Vitamin D as Calcifediol is now available in the UK

 Calcifediol

Calcifediol available in Spain

During the Covid-19 pandemic of 2020 there was a great deal of  pressure on the intensive care units of our hospitals to admit patients who were seriously ill, and there appeared to be no way of preventing this. 

However, there was good news from Córdoba in Spain.

Before the pandemic I was aware of the importance of optimising defensive immunity so as to minimise the effect of infection on our bodies. The way to achieve this was to correct vitamin D deficiency, knowing of the vital importance of vitamin D in initiating and maintaining the necessary escalation of the defensive immune process at the time of infection. It was also known that vitamin D deficiency is very common.

Vitamin D in critical care

When I was attempting to advocate the use of vitamin D in the community and in the hospitals at the time of the emergence of the Covid-19 pandemic, my attention was drawn to a research paper published in the New England Journal of Medicine in December 2019. This paper described that the use of vitamin D when given to patients in an intensive care unit conferred no advantage compared to patients who had not received vitamin D. 

The study was a randomised controlled trial (RCT) involving 1360 patients who were vitamin D deficiency and who required intensive care support. 1078 were severely deficient with blood levels of vitamin D less than 20ng/ml (50nmol/L). The half who were randomised to receive vitamin D were given a single dose of 540,000 units by mouth or by feeding tube.

https://www.nejm.org/doi/full/10.1056/NEJMoa1911124

This was very discouraging as it was clear in my mind that vitamin D and imporvement of defensive immunity should have been of considerable benefit. Information from Brazil became available later during the pandemic with the same conclusion, that vitamin D conferred no benefit when given to Covid-19 patients on admission to intensive care units. 

But there was information available at the time explaining that it was inevitable that vitamin D given to critically ill patients was unlikely to be of benefit.

All became clear when we received the results of randomised controlled clinical trials from Spain, from Córdoba and then from Barcelona. 

Hydroxylation of Vitamin D to Calcifediol

What was known before the pandemic is the slow process of activation of vitamin D in the liver. When vitamin D is produced in the skin as the pre-hormone cholecalciferol, or when taken by mouth or by injection, it is taken in the blood to the liver. It is there hydroxylated, that is a hydroxyl group (-OH) is added to the molecule, which then becomes 25(OH)D, also known as calcifediol (or calcidiol). It then circulates in the blood as this reservoir form. When necessary, it is taken up by appropriate cells (such as the cells of the immune system, especially T-lymphocytes) to be converted immediately into the active form 1,25(OH)D, also known as calcitriol.

Figure 1. Hydroxylation of vitamin as cholecalciferol to 25(OH)D, calcifediol, and to 1,25(OH)D, calcitriol, leading to activation of nuclear genes and optimisation of the immune process.

Within the cells 1,25(OH)D attaches to and completes the Vitamin D Receptor (VDR) molecule, thus enabling activation of the genes that escalate the defensive immune process. At this stage the escalation process is very rapid. The cells can synthesise any number of VDR molecules, but the 1,25(OH)D molecule can be used only once and then it is inactivated by conversion into 24,25(OH)D. This means that there must be a constant supply of 25(OH)D, calcifediol, available from its reservoir in the blood. 

Unfortunately most people have sub-optimal blood levels of vitamin D as 25(OH)D, and so the supply might not be adequate to maintain the immune process at a time of crisis. A further supply would be essential during a serious illness, for example sepsis or Covid-19, in which the risk of death is high if admission to hospital has been necessary.

Optimisation of Defensive Immunity

Because defensive immunity is so important in the event of serious infection, it would seem to be essential for blood levels of vitamin D as 25(OH)D, calcifediol, to be at an optimal level. The purpose of vaccinations is to enhance the immune process, but they are targeted on a specific micro-organism, whereas natural immunity being so adaptable is of a much wider benefit. The vaccinations (targeted mRNA) were not available during the Covid-19 pandemic of 2020 and so optimisation of natural immunity would have been the logical approach, even though in practice it was neglected.

