A New Safe Blood Test to Diagnose Down Syndrome

The established method to prenatally diagnose chromosomal gross abnormalities is to obtain fetal cells from the womb with a fine needle, either by Amniocentesis (a sample of the fluid surrounding the foetus in the womb)  or by Chorionic villus sampling (CVS, a sample of the placenta taken via the vaginal route).
The procedures are not to be sneezed at. I’ve undergone both, so I talk from experience. It is kind of horrifying to see a needle entering the womb near to your baby, also because you realize that there is a (small) chance that the procedure will cause a miscarriage. Furthermore, in my case  (rhesus negative) I also had to get an injection of human anti-D immunoglobulin as a precaution to prevent rhesus disease after birth. Finally it takes ages (ok 2-3 weeks) to hear the results. At that point the fetus is already 14-18 weeks old and there is little time to intervene, if that is what is decided.

Image via Wikipedia

Over the years many non-invasive alternatives have been sought to test for Down Syndrome, the most common chromosomal abnormality,  affecting chromosome 21. Instead of one pair of  chromosomes, there is (usually) a third chromosome 21 (hence trisomy 21) (see Fig).

An older non-invasive test is a simple blood test to check the levels of some proteins and hormones in the mother’s blood, that are somehow related to Down Syndrome. However, this test is not very accurate.

The same is true for another non-invasive method: the ultrasound scan of the neck of the fetus. An increased amount of translucent fluid behind the neck (‘nuchal translucency‘) is associated with Down syndrome and a few other chromosomal defects.

A combination of serum tests and nuchal translucency in the 11th week correctly identifies fetuses with Down syndrome 87 percent of the time, whereas it misidentifies healthy fetuses as having Down Syndrome in 5% of the cases (5% false positive rate).

For this reason these non-invasive tests are usually used to “screen”, not to diagnose trisomy 21.

Ever since circulating fetal cells and free fetal DNA were found in the maternal blood, researchers try to enrich for this fetal sources and try to characterize chromosomal aberrations, using very sensitive molecular diagnostic tools, like polymerase chain reaction PCR (i.e. see this post) . The first attempts were directed at detecting the Y chromosome of male babies in the blood of the mother [1].

This January, Chiu et al published an article in the BMJ showing that Down’s syndrome can be detected with greater than 98% accuracy in maternal blood [2]. The group of Lo tested 753 pregnant women at high risk for carrying a fetus with trisomy 21 with this new blood test and compared it with the results obtained by karyotyping (analyzing number and appearance of chromosomes). The new technique is called multiplexed massively parallel DNA sequencing. This is a high throughput sequencing technique in which many DNA-fragments are sequenced in parallel. Sequencing means that the genetic code is unraveled. It is even possible to analyze 2 to 8 labeled maternal samples in parallel (2- and 8-plex reaction).

This parallel DNA sequencing method is “just” a counting method, in which the overall number of chromosomes is counted and one looks at an overrepresentation of chromosome 21.

With the superior 2-plex approach, 100% of the 86 known trisomy 21 fetuses were detected at a 2.1% false positive rate. In other words  the duplex approach had 100% sensitivity (all known positives were detected) and 97.9% specificity (2 were positive according to the test, whereas they were not in reality).

Thus it is a good and non-invasive technique to exclude Down syndrome in pregnant women known to have a high risk of Down syndrome. The approach might perform less well in a low risk group. Furthermore the study was not fully blinded. A practical disadvantage of this new test is that it is expensive, requiring machines not yet available in most hospitals (A spoonful of Medicine).

Another approach, recently published in Nature Medicine doesn’t have this disadvantage [3]. It involves the application of methylated DNA immunoprecipitation (MeDiP) and real-time quantitative PCR (rt-qPCR), which are accessible in all basic diagnostic laboratories. MedDiP is a technique to enrich for methylated DNA sequences, which are more preponderant in the fetus. Next rt-qPCR (amplification of DNA) is used to assess whether the fetus has an extra copy of the fetal-specific methylated region compared to a normal fetus.

In an initial series of 20 known normal cases and 20 known trisomy 21 cases, the researchers tested several differentially methylated regions (DMRs).  The majority of the ratio values in normal cases were at or below a value of 1, whereas in trisomy 21 cases the ratio values were above a value of 1. A combination of 8 specific DMRs out of 12 enabled the correct diagnosis of all the cases.

