Vitamin D and Schizophrenia

A number of studies have suggested an association between an increased risk of schizophrenia and being born in winter months. However, it is not clear why this is. There are a number of possible explanations for the association, such as an increase in maternal infections during the winter, seasonal availability of fruits and vegetables during pregnancy, or an increase in environmental toxins during the summer. Another explanation put forward is exposure to and levels of prenatal vitamin D. A research team from Australia and Denmark [1] looked at archived dried blood spots taken at the birth of 1,301 Danes who had received a schizophrenia diagnosis, and compared them to those taken from matched controls. They found that those in the lowest quintile for vitamin D concentration had a significantly increased risk of schizophrenia (incidence rate ratio = 1.44, 95%CI 1.12-1.85, p=0.004). Their level of vitamin D was consistent with the standard definition of being vitamin D deficient. Further analyses also showed that there were seasonal fluctuations in vitamin D levels, with the lowest being found in people born in winter or spring. The authors suggest conducting an RCT to provide vitamin D supplements to pregnant women should be the next step, though the CLAHRC WM Director does not think the sample size calculation would ‘stand up’.

— Peter Chilton, Research Fellow

Reference:

1. Eyles DW, Trzaskowski M, Vinkhuyzen AAE, et al. The association between neonatal vitamin D status and risk of schizophrenia. Nature Scientific Reports. 2018; 8: 17692.

Corroboration of Previous Reports on Vitamin D and on Coffee

In recent News Blogs we have provided evidence that vitamin D and calcium are useless in preventing osteoporotic fractures in elderly people with no obvious risk factors.[1] [2] This is now powerfully corroborated in a paper in JAMA by Zhao, et al.,[3] who carried out a systematic review and meta-analysis involving over 50,000 participants. They found absolutely no beneficial or harmful effects of either vitamin D or calcium or a combination of the two compared to placebo in reducing the risk of either vertebral hip or other non-vertebral fractures. The absolute risk difference was zero with an upper confidence limit of 0.01. Hopefully this puts the matter to bed once and forever.

Likewise a recent umbrella review in the BMJ [4] corroborated previous news blogs on the generally health promoting effects of coffee.[5] It would appear that these benefits are also seen in equal measure with de-caffeinated coffee, suggesting that it is the other components of coffee that benefit health.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Effects of Vitamin D Supplements. NIHR CLAHRC West Midlands News Blog. 24 March 2017.
2. Lilford RJ. Yet Another Null Result on Vitamin D and Calcium Supplementation in Older Women. NIHR CLAHRC West Midlands News Blog. 5 May 2017.
3. Zhao J-G, Zeng X-T, Wang J, et al. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. JAMA. 2017; 318(24): 2466-82.
4. Poole R, Kennedy OJ, Roderick P, Fallowfield JA, Hayes PC, Parkes J. Coffee consumption and health: umbrella review of meta-analyses of multiple health outcomes. BMJ. 2017; 359: j5024.
5. Lilford RJ. Should You Keep Drinking Coffee? NIHR CLAHRC West Midlands News Blog. 1 September 2017.

Antioxidants and Age-Related Macular Degeneration

It is estimated that around 5% of the general population suffer from age-related macular degeneration (AMD),[1] where extracellular material known as drusen accumulate under the retina at the back of the eye and which can eventually lead to blurred or a loss of vision. It has been suggested that antioxidants may help prevent or delay development of AMD in people who do not suffer the condition by protecting the retina against oxidative stress, but it is unclear as to whether this is the case.

A systematic review in the Cochrane Database by Evans and Lawrenson looked at the effectiveness of antioxidant supplements as treatment in people who already had AMD,[2] and found that taking a multivitamin antioxidant vitamin may delay the progression of AMD when compared to a placebo or no treatment (odds ratio 0.72, 95% CI 0.58-0.90). The authors also conducted a systematic review looking at whether there was an association between taking antioxidant vitamins (carotenoids, vitamin C, vitamin E) or minerals (selenium, zinc) and the development of AMD in people without AMD.[3] Five RCTs were included, with a total of 76,756 individuals without AMD. These studies all looked at the use of various supplements against placebo. Generally, the various studies found that there was no effect of supplements on development of AMD, while in some cases there was evidence of an increased risk (see table below).

Comparison	No. of studies	Disease	Risk Ratio (95% Confidence Interval)
Vitamin E vs. placebo	4	AMD	0.97 (0.90-1.06)
		Late-stage AMD	1.22 (0.89-1.67)
Beta-carotene vs. placebo	2	AMD	1.00 (0.88-1.14)
		Late-stage AMD	0.90 (0.65-1.24)
Vitamin C vs. placebo	1	AMD	0.96 (0.79-1.18)
		Late-stage AMD	0.94 (0.61-1.46)
Multivitamin vs. placebo	1	AMD	1.21 (1.02-1.43)
		Late-stage AMD	1.22 (0.88-1.69)

— Peter Chilton, Research Fellow

References:

1. Owen CG, Jarrar Z, Wormald R, Cook DG, Fletcher AE, Rudnicka AR. The estimated prevalence and incidence of late stage age related macular degeneration in the UK. Br J Ophthalmol. 2012; 96(5): 752-6.
2. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000254.
3. Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for preventing age-related macular degeneration. Cochrane Database Sys Rev. 2017; 7: CD000253.

Yet Another Null Result on Vitamin D and Calcium Supplementation in Older Women

Hard on the heels of the results of a systematic review in a recent blog,[1] yet another RCT of calcium and vitamin D in healthy people.[2] This time the end-point is cancer, and again the result is null. The authors call for yet more research but, again, one wonders whether this topic should not just be put to bed. It is true, of course, that exposure to sunlight is associated with lower risk of cancer, but this might not be a causal relationship, and even if it is, sunlight and oral vitamin D are not the same thing, just as oral and ovarian oestrogen are not equivalent.

