{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T08:26:16Z","timestamp":1781771176783,"version":"3.54.5"},"reference-count":19,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T00:00:00Z","timestamp":1606089600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Medical Research Council","award":["MR\/R021376\/1"],"award-info":[{"award-number":["MR\/R021376\/1"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background<\/jats:title>\n<jats:p>Pre-eclampsia is a pregnancy complication characterised by high blood pressure and multi-organ dysfunction in the mother. It is a leading contributor to maternal and perinatal mortality, with 99% of these deaths occurring in low- and middle-income countries (LMIC). Whilst clear guidelines exist for management of early-onset (&lt;\u200934\u2009weeks) and term (\u2265\u200937\u2009weeks) disease, the optimal timing of delivery in pre-eclampsia between 34<jats:sup>+\u20090<\/jats:sup> and 36<jats:sup>+\u20096<\/jats:sup> weeks is less clear. In a high-income setting, delivery may improve maternal outcomes without detriment to the baby, but this intervention is yet to be evaluated in LMIC.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>The CRADLE-4 Trial is a non-masked, randomised controlled trial comparing planned early delivery (initiation of delivery within 48\u2009h of randomisation) with routine care (expectant management) in women with pre-eclampsia between 34<jats:sup>+\u20090<\/jats:sup> and 36<jats:sup>+\u20096<\/jats:sup> weeks\u2019 gestation in India and Zambia. The primary objective is to establish whether a policy of planned early delivery can reduce adverse maternal outcomes, without increasing severe neonatal morbidity.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Discussion<\/jats:title>\n<jats:p>The World Health Organization recommends delivery for all women with pre-eclampsia from 37\u2009weeks onwards, based on evidence showing clear maternal benefit without increased neonatal risk. Before 34\u2009weeks, watchful waiting is preferred, with delivery recommended only when there is severe maternal or fetal compromise, due to the neonatal risks associated with early preterm delivery. Currently, there is a lack of guidance for clinicians managing women with pre-eclampsia between 34<jats:sup>+\u20090<\/jats:sup> and 36<jats:sup>+\u20096<\/jats:sup> weeks. Early delivery benefits the mother but may increase the need for neonatal unit admission in the infant (albeit without serious morbidity at this gestation). On the other hand, waiting to deliver may increase the risk of stillbirth, fetal growth restriction and hypoxic brain injury in the neonate as a result of severe maternal complications. This is especially true for LMIC where there is a higher prevalence of adverse events. The balance of risks and benefits therefore needs to be carefully assessed before making firm recommendations. This is the first trial evaluating the optimal timing of delivery in pre-eclampsia in LMIC, where resources and disease burden are considerably different.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Trial registration<\/jats:title>\n<jats:p>ISRCTN <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.isrctn.com\/ISRCTN10672137\">10672137<\/jats:ext-link>. Registered on 28 November 2019.<\/jats:p>\n<\/jats:sec>","DOI":"10.1186\/s13063-020-04888-w","type":"journal-article","created":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T15:10:21Z","timestamp":1606144221000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Planned early delivery versus expectant management to reduce adverse pregnancy outcomes in pre-eclampsia in a low- and middle-income setting: study protocol for a randomised controlled trial (CRADLE-4 Trial)"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9923-4912","authenticated-orcid":false,"given":"Alice","family":"Beardmore-Gray","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Vousden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Umesh","family":"Charantimath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geetanjali","family":"Katageri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mrutyunjaya","family":"Bellad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kunda","family":"Kapembwa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebastian","family":"Chinkoyo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bellington","family":"Vwalika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Clark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachael","family":"Hunter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Seed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shivaprasad","family":"Goudar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucy C.","family":"Chappell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Shennan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,23]]},"reference":[{"issue":"9741","key":"4888_CR1","doi-asserted-by":"publisher","first-page":"631","DOI":"10.1016\/S0140-6736(10)60279-6","volume":"376","author":"EAP Steegers","year":"2010","unstructured":"Steegers EAP, von Dadelszen P, Duvekot JJ, Pijnenborg R. Pre-eclampsia. Lancet. 