{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:26:59Z","timestamp":1790778419332,"version":"4.1.0"},"reference-count":35,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T00:00:00Z","timestamp":1664236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008403","name":"Finnish Medical Society Duodecim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008403","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,11,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>STUDY QUESTION<\/jats:title>\n                  <jats:p>Is the health of singletons born after frozen embryo transfer (FET) comparable to that of singletons born after fresh embryo transfer (ET) until early adulthood?<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY ANSWER<\/jats:title>\n                  <jats:p>The health of singletons born after FET does not differ from that of singletons born after fresh ET.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WHAT IS KNOWN ALREADY<\/jats:title>\n                  <jats:p>The differences in perinatal outcomes of children born after FET and fresh ET are well known. FET is associated with an increased risk of large-for-gestational-age but diminished risks of preterm birth (PTB), small-for-gestational-age and decreased perinatal mortality compared to fresh ET. However, knowledge on the long-term health after FET is scarce.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY DESIGN, SIZE, DURATION<\/jats:title>\n                  <jats:p>This retrospective register-based cohort study compares singletons born after FET (n\u2009=\u20091825) between the years 1995 and 2006 to those born after fresh ET (n\u2009=\u20092933) and natural conception (NC, n\u2009=\u200931\u200a136) with a mean follow-up time of 18\u201320\u2009years.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>PARTICIPANTS\/MATERIALS, SETTING, METHODS<\/jats:title>\n                  <jats:p>Singletons born after FET were compared to those born after fresh ET and NC regarding the frequencies of diagnoses in the main ICD-10 chapters (International Statistical Classification of Diseases and Related Health Problems, 10th revision), the number of outpatient visits and hospital admissions, and mortality. Adjustments were made for PTB, maternal age, parity, socioeconomic status based on mother\u2019s occupation and offspring sex. The study combines data from the Finnish Medical Birth Register, the Finnish Care Register for Health Care (CRHC) and the Cause-of-Death Register at Statistics Finland. The Student\u2019s T-test was used for continuous variables, and the Chi-square test was used for categorical variables. Cox regression was used to estimate crude and adjusted hazard ratios (HRs and aHRs, respectively). A general linear model was used to compare the means of outpatient visits, hospital admissions and lengths of hospital stays per person.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>MAIN RESULTS AND THE ROLE OF CHANCE<\/jats:title>\n                  <jats:p>No significant differences between the FET and fresh ET groups were found in the frequency of diagnoses in any of the ICD-10 chapters or in the parameters describing the need for hospital care. However, compared to the NC group, higher proportions in the FET group had outpatient visits in the hospital (93.5% vs 92.2%, aHR 1.23, 95% CI 1.17, 1.30) or hospital admissions (48% vs 46.5%, aHR 1.28, 95% CI 1.19, 1.37). Compared to the NC group, the FET group had elevated adjusted risks of diagnoses of infectious and parasitic diseases (aHR 1.24; 95% CI 1.11, 1.38), neoplasms (aHR 1.68; 95% CI 1.48, 1.91), diseases of the eye and adnexa, the ear or mastoid process (aHR 1.11; 95% CI 1.01, 1.21), the respiratory system (aHR 1.15; 95% CI 1.06, 1.23), the digestive system (aHR 1.17; 95% CI 1.05, 1.32), the skin or subcutaneous tissue (aHR 1.28; 95% CI 1.14, 1.43) and the genitourinary system (aHR 1.27; 95% CI 1.11, 1.45), as well as congenital malformations or chromosomal abnormalities (aHR 1.31; 95% CI 1.14, 1.50) and symptoms, signs or abnormal clinical or laboratory findings (aHR 1.25, 95% CI 1.16, 1.34).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>LIMITATIONS, REASONS FOR CAUTION<\/jats:title>\n                  <jats:p>Only hospital-based inpatient and outpatient care is covered by the CRHC register, excluding milder cases diagnosed elsewhere. We were not able to study the effect of ART treatments and subfertility separately in our setting. In addition, although our cohort is reasonably sized, even larger cohorts would be needed to reliably study rare outcomes, such as cancer.