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.