Giving vitamin D in its raw form to patients critically ill in general and with Covid-19 in particular was not effective for a very good reason, although it was not immediately recognised. The hydroxylation process in the liver, converting vitamin D into 25(OH)D, calcifediol, is very slow. Under normal resting circulstances there is no need for speed as the conversion is a steady process that would take place every day, vitamin D / cholecalciferol being derived from the skin or from the diet. 

Figure 2. Blood levels of 25(OH)D, calcifediol in healthy but vitamin D deficient people when given vitmain D, cholecalciferol, by mouth. Red line (top) 10,000 units daily; Blue line (3rd) 50,000 units twice weekly; Green line (4th) 100,000 units bi-weekly; Black line (2nd) all subjects.

It takes several days for a single dose of vitamin D to be converted into 25(OH)D, calcifediol. This is fine for someone who is well, but when someone is critically ill on account of sepsis or Covid-19, giving treatment (perhaps an antibiotic) that would have no effect for perhaps a week would not be expected to be helpful. The slow conversion (hydroxylation) of vitamin D into calcifediol is a serious barrier to its use in patients who are seriously ill. But there is an answer. 

The value of Calcifediol

When maintaing the defensive immune response, the limiting factor is the slow conversion of vitamin D into calcifediol, but this can be by-passed by giving calcifediol itself to people who are ill and vitamin D deficient. The objective is to achieve a blood level of 40–60ng/ml, 100–150nmol/L.

Calcifediol has been available commercially in the UK for several years, but not for human use. It has been used almost exclusively in animal feed, especially for cattle. Because in recent years cattle have spent most if not all of the year indoors, their inevitable vitamin D deficiency has been taken seriously by vets, much more so than physicians dealing with human beings.

The point is that when calcifediol is given by mouth, it achieves excellent blood levels by three hours. It can therefore be viewed as having great potential in the treatment of patients seriously ill on account of infection, in whom rapid action is essential. Calcifediol would act in co-operation (synergism) with anti-microbial compounds if these might be available.  

Figure 3. Blood levels of 25(OH)D, calcifediol, after taking a single dose.

In 2020 calcifediol was not licensed for human use in the UK, nor in the USA, but it was available in Spain and Italy, and it could be purchased in a pharmacy without a prescription. Physicians in Spain took advantage of the availability of calcifediol and within the constraints of undertaking a randomised controlled trial in a hospital in Córdoba, they investigated the possible benefit of calcifediol.

Córdoba

The results of the trial are summarised as follows:

Controls: 26 patients received standard high quality treatment only. Of these,13 (50%) required transfer to ICU, two died.

Calcifediol treated group: 50 patients received standard high quality treatment + immediate calcifediol. Only 1 (2%) required transfer to ICU, no deaths.

This means that compared to the control group, we would have expected 25 patients (50% of 50) in the calcifediol treatment group to require transfer to ICU, but this was reduced to 1. A 24 out of 25 reduction is an absolute 96% reduction, (24/25)x100. This is 96% efficacy.

This was a dramatic result, but the UK National Institute for Health and Care Excellence (NICE) advised doctors in the UK that this result should not influence their treatment of patients, that is, they were not to use it and it would not be made available. There were criticisms of the conduct of the trial, but a re-analysis by an independent  team from the Massachusetts Institute of Technology (MIT) felt that it was without significant fault.

Calcifediol did not become available in the UK for human use.

Barcelona

A further randomised controlled trial (RCT) was undertaken in Barcelona. Of the 930 subjects in the trial, 752 had blood vitamin D levels measured on admission. The median average level was 14 ng/ml (35 nmol/L). By definition of median, 50% had levels less than this very low level, perhaps surprising for Barcelona and perhaps reduced slghtly by active disease. 

Patients with a blood vitamin D level of 20ng/ml (50nmol/L) or greater were at about half the risk of ICU admission compared to those vitamin D deficient, relative risk 0.45.

110 of the 930 patients required ICU transfer. These included 80 of the 379 (21.1%) of the control patients, and 30 of the 551 (5.4%) of the calcifediol treated patients. We can immediately see a dramatic benefit of calcifediol in respect of the first end-point of the trial, reduction of ICU transfer from 21.1% to 5.4%.