Next the authors validated the technique by applying the above method to 40 new samples in a blinded fashion. These samples contained 26 normal cases and 14 trisomy 21 cases (as later defined by karyotyping). Normal and trisomy 21 cases were all correctly identified.

The authors conclude that they achieved 100% sensitivity and 100% specificity in 80 samples. However, the first 40 samples were used to calibrate the test, thus the real validation study was done in a small set of 40, containing only 14 trisomy cases. One can imagine that a greater sample could have a few more false negatives or false positives. Indeed, small initial studies are likely to overestimate the true effect.

Furthermore, there was an overrepresentation of trisomy 21 cases (1/3 of the sample). Thus it is to soon to say that this trisomy 2 method is “to be potentially employed in the routine practice of all diagnostic laboratories and be applicable to all pregnancies”, as the authors did. To this end the method should be confirmed in larger studies and in low risk pregnancies.

In conclusion, the relative easy and cheap methylated DNA immunoprecipitation/real-time quantitative PCR combo test, seems a promising approach to screen for Down syndrome in high risk pregnancies. Larger studies are needed to confirm the extreme accuracy of 100% and must demonstrate the applicability to low risk pregnancies. If confirmed, this blood test could eliminate the need for invasive procedures. Another positive aspect is that the test can be performed early, from the 11th week of gestation, and the results can be obtained within 4-5 days. Moreover the researchers can easily adapt the current technique to demonstrate abnormal numbers (aneuploidy) of chromosomes 13, 18, X and Y.

References

• LO, Y., CORBETTA, N., CHAMBERLAIN, P., RAI, V., SARGENT, I., REDMAN, C., & WAINSCOAT, J. (1997). Presence of fetal DNA in maternal plasma and serum The Lancet, 350 (9076), 485-487 DOI: 10.1016/S0140-6736(97)02174-0
• Chiu, R., Akolekar, R., Zheng, Y., Leung, T., Sun, H., Chan, K., Lun, F., Go, A., Lau, E., To, W., Leung, W., Tang, R., Au-Yeung, S., Lam, H., Kung, Y., Zhang, X., van Vugt, J., Minekawa, R., Tang, M., Wang, J., Oudejans, C., Lau, T., Nicolaides, K., & Lo, Y. (2011). Non-invasive prenatal assessment of trisomy 21 by multiplexed maternal plasma DNA sequencing: large scale validity study BMJ, 342 (jan11 1) DOI: 10.1136/bmj.c7401
• Papageorgiou, E., Karagrigoriou, A., Tsaliki, E., Velissariou, V., Carter, N., & Patsalis, P. (2011). Fetal-specific DNA methylation ratio permits noninvasive prenatal diagnosis of trisomy 21 Nature Medicine DOI: 10.1038/nm.2312

Related Articles

• Simple blood test for Down’s syndrome is on its way, say scientists (guardian.co.uk)
• Blood test for pregnant women reveals if unborn baby has Down’s syndrome (dailymail.co.uk)
• Amniocentesis: Could I have forgiven myself for terminating a pregnancy? (telegraph.co.uk)
• Blood test can detect Down syndrome in fetus: study (ctv.ca)
• Mom’s blood test can reveal Down syndrome (msnbc.msn.com)
• A Safer Way to Spot Down Syndrome (news.sciencemag.org)
• Down’s syndrome blood check could end invasive test (dailymail.co.uk)

Stories [8] How Not to Reassure (or Treat) a Patient

The host of the next edition of the Grand Rounds is Fizzziatrist at A Cartoon Guide to Becoming a Doctor. Thus it is no surprise that the theme of this edition is “Humor in Medicine”. The Fizzziatrist:

When I host Grand Rounds, I will post the links in order of how many times each one made me go “ha!” (…) It’s all quite scientific.

Well that’s a tough job. First both as a medical librarian and  a patient, I’m not in the situation to experience a lot of the humorous aspects of a doctors job. Furthermore I’m not the HA-HA-HA LOL-REAL SCREAM type. I’m more of the smile and the grin.

So what to do? I hope you find the following enjoyable. And perhaps many little ha’s do make one big HA.

——————–

How not to reassure (or treat) your patients (own experience)

My GP (the leading character in this story; he resembles a bull in a china shop, sometimes, but other than that, he is o.k.)

