Friday, 17 September 2021

Covid-19 & Vitamin D: Success of Calcitriol in New York study

New York: the successful RCT of Calcitriol, activated Vitamin D



To understand the basis of this important paper (details below), it is necessary to have some understanding of Vitamin D metabolism and activation. A recap:

Vitamin D (cholecalciferol) is produced only by the action of UV from the sun on the oil 7-dehydrocholesterol (7-DHC), which is synthesised in our skin and that of many other mammals. It is also synthesised in plankton in the sea, the food of fish. Vitamin D is thus produced directly in our skin (about 80%) or it is taken in our food (about 20%), mainly oily fish.

Whether produced in our skin or consumed in our food, Vitamin D is taken in the blood-stream to the liver. It is there stored while it is slowly converted into its part-activated form 25(OH)D, otherwise known as Calcifediol. If Vitamin D is taken by mouth by someone deficient, it takes up to two weeks before it achieves blood levels that are appropriate for optimal defensive immunity (greater than 30ng/ml, 75nmol/L). This is too slow for correction of vitamin D deficiency at the time of critical Covid-19 infection, and giving Vitamin D itself to the critically ill has been predictably without benefit.

It would always be sensible to correct Vitamin D deficiency in advance of possible infection so as to optimise defensive immunity. It is much more urgent to optimise defensive immunity in someone already very ill with Covid-19, whether vaccinated or not. An imaginative approach was pioneered in Spain, in C√≥rdoba and Barcelona, by treating patients admitted to hospital on account of serious Covid-19 with the activated form Calcifediol. The results have shown spectacular benefit. 

For reasons explained previously, these results have been ignored and the papers have been rubbished by individuals who should have know better. The UK National Institute for Health and Care Effectiveness (NICE) advised that doctors should not use Calcifediol. This would inevitable have contributed to the 133,000 Covid-19 deaths in the UK, and many more thousands in other countries.

A huge amount of Calcifediol is produced each year, mainly in China, but a problem has been that the great majority is destined for cattle. We accept without question the common occurence vitamin D deficiency in human beings, even at times of crisis, but it is not acceptable in cattle. Calcifediol is readily available across the counters of pharmacies in Spain and Italy, but not in other countries. Approval for human use in Covid-19 would have been a simple process but it did not happen.

Calcifediol circulates in the blood as a reservoir, ready for instant use when required. Natural vitamin D has one -OH group. The part-activation to Calcifediol requires a second -OH groups, hence -diol. When Calcifediol is required, is is taken up into target cells (including cells of immunity) and a third -OH group is added, and thereby it is converted into the fully-active form Calcitriol. When Calcitriol, 1,25(OH)D, has been used, and it can only be used once, it is inactivated by the addition of another -OH group to form 24,25(OH)D.

Most Calcitriol is created and used within cells, but there is a biological need for a tiny amount of Calcirtriol to circulate in the blood. This is created in cells of the kidneys and its purpose is calcium homeostasis, to maintain a steady blood level of ionised calcium. Clinical problems arise in advanced kidney disease, when there are insufficient specialised kidney cells to produce adequate Calcitriol, and this has been recognised for more than forty years. Calcitriol as a pharmaceutical product is now readily available for human use, and there is considerable experience of its use.

Because vitamin D is activated too slowly for use in those very ill with Covid-19, and because the proven Calcifediol is not available for human use in most countries (Spain, Italy and I think now Australia excepted), it has been suggested that the readily-available and immediately-active Calcitriol be of clinical value. 

It has now been tested as a pharmaceutical agent in severe Covid-19 infection and the result is available.

The RCT of Calcitriol

https://pubmed.ncbi.nlm.nih.gov/34508882/


Bone  2021 Sep 8;116175. doi: 10.1016/j.bone.2021.116175. Online ahead of print.

Elamir YM et al.


Mount Sinai Beth Israel, Mount Sinai Morningside, Mount Sinai West Hospitals, New York.


The clinical trial has been undertaken in New York and it was published on-line September 8th 2021 as a pre-print.

It is a study of 50 patients admitted to three hospitals on account of Covid-19 pneumonia. 25 of the 50 were randomly allocated (electronically) to receive Calcitriol in a dose of 0.5 micrograms daily for 14 days, or until discharge from hospital if earlier.

Please note that 0.5 microgram is a very tiny amount and it must not be confused with milligrams, and so it is better to avoid abbreviations. 0.5 microgram is 500 nanograms.

