|Coast of Cumbria UK, May 22: the Sun keeps us healthy|
Covid-19 & Vitamin D : dangers in pregnancy
During the Covid-19 pandemic there has been a disproportionately high incidence of disease and death among black African and Asian minority ethnic (BAME) communities. For example, a publication as early as April 10th 2020 showed that of 3883 patients with confirmed Covid-19, 14% were of Asian ethnicity and 12% were of black African ethnicity, much higher than their proportion in the UK population (Intensive Care National Audit and Research Centre).
A little-discussed aspect of the Covid-19 pandemic has been its particularly damaging effect in pregnancy.
There has been an increased incidence of Covid-19 in pregnant women, and especially in ethnic black and Asian pregnant women who are far more likely to be admitted to hospital on account of Covid-19.
Compared to pregnant ethnic white women, pregnant ethnic black African women in the UK have been eight times more likely to be admitted to hospital on account of Covid-19, and ethnic Asian women four times more likely.
Of 427 pregnant women in the UK admitted to hospital on account of Covid-19, more than half (55%) were from black African and Asian ethnic groups. There was no mention of vitamin D deficiency being a possible important factor, with only psychological and social pressures being identified. (British Journal of Midwifery, October 2020).
Black African and Asian ethnic (BAME) women, whether pregnant or not, have a had particularly high death rate from Covid-19 when on Intensive Care Units (Knight et al 2020).
Before the Covid-19 pandemic, it had been recognised in the UK that ethnic black African women have a five-fold incidence of death during pregnancy, and women of Asian ethnicity a two-fold incidence (Nair et al, 2014).
Pakistani women living in the UK have been more likely to have a premature baby or neonatal death than had they been living in Pakistan.
Pregnant BAME women have been disproportionately destined to die from Covid-19.
Overall, the Covid-19 death rate of people of black African ethnicity has been 3.5 times greater than for ethnic white UK people, for black Caribbean ethnicity 1.7 times, and for those of Pakistani descent was 2.7 times higher (Kirby 2020).
The obvious disadvantage of these BAME women has been attributed to racial discrimination, that they have been treated less favourably by the maternity and other parts of the health service. However had they been discriminated against, they would not have had a much higher admission rate to hospital but might have languished at home.
Of 240 pregnant women with Covid-19, 10% required admission to hospital, a higher proportion than expected that indicates a particular susceptibility to severe Covid-19 when pregnant.
It has been suggested that unfamiliarity with accessing health services because of language difficulties, discrimination and immigration status impede the treatment of ethnic minority women. Although there might be truth in this, the very high admission rate of ethnic minority pregnant women with Covid-19 to hospital and intensive care suggests that there has been no impediment to necessary care.
For example in a study of 240 pregnant women in Washington, USA, the hospital admission rate for COVID-19 was 3.5-fold higher (10%) than non-pregnant women.
In this study 3 out of 240 pregnant women with COVID-19 died, which equates to a maternal mortality rate of 1,250 out of 100,000 pregnancies. COVID-19 mortality rate was therefore 13.6-fold higher than the rate in similarly aged non-pregnant women.
The papers providing the data presented above show a frightening disadvantage experienced by BAME women in pregnancy. However, apart from suggested neglect by health professionals, no explanation is proposed. As with other health disadvantages of BAME people, no answers but continuing disadvantage, including early death.
Vitamin D was not mentioned in any of the papers that I have read. We know that vitamin D deficiency is widespread, but particular so in people with ethnically determined melanin-rich dark skin. It is very likely that vitamin D deficiency is the crucial and immediately reversible factor that is responsible for these tragically high death rates in pregnancy.
How common is vitamin D deficiency in pregnancy? Is there ethnic variation?
One thing is certain: the foetus takes whatever it needs from its mother, with possible disadvantage to its mother. We know that the foetus requires iron, and so iron deficiency anaemia is common in pregnant women, with iron supplement being standard care. We know that folic acid deficiency is common in pregnant women, as folic acid is necessary for a the high cell division rate in the foetus. Deficiency of folic acid becomes a great disadvantage to the foetus and to the mother. Folic acid is also a standard supplement in pregnancy.
Vitamin D is essential for the development of the foetus, and in particular for neurological maturation in the later stages of pregnancy. The foetus must obtain its vitamin D from its mother, who is therefore at risk of development of vitamin D deficiency during pregnancy, as with iron and folic acid.
If the mother is deficient of vitamin D at the onset of pregnancy, the deficiency will worsen when the foetus takes as much as it can. The vitamin D deficient expectant mother will have impaired immunity. As a specific result, during the past year she will be susceptible to critical or fatal Covid-19.
The result of vitamin D deficiency in the foetus will be an impairment of brain development in particular. The main result in the infant will be the development of the bone disease rickets, most obvious when walking commences. This has been seen in recent years in the children of ethnic black African and South Asian mothers in the UK and the USA.
Unfortunately I have not been able to locate any studies that show the effect of pregnancy on blood levels of vitamin D. However if low levels of vitamin D were identified during early pregnancy a supplement would be given, or at least I hope so. Medical ethics should determine that we will never know the effect of pregnancy on maternal blood levels of vitamin D.
In a study of 239 women in early pregnancy in Indonesia, 82% were deficient in vitamin D as judged by blood level less than 20ng/ml (50nmol/L). If we now consider from our experience of Covid-19 that a blood level of 40ng/m (100nmol/L) is ideal, then perhaps all were deficient.
