{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:51:03Z","timestamp":1787021463118,"version":"build-2736575974"},"update-to":[{"DOI":"10.12688\/gatesopenres.14710.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000}}],"reference-count":28,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T00:00:00Z","timestamp":1702857600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-004505"],"award-info":[{"award-number":["INV-004505"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["gatesopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Gates Open Res"],"abstract":"<ns4:p>\n                    Background Anemia affects 40% of pregnant women globally, leading to maternal mortality, premature birth, low birth weight, and poor baby development. Iron deficiency causes over 40% of anemia cases in Africa. Oral iron supplementation is insufficient for Low-and-Middle-Income-Countries (LMICs) to meet current WHO targets. We hypothesized that a single intravenous dose of Ferric Carboxymaltose (FCM) may be more effective than oral iron treatment for anemia recovery, particularly in these settings where women present late for antenatal care. Methods This is a two-arm parallel open-label individual-randomized controlled trial in third trimester, in malaria Rapid Diagnostic Test-negative pregnant women with moderate or severe anemia - capillary hemoglobin &lt;10 g\/dL \u2013 who are randomized to receive either parenteral iron \u2013 with FCM \u2013 or standard-of-care oral iron for the remainder of pregnancy. This is the sister trial to the second-trimester\n                    <ns4:bold>REVAMP<\/ns4:bold>\n                    trial, funded by the Bill and Melinda Gates Foundation (trial registration ACTRN12618001268235, Gates Grant number INV-010612). In REVAMP-TT, recruitment and treatment are performed within primary health centers. The trial will recruit 590 women across Zomba district, Malawi. The primary outcome is the proportion of anemic women - venous hemoglobin &lt;11 g\/dL - at 36 weeks\u2019 gestation or delivery (whichever occurs first). Other pre-specified key secondary clinical and safety outcomes include maternal iron-status and hypophosphatemia, neonate birth weight, infant growth and infant iron and hematological parameters. Discussion This study will determine whether FCM, delivered within primary health centers, is effective, safe and feasible for treating moderate to severe anemia in third-trimester pregnant Malawian women. This intervention could have long-term benefits for maternal and child health, resulting in improved survival and child development.\n                  <\/ns4:p>","DOI":"10.12688\/gatesopenres.14710.2","type":"journal-article","created":{"date-parts":[[2023,12,18]],"date-time":"2023-12-18T06:05:07Z","timestamp":1702879507000},"page":"117","update-policy":"https:\/\/doi.org\/10.12688\/gatesopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["Protocol and statistical analysis plan for a randomized controlled trial of the effect of intravenous iron on anemia in Malawian pregnant women in their third trimester (REVAMP \u2013 TT)"],"prefix":"10.12688","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4267-716X","authenticated-orcid":false,"given":"Rebecca","family":"Harding","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest","family":"Moya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1014-0432","authenticated-orcid":false,"given":"Ricardo","family":"Ata\u00edde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5952-7155","authenticated-orcid":false,"given":"Zinenani","family":"Truwah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7277-9987","authenticated-orcid":false,"given":"Glory","family":"Mzembe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gomezgani","family":"Mhango","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ay\u015fe V.","family":"Demir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0699-2381","authenticated-orcid":false,"given":"William","family":"Stones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louise","family":"Randall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Seal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2029-163X","authenticated-orcid":false,"given":"Katherine","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0258-7795","authenticated-orcid":false,"given":"Stefan","family":"Bode","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8358-4448","authenticated-orcid":false,"given":"Martin 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Haider","year":"2013","journal-title":"BMJ."},{"key":"ref-3","doi-asserted-by":"publisher","first-page":"1654-62","DOI":"10.1111\/1471-0528.13978","article-title":"Risk factors and newborn outcomes associated with maternal deaths in the UK from 2009 to 2013: a national case-control study.","volume":"123","author":"M Nair","year":"2016","journal-title":"BJOG."},{"key":"ref-4","doi-asserted-by":"publisher","first-page":"2087-93","DOI":"10.1111\/1471-0528.14263","article-title":"The effect of maternal haematocrit on offspring iq at 4 and 7 years of age: A secondary analysis.","volume":"123","author":"D Drassinower","year":"2016","journal-title":"BJOG."},{"key":"ref-5","first-page":"1-7","article-title":"Global nutrition targets 2025: Anaemia Policy Brief","year":"2012"},{"key":"ref-6","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD004736.pub5","article-title":"Daily oral iron supplementation during pregnancy.","volume":"2015","author":"J Pe\u00f1a-Rosas","year":"2015","journal-title":"Cochrane Database Syst Rev."