The success of randomisation is given in the text of the paper, comparing baseline characteristics in the two groups. Randomisation was not absolutely perfect, and for example the average age of the control group was 64 years compared to 69 in the Calcitriol group. On the other hand 19 of the control group were over the age of 65 compared to 14 in the Calcitriol group.  There are no differences between the treatments and control groups that would be expected to have a significant influence on the outcome of the trial should there be major outcome differences, and that was the case.

The outcome measures are as follows:

Increase of oxygen concentration in the blood:

The unit of measurement is ratio of peripheral arterial oxygen saturation to the inspired fraction of oxygen (SpO2/FIO2), the greater the better.

Control group      31.2                  Calcitriol group    94.0

Discharged with no need for supplementary oxygen:

Control group      21 / 25               Calcitriol group    24 / 25

Length of stay (mean of 25 patients):

Control group      9.24 days           Calcitriol group    5.5 days

Transfer to ICU:

Control group      8 / 25                 Calcitriol group   5 / 25 

Need for invasive ventilation:

Control group      2 / 8                  Calcitriol group   0 / 5

Deaths:

Control group      3 / 25                 Calcitriol group    0 / 25

Readmission within 30 days:

Control group      4                        Calcitriol group    2

There were no ill-effects from Calcitriol and no examples of elevation of blood levels of calcium (hypercalcaemia) in the two groups. 


Conclusion

In all measures of outcome, there was a clear advantage among the patients randomised to Calcitriol. 

The most important are:

Out of 8 control patients requiring transfer to ICU, there was a reduction by 3 in the Calcitriol group. This is a 37.5% reduction and it would be great importance in reducing the pressures on ICUs.

3 control patients died, but no patients treated with Calcitriol died. 3 out of 25 deaths were eliminated, which is 12% death rate becoming zero.

Do not consider this clinical trial in isolation

This Calcitriol trial must not be considered on its own, and no clinical trial must be considered in isolation. The Criteria of Sir Austin Bradford Hill must always be in our minds, the several dimensions of proof. Is there evidence of vitamin D deficiency leading to critical or fatal Covid-19? Yes. Have there been previous studies of association and temporality? Yes. Is there consistency in the studies? Yes. Is there evidence from basic science that Vitamin D and its activated forms Calcifediol and Calcitriol would help in defensive immunity? Yes. Is it plausible that Calcitriol would be of benefit in someone critically ill with Covid-19? Yes. Are there other clinical experiments that indicate benefit from Vitamin D in its activated forms? Yes. Add this evidence to the New York clinical trial and we can see justification for using Calcitriol in the treatment of people admitted to hospital on account of serious Covid-19.

What next?

There is clearly an international directive that any benefits of Vitamin D (or its active metabolites) must be denied, so as to enable Emergency Use Authorisation (EUA) for the unlicensed vaccines.

What can be done by official bodies to silence this study of Calcitriol? Some criticism will be found.

Can Calcitriol come into clinical use for patients with Covid-19 pneumonia? Yes, quite easily. It is in the power of any clinical doctor to prescribe Calcitriol in the protocol used in this trial. Will such doctors be over-ruled by hospital managers? If so what would be the logic? It would be a major interference with legitimate clinical responsibility.

Calcitriol is licensed for clinical use, but this obviously does not yet extend to serious Covid-19 infection. However off-label prescribing is acceptable. As stated by the UK General Medical Council (GMC):

"The physician must be satisfied that there is sufficient evidence or experience of using the medicine to demonstrate safety ad efficacy. Prescribing may be necessary when no suitably licensed medicine is available to meet the patient's need (or when prescribing is part of approved research)."

The respect paid to Hill's Criteria is obviously of great importance.

The New York RCT stated at the end, rather modestly, that further larger scale trials should follow. To state this is not the reponsibility of the researchers. Benefit has clearly been demonstrated and to this we must add the powerful scientific basis, and the results of positive trials of Calcifediol. 

It is perhaps logical that a second trial might be undertaken, but there are ethical constraints as we are dealing with life and death.

If a further clinical trial of Calcitriol were to take place, it must be with informed consent of the subjects. Would such informed subjects agree to be controls and deny themselves treatment demonstarted to eliminate a 12% death rate and other disadvantages?

Would any informed person refuse treatment with Calcitriol if admitted to hospital with Covid-19 pneumonia?

It will be interesting to watch the sequence of events to silence this RCT and prevent the use of Calcitriol.

What about Calcifediol

The use of Calcifediol is more physiological, optimising circulating blood levels and provide a source of the precursor of Calcitriol to be produced within the immune cells. Normally we would not expect Calcitriol from the circulation to become active within immune cells where so much of it can be produced.