50 of the 80 controls transferred to ICU were then given calcifediol as in view of the positive result of the first phase, it was thought to be unethical to withhold calcifediol at this stage. 

Once again the conduct of the trial was criticised, and under pressure the paper was taken down from the Lancet web-site. The obsession of a "perfect" RCT over-rode clinical judgment and ethical pragmatism, Calcifediol was side-lined again.

It is interesting to note that studies showing benefit from vitamin D always seemed to attract strong criticism, but those showing no benefit (eg Brazil studies) were not criticised.

Calcifediol is now available in the UK

It was brought to my attention in early 2024 that calcifediol is now available for human use in the UK. This came as a surprise to me because there had been no announcement, even by vitamin D support groups. But it is true, despite the NICE hostility in 2020.  Calcifediol can be found via NICE in the British National Formulary (BNF). 

Calcifediol is quite new and so it has been measured in mass units from the start. There no need to use international standard biological units in which vitamin D and insulin were originally measured, and are still expressed today. There is a confusing attempt to express vitamin D in microgram units, but it is not a good idea. The vast majority of the population have no understanding of micrograms and therefore confusion might and does result. Fortunately there is no attempt to express insulin in micrograms. 

Calcifediol was developed commercially only in recent years and so it is measured and expressed in mass units. The suppliers in Spain and Italy chose milligrams, with which people are familiar, but this necessitates decimal points that could also cause confusion. In the UK BNF we see that micrograms have been preferred.

The use of calcifediol

Vitamin D is mainly a self medication and so there is a great imperative to avoid confusion and keep to units. But calcifediol in the UK is not available for self medication and it is available only through a prescription issued by a doctor. There is just one capsule size contains 266 micrograms (0.266mg), which is equivalent to 10,000 units of vitamin D.

Calcifediol need not be used as a routine supplement in people who are well, even though perhaps vitamin D deficient. There remains the issue of the number of units per day or per week that is appropriate. 3,000 or 4,000 units per day is usually about right, as judged by subsequent blood levels. Taking two capsules of calcifediol once a week (20,000 units, 532 micrograms) is equivalent to this. 

It is when people are ill that calcifediol has a great advantage, not just on its own but with other treatments including antibiotics. 

Indications might be as follows, and it is perfectly possible to test blood levels of vitamin D before giving calcifediol:

Complications occuring in late pregnancy. Ideally vitamin D deficiency should have been corrected with vitamin D supplement in early pregnancy, but this does not usually happen. At a time of clinical crisis, calcifediol would give a more rapid response.

Pre-operative. It is known (perhaps only by a few) that the risk of post-operative infections is high when the blood level of vitamin D is low, and very low when the blood level of vitamin D is about 60ng/ml (150nmol/L). Vitamin D deficiency should be corrected by vitamin D supplement in advance of elective surgery. But this is not possible before an emergency operation, and then calcifediol should be given immediately before surgery.

Figure 4. Risk of post-operative infection related to blood level of vitamin D as calcifediol.

https://pubmed.ncbi.nlm.nih.gov/24284777/

Critical Care / Intensive care. Patients in critical care usually have sepsis or following major surgery. Also in 2020 they would have had Covid-19. There is always a significant risk of death. Treatment is required urgently and optimal immunity is essential. This is the time that calcifediol must be used. We know that vitamin D acts too slowly, but calcifediol will be active by four hours.

A recent 2024 review identifies the protective role of vitamin D in severe infection and sepsis. It descibes a multi-national RCT that started in 2017 and which is designed to include 2,400 critically ill adults. However like the RCT publiched in 2019 and descibed above, it is to use vitamin D as cholecalciferol in a dose of 540,000 units. The trial does not include the up-to-date information on the superiority of caclifediol.

The trial is over-ambitious in respect of such a large number of subjects, large numbers being necessary only to detect small differences. It is typical that as a result of medical-scientific knowledge having progressed during the trial period, an important opportunity has been missed.

https://janesthanalgcritcare.biomedcentral.com/articles/10.1186/s44158-024-00139-5  

All infections. Infections are generally opportunistic, in that they take advantage of defects in our body defences. For example damage to the skin becomes an opportunity for bacterial infection. But impairment of immunity is more important, examples being AIDS, the depressed white cell count resulting from chemotherapy, and also vitamin D deficiency. Bacterial infections are generally treated with antiseptics or antibiotics, but optimising defensive immunity by giving vitamin D as calcifediol would be an advantage.

