Trial of Vitamin D Supplements to Raise Calcidiol Levels of Pregnant Women in Mongolia

Study Overview
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Brief Summary
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A double-blind randomized, placebo-controlled trial comparing the impact of 600 IU, 2000 IU, or 4000 IU of Vitamin D3 on third trimester 25(OH)D levels and change from baseline. The Vitamin D will be integrated in a standard prenatal vitamin, which will be taken from 12-16 weeks' gestation and continue throughout pregnancy. Umbilical cord 25(OH)D levels will also be determined. The investigators will generate preliminary data regarding Vitamin D intake and hypertensive disorders, blood pressure, and arterial function measured by tonography. The investigators will independently test blood pressure and proteinuria to identify preeclampsia cases.

Detailed Description
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Vitamin D deficiency (serum 25(OH)D levels <20 ng/ml or 50 nmol/l) is widespread among Mongolians and is nearly universal during the winter months. The investigators have conducted a series of studies which have shown nearly universal Vitamin D deficiency in the winter months. Observational studies in the U.S. have linked low 25(OH)D levels in women to a higher risk of preeclampsia. Mongolians also report levels of preeclampsia that are 3 times higher than those in the U.S (official reports cite 15%, though this may include gestational hypertension). Given the widespread Vitamin D deficiency in Mongolian women, the high prevalence of hypertensive pregnancy in Mongolia, and the observational studies linking low 25(OH)D levels with preeclampsia risk, the investigators are conducting a pilot Vitamin D dosing trial to: Determine what level of Vitamin D supplementation is needed to secure 25(OH)D levels of at least 20 ng/ml in pregnant Mongolian women Generate preliminary data in support of a funding application for a larger trial of Vitamin D supplements to prevent preeclampsia in Mongolia A double-blind randomized, placebo-controlled trial comparing the impact of 600 IU, 2000 IU, or 4000 IU of Vitamin D3 on third trimester 25(OH)D levels and change from baseline. The Vitamin D will be integrated in a standard prenatal vitamin, which will be taken from 12-16 weeks' gestation and continue throughout pregnancy. Umbilical cord 25(OH)D levels will also be determined. The investigators will generate preliminary data regarding Vitamin D intake and hypertensive disorders, blood pressure, and arterial function measured by tonography. The investigators will independently test blood pressure and proteinuria to identify preeclampsia cases. The investigators will enroll 360 women who plan to receive their prenatal care and deliver at Zuun Kharaa Hospital in the Selenge province in northern Mongolia. Enrollment will be stratified by season. 120 women will be randomized to each of the three doses of vitamin D (600, 2000, 4000 IU) included in a standard prenatal vitamin. Calcemia will be monitored two months after randomization and weeks 36-40 of pregnancy. Adverse events of pregnancy will be reported to the Data Safety and Monitoring Board (DSMB) and Institutional Review Board (IRB) per protocol. Data will be gathered by a Mongolian study coordinator and local clinicians. A DSMB comprised of a U.S. and Mongolian clinicians and statisticians will monitor study data for safety.

Official Title
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Trial of Vitamin D Supplements to Raise Calcidiol Levels of Pregnant Women in Mongolia

Conditions
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Pregnancy, Vitamin D Deficiency