In practical terms it would seem to be the best plan for clinical doctors to prescribe Calcitriol 0.5 micrograms daily for 14 days in the treatment of patients with Covid-19 pneumonia, until our national leaders approve of Calcifediol to be used in appropriate dose (already worked out) in the treatment of human beings, in addition to cattle.

The pandemic continues. Covid-19 deaths continue. WHO states "population controls and vaccines", but we clearly need something in addition. The New York study provides the immediate answer.










Saturday, 11 September 2021

Covid-19 & Vitamin D : "How do we get out of this mess?"

 "How do we get out of this mess?"


Scene: 10 Downing Street, Prime Minister’s office.


PM – UK Prime Minister, Boris Johnson


Well, er, thanks you for coming in to se me today


PV – Sir Patrick Vallance, Chief Scientist


It is always a great pleasure to see you Prime Minister..


CW – Professor Chris Whitty, Chief Medical Officer


Yes, and also a great honour.


Prime Minister

Well, thank you. But today we have a very serious problem. It looks as though we are in a bit of a mess.


Patrick Vallance

Really, PM. I thought the vaccination programme had gone really well with most adults being vaccinated.


Prime Minister

Well, yes. But it does not seem to be working.


Chris Whitty

What, Prime Minister? The vaccines are not working?


Prime Minister

That is the view of many Members of Pariament who have been contacting me, and also some newspaper editors.


Patrick Vallance

They can’t really mean it. If this news were to be broadcast they would be no end of disruption. There would be a riot.


Prime Minister

They have spoken me very confidentially and no news of this sort has been issued. But they point out to me that despite all the work of our mathematician advisors, the numbers are not going down as they should and are in fact going up!


Chris Whitty

What do you mean Prime Minister?


Prime Minister

To put it simply, they tell me that there have been more Covid-19 cases and deaths in 2021 than in 2020. They expected that the vaccination programme would have made the pandemic better, not worse. Patrick, please tell me precisely what is happening out there.


Patrick Vallance

It is all very difficult, Prime Minister.


Prime Minister

I want you to explain it to me in clear and simple terms.


Patrick Vallance

Well yes, there have been more Covid-19 cases and deaths in 2021 than in 2020. The Worldometer data informs everyone that we have just passed 7 million cases. In 2020 there we had about 2.5 million cases, but this year we have had 4.5 million cases –


Prime Minister

This is terrible, and it is only early September! Is it going to go away or is it going to get even worse?


Patrick Vallance

We hope that the pandemic will come to an end, but the mathematicians think that there might be another peak.


Prime Minister 

They always say that there is going to be another peak but I suspect that they have no real idea. They have got it so wrong previously, predicting major epidemics that did not happen. We might as well appoint a government Chief Astrologer as ask the mathematicians what will happen in the future.


Chris Whitty

I agree, Prime Minister.  The leaders of the medical professional organisations have no confidence in the mathematical projections and are fed up with covering up for what is going wrong.


Prime Minister

We must give a  positive impression to the public, no matter how negative the news. At a time like this we could do with Dom. He would be able to spin the bad news to make it look good, with a quick catch-phrase.


Patrick Vallance

We must continue the policy of vaccinating the entire population, with comprehensive vaccination of all young people in secondary schools, and as soon  possible those in primary schools.


Prime Minister

Well said. This will be a positive step which might keep bad news out of the headlines.


Chris Whitty

There is a problem with vaccinating children in that doctors are very unhappy about it, especially paediatricians. They are very concerned about the known side-effect of myocraditis, heart damage, and even more about unknown side-effects in the future.


Prime Minister

But the paediatricians do not see the big picture, and that is our responsibility. We must stop Covid-19 now. The future is less important than the present, and the future will be somebody else’s problem, not our's. Did the clinical trials not show that the vaccines are very effective and very safe?


Patrick Vallance

Yes, but there has been a re-analysis of the data. The vaccines did show a reduction of Covid-19 cases, but when all illness were put together, the subjects vaccinated were at a slight disadvantage. It is possible that in young people disadvantages outweigh benefits to the individual.


Prime Minister

We must keep that quiet. I have not heard of it in the newspapers. We must emphasise benefits to the population at large rather than to an individual. It is the duty of people to be vaccinated. But my MPs are telling me that there are reports that most of the Covid-19 cases and deaths are in people who have been vaccinated.


Chris Whitty

That is true, but only in very recent studies. If we look at the first six months of this year, we find that most cases and deaths are in the non-vaccinated. This is obvious because so few people had been vaccinated early in the year. Using the old data in the USA has enabled there to be continuing reports of a pandemic of the unvaccinated.


