High-dose vitamin D in pregnancy did not leave children with stronger bones at 13, a Danish trial found

Six years ago a Danish research group reported that children whose mothers took a high dose of vitamin D in late pregnancy had more mineral in their bones at ages 3 and 6. The same group has now scanned those children at 13. The advantage was gone.

The follow-up, published on September 25 in The Lancet Regional Health - Europe, found no difference in bone mineral between teenagers whose mothers had taken 2,800 international units a day and those whose mothers had taken the standard 400. Fractures up to age 13 did not differ either. The trial was not designed around bone, so it cannot exclude a small effect in either direction, and every mother took at least the standard dose.

Why vitamin D in pregnancy was tested for child bone

Vitamin D helps the body take up calcium and phosphate, which are the main components forming bone mineral. A baby’s skeleton is laid down before birth from what the mother supplies.

The longer-term hope concerns peak bone mass. Peak bone mass means the greatest amount of bone a person ever has, reached in early adulthood. The National Osteoporosis Foundation, a US body, has described raising it as an important strategy aimed at reducing risk of osteoporosis or low bone mass later in life. Osteoporosis is a condition in which bones become thin and break easily.

The Danish authors cite a calculation that shows why small early gains attract attention. A mathematical analysis has predicted that a 10% increase in peak bone mass around age 20 years could delay the osteoporosis risk later in adulthood by 13 years. If a few months of extra vitamin D before birth could nudge the skeleton onto a higher track for life, it would be a cheap way to prevent fractures decades later.

Studies that simply measured mothers’ vitamin D levels had pointed both ways. A large one, from the Avon Longitudinal Study of Parents and Children in England, covered 3960 mother-and-offspring pairs, mainly of white European origin. It found no relevant association between maternal vitamin D status in pregnancy and offspring BMC in late childhood. BMC stands for bone mineral content, the weight of mineral in the skeleton. Only a randomized trial could separate the vitamin from everything else that differs between mothers with high and low levels.

How the pregnancy vitamin D trial worked

The trial sits inside a Danish study of childhood asthma called COPSAC2010, run from Copenhagen. Its registration on ClinicalTrials.gov, the US government’s public register of trials, states the original purpose. The aim of this study is to prevent asthma symptoms (recurrent wheeze) in childhood, it says. Bone was a planned secondary question.

The Danish population-based COPSAC2010 cohort enrolled 623 mother-child pairs in pregnancy week 24, between March 2009 and November 2010. The women were assigned at random to one of two groups. One took 2,400 international units (IU) of vitamin D3 a day. International units are the standard measure of vitamin D dose, and 400 IU equals 10 micrograms. The other group took 2 placebo tablets with no active substance, identical to the active tablets.

On top of this, the plan for every woman included the 400 IU a day that the Danish Health Authority sets as the standard intake in pregnancy, making it a dose-comparison study of 2800 IU/day vs. 400 IU/day. No group was assigned to go without vitamin D. The tablets were taken from pregnancy week 24 until 1 week after birth.

The trial was double-blind, which means neither the families nor the researchers knew who was in which group. The study was unblinded at age 3 years, after the asthma question had been answered. Unblinded means the group assignments were revealed, so the scans and fracture counts at 6 and 13 came after that point. Women were not eligible if they already had an intake of more than 400 IU of vitamin D during the last 6 months.

After withdrawals before birth, 584 children were available for analysis. At 13 they were invited for a scan by dual-energy X-ray absorptiometry (DXA), a low-dose X-ray that measures how much mineral bones contain. The paper notes that the children were scanned for approximately 3 min in one movement, and that this method was chosen for its low radiation dose and short scan time. All scans were validated by two independent experienced specialists who did not know which group each child was in.

Two measures came from each scan. Bone mineral content is the total weight of mineral, in grams. Bone mineral density (BMD) is that mineral divided by the area of bone scanned. These outcomes were predefined secondary outcomes of the trial. A secondary outcome is a result a trial plans to report but was not sized to answer.

The team also counted broken bones. Fractures from birth to 13 were gathered from interviews with parents and from medical records, and all fractures were radiologically verified by physicians, meaning confirmed on an X-ray.

What the trial found in children’s bones at 13

At 13, 416 children (71%) had a whole-body DXA scan with 219 (53%) boys and 197 (47%) girls. Of the 297 children in the high-dose group, 212 were scanned. Of the 287 in the standard-dose group, 204 were.

Comparing the two groups, there were no differences in the overall population on any of the bone mineral outcomes. Total-body bone mineral content was 6.7 grams higher in the high-dose group, with a range from 28.3 grams lower to 41.6 grams higher. Total-body bone mineral density was 0.003 grams per square centimeter lower, with a range from 0.017 lower to 0.011 higher. Both ranges sit squarely across zero.

The researchers looked for a group in which the vitamin might still have mattered. They split the children by sex, by season of birth and by the mother’s vitamin D level before the tablets began. None of those groups showed a difference. Thirteen is an age when some children are well into puberty and others are not, and the paper reports that when adjusting for Tanner Stages reflecting puberty the results were unchanged. Tanner stages are a standard five-step scale of how far puberty has progressed.

Fractures told the same story. Among the 550 children (94%) followed all the way to 13, 114 fractures were registered, spread among 99 children. Of those fractures, 53 were in the high-dose group and 61 in the standard-dose group. The rate of a first fracture was 15% lower in the high-dose group, with a range from 43% lower to 25% higher. An interval that wide is compatible with a real reduction, with no change and with a modest increase.