• At one of my first visits he was trying to (manually) find the card of my husband. 
  When he thought he found it, he muttered: “that old guy?”
  Apparently he had mistaken my father (I still had my maiden name) for my partner.
  Lucky (both for me and my gp)  he was wrong. But how embarrassing if he had been right.
  
  

  wikipedia (CC)

• Once I phoned him for I don’t know what and he said:
  “I’m not seeing  you often”
  “Why, is that bad?”
  “Well, it is exceptional”
  “Exceptional?”
  “Yes, I see women of your age regularly”
  “For what kind of disease, if I may ask”.
  “Well, the flu .. and for pill or IUD-controls”
  [sneering] “Sure, but I’m never seriously ill and I have a gynecologist for the latter”.
  
• When I was pregnant of my second child, I phoned him for a prescription for anti-Rh antibodies, which I needed for prenatal testing. Since I hadn’t visited my gynecologist after my first child, and the hospital nurses had assured me that gp’s and midwives normally prescribed, this should not be a problem.
  I began: “I’m a few weeks pregnant and ….”
  He interrupted me, confused: “but that..….. but ….. you were pregnant a few months ago“.
  He was half right. I had had a miscarriage then. (Dang! A heavy blow)
  After a curt explanation, I hung up.
• Later he phoned me back (with a thin excuse) and I asked him for the anti-Rh antibodies, but he just didn’t get it.
  “Ask your  midwife”.
  “But I don’t have a midwife”
  “Everyone has got a midwife, nowadays”
  “No, I got a gynecologist”
  “Then  ask your gynecologist”
  “But  I’m not his patient anymore”
  “Then ask him to be your doctor again”
  “But I need the prescription right now“.
  I tried to convince him in vain. He finally mumbled something like: That is of my beat, I don’t do pregnancies and deliveries anymore.
  [luckily one phone call to the gynecologists’ wife was enough to get the prescription. She passed the message immediately, and said that if I liked him to take care of me again, it was best to make an appointment soon after the test.]
• My gp had the same attitude another time.  I had signs of a Addison crisis. I tried to explain to him what might be wrong. He asked one or two things, shrugged and then said: “You better make an appointment with your specialists. This disease is beyond my practice.”
  At the time it seemed ok to me, but my endocrinologist said it was irresponsible: “Suppose he wouldn’t immediately refer someone with an acute crisis: that could be fatal. [I was hospitalized in this case, but it was not that urgent] See also “the Doctor and the Patient”

Image via Wikipedia

My gynecologist/obstetrician [a friend of mine recommended him, because he was kind and puts you at ease. It really is a wonderful doctor, and after all those deliveries he still considered birth a miracle. However, his way of reassuring was not always effective]. 

• March 31, late afternoon: “It is time to get your baby ( 2,5 weeks post-term), but we better postpone it for two days. It is not such a nice day to celebrate the child’s birthday, don’t you think” (meaning April Fools day)
• When I had my first check-up he warmed the speculum, trying to break the ice with some humor: “they do warm the cutlery for each course at the Chinese”, don’t they?
  (I found it rather tasteless, but remained silent: he meant it well)
• When we discussed where I would deliver, he said that that would be in his hospital. I sighed with relief. As any new mother I was nervous about it.
  But he didn’t want me to have false expectations:
  “Of course I hope I can personally deliver your baby. However, the chances are real that someone else will be around at that time. But believe me, if the moment is there, you don’t care who stands at the foot of your bed. Even if it is a gorilla..”
  

My Dentist (the best, most skillful, pleasant dentist there is, but still ….  a dentist)

• Once, just finished drilling, she said carefully: “Don’t be scared when you look into the mirror….. I just touched your tongue”.

This concludes my experiences.  If you would like to read more serious stuff about “how (not) to reassure”, then you can read this old article The Art Of Reassurance (PDF) or this recent blog post at « HealthSkills Weblog: Is reassurance reassuring?

One main advise (from the latter blog):

“Never reassure a patient about something they are not already worried about. It would be a mistake, for example, to earnestly reassure patients that they do not have cancer when the thought had never entered their minds!”

Related Articles

• 10 Random Tips for Nurses (laikaspoetnik.wordpress.com)
• grand rounds (other-things-amanzi.blogspot.com)
• What’s Wrong with Your Doctor-Patient Relationship? (lifescript.com)
• Family doctors cannot be obsolete, for patients’ sake (kevinmd.com)
• 10 Things Your OB-GYN May Not Tell You (lifescript.com)
• Grand Rounds – July 27, 2010 (Vol. 6, No. 44) (insidesurgery.com)

NOT ONE RCT on Swine Flu or H1N1?! – Outrageous!

