Clinical Context

The role of vitamin D in pregnancy is controversial, and an editorial by Steer, which accompanies the current article, describes the conflicting evidence and recommendations regarding vitamin D supplementation during pregnancy. First, according to current standards from the US National Institutes of Health, nearly half of pregnant white women might be considered to be vitamin D deficient. The rate of vitamin D deficiency is even higher among pregnant women of color. This had led national societies in England and Canada to recommend the consideration of routine vitamin D supplementation among pregnant women at doses of 400 to 2000 IU daily.

However, other important health agencies recommend against routine testing of 25-hydroxyvitamin D (25[OH]D) levels during pregnancy or routine vitamin D supplementation. Some research has found no association between maternal 25(OH)D levels and outcomes such as recurrent preterm birth, diabetes, or mode of delivery. A systematic review found insufficient evidence regarding the potential benefits and harms of vitamin D supplements during pregnancy to make any meaningful practice recommendations.

The current study by Lawlor and colleagues addresses an important aspect of the controversy of vitamin D in pregnancy: the effect of maternal 25(OH)D levels on the bone density of offspring.

Study Synopsis and Perspective

A large, prospective cohort study has found no association between vitamin-D levels of mothers in pregnancy and the subsequent bone-mineral content of their children at age 9 years. The findings should lead to a reexamination of UK guidelines for vitamin-D supplementation in pregnancy, say the authors.

"We believe...that there is no strong evidence that pregnant women should receive vitamin-D supplementation to prevent low bone-mineral content in their offspring," say Debbie A Lawlor, PhD, from the University of Bristol, United Kingdom, and colleagues in their paper published online March 19, 2013, in the Lancet. However, they caution: "We cannot comment on other possible effects of vitamin D in pregnant women."

In an accompanying comment, Philip J Steer, MD, from Imperial College London, United Kingdom, notes that current UK (National Institute for Health and Clinical Excellence [NICE]) guidelines recommend that all pregnant and breast-feeding women should take a 10-µg vitamin-D supplement every day, despite prior inconsistent results of studies examining vitamin D and various outcomes in pregnancy. Similarly, the Canadian Paediatric Society recommends administering 2000 IU of vitamin D daily to pregnant and lactating women.

But in contrast, the American College of Obstetricians and Gynecologists concluded in July 2011 that "there is insufficient evidence to support a recommendation for screening all pregnant women for vitamin-D deficiency," he notes. The Americans further suggested that "vitamin-D supplementation during pregnancy beyond that contained in a prenatal vitamin should await the completion of ongoing randomized clinical trials," he observes.

Optimum Approach Unclear; Wait for Long-Term Trials

Given the new findings of Dr. Lawlor and colleagues, Dr. Steer says: "The safest approach is probably routinely to supplement pregnant women at greatest risk, as defined by the NICE guidelines: women of south Asian, black African, black Caribbean, or Middle Eastern origin; women who have limited exposure to sunlight (eg, those who are predominantly housebound or are generally fully covered when outdoors); women who eat a diet particularly low in vitamin D (eg, no oily fish, eggs, meat, or vitamin D-fortified margarine or breakfast cereal); and women with a body mass index higher than 30 kg/m² before pregnancy."

"For other women, the optimum approach is unclear, and long-term randomized trials of supplementation are justified," he stresses.

Largest Observational Study to Look at Vitamin D in Pregnancy

Dr. Lawlor's research is the largest-ever observational study of the effects of a mother's vitamin-D levels in pregnancy on her children’s bone health. Very low levels of vitamin D are known to cause rickets, and suboptimal levels can still cause thinning of the bones (osteomalacia), she and her colleagues note.

They assessed vitamin-D levels in 3960 pregnant women, mostly of white European origin, recording data from all 3 trimesters. When their children had reached an average age of 9 years and 11 months, their bone-mineral content — total body less head (TBLH; n=3960) and spinal (n=3196) was assessed using dual-energy X-ray absorptiometry.

Of the women, 2644 (67%) had sufficient, 1096 (28%) insufficient, and 220 (6%) deficient vitamin D, as measured by 25(OH)D concentrations, but TBLH and spinal bone-mineral content did not differ between offspring of mothers in the lower 2 groups vs sufficient 25(OH)D concentration.

No associations with offspring bone-mineral content were found for any trimester, including the third trimester, which is thought to be most relevant (TBLH bone-mineral content confounder-adjusted mean difference –0.03 g per 10.0 nmol/L; spinal bone-mineral content 0.04 g per 10.0 nmol/L).

In an interview with Lancet TV, Dr. Lawlor said this is a cohort study, "and you worry that what you are seeing is explained by confounding. We did a lot of sensitivity analysis, trying to unpick whether somehow we might have gotten [it] wrong, and we absolutely couldn't find anything."

'Normal' Vitamin-D Levels in Pregnancy Not Known

In his comment, Dr. Steer notes that an extensive review published this year concluded that long-term safety data on vitamin-D supplementation "remain limited," and other recent reports suggest "no link between maternal 25 (OH)D concentrations and important pregnancy outcomes such as recurrent preterm birth, diabetes, or mode of delivery." In addition, a 2012 review surmised that the evidence for vitamin-D supplementation in pregnancy was "too limited to draw any conclusions on usefulness and safety and...further rigorous randomized trials are required."

He adds that "a particular difficulty" in deciding who should be supplemented is "the paucity of studies to define the normal range of 25(OH)D...during pregnancy." Dr. Lawlor agreed: "In pregnant women, it's not really clear what a normal level [of vitamin D] should be; when you are pregnant, your whole physiology changes. The evidence for what is normal in pregnancy is not fully understood."

Dr. Steer goes on to explain, however, that black and Asian women routinely have lower concentrations of 25(OH)D, and notes that in published reports about cases of rickets from Canada and the United Kingdom, the majority of affected children are nonwhite. In the Canadian report, 92% of those with rickets had dark skin, and only 1 out of 74 infants with rickets in the UK study was of white European origin (62% were Asian).

Hence his recommendation that women with dark skin and others who might be vitamin-D deficient due to diet or other reasons probably should still routinely receive vitamin-D supplements in pregnancy.

Dr. Lawlor and colleagues as well as Dr. Steer have disclosed no relevant financial relationships.

Lancet. Published online March 19, 2013. Abstract

Clinical Implications

• Many pregnant women may be considered to be deficient for vitamin D, particularly women of color. Conflicting evidence exists as to whether 25(OH)D levels or vitamin D supplementation is important for pregnancy and childhood outcomes. Nonetheless, some national societies recommend the consideration of routine supplementation with vitamin D during pregnancy.
• In the current study by Lawlor and colleagues, maternal 25(OH)D levels in any trimester failed to significantly affect the bone-mineral content of offspring.

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