICSI. Moreover, singletons conceived from frozen/thawed embryos had higher birth weights when compared to their fresh embryo transfer counterparts. The causal pathway is unknown; however, it could be due to the impact on embryos of the freeze/thaw process, self-selection of embryos from couples who produce a surplus of embryos, and/or embryo replacement into a more receptive maternal environment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the EU FP7 project grant, EpiHealthNet (FP7-PEOPLE-2012-ITN-317146). The authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.
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