Last week doctorblogs (Annabel Bentley) tweeted: “Outrageous- there isn’t ONE randomised trial on swine flu or #H1N1“

Annabel referred to an article at Trust the Evidence, the excellent blog of the Centre for Evidence-Based Medicine (CEBM) in Oxford, UK.

In the article “Is swine flu the most over-published and over-hyped disease ever?” Carl Heneghan first showed the results of a quick PubMed search using the terms ‘swine flu’ and ‘H1N1’: this yielded 4,475 articles on the subject, with approximately one third (1,437 articles) published in the last 7 months (search: November 27th). Of these 107, largely news articles, were published in the BMJ, followed by the Lancet and NEJM at 35 each.

Top News stories on H1N1 generated appr. 2000 to 4000 news articles each (in Google). Items included outbreak of a new form of ‘swine flu’ which prompted the United States and the World Health Organization to declare a public health emergency (April), Southern Hemisphere being mostly spared in the swine flu epidemic (May), Tamiflu, i.e. the effects of Tamiflu in children in the BMJ (co-authored by Carl) in August and the availability of the vaccine H1N1 vaccine clinics to offer seasonal flu shots in November.

According to Heneghan this must be the most over-hyped disease ever, and he wonders: “are there any other infections out there?”

Finally he ends with: “Do you know what the killer fact is in all of this? There isn’t one randomized trial out there on swine flu or H1N1 – outrageous.”

My first thoughts were: “is H1N1 really so over-published compared to other (infectious) diseases?”, “Is it really surprising that there are no RCTs yet? The H1N1-pandemics just started a few months ago!” and even “are RCT’s really the study designs we urgently need right now?”

Now the severity of the H1N1 flu seems less than feared, it is easy to be wise. Isn’t is logic that there are a lot of “exploratory studies” first: characterization of the virus, establishing the spread of H1N1 around the world, establishing mortality and morbidity, and patterns of vulnerability among the population? It is also understandable that a lot of news articles are published, in the BMJ or in online newspapers. We want to be informed. In the Netherlands we now have a small outbreak of Q-fever, partly because the official approach was slow and underestimated the public health implications of Q-fever. So the public was really underinformed. That is worse than being “overexposed”.

News often spreads like wildfire, that is no news. When I google “US Preventive Services Task Force” (who issued the controversial US breast cancer screening guidelines last month) 2,364 hits still pop up in Google News (over the last month). All papers and other news sources echo the news. 2,000 hits are easily reached.

4,475 PubMed articles on ‘swine flu’ and ‘H1N1’ isn’t really that much. When I quickly search PubMed for the rather “new” disease Q-fever I get 3,752 hits, a search for HPV (Alphapapillomavirus OR papilloma infections OR HPV OR human papilloma virus) gives 19,543 hits (1,330 over the last 9 months), and a quick search for (aids) AND “last 9 months”[edat] yields 4,073 hits!

The number of hits alone doesn’t mean much, certainly not if news, editorials and comments are included. But lets go to the second comment, that there is “not ONE RCT on H1N1.”

Again, is it reasonable to expect ONE RCT published and included in PubMed over a 9 month period? Any serious study takes time from concept to initiation, patient-enrollment, sufficient follow-up, collection of data, writing and submitting the article, peer review, publication, inclusion in PubMed and assignment of MeSH-terms (including the publication type “Randomized Controlled Trial”).

Furthermore RCTs are not always the most feasible or appropriate study designs for answering certain questions. For instance for questions related to harm, etiology, epidemiology, spreading of virus, characteristics, diagnosis and prognosis. RCTs may be most suitable to evaluate the efficacy of treatment or prevention interventions. Thus in case of H1N1 the efficacy of vaccines and of neuraminidase inhibitors to prevent or treat H1N1 flu. However, it may not always be ethical to do so (see below).

I’ve repeated the search, and using prefab “My NCBI filters” for RCTs discussed before I get the following results:

Using the Randomized Controlled Trials limits in PubMed I do get 7 hits, and using broader filters, like the Therapy/Narrow Filter under  Clinical Queries I even find 2 more RCTs that have not yet been indexed by PubMed. With the Cochrane Highly sensitive Filter even more hits are obtained, most of which are “noise”, inherent to the use of a broad filter.