2010;376(9741):631\u201344.","journal-title":"Lancet."},{"issue":"S1","key":"4888_CR2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1002\/ijgo.12802","volume":"145","author":"LC Poon","year":"2019","unstructured":"Poon LC, Shennan A, Hyett JA, Kapur A, Hadar E, Divakar H, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on pre-eclampsia: a pragmatic guide for first-trimester screening and prevention. Int J Gynecol Obstet. 2019;145(S1):1\u201333.","journal-title":"Int J Gynecol Obstet"},{"issue":"3","key":"4888_CR3","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1053\/j.semperi.2009.02.010","volume":"33","author":"L Duley","year":"2009","unstructured":"Duley L. The global impact of pre-eclampsia and Eclampsia. Semin Perinatol. 2009;33(3):130\u20137.","journal-title":"Semin Perinatol"},{"key":"4888_CR4","unstructured":"World Health Organisation. WHO recommendations for prevention\u00a0and treatment of pre-eclampsia and eclampsia. 2011. http:\/\/apps.who.int\/iris\/bitstream\/10665\/44703\/1\/9789241548335_eng.pdf. Accessed 21 July 2020."},{"key":"4888_CR5","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1016\/S0140-6736(19)31963-4","volume":"394","author":"LC Chappell","year":"2019","unstructured":"Chappell LC. Planned early delivery or expectant management for late preterm pre-eclampsia: a randomised controlled trial (PHOENIX trial). Lancet. 2019;394:1181\u201390.","journal-title":"Lancet."},{"issue":"9986","key":"4888_CR6","doi-asserted-by":"publisher","first-page":"2492","DOI":"10.1016\/S0140-6736(14)61998-X","volume":"385","author":"K Broekhuijsen","year":"2015","unstructured":"Broekhuijsen K, Van Baaren GJ, Van Pampus MG, Ganzevoort W, Sikkema JM, Woiski MD, et al. Immediate delivery versus expectant monitoring for hypertensive disorders of pregnancy between 34 and 37 weeks of gestation (HYPITAT-II): an open-label, randomised controlled trial. Lancet. 2015;385(9986):2492\u2013501.","journal-title":"Lancet."},{"issue":"4","key":"4888_CR7","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1002\/uog.20224","volume":"53","author":"TP Bernardes","year":"2019","unstructured":"Bernardes TP, Zwertbroek EF, Broekhuijsen K, Koopmans C, Boers K, Owens M, et al. Delivery or expectant management for prevention of adverse maternal and neonatal outcomes in hypertensive disorders of pregnancy: an individual participant data meta-analysis. Ultrasound Obstet Gynecol. 2019;53(4):443\u201353.","journal-title":"Ultrasound Obstet Gynecol"},{"issue":"9968","key":"4888_CR8","doi-asserted-by":"publisher","first-page":"629","DOI":"10.1016\/S0140-6736(14)61651-2","volume":"385","author":"F Althabe","year":"2015","unstructured":"Althabe F, Beliz\u00e1n JM, McClure EM, Hemingway-Foday J, Berrueta M, Mazzoni A, et al. A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial. Lancet. 2015;385(9968):629\u201339.","journal-title":"Lancet."},{"issue":"3","key":"4888_CR9","first-page":"1","volume":"2","author":"JP Vogel","year":"2017","unstructured":"Vogel JP, Oladapo OT, Pileggi-Castro C, Adejuyigbe EA, Althabe F, Ariff S, et al. Antenatal corticosteroids for women at risk of imminent preterm birth in low-resource countries: the case for equipoise and the need for efficacy trials. BMJ Glob Heal. 2017;2(3):1\u20137.","journal-title":"BMJ Glob Heal"},{"issue":"1","key":"4888_CR10","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1161\/HYPERTENSIONAHA.117.10803","volume":"72","author":"MA Brown","year":"2018","unstructured":"Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito S, et al. Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice. Hypertension. 2018;72(1):24\u201343.","journal-title":"Hypertension."},{"key":"4888_CR11","doi-asserted-by":"publisher","unstructured":"Payne BA, Hutcheon JA, Ansermino JM, Hall DR, Bhutta ZA, Bhutta SZ, et al. A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) Multi-country Prospective Cohort Study. PLoS Med. 2014;11(1):e1001589. https:\/\/doi.org\/10.1371\/journal.pmed.1001589.","DOI":"10.1371\/journal.pmed.1001589"},{"issue":"7872","key":"4888_CR12","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/S0140-6736(74)91639-0","volume":"304","author":"G Teasdale","year":"1974","unstructured":"Teasdale G, Jennett B. Assessment of coma and impaired consciousness. Lancet. 