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?







Monday, 9 August 2021

Covid-19 & VItamin D – something strange is happening in 2021

Mid-summer sunset across the Ribble Valley

2020 was memorable for the Covid-19 pandemic, but the behaviour of the pandemic conformed to the pattern that we expect in the natural world. 

The pandemic became significant in the UK during the month of March 2020, and on March 23rd lockdown was introduced as we had experienced 258 deaths. Despite this, cases and deaths continued to increase until mid-April 2020, when we experienced a maximum of 919 deaths in one day.

Mid-April is the time in the UK when the mid-day sun becomes more than 45 degrees above the horizon, and so vitamin D production starts. As a result, immunity becomes more effective and so there was a steady decline in Covid-19 deaths to a minimum level in August, with fewer than ten deaths per day. This is the same pattern for all respiratory infections, the non-specific beneficial effects of the summer enhancement of immunity. It is not difficult to understand.

As predicted by the natural annual cycle of respiratory infections, the incidence and deaths from Covid-19 increased in the early winter, when vitamin D production ceased and vitamin D reserves were reducing. A steady state was observed during November and December. This was seen in all European countries and in North America.

Figure 1. Covid-19 deaths in the UK during 2020



Figure 2. Covid-19 deaths in the Netherlands during 2020


Figure 3. Covid-19 deaths in Canada during 2020


However a sudden and unexpected increase in Covid-19 cases and deaths occurred in January 2021. What was even less expected and which remains unexplained is the sudden decrease in cases and deaths that followed in February. There was no obvious natural or therapeutic enhancement of immunity that could account for it. There was of course the introduction of the vaccination programme in mid-late December, but if it is viewed as causing the decline in deaths (much too rapid) it could equally be viewed as somehow causing the increase. 


Figure 4. Covid-19 deaths in the UK during 2020 and 2021

I have described previously the winter increase in Covid-19 deaths in the Andalucía region of Spain. A public health initiative in late November 2020 was to use Vitamin D in its activated form calcifediol, 25(OH)D, to protect the vulnerable elderly. It appeared to have a dramatic effect as there was a sudden drop in the number of deaths during December, with no obvious alternative explanation.

However this dramatic benefit was reversed by an equally dramatic increase in deaths in January. As in the UK it was was brief peak, but the experience in Andalucía indicated that this peak appeared to be vitamin D / immunity resistant. Most strange, and still unexplained.

Figure 5. Covid-19 deaths in Andalucía, Spain, during 2020-21


The end of the winter saw the expected decrease in cases and deaths as the vitamin D season started again, and in 2021 this was supplemented by the immunity benefits of the vaccination roll-out programme. 

All was going well in the early summer of 2021 in Europe, and then something else happened that was completely unexpected. In the UK, in June and continuing into July, there was a sudden peak of Covid-19 cases, five times greater than the April 2020 peak.

Figure 6. Covid-19 cases in the UK during 2020-21



The strange thing about this peak is not just its size, but that it occurred during the summer months when we would not expect a sudden outbreak of a respiratory virus. The number of cases is far greater than in the early stages of the pandemic in 2020. 

There are many more Covid-19 "tests" being performed in 2021 than in 2020 and there are concerns about a large number of "false positives", but this would not explain the huge difference between May and July 2021. There is something happening that is real rather than a change in testing methodology.

This 2021 peak has perhaps been defying not just expectations but also the natural cycle as we have known it and which we experienced in 2020. The implication of this peak is that it is resistant to natural immunity (and also to the vaccination programme).

The high transmissibility of the "Delta Variant" would not automatically translate into clinical illness in mid-summer. It has been suggested that this peak in the UK was the result of crowds congregating for soccer matches in Euro-2021 during June, but this is far from robust an explanation.

The point is that the June – July peak is not just a UK phenomenon. It has been more dramatic in the Netherlands, with a much more sudden onset and a little later in July.

Figure 7. Covid-19 cases in the Netherlands during the summer of 2021


But on the other hand it is not particularly dangerous. Although the number of cases has risen dramatically, the number of deaths from Covid-19 has remained low in the Netherlands and in the UK (with a slight upturn in August).

Figure 8. Covid-19 deaths in the UK during 2020 (blue) and 2021 (green)


The natural fall in deaths in the late Spring and Summer of 2020 is clear, and the low number of deaths in 2021 is very reassuring, a result of natural immunity and vaccine immunity. 

It is a mystery why the number of cases behaved so very differently from deaths, and why cases increased so dramatically. No doubt the reason will emerge.

But I have just come across the steepest increase in cases per day, which has taken place in Iceland during late July. Why has vitamin D immunity not suppressed it? What can possibly be causing it, again in the middle of the summer? 

Figure 9. Iceland : Covid-19 cases per day 2020 and 2021
(Source: Our World in Data)