Effect of Vitamin D Replacement on Maternal and Neonatal Outcomes

Pregnancy Complications Clinical Trial

Official title:

Effect of Vitamin D Replacement on Maternal and Neonatal Outcomes: a Randomized Controlled Trial in Pregnant Women With Hypovitaminosis D

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02434380
• Other study ID #: AUBMC-GE-HF-2
• Secondary ID: AUBMC-IM-GE-HF-2
• Status: Completed
• Phase: Phase 3
• Start date: July 2015
• Est. completion date: October 2018

Study information

• Verified date: March 2023
• Source: American University of Beirut Medical Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 330
• Est. completion date: October 2018
• Est. primary completion date: October 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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

Related Conditions & MeSH terms

• Avitaminosis
• Hypovitaminosis D
• Infant, Newborn, Diseases
• Pregnancy Complications
• Rickets
• Vitamin D Deficiency

Intervention

Dietary Supplement:
• Euro D
Vitamin D3 Euro D 10,000 IU (1 tablet) plus Euro D Placebo (1 tablet) weekly, alternating with Euro D Placebo (2 tablets) weekly, starting at the second trimester and continued until delivery.
• Euro D
Vitamin D3 Euro D 10,000 IU (2 tablets, equivalent to 20,000 IU) weekly, starting at the second trimester and continued until delivery.

Locations

Country	Name	City	State
Lebanon	American University of Beirut	Hamra

Sponsors (3)

Lead Sponsor	Collaborator
American University of Beirut Medical Center	Bahman Hospital Beirut Lebanon, University of Southampton

Country where clinical trial is conducted

Lebanon, 

References & Publications (20)

Al-Shaar L, Mneimneh R, Nabulsi, Maalouf J, Fuleihan Gel-H. Vitamin D3 dose requirement to raise 25-hydroxyvitamin D to desirable levels in adolescents: results from a randomized controlled trial. J Bone Miner Res. 2014 Apr;29(4):944-51. doi: 10.1002/jbmr.2111. — View Citation

Arabi A, El Rassi R, El-Hajj Fuleihan G. Hypovitaminosis D in developing countries-prevalence, risk factors and outcomes. Nat Rev Endocrinol. 2010 Oct;6(10):550-61. doi: 10.1038/nrendo.2010.146. — View Citation

Bassil D, Rahme M, Hoteit M, Fuleihan Gel-H. Hypovitaminosis D in the Middle East and North Africa: Prevalence, risk factors and impact on outcomes. Dermatoendocrinol. 2013 Apr 1;5(2):274-98. doi: 10.4161/derm.25111. — View Citation

Dawodu A, Saadi HF, Bekdache G, Javed Y, Altaye M, Hollis BW. Randomized controlled trial (RCT) of vitamin D supplementation in pregnancy in a population with endemic vitamin D deficiency. J Clin Endocrinol Metab. 2013 Jun;98(6):2337-46. doi: 10.1210/jc.2013-1154. Epub 2013 Apr 4. — View Citation

De-Regil LM, Palacios C, Ansary A, Kulier R, Pena-Rosas JP. Vitamin D supplementation for women during pregnancy. Cochrane Database Syst Rev. 2012 Feb 15;2(2):CD008873. doi: 10.1002/14651858.CD008873.pub2. — View Citation

El-Hajj Fuleihan G, Nabulsi M, Tamim H, Maalouf J, Salamoun M, Khalife H, Choucair M, Arabi A, Vieth R. Effect of vitamin D replacement on musculoskeletal parameters in school children: a randomized controlled trial. J Clin Endocrinol Metab. 2006 Feb;91(2):405-12. doi: 10.1210/jc.2005-1436. Epub 2005 Nov 8. — View Citation

Harvey N, Dennison E, Cooper C. Osteoporosis: a lifecourse approach. J Bone Miner Res. 2014 Sep;29(9):1917-25. doi: 10.1002/jbmr.2286. — View Citation

Harvey NC, Moon RJ, Sayer AA, Ntani G, Davies JH, Javaid MK, Robinson SM, Godfrey KM, Inskip HM, Cooper C; Southampton Women's Survey Study Group. Maternal antenatal vitamin D status and offspring muscle development: findings from the Southampton Women's Survey. J Clin Endocrinol Metab. 2014 Jan;99(1):330-7. doi: 10.1210/jc.2013-3241. Epub 2013 Dec 20. — View Citation

Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM; Endocrine Society. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011 Jul;96(7):1911-30. doi: 10.1210/jc.2011-0385. Epub 2011 Jun 6. Erratum In: J Clin Endocrinol Metab. 2011 Dec;96(12):3908. — View Citation

Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011 Oct;26(10):2341-57. doi: 10.1002/jbmr.463. Erratum In: J Bone Miner Res. 2011 Dec; 26(12):3001. — View Citation

Hollis BW, Wagner CL. Vitamin D and pregnancy: skeletal effects, nonskeletal effects, and birth outcomes. Calcif Tissue Int. 2013 Feb;92(2):128-39. doi: 10.1007/s00223-012-9607-4. Epub 2012 May 24. — View Citation

Hoteit M, Al-Shaar L, Yazbeck C, Bou Sleiman M, Ghalayini T, Fuleihan Gel-H. Hypovitaminosis D in a sunny country: time trends, predictors, and implications for practice guidelines. Metabolism. 2014 Jul;63(7):968-78. doi: 10.1016/j.metabol.2014.04.009. Epub 2014 Apr 23. — View Citation

