Prevention of Adverse Pregnancy Outcome With Vitamin D Supplementation During Pregnancy
|First Received Date ICMJE||August 15, 2011|
|Last Updated Date||April 21, 2016|
|Start Date ICMJE||September 2010|
|Primary Completion Date||May 2012 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Prevention of adverse pregnancy outcome, viz preeclampsia, small for gestational age (SGA), preterm labor [ Time Frame: 18 months ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT01418664 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE
||Cord levels and maternal serum levels of 1,25(OH), after supplementation at the time of delivery. [ Time Frame: 18 months ]|
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Prevention of Adverse Pregnancy Outcome With Vitamin D Supplementation During Pregnancy|
|Official Title ICMJE||Prevention of Adverse Pregnancy Outcome With Vitamin D Supplementation During Pregnancy|
|Brief Summary||We hypothesized that vitamin D supplementation during pregnancy can prevent adverse pregnancy outcome.|
Vitamin D deficiency has been associated with many chronic diseases. These include cardiovascular diseases, diabetes mellitus, multiple sclerosis, breast and prostate cancers. Recently, its role in pregnancy has been explored. Vitamin D deficiency has been found to be associated with adverse pregnancy outcome. These include pre eclampsia, gestational diabetes mellitus, preterm labor and low birth weight.
Bodnar et al, evaluated role of vitamin D deficiency during pregnancy in PE in a nested case control study. The investigators looked at the role of vitamin D at gestational age of < 22 weeks. Women who developed PE were found to have low levels of vitamin D. These women had serum levels of vitamin D < 15 ng/ml, were supplemented during pregnancy with prenatal vitamins, were still found to have 5 fold greater chances of developing PE (adjusted odds ratio, 5.0; 95% confidence interval, 1.7-14.1).Children of above group of women were also found to have low levels of vitamin D. The authors concluded that vitamin D deficiency may be an independent factor for the development of PE.(1)
In an epidemiological study from Norway, involving 23,423 primigravidae, the rsik of PE was found to be 27% greater in women who did not receive D supplements, compared to women who received 10-15µg/day of vitamin D(2).
Circulating levels of 1-25(OH) have been found to be low in women with PE.(3) This has been attributed to reduced expression and activity of 1α-hydroxylase in human placenta from preeclamptic pregnancies.(4) This association with PE has also been found to be influenced by VEGF (Vascular endothelial growth factor). Active forms of vitamin D have been found to increase the expression of VEGF , and its release in vascular smooth cells, in in-vitro studies.(5)
Vitamin D deficiency has also been associated with small for gestational age (SGA) (6) The difference has been found to be more subtle for Caucasians as compared to African-Americans in West. The investigators showed a U shaped association between D levels and SGA. After confounder adjustment, compared with serum 25(OH)D 37.5-75 nmol/L, SGA odds ratios (95% CI) for levels <37.5 and >75 nmol/L were 7.5 (1.8, 31.9) and 2.1 (1.2, 3.8), respectively. In a similar study by Brooke, among Asian women resident in UK, vitamin D supplementation with 1000IU in third trimester, compared with placebo, was associated with decreased incidence of small for gestational age (15% versus 29%). Investigators suggested supplementation with vitamin D among Asians living in UK.(7)
Vitamin D deficiency has been related to gestational diabetes mellitus (GDM) in pregnant women. Zhang et al, found that vitamin D deficiency in early pregnancy is linked with increased risk for GDM. Vitamin D deficiency was associated with a 2.66-fold (OR (95% CI): 2.66 (1.01-7.02)) increased GDM risk. Moreover, each 5 ng/ml decrease in 25-[OH] D concentrations was related to a 1.29-fold increase in GDM risk (OR (95% CI): 1.29 (1.05-1.60)).(8) Similarly, in an Iranian study, women who were found to have GDM, were found to have lower levels of serum 1,25 (OH), as compared to normoglycemic women. (9) Serum levels of <12 nmol/L were found associated with GDM. This may be linked to the fact that 1,25(OH) stimulates insulin secretion.
