The BRAzil MAGnesium (BRAMAG) trial: a randomized clinical trial of oral magnesium supplementation in pregnancy for the prevention of preterm birth and perinatal and maternal morbidity

BMC Pregnancy and Childbirth

Joel G Ray¹  Angélica C Guimarães³  Isabelle E A Pontes²  Carla Adriane Fonseca Leal de Araújo²  Joao Guilherme B Alves² 

[1] Departments of Medicine, Obstetrics and Health Policy Management Evaluation, University of Toronto, St. Michael’s Hospital, 30 Bond Street, Toronto, ON M5B 1 W8, Canada;Department of Paediatrics, Instituto Materno Infantil Prof. Fernando Figueira-IMIP, Recife, Brazil;Dom Malan Hospital, Petrolina, Brazil

关键词: Stillbirth;    Small for gestational age;    Prematurity;    Preterm birth;    Perinatal;    Placenta;    Hypertension;    Preeclampsia;    Prevention;    Pregnancy;    Magnesium;   

Others  :  840667
DOI  :  10.1186/1471-2393-14-222

 received in 2014-06-10, accepted in 2014-07-04,  发布年份 2014

【 摘 要 】

Background

Preterm birth is the leading cause of infant mortality globally, including Brazil. We will evaluate whether oral magnesium citrate reduces the risk of placental dysfunction and its negative consequences for both the fetus and mother, which, in turn, should reduce the need for indicated preterm delivery.

Methods/Design

We will complete a multicenter, randomized double-blind clinical trial comparing oral magnesium citrate 150 mg twice daily (n = 2000 women) to matched placebo (n = 1000 women), starting at 12^1/7 to 20^6/7 weeks gestation and continued until delivery. We will include women at higher risk for placental dysfunction, based on clinical factors from a prior pregnancy (e.g., prior preterm delivery, stillbirth or preeclampsia) or the current pregnancy (e.g., chronic hypertension, pre-pregnancy diabetes mellitus, maternal age > 35 years or pre-pregnancy maternal body mass index > 30 kg/m²). The primary perinatal outcome is a composite of preterm birth < 37 weeks gestation, stillbirth > 20 weeks gestation, neonatal death < 28 days, or SGA birthweight < 3rd percentile. The primary composite maternal outcome is preeclampsia arising < 37 weeks gestation, severe non-proteinuric hypertension arising < 37 weeks gestation, placental abruption, maternal stroke during pregnancy or ≤ 7 days after delivery, or maternal death during pregnancy or ≤ 7 days after delivery.

Discussion

The results of this randomized clinical trial may be especially relevant in low and middle income countries that have high rates of prematurity and limited resources for acute newborn and maternal care.

Trial registration

ClinicalTrials.gov Identifier NCT02032186, registered December 19, 2013.

