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      The longer-term effects of IVF on offspring from childhood to adolescence

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          Abstract

          It is well established that there are increased pregnancy-related complications for a woman who conceives through assisted reproductive treatment (ART). Furthermore, it is known that the risk to the child born is greater, believed to be related to prematurity and growth restriction. Studies have also reported epigenetic changes in the DNA of offspring conceived through ART. In addition, it is believed that they have a greater risk of congenital malformations, although some of these risks may relate to underlying infertility, rather than the ART treatment per se. As a result, it may be expected that there is a greater risk to the longer-term health of the child who is born from ART; however, evidence about the long-term health of children conceived through ART is reassuring. Even though, it is recognised that many of the studies in this field come with limitations. Low numbers of participants is one of the major limitations, which makes subgroup analyses for diverse types of ART, or diverse types of infertility, not feasible. Furthermore, studies are often limited by short follow-up periods because of the difficulty and costs involved in longitudinal study designs. In addition, the rapid changes over time in ART limit the generalisability and significance of long-term findings. Well-designed studies investigating the long-term health outcomes of ART-conceived offspring and the potential influences of various aspects of the ART procedure, as well as studies of the potential underlying epigenetic mechanisms, are imperative. Furthermore, conclusions from childhood hospitalisation data from the United Kingdom, the long-term follow-up and quality of life study from researchers in Melbourne, and the data published from the Western Australian Growing Up Healthy Study will go a long way to help reassure current and prospective parents who may require ART to conceive.

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          Most cited references66

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          Origins of lifetime health around the time of conception: causes and consequences

          Parental environmental factors including diet, body composition, metabolism and stress affect the health and chronic disease risk of people throughout their lives, as captured in the ‘Developmental Origins of Health and Disease’ (DOHaD) concept. Research across epidemiological, clinical and basic science fields has identified the period around conception as being critical in the processes mediating parental influences on the next generation’s health. During this time, from the maturation of gametes through to early embryonic development, parental lifestyle can adversely influence long-term risks of offspring cardiovascular, metabolic, immune and neurological morbidities, often termed ‘developmental programming’. We review ‘periconceptional’ induction of disease risk from four broad exposures: maternal overnutrition and obesity; maternal undernutrition; related paternal factors; and from the use of assisted reproductive treatment. Human studies and animal models demonstrate the underlying biological mechanisms, including epigenetic, cellular, physiological and metabolic processes. A novel meta-analysis of mouse paternal and maternal protein undernutrition indicate distinct parental periconceptional contributions to postnatal outcomes. We propose that the evidence for periconceptional effects on lifetime health is now so compelling that it calls for new guidance on parental preparation for pregnancy, beginning before conception, to protect the health of offspring.
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            Obstetric and perinatal outcomes in singleton pregnancies resulting from IVF/ICSI: a systematic review and meta-analysis.

            Earlier reviews have suggested that IVF/ICSI pregnancies are associated with higher risks. However, there have been recent advances in the way IVF/ICSI is done, leading to some controversy as to whether IVF/ICSI singletons are associated with higher perinatal risks. The objective of this systematic review was to provide an up-to-date comparison of obstetric and perinatal outcomes of the singletons born after IVF/ICSI and compare them with those of spontaneous conceptions. Extensive searches were done by two authors. The protocol was agreed a priori. PRISMA guidance was followed. The data were extracted in 2 × 2 tables. Risk ratio and risk difference were calculated on pooled data using Rev Man 5.1. Quality assessment of studies was performed using Critical Appraisal Skills programme. Sensitivity analysis was performed when the heterogeneity was high (I(2) > 50%). There were 20 matched cohort studies and 10 unmatched cohort studies included in this review. IVF/ICSI singleton pregnancies were associated with a higher risk (95% confidence interval) of ante-partum haemorrhage (2.49, 2.30-2.69), congenital anomalies (1.67, 1.33-2.09), hypertensive disorders of pregnancy (1.49, 1.39-1.59), preterm rupture of membranes (1.16, 1.07-1.26), Caesarean section (1.56, 1.51-1.60), low birthweight (1.65, 1.56-1.75), perinatal mortality (1.87, 1.48-2.37), preterm delivery (1.54, 1.47-1.62), gestational diabetes (1.48, 1.33-1.66), induction of labour (1.18, 1.10-1.28) and small for gestational age (1.39, 1.27-1.53). Singletons pregnancies after IVF/ICSI are associated with higher risks of obstetric and perinatal complications when compared with spontaneous conception. Further research is needed to determine which aspect of assisted reproduction technology poses most risk and how this risk can be minimized.
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              Reproductive technologies and the risk of birth defects.

              The extent to which birth defects after infertility treatment may be explained by underlying parental factors is uncertain. We linked a census of treatment with assisted reproductive technology in South Australia to a registry of births and terminations with a gestation period of at least 20 weeks or a birth weight of at least 400 g and registries of birth defects (including cerebral palsy and terminations for defects at any gestational period). We compared risks of birth defects (diagnosed before a child's fifth birthday) among pregnancies in women who received treatment with assisted reproductive technology, spontaneous pregnancies (i.e., without assisted conception) in women who had a previous birth with assisted conception, pregnancies in women with a record of infertility but no treatment with assisted reproductive technology, and pregnancies in women with no record of infertility. Of the 308,974 births, 6163 resulted from assisted conception. The unadjusted odds ratio for any birth defect in pregnancies involving assisted conception (513 defects, 8.3%) as compared with pregnancies not involving assisted conception (17,546 defects, 5.8%) was 1.47 (95% confidence interval [CI], 1.33 to 1.62); the multivariate-adjusted odds ratio was 1.28 (95% CI, 1.16 to 1.41). The corresponding odds ratios with in vitro fertilization (IVF) (165 birth defects, 7.2%) were 1.26 (95% CI, 1.07 to 1.48) and 1.07 (95% CI, 0.90 to 1.26), and the odds ratios with intracytoplasmic sperm injection (ICSI) (139 defects, 9.9%) were 1.77 (95% CI, 1.47 to 2.12) and 1.57 (95% CI, 1.30 to 1.90). A history of infertility, either with or without assisted conception, was also significantly associated with birth defects. The increased risk of birth defects associated with IVF was no longer significant after adjustment for parental factors. The risk of birth defects associated with ICSI remained increased after multivariate adjustment, although the possibility of residual confounding cannot be excluded. (Funded by the National Health and Medical Research Council and the Australian Research Council.).
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                Author and article information

                Contributors
                Journal
                Front Reprod Health
                Front Reprod Health
                Front. Reprod. Health
                Frontiers in Reproductive Health
                Frontiers Media S.A.
                2673-3153
                2673-3153
                08 December 2022
                2022
                : 4
                : 1045762
                Affiliations
                [ 1 ]Division of Obstetrics and Gynaecology, University of Western Australia , Perth, WA, Australia
                [ 2 ]Fertility Specialists of Western Australia, Bethesda Hospital , Claremont, WA, Australia
                [ 3 ]City Fertility Clinic , Brisbane, QLD, Australia
                Author notes

                Edited by: Theologos M. Michaelidis, University of Ioannina, Greece

                Reviewed by: David Yiu Leung Chan, The Chinese University of Hong Kong, China

                [* ] Correspondence: R. J. Hart roger.hart@ 123456uwa.edu.au

                Specialty Section: This article was submitted to Assisted Reproduction, a section of the journal Frontiers in Reproductive Health

                Article
                10.3389/frph.2022.1045762
                9773093
                36570043
                88696713-b8ea-4408-8727-17d7803bc67e
                © 2022 Hart and Wijs.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 21 September 2022
                : 15 November 2022
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 68, Pages: 0, Words: 0
                Funding
                Funded by: NHMRC, doi 10.13039/501100000925;
                Award ID: 1042269
                Categories
                Reproductive Health
                Mini Review

                ivf,long-term,adolescent,outcome,offspring,health,children,assisted reproductive technologies (art)

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