Prescribing calcifediol

Calcifediol used in Córdoba was in capsules of 0.266mg (= 266 micrograms, μg, mcg).

Calcifediol 0.266mg (266mcg) is equvalent to 10,000 units of vitamin D.

The regime was two capsules, 0.532mg, immediately, one capsule 0.266mg on day 3, again on day 7, then repeated every 7 days until the illness was resolved.

This seems to be a reasonable regime for general use. In the UK the dose of calcifediol (Domnisol, Flynn Pharma Ltd) is in capsules expressed as 266 micrograms. As there is only one capsule size and strength, it is reasonable to get around units by prescribing capsules, one or two.

The NHS indicative price of one capsule of calcifediol is £2.15 ($2.82, €2.55). A usual course of treatment would be five capsules, £10.75 ($14.12, €12.74).

This is staggeringly cheap. No untoward events were seen in Córdoba and Barcelona. This dose is equivalent to 50,000 units of vitamin D and would not cause untoward events in people not deficient of vitamin D. The dose is only one tenth of that used in the ICU trials described above. Blood levels should be checked early in treatment, but treatment with calcifediol should not be delayed while awaiting the result of the blood test.

Calcifediol: Domnisol, Flynn Pharma Ltd

In the UK this seems to be the only preparation of calcifediol available. Domnisol is the trade name, calcifediol is the pharmaceutical name.

The company product sheet, readily available on the Internet, identifies Domnisol / calcifediol as a vitamin D preparation. The indication is vitamin D deficiency, as with all vitamin D preparations. It is identified as being important for bones and joints, and also immune support.

The bio-dynamics of calcifediol, as distinct from vitamin D / cholecalciferol, do not appear on the data-sheet. The great advantage of the rapid onset of action is not mentioned. The results of the studies in Spain must have been known, but the advantage of calcifediol over vitamin D does not appear to be appreciated.

In vew of the very negative reponse of NICE to the benefit of calcifediol in the Córdoba trial, it is possible, indeed likely, that Flynn Pharma was given authorisation for calcifediol only if was marketed as a vitamin D preparation (as it is) without mentioning its bio-medical advantage.

However the price of Domnisol / calcifediol is so low at about £10 per course of treatment that the profit margin will be very low. As calcifediol is a natural compound it cannot be patented. For Flynn Pharma to undertake promotion of Domnisol / calcifediol would led to a large cost with no anticipation of financial return.

Who knows about Domnisol / calcifediol ?

Flynn Pharma received authorisation for Domnisol / calcifediol on June 2nd 2023. I was informed of the availability of calcifediol by an email from a Blog follower, but otherwise I would have remained in total ignorance.  

I assume that practising clinical doctors in the UK have not been informed of the availability and advantages of calcifediol, and I doubt that it has entered clinical practice. This applies to both family doctors and hospital doctors. Calcifediol can be obtained in the UK only on prescription and unlike in Spain and Italy, it is not available by direct purchase from a pharmacy. 

Time for action?

We know from the experience of Covid-19 that the ideal blood level of vitamin D is 40 to 60 ng/ml, 100 to 150 nmol/L, preferably at the higher end of the range. This is the range that leads to a low incidence of serious or critical Covid-19, and presumably other infections. We also know that in an emergency calcifediol but not "raw" vitamin D, cholecalciferol, reduces the need for critical care support and mortality. 

We know that vitamin D from the skin or from supplements achieves higher blood levels of calcifediol, 25(OH)D, very slowly, over several days, whereas calcifediol given by mouth achieves a good blood level within 3 hours, obviously preferable to 3 or more days when critically ill.

What is required is for calcifediol to be championed by a clinical team, ideally in a critical care setting. A clinical trial could be undertaken very simply.