Patrick Vallance

Yes, that is a clever spin, as during the early part of the year not many people had been vaccinated and so they inevitably made up the majority of cases and deaths. 


Prime Minister

This is the line that we must take. 


Patrick Vallance

Yes, and it is going well. The press have been very helpful. I noted a headline in the Guardian on September 14th that  informs its readers that only 1.2% of those dying from Covid-19 had been fully vaccinated. It was in smaller print that it was revealed that the data were from January to July when initially very few if any people had been double vaccinated, in fact virtually no-one before the end of March.


Chris Whitty

The other point is that there was a very large number of deaths from Covid-19 in January and February, about 1,000 each day, and at that time vaccination rates were very low, with large numbers of non-vaccinated people dying. In the early summer death numbers were very few, just single figures each day in May and June, with very little influence on the six month total. 


Prime Minister

I hope we will be able to suppress the very recent data. I am told that August data will show a very different and much higher proportion of double vaccinated people dying from Covid-19.


Chris Whitty

I doubt if we will be able to keep the recent data hidden from the public for long, Prime Minister. The data are on the Worldometer and Our World in Data every day, and these websites are closely followed.


Prime Minister

Yes, there are too many amateur epidemiologists.


Chris Whitty

Many people follow me on Twitter. On August 20th I tweeted: “Four weeks working on a Covid ward makes stark the reality that the majority of our hospitalised Covid patients are unvaccinated and regret delaying. Some are very sick including young adults. Please don’t delay your vaccine”.


Prime Minister

Very good Chris. That is excellent. I hope many people have re-tweeted it. But I hear that the majority of Covid cases and deaths are now in people double vaccinated. Perhaps your information is out of date.


Patrick Vallance

Recent data is that most of those with Covid-19 are fully double-vaccinated. The numbers published by Public Health England are that up to August 15th, of Covid-19 hospital admissions in those over the age of 50, 31% were unvaccinated, 10% single vaccination, 58% double vaccinated.

When it comes to deaths there is a very similar picture. Just 30% unvaccinated, 9% single vaccination, 61% double vaccination.


Prime Minister

Gosh, that is terrible news. Are the vaccines really helping? What about those below the age of 50?


Patrick Vallance

Better news. With hospital admissions 74% unvaccinated, 15% single vaccination, 9% double vaccination. With deaths, 64% unvaccinated, 10% single and 24% double vaccinated.


Prime Minister

That is much better. Well we must concentrate on these numbers for the younger age groups so as to encourage more vaccinations. However, we must be aware of what I am being told about the pandemic getting completely out of hand, mainly in the far East.


Chris Whitty

People are becoming aware about what is happening in Israel. Although it is about the first and the most vaccinated nation in the world, there is now an increasing peak of cases and deaths almost entirely among the double vaccinated. People are very alarmed. In fact during the past week the number of vaccinations per day has gone down my more than a half. 


Prime Minister

Perhaps people in Israel are starting to suspect that vaccinations are more of a problem than a help.


Patrick Vallance

But the goverment of Israel is proposing booster vaccinations as soon as possible. Also there is a major peak in Japan, even more dramatic than in Israel.


Prime Minister

I had also heard about Israel, and that the proposal is for extensive third vaccinations. I suppose the peak in Japan could be due to the Olympic Games.


Patrick Vallance

Third vaccines for all would certainly be good news for the vaccine manufacturers. Even more so if vaccines had to be given every few months in the forseeable future.


Chris Whitty

But there is concern expressed that the vaccines might doing more harm than good,  and that natural immunity is better than immunity provided by vaccines.  Vaccines seem to be losing their benefit much earlier than expected, and the risk of the Delta variant is much higher among those vaccinated. The evidence is that people vaccinated are several times more likely to be infected than those who have natural immunity from previous infection.


Prime Minister

That makes me feel good having had Covid-19. What exactly is the Delta Variant?


Patrick Vallance

It emerged in India, immediately after the vaccination programme took off. It is sometimes called the Vaccine Variant, but only behind closed doors.


Prime Minister

I am told that in the Observer on August 29th there was a report that Covid-19 cases in the UK are 26 times higher than a year ago. Is this true?


Patrick Vallance

I am afraid it is. We expected that with the vaccination programme cases and deaths would be even lower in 2021 than in 2020, but it is not working out that way.


Chris Whitty

I also read the Observer article. In addition it stated that hospital admissions and deaths are a fraction of what they were in August 2020.


Prime Minister

Is this true?


Chris Whitty

I suspect not. According to Worldometer Covid-19 deaths suddenly started to increase in mid-August and now exceed 2020 figures. For example on September 7th 2020 there were just 3 Covid-19 deaths, but on the same day this year there were 209. This is the general pattern at present.