Generally there has been very little research into the importance of vitamin D in pregnancy. What is theoretically necessary is recording the natural history by observation of the vitamin D status of pregnant women at first booking in the ante-natal clinic, and then following the pregnancy, birth, and the development of the baby. As mentioned this is unlikely to happen. We cannot observe the natural history of any condition when treatment is readily available and safe. This applies particularly to a hormone, vitamin, or essential nutrient deficiency. Furthermore, during the Covid-19 pandemic the value of careful observation has been constantly downplayed, despite it being the foundation of science since the time of Francis Bacon (c1620) and through the Age of Enlightenment.
Research into the human condition is constrained by ethical considerations and the Nuremberg Code. Research might therefore be inconclusive and doctors will need to use judgement on what is to be done in the best interests of their patients. Identification of a deficiency (for example iron or vitamin D) should be looked for as a routine when its probability is high, and correction should be undertaken as a medical duty.
This is an example of "Perfection must not become the enemy of the good", wisdom from my friend Linda Benskin. Medical practice must not stand still while awaiting the perfect research study: it must acknowledge and act on the results of good research.
As an aside, research into the importance of vitamin D and its deficiency during the Covid-19 pandemic has on some occasions led to blood being taken at the onset of illness but only afterwards analysing it for vitamin D, and so being able to associate blood level with outcome, the natural history. These studies could be regarded as cynical disregard of the Nuremberg Code: testing the blood at the time of it being taken and then correcting deficiency might have prevented many deaths. However the studies have the clear result of temporality, that vitamin D deficiency results in an increased risk of Covid-19 death.
Vitamin D and pregnancy
The major complication of pregnancy is toxaemia, or pre-eclamptic toxaemia (PET), or pre-eclampsia (PE) which is the preferred term at present. It is characterised by high blood pressure, ankle swelling, kidney damage with protein in the urine, and if uncontrolled it leads to convulsions (eclampsia). It was first described by Hippocrates in the 5th century BCE, and term "eclampsia" comes from the Greek word for "lightning". There is a high risk of foetal death in pre-eclampsia, but these days medical control is usually successful, with emergency caesarian section delivery sometimes being necessary.
Pre-eclampsia is related to vitamin D deficiency and the association has been identified on many occasions. PE appears to be driven by inflammatory processes that originate in the placenta, and with Covid-19 pneumonia these inflammatory processes have come to be called a "cytokine storm". It is very damaging. It is known that vitamin D down-regulates these otherwise uncontrolled inflammatory processes by linking with VDR and down-regulating specific genes. What initiates the inflammatory processes originating within the placenta is unknown.
As with Covid-19 and vitamin D deficiency, the huge background of observational and basic scientific research has not led to an adequate exploration of the therapeutic potential of vitamin D in pre-eclampsia. The problems are a lack of the necessary medical knowledge within maternity care, and once again the ethical constraints on clinical research. But as we are dealing with serious deficiency of a known vitamin/hormone, correction of this is a clinical duty without the necessity of delays while awaiting further research.
If pregnant women were to be tested and found to be deficient of vitamin D in early pregnancy, could a random half of them give informed consent to be given a placebo rather than vitamin D? This marks the limitation of the randomised controlled trial. Is it ethical to withhold (with full informed consent) vitamin D at such an important time, knowing that the pregnant woman is deficient?
Also, if vitamin D is given it must be followed up to achieve a target blood level, and this should be 40ng/ml, 100nmol/L. It is of no help to give a sub-optimal dose of vitamin D and conclude that vitamin D is of no value. Giving two units of insulin will not help someone with diabetes, but this does not mean that insulin is of no value. Meeting pre-determined blood effects must be achieved.
A policy of correcting vitamin D deficiency in early pregnancy would be to help the foetus during gestation and following birth. But the initial benefit would be for the prevention of pre-eclampsia.
If the serious illness of pre-eclampsia were to occur and emergency treatment be required, then as with serious Covid-19 pneumonia, vitamin D treatment should be given in its natural activated form 25(OH)D, calcifediol. The reason for this is that, starting from deficiency, vitamin D itself will take about two weeks to reach a good blood level because it must be activated by the liver to 25(OH)D, and this is a slow process. However when 25(OH)D calcifediol itself is given a good level is achieved in two hours. This has been shown to be very effective in the treatment of serious Covid-19 pneumonia. Could it be of similar dramatic benefit in pre-eclampsia? Clinical observation of this treatment could show a dramatic benefit, far superior to any other treatment.
Research and action are required.
The Covid-19 pandemic has brought to attention the importance of vitamin D deficiency and the potential of its correction to help human health and reverse specific conditions associated with reduced immunity and uncontrolled inflammation. This must be taken very seriously and not simply ignored or discarded as has happened during the past year.
Vitamin D, seasonality, and effects on the offspring
This will be the subject of a future Blog post.
Additional information from Bruce Hollis and Carol Wagner
Work undertaken at the Department of child health, University of South Carolina, USA, and published in 2012.
Unfortunately I was unaware of this excellent paper when I first posted this Blog.
Vitamin D Supplementation during Pregnancy: Double Blind, Randomized Clinical Trial of Safety and Effectiveness
350 pregnant women were given vitamin D 400, 2,000, or 4,000 units daily throughout pregnancy.
Those taking 400units per day, mean blood level at end of pregnancy 78.9 nmol/L (31.6ng/ml)
Those taking 2,000units per day, mean blood level at end of pregnancy 98.3 nmol/L (39.3ng/ml)
Vitamin D 4,000 units per day was most effective in achieving a good blood level with no indication of excess.