The authors’ own summary is that there was no lasting effect of pregnancy supplementation with vitamin D on child bone mineralization and fracture risk.

What the same children showed at 3 and 6

An earlier advantage in the same trial did not last. In 2020 the group reported scans at ages 3 and 6 in JAMA Pediatrics, and concluded that high-dose vitamin D supplementation in pregnancy improved offspring bone mineralization through age 6 years compared with the standard dose. Whole-body bone mineral content was 11.5 grams higher in the high-dose group, with a range from 2.3 to 20.7 grams. There were 23 fractures in the high-dose group and 36 in the standard-dose group by then, a gap that fell just short of the usual test for ruling out chance.

On the strength of that, the 2020 paper said the result was suggesting an increased recommended gestational intake, which may influence peak bone mass, fracture risk, and risk of osteoporosis later in life. Gestational means during pregnancy.

A second paper went further. It combined the mother’s dose with the child’s own vitamin D level at six months. It counted a level of at least 75 nanomoles per liter of blood as sufficient. The 179 children at or above that level whose mothers had taken the high dose had a 60% reduced incidence of fractures compared with the 93 children below it whose mothers had taken the standard dose.

When the new analysis pooled all the scans from ages 3, 6 and 13, the overall difference was 3.79 grams of bone mineral content, with a range from 20.3 grams lower to 27.9 grams higher. The paper now describes the early benefit as a transient beneficial effect only observed in younger children. Transient means short-lived.

One thread from the earlier work survived in weaker form. Among children whose mothers took the high dose, those who also had sufficient levels, by the same definition, at 6 months had overall higher bone mineral content at 13. This was an exploratory comparison made after the main analysis, and children with good vitamin D levels at six months may differ from other children in many ways.

What other trials of pregnancy vitamin D and bone found

Few trials have tested the question. The paper says it is the first randomized trial to investigate long-term effects of prenatal high-dose vitamin D supplementation on offspring bone health.

The other large one is British. The Maternal Vitamin D Osteoporosis Study, known as MAVIDOS, recruited pregnant women from three study sites in the UK and assigned 1,134 of them to 1,000 IU a day or placebo. Its main result, in newborns, was null. Supplementation did not lead to increased offspring whole-body BMC compared with placebo.

Later scans of some of those children looked better. A total of 454 children were followed up at ages 6-7 y, all from one of the three sites. Vitamin D in pregnancy resulted in greater offspring BMD and lean mass in mid-childhood compared with placebo in this exploratory post-hoc analysis. Post hoc means the analysis was not part of the original plan. The size of the gain was similar to the Danish result at the same age.

The British team has not yet reported beyond that age. Their 2024 paper says further follow-up of this cohort of children during early adolescence is ongoing. The Danish authors write that it will be interesting to follow their trial to see whether the vitamin D effects attenuate in the same way. Attenuate means fade.

A third trial, in Dhaka, Bangladesh, found nothing at any age it examined. It followed 642 children to age 4 after their mothers had taken one of several weekly doses or placebo. The authors concluded that in a population with a high prevalence of vitamin D deficiency, vitamin D in pregnancy did not increase bone mineral or grip strength. They noted that all the women had also been given calcium, and that this co-intervention may have compensated for the relative vitamin D deficiency of women in the control group.

On other influences on young bones, the evidence is firmer. The National Osteoporosis Foundation’s position statement graded what is known about building peak bone mass. The best evidence (grade A) is available for positive effects of calcium intake and physical activity, it says, especially in late childhood and around puberty.

What the vitamin D trial cannot show

It was not sized for bone. The number of women was chosen to detect an effect on wheeze. The authors say they were potentially underpowered for bone because the study was powered for persistent wheeze/asthma. Underpowered means too small to detect a modest effect reliably. The ranges around the results leave room for a small benefit or a small harm.

Missing scans. The paper lists as a limitation 29% of the children not having a DXA scan performed at age 13 years. Children with and without a scan did not differ in their characteristics at the start of the trial.

Few fractures, analyzed after the fact. The authors point to the relatively few fractures in the post hoc analysis. They add that fracture risk among children is also correlated with physical activity and subsequent accidents not accounted for. An active child has more chances to break an arm, whatever their bone density.

Thirteen is an awkward age to measure. Bone density is hard to interpret around the teenage growth spurt, and the paper warns that areal BMD may decrease despite normal growth. Areal means calculated from the flat area of bone on the scan. Two kinds of scanner were also used, though neither showed an effect on its own.

It compared two doses. Both groups took at least 400 IU a day, and women already taking more than that were excluded. The trial says nothing about taking no vitamin D in pregnancy.

One country, one population. The 2020 report noted that all participants were Danish and white. The results describe children in that population.

Thirteen is not adulthood. Peak bone mass comes around age 20. The authors write that the question of whether vitamin D before birth changes it remains an important area of investigation for future research, while saying their own results do not support the idea.

The paper declares that the funding agencies did not have any role in design or conduct of the study, and the authors report no conflicts of interest.

Whether a vitamin D supplement, and at what dose, suits a particular person in pregnancy is assessed by their doctor.

A head start in bone mineral that was visible at 3 and 6 had disappeared by 13 in the one trial that has followed children that far.