Prime Minister

Cripes! This is terrible. What can we do?


Patrick Vallance

We can hope that it improves, but otherwise we must divert attention. We must continue to make vaccination for the young our main priority, and blame the unvaccinated young for the deteriorating situation.


Prime Minister

But what if there is a backlash against vaccinations?


Patrick Vallance

Well Prime Minister, the main impact will be on the share prices of the pharmaceutical companies. Many of us have a lot to lose.


Chris Whitty

We must continue to emphasise the importance of vaccinations.


Prime Minister

What about the other things, vitamin D, ivermectin, hydoxychloroquine and so on?


Chris Whitty

We have followed your instructions and kept these out of the news and out of clinical use. I must say that the doctors have been very unhappy about this. They are aware that we have had 133,000 Covid-19 deaths and they think that most of these could have been avoided had we used vitamin D in particular from the very beginning.


Prime Minister

Well, that is just speculation.


Chris Whitty

The doctors have been concerned that they have been unable to offer any treatment to Covid-19 patients until they arrive on the intensive care units. If Pfizermectin materialises, that will be a help.


Prime Minister

As I have said I appreciate your success in keeping vitamin D in particular hidden from view, but I am very pleased to have received it myself when I was so very ill with Covid-19. We have had to follow WHO and FDA instructions that there must be no alternative to vaccines, otherwise the Emergency Use Authorisations would not have been granted.


Patrick Vallance

Whatever the benefits Prime Minister, if we bring Vitamin D and its activated form Calcifediol into use now, there will be public outcry from the relatives of the dead as to why we did not do so at the beginning.


Prime Minister

It is all very difficult. We really are in a mess but at present beneath the surface. We simply must continue with vaccinations, otherwise the public will lose confidence in us.


Patrick Vallance

And if cases and deaths increase we must blame it on new variants.


Prime Minister

And people who have not been vaccinated.


Chris Whitty

Prime Minister, I am still concerned that the public might become aware of what is happening around the world. The public have been expecting that the vaccinations would make things better. What will happen if the pandemic continues to get worse?


Patrick Vallance

It is inevitable that the pandemic will settle in time, and the official line is that when it does, it will be the result of the highly successful vaccination programmes.


Prime Minister

While we are here, what is the situation with deaths and ill-effects from the vaccines?


Chris Whitty

The Yellow Card system is functioning but there seems to be little notice taken and certainly no actions. We rely on the fact that in individual cases, proof is not possible and we emphasise that co-incidences do happen.


Patrick Vallance

I read that the coroner concluded that the death of Lisa Shaw, the BBC presenter, was the direct result of the very recent vaccination. 


Prime Minister

I am told that the BBC will keep quiet about this unfortunate case. Let’s hope so. The last thing we want is a succession of claims of vaccine damage,


Patrick Vallance

Especially as the government has accepted financial liability.  


Prime Minister

I certainly never expected the Covid-19 pandemic to turn out to be anything like as bad and complicated as it has turned out to be. And it seems to be far from over. The end of September is likely to see the mess even worse, unless the pandemic goes away. I am sure we will be meeting again very soon. 


Exit Patrick Vallance and CW.




Tuesday, 24 August 2021

Covid-19 vaccination and miscarriage - ERROR




My recent Blog post was an analysis of an important study published in the New England Journal of Medicine.

The conclusion in this paper was obviously wrong giving false reassurance. It describes 104 miscarriages, but in calculating the risk of miscarriage the denominator used was 827, the number of women whose pregancies had been completed. 104/827 gave a very low risk.

The mistake in the paper was that of the 827 pregnant women whose pregnancy had been completed, 700 had been vaccinated only in the third trimester, after 27 weeks. They could not have had a miscarriage as the definition in the paper was that a miscarriage is before 20 weeks. The 700 had either full-term, premature, or still-births.

My mistake was to over-simplify in an attempt to obtain a true result from this paper. To do so I simply removed the 700 from the 827, finding the 127 who had been vaccinated early, 92 of them being peri-concepriion vaccinations. It appeared that only these 127 were at risk of miscarriage.

104/127 = 82% miscarriage risk. WRONG.


Vaccination and pregnancy - Correction


After a few more reads of the paper:


3958 pregnant subjects enrolled in the original studies.

The data analysis was during just 76 days, Dec 14 to Feb 28.

This meant that during this short window, only 827 had completed pregnancy, but all the others remained pregnant. It was only the 827 completed pregnancies that were the subject of this preliminary paper.