Javaid MK, Crozier SR, Harvey NC, Gale CR, Dennison EM, Boucher BJ, Arden NK, Godfrey KM, Cooper C; Princess Anne Hospital Study Group. Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study. Lancet. 2006 Jan 7;367(9504):36-43. doi: 10.1016/S0140-6736(06)67922-1. Erratum In: Lancet. 2006 May 6;367(9521):1486. — View Citation

Kovacs CS, Fuleihan Gel-H. Calcium and bone disorders during pregnancy and lactation. Endocrinol Metab Clin North Am. 2006 Mar;35(1):21-51, v. doi: 10.1016/j.ecl.2005.09.004. No abstract available. — View Citation

Mithal A, Wahl DA, Bonjour JP, Burckhardt P, Dawson-Hughes B, Eisman JA, El-Hajj Fuleihan G, Josse RG, Lips P, Morales-Torres J; IOF Committee of Scientific Advisors (CSA) Nutrition Working Group. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009 Nov;20(11):1807-20. doi: 10.1007/s00198-009-0954-6. Epub 2009 Jun 19. Erratum In: Osteoporos Int. 2009 Nov;20(11):1821. — View Citation

Morley R, Carlin JB, Pasco JA, Wark JD. Maternal 25-hydroxyvitamin D and parathyroid hormone concentrations and offspring birth size. J Clin Endocrinol Metab. 2006 Mar;91(3):906-12. doi: 10.1210/jc.2005-1479. Epub 2005 Dec 13. — View Citation

Nassar N, Halligan GH, Roberts CL, Morris JM, Ashton AW. Systematic review of first-trimester vitamin D normative levels and outcomes of pregnancy. Am J Obstet Gynecol. 2011 Sep;205(3):208.e1-7. doi: 10.1016/j.ajog.2011.03.058. Epub 2011 Apr 7. — View Citation

Parkes I, Schenker JG, Shufaro Y. Parathyroid and calcium metabolism disorders during pregnancy. Gynecol Endocrinol. 2013 Jun;29(6):515-9. doi: 10.3109/09513590.2012.754880. Epub 2013 Jan 25. — View Citation

Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011 Jan;96(1):53-8. doi: 10.1210/jc.2010-2704. Epub 2010 Nov 29. — View Citation

Thorne-Lyman A, Fawzi WW. Vitamin D during pregnancy and maternal, neonatal and infant health outcomes: a systematic review and meta-analysis. Paediatr Perinat Epidemiol. 2012 Jul;26 Suppl 1(0 1):75-90. doi: 10.1111/j.1365-3016.2012.01283.x. — View Citation

* Note: There are 20 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Composite outcome (incidence of C-section and gestational diabetes mellitus (GDM))	We will assess the incidence of a composite outcome (C-section and gestational diabetes mellitus (GDM)) in a subgroup of women who has no previous C-section.	At delivery
Other	Maternal weight		At delivery
Other	Maternal Blood Pressure (BP)		At delivery
Other	Number of ill days		At 28-32 weeks Gestational Age (GA) and at delivery
Other	Intrauterine fetal skeletal measures	We will collect intrauterine fetal skeletal measures including crown-rump, femur length, abdominal circumference, head circumference, biparietal diameter	At 11-13 weeks and at 20 weeks
Other	APGAR score	Proportion of neonates with low APGAR (<7) score at 1 and 5 minutes, at delivery	At delivery
Other	Neonatal weight		At birth
Other	Neonatal length		At birth
Other	Placental weight		At delivery
Other	Placental 1a hydroxylase activity		At delivery
Other	Sub-group analysis: The proportions of women who will reach the IOM defined desirable 25(OH)D level =20ng/ml.	Subgroup analysis based on baseline 25(OH)D, less than 20 ng/ml versus less than 30 ng/ml and season of birth will be performed	At delivery
Other	Sub-group analysis:Infant bone mineral content (BMC)	Subgroup analysis based on baseline 25(OH)D, less than 20 ng/ml versus less than 30 ng/ml and season of birth will be performed.	One month of age
Primary	The proportions of women who will reach the IOM defined desirable 25(OH)D level =20ng/ml.		At delivery
Primary	Infant bone mineral content (BMC)	We will assess Infant bone mineral content (BMC) by whole body dual-energy x-ray absorptiometry (DEXA) scan	one to six weeks
Secondary	Maternal 25(OH)D level	We will assess mean maternal 25(OH)D level	At delivery
Secondary	Neonatal 25(OH)D level, at delivery	We will assess mean neonatal 25(OH)D level	At birth
Secondary	Mean infant fat mass	We will assess Infant fat mass by whole body dual-energy x-ray absorptiometry (DEXA) scan	At one month of age
Secondary	Neonatal Knee to heel length at birth	We will assess neonatal Knee to heel length at birth using simple vernier calipers	At birth
Secondary	Maternal Parathyroid Hormone (PTH) Level	We will assess mean maternal PTH level	At delivery
Secondary	Neonatal Parathyroid Hormone (PTH) Level	We will assess mean neonatal PTH level	At birth
Secondary	Mean change in maternal urine calcium	We will assess the change in urine calcium level after 3 months of vitamin D supplementation.	Change between baseline and 3 months following intervention