{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:53:35Z","timestamp":1774529615056,"version":"3.50.1"},"reference-count":144,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":3,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,1]],"date-time":"2026-03-01T00:00:00Z","timestamp":1772323200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Birth Defects Research"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>No consistent genetic etiology has been found for a group of six different conditions in humans with multiple malformations called \u201crecurrent constellations of embryonic malformations\u201d (RCEM). Recent studies indicate hypoxia\/reoxygenation and generation Reactive Oxygen Species (ROS) as an underlying mechanism for RCEM with the specific manifestations related to the timing, severity and duration of the ROS exposure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Medical literature was evaluated in relation to a hypoxia\/ROS related mechanism for RCEM. Special attention was paid to investigate if the reported spectrum of multiple human malformations for Hormone Pregnancy Tests (HPTs), which have been associated with embryonic hypoxia due abnormal uterine contractions in early pregnancy, agrees with the RCEM spectrum.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The pattern of human multiple and single malformations associated with HPTs in 44 case reports with multiple defects, 86% (38\/44) were consistent with RCEM spectrum, the most common was VACTERL. There was also a high consistency with regards to increases in single HPT malformations within the RCEM spectrum in a large case report study (&gt;\u2009225 cases) and in more than 25 human epidemiological studies evaluating HPT teratogenicity. The RCEM spectrum is also consistent with reported malformations when the embryo has been exposed to periods of transient embryonic hypoxia\/ROS in animal studies and when exposed to drugs associated with embryonic hypoxia\/ROS (e.g., cocaine) and in some genetic diseases with malformations (e.g., NAD+ deficiency) when ROS overwhelms the antioxidant defense.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>This review shows that HPTs are associated with human teratogenicity and ROS to be the proximate teratogen underlying RCEM.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bdr2.70036","type":"journal-article","created":{"date-parts":[[2026,3,9]],"date-time":"2026-03-09T03:01:34Z","timestamp":1773025294000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Recurrent Constellations of Embryonic Malformations (\n                    <scp>RCEM<\/scp>\n                    ): Teratogenicity Linked to Transient Hypoxia and Hormone Pregnancy Tests Agrees With\n                    <scp>RCEM<\/scp>\n                    and Suggest a Reactive Oxygen Species Pathogenesis"],"prefix":"10.1002","volume":"118","author":[{"given":"Aaron P.","family":"Adam","sequence":"first","affiliation":[{"name":"Seattle Children\u2019s Research Institute  Seattle Washington US"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9794-5702","authenticated-orcid":false,"given":"Helen E.","family":"Ritchie","sequence":"additional","affiliation":[{"name":"School of Medical Sciences, Faculty of Medicine and Health University of Sydney  Sydney New South Wales Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Margaret P.","family":"Adam","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Pediatrics University of Washington  Seattle Washington USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bengt R.","family":"Danielsson","sequence":"additional","affiliation":[{"name":"Division of Clinical Pharmacology Karolinska Institute  Stockholm Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,4]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.61847"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62235"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.1276"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2015.08.005"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mrfmmm.2009.01.013"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1528-1157.2002.28999.x"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2013.287"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.63582"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-0773.2000.pto870209.x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/299271a0"},{"key":"e_1_2_6_12_1","unstructured":"Beynon J. andS.Seabroke.2017.\u201cExpert Working Group on Hormonal Pregnancy Tests.\u201dAnnex 24. 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