"Maternal infection during pregnancy may be responsible for some portion of autism..."

The quote heading this post - "Maternal infection during pregnancy may be responsible for some portion of autism..." - comes from the paper published by Benjamin al-Haddad and colleagues [1]. They continue a research theme observing that pregnancy infection may have some quite far-reaching effects on the unborn child and their subsequent risk for various conditions / labels / diagnoses (see here for example).

So: "A total of 1 791 520 Swedish children born between January 1, 1973, and December 31, 2014, were observed for up to 41 years using linked population-based registries." As per use of the term 'population-linked registries', this was another study originating in Scandinavia (this time in Sweden) and their important research registries (see here). The important variables being analysed were the presence of "fetal exposure to any maternal infection while hospitalized during pregnancy" and "diagnosis of autism, depression, bipolar disorder, or psychosis among offspring."

Results: "fetal exposure to any maternal infection increased the risk of an inpatient diagnosis in the child of autism... or depression" but not seemingly for bipolar disorder or psychosis. The magnitude of the risk could be described as 'notable' but perhaps not exceptional. 'Urinary tract infection' (UTI) is mentioned as one infection that seemed to increase the risk of offspring diagnosis; something that has been kinda hinted at in other research literature [2] outside of the classic 'acute psychosis and UTI' research that appears in the peer-reviewed literature (see here).

Mechanisms? Well, it doesn't take a genius to figure out that most infection has a bearing on immune system functions and onward concepts like inflammation. There's quite a long history of immune system 'issues' and inflammatory processes being potentially connected to labels like autism and depression (see here and see here respectively) that provide a template for further investigation. This, bearing in mind, that pregnancy is already a time of 'reprogrammed' immune function so that a mothers body can 'tolerate' the developing fetus. As good as any place to start for further investigations...

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[1] al-Haddad BJS. et al. Long-term Risk of Neuropsychiatric Disease After Exposure to Infection In Utero. JAMA Psychiatry. 2019. March 6.

[2] Hadjkacem I. et al. Prenatal, perinatal and postnatal factors associated with autism spectrum disorder. J Pediatr (Rio J). 2016 Nov - Dec;92(6):595-601.

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"The MMR Vaccine Is Not Associated With Risk for Autism"

The quote heading this rather long post - "The MMR [measles, mumps and rubella] Vaccine Is Not Associated With Risk for Autism" - comes from a patient summary covering the the findings reported by Anders Hviid and colleagues [1].

Hviid et al utilised some of those oh-so-useful Scandinavian population registries to provide support for the hypothesis that "MMR vaccination does not increase the risk for autism, does not trigger autism in susceptible children, and is not associated with clustering of autism cases after vaccination." As per some media reporting of the study (see here), such a finding comes at a time when cases of measles in particular, are on the rise (see here) in various parts of the developing and developed world (see here) as a possible/probable consequence of specific viewpoints around vaccination (see here).

The Hviid data, as important as it is, is nothing new in terms of research that has been done on the topic of childhood vaccination and autism risk (see here). Indeed, the author is no stranger to this area of the autism research 'scene' as per other population-based cohort studies looking at "whether vaccination with a thimerosal-containing vaccine is associated with development of autism" [2]. The answer on that peer-reviewed research occasion was probably not: "results do not support a causal relationship between childhood vaccination with thimerosal-containing vaccines and development of autistic-spectrum disorders." The authors have also previously looked specifically at the MMR vaccine and autism risk too [3] albeit with caveats, some of which they addressed in this more recent investigation...

The basics this time around: look through the registry data of some 650,000 children "born in Denmark from 1999 through 31 December 2010, with follow-up from 1 year of age and through 31 August 2013." Collect and collate various information - use of "MMR and other childhood vaccinations, autism diagnoses, sibling history of autism" - and undertake some statistical analysis pertinent to the question of "whether autism developed in children who got the MMR vaccine compared with those who did not during the follow-up period." Researchers also included various potential confounders in their statistical analyses: "maternal age, paternal age, smoking during pregnancy, method of delivery, preterm birth, 5-minute Apgar score, low birthweight, and head circumference."

