A Randomized Clinical Trial of Oral Magnesium Supplementation in Pregnancy
Condition: Magnesium Deficiency; Preterm Birth; Extreme Immaturity
MeSH terms: Premature Birth; Magnesium Deficiency
Study type: Interventional
Phase: Phase 3

Summary: 
      The investigators propose a preventive strategy that may reduce the risk of placental
      vascular disease and its negative consequences for both the fetus (e.g., poor fetal growth or
      stillbirth)and mother (e.g., the hypertensive disorders of pregnancy), and which, in turn,
      should reduce the need for indicated preterm delivery. This strategy is a multicenter,
      randomized double-blind, placebo-controlled clinical trial (RCT) comparing magnesium citrate
      supplementation with placebo, each starting at 12 to 20 weeks gestation and continued until
      delivery. Magnesium citrate is a safe and inexpensive compound that is easily absorbed by the
      intestinal tract. The results of this RCT 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.
    

Detailed description: 
      The investigators will complete a multicenter double-blind, placebo-controlled randomized
      clinical trial of oral Mg++citrate supplementation.

      Setting: (1) Instituto de Medicina Integral Prof. Fernando Figueira (IMIP),
      Recife-Pernambuco: IMIP maintains the largest hospital in Brazil exclusively dedicated to
      Brazilian Health System, [Sistema Único de Saúde] (SUS). IMIP has 1,032 beds and performs
      more than 2,000 clinical daily visits. IMIP enrolls about 6,000 deliveries per year and has
      an obstetric intensive care unit. IMIP is a teaching hospital (degree programs in medicine,
      nursing, nutrition, physical therapy, pharmacology and psychology and postgraduate -
      residency, master and doctoral) and is a reference center to woman assistance in Northeast
      Brazil by the Ministry of Health of the Federal Government. (2) Dom Malan Hospital (HDM),
      Petrolina-Pernambuco: HDM assists the population of about 1 million people in 55
      municipalities of Pernambuco, Bahia and Piauí States. HDM assists about 1,500 pregnant women
      monthly in emergency service and performs an average of 528 prenatal visits including
      high-risk pregnancy (±35%). HDM enrolls about 600 deliveries/month and also has an obstetric
      intensive care unit. HDM has a teaching program for medical and nursing students and also
      develops a residence program.

      Data collection will be conducted from March 2014 to August 2015. Study population will be
      all pregnant women since they started their prenatal care visits at IMIP and/or HDM before
      20th gestational week.

      At a sample size of 1000 women assigned to placebo and 2000 women assigned to Mg++ citrate,
      with power of 80% and a 2-sided P-value of 0.05, we will be able to detect at least a 22%
      relative risk reduction in the primary perinatal composite outcome, assuming a primary
      perinatal composite outcome rate of 18% in the placebo group and 14% in the Mg++ group. In
      Recife there are 25,000 births a year. Of these 25,000, at least 30% (7,500) would attend one
      of the study prenatal clinics, & of those 7,500, 60% (4,500) would meet ≥1 of the eligibility
      criteria. With a participation rate of 50%, 2,250 women can be recruited in a year, thus
      requiring 1.25 years to recruit all women, and 2 years ascertain all primary outcome events.

      A systematic sample will be obtained from low risk pregnant women who begin prenatal care
      visits before 20th gestational week at IMIP or HDM, during the study period.

      Pregnant women admitted to the study will continue with their normal attendance at IMIP or
      HDM. There will be no interference by the researchers in obstetric management of patients
      involved in the study. All pregnant women will be followed until the postpartum and the
      newborn until hospital discharge.Hematologic and urine tests will be performed every month
      (four times) to evaluate Mg++ concentration from each pregnant woman. After inclusion in the
      study, pregnant women will be monitored monthly until delivery. Pregnant women who do not
      attend the clinic visit schedule, will be contacted by phone and/or visited. Losses after
      randomization will be registered with the respective reason.

      Randomization will be performed by the "Random Allocation" software, version 1.0. After
      signing the consent form each participant will be allocated to the "magnesium" or "placebo"
      group.

      Oral Mg++citrate, 150 mg twice daily. Each capsule will contained 150 mg of elemental
      magnesium citrate. The participants will be instructed to take one capsule twice daily until
      delivery.

      Compliance/adherence, adverse events, and clinical intercurrence will be monitored by the
      research team at each routine prenatal visit until the completion of the treatment. Adherence
      will be defined as the ingestion of at least 80% of the prescribed dose.

      Quality Control of Information: The forms will be completed by the researcher and stored in a
      specific folder. All data collection will be checked by a monitor.

      Analysis: Primary and secondary endpoints will be compared between groups. Continuous data
      will be tested using the unpaired two-tailed t-test (if normally distributed) and the
      Mann-Whitney U-test (if non-normally distributed). Fisher's exact test will be used for
      nominal data. A significance value <0.05 will be used in all tests.

      Ethical aspects: This project will be submitted to IMIP's and Dom Malan Hospital Committee on
      Ethical Research. Each participating woman in the study will sign an informed consent. They
      will be free to withdraw from the trial at any time. The trial will be conducted according to
      the WHO guidelines for good clinical trial practice.

      To ensure the safety of participants and the validity and integrity of the data a Data and
      Safety Monitoring Board (DSMB) will be created to follow the study. The DSMB will consist of
      5 experts members representing the following institutions and not involved with this trial:
      Bill and Melinda Gates Foundation, Ministry of Health of Brazilian Government, IMIP, Dom
      Malan Hospital and an statistician. The DSMB will periodically review the accumulated study
      data for pregnant women and fetus safety, study conduct, progress and efficacy. DSMB also can
      make recommendations to continuation, modification or termination of this trial.

      Conflict of interest: Nothing to declare. This project will be entered in the international
      registry of clinical trials.
    

Intervention name(s): Magnesium citrate
Intervention type(s): Drug
Intervention description(s): Oral Mg++citrate, 160 mg twice daily. Each capsule will contained 160 mg of elemental magnesium citrate. The participants will be instructed to take one capsule twice daily until delivery.
Other intervention name(s): Citrato de Magnésio
Intervention MeSH terms: Magnesium citrate
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Prevention
Keywords: magnesium; prematurity