Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort studyBMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4151 (Published 10 July 2019) Cite this as: BMJ 2019;366:l4151
All rapid responses
It is taboo to suggest that Influenza vaccines are ineffective or could be harmful. Suggesting a link to autism adds insult to injury. Possibly this is why Walsh and her colleagues did not acknowledge data indicating a 20% increase in the risk of autism spectrum disorder/ASD among the offspring of women who received flu shots during the first trimester of pregnancy. (BMJ 2019;366:l4151) I write to reinforce the comments of Doshi, Jefferson, Stone and Stephen regarding the Walsh article. (BMJ rr Aug 2-5, 2019)
Autism is associated with increased levels of maternal cytokines during gestation (Jones, Mol Psychiatry 2017;22:273), and influenza vaccines induce proinflammatory cytokine responses during pregnancy (Christian, Am J Reproduc Immunol 2013;70:45). Therefore, a causal link between flu shots in pregnancy and ASD is biologically plausible. We assume that inflammation from infection is more dangerous to the fetus than inflammation from vaccination. However, inflammation exposure from vaccination is far more frequent than exposure from infection. In the Zerbo California cohort there were 196,929 pregnant women. In the first trimester only 443 women had influenza infections while 13,477 received flu shots. (Table 3, JAMA Pediatr 2017;171( 1):e163609)
Maternal vaccines have been called “the next frontier in vaccinology.” (Omer, NEJM 2017;376:1256) Where flu shots are concerned some of us think it is a frontier that should never have been crossed, partly because of the autism link, and are calling for unbiased and well-controlled trials before adhering to routine recommendation in developed nations. It is just one example of the vexed situation of influenza vaccines. There are others.
In the US we are now entering our acute flaccid myelitis/AFM season. As of August 2 there have been 574 confirmed AFM cases in the US since August 2014. (CDC, AFM Investigation) AFM predominates in schoolchildren and coincides with the annual campaign for seasonal influenza vaccination and back-to-school shots. AFM is probably caused by non-polio enteroviruses. However, we know that a substantial proportion of poliomyelitis is provoked by injections as co-factors (Mawdsley, Lancet 2014;384:300), and the possibility has been suggested that the same is also true of AFM. (Gromeier, J Virology 1998;72:5056. Cunningham, BMJ rr 2015-2019) US public health authorities are aware of this but so far have not publicly acknowledged or investigated the possibility.
There are too many ways to obscure serious vaccine safety issues from the general public and even from health professionals.
ALLAN S. CUNNINGHAM 7 August 2019
Competing interests: No competing interests
Re: Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort study
Peter Doshi and Tom Jefferson have highlighted some very important points ie although vaccines may be listed under a common heading, they are in fact, very “distinct products”.
Failure to recognise this is common, with the MMR vaccines from twenty years ago being an excellent example. Just as there were and are, numerous different brands of influenza vaccine, so too are there numerous different brands of MMR vaccine (all distinct products).
When introduced into the UK, the safety of the MMR vaccine was based upon data from the use of MMR II vaccine in Finland, Sweden and the USA. Unfortunately the UK granted the lion’s share of the market to two brands containing the Urabe mumps strain neither of which had been used in those countries. It follows, just as highlighted by Doshi and Jefferson in respect of influenza vaccines that, “you cannot study one vaccine and extrapolate conclusions to another”. Data from the use of MMR II vaccine could only be visited on to that brand and no other.
The removal of the two Urabe containing MMR brands in 1992 (but not the MMR II brand) due to an increased risk of mumps meningitis, evidences a further point made by Peter Doshi and Tom Jefferson ie “seemingly similar products can have different risk profiles”.
The actions of the CSM in September 1989 in offsetting 10 reported cases of mumps meningitis against 2.5 million doses of MMR distributed in the UK is an example of how in “analyzing” brands together “harms associated with one vaccine but not the other could go undetected.”
Only one of the brands of MMR on the market at that time was later associated with a increased risk of mumps meningitis. By analyzing the brands together, the “harms” were not immediately picked up on as brand specific.
Just as positive safety profiles in respect of one brand cannot be applied to another, nor can the adverse events from one brand be visited on to another either. This is evidenced by the fact that, as in the case of the MMR, a problematic brand can be removed without impacting on all the others. This was possible because of the differences between brands.
