Nicklas Brustad, MD, on Maternal Vitamin D Supplementation and Offspring Bone Health

While previous research has suggested a relationship between maternal vitamin D status and anthropometry and bone mineralization in offspring, few studies on the topic have been conducted and results have been mixed.

To explore this association, researchers conducted an analysis of a double-blind, randomized clinical trial including 623 pregnant women and 584 children from the Copenhagen Prospective Studies on Asthma in Childhood 2010 mother-child cohort.

The participants were assigned 1:1 to receive either 2400 IU vitamin D3 (cholecalciferol) or matching placebo capsules from week 24 of pregnancy through the first week after birth. All of the participants were encouraged to also take 400 IU of vitamin D3 each day, as recommended by the Danish Health Authority. Because of this, the study dose comparison was 2800 IU/d (7-fold dose) vs 400 IU/d (standard dose).

Overall, results of a mixed-effects model analysis of dual-energy radiography absorptiometry scan outcomes from ages 3 years and 6 years showed that whole-body bone mineral content was higher among children in the vitamin D group vs those in the placebo group. The effects were greatest among children with mothers who were vitamin D deficient and children born during winter months. In a post hoc analysis, borderline lower incidence of fractures was observed in the vitamin D group, but no differences were observed in anthropometric outcomes.

Consultant360 reached out to study author Nicklas Brustad, MD, Copenhagen Prospective Studies on Asthma in Childhood (COPSAC), Herlev and Gentofte Hospital, University of Copenhagen, to discuss these findings further.

Consultant360: Few studies have investigated the relationship between maternal vitamin D status during pregnancy and its effects on childhood bone mineralization. How and why did you decide on this topic for your research?

Nicklas Brustad, MD: Before planning our double-blinded, randomized clinical trial, the important role of vitamin D in the pathophysiology of bone disorders such as rickets was already known. Interestingly, recent studies suggested that maternal gestational vitamin D status also seemed to influence offspring bone health, where low levels of vitamin D in pregnancy were linked to reduced bone mineralization status. Therefore, we decided to investigate whether the intervention of a high-dose (7-fold dose) compared with standard-dose of vitamin D during pregnancy would improve offspring bone health in childhood.

C360: For your study, you chose 400 IU/d and 2800 IU/d to represent standard- and high-dose supplementation. How did you decide on these dosages, and how do they compare to guideline-recommended levels of supplementation for pregnant women and for the population as a whole?

NB: The Danish Health Authority, and many other health authorities worldwide, recommends 400 IU of vitamin D per day to all pregnant women, which is similar to the standard-dose in the trial. The administration of 2800 IU of vitamin D per day as the high-dose to the pregnant women was chosen as this dose was the maximum dose approved by the local ethics committee. This dose compared with standard-dose resulted in higher vitamin D levels and improved offspring bone mineralization in our population-based mother-child cohort. Other studies have suggested even higher doses (up to 5000 IU/d) to be safe.  

C360: Overall, you observed a borderline lower incidence of fractures in the vitamin D group, but no differences in anthropometric outcomes. Was this outcome surprising to you?

NB: Our post hoc childhood fracture analysis, which is likely to be underpowered given the trial design, suggested a 40% reduced incidence of fractures in offspring from mothers receiving high-dose of vitamin D. We believe that this finding is clinically important as an indicator of bone strength at an early stage in life and may indicate a reduced risk of developing osteoporosis later in life. We already know that tracking of bone mineralization from early life to adulthood plays a major role in the final peak bone mass gained.

Our null finding on anthropometrics is in line with a recent meta-analysis of intervention trials with doses ranging up to 4000 IU per day, so this finding was not as surprising. 

C360: What knowledge gaps still exist in this area of study, and how could your results impact clinical practice?

NB: We demonstrated an effect of a 7-fold increased vitamin D intake in pregnancy on offspring bone mineralization status in the first 6 years of life in a general Danish population from a dose, which is considered safe in many studies. Further studies supporting this finding should be conducted, but our results may pave the way for possible new recommended guidelines of gestational vitamin D intake as vitamin D deficiency has increased during the last decades.

The fact that we found the largest effect in children born to mothers having low vitamin D levels or born during months with low sunlight exposure, suggests that other populations could benefit even more from this owing to different population characteristics. 

Reference:

Brustad N, Garland J, Thorsen J, et al. Effect of high-dose vs standard-dose vitamin D supplementation in pregnancy on bone mineralization in offspring until age 6 years: a prespecified secondary analysis of a double-blinded, randomized clinical trial. JAMA Pediatr. 2020;174(5):419-427. doi:10.1001/jamapediatrics.2019.6083