But there is no powerful pharmaceutical company involved, no clinical trial expertise immediately available, and as calcifediol is so cheap there is no significant profit to be made.

Medical-scientific establishments have shunned the importance of vitamin D during and since the 2020 pandemic. Are they likely to change now?

Despite a great deal of evidence concerning the importance of vitamin D that has been generated during the Covid-19 pandemic, it has been officially suppressed, and very successfully. But unofficially the word has been transmitted and people in greater numbers are now taking a vitamin D supplement. 

Even though there is a great opportunity to help patients at times of surgery, pregnancy, sepsis, epidemics, and infections generally, lack of official encouragement means that it is very likely that the opportunity to use calcifediol will be lost for several years.

Vitamin D: perinatal mental illness in ethnic Black women

 Why do black mothers in the UK have an increased risk of perinatal mental illness?

The journalist Tobi Thomas continued her concern about the health profile of ethnic Black women in an article in the Guardian on May 7th 2024.

In my recent Blog posts I have presented her concerns about the increased risk of complications following appendix surgery in Black children in the UK, and also about the increased risk of childbirth complications in Black women. They were published in the Guardian earlier in 2024.

Both concerns were stated or assumed to be the result of sociological factors, including racism. It is my concern that there was no mention of the known biological factor of vitamin D deficiency.

The third article to which I draw your attention concerns a high risk of peri-natal mental illness in Black women in the UK. It was based on a Guardian analysis of NHS data. 

There had been 777 admissions to NHS England hospitals on account of puerperal mental illness (within six weeks of childbirth) between 2020 and 2023. 12% were ethnic Black women, despite them having only 5% of the deliveries. 

They were twice as likely to be admitted to hospital, suggesting that medical neglect and failure to use services might not have been a problem, despite a psychiatry commentator suggesting that difficulties in accessing services might be important. 

Other contributing factors suggested were structural inequality, socio-economic disadvantage, and cultural attitudes to mental illness. Dr Rosena Allin-Khan, Labour MP and medical doctor who trained at Cambridge University made the unhelpful suggestion that the reason might be “14 years of Tory mismanagement of our NHS”. 

These factors might be important but correcting them might take many years, and there is no evidence that elusive socio-economic corrections would reverse this “horrifying” problem of excess puerperal mental illness in ethnic Black mothers. Imagine the challenges to constructing a randomised controlled trial.

Several other commentators interviewed by Tobi Thomas repeated the social narrative. There was not a single mention of the biological factor of vitamin D deficiency, known to be very common in this ethnic group.

Why is there so much ignorance?

Most of the published reports and comments on the health disadvantages of ethnic Black African and South Asian people are made by sociologists, such as Tobi Thomas herself, and we might be surprised if they were to have significant knowledge of biomedical science. But some of the comments have been made by health professionals and I would have expected them to have some knowledge of the geography and the ethnicity of vitamin D deficiency. But this has not been apparent. It is possible, perhaps likely that the senior health professionals have knowledge of the importance of vitamin D and themselves take supplements, but if so they are not prepared to say so in public. Why not?

 

My previous Blog post described some of the large evidence of the importance of maternal vitamin D in brain development of the offspring, with benefits extending into adult life. The benefits of vitamin D acquired in adult lfe have also been investigated.

There is a great deal of evidence that low levels of vitamin D in the blood are associated with brain dysfunction. I first became aware of this with reports of seasonality of presentation with schizophrenia. This incidence was higher during the winter months in the Northern Hemisphere, and then the same in Australia during the winter months of the Southern Hemisphere. In  Singapore, which lies on the equator there was no seasonal variation. 

A review has shown that more than 250 studies, covering 29 Northern and five Southern Hemisphere countries, have been published on the birth seasonality of individuals who develop schizophrenia and/or bipolar disorder. Despite methodological problems, the studies are remarkably consistent in showing a 5-8% winter-spring excess of births for both schizophrenia and mania/bipolar disorder. This seasonal birth excess is also found in schizoaffective disorder (December-March), major depression (March-May), and autism (March).

