{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T07:59:10Z","timestamp":1793174350834,"version":"4.5.0"},"update-to":[{"DOI":"10.12688\/f1000research.16758.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T00:00:00Z","timestamp":1548720000000}}],"reference-count":30,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T00:00:00Z","timestamp":1548720000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["ProjectNumber390"],"award-info":[{"award-number":["ProjectNumber390"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p><ns3:bold>Background: <\/ns3:bold>Oral hormone pregnancy tests (HPTs), such as Primodos, containing ethinylestradiol and high doses of norethisterone, were given to over a million women from 1958 to 1978, when Primodos was withdrawn from the market because of concerns about possible teratogenicity. We aimed to study the association between maternal exposure to oral HPTs and congenital malformations.<\/ns3:p><ns3:p> <ns3:bold>Methods:<\/ns3:bold> We have performed a systematic review and meta-analysis of case-control and cohort studies that included data from pregnant women and were exposed to oral HPTs within the estimated first three months of pregnancy, if compared with a relevant control group. We used random-effects meta-analysis and assessed the quality of each study using the Newcastle\u2013Ottawa Scale for non-randomized studies.<\/ns3:p><ns3:p> <ns3:bold>Results: <\/ns3:bold>We found 16 case control studies and 10 prospective cohort studies, together including 71\u00a0330 women, of whom 4,209 were exposed to HPTs. Exposure to oral HPTs was associated with a 40% increased risk of all congenital malformations: pooled odds ratio (OR) = 1.40 (95% CI 1.18 to 1.66; P&lt;0.0001; I<ns3:sup>2<\/ns3:sup> = 0%). Exposure to HPTs was associated with an increased risk of congenital heart malformations: pooled OR = 1.89 (95% CI 1.32 to 2.72; P = 0.0006; I<ns3:sup>2<\/ns3:sup>=0%); nervous system malformations \u00a0OR = 2.98 (95% CI 1.32 to 6.76; P = 0.0109 I<ns3:sup>2<\/ns3:sup> = 78%); gastrointestinal malformations, OR = 4.50 (95% CI 0.63 to 32.20; P = 0.13; I<ns3:sup>2<\/ns3:sup> = 54%); musculoskeletal malformations, OR = 2.24 (95% CI 1.23 to 4.08; P= 0.009; I<ns3:sup>2<\/ns3:sup> = 0%); the VACTERL syndrome (Vertebral defects, Anal atresia, Cardiovascular anomalies, Tracheoesophageal fistula, Esophageal atresia, Renal anomalies, and Limb defects), OR = 7.47 (95% CI 2.92 to 19.07; P &lt; 0.0001; I<ns3:sup>2<\/ns3:sup> = 0%).<\/ns3:p><ns3:p> <ns3:bold>Conclusions:<\/ns3:bold> This systematic review and meta-analysis shows that use of oral HPTs in pregnancy is associated with increased risks of congenital malformations.<\/ns3:p>","DOI":"10.12688\/f1000research.16758.2","type":"journal-article","created":{"date-parts":[[2019,1,29]],"date-time":"2019-01-29T11:17:11Z","timestamp":1548760631000},"page":"1725","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis"],"prefix":"10.12688","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1009-1992","authenticated-orcid":false,"given":"Carl J.","family":"Heneghan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey K.","family":"Aronson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Spencer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bennett","family":"Holman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal R.","family":"Mahtani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2418-2091","authenticated-orcid":false,"given":"Rafael","family":"Perera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2420-0811","authenticated-orcid":false,"given":"Igho","family":"Onakpoya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2019,1,29]]},"reference":[{"key":"ref-1","doi-asserted-by":"publisher","first-page":"34-44","DOI":"10.1016\/j.rbms.2018.09.003","article-title":"A historical argument for regulatory failure in the case of Primodos and other hormone pregnancy tests.","volume":"6","author":"J Olszynko-Gryn","year":"2018","journal-title":"Reprod Biomed Soc Online."},{"key":"ref-2","article-title":"Medicines and Healthcare products Regulatory Agency. 2015 Call for Evidence."},{"key":"ref-3","article-title":"Report of the Commission on Human Medicines\u2019 Expert Working Group on Hormone Pregnancy Tests."