At this stage, there were:

104 miscarriages, 

96 before 13 weeks

These can be chosen as numerators for miscarriage risk as it is the miscarriage rate that is of interest at present, and which was reported wrongly in the paper.

Let us keep to 104 miscarriages as the numerator of the miscarrige risk: 104 pregnant women had a miscarriage – fact.


The paper used 827 as the denominator of 104/827. This is clearly the wrong way to calculate the miscarriage risk, as described above and in my initial analysis. 700 were not at risk of miscarriage because they had been vaccinated in the third trimester.


I simply subtracted 700 from the 827 denominator, giving a risk of 104/127. 

This was an oversimplification.


92 subjects received vaccination in the peri-conception days, between one month before last menstrual period and 14 days afterwards.

This is not a possible denominator if 104 is the numerator. We must add some early first trimester vaccinations, but how many? 


1132 subjects were vaccinated during the first trimester, up to 13 weeks. How many miscarried? We are not told.


Impossibility of a conclusion


It is not possible to be clear about the denominator as we do not know the outcome of the 92 peri-conception vaccinations.


Nor do we know the outcome of the 1132 first trimester vaccinations, most of the women still being pregnant at the end of the short window of the study. We do not know how many of the 1132 pregnancies resulted in miscarriages overall, but 12 of them did during the window of the study (104-92).


The denominator could be any number from 127 to 1224 (92+1132), the number at risk of miscarriage (all peri-conception + first trimester vaccinations).


The future of this study


Perhaps my 82% risk could be correct, but this is most unlikely. We simple do not have the data necessary to reach a robust conclusion.


The study was “Preliminary”. More detail and more comprehensive presentation of data might be available in a later paper.


The paper as published is not good. It appears that the main outcome measure is birth defects, hence it being an end of pregnancy study. The full-term and late births revealed no major problems.


It is not possible to reach a conclusion concerning the miscarriage rate, and it will require a longer follow up. 


As it stands the NEJM paper is rubbish. It should not have mentioned miscarriages without supportive information. I was trying to salvage a result more accurate than that in the conclusion, which was obviously wrongly based reassurance.


At present, on the basis of data presented, we can accept that Covid-19 vaccination appears to be safe in late pregnancy, but small sample size with no controls. However vaccination is best avoided in peri-conception days.


UK MHRA

A few days following my previous Blog, the UK Medicine and Healthcare products Regulatory Authority issued a report that stated that vaccination during pregnancy is safe.

It is not a research study but it is data based on a spontaneous and  informal self-reporting system of untoward effects after taking medicine or using healthcare products, the Yellow Card system. It was a brief report with just a conclusion, no numbers of miscarriages. It does not compare with the detailed prosepctive study in the NEJM, imperfect as this is.

The MHRA report tells us that vaccination during pregnancy is safe, but it does not identify the relatively small number of women who might have been vaccinated before they realised that they were pregnant, those who had missed a period by just two weeks. It is these women with peri-conception vaccination who are at risk of embryo damage or implanation failure, and consequently miscarriage. 

The report concluded that there was no excess of untoward obstertric events following vaccinations. As vaccinations have been in progress for only eight months, this "conclusion" must be regarded as premature.

Ref: UK MRHA

https://www.gov.uk/government/publications/coronavirus-covid-19-vaccine-adverse-reactions/coronavirus-vaccine-summary-of-yellow-card-reporting


NEJM: further analysis

I have just received a paper that is severely critical of the NEJM paper. I wish that I had known about this earlier.


It will be available by email.



Sunday, 15 August 2021

Urgent: Covid-19 vaccines and miscarriage risk


Corrected on August 26th 2021


Carrie Johnson, wife of the UK Prime Minister



This was the headline of news media in the UK on the evening of Saturday August 14th. It shows that Carrie Johnson, the wife of the Prime Minister, has been seriously misinformed, and that she is not an appropriate person to be advising the public on health issues. She is not a medical scientist.

Unfortunately, she does not realise that her recent miscarriage, sad as it was, almost certainly resulted from her first vaccination, but I do not have the precise time-line. Did she complete a Yellow Card to record the time-link between her first vaccination and the miscarriage? Do any women who have miscarried do this if the miscarriage occurs within three months of peri-conception vaccination?

Carrie Johnson is not the only person to be urging pregnant women to be vaccinated:




I have indicated in a previous Blog post that I have been concerned about deaths from Covid-19 of pregnant women in the UK, especially as most of them are of South Asian ethnicity. Vitamin D deficiency was almost certainly the major causative factor, and certainly the only factor that could have been corrected immediately. By government directive, vitamin D, like ivermectin and hydroxychloroquine has not been used in the UK for the sick and dying from Covid-19, a national disgrace.