With knowledge that blood levels of vitamin D are at their lowest in the early sprong, these studies give an impression that vitamin D deficiency might have a role in brain malfunction and mental illness. In recent years confirmatory research has been undertaken, including the role of vitamin D on gene expression in the brain and the production of neurotransmitters.

For example, a great deal of detail can be found in: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210535/

It might be several years before more details become understood, but in the meantime we must remember that it is not only puerperal mental health issues (psychosis) to which ethnic Black women are particularly susceptible. We must take this report in conjuction with my two recent Blog posts, which concerned difficulties and death involving childbirth among ethnic Black women in the UK, problems with neurodevelopment of the offspring, and the susceptibility to post-operative problems among their children.

We must not forget that adults of Black African and South Asian ethnicity were very susceptible to death from Covid-19 during the 2020 pandemic.

There is a great deal of research evidence concerning vitamin D and brain malfunction, including mental illness. While research continues it would be in the best interests of ethnic Black women to be checked for vitamin D deficiency, and if found it should be corrected as soon as possible during pregnancy.

This Blog post is not intended to be a full review of vitamin D deficiency in mental illness. It is intended to draw to attention the fact that many health disadvantages of ethnic Black people in the UK are being neglected because of an assumption of sociological causes, without any consideration of biological causes, of which vitamin D deficiency is the most obvious and most easily reversed. 

The ignoring of vitamin D in ethnic Black African and South Asian people in the UK is difficult to understand. There are many doctors of these ethnic groups, but they are silent. This is a very serious problem.

Vitamin D: fœtal and neonatal neuro-development

A window in Rajasthan

My two recent Blog posts were on the subjects of the high risk of post-operative complications in ethnic Black children, and the high risk of maternal complications in Black women, both taken from articles in the UK Guardian newspaper. 

Although sociological reasons were suggested in the newspaper articles, I was particularly concerned about the absence of consideration of the vitally important and well-recognised problem of serious vitamin D deficiency in these population groups. There might be some truth in the sociological factors, namely racism, but correction of these is difficult and a randomised controlled trial, if demanded, would be impossible. However correction of vitamin D deficiency could take place immediately, and a randomised controlled trial would be theoretically possible. However it would require major committment by the government public health bodies and funding would need to be found. In the present climate of ignoring vitamin D, both would be unlikely.

The second of these Blog posts, considering maternal risk, was published on June 21st. On the following day a reader, John Enebak, brought to my attention a medical-scientific paper published on-line only on June 19th 2024.

This was a research paper from a team of paediatricians working in Jodhpur, western Rajasthan, India, and it is published in Nutritional Neuroscience, an International Journal on Nutrition, Diet and Nervous System.

In the study 175 mother-child pairs were enrolled. In the third trimester of pregnancy the maternal blood level of vitamin D was measured in the usual way as 25(OH)D.

The maternal blood  level of vitamin D was found to have a significant positive relationship to the cognitive development of the infants as measured at 6 months of age (p=0.047).

Umbilical cord blood was measured immediately after birth. There was a high correlation between vitamin D levels in maternal blood 18.86 +/- 8.53ng/ml (47.15 +/- 21.33nmol/L ) and in cord blood 17.39 +/- 8.87 ng/ml (43.48 +/- 22.18nmol/L).

Cord blood vitamin D levels had a significant associatiion with socio-emotional development of the infants at 6 months (p=0.023) and at 9 months of age (p=0.01).

In this study we have good evidence of the importance of vitamin D during pregnancy to optimise neuro-development of the offspring.

More evidence

The sceptic might say "But this is not proof". I would counter this asking the sceptic of the definition of proof, to which there is most unlikely to be an answer. Very few people seem to know the meaning of "proof", which is the fulfillmentf of pre-determined criteria. "Proof" is often confused with "evidence", and the study above is most certainly evidence. "But it is only observation", might be the retort. 

But science is based on observation. Science is then like a revolving wheel, each revolution representing research producing more evidence. Evidence must be repeated, or supported by complementary evidence. Alternatively reproducible evidence that is in conflict with the hypothesis (the black swan in a world of white swans, after Karl Popper) should bring the line of research to an end.