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>WIDER IMPLICATIONS OF THE FINDINGS<\/jats:title>\n                  <jats:p>For many ICD-10 chapters, we present the first published data on the long-term outcome of singletons born after FET. The results on FET versus fresh ET are reassuring, whereas the results on FET versus NC warrant further investigation.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>STUDY FUNDING\/COMPETING INTEREST(S)<\/jats:title>\n                  <jats:p>Finnish government research funding was obtained for this study. Funding was also obtained from the Finnish Medical Society Duodecim, the P\u00e4ivikki and Sakari Sohlberg Foundation, Orion Research Foundation, Finnish Society of Obstetrics and Gynaecology (research grants to A.M.T.) and Finnish government research funding. The funding sources were not involved in the planning or execution of the study. The authors have no competing interests to declare.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>TRIAL REGISTRATION NUMBER<\/jats:title>\n                  <jats:p>N\/A.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/humrep\/deac211","type":"journal-article","created":{"date-parts":[[2022,9,27]],"date-time":"2022-09-27T19:39:23Z","timestamp":1664307563000},"page":"2899-2907","source":"Crossref","is-referenced-by-count":11,"title":["Health of singletons born after frozen embryo transfer until early adulthood: a Finnish register study"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3957-3466","authenticated-orcid":false,"given":"A M","family":"Terho","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, PEDEGO Research Unit & Medical Research Center Oulu, Oulu University Hospital, University of Oulu , Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3088-5594","authenticated-orcid":false,"given":"A","family":"Tiitinen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Helsinki University Hospital and University of Helsinki , Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H","family":"Martikainen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, PEDEGO Research Unit & Medical Research Center Oulu, Oulu University Hospital, University of Oulu , Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8254-7525","authenticated-orcid":false,"given":"M","family":"Gissler","sequence":"additional","affiliation":[{"name":"Information Services Department, Finnish Institute for Health and Welfare , Helsinki, Finland"},{"name":"Department of Neurobiology, Care Science and Society, Karolinska Institute , Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6272-7043","authenticated-orcid":false,"given":"S","family":"Pelkonen","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, PEDEGO Research Unit & Medical Research Center Oulu, Oulu University Hospital, University of Oulu , Oulu, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,9,27]]},"reference":[{"key":"2022120105531802400_deac211-B1","doi-asserted-by":"crossref","first-page":"1468","DOI":"10.1016\/j.fertnstert.2021.08.014","article-title":"Do frozen embryo transfers modify the epigenetic control of imprinted genes and transposable elements in newborns compared with fresh embryo transfers and natural conceptions?","volume":"116","author":"Barberet","year":"2021","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B2","doi-asserted-by":"crossref","first-page":"2403","DOI":"10.1093\/humrep\/deab137","article-title":"Association of medically assisted reproduction with offspring cord blood DNA methylation across cohorts","volume":"36","author":"Caramaschi","year":"2021","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B3","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1093\/humrep\/des398","article-title":"Asthma in children born after infertility treatment: Findings from the UK Millennium Cohort Study","volume":"28","author":"Carson","year":"2013","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B4","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1093\/humrep\/dex366","article-title":"The epigenetic control of transposable elements and imprinted genes in newborns is affected by the mode of conception: ART versus spontaneous conception without underlying infertility","volume":"33","author":"Choux","year":"2018","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B5","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1007\/s00404-020-05593-4","article-title":"Neonatal outcomes in singleton pregnancies conceived by fresh or frozen embryo transfer compared to spontaneous conceptions: a systematic review and meta-analysis","volume":"302","author":"Elias","year":"2020","journal-title":"Arch Gynecol Obstet"},{"key":"2022120105531802400_deac211-B6","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/j.fertnstert.2016.05.006","article-title":"Assisted reproductive technology alters deoxyribonucleic acid methylation profiles in bloodspots of newborn infants","volume":"106","author":"Estill","year":"2016","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B7","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.fertnstert.2012.10.034","article-title":"Maternal fecundity and asthma among offspring\u2014is the risk programmed preconceptionally? Retrospective observational study","volume":"99","author":"Harju","year":"2013","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B8","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1016\/j.fertnstert.2019.07.010","article-title":"Health outcomes for Massachusetts infants after fresh versus frozen embryo transfer","volume":"112","author":"Hwang","year":"2019","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B9","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1016\/j.fertnstert.2016.09.009","article-title":"Fertility treatment and childhood type 1 diabetes mellitus: a nationwide cohort study of 565,116 live births","volume":"106","author":"Kettner","year":"2016","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B10","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1111\/ijd.13903","article-title":"Long-term pediatric skin eruption-related hospitalizations in offspring conceived via fertility treatment","volume":"57","author":"Krieger","year":"2018","journal-title":"Int J Dermatol"},{"key":"2022120105531802400_deac211-B11","doi-asserted-by":"crossref","first-page":"653","DOI":"10.1080\/15592294.2017.1336589","article-title":"Placental imprinting variation associated with assisted reproductive technologies and subfertility","volume":"12","author":"Litzky","year":"2017","journal-title":"Epigenetics"},{"key":"2022120105531802400_deac211-B12","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1136\/thoraxjnl-2018-211886","article-title":"Maternal history of miscarriages and measures of fertility in relation to childhood asthma","volume":"74","author":"Magnus","year":"2019","journal-title":"Thorax"},{"key":"2022120105531802400_deac211-B13","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1093\/humupd\/dmx031","article-title":"Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer?","volume":"24","author":"Maheshwari","year":"2018","journal-title":"Hum Reprod Update"},{"key":"2022120105531802400_deac211-B14","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1093\/humrep\/dez227","article-title":"Type 1 diabetes in children born after assisted reproductive technology: a register-based national cohort study","volume":"35","author":"Norrman","year":"2020","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B15","author":"Official Statistics of Finland (OSF): Causes of death","year":"2022"},{"key":"2022120105531802400_deac211-B16","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1093\/humrep\/dev203","article-title":"Physical health of singleton children born after frozen embryo transfer using slow freezing: a 3-year follow-up study","volume":"30","author":"Pelkonen","year":"2015","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B17","doi-asserted-by":"crossref","first-page":"1552","DOI":"10.1093\/humrep\/deu088","article-title":"Major congenital anomalies in children born after frozen embryo transfer: a cohort study 1995-2006","volume":"29","author":"Pelkonen","year":"2014","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B18","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1093\/humrep\/dep477","article-title":"Perinatal outcome of children born after frozen and fresh embryo transfer: the Finnish cohort study 1995-2006","volume":"25","author":"Pelkonen","year":"2010","journal-title":"Human Reproduction"},{"key":"2022120105531802400_deac211-B19","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1093\/humrep\/deab078","article-title":"DNA methylation patterns within whole blood of adolescents born from assisted reproductive technology are not different from adolescents born from natural conception","volume":"36","author":"Penova-Veselinovic","year":"2021","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B20","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1186\/s12887-021-03103-2","article-title":"Maternal advanced age, single parenthood, and ART increase the risk of child morbidity up to five years of age","volume":"22","author":"Pettersson","year":"2022","journal-title":"BMC Pediatr"},{"key":"2022120105531802400_deac211-B21","doi-asserted-by":"crossref","first-page":"1026","DOI":"10.1016\/j.fertnstert.2022.01.010","article-title":"The neurodevelopmental morbidity of children born after assisted reproductive technology: a Nordic register study from the Committee of Nordic Assisted Reproductive Technology and Safety group","volume":"117","author":"R\u00f6n\u00f6","year":"2022","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B22","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.fertnstert.2017.10.019","article-title":"Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis","volume":"109","author":"Sha","year":"2018","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B23","doi-asserted-by":"crossref","first-page":"105021","DOI":"10.1016\/j.earlhumdev.2020.105021","article-title":"Fertility treatments and gastrointestinal morbidity of the offspring","volume":"144","author":"Shachor","year":"2020","journal-title":"Early Hum Dev"},{"key":"2022120105531802400_deac211-B24","doi-asserted-by":"crossref","first-page":"e190392","DOI":"10.1001\/jamapediatrics.2019.0392","article-title":"Association of in vitro fertilization with childhood cancer in the United States","volume":"173","author":"Spector","year":"2019","journal-title":"JAMA Pediatr"},{"key":"2022120105531802400_deac211-B25","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1177\/1403494812456637","article-title":"Quality of the Finnish Hospital Discharge Register: a systematic review","volume":"40","author":"Sund","year":"2012","journal-title":"Scand J Public Health"},{"key":"2022120105531802400_deac211-B26","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1093\/humrep\/deaa304","article-title":"High birth weight and large-for-gestational-age in singletons born after frozen compared to fresh embryo transfer, by gestational week: a Nordic register study from the CoNARTaS group","volume":"36","author":"Terho","year":"2021","journal-title":"Hum Reprod"},{"key":"2022120105531802400_deac211-B27","author":"THL","year":"2019"},{"key":"2022120105531802400_deac211-B28","author":"THL","year":"2021"},{"key":"2022120105531802400_deac211-B29","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1017\/S2040174420000938","article-title":"Assisted reproductive technology and long-term ophthalmic morbidity of the offspring","volume":"12","author":"Tsumi","year":"2021","journal-title":"J Dev Orig Health Dis"},{"key":"2022120105531802400_deac211-B30","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1016\/j.fertnstert.2019.07.1325","article-title":"Fertility treatments and offspring pediatric infectious morbidities: results of a population-based cohort with a median follow-up of 10 years","volume":"112","author":"Wainstock","year":"2019","journal-title":"Fertil Steril"},{"key":"2022120105531802400_deac211-B31","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1001\/jamapsychiatry.2021.3647","article-title":"Long-term follow-up of psychiatric disorders in children and adolescents conceived by assisted reproductive techniques in Sweden","volume":"79","author":"Wang","year":"2022","journal-title":"JAMA Psychiatry"},{"key":"2022120105531802400_deac211-B32","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1093\/humupd\/dmab031","article-title":"Asthma and allergies in offspring conceived by ART: a systematic review and meta-analysis","volume":"28","author":"Wijs","year":"2021","journal-title":"Hum Reprod Update"},{"key":"2022120105531802400_deac211-B33","doi-asserted-by":"crossref","first-page":"hoaa032","DOI":"10.1093\/hropen\/hoaa032","article-title":"ART in Europe, 2016: results generated from European registries by ESHRE","volume":"2020","author":"Wyns","year":"2020","journal-title":"Hum Reprod Open"},{"key":"2022120105531802400_deac211-B34","doi-asserted-by":"crossref","first-page":"hoab026","DOI":"10.1093\/hropen\/hoab026","article-title":"ART in Europe, 2017: results generated from European registries by ESHRE","volume":"2021","author":"Wyns","year":"2021","journal-title":"Hum Reprod Open"},{"key":"2022120105531802400_deac211-B35","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/j.ejca.2020.08.001","article-title":"The association between fertility treatments and the incidence of paediatric cancer: a systematic review and meta-analysis","volume":"138","author":"Zhang","year":"2020","journal-title":"Eur J Cancer"}],"container-title":["Human Reproduction"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/37\/12\/2899\/47257333\/deac211.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/humrep\/article-pdf\/37\/12\/2899\/47257333\/deac211.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,1]],"date-time":"2022-12-01T05:53:37Z","timestamp":1669874017000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/humrep\/article\/37\/12\/2899\/6724349"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,9,27]]},"references-count":35,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,9,27]]},"published-print":{"date-parts":[[2022,11,24]]}},"URL":"https:\/\/doi.org\/10.1093\/humrep\/deac211","relation":{},"ISSN":["0268-1161","1460-2350"],"issn-type":[{"value":"0268-1161","type":"print"},{"value":"1460-2350","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,12,1]]},"published":{"date-parts":[[2022,9,27]]}}}