1974;304(7872):81\u20134.","journal-title":"Lancet."},{"issue":"6","key":"4888_CR13","first-page":"20","volume":"18","author":"D Robinson","year":"1996","unstructured":"Robinson D. The integrated management of childhood illness. Afr Health. 1996;18(6):20\u20131.","journal-title":"Afr Health"},{"issue":"7879","key":"4888_CR14","first-page":"1","volume":"345","author":"BC Kahan","year":"2012","unstructured":"Kahan BC, Morris TP. Reporting and analysis of trials using stratified randomisation in leading medical journals: review and reanalysis. BMJ. 2012;345(7879):1\u20138.","journal-title":"BMJ."},{"issue":"7321","key":"4888_CR15","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1136\/bmj.323.7321.1123","volume":"323","author":"AJ Vickers","year":"2001","unstructured":"Vickers AJ, Altman DG. Analysing controlled trials with baseline and follow up measurements. Br Med J. 2001;323(7321):1123\u20134.","journal-title":"Br Med J"},{"key":"4888_CR16","first-page":"221","volume-title":"Behavior of maximum likelihood estimates under nonstandard conditions. Proc 5th Berkeley Sympt Math Stat Prob","author":"P Huber","year":"1967","unstructured":"Huber P. Behavior of maximum likelihood estimates under nonstandard conditions. Proc 5th Berkeley Sympt Math Stat Prob; 1967. p. 221\u201333."},{"issue":"3","key":"4888_CR17","doi-asserted-by":"publisher","first-page":"262","DOI":"10.3109\/10641950902777697","volume":"29","author":"L Kenneth","year":"2010","unstructured":"Kenneth L, Hall DR, Gebhardt S, Grov\u00e9 D. Late onset preeclampsia is not an innocuous condition. Hypertens Pregnancy. 2010;29(3):262\u201370.","journal-title":"Hypertens Pregnancy"},{"issue":"11","key":"4888_CR18","doi-asserted-by":"publisher","first-page":"e1186","DOI":"10.1016\/S2214-109X(18)30389-9","volume":"6","author":"C Arsenault","year":"2018","unstructured":"Arsenault C, Jordan K, Lee D, Dinsa G, Manzi F, Marchant T, et al. Equity in antenatal care quality: an analysis of 91 national household surveys. Lancet Glob Heal. 2018;6(11):e1186\u201395.","journal-title":"Lancet Glob Heal"},{"key":"4888_CR19","doi-asserted-by":"publisher","unstructured":"DAMOCLES Study Group, NHS Health Technology Assessment Programme. A proposed charter for clinical trial data monitoring committees: helping them to do their job well. Lancet. 2005;365(9460):711\u201322. https:\/\/doi.org\/10.1016\/S0140-6736(05)17965-3.","DOI":"10.1016\/S0140-6736(05)17965-3"}],"container-title":["Trials"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04888-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/article\/10.1186\/s13063-020-04888-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/link.springer.com\/content\/pdf\/10.1186\/s13063-020-04888-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,23]],"date-time":"2020-11-23T15:43:54Z","timestamp":1606146234000},"score":1,"resource":{"primary":{"URL":"https:\/\/trialsjournal.biomedcentral.com\/articles\/10.1186\/s13063-020-04888-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,23]]},"references-count":19,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,12]]}},"alternative-id":["4888"],"URL":"https:\/\/doi.org\/10.1186\/s13063-020-04888-w","relation":{},"ISSN":["1745-6215"],"issn-type":[{"value":"1745-6215","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,23]]},"assertion":[{"value":"29 July 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The trial will be conducted according to the principles of the Declaration of Helsinki (October 2008) and all applicable regulatory requirements. The conduct of this study will be in full compliance with Good Clinical Practice. Copies of the protocol, participant information leaflet and informed consent form have been approved by national or institutional research ethics committees in both India and Zambia, and in the UK:King\u2019s College London: HR-19\/20-13535University of Zambia: UNZA-301\/2019Bagalkot (India): SNMCIEC\/1.1\/2019-2020Belagavi (India): KAHER\/IEC\/2019-20\/D-251119016The chief investigator or their delegate will submit and, where necessary, obtain approval from the relevant research ethics committee (REC) for any substantial amendments. All protocol modifications will be communicated promptly to sites once approved by the sponsor and the REC. Written informed consent will be obtained by the principal investigator or another member of the study team with delegated authority.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"960"}}