},{"key":"ref-7","doi-asserted-by":"publisher","first-page":"1009-20","DOI":"10.1001\/jama.2015.9496","article-title":"Effect of daily antenatal iron supplementation on plasmodium infection in kenyan women: A randomized clinical trial.","volume":"314","author":"M Mwangi","year":"2015","journal-title":"JAMA."},{"key":"ref-8","article-title":"Iron and Folate Supplementation: Intergrated Management of Pregnancy and Childbirth (IMPAC).","year":"2006"},{"key":"ref-9","article-title":"Essential Nutrition Actions: improving maternal, newborn, infant and young child health and nutrition.","year":"2013"},{"key":"ref-10","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD009747.pub2","article-title":"Daily iron supplementation for improving anaemia, iron status and health in menstruating women.","volume":"4","author":"M Low","year":"2016","journal-title":"Cochrane Database Syst 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Aust."},{"key":"ref-14","doi-asserted-by":"publisher","first-page":"129-36","DOI":"10.1080\/17474086.2019.1575202","article-title":"A systematic literature review and indirect comparison of iron isomaltoside and ferric carboxymaltose in iron deficiency anemia after failure or intolerance of oral iron treatment.","volume":"12","author":"R Pollock","year":"2019","journal-title":"Expert Rev Hematol."},{"key":"ref-15","article-title":"Ferinject in Pregnancy and the Postpartum Period","year":"2018"},{"key":"ref-16","doi-asserted-by":"publisher","first-page":"1595-1609","DOI":"10.1016\/S0140-6736(23)00278-7","article-title":"Ferric carboxymaltose versus standard-of-care oral iron to treat second-trimester anaemia in Malawian pregnant women: a randomised controlled trial.","volume":"401","author":"S Pasricha","year":"2023","journal-title":"Lancet."},{"key":"ref-17","doi-asserted-by":"publisher","DOI":"10.1186\/s43058-022-00299-x","article-title":"An implementation research programme to support an intravenous iron intervention for pregnant women with moderate and severe anaemia in Malawi: study protocol.","volume":"3","author":"K Prang","year":"2022","journal-title":"Implement Sci Commun."},{"key":"ref-18","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2021-053288","article-title":"Protocol for a multicentre, parallel-group, open-label randomised controlled trial comparing ferric carboxymaltose with the standard-of-care in anaemic Malawian pregnant women: the REVAMP trial.","volume":"11","author":"M Mwangi","year":"2021","journal-title":"BMJ Open."},{"key":"ref-19","doi-asserted-by":"publisher","first-page":"174","DOI":"10.12688\/gatesopenres.13457.2","article-title":"A Randomized controlled trial of the Effect of intraVenous iron on Anaemia in Malawian Pregnant women (REVAMP): Statistical analysis plan [version 2; peer review: 2 approved].","volume":"5","author":"R Harding","year":"2022","journal-title":"Gates Open Res."},{"key":"ref-20","doi-asserted-by":"publisher","first-page":"257S-264S","DOI":"10.1093\/ajcn\/72.1.257S","article-title":"Iron requirements in pregnancy and strategies to meet them.","volume":"72","author":"T Bothwell","year":"2000","journal-title":"Am J Clin Nutr."},{"key":"ref-21","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.e7586","article-title":"SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials.","volume":"346","author":"A Chan","year":"2013","journal-title":"BMJ."},{"key":"ref-22","doi-asserted-by":"publisher","DOI":"10.1186\/s13063-017-1878-7","article-title":"Advancing engagement methods for trials: The CORE study relational model of engagement for a stepped wedge cluster randomised controlled trial of experience-based co-design for people living with severe mental illnesses.","volume":"18","author":"L Richard","year":"2017","journal-title":"Trials."},{"key":"ref-23","article-title":"Malawi National Reproductive Health Service Delivery Guidelines 2014-2019"},{"key":"ref-24","doi-asserted-by":"publisher","first-page":"982-995","DOI":"10.1056\/NEJMoa2034187","article-title":"Benefits and Risks of Iron Interventions in Infants in Rural Bangladesh.","volume":"385","author":"S Pasricha","year":"2021","journal-title":"N Engl J Med."},{"key":"ref-25","doi-asserted-by":"publisher","first-page":"443-453","DOI":"10.1515\/jpm-2016-0050","article-title":"Ferric carboxymaltose vs. oral iron in the treatment of pregnant women with iron deficiency anemia: An international, open-label, randomized controlled trial (FER-ASAP).","volume":"45","author":"C Breymann","year":"2017","journal-title":"J Perinat Med."},{"key":"ref-26","doi-asserted-by":"publisher","first-page":"3267-84","DOI":"10.1002\/sim.4102","article-title":"Adaptive increase in sample size when interim results are promising: A practical guide with examples.","volume":"30","author":"C Mehta","year":"2011","journal-title":"Stat Med."