"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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Acute psychosis and urinary tract infection (again)

Consider this short blog post an extension of some previous discussions (see here and see here) on a rather peculiar 'association' between urinary tract infections (UTIs) and psychosis. UTIs basically refer to an infection in any part of the urinary system (kidneys, bladder, etc) typically treated with antibiotics. Psychosis is a state that causes a person to perceive or interpret things around them in an atypical way, usually accompanied by delusions or hallucinations. For a while now research has been connecting these two conditions.

The paper by Chelsea Carson and colleagues [1] further adds to the peer-reviewed literature in this area with the observation of: "an association between UTIs and children and adolescents with acute non-affective psychosis." Based on a "retrospective chart review of 227 subjects ages 10–18 who were hospitalized between 2005 and 2014 for an acute episode of DSM-IV non-affective psychosis" compared with those presenting with depression with and without psychotic features, researchers noted that a UTI was not an uncommon diagnosis (20%). Bearing in mind the lack of any asymptomatic control group, authors concluded that screening for [comorbid] UTI in those presenting with acute psychosis might be warranted.

I can't disagree with these findings and conclusions. Combined with other work [2] looking at "an association between an increased prevalence of UTI and acute psychotic relapse" in those diagnosed with schizophrenia, the idea that infection or immunological response to infection might have behavioural as well as physiological outcomes gathers strength from such findings. We still don't know all the hows-and-whys of such an association outside of the idea that inflammatory mechanisms may be at work (see here) but further investigations are most definitely implied.

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[1] Carson CM. et al. Urinary tract infections in children and adolescents with acute psychosis. Schizophrenia Research. 2016. Nov 10.

[2] Miller BJ. et al. A prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry. 2013 Mar;74(3):271-7.

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Carson, C., Phillip, N., & Miller, B. (2016). Urinary tract infections in children and adolescents with acute psychosis Schizophrenia Research DOI: 10.1016/j.schres.2016.11.004

Hospitalisation for mania following antibiotic exposure?

"Individuals hospitalized with acute mania have a markedly increased rate of bacterial infections, as evidenced by the recent prescription of antimicrobial agents. The prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania."

That was the research bottom-line reported by Robert Yolken and colleagues [1] (yes, that Robert Yolken) who continued a theme of how immune function/response might be something pretty important when it comes to all-things psychiatry and in particular, when it comes to diagnoses like mania (see here). Some media interest in this work can be seen here.

On this occasion, the name of the game was to investigate "whether individuals hospitalized with acute mania have evidence of bacterial infections as determined by the prescription of systemic antimicrobial agents." Antimicrobial agents normally means antibiotics; evidence of their use was searched for in over 230 people "hospitalized for acute mania in either an inpatient unit or a day hospital" compared with some 550 controls.

Researchers reported that among their cohort there was "a substantially increased rate of recent antimicrobial prescription, defined as exposure within three days of ascertainment." 'Substantial' in this respect meant 18 of 234 hospitalised people (~7%) compared with 7 of 555 controls (~1%). Interestingly, authors also reported that the site of bacterial infection for which antimicrobials were given was most commonly urinary tract infection for women "while the respiratory tract and mucosal surfaces were the most common sites in men." Mention of the the urinary tract as a source of infection brought me back to another post a while back (see here) and some intriguing data about urinary tract infection and risk of acute psychosis.

This latest Yolken data further add to the growing body of research suggesting that either cause or effect, the immune system does seem to be associated with various behavioural and psychiatric labels. My reading of this work suggests that the authors favour the idea that the infection itself (or response to infection) might be the more important aspect to any relationship but I'm not so sure that things are so straight-forward. Indeed, on the other occasions where I've talked about infection and psychiatry, the use of antibiotics - particularly recurrent prescriptions of antibiotics - might not be without possible side-effects (see here) in certain contexts.

There is more to do in this area, not least with regards to possible mechanisms of effect and whether the "prevention and effective treatment of bacterial infections may be important interventions for the management of individuals with mania." I would also hope that given the 'when you swallow a grenade' sentiments associated with antimicrobial use, the trillions of wee beasties that call us home (the gut microbiota) might also figure in any future research strategy.

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[1] Yolken R. et al. Individuals hospitalized with acute mania have increased exposure to antimicrobial medications. Bipolar Disorders. 2016. 17 July.

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Yolken R, Adamos M, Katsafanas E, Khushalani S, Origoni A, Savage C, Schweinfurth L, Stallings C, Sweeney K, & Dickerson F (2016). Individuals hospitalized with acute mania have increased exposure to antimicrobial medications. Bipolar disorders PMID: 27425597

The gut microbiome and coeliac disease risk

"Elective caesarean delivery and repeated maternal urinary tract infections during pregnancy are associated with increased risk of CD [coeliac disease] onset during childhood, suggesting the role of dysbiosis during early life."

Those were some of the rather surprising findings reported by Fredinah Namatovu and colleagues [1] (open-access) following their pretty well-powered study covering "1 912 204 children born between 1991 and 2009, 6 596 of whom developed CD before 15 years of age" living in Sweden. With the aim of exploring "how conditions related to maternity, delivery and the neonatal period influence CD onset during childhood" quite a few variables were thrown into the statistical mix with some rather interesting results. Indeed, researchers also reported that: "High maternal age and high income reduced the risk of CD, which might be due to infant-feeding practices and life style."

Aside from the rather large participant numbers included for study "based on the entire child population in Sweden born during between 1991 and 2009" Namatovu et al were also able to accumulate enough cases of CD so as to ensure "high precision in [their] estimates and enabled adjustment for several variables." Said CD cases were also rigorously confirmed, being "identified through the Swedish National Childhood CD Incidence Register reported from all paediatric departments across the country."

The idea that although there is a pretty well-defined course of genetic and biological events tied into CD (see here) onset might also be moderated by some impact of those trillions of wee beasties that call us home (the gut microbiome) for example, is not a new one. I've already covered the peer-reviewed idea that antibiotic use potentially 'altering' the gut microbiome might have implications for CD on this blog (see here). I note also that a recent review by Simon Murch [2] also mentions a possible role for the gut microbiome too, and with it the requirement for greater scrutiny of this important organ [3]. This all falling under the general suggestion that antibiotics during infancy 'might change their gut microbes for years'.

"In future, preventive strategies could benefit by taking measures to prevent gut dysbiosis." Further: "Reduced prescription of antibiotics is one way that would also work to counteract the enormous problem with development of bacterial resistance to antibiotics. Promoting normal delivery would also be in line with goals in the field of maternal and child health." I, personally, would like to see a little more investigation done on such variables before anyone jumps to too many conclusions. The jury is for example, currently out when it comes to infant feeding and risk of CD [4] on the basis of the suggestion by Namatovu et al that: "older mothers are more likely to practise prolonged and exclusive breastfeeding." There is slightly more support for the idea that a child's mode of entry into the world might influence the development of CD [5] but the absolute risk seems to be rather small.