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1136\/bmj.2.4989.419","article-title":"Pregnancy test.","volume":"2","author":"H Britton","year":"1956","journal-title":"Br Med J."},{"key":"ref-5","article-title":"Review launched to respond to patient concerns about NHS treatments."},{"key":"ref-6","article-title":"Ottawa Hospital Research Institute"},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1186\/1471-2377-13-41","article-title":"Surgery and risk for multiple sclerosis: a systematic review and meta-analysis of case-control studies.","volume":"13","author":"C Lunny","year":"2013","journal-title":"BMC Neurol."},{"key":"ref-8","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1016\/S0895-4356(99)00226-7","article-title":"Re-analysis of previous meta-analysis of clinical trials of homeopathy.","volume":"53","author":"E Ernst","year":"2000","journal-title":"J Clin Epidemiol."},{"key":"ref-9","doi-asserted-by":"publisher","first-page":"61-6","DOI":"10.1136\/bmj.316.7124.61","article-title":"meta-analysis bias in location and selection of studies.","volume":"316","author":"M Egger","year":"1998","journal-title":"BMJ."},{"key":"ref-10","doi-asserted-by":"publisher","first-page":"1539-58","DOI":"10.1002\/sim.1186","article-title":"Quantifying heterogeneity in a meta-analysis.","volume":"21","author":"J Higgins","year":"2002","journal-title":"Stat Med."},{"key":"ref-11","doi-asserted-by":"publisher","first-page":"2008-12","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group.","volume":"283","author":"D Stroup","year":"2000","journal-title":"JAMA."},{"key":"ref-12","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1038\/216083a0","article-title":"Hormonal pregnancy tests and congenital malformation.","volume":"216","author":"I Gal","year":"1967","journal-title":"Nature."},{"key":"ref-13","doi-asserted-by":"publisher","first-page":"241-2","DOI":"10.1038\/240241a0","article-title":"Risks and benefits of the use of hormonal pregnancy test tablets.","volume":"240","author":"I Gal","year":"1972","journal-title":"Nature."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"2917","DOI":"10.1038\/s41598-018-21318-9","article-title":"The Primodos components Norethisterone acetate and Ethinyl estradiol induce developmental abnormalities in zebrafish embryos.","volume":"8","author":"S Brown","year":"2018","journal-title":"Sci Rep."},{"key":"ref-15","doi-asserted-by":"publisher","first-page":"53-61","DOI":"10.1006\/rtph.2001.1483","article-title":"Pharmacology and toxicology of ethinyl estradiol and norethindrone acetate in experimental animals.","volume":"34","author":"W Maier","year":"2001","journal-title":"Regul Toxicol Pharmacol."},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"165-70","DOI":"10.1016\/j.fertnstert.2003.05.028","article-title":"Effects of levonorgestrel, medroxyprogesterone acetate, norethindrone, and 17beta-estradiol on vascular endothelial growth factor isomers 121 and 165 in Ishikawa cells.","volume":"81","author":"D Archer","year":"2004","journal-title":"Fertil Steril."},{"key":"ref-17","article-title":"OCEBM Levels of Evidence","year":"2016"},{"key":"ref-18","doi-asserted-by":"publisher","first-page":"51-63","DOI":"10.1016\/0021-9681(79)90012-2","article-title":"Bias in analytic research.","volume":"32","author":"D Sackett","year":"1979","journal-title":"J Chronic Dis."},{"key":"ref-19","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2012-001368","article-title":"Inter-rater and test-retest reliability of quality assessments by novice student raters using the Jadad and Newcastle-Ottawa Scales.","volume":"2","author":"M Oremus","year":"2012","journal-title":"BMJ Open."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"i851","DOI":"10.1136\/bmj.i851","article-title":"Second malignancies after radiotherapy for prostate cancer: systematic review and meta-analysis.","volume":"352","author":"C Wallis","year":"2016","journal-title":"BMJ."},{"key":"ref-21","doi-asserted-by":"publisher","first-page":"j4452","DOI":"10.1136\/bmj.j4452","article-title":"Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis.","volume":"359","author":"F Croles","year":"2017","journal-title":"BMJ."},{"key":"ref-22","doi-asserted-by":"publisher","first-page":"j5855","DOI":"10.1136\/bmj.j5855","article-title":"Low cigarette consumption and risk of coronary heart disease and stroke: meta-analysis of 141 cohort studies in 55 study reports.","volume":"360","author":"A Hackshaw","year":"2018","journal-title":"BMJ."