The found RCTs are safety/immunogenicity/stability studies of subunit or split vaccines to H1N1, H3N2, and B influenza strains. This means they are not restricted to H1N1, but this is true for the entire set of H1N1 publications. 40 of the 1443 hits are even animal studies. Thus the total number of articles dealing with H1N1 only -and in humans- is far less than 1443.
By the way, one of the 15 H1N1-hits in PubMed obtained with the SR-filter (see Fig) is a meta-analysis of RCTs in the BMJ, co-authored by Heneghan. It is not about H1N1, but contains the sentence: “Their (neuraminidase inhibitors) effects on the incidence of serious complications, and on the current A/H1N1 influenza strain remain to be determined.”

More important, if studies have been undertaken in this field they are probably not yet published. Thus, the place to look is a clinical trials register, like Clinical trials.gov (http://clinicaltrials.gov/), The International Clinical Registry Platform Search Portal at the WHO (www.who.int/trialsearch) , national or pharmaceutical industry trials registers.

A search for H1N1 OR swine flu in Clinical trials.gov, that offers the best searching functions, yields 132 studies, of which 116 were first recieved this year.

Again, most trials concern the safety and efficacy of H1N1 vaccines and include the testing of vaccines on subgroups, like pregnant women, children with asthma and people with AIDS. 30 trials are phase III.
Narrowing the search to H1N1 OR swine flu | neuraminidase inhibitors OR oseltamivir OR zanamivir (treatment filled in in the filed “Interventions”) yields 8 studies. One of the studies is a phase III trial.

This yield doesn’t seem bad per se. However, numbers of trials don’t mean a lot and a more pertinent issue is, whether the most important and urgent questions are investigated.

Three issues are important with respect to interventions:

1. Are H1N1 vaccines safe and immunogenic? in subpopulations?
2. Do H1N1 vaccines lower morbidity and mortality due to the H1N1 flu?
3. Are neuraminidase inhibitors effective in preventing or treating H1N1 flu?

Question [1] will be answered by current trials.
Older Cochrane Reviews on the seasonal influenza flu (and updates) cast doubt on the efficacy of [2] vaccines (see the [poor*] Atlantic news article) ànd [2] neuraminidase inhibitors in children (Cochrane 2007 and BMJ 2009) ànd adults  (Cochrane 2006, update 2008 and BMJ 2009) against symptoms or complications of the seasonal flu. The possibility has even been raised that seasonal flu shots are linked to swine flu risk.

However, the current H1N1 isn’t a seasonal flu. It is a sudden, new pandemic that requires different actions. Overall H1N1 isn’t as deadly as the regular influenza strains, but it hits certain people harder: very young kids, people with asthma and pregnant women. About the latter group, Amy Tuteur (obstetrician-gynecologist blogging at The Skeptical OB) wrote a guest post at Kevin MD:

(…) the H1N1 influenza has had an unexpectedly devastating impact among pregnant women. According to the CDC, there have been approximately 700 reported cases of H1N1 in pregnant women since April.** Of these, 100 women have required admission to an intensive care unit and 28 have died. In other words, 1 out of every 25 pregnant women who contracted H1N1 died of it. By any standard, that is an appalling death rate. (……)
To put it in perspective, the chance of a pregnant woman dying from H1N1 is greater than the chance of a heart patient dying during triple bypass surgery. That is not a trivial risk.

The H1N1 flu has taken an extraordinary toll among pregnant women. A new vaccine is now available. Because of the nature of the emergency, there has not been time to do any long term studies of the vaccine. Yet pregnant women will need to make a decision as soon as possible on whether to be vaccinated. (Emphasis mine)

…. Given the dramatic threat and the fact that we know of no unusual complications of vaccination, the decision seems clear. Every pregnant woman should get vaccinated as soon as possible.

Thus the anticipated risks must be balanced against the anticipated benefits, Amy urges pregnant women to get vaccinated, even though no one can be sure about side effects ànd about the true efficacy of the vaccine.

For scientific purposes it would be best to perform a double randomized trial with half of a series of pregnant women receiving the vaccine, and the other half a placebo. This would provide the most rigid evidence for the true efficacy and safety of the vaccine.