【 授权许可】

   
2014 Alves et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

【 参考文献 】

• [1]Preterm birth http://www.who.int/mediacentre/factsheets/fs363/en/ webcite
• [2]Rubens CE, Gravett MG, Victora CG, Nunes TM, GAPPS Review Group: Global report on preterm birth and stillbirth (7 of 7): mobilizing resources to accelerate innovative solutions (Global Action Agenda). BMC Pregnancy Childbirth 2010, 10(Suppl 1):S7.
• [3]Muglia LJ, Katz M: The enigma of spontaneous preterm birth. N Engl J Med 2010, 362:529-535.
• [4]Simhan HN, Caritis SN: Prevention of preterm delivery. N Engl J Med 2007, 357:477-487.
• [5]Romero R, Espinoza J, Kusanovic JP, Gotsch F, Hassan S, Erez O, Chaiworapongsa T, Mazor M: The preterm parturition syndrome. BJOG 2006, 113:17-42.
• [6]Seubert DE, Huang WM, Wasserman-Hoff R: Medical legal issues in the prevention of prematurity. Clin Perinatol 2007, 34:309-318.
• [7]Hubinont C, Debieve F: Prevention of preterm labour: 2011 update on tocolysis. J Pregnancy 2011, 2011:941057.
• [8]Flood K, Malone FD: Prevention of preterm birth. Semin Fetal Neonatal Med 2012, 17:58-63.
• [9]Estatísticas vitais http://www2.datasus.gov.br/DATASUS/index.php?area=0205 webcite
• [10]Blencowe H, Cousens S, Oestergaard MZ, Chou D, Moller AB, Narwal R, Adler A, Vera Garcia C, Rohde S, Say L, Lawn JE: National, regional, and worldwide estimates of preterm birth rates in the year 2010 with time trends since 1990 for selected countries: a systematic analysis and implications. Lancet 2012, 379:2162-2172.
• [11]Henderson JJ, McWilliam OA, Newnham JP, Pennell CE: Maternal factors associated with three phenotypes: spontaneous preterm labour, preterm pre-labour rupture of membranes and medically indicated preterm birth. J Matern Fetal Neonatal Med 2012, 25:642-647.
• [12]Ananth CV, Getahun D, Peltier MR, Salihu HM, Vintzileos AM: Recurrence of spontaneous versus medically indicated preterm birth. Am J Obstet Gynecol 2006, 195:643-650.
• [13]Zeitlin J, Ancel PY, Saurel-Cubizolles MJ, Papiernik E: The relationship between intrauterine growth restriction and preterm delivery: an empirical approach using data from a European case–control study. BJOG 2000, 107:750-758.
• [14]Barros FC, Victora CG, Matijasevich A, Santos IS, Horta BL, Silveira MF, Barros AJ: Preterm births, low birth weight, and intrauterine growth restriction in three birth cohorts in Southern Brazil: 1982, 1993 and 2004. Cad Saude Publica 2008, 24(Suppl 3):S390-S398.
• [15]Silveira MF, Victora CG, Barros AJ, Santos IS, Matijasevich A, Barros FC: Determinants of preterm birth: Pelotas, Rio Grande do Sul State, Brazil, 2004 birth cohort. Cad Saude Publica 2010, 26:185-194.
• [16]Clausson B, Cnattingius S, Axelsson O: Preterm and term births of small for gestational age infants: a population-based study of risk factors among nulliparous women. Br J Obstet Gynaecol 1998, 105:1011-1017.
• [17]Hershkovitz R, Erez O, Sheiner E, Bashiri A, Furman B, Shoham-Vardi I, Mazor M: Comparison study between induced and spontaneous term and preterm births of small-for-gestational-age neonates. Eur J Obstet Gynecol Reprod Biol 2001, 97:141-146.
• [18]Kase BA, Carreno CA, Blackell SC, Sibai BM: The impact of medically indicated and spontaneous preterm birth among hypertensive women. Am J Perinatol 2013, 30:843-848.
• [19]McCowan LM, Bulst RG, North RA, Gamble G: Perinatal morbidity in chronic hypertension. Br J Obstet Gynaecol 1996, 103:123-129.
• [20]Palo P, Erkkola R: Risk factors and deliveries associated with preterm, severely small for gestational age fetuses. Am J Perinatol 1993, 10:88-91.
• [21]Groom KM, North RA, Poppe KK, Sadler L, McCowan LM: The association between customised small for gestational age infants and pre-eclampsia or gestational hypertension varies with gestation at delivery. BJOG 2007, 114:478-484.
• [22]Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA: Cardiovascular health after maternal placental syndromes (CHAMPS): population-based retrospective cohort study. Lancet 2005, 366:1797-1803.
• [23]Roberts DJ, Post MD: The placenta in pre-eclampsia and intrauterine growth restriction. J Clin Pathol 2008, 61:1254-1260.