Vitamin D deficiency has also been linked to increased risk for cesarean section. In a study of 253 women, who underwent cesarean section, multivariable logistic regression analysis controlling for race, age, education level, insurance status, and alcohol use, women with 25(OH)D less than 37.5 nmol/liter were almost 4 times as likely to have a cesarean than women with 25(OH)D 37.5 nmol/liter or greater (adjusted odds ratio 3.84; 95% confidence interval 1.71 to 8.62).(10) Poor muscular performance due to vitamin D deficiency may be the reason for the increased cesarean section rate.
Preterm labor, is the other adverse pregnancy outcome, which is thought to be affected by maternal serum levels of 1,25(OH). In a recently concluded RCT, a comparison was made between 400IU, 2000IU and 4000IU of daily supplementation with vitamin D. Women who were prescribed highest doses had significant less chances of spontaneous preterm birth at < 37 and at < 32 weeks.(11) Inflammation plays a key role in the etiology of preterm labor. And vitamin D is known to influence the production of inflammatory mediators like interleukin 1, interleukin -6 and tumor necrosis factor by macrophages.(12) This may be a reason for decreased incidence of preterm birth in women who received vitamin D supplementation.
Birth weight of newborn is also affected by maternal serum D levels. In a study from neighboring Iran, of 449 women, birth weight, length and apgar score were significantly better in women who took diet adequate in calcium and vitamin D.(13) Vitamin D supplementation during pregnancy leads to increased calcium stores in infants and improved weight gain as well. Levels < 25ng/ml are associated with rickets and osteomalacia. There is positive correlation between maternal and neonatal cord levels of vitamin D. This relationship has also been shown in studies from other part of world. (14-16)This indicates that these newborns are entering the world, with deficiency of vitamin D, which starts in utero. Apart from affecting skeletal development, it also affects the innate immune system of newborn. In a case-control study, children who were deficient in vitamin D were found to be more prone to acute respiratory tract infections. The mean serum 25(OH)D concentrations in the study group newborns were lower than those of the control group (9.12+/-8.88 ng/ml and 16.33+/-13.42 ng/ml, respectively) (P=0.011). (17) It has been observed that infants born to D replete mothers will become D deficient, 8 weeks after birth, unless they are supplemented with vitamin D. In an earlier cross sectional study, from Karachi city Atiq M, had found low levels of vitamin D in newborns who were breastfed. The age group was from 6 weeks to 11 months. Thirty-four (48%) mothers and 37 (52%) infants had levels less than 25 nmol/ L (i.e. <10ng/ml). The investigators found a significant correlation between serum 25(OH)D levels of infants under three months of age and their mothers (p<0.01).(18) Though this study was carried out in a private university hospital, where majority of mothers belonged to upper socio economic class.
Content of vitamin D in breast milk is dependant upon the serum levels in mothers. Supplementation of lactating mothers has been recommended to avoid deficiency in newborn, but is not a norm in our practice. There is also increased motivation for exclusive breast feeding for the first 4-6 months in our society. Hence with prevalence of vitamin D deficiency as high as 90% in our population (data submitted for publication), our newborns are more at risk for vitamin D deficient rickets
|Study Type ICMJE||Interventional|
|Study Phase||Not Provided|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
|Intervention ICMJE||Dietary Supplement: D Max drops
Women in study arm will be cases, and will recieve ferrous sulphate and calcium lactate, along with 4000IU D Max drops
|Publications *||Hossain N, Kanani FH, Ramzan S, Kausar R, Ayaz S, Khanani R, Pal L. Obstetric and neonatal outcomes of maternal vitamin D supplementation: results of an open-label, randomized controlled trial of antenatal vitamin D supplementation in Pakistani women. J Clin Endocrinol Metab. 2014 Jul;99(7):2448-55. doi: 10.1210/jc.2013-3491. Epub 2014 Mar 19.|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Completion Date||May 2012|
|Primary Completion Date||May 2012 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years to 45 Years (Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Pakistan|
|Removed Location Countries|
|NCT Number ICMJE||NCT01418664|
|Other Study ID Numbers ICMJE||786
other Grant ( Other Grant/Funding Number: Pakistan Medical Research Council )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Nazli Hossain, Dow University of Health Sciences|
|Study Sponsor ICMJE||Dow University of Health Sciences|
|Collaborators ICMJE||Yale University|
|PRS Account||Dow University of Health Sciences|
|Verification Date||April 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP