{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T13:15:49Z","timestamp":1783516549145,"version":"3.55.0"},"reference-count":24,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T00:00:00Z","timestamp":1637712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1172660"],"award-info":[{"award-number":["OPP1172660"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["K24 DK104676"],"award-info":[{"award-number":["K24 DK104676"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["None"],"award-info":[{"award-number":["None"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Trials"],"published-print":{"date-parts":[[2021,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Hypertensive disorders of pregnancy are important causes of maternal morbidity and mortality, as well as preterm birth, the leading cause of death for children under 5\u2009years globally. The World Health Organization currently recommends that pregnant women receive high-dose calcium supplementation (1500\u20132000\u2009mg elemental calcium) for prevention of preeclampsia in populations with low dietary calcium intake. Trials of low-dose calcium supplementation (&lt;\u20091000\u2009mg elemental calcium\/day) during pregnancy have also shown similar reductions in the risk of preeclampsia; however, no trials to date have directly compared low-dose to the standard high-dose calcium supplementation. Our objective is to assess the non-inferiority of low-dose as compared to standard high-dose calcium supplementation in pregnancy.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods\/design<\/jats:title>\n                <jats:p>We will conduct two independent trials in Bangalore, India (<jats:italic>n<\/jats:italic> = 11,000 pregnancies), and Dar es Salaam, Tanzania (<jats:italic>n<\/jats:italic> = 11,000 pregnancies). The trial designs are individually randomized, parallel group, quadruple-blind, non-inferiority trials of low-dose calcium supplementation (500\u2009mg elemental calcium\/day) as compared to standard high-dose calcium supplementation (1500\u2009mg elemental calcium\/day) among nulliparous pregnant women. Pregnant women will be enrolled in the trial before 20\u2009weeks of gestation and will receive the randomized calcium regimen from randomization until the time of delivery. The co-primary outcomes are (i) preeclampsia and (ii) preterm birth; we will test non-inferiority of the primary outcomes for low-dose as compared to the standard high-dose supplementation regimen in each trial. The trials\u2019 secondary outcomes include gestational hypertension, severe features of preeclampsia, pregnancy-related death, third trimester severe anemia, fetal death, stillbirth, low birthweight, small-for-gestational age birth, and infant death.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Discussion<\/jats:title>\n                <jats:p>The trials will provide causal evidence on the non-inferiority of low-dose as compared to the standard high-dose supplementation in India and Tanzania. A single tablet, low-dose calcium supplementation regimen may improve individual-level adherence, reduce programmatic costs, and ultimately expand implementation of routine calcium supplementation in pregnancy in populations with low dietary calcium intake.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Trial registration<\/jats:title>\n                <jats:p><jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/clinicaltrials.gov\">ClinicalTrials.gov<\/jats:ext-link> identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03350516\">NCT03350516<\/jats:ext-link>; registered on 22 November 2018. Clinical Trials Registry\u2014India identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/ctri.nic.in\/Clinicaltrials\/showallp.php?mid1=21313&amp;EncHid=&amp;userName=CTRI\/2018\/02\/012119\">CTRI\/2018\/02\/012119<\/jats:ext-link>; registered on 23 February 2018.<\/jats:p>\n                <jats:p>Tanzania Medicines and Medical Devices Authority Trials Registry identifier: <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/imis2.tmda.go.tz\/portal\/#\/public\/clinical-trials\">TFDA0018\/CTR\/0010\/5<\/jats:ext-link>; registered on 20 December 2018.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13063-021-05811-7","type":"journal-article","created":{"date-parts":[[2021,11,24]],"date-time":"2021-11-24T12:03:17Z","timestamp":1637755397000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Non-inferiority of low-dose compared to standard high-dose calcium supplementation in pregnancy: study protocol for two randomized, parallel group, non-inferiority trials in India and Tanzania"],"prefix":"10.1186","volume":"22","author":[{"given":"Pratibha","family":"Dwarkanath","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfa","family":"Muhihi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Sudfeld","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shobha","family":"Rani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher P.","family":"Duggan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary M.","family":"Sando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blair J.","family":"Wylie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Fernandez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shabani","family":"Kinyogoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Munk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandita","family":"Perumal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Michael","family":"Raj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nirmala","family":"Buggi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ndeniria","family":"Swai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tinku","family":"Thomas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anura V.","family":"Kurpad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Honorati","family":"Masanja","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas B.","family":"Pembe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wafaie W.","family":"Fawzi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,24]]},"reference":[{"key":"5811_CR1","unstructured":"American College of Obstetricians and Gynecologists. 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H. Chan School of Public Health Institutional Review Board (Ref. No. IRB18-0157), the St. John\u2019s Institutional Ethics Committee (IEC Study Ref. No. 197\/2017), and the Indian Council of Medical Research (Ref. No. 2018-0380). The Tanzania trial protocol was approved by the Harvard T. H. Chan School of Public Health Institutional Review Board (Ref. No. IRB17-1874), the Ifakara Health Institute Institutional Review Board (IHI\/IRB\/No: 002-2018), the Muhimbili University of Health and Allied Sciences Institutional Review Board (MUHAS-REC-3-2020-107), the National Health Research Ethics Sub-Committee (NatHREC) (Ref. No. NIMR\/HQ\/R.8a\/Vol. IX\/2752), and the Tanzania Medicines and Medical Devices Authority (TMDA) (Ref No. TFDA0018\/CTR\/0010\/01). All participants in the India and Tanzania trials will provide written informed consent for trial enrollment.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"No competing interests to report for any authors or trial staff member.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"838"}}