},{"key":"ref-27","article-title":"A Simple Sequentially Rejective Multiple Test Procedure.","author":"S Holm","year":"1979"},{"key":"ref-28","article-title":"Longitudinal Data Analysis of Continuous and Discrete Responses for Pre-Post Designs.","author":"K Liang","year":"1960"}],"container-title":["Gates Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,9]],"date-time":"2024-02-09T07:05:14Z","timestamp":1707462314000},"score":1,"resource":{"primary":{"URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,18]]},"references-count":28,"URL":"https:\/\/doi.org\/10.12688\/gatesopenres.14710.2","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/gatesopenres.16541.r35686","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/gatesopenres.16541.r35686","asserted-by":"object"}]},"ISSN":["2572-4754"],"issn-type":[{"value":"2572-4754","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,18]]},"assertion":[{"value":"Indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/gatesopenres.16036.r35088, Adam Lewkowitz, Department of Obstetrics and Gynecology, Women and Infants Hospital of Rhode Island, Brown University, Providence, Rhode Island, 05 Oct 2023, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v1#referee-response-35088","order":0,"name":"referee-response-35088","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Ricardo Ataide<\/b>; \n<i>Posted: 13 Dec 2023<\/i>; We would like to thank all the reviewers for the time taken to carefully read through the manuscript and help us improve it. We have replied to each reviewer independently and highlighted the changes made to the manuscript (where needed) in black bold italic text.&nbsp;  \n<b>Reviewer&nbsp;1 \u2013 Adam Lewkowitz, Brown University, Providence, USA<\/b> &nbsp; Thank you for your positive feedback and endorsement of our manuscript. We have addressed your comments below: &nbsp;  The heterogeneous primary aim; (\u2026) the potential influence that delivery prior to 36 weeks may have on the primary outcome can be mitigated by conducting a stratified analysis limiting to only those who delivered at 36 weeks.   Thank you for this suggestion. To explore the potential influence of delivery prior to 36 weeks\u2019 gestation on the primary outcome and thus provide further insight into the treatment effect at 36 weeks\u2019 gestation, we propose conducting an additional analysis by analysing the outcome data at the 36 weeks\u2019 gestation visit for all randomised participants. In this analysis, the statistical model will use outcome data at the 36 weeks\u2019 gestation visit for participants who did not deliver prior to or at this visit. For participants who delivered prior to or at 36 weeks\u2019 gestation, no outcome data at 36 weeks\u2019 gestation during pregnancy could be obtained and the statistical model will consider the outcome data as missing at the 36 week\u2019s gestation visit. The following bold italic text has been added\/amended in the additional analyses section on page 16:  \n<i>\u201c<b>Using a model similar to the main analysis model of the primary outcome described above, the treatment effect at 36 weeks\u2019 gestation will be examined for the primary outcome. <\/b>Adjusted analyses for pre-specified covariates and analysis excluding participants with protocol violations (e.g., multiple births) will be included in additional analyses of primary, key secondary and other secondary outcomes. To determine the heterogeneity of the differences between IV iron and standard-of-care oral iron six pre-specified subgroup analyses will be performed for primary and key secondary maternal and neonate outcomes. The missing-at-random assumption will be used to fit the model for the primary maternal outcome (anemia) and the missing-completely-at-random assumption will be used to fit the model for the primary neonate outcome (birth weight). Pattern-mixture models will be conducted to assess sensitivity of the results to these assumptions.\u201d<\/i>  The lack of confirmation of iron deficiency anemia (IDA) before randomization. (\u2026) the authors note that &quot;serum for iron markers tests&quot; will be drawn at enrolment. Thus, it may be possible to limit analysis only to those who had confirmed IDA by ferritin or other iron studies (with whatever ferritin threshold they elect to use).   We agree that IDA before randomisation may be predictive of the effect of IV iron. Therefore, a pre-planned subgroup analysis for IDA will explore the heterogeneity of treatment effect between those with and without IDA at baseline. We have amended the text to more explicitly state our pre-specified subgroup analyses. It now reads as follows, under \u2018Additional Analyses\u2019 in page 17:  \n<i>\u201cTo determine the heterogeneity of the differences between IV iron and standard-of-care oral iron six pre-specified subgroup analyses <b>(gravidity (primigravida vs. multigravida), baseline HIV status (positive vs negative), baseline severe anaemia status (yes vs no severe anaemia), baseline iron-deficient status (yes vs no ID), baseline iron-deficient anaemia status (yes vs no IDA), baseline inflammation status (yes vs no elevated CRP))<\/b> will be performed for primary and key secondary maternal and neonate outcomes.\u201d<\/i>","URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2#referee-comment-3655","order":1,"name":"referee-comment-3655","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/gatesopenres.16541.r35686, Sue Pavord, Department of Haematology, Oxford University Hospitals NHS Foundation Trust, Oxford, 09 Feb 2024, version 2, indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/7-117\/v2#referee-response-35686","order":2,"name":"referee-response-35686","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This work was supported by the Bill and Melinda Gates Foundation [INV-004505]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":3,"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.","order":0,"name":"copyright-info","label":"Copyright"}]}}