Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT03537443 |
| Other study ID # |
1000060961 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 21, 2018 |
| Est. completion date |
February 5, 2020 |
Study information
| Verified date |
August 2020 |
| Source |
The Hospital for Sick Children |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Vitamin D deficiency in childhood leads to poor bone growth and muscle weakness, yet it is
unknown if the amount of vitamin D a woman consumes during her pregnancy affects her child's
bone and muscle development. In collaboration with researchers in Bangladesh, the
investigators recently completed a study of vitamin D supplementation during pregnancy in
which women were assigned to 1 of 5 groups containing vitamin D or placebo (no vitamin D).
The investigators now aim to conduct a follow-up study of a sample of 600 4 year old children
born to these mothers to test the possible effects of vitamin D supplementation in pregnancy
on children's bones, their body composition and the strength of their muscles.
Description:
Vitamin D is a modifiable regulator of bone mineral metabolism and muscle function; yet
little is known about the role of in utero vitamin D exposure on bone mineral accrual and
muscle development in early childhood. Observational findings suggest associations between
prenatal vitamin D status and infant bone, lean and fat mass and muscle function, but data
from intervention trials is either unavailable or limited to early infancy. The investigators
of the proposed study have previously shown that prenatal vitamin D supplementation safely
improves maternal-fetal vitamin D status and perinatal calcium metabolism. Given the current
interest in the potential role of vitamin D in perinatal health, adequately powered and
well-designed randomized trials are required to investigate the effect of maternal vitamin D
supplementation on offspring musculoskeletal health and body composition.
The investigators recently conducted the Maternal Vitamin D for Infant Growth (MDIG) trial
(NCT01924013), a randomized placebo-controlled dose-ranging trial of vitamin D
supplementation in pregnancy and lactation in Bangladesh, where severe vitamin D deficiency
is common. Women at 17-24 weeks' gestation were randomized to 1 of 5 dose groups comprising a
prenatal:postpartum regimen of placebo:placebo, 4200:0, 16800:0, 28000:0 or 28000:28000 IU
vitamin D3/week until 26 weeks postpartum. Enrolment (n=1300) was completed in September
2015, and all infants were delivered by February 2016. The MDIG trial was primarily designed
to determine the effect of maternal vitamin D on infant length at 12 months of age, with
follow-up continuing until infants reached 24 months of age (completed in March 2018).
In the proposed observational follow-up study, the investigators will leverage the design and
infrastructure of the MDIG trial to investigate effects of vitamin D on early childhood bone
and muscle outcomes in a sample of MDIG participants at 4 years of age (target n=600 with 120
participants per maternal vitamin D treatment group; to allow for an expected attrition rate
of 15%, the required sample size will be inflated to 140 children per group, giving an
overall target sample size of 700 children).
The primary objective is to quantify the effects of prenatal vitamin D supplementation versus
placebo on offspring total-body-less head (TBLH) bone mineral content and density. Secondary
objectives are to examine the effect of vitamin D on TBLH lean and fat mass, and muscle
function. Bone, lean and fat mass will be measured using dual-energy x-ray absorptiometry
(DXA). Muscle strength (handgrip test), anthropometry, dietary intake and vitamin D status
will also be assessed, in addition to biomarkers of bone turnover that may affect
musculoskeletal health in young children.
The proposed follow-up study of a large randomized trial will contribute new evidence
regarding the effects of vitamin D supplementation during pregnancy on musculoskeletal health
in childhood.
Data analysis
Owing to the large contribution of head BMC values to whole-body BMC, in addition to
difficulties in obtaining accurate head positioning without motion artifact in young
children, TBLH BMC will be considered as the primary outcome in the present study. While TBLH
BMC and TBLH areal BMD are closely related and complementary measures of bone mass, and both
will be examined in the main analyses, TBLH BMC will be considered as the primary outcome
measure. Whole-body measurements will be examined as secondary outcomes, in addition to BMC
and areal BMD measurements of the head alone. DXA-derived estimates of lean and fat mass will
also first be explored as TBLH measures, and later explored as whole-body measurements.
Primary analyses will be conducted without adjustment for covariates; however, adjustment for
concurrent body size, age or child sex will be explored in additional analyses.
Placebo versus high-dose prenatal vitamin D supplementation: To address the objectives with
maximum statistical efficiency, the 2 high-dose prenatal vitamin D groups will be combined
for a comparison of children of mothers who received 28000 IU/week of vitamin D prenatally
(with or without 28000 IU/week of vitamin D postpartum) versus those children whose mothers
received placebo prenatally. Differences will be expressed as mean differences with 95% CIs,
and tested for statistical significance using t-tests. In sub-group analyses, we will
stratify by baseline maternal vitamin D status (25(OH)D ≥ 30 nmol/L vs < 30 nmol/L) or infant
sex (boys vs girls). A restricted analysis will also be completed, limited to term-born
infants only (≥37 weeks' gestation).
Dose-response effect of prenatal and postpartum vitamin D supplementation: For the
dose-response analysis including data from all treatment groups, we will regress each outcome
(as a continuous variable) on the assigned dose of vitamin D (as a categorical variable)
during the prenatal period (with the 2 high-dose prenatal vitamin D treatment groups
combined). In this way, mean differences of each prenatal supplementation group will be
compared to the placebo group, to test the effect of prental supplementation only. We will
also regress each outcome on the average weekly dose of vitamin D assigned as a continuous
variable during the prenatal period. Similar regression models will be conducted using more
precise estimates of the vitamin D dose received, based on manufacturer analysis of the
vitamin D composition of each batch of tablets provided and individual compliance with study
tablets. We will use linear regression splines to accommodate non-linear outcome-dose
relationships if warranted based on non-parametric visualization (e.g. LOWESS). To ensure
precision of the 95% CIs, and therefore ensure robust inferences, 95% CIs from the linear
regression models will be obtained using bootstrapping (with 1000 replications).
To explore potential effects of prenatal only versus prenatal plus postpartum vitamin D
supplementation, a similar dose-response analysis will be conducted across all 5 treatment
groups (i.e., disaggregation of the 2 high-dose prenatal vitamin D groups), for which we will
regress each outcome (as a continuous variable) on the vitamin D treatment group assigned
during the prenatal and postpartum periods (as a categorical variable). Mean differences of
each supplementation group will therefore be compared to the placebo group. Estimates of the
95% CIs from all regression models will be obtained using bootstrapping (with 1000
replications).
Further exploratory analyses of primary and secondary outcomes: Multivariable regression
models will enable adjustment for other potential determinants of bone mass, muscle function
and body composition including: baseline covariates that differed by treatment group (if
present) and thus may confound treatment effects; child characteristics at the time of
assessment (e.g. vitamin D status); maternal characteristics (e.g. education level) and
socioeconomic status of the household. We will include measures of height or weight (e.g.,
height-for-age Z-scores) as covariates to test their roles in mediating the effect of the
vitamin D intervention on bone mass or other outcomes (muscle strength, body composition).
Linear regression models will also be used to assess between-group differences in calcium
metabolism and bone turnover markers.
