{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T21:16:51Z","timestamp":1781126211996,"version":"3.54.1"},"reference-count":42,"publisher":"BMJ","issue":"9","license":[{"start":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T00:00:00Z","timestamp":1632182400000},"content-version":"unspecified","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Amsterdam Reproduction & Development (AR&D) Institute","award":["v.000296"],"award-info":[{"award-number":["v.000296"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2021,8,27]]},"published-print":{"date-parts":[[2021,9]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Preterm birth is one of the main problems in obstetrics, and the most important cause of neonatal mortality, morbidity and neurodevelopmental impairment. Multiple gestation is an important risk factor for preterm birth, with up to 50% delivering before 37 weeks. Progesterone has a role in maintaining pregnancy and is frequently prescribed to prevent (recurrent) preterm birth and improve pregnancy outcomes in high-risk patients. However, little is known about its long-term effects in multiple gestations. The objective of this follow-up study is to assess long-term benefits and harms of prenatal exposure to progesterone treatment in multiple gestations on child development.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>\n                      This is a follow-up study of a multicentre, double-blind, placebo-controlled randomised trial (AMPHIA trial,\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"isrctn\" xlink:href=\"40512715\">ISRCTN40512715<\/jats:ext-link>\n                      ). Between 2006 and 2009 women with a multiple gestation were randomised at 16\u201320 weeks of gestation to weekly injections 250\u2009mg 17\u03b1-hydroxyprogesterone caproate or placebo, until 36 weeks of gestation or delivery. The current long-term follow-up will assess all children (n=1355) born to mothers who participated in the AMPHIA trial, at 11\u201314 years of age, with internationally validated questionnaires, completed by themselves, their parents and their teachers.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Main outcomes are child cognition and behaviour<\/jats:title>\n                    <jats:p>Additional outcomes are death (perinatal and up to age 14), gender identity, educational performance and health-related problems. We will use intention-to-treat analyses comparing experimental and placebo group. To adjust for the correlation between twins, general linear mixed-effects models will be used.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>Amsterdam UMC MEC provided a waiver for the Medical Research Involving Human Subjects Act (W20_234#20.268). Results will be disseminated through peer-reviewed journals and summaries shared with stakeholders, patients and participants. This protocol is published before analysis of the results.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>NL8933.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2021-053066","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T13:59:45Z","timestamp":1632232785000},"page":"e053066","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Long-term follow-up of children exposed in-utero to progesterone treatment for prevention of preterm birth: study protocol of the AMPHIA follow-up"],"prefix":"10.1136","volume":"11","clinical-trial-number":[{"clinical-trial-number":"isrctn40512715","registry":"10.18810\/isrctn"},{"clinical-trial-number":"isrctn40512715","registry":"10.18810\/isrctn"},{"clinical-trial-number":"isrctn40512715","registry":"10.18810\/isrctn"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9109-0800","authenticated-orcid":false,"given":"Noor E","family":"Simons","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development, Amsterdam UMC Location AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie V J","family":"van Limburg Stirum","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Amsterdam Reproduction & Development, Amsterdam UMC Location AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleid G","family":"van Wassenaer-Leemhuis","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Paediatrics, Emma Children\"s Hospital, Amsterdam Reproduction & Development, Amsterdam UMC Location AMC, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-9788","authenticated-orcid":false,"given":"Martijn J J","family":"Finken","sequence":"additional","affiliation":[{"name":"Department of Paediatric Endocrinology, Emma Children\"s Hospital Amsterdam, Amsterdam Reproduction & Development, Amsterdam UMC Location VUmc, Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cornelieke S H","family":"Aarnoudse-Moens","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Paediatrics, Emma Children\"s Hospital, Amsterdam Reproduction & Development, Amsterdam UMC Location AMC, Amsterdam, The 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