As per the opening paragraph, the results did not detect any link: "Comparing MMR-vaccinated with MMR-unvaccinated children yielded a fully adjusted autism hazard ratio of 0.93 (95% CI, 0.85 to 1.02)." This based on data where around 95% of the population received the vaccine (around 31,000 were classed as 'MMR-unvaccinated') and 1% (n=6,517) of the total population were diagnosed with autism. A few other observations were also noted by Hviid and colleagues: "The highest risk for autism was conferred by being a boy..., being born in a late birth cohort (2008-2010...), having no early childhood vaccinations..., and having siblings with autism at study entry." Such observations have some important links to other independent findings; for example, children with a sibling already diagnosed with autism are more likely to be diagnosed with autism (see here) and children who did not receive the MMR vaccine were actually slightly more likely to be diagnosed with autism than those who were vaccinated (a trend particularly noted in girls I believe). That last result might tie into other independent findings too (see here).

As with any research study, there were limitations attached to the Hviid investigation. So: "No individual medical chart review was performed" meaning that registry data, as strong as it is, is not the same as "medical records or direct examination of the children by research staff." The use of such population registries across a wide variety of different research topics (see here and see here for examples) carries the same limitation. I'm also minded to mention that population registry data is good for ascertaining population trends, but tends to say little about rare events. Individual issues can sometimes get lost in the statistical noise [4]. The focus of the Hviid study was also specifically on the MMR vaccine. Although not completely au-fait with the vaccination schedule in Denmark (see here) the data say little about the use of other vaccinations, their timing, and any connection (or not) to autism. And finally, I might quibble with the idea that Hviid et al looked at 'susceptible groups' on the basis of the variables they included in their 'autism risk score'. 'Smoking during pregnancy' for example has shown little to no association with autism (see here and see here) (something we can't say when it comes to offspring risk of ADHD for example). Other variables such a maternal metabolic syndrome signs and symptoms during pregnancy (see here) or maternal vitamin supplementation during pregnancy (see here) might have provided some stronger indications of autism risk/susceptibility. And then there's the recent results from Xie and colleagues [5] to also consider...

Still, the Hviid data provide further pretty powerful evidence disproving any population-wide link between MMR vaccine receipt and autism risk. The big question is whether such results, added to quite a lot of other science on this topic, are actually going to make any difference to something like vaccination rates against diseases like measles?

As per an editorial [6] accompanying the Hviid paper we live in an age where scientific data seems to have 'limited persuasive value' for some people and where the concept of 'risk' is often not well understood. The editorial authors also opine that "an alternative explanation of the perceived phenomenon should be provided" which is something else rather important. Not least because some parents, right or wrong, are still adamant that their child had a reaction to one or more of their childhood vaccinations (see here and see here). Autism research has tended to shy away from looking at this specific scenario (see here) thus leaving it unchallenged. Perhaps therefore the time is right for some brave researcher to study those children who were reported to have allegedly undergone a reaction to vaccination and see if anything is significantly 'different' about them on a behavioural and/or biological level? Whether indeed an alternative explanation could be provided for their clinical regression including the influence of variables immediately after the vaccination event [7]?

And as for the message about ensuring children (and adults, particularly vulnerable adults) are vaccinated and protected against diseases, I once again turn to the writings of Roald Dahl, and how measles devastated his family (see here) and what vaccination would have meant to his daughter. A powerful personal message that perhaps needs to be used a little more often alongside the dissemination (and translation) of scientific data to promote the benefits of vaccination to individuals and populations alike...

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[1] Hviid A. et al. Measles, Mumps, Rubella Vaccination and Autism: A Nationwide Cohort Study. Ann Intern Med. 2019 Mar 5.

[2] Hviid A. et al. Association between thimerosal-containing vaccine and autism. JAMA. 2003 Oct 1;290(13):1763-6.