},{"key":"ref-23","doi-asserted-by":"publisher","first-page":"271-9","DOI":"10.7326\/0003-4819-158-4-201302190-00008","article-title":"Comparative effectiveness of treatments for open-angle glaucoma: a systematic review for the U.S. Preventive Services Task Force.","volume":"158","author":"M Boland","year":"2013","journal-title":"Ann Intern Med."},{"key":"ref-24","doi-asserted-by":"publisher","first-page":"e1002591","DOI":"10.1371\/journal.pmed.1002591","article-title":"Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis.","volume":"15","author":"E Harausz","year":"2018","journal-title":"PLoS Med."},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"1001-1015","DOI":"10.1111\/obr.12309","article-title":"Inverse relationship between body mass index and mortality in older nursing home residents: a meta-analysis of 19,538 elderly subjects.","volume":"16","author":"N Veronese","year":"2015","journal-title":"Obes Rev."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"e2016014","DOI":"10.4178\/epih.e2016014","article-title":"A suggestion for quality assessment in systematic reviews of observational studies in nutritional epidemiology.","volume":"38","author":"J Bae","year":"2016","journal-title":"Epidemiol Health."},{"key":"ref-27","doi-asserted-by":"publisher","first-page":"982-93","DOI":"10.1016\/j.jclinepi.2013.03.003","article-title":"Testing the Newcastle Ottawa Scale showed low reliability between individual reviewers.","volume":"66","author":"L Hartling","year":"2013","journal-title":"J Clin Epidemiol."},{"key":"ref-28","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1038\/240242a0","article-title":"Reply to Gal.","volume":"240","author":"K Laurence","year":"1972","journal-title":"Nature."},{"key":"ref-29","doi-asserted-by":"publisher","first-page":"563-74","DOI":"10.1093\/oxfordjournals.aje.a113133","article-title":"The relationship between hormonal pregnancy tests and congenital anomalies: a prospective study.","volume":"113","author":"C Torfs","year":"1981","journal-title":"Am J Epidemiol."},{"key":"ref-30","doi-asserted-by":"crossref","first-page":"1725","DOI":"10.12688\/f1000research.16758.2","article-title":"Dataset 1 in: Oral hormone pregnancy tests and the risks of congenital malformations: a systematic review and meta-analysis.","volume":"17","author":"C Heneghan","year":"2019","journal-title":"F1000Research."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,8,25]],"date-time":"2021-08-25T09:45:17Z","timestamp":1629884717000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,29]]},"references-count":30,"URL":"https:\/\/doi.org\/10.12688\/f1000research.16758.2","relation":{},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,29]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.18318.r40053, David Healy, School of Medical Sciences, Bangor University, Bangor, UK, 05 Nov 2018, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v1#referee-response-40053","order":0,"name":"referee-response-40053","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Carl Carl<\/b>; \n<i>Posted: 16 Jan 2019<\/i>; Many thanks for these positive comments.Signature defects are only likely to occur if the timing of exposure is the same in all cases. However, when the timing of exposure varies, fetuses will be affected in different ways, depending on the tissues that are developing at the time of exposure, giving rise to a variety of malformations. The large range of times of exposure during embryogenesis determines which developmental processes are most affected, resulting in a wide variety of potential defects as seen in our review and in alleged Primodos survivors. Furthermore, different fetuses may have different epigenetic susceptibilities to different teratogenic outcomes.&nbsp;The Primodos components norethisterone acetate and ethinyl estradiol induce developmental abnormalities in zebrafish embryos [Brown S, Fraga LR, Cameron G, Erskine L, Vargesson N. Sci Rep. 2018 Feb 13;8(1):2917. doi: 10.1038\/s41598-018-21318-9]. Brown's data in Zebrafish show acetate and ethinylestradiol teratogenicity depends on dose and the embryonic stage of development, embryos at an early stage being more sensitive than those at a later stage.The comments are interested&nbsp;in why the regulator (MHRA) did not find comparable results but this is not a matter that should be addressed in this article.