Sadly, it is often the case that an unfounded commonality is implied between brands of MMR with the risks and problems specific to the Urabe containing brands in particular suggested in respect of “the” MMR vaccine overall. In addition it is often implied, in the absence of any evidence, that causation exists between Urabe and conditions other than that for which it was removed from use ie an increased risk of mumps meningitis. It also needs to be remembered that the Urabe vaccine strain has not been used in the UK since 1992 and is of no relevance to todays brands of MMR.
I congratulate Peter Doshi and Tom Jefferson on the points they make in respect of influenza vaccines and applaud them for reminding us of the reasons why commonality cannot be established across different brands of vaccines. Against that backdrop, I am mindful of the many scientific and medical papers, articles, collaborations, statements, speeches and press releases down through the years which have referred to “the” MMR or “the” DTP vaccine etc when, for the reasons Peter Doshi and Tom Jefferson have drawn to our attention, there is no such thing.
(2) Minutes of meeting CSM 28th September 1989.
Competing interests: No competing interests
It is interesting that Peter Doshi and Tom Jefferson  note Zerbo et al's finding about autism , and the appropriateness of Zerbo's employment of a Bonferroni correction has been controversial [2-4] as Allan Cunningham  already pointed in a Rapid Response to the accompanying editorial by Håberg and Wilcox .
As someone who is appalled and bewildered by the apparent indifference of governments to the rise in autism (which is reaching budget breaking levels)  I would have thought we need to be pursuing every possible lead without fear or favour.
 Peter Doshi & Tom Jefferson, 'Influenza vaccines in pregnancy: the authors have extrapolated beyond their data', 2 August 2019, https://www.bmj.com/content/366/bmj.l4151/rr
 Brian S Hooker, 'Influenza Vaccination in the First Trimester of Pregnancy and Risk of Autism Spectrum Disorder', JAMA Pediatr. 2017;171(6):600. doi:10.1001/jamapediatrics.2017.0734
 Donzelli et al, 'Influenza Vaccination in the First Trimester of Pregnancy and Risk of Autism Spectrum Disorder', AMA Pediatr. 2017;171(6):601. doi:10.1001/jamapediatrics.2017.0753
 Zerbo et al, 'Influenza Vaccination in the First Trimester of Pregnancy and Risk of Autism Spectrum Disorder—Reply', JAMA Pediatr. 2017;171(6):601-602. doi:10.1001/jamapediatrics.2017.0737
 Allan S Cunningham, 'Re: Flu vaccination in pregnancy - FIRST TRIMESTER FLU SHOTS: NOT A GOOD IDEA', https://www.bmj.com/content/366/bmj.l4454/rr-0
 Håberg and Wilcox, 'Flu vaccination in pregnancy',
BMJ 2019; 366 doi: https://doi.org/10.1136/bmj.l4454 (Published 10 July 2019)
 John Stone, 'Re: Social care: pressure mounts for urgent and radical reform - the cost of Brexit is a blip compared with the cost of the unexplained surge in ASD', https://www.bmj.com/content/366/bmj.l4564/rr-1
Competing interests: No competing interests
We have several concerns about this article and are unclear what relevance it has to current clinical practice.
The authors apparently wished to inform decision making regarding vaccination of pregnant women in the course of annual influenza vaccination programs. If so, the authors studied the wrong vaccines. Instead of studying currently licensed influenza vaccines, they studied pandemic influenza vaccines, no longer in use.
Worldwide there are many currently licensed seasonal influenza vaccine products and many additional vaccines that are no longer licensed. Each of these vaccines went through its own licensing process because they are distinct products. And even seemingly similar products can have different risk profiles, as was evident after narcolepsy was reported in association with Pandemrix but not Arepanrix, a near identical 2009 pandemic influenza vaccine made by the same manufacturer. You cannot study one vaccine and extrapolate conclusions to another.
Even describing their study as about “2009 pandemic H1N1 influenza vaccination” is misleading as the findings cannot be generalized to all 2009 pandemic H1N1 influenza vaccines. There were many 2009 pandemic H1N1 vaccines used globally, only two of which are analyzed in this report. In addition to the Pandemrix and narcolepsy link, two other 2009 pandemic influenza vaccines, Fluvax and Fluvax Junior, were associated with febrile convulsions in Western Australia.