Intervention / Treatment
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* Dietary Supplement: 600 IU Vitamin D3 in prenatal vitamin
* Dietary Supplement: 2000 IU Vitamin D3 in prenatal vitamin
* Dietary Supplement: 4000 IU Vitamin D3 in prenatal vitamin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 or older 12-16 weeks pregnant Receiving prenatal care at Zuun Kharaa Hospital and planning to deliver at Zuun Kharaa Hospital Willing not to take any additional vitamin D supplements, other than the study dispensed pills Exclusion Criteria: Existing known seizure disorder, renal failure, parathyroid disease, thyroid disease, sarcoidosis, cancer, or tuberculosis. (Tuberculosis is routinely screened in pregnancy) History of kidney stones Known sensitivity to multivitamin preparations Taking vitamin D supplements containing >600 IU/day.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: 600 IU<br>Women will receive prenatal vitamins containing 600 IU of Vitamin D. | Dietary Supplement: 600 IU Vitamin D3 in prenatal vitamin<br>* Women will receive 600 IU 25(OH)D in prenatal vitamin.<br>|
| Experimental: 2000 IU<br>Women will receive prenatal vitamins containing 2000 IU of Vitamin D. | Dietary Supplement: 2000 IU Vitamin D3 in prenatal vitamin<br>* Women will receive 2000 IU 25(OH)D in prenatal vitamin.<br>|
| Experimental: 4000 IU<br>Women will receive prenatal vitamins containing 4000 IU of Vitamin D. | Dietary Supplement: 4000 IU Vitamin D3 in prenatal vitamin<br>* Women will receive 4000 IU 25(OH)D in prenatal vitamin.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Serum 25(OH)D Concentration | Circulating vitamin D at the end of the study as measured by VIDAS® enzyme linked fluorescent assay (ELFA) | 36 weeks gestation or delivery, if delivery occurred before 36 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of Participants With Preeclampsia | Preeclampsia as measured by new onset hypertension after 20 weeks gestation and proteinuria. | After 20 weeks gestation | 
| Average Monthly Blood Pressure | Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) were measured in mm Hg at each antenatal care visit by the Study Coordinator, using the Omron- Elite 7300 (Omron Healthcare, Bannockburn, Illinois, USA) automated blood pressure monitor. Three blood pressure readings were taken after at least five minutes seated rest. For the analysis of mean blood pressures at each antenatal visit, the three readings were averaged for each participant. | During pregnancy | 
| Arterial Tonometry | Investigators will assess Augmentation Index (AIx) and Pulse Wave Velocity (PWV) by study arm, as measured by AtCor Medical SphygmoCor device. THIS TONOMETER FAILED AND COULD NOT BE REPAIRED, SO WE ARE NOT PRESENTING THESE DATA AS OUTCOMES. | 36 weeks gestation | 
| Number of Patients With Preterm Delivery as Measured by Clinical Diagnosis | Gestational age was determined clinically by last menstrual period and by routine first trimester ultrasound which was universal; where these differed by more than 10 days, the ultrasound date was used. Gestational age at delivery was recorded by clinicians and rounded to the nearest week. Preterm delivery was defined as delivery before the 37th week of gestation. | During pregnancy | 
| Casarean Section as Measured by Medical Record Abstraction | Cesarean section was abstracted from the labor and delivery chart. | Delivery | 
| Assisted Vaginal Delivery as Measured by Medical Record Abstraction | Assisted vaginal delivery with forceps delivery was abstracted from the labor and delivery chart. | Delivery | 
| Number of Small for Gestational Age (SGA) Neonates as Measured by Medical Record Abstraction | SGA defined by the lowest 10th percentiles of sex-specific birthweight for gestational age charts of the INTERGROWTH-21st study | Delivery | 
| Number of Large for Gestational Age (LGA) Neonates as Measured by Medical Record Abstraction | LGA defined by the highest 10th percentiles of sex-specific birthweight for gestational age charts of the INTERGROWTH-21st study | Delivery | 
| Mean Calcemia as Measured by Serum Calcium Test (2mo) | Measured on a semi-automated photometer (Humalyzer 3500, Human Diagnostics, Magdeburg, Germany) | 2 months after randomization | 
| Number of Patients With Proteinuria as Measured by Urine Dipstick | Proteinuria at last antenatal visit (usually 36-40 weeks' gestation), measured by 1+ Standard Diagnostics UroColor 10 10 (Kyonggi-do, South Korea) reagent strips | 36-40 weeks gestation/delivery | 
| Number of Patients With Hypertensive Disorders of Pregnancy as Measured by Clinical Diagnosis | In Mongolia, clinician-diagnosed preeclampsia may include a blood pressure increases >30 mm Hg above early pregnancy, with or without documented hypertension, proteinuria, or symptoms such as headache and edema | During pregnancy | 
| Number of Patients With Bacterial Vaginosis as Measured by Potassium Hydroxide (KOH) Wet Mount | Bacterial vaginosis was routinely screened by potassium hydroxide wet mount at the first antenatal visit, at 28 weeks' and 32 weeks' gestation. It was also diagnosed by whiff test. We included both wet mount and whiff test positive in the bacterial vaginosis endpoint | During pregnancy | 
| Mean Calcemia as Measured by Serum Calcium Test (36-40 Weeks) | Measured on a semi-automated photometer (Humalyzer 3500, Human Diagnostics, Magdeburg, Germany) | 36-40 weeks of pregnancy/delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pregnancy, Mongolia, Vitamin D, preeclampsia