Clinical trial NCT02434380: Effect of Vitamin D Replacement on Maternal and Neonatal Outcomes
Official title: Effect of Vitamin D Replacement on Maternal and Neonatal Outcomes: a Randomized Controlled Trial in Pregnant Women With Hypovitaminosis D
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypovitaminosis D
Pregnancy Complications
Infant, Newborn, Diseases
Keywords: Vitamin D
Bone mineral content
Knee-heel length
Middle East
Lead sponsor: American University of Beirut Medical Center
Sponsor class: OTHER
Collaborators: name: University of Southampton
name: Bahman Hospital Beirut Lebanon
First posted: 2015-05-05
Enrollment: 330
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The optimal vitamin D replacement dose during pregnancy remains undefined. Therefore, the aim of this study is to test the hypothesis that a daily equivalent dose of vitamin D of 3,000 IU/day is needed for Middle Eastern women, to optimize maternal vitamin D level and neonatal musculoskeletal parameters, specifically knee-heel length at birth and bone mineral content at one month of age.

Detailed description: Hypovitaminosis D is prevalent worldwide across the lifecycle, including pregnant women, and particularly in the Middle East. It has been associated with adverse maternal and neonatal outcomes. While the Institute of Medicine (IOM) recommends 600 IU of vitamin D per day to reach a 25-Hydroxyvitamin D (25(OH)D) level ≥ 20 ng/ml, the Endocrine Society (ES) recommends 1,500-2,000 IU/day to reach a level ≥ 30 ng/ml, and the WHO guidelines do not recommend any supplementation as part of routine prenatal care. They do however underscore the fact that subjects with the lowest levels may be the ones to benefit most from vitamin D replacement. The benefits of such an approach and the doses needed to reach desirable levels have not been tested. This randomized trial proposes to do so, testing the effect of two vitamin D doses, a low dose of 600 IU daily and a high dose of 3,000 IU daily.

330 pregnant women, with 25(OH)D level 10-30 ng/ml during the early second trimester will be recruited form the American University of Beirut-Medical Center (AUB-MC), and Bahman Hospital. They will be randomized, in a double blinded fashion, to receive daily equivalent doses of cholecalciferol, 600 IU or 3,000 IU until delivery. Maternal clinical information and a food frequency questionnaire will be obtained at each visit until delivery. Maternal 25(OH)D and chemistries, including Calcium, creatinine, lipid profile, glucose and Insulin will be assessed at study entry, during third trimester and at delivery. Fetal measurements will be collected at study entry and during the second trimester. Neonatal anthropometric variables and venous umbilical cord 25(OH)D level will be measured at birth and infants will also undergo dual-energy x-ray absorptiometry (DEXA) scan assessment, for bone and fat mass, at one to 6 weeks. Maternal and neonatal genetic studies for vitamin D genes polymorphism, and other modules of placnetal calcium transport will be also performed.

Throughout the study, adverse events will be collected systematically and an independent Data and Safety Monitoring Board will be asked to review serious adverse events.

The percent of women achieving 25(OH)D ≥ 20ng/ml in the low dose will be compared to that in the high dose using Chi-Square. Independent t-test will be used to compare mean neonatal bone mineral content at one month of age between the 2 arms. For other outcomes, t-test will be used for continuous outcomes and Chi-square will be used for binary outcomes to compare means and proportions, respectively. The primary analysis is an intention-to-treat analysis (ITT) of unadjusted results. For the primary outcomes, p- values will be considered statistically significant if ≤ 0.025.

The investigators study would be the only randomized controlled trial in the Middle East, to investigate the recommended daily allowance for vitamin D, and the desirable dose to optimize neonatal musculoskeletal health, in women with low 25(OH)D levels, levels that are reflective of those in most countries from the Middle East.

Eligibility criteria: Inclusion Criteria:

* Pregnant women gestational age (GA)\< 14 weeks at screening visit. Middle Eastern woman (Middle East countries defined by WHO: Bahrain, Egypt, Iran, Iraq, Palestine, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Syria, , United Arab Emirates, Yemen)
* 25(OH)D level between 10ng/ml and 30ng/ml
* Age \> 18 years
* Vitamin D supplementation ≤ 200 IU daily (If daily vitamin D supplementation \> 200 IU daily, at enrollment, the pregnant women will be advised to adjust prenatal multivitamin doses in such a way that total vitamin D supplementation per week doesn't exceed 1400 IU per week, in consultation with primary Obstetric and Gynecology (OB-GYN) physician.)

Exclusion Criteria:

* 25(OH)D level \< 10 ng/ml or \> 30 ng/ml.
* Known metabolic bone disease
* Current medications likely to interfere with vitamin D metabolism (enzyme inducing anticonvulsants, anti -TB)
* Vitamin D supplementation \> 600 IU daily
* Pregnant women with twins

Primary outcomes:
measure: The proportions of women who will reach the IOM defined desirable 25(OH)D level ≥20ng/ml.
timeFrame: At delivery
measure: Infant bone mineral content (BMC)
timeFrame: one to six weeks
Secondary outcomes:
measure: Maternal 25(OH)D level
timeFrame: At delivery
measure: Neonatal 25(OH)D level, at delivery
timeFrame: At birth
measure: Mean infant fat mass
timeFrame: At one month of age
measure: Neonatal Knee to heel length at birth
timeFrame: At birth
measure: Maternal Parathyroid Hormone (PTH) Level
timeFrame: At delivery
measure: Neonatal Parathyroid Hormone (PTH) Level
timeFrame: At birth
measure: Mean change in maternal urine calcium
timeFrame: Change between baseline and 3 months following intervention
Other outcomes:
measure: Composite outcome (incidence of C-section and gestational diabetes mellitus (GDM))
timeFrame: At delivery
measure: Maternal weight
timeFrame: At delivery
measure: Maternal Blood Pressure (BP)
timeFrame: At delivery
measure: Number of ill days
timeFrame: At 28-32 weeks Gestational Age (GA) and at delivery
measure: Intrauterine fetal skeletal measures
timeFrame: At 11-13 weeks and at 20 weeks
measure: APGAR score
timeFrame: At delivery
measure: Neonatal weight
timeFrame: At birth
measure: Neonatal length
timeFrame: At birth
measure: Placental weight
timeFrame: At delivery
measure: Placental 1α hydroxylase activity
timeFrame: At delivery
measure: Sub-group analysis: The proportions of women who will reach the IOM defined desirable 25(OH)D level ≥20ng/ml.
timeFrame: At delivery
measure: Sub-group analysis:Infant bone mineral content (BMC)
timeFrame: One month of age
Locations:
city: Hamra
country: Lebanon
facility: American University of Beirut
Study officials:
affiliation: American University of Beirut Medical Center
name: Ghada El Hajj Fuleihan, Professor of Medicine
role: PRINCIPAL_INVESTIGATOR
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