However it would not be ethical to do so. As “Orac” of Orac Knows explains so well  in his post “Vaccination for H1N1 “swine” flu: Do The Atlantic, Shannon Brownlee, and Jeanne Lenzer matter?” RCTs are only acceptable from an ethical standpoint if we truly do not know whether one treatment is superior to another or a treatment is better than a placebo. There is sufficient reason to believe that vaccination for H1N1 will be more efficacious than “doing nothing”. Leaving a control group unvaccinated will certainly mean that a substantial percentage of pregnant women is going to die. To study the efficacy of the H1N1 among pregnant women observational studies (like cohort studies) are also suitable and more appropriate.

Among the studies found in ClinicalTrials.gov there are a few H1N1 Vaccine Clinical Studies in Pregnant Women, including RCTs. But these RCT’s never compare vaccinated women with a non-vaccinated women. All pregnant women are vaccinated, but the conditions vary.

In one Danish study the arms (study groups) are as follows:

Thus two doses of H1N1 with adjuvant are compared with a higher dose H1N1 without adjuvant. As a control non-pregnant women are vaccinated with the adjuvant H1N1.*** The RCT is performed within a prospective, birth-cohort study recruiting 800 pregnant mothers between Q1- 2009 and Q4-2010. As a natural control women pregnant in the H1N1 season (Q4) will be compared with women outside the season. Please note that the completion date of this study will be 2012, thus we will have to wait a number of years before the study describing the results will be found in PubMed….

To give an impression of the idea behind the study, here is the summary of that trial in the register (not because it is particularly outstanding, but to highlight the underlying thoughts):

“Pregnant women are at particular risk during the imminent H1N1v influenza pandemic. The new H1N1v virus requires urgent political and medical decisions on vaccination strategies in order to minimize severe disease and death from this pandemic. However, there is a lack of evidence to build such decisions upon. A vaccine will be provided in the fourth quarter of 2009, but there is little knowledge on the immunogenicity. Particularly its clinical effectiveness and duration of immunity in pregnant women and their newborn infants is unknown. Therefore, it will be important to study the optimal vaccination regimens with respect to dosing and use of adjuvant to decide future health policies on vaccination of pregnant women. We have a unique possibility to study these aspects of H1N1v infection in pregnant women in our ongoing unselected, prospective, birth-cohort study recruiting 800 pregnant mothers between Q1- 2009 and Q4-2010. Pregnant women from East-Denmark are being enrolled during the 2nd trimester and their infant will undergo a close clinical follow-up. The H1N1v pandemic is expected to reach Denmark Q4-2009. The timing of this enrollment and the imminent pandemic allows for an “experiment of nature” whereby the first half of the mothers completes pregnancy before the H1N1v pandemic. The other half of this cohort will be pregnant while H1N1v is prevalent in the community and will require H1N1v vaccination.The aim of this randomized, controlled, trial is to compare and evaluate the dose-related immune protection conferred by vaccine and adjuvant (Novartis vaccine Focetria) in pregnant women and non-pregnant women. In addition the protocol will assess the passive immunity conferred to the newborn from these vaccine regimes. The study will provide evidence-based guidance for health policies on vaccination for the population of pregnant women during future H1N1v pandemics.”

Although with regard to H1N1-vaccination, appropriate studies are being done, it is feasible that certain measures might not be appropriate on basis of what we know. For instance, pretreating people in the non-risk groups (healthy young adults) with neuraminidase-inhibitors, because they are “indispensable employees”. Perhaps Heneghan, who as you remember is a co-author of the BMJ paper on neuraminidase -inhibitors in children with the seasonal flu, was thinking of this when writing his post.
If Heneghan would have directed his arrows at certain interventions in certain circumstances in certain people he might have had a good point, but now his arrows don’t hit any target. Revere from Effect Measure and Orac from Orac Knows might well have diagnosed him as someone who suffers from “methodolatry,” which is, as Revere puts it, the “profane worship of the randomized clinical trial as the only valid method of investigation.”

Notes

* But see the excellent post of Orac who trashes the Atlantic paper in Flu vaccination: Do The Atlantic, Shannon Brownlee, and Jeanne Lenzer matter? (scienceblogs.com). He also critiques the attitude of the Cochrane author Jefferson, who has a different voice in the media compared to the Cochrane Reviews he co-authors. Here he is far more neutral.

** There is no direct link to the data in the post. I’m not sure whether all pregnant women in the US are routinely tested for H1N1. (if not the percentage of H1N1 deaths among H1N1 infected pregnant women might be overestimated)

***In the US, vaccins given to pregnant women are without adjuvant.

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