— Richard Lilford, CLAHRC WM Director

References:

1. Lilford RJ. Effects of Vitamin D Supplementation. NIHR CLAHRC West Midlands News Blog. 24 March 2017.
2. Lappe J, Watson P, Travers-Gustafson D, et al. Effect of Vitamin D and Calcium Supplementation on Cancer Incidence in Older Women. A Randomized Clinical Trial. JAMA. 2017; 317(12): 1234-43.

Computer Interpretation of Foetal Heart Rates Does Not Help Distinguishing Babies That Need a Caesarean from Those That Do Not

In an earlier life I was involved in obtaining treatment costs for a pilot trial of computerised foetal heart monitoring versus standard foetal heart monitoring (CTG). The full trial, funded by NIHR, has now been published in the Lancet,[1] featuring Sara Kenyon from our CLAHRC WM theme 1. With over 46,000 participants the trial found no difference in a composite measure of foetal outcome or intervention rates. Perinatal mortality was only 3 per 10,000 women across both arms and the incidence of hypoxic encephalopathy was less than 1 per 1,000. Of course, the possibility of an educational effect from the computer decision support (‘contamination’) may have reduced the observed effect, but this could only be tested by a cluster trial. However, such a design would create its own set of problems, such as loss of precision and bias through interaction between method used and baseline risk across interventions and control sites. Also, the control group was not care as usual, but the visual display IT system shorn of its decision support (artificial intelligence) module.[2] Some support for the idea that control condition affected care in a positive direction, making any marginal effect of decision support hard to detect, comes from the low event rate across both study arms. Meanwhile, the lower than expected baseline event rates mean that any improvement in outcome will be hard to detect in future studies. So here is another topic that, like vitamin D given routinely to elderly people,[3] now sits below the “horizon of science” – the combination of low event rates and low plausible effect sizes mean that we can move on from this subject – at least in a high-income context. If you want to use the computerised method, and its costs are immaterial, then there is no reason not to; economics aside there appear to be no trade-offs here, since both benefits and harms were null.

— Richard Lilford, CLAHRC WM Director

References:

1. The INFANT Collaborative Group. Computerised interpretation of fetal heart rate during labour (INFANT): a randomised controlled trial. Lancet. 2017.
2. Keith R. The INFANT study – a flawed design foreseen. Lancet. 2017.
3. Lilford RJ. Effects of Vitamin D Supplements. NIHR CLAHRC West Midlands News Blog. 24 March 2017.

Effects of Vitamin D Supplements

Bolland and colleagues have written a lovely summary of the evidence on the effects of vitamin D supplements, with or without calcium, on health.[1] Their careful and comprehensive systematic overview based on a large sample, and providing narrow confidence limits, finds that there is no evidence that vitamin D, with or without calcium, reduces the risk of fractures in elderly people with no known bone disease. It is, as expected, efficacious in people with established osteomalacia. Systematic reviews of lower quality or based on per protocol analyses, tend to find the more optimistic results, but the data, taken in the round, yield a null result. The reviewers find that additional research is unlikely to further clarify the issue, as an effect of more than a 10% reduction in fracture has been ‘excluded’ by the existing studies. From a Bayesian perspective, further data are unlikely to have much effect on credible limits. The studies do not find any evidence that calcium plus vitamin D have either harmful or beneficial effects on the other (non-skeletal) outcomes, such as cancer or heart disease. Perhaps this is an example of the horizon of science; science cannot prove a null result, merely exclude a positive or negative effect beyond certain limits. We will never know everything, but let’s just forget about the use of vitamin D and calcium as prophylaxis in healthy people as any benefit must be nugatory – less than 10% relative risk reduction, which equates to a very small absolute reduction.

— Richard Lilford, CLAHRC WM Director

Reference:

1. Bolland MJ, Leung W, Tai V, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015; 350: h4580.

 

Golden Rice Controversy

Genetically modified rice – called ‘golden rice’ – can increase yields and, since it produces beta-carotene, can prevent the sequelae of vitamin A deficiency that is common in those with a predominantly rice-based diet. For an interesting article on the controversy over use of this GM crop in Bangladesh, and its potential costs-benefit, please read Uttam Deb’s article from the Copenhagen Consensus Center.[1]

— Richard Lilford, CLAHRC WM Director

Reference:

1. Deb U. Returns to Golden Rice Research in Bangladesh: An Ex-ante Analysis. Bangladesh Priorities, Copenhagen Consensus Center, 2016.

 

Vitamin A Supplementation at Birth in Populations with High Mortality and Putative Low Levels of Vitamin A

Three trials have recently reported on this topic from Ghana,[1] Tanzania,[2] and India [3] with a total of 100,038 participants. The African trials are statistically null with point estimates showing increased risk in the intervention group, while the Indian trial was borderline positive (at the 0.05 significance level). Taken in the round, results are null. Vitamin A supplementation also yields null results in separate studies of babies 1–5 months of age, but it is effective in older babies. The CLAHRC WM Director surmises that vitamin A only becomes effective once the child has reached an age where it has lost the passive immunity it acquired from its mother while it was in the womb.

— Richard Lilford, CLAHRC WM Director

References:

1. Edmond KM, Newton S, Shannon C, et al. Efficacy of early neonatal vitamin A supplementation on mortality during infancy in Ghana (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 1315-23.
2. Masanja H, Smith ER, Muhihi A, et al. Effect of neonatal vitamin A supplementation on mortality in infants in Tanzania (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 385: 1324-32.
3. Mazumder S, Taneja S, Bhatia K, et al. Efficacy of early neonatal supplementation with vitamin A to reduce mortality in infancy in Haryana, India (Neovita): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385: 1333-42.