[3] Madsen KM. et al. A population-based study of measles, mumps, and rubella vaccination and autism. N Engl J Med. 2002 Nov 7;347(19):1477-82.

[4] Poling JS. et al. Developmental regression and mitochondrial dysfunction in a child with autism. J Child Neurol. 2006 Feb;21(2):170-2.

[5] Xie S. et al. Family History of Mental and Neurological Disorders and Risk of Autism. JAMA Network Open. 2019; 2: e190154.

[6] Omer SB. & Yildirim I. Further Evidence of MMR Vaccine Safety: Scientific and Communications Considerations. Ann Intern Med. 2019 Mar 5.

[7] Schultz ST. et al. Acetaminophen (paracetamol) use, measles-mumps-rubella vaccination, and autistic disorder: the results of a parent survey. Autism. 2008 May;12(3):293-307.

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"a neurodevelopmental abnormality possibly associated with congenital Zika virus infection"

I'm a little late getting to the findings reported by Marion Rice and colleagues [1] (open-access available here) but I did want to cover them because of their current importance and perhaps future implications. The topic in question was the Zika virus and specifically the research efforts of the U.S. Zika Pregnancy and Infant Registry (USZPIR) used to track those infants exposed to the virus during the important nine months than made them. Just in case you didn't follow the hows-and-whys of the Zika virus outbreak and its effects a while back, some background can be found here.

Rice et al report findings for nearly 1500 children "of mothers with laboratory evidence of confirmed or possible Zika virus infection during pregnancy" in terms of their level of care and clinical follow-up and also "to identify Zika-associated birth defects and neurodevelopmental abnormalities possibly associated with congenital Zika virus infection." Aside from reporting that the majority of their cohort had "some follow-up care reported" ('some' that included very basic "length/height, weight, or head circumference measurements and date of measurements" reported back to the USZPIR), a few other observations were also made. This included findings such as: "approximately one in seven (14%) were identified during infancy or early childhood as having either a Zika-associated birth defect, a neurodevelopmental abnormality possibly associated with congenital Zika virus infection, or both."

Although the talk about birth defects is important to Zika virus exposure (microcephaly being only one part of this), I was specifically interested in the 'neurodevelopmental' side of things reported in the Rice paper as affecting 9-10% of the cohort depending on what laboratory testing for Zika virus exposure was carried out. Bearing in mind the age group of the cohort (1 year old and above), and that such neurodevelopmental issues covered a lot of clinical ground (e.g. "hearing abnormalities; congenital contractures; seizures; body tone abnormalities; movement abnormalities; swallowing abnormalities; possible developmental delay; possible visual impairment; and/or postnatal-onset microcephaly") it's important to understand how infections such as Zika might have the ability to affect cognitive and/or neurodevelopmental outcomes. What's also important too is the realisation that given the young age of the cohort, "the full spectrum of adverse outcomes related to congenital Zika virus infection is not yet known." So developmental delay for example, *could* eventually develop into something else, and why appropriate monitoring will continue through initiatives like the USZPIR.

From a cold, objective science perspective and without wishing to diminish the very human effects associated with this event, the 2016 Zika outbreak that struck the Americas provides an ideal opportunity to study our important interaction with the environment around us. It emphasises how facets of our environment can very much influence both physical and psychological health, particularly at critical times of development. A lesson that perhaps is transferable to many different neurodevelopmental labels [2]...

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[1] Rice ME. et al. Vital Signs: Zika-Associated Birth Defects and Neurodevelopmental Abnormalities Possibly Associated with Congenital Zika Virus Infection - U.S. Territories and Freely Associated States, 2018. MMWR Morb Mortal Wkly Rep. 2018 Aug 10;67(31):858-867.

[2] Lydholm CN. et al. Parental infections before, during and after pregnancy as risk factors for mental disorders in childhood and adolescence – a nationwide Danish study. Biological Psychiatry. 2018. Oct 1.

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