Now there is the issue of whether or not pregnant women should be vaccinated against Covid-19. It is a contentious issue because we know that medicines given during pregnancy can have damaging effects. It is vital that new medicines are tested thoroughly before being given to pregnant women. Covid-19 vaccines are new medicines, and similar medicines have never been used in the past. 

Human testing of a new medicine must be with careful randomised controlled trials, and these must include signed informed consent. This is particularly important in the new vaccines because they are not yet licensed: they are used under Emergency Use Authorisation, which implies that they remain experimental.

Randomised controlled trials of vaccines given in pregnancy have not been undertaken, but many pregnant women in the USA in particular have received vaccines. Did the women give signed informed consent?

The rhetoric

"Language designed to have a persuasive or impressive effect, but which is often regarded as lacking in sincerity or meaningful content."

The debate continues in the UK, but debate and science are by-passed by media pressure for pregnant women to be vaccinated. Pregnant women are understandably hesitant, but rather than listening to their concerns and looking at the science, pressure is put upon them to change their minds. 

The pressure is even coming from "England's Top Midwife": 

Jacqueline Dunkley-Bent, Chief Midwifery Officer for England, said: “Vaccines save lives, and this is another stark reminder that the Covid-19 jab can keep you, your baby and your loved ones, safe and out of hospital".5 Aug 2021

Powerful rhetoric, but wrong. 


Headline in the Guardian, July 30th 2021


Jacqueline Dunkley-Bent and Linda Geddes are seriously misinformed.

The data

The data presented appear to be dramatic, in fact too dramatic:

171 pregnant women admitted to hospital in the UK on account of Covid-19.

168 had not been vaccinated (98%).

3 had been vaccinated (2%). 

Such a huge difference is very surprising. Is vaccine hesitancy in pregnant women really so strong, 98%? If so, notice should be taken of this rather than just persuading them to change their minds. 

This is of course observational data, not a randomised controlled trial. But as we have seen in respect of vitamin D studies (and cigarette smoking in the 1950s), observational data are of immense importance. In human investigation, we usually need to rely on observational data.

The data have two, perhaps three theoretical explanations:

1. Vaccination is spectacularly successful in preventing Covid-19 in pregnancy (hence only 3 vaccinated pregnant women with Covid-19 in this study of 171).

2. Vaccination is spectacularly successful in preventing successful pregnancy (hence only 3 vaccinated pregnant women in this study of 171).

3. A combination of 1 and 2.

We need more information, and it is readily available from observation of pregnant women vaccinated against Covid-19 in the USA. 


The study in the New England Journal of Medicine.

https://www.nejm.org/doi/full/10.1056/nejmoa2104983

In this study the manufacturers of the vaccines were either Pfizer-BioNTech or Moderna.

From a database of 3958 participants in the "V-Safe Pregnancy Registry", the study identified 827 women, aged 16 to 54 years, who had been vaccinated between December 14th 2020 and February 28th 2021 and who had completed pregnancy. Slightly more than 60% were in the age range 25 to 34.

The overall pregnancy loss was 115 (14%), 104 miscarriages, 1 stillbirth, 10 induced abortion or ectopic pregnancy.

127 were vaccinated in early pregnancy, 92 of them during peri-conception, that is, shortly before pregnancy or during early pregnancy, up to 30 days before the last menstrual period (LMP) or up to 14 days after the LMP.

We are not given a breakdown of data on the 92 and the remainder of the 127, so they must be analysed together.

700 received vaccine in third trimester of pregnancy, this being after 27 weeks (27/40)

104 of the pregnant women had a miscarriage, spontaneous abortion (SA) in medical terminology.

104 miscarriages out of 827 pregnancies = 104/827, which expressed as a percentage = 12.6%.

This formed the conclusion of the paper, reassuring women all over the world that this is an acceptable miscarriage rate, not dissimilar from "normal experience".


BUT THERE IS SOMETHING SERIOUSLY WRONG WITH THIS CALCULATION

 STATISTICAL SPIN


This section has been corrected


We can be clear about the numerator, 104 miscarriages. This is what we are investigating.

2/4=50%. If we want to reduce this percentage, we need to make the denominator bigger.

2/40=5%

What has happened in this paper is that the denominator has been made bigger, from 127 to 827.

A few simple facts are necessary to help understanding about pregnancy, perhaps those conducting the study were ignorant of thes facts..

