We welcome our readers to the October issue of the VOICE, we hope again packed with interesting and relevant information for patients, colleagues, and any other party interested in reproductive sciences and clinical infertility. October is ...
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That the World Health Organization (WHO) needs help, has been rather obvious for some time. Whether its disastrous performance at the beginning of the COVID-19 pandemic was professional incompetence or political corruption, has remained in dispute; but what happened in the last week of January very clearly can only be described as confused incompetence.
Just last month we pointed out that practically all major professional organizations in the U.S., Europe and even Israel, finally (in our opinion with undue delays), reached the conclusion that, even though pregnant and lactating women had not been included in safety studies of anti-COVID-19 vaccines, pregnant and lactating women should not be excluded from being offered vaccination. ASRM extended this recommendation also to those “who seek to get pregnant” (i.e., patients in fertility treatments). Israel, indeed, included pregnant women on the priority list for the COVID-19 vaccine, a decision we fully concur with, especially considering newly published pregnancy outcome data which somewhat differ from earlier data.
Yet, here came the WHO and, out of the blue, issued an advisory against using the vaccine in pregnant women, “unless they are health care workers or have preexisting conditions.” This announcement elicited an immediate response form most of the professional organization that earlier recommended unrestricted vaccinations, many publishing strong reaffirmations of their earlier recommendations. After approximately 48 hours of considerable confusion, the WHO withdrew its earlier opinion, falling in line with recommendations of most relevant professional organizations.
This issue is by no means the first time that the WHO had to withdraw statements when it comes to COVID-19. It was, therefore, somewhat surprising to hear President Biden’s new ‘Health Czar,’ Anthony Fauci, MD, praising the WHO’s performance when formally announcing the U.S.’ rejoining of the WHO. But then Dr. Fauci himself is no stranger to controversy and confusion, considering his frequent opinion changes since the pandemic erupted, depending on where the political winds are blowing.
We have previously addressed the credibility deficit of so-called ‘experts’ in the eyes of the public (and among many scientists). Earning this mistrust for all the right reasons, not the least because of their apparent inability to acknowledge the profound unknowns surrounding the SARS-CoV-2 virus. As the public constantly received contradictory information, illogical advice, and authoritative government instructions that, often, make no sense, this deficit rapidly expanded.
The WHO was, by no means, the only major agency that lost credibility. The U.S. Center for Disease Control (CDC) did not fare much better during the pandemic. One can only hope the new head of the agency will be able to regain direction on what, from the very beginning of the pandemic, appeared to be a rudderless, out-of-control agency. No wonder 'experts’ have lost much of their credibility! One also must wonder whether Fauci, as the principal medical voice of the Biden administration, is really the right person to restore it?
Conventional wisdom dictates that the more we test, the better. However, like with many issues surrounding COVID-19, things are not always what they appear. Testing for the virus is important for containing the virus. By identifying asymptomatic carriers, we can minimize further contamination. To achieve this, testing much quickly and reliability produce results. Unfortunately, current testing standards fail in this regard.
The gold standard for viral testing is so-called PCR testing which looks for genetic material of the virus. That material, however, does not have to come from a live virus. It, indeed, not uncommonly may be found in remnants of already long dead virus fragments. When this occurs, the test is considered a false positive.
This is, however, not the only reason why many PCR test for the virus show false positives. An important second reason is so-called amplification: PCR stands for polymerase chain reaction, a technique that relies on the amplification of genetic material. This means even minute amounts of (viral) DNA are replicated repeatedly, until enough genetic material is available for accurate diagnosis. Most PCR tests replicate up to 40+ times and that can also result in false positives. How many cycles are needed to get a positive result, also correlates with so-called viral load. The higher the viral load the higher the risk of contamination but also the higher the risks for severe COVID-19 disease.
For these reasons, the WHO (yes, that WHO again!) on January 20, 2021, published new guidelines regarding how the SARS-CoV-2 virus should be diagnosed in individuals, making the point that, in addition to a PCR result, “the patient’s history and epidemiological risk factors should also be considered.”
A newspaper reporting on this new guideline, correctly concluded this would noticeably reduce the number of diagnosed cases. The paper furtherasked why the WHO waited over a year to release those guidelines. Moreover, WHO, in its perpetual lack of wisdom, failed to specify what value of viral load(or cycle number) should be used for a definite positive diagnosis, deferring this to the manufacturer of a given PCR kit. The CDC apparently recommends 40 cycles as maximal cut-off, but many experts believe that this threshold is much too high, unquestionably resulting in large false positive rates.
From this confusion the WHO now concludes that, if a positive PCR does not correspond to a patient’s history (of exposure) and symptoms, a new specimen should be obtained, and the individual should be retested before reaching a diagnosis of asymptomatic infection. In the U.K, the director of the National Health Service, Dr. Layla McCay, acknowledged that patients, due to false-positive results officially counted as COVID -19 patients, were in hospitals treated for unrelated conditions.
We must also contend with the possibility of a false-negative test, driven by the turnaround time for a PCR test of 2-3 days. The newly mandated PCR testing three days before any flight now required for all flights to the U.S. from abroad, does not ensure that an individual did not get infected in those three days between test and flight. Rapid 1-2 hour PCR testing is, therefore essential if testing is really to make an impact.
Considering all of this, PCR should still be considered the gold standard. With increasing numbers of tests coming to market, many ‘quick’ or ‘home’ tests, utilizing other assay techniques, may be inferior to PCR tests, therefore, increasing the risk of false-positive as well as false-negative tests. Those tests are usually ‘approved’ by the FDA but such approvals are usually based on self-validations of the tests by the manufacturer. Just because the FDA approved a test, therefore, does not mean that this test has been properly validated. The FDA, indeed, has already issued some warnings regarding such tests.