We are also concerned that, apparently due to limitations in the data source, the authors could only report on the combined effects of two different vaccines: one AS03 adjuvanted pandemic influenza vaccine (Arepanrix) and one unadjuvanted pandemic influenza vaccine (with no trade name). Again, these are distinct products and presumably have different risk profiles and therefore should be analyzed separately. By analyzing them together, harms associated with one vaccine but not the other could go undetected.
Finally, the authors inappropriately cited published research on the safety of influenza vaccines in pregnancy. Zerbo et al assessed influenza vaccines in pregnancy and autism, and in the “Comparison with other studies” section of their article, the authors describe Zerbo’s study in reassuring ways: "Finally, no overall increase in the risk of autism spectrum disorder was observed following influenza vaccination during pregnancy (seasonal trivalent influenza vaccine or unadjuvanted pH1N1 influenza vaccine) in a California based cohort study of infants born between 2000 and 2010.” However the authors fail to mention that their study did NOT look at autism (see p.13 of author response letter ), so the comparison to Zerbo is puzzling. Furthermore, Zerbo found a statistically significant association between first trimester vaccination and autism, a finding that lost statistical significance following a Bonferroni correction introduced into the analysis during peer review.
1. Walsh LK, Donelle J, Dodds L, Hawken S, Wilson K, Benchimol EI, et al. Health outcomes of young children born to mothers who received 2009 pandemic H1N1 influenza vaccination during pregnancy: retrospective cohort study. BMJ. 2019 Jul 10;366:l4151.
2. Doshi P. Pandemrix vaccine: why was the public not told of early warning signs? BMJ. 2018 Sep 20;362:k3948.
3. Stokes B. Ministerial review into the public health response into the adverse events to the seasonal influenza vaccine [Internet]. Department of Health, Government of Western Australia; 2010 Aug [cited 2019 Aug 2]. Available from: https://ww2.health.wa.gov.au/~/media/Files/Corporate/Reports%20and%20pub...
4. Zerbo O, Qian Y, Yoshida C, Fireman BH, Klein NP, Croen LA. Association Between Influenza Infection and Vaccination During Pregnancy and Risk of Autism Spectrum Disorder. JAMA Pediatr. 2017 Jan 2;171(1):e163609.
5. Zerbo O, Klein NP, Croen LA. Influenza Vaccination in the First Trimester of Pregnancy and Risk of Autism Spectrum Disorder-Reply. JAMA Pediatr. 2017 Jun 1;171(6):601–2.
Competing interests: Peter Doshi: Peter Doshi has received travel funds from the European Respiratory Society (2012) and Uppsala Monitoring Center (2018); grants from the Laura and John Arnold Foundation (2017-20), American Association of Colleges of Pharmacy (2015), Patient-Centered Outcomes Research Institute (2014-16), Cochrane Methods Innovations Fund (2016-18), and UK National Institute for Health Research (2011-14); and is an editor at The BMJ (but had no editorial involvement in the Walsh et al. study) and unpaid member of the Reagan-Udall Foundation for the FDA. Tom Jefferson: TJ was a recipient of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza. In addition, TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in litigation related to the antiviral oseltamivir, in two litigation cases on potential vaccine-related damage (including the vaccine Pandemrix (2015-2017) and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997-99), GSK (2001-2), Sanofi-Synthelabo (2003), and IMS Health (2013).In 2014 he was retained as a scientific adviser to a legal team acting on oseltamivir. TJ has a potential financial conflict of interest in the drug oseltamivir. In 2014-16, TJ was a member of three advisory boards for Boerhinger Ingelheim. TJ was holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. Between 1994 and 2013, TJ was the coordinator of the Cochrane Vaccines Field. TJ was a co-signatory of the Nordic Cochrane Centre Complaint to the European Medicines Agency (EMA) over maladministration at the EMA in relation to the investigation of alleged harms of HPV vaccines and consequent complaints to the European Ombudsman. TJ is co-holder of a John and Laura Arnold Foundation grant for development of a RIAT support centre (2017-2020) and Jean Monnet Network Grant, 2017-2020 for The Jean Monnet Health Law and Policy Network. TJ is an unpaid collaborator to the project Beyond Transparency in Pharmaceutical Research and Regulation led by Dalhousie University and funded by the Canadian Institutes of Health Research (2018-2022). TJ is a consultant to CMR Ltd.