Month of birth and subsequent Multiple Sclerosis

There is other evidence linking brain function to vitamin D. An example is a study of the results of 42,045 people with multiple sclerosis assembled from individual studies undertaken in Denmark, Sweden, Canada and the UK. It demonstrated that the number of sufferers born in the Spring was above the annual average and the number born in the Autumn was below the annual average. 

This suggests that summer gestation, maximising increased sun exposure and vitamin D production during the third trimester, gives to the offspring an advantage of brain integrity that persists into adult life, and conversely winter gestation gives a disadvantage.

Willer CJ, Dyment DA, Sadovnick AD, et al. Timing of birth and risk of multiple sclerosis: populationbased study. BMJ 2005; 330: 120-123.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC544426/

We can see the relationship between vitamin D blood levels (male and female) throught the year, and the timing of conception and subsequent delivery.

We can also see the risk of developing multiple sclerosis in relationship to month of birth, remembering the annual cycle of blood levels of vitamin D.

Spring birth after third trimester of pregnancy in the winter gives the greatest risk of multiple sclerosis.

We also know that multiple sclerosis is related to previous low intake of vitamin D.

Child Neurodevelopment : Study published in October 2023

Bruce Hollis has brought to my attention this study of the effect of vitamin D supplementation during pregnancy on subsequent neurodevopment of of offspring. The study was undertaken and the Medical University of Charleston, South Carolina, USA.

350 women were given a vitamin D supplement during pregnancy, randomised to receive either 400units (standard recommendation), 2,000units, or 4,000units each day. 172 consented to allow their offspring to participate in a follow-up study, and 156 were included in the final analysis.

Expressed as ng/ml, as in the paper

Figures:  Average blood vitamin D levels are shown for each group

Expressed as nmol/L

We can see the vitamin D characteristics in the Figures. In all randomised groups the initial blood vitamin D levels were less than 30ng/ml, 75nmol/L, and this is sub-optimal.

Maternal blood testing was repeated within one month of delivery. In all dose groups there was a significant increase in blood levels of vitamin D, the higher the dose, the greater the blood level achieved. 2,000 or 4,000units per day achieved a blood level of 40ng/ml, 100nmol/L and this is satisfactory.

Vitamin D supplements of 2,000 or 4,000 units per day during pregnancy achieved the first benefit of increasing blood levels, but th main purpose of the study was to look at possible benefits in respect of neurodevelopment of the offspring. This was assessed at between 3 and 5 years of age.

The method of assessment was the Brigance Screen II, a validated neurodevelopmental assessment tool. I must admit that I had no prior knowledge of this, but it is from a highly specialised area outside my clinical experience. 

I will not go into detail, but it is available in the original paper. Overall the study found evidence to support the important role that maternal vitamin D status during pregnancy influences child neurodevelopment. This was particularly noticable in respect of language development (also influenced by maternal educational level), in which vitamin D 2,000units per day was clearly superior to the "official" 400units per day, but in this study 4,000units per day showed no further advantage.

There was no analysis of vitamin D status in African American and Hispanic mothers.

https://www.mdpi.com/2072-6643/15/19/4250

Do no harm, but do your best

Medical practice is based on safety ("First do no harm") and also doing one's best to help a patient. "What can I do to help this pregnant mother-to-be to have a healthy baby?" One approach might be to detect and if necessary correct deficiency of the hormone cholecalciferol, that we know as vitamin D. The objective would be to use up-to-date information such as we have seen, to ensure that the maternal blood level of vitamin D is above 30ng/ml (75nmol/L), the maximum and safe level as judged by the valuable studies from India and the USA.  

Experience from the 2020 Covid-19 pandemic indicates that in respect of immunity and prevention of serious or fatal illness, a target blood level of vitamin D should be above 40ng/ml (100nmol/L).

Vitamin D: excess birth complications suffered by ethnic Black women

 Why do Black women in England suffer from more serious birth complications?

On April 8th 2024 we read in the Guardian that ”Black women in England suffer more serious birth complications, analysis finds”. Whether “more serious” meant than the complications were more serious or that there were more of the complications was not immediately clear. I was alerted to this article because as a previously practising physician I am concerned about a group of people who are medically disadvantaged, and at an extremely important moment in their lives.