The SARS CoV-2 virus, the culprit causing the COVID-19 pandemic, constantly offers new surprises. At the same time, however, one must view newly published data with caution since not everything, even when published in credible medical journals, necessarily turns out to be correct information. Even more often, however, how data are incorrectly interpreted by authors, themselves, or by the media reporting on studies. These facts must be considered in view of several new studies published over the last month,
suggesting that COVID-19 in pregnancy may be “more dangerous” than previously reported.
Here is a good example and it, unfortunately, comes from an official daily web-based publication of the American College of Obstetricians and Gynecologists (ACOG). On January 22, 2021 ACOG Today’s Headline started the daily section of Top New Stories with the following headline: “Researchers say rates of death are increased among women in US with COVID-19 hospitalized for childbirth.” This headline, of course, attracted immediate attention because, as noted in the January VOICE, though (like the flu) disease was more severe than in non-pregnant women, maternal mortality in pregnancy from COVID-19 in several studies was not found to increase.
Looking up the original publication (Jerring et al., JAMA Intern Med; doi:10.1001/jamainternmed. 2020. 9241, January 15,2021) the real message of the study was, however, subtly different: First, the title of the study did not mention increased maternal mortality. The heading of this study from Boston, MA, was, “Clinical characteristics and outcomes of hospitalized women giving birth with COVID-19.” Second, the study’s main findings were: (i) Only 1.6% of women admitted for childbirth over the 8 months of the study had COVID-19. (ii) They were younger than controls, more frequently Black and/or Hispanic and more frequently suffered from diabetes and obesity. Among those women, 3.3% needed intensive care, 1.3% required mechanical ventilation and only 0.1% (9 women) unfortunately died.
The authors concluded that, “though in-hospital mortality was low, it was, still, significantly higher than in women without COVID-19 [141 (95% CI, 65-268) vs. 5.0 (95%CI, 1.11-1.33] deaths per 100,000 women. Specifically, odds of myocardial infarctions and venous thromboembolism were higher, as were odds for preeclampsia and premature birth; but odds of stillbirth were not increased.
The ACOG headlines were, thus, didactically correct when stating that mortality was significantly higher in cases of pregnant women affected by COVID-19 than in pregnant women without the virus 141 vs. 5 death per 100,000). But what do those data really tell us?
The literature so-far has repeatedly pointed out that women with COVID-19 (in analogy to women with influenza) in pregnancy are often more sick than non-pregnant women; but the literature has also claimed that (in analogy to the flu) pregnancy does *not increase the mortality of COVID-19. This study by Boston investigators does not* suggest otherwise because what the study did not address is whether this increased mortality was due to the women being pregnant or whether these women would also have died had they not been pregnant. Just because mortality was higher in women with than without COVID-19 does not mean that being pregnant caused those unfortunate 9 deaths. Those women might have died of COVID-19 also if they had not been pregnant.
The ACOG announcement, therefore, really failed to put the study’s findings into the right context. The announcement also failed to emphasize that the reported numerically elevated mortality in absolute terms was still infinitesimally small. We cannot overemphasize that interpretation and presentation of data to laypeople, but also to professionals, matters and only too often is unfortunately confusing!
A much smaller but, otherwise similar study (also still in press) made the same comparisons on the Westcoast (Lokken et al., Am J Obstet Gynecol 2021; doi.org/10.1016/j.ajog.2020. 12.1021. January 26, 2021). Here, 9.1% of COVID-19 patients developed severe or critical disease; 10% were hospitalized and 1.25% (1/80) died. 12.5-times the East Coast rate, As the authors pointed out, the risk of hospitalization in pregnancy was 3.5-times higher with than without COVID-19. That is, however, of course, once again, not the relevant question to ask because, even in non-pregnant women, those with COVID-19 will demonstrate much more hospitalizations (and deaths) than those without the disease. Once again, a publication in a credible medical journal sent an obviously inaccurate message!
What can we, therefore, take away from both publications? (i) Getting COVID-19 is potentially dangerous (not a new finding at all) to mothers but less so to offspring, though the risk of preeclampsia and premature delivery appears increased. (ii) Whether, and in what possible ways, pregnancy affects the severity of COVID-19 is still unclear. (iii) The mortality of pregnant women with COVID-19 is significantly higher than the mortality on uninfected pregnant women. But that also applies to non-pregnant women. Whether pregnancy increases the risk of mortality is presently still unresolved.
If one is to believe an article on January 13, 2021 by Eliana Dockterman in TIME magazine, the answer is a clear yes. Quoting five known IVF centers with large egg freezing programs, the argument is that COVID-19, maybe forever, changed dating habits. Moreover, women perceive to have “lost” a year in their ability to find partners; they, therefore, now freeze eggs at accelerated rates!
But is that the truth?
We are not certain! The whole argument appears somewhat farfetched. In addition, CHR has not seen increased demand for egg-freezing; very much to the contrary, demand for all forms of IVF has weakened during COVID-19, a fact also confirmed by many colleagues we have been in touch with. The more we ask around, the more suspicious we have become that the whole story in TIME may just be “wishful thinking” and/or a somewhat desperate marketing tactic of the egg-freezing industry that has not been doing too well in 2020. What we are increasingly hearing, on the periphery also referred to in the TIME article, the egg-freezing industry is in considerable financial trouble. Concerns are further aggravated by rumors that many large employers who have considered egg-freezing a medical benefit for female employees, are now planning on terminating this coverage.
These articles are part of the February VOICE
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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