• [24]Salafia CM, Vogel CA, Vintzileos AM, Bantham KF, Pezzullo J, Silberman L: Placental pathologic findings in preterm birth. Am J Obstet Gynecol 1991, 165:934-938.
• [25]Ferraz EM, Gray RH: A case–control study of stillbirths in northeast Brazil. Int J Gynaecol Obstet 1991, 34:13-19.
• [26]Bring HS, Varli IA, Kublickas M, Papadogiannakis N, Petersson K: Causes of stillbirth at different gestational ages in singleton pregnancies. Acta Obstet Gynecol Scand 2014, 93:86-92.
• [27]Salafia CM, Pezzullo JC, López-Zeno JA, Simmens S, Minior VK, Vintzileos AM: Placental pathologic features of preterm preeclampsia. Am J Obstet Gynecol 1995, 173:1097-1105.
• [28]Bernal AL: The regulation of uterine relaxation. Semin Cell Dev Biol 2007, 18:340-347.
• [29]King DE, Mainous AG, Geesey ME, Woolson RF: Dietary magnesium and C-reactive protein levels. J Am Coll Nutr 2005, 24:166-171.
• [30]Nordic Council of Ministers: Nordic Nutrition Recommendations. Scand J Nutr 1996, 40:161-165.
• [31]Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, Institute of Medicine: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, And Fluoride. National Academies Pressin press
• [32]Mittendorf R, Dambrosia J, Dammann O, Pryde PG, Lee KS, Ben-Ami TE, Yousefzadeh D: Association between maternal serum ionized magnesium levels at delivery and neonatal intraventricular hemorrhage. J Pediatr 2002, 140:540-546.
• [33]Arikan GM, Panzitt T, Gücer F, Scholz HS, Reinisch S, Haas J, Weiss PA: Course of maternal serum magnesium levels in low-risk gestations and in preterm labor and delivery. Fetal Diagn Ther 1999, 14:332-336.
• [34]Wynn A, Wynn M: Magnesium and other nutrient deficiencies as possible causes of hypertension and low birthweight. Nutr Health 1988, 6:69-88.
• [35]Makrides M, Crowther CA: Magnesium supplementation in pregnancy. Cochrane Database Syst Rev 2001, 4:CD000937.
• [36]Harrison V, Fawcus S, Jordaan E: Magnesium supplementation and perinatal hypoxia: outcome of a parallel group randomised trial in pregnancy. BJOG 2007, 114:994-1002.
• [37]Walker AF, Marakis G, Christie S, Byng M: Mg citrate found more bioavailable than other Mg preparations in a randomised, double-blind study. Magnes Res 2003, 16:183-191.
• [38]Doyle LW, Crowther CA, Middleton P, Marret S, Rouse D: Magnesium sulphate for women at risk of preterm birth for neuroprotection of the fetus. Cochrane Database Syst Rev 2009, 1:CD004661.
• [39]Costantine MM, Weiner SJ, Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network: Effects of antenatal exposure to magnesium sulfate on neuroprotection and mortality in preterm infants: a meta-analysis. Obstet Gynecol 2009, 114:354-364.
• [40]Duley L, Gülmezoglu AM, Henderson-Smart DJ, Chou D: Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev 2010, 11:CD000025.
• [41]Rocha VS, Lavanda I, Nakano EY, Ruano R, Zugaib M, Colli C: Calcium and magnesium status is not impaired in pregnant women. Nutr Res 2012, 32:542-546.
• [42]Cholst IN, Steinberg SF, Tropper PJ, Fox HE, Segre GV, Bilezikian JP: The influence of hypermagnesemia on serum calcium and parathyroid hormone levels in human subjects. N Engl J Med 1984, 310:1221-1225.
• [43]Kawano Y, Matsuoka H, Takishita S, Omae T: Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension 1998, 32:260-265.
• [44]Rodríguez-Morán M, Guerrero-Romero F: Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Diabetes Care 2003, 26:1147-1152.
• [45]Lurie S, Gur D, Sadan O, Glezerman M: Relationship between uterine contractions and serum magnesium levels in patients treated for threatened preterm labour with intravenous magnesium sulphate. J Obstet Gynecol 2004, 24:247-248.
• [46]Lu JF, Nightingale CH: Magnesium sulfate in eclampsia and pre-eclampsia: pharmacokinetic principles. Clin Pharmacokinet 2000, 38:305-314.
• [47]Robinson RR, Murdaugh HV Jr, Peschel E: Renal factors responsible for the hypermagnesemia of renal disease. J Lab Clin Med 1959, 53:572-576.
• [48]Simchen MJ, Dulitzky M, Mashiach S, Friedman SA, Schiff E: Adjustment of magnesium sulfate infusion rate in patients with preterm labor. Am J Obstet Gynecol 1998, 179:994-998.