It was clarified that “Black women are up to six times more likely to experience some of the most serious birth complications during hospital delivery across England than their White counterparts”. They are "1.5 times more likely to develop pre-eclampsia”. They were “almost four times more likely to die in pregnancy and childbirth than White women”, and “Black children were twice as likely to be still-born”.

The analysis had been undertaken by the Guardian based on NHS data from 2022–23.

Professor Asma Khalil, vice president of the Royal College of Obstetricians and Gynaecologists, was asked for comments. First, she expressed lack of surprise, that it was already known. This in itself displays serious complacency. She suggested “structural racism” and the “unconscious bias of healthcare professionals”, and that the problem is “multifactorial”.

She went on to suggest that “Healthcare professionals and doctors cannot fix the problem on their own....”

WRONG: DOCTORS CAN FIX THE PROBLEM.

Comments were also made by Dr Anita Banerjee, an Obstetric Physician with expertise in high risk pregnancies. She regarded the results as “disheartening”, and “trust is essential for reducing health inequalities”.

An NHS spokesperson suggested “more holistic support”. Vaguely correct.

The assumptions were that the problem was somehow sociological, someone else’s responsibility, but not that of medical professionals. Why is this? Where is the voice of medical scientists and responsible doctors?

It has been recognised that complications of pregnancy are more likely to occur in association of low blood levels of vitamin D. 

"Adverse health outcomes such as preeclampsia, low birthweight, neonatal hypocalcemia, poor postnatal growth, bone fragility, and increased incidence of autoimmune diseases have been linked to low vitamin D levels during pregnancy and infancy."  Reference

It is arguably not sensible or desirable for pregnant women to have low blood levels of vitamin D. It would be sensible if women were to have blood levels of vitamin D tested at least at the time of their first ante-natal clinic attendance, and ideally at pre-conception clinics or general practice opportunities. Hormone deficiencies should always be taken seriously, and this must apply to deficiency of the hormone cholecalciferol, that we know as vitamin D. It is unfortunate that the vice-president of the Royal College of Obstetricians and Gynaecologists appears to unaware of it.

In the Guardian report and commentaries by “experts”, there was not a single mention of vitamin D deficiency among ethnic Black women and their offspring. This itself is “disheartening”, especially as the two obstetric experts giving their opinions appear to be of South Asian ethnicity and are therefore likely to be seriously vitamin D deficient. But are they themselves taking a vitamin D supplement (I hope so): are they “drinking wine while preaching water”?

If our medical-scientific leaders would accept the correction of this well-recognised human hormone deficiency early in pregnancy, once again they would almost certainly demand an RCT.

It would need to be explained to ethnic Black pregnant women that their collective experience of pregnancy indicates a high incidence of misfortune, and this is probably the result of deficiency of the natural hormone that we know as vitamin D. “We are conducting a study in which half the pregnant women who participate would have the vitamin D deficiency corrected and half would receive a placebo, but no participant or obstetrician would know who was receiving which”. It is unlikely that a pregnant ethnic black woman would agree to receive the placebo.

While we wait for a randomised controlled trial (RCT) to be agreed, to be funded, to receive ethical approval, to be conducted and for the results be analysed, how many more serious birth complications will occur?

If the blood levels of vitamin D are checked early in pregnancy, are half of those with low levels going to be randomised to placebo?

But what about the proposal that racism is the cause of the excess childbirth complications among Black women in the UK? How can this be "treated"? Must Black women and their offspring continue to be disadvantaged in the process and outcome of pregnancy? How long will it take to test this hypothesis? How long will it take to organise an RCT of reduction of racism?

This of course indicates the absurdity of demanding an RCT in all circumstances of patients care. The hypothesis of racism affecting the outcome of pregnancy is assumed, but is untested and untestable. It is also preventing the serious consideration of vitamin D deficiency being the key to the health disadvantages of ethnic Black African and South Asian people, and especially the maternity disadvantages of Black women. 

This Blog post should be taken in conjuction with the previous Blog post concerning the high risk of post-appendicectomy complications of Black children.