&nbsp;We agree with this issue - no change required.We have removed the spacing between numbers to eliminate the odd spacing&nbsp;effect.","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2#referee-comment-4363","order":1,"name":"referee-comment-4363","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.18318.r40291, Jesse Olszynko-Gryn, Cyrille Jean, Department of History and Philosophy of Science, University of Cambridge, Cambridge, UK, 29 Nov 2018, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v1#referee-response-40291","order":2,"name":"referee-response-40291","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Carl Carl<\/b>; \n<i>Posted: 16 Jan 2019<\/i>; Many thanks for these positive comments.&nbsp;We have amended the introduction with the following text: 'Oral hormone pregnancy tests (HPTs), such as Primodos (known as Duogynon in Germany), were available as injections from 1950 and in tablet form in the UK from 1956 onwards, before the modern forms of urine pregnancy tests became available [1]\u2019&nbsp;We have cited: Olszynko-Gryn J, Bj&oslash;rvik E, We&szlig;el M, J&uuml;lich S, Jean C. A historical argument for regulatory failure in the case of Primodos and other hormone pregnancy tests. Reprod Biomed Soc Online. 2018 Oct 23;6:34-44. Doi: 10.1016\/j.rbms.2018.09.003. eCollection 2018 Aug.&nbsp;We have&nbsp;amended the introduction text as per the reviewer's suggestion :&quot;Warnings about HPTs in pregnancy first emerged in 1956: accumulating concerns over an increased risk of malformations led to their withdrawal in a number of countries at different times. Norway cancelled the indication in pregnancy for HPTs in 1970; the UK did so in 1978, when the manufacturers of Primodos, Schering AG (taken over by Bayer AG in 2008), voluntarily stopped marketing the product; in Germany, Duogynon was taken off the market in 1981&nbsp; [ref Olszynko-Gryn J].'We have&nbsp;amended the introduction text as per the reviewer's suggestion:\u2018The test principle was that they would induce bleeding similar to menstruation in those who were not pregnant.\u2019'Warnings about HPTs in pregnancy first emerged in 1956.'And referenced the&nbsp;Britton H.G. Pregnancy test. Br. Med. J. 1956;2(18 Aug.):419. paper&nbsp;&nbsp;The benefits of our systematic review include that it quantifies the magnitude of the association and tests the robustness of this association across multiple studies by meta-analysis. We, therefore, perceive that they are rationale and the objectives are clear.","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2#referee-comment-4362","order":3,"name":"referee-comment-4362","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.18318.r40887, Olalekan A. Uthman, Division of Health Sciences, Warwick Centre for Applied Health Research and Delivery, Warwick Medical School, University of Warwick, Coventry, UK, 14 Dec 2018, version 1, indexed","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v1#referee-response-40887","order":4,"name":"referee-response-40887","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Carl Carl<\/b>; \n<i>Posted: 16 Jan 2019<\/i>; Many thanks for these positive comments. The methods and results are clear about the type of studies included, and we consider the conclusions do not require the addition of the study type. This is in line with previous systematic reviews our group has published.","URL":"https:\/\/f1000research.com\/articles\/7-1725\/v2#referee-comment-4361","order":5,"name":"referee-comment-4361","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"The Evidence Synthesis Working Group is funded by the National Institute for Health Research School for Primary Care Research (NIHR SPCR) [Project Number 390]. The views expressed are those of the author(s) and not necessarily those of the NIHR, the NHS or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":6,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Data associated with the article are available under the terms of the Creative Commons Zero \"No rights reserved\" data waiver (CC0 1.0 Public domain dedication).","order":0,"name":"copyright-info","label":"Copyright"}]}}