By definition, a miscarriage (SA), the end of an unviable pregnancy, must occur before about the half-way point of a normal pregnancy. In practice 23 weeks is usually chosen for definition as before 23 weeks a delivered foetus will not be viable. A miscarriage is before 23 weeks (23/40). In the study miscarriage was defined as end of pregancy before 20 weeks, but this will not make a difference to the analysis.

If a pregnancy comes to an end after 23 weeks but before full term normal birth (40/40) it is called a premature birth, or a stillbirth if the foetus has died in utero.

The first trimester, up to 13 weeks, is the embryonic stage, and understanding this is of vital importance. The embryo develops from a single fertilsed cell which divides and differentiates into its human form. It is during this differentiation and formation that the embryo is highly vulnerable to damage with consequent abnormalities. Examples are medical teratogenicity due to thalidomide or anti-epileptics, also viral damage due to rubella. Severe damage can result in miscarriage. 

When the embryo has reached its human form, at just before 13 weeks, it becomes a foetus. The process for the remaining two-thirds of gestation is for growth and maturation rather than differentiation. Brain maturation is particularly important in the third trimester.

The NEJM paper tells us that 700 of the 827 were vaccinated only in the third trimester, 27 to 40/40. By definition this is much too late for a miscarriage. These 700 pregnant women could not have had a miscarriage, and so they cannot be included in the denominator of the calculation of miscarriage risk. 

The reality is this:

127 pregnant women received very early or peri-conception vaccination, before or very early in pregnancy.

104 of them had a miscarriage, the great majority we are told being in the first 13 weeks, the embryonic stage. Miscarriage is embryo loss.

But the 127 were only a subgroup of 1132 pregnant women who received the vaccination during the first trimester with the great majority remaining pregnancy at the time of the study. 

104 miscarriages out of how many? We do not know. It might have been 127 (= 82% miscarriage rate), but it might have been 92+1132 = 1224.

Read more of this in the next Blog post.


WHY DID THIS DISTORTION OF STATISTICS HAPPEN ?

This true miscarriage rate has been hidden from the world by a paper that is so badly written that the large number of words disguises the important numbers. The conclusion is either seriously at fault or is fraudulent. How it passed peer review to be be published in the prestigious NEJM is a mystery. 

It seems to me that there was a failure to understand the difference between an embryo and a foetus, and the huge difference between exposure of an embryo and exposure of a foetus to a potential poison, whether biological or chemical. It is important to note that the miscarriages occurred during the embryonic phase. Pregnancy is divided into three trimesters for a good reason, as the stages are distinct and should not be combined into one in scientific analysis.

We have much to learn from the thalidomide tragedy of the late 1950s. If the pregnant women took thalidomide (to help with sickness) in the embryonic stage, the baby was in danger of being born with brain mal-development, eyes incompletely formed, or serious limb shortening. If however thalidomide was taken after day 42 following conception there was no damage to what by then would be be the foetus. 

And so it is with vaccinations. There is serious damage or implantation failure in the embryonic stage, the first trimester, but no damage in the third trimester, during which pregnant women could perhaps be vaccinated safely. Although thalidomide appeared to be safe in the third trimester, medicines regulatory agencies banned it completely.  

Few people will take the trouble to access and look at the paper, and those who do will probably read just the abstract and perhaps the conclusion. These can be effectively fiction, the conclusion that is politically convenient.


What do we do now?

As a clinical doctor I have always been cautious, well-aware of the dictum "Primum non nocere" (first do no harm), part of the Hippocratic oath. I am only too aware that it is much easier to do medical harm to people than to do good, and so restraint and caution are very important. "Evidence-based medicine" has become a dictum in recent years, but during this pandemic control of medicine has shifted from professional to government authorities, which have shown restraint only in treatments other than vaccines, and then total restraint without science. 

Vaccinations are being given on Emergency Use Authorisation and use should be scientific, based on a prospective research protocol so that we can learn. But this is not happening. The study described above was retrospective and opportunistic. It provided very useful data, and it is the best that we have. It is probably too late for prospective structured research into the effect of vaccination on the outcome of early pregnancy. 

To continue to vaccinate women in late pregnancy is reasonable, as it would have been reasonable to continue prescribe thatlidomide to women late in pregnancy. We have seen clearly that the miscarriages occured early and perhaps mainly before the pregnancies would have been officially recorded. Research into the outcome of pregnancy must therefore be based on a data-set of vaccination of all women of child-bearing age, including those not yet pregnant, as was the study published in the NEJM. 

However this will no longer be possible prospectively  as informed consent for vaccination of such women must include information that very early and peri-conception vaccination will give risk of miscarriage at present unknown, but not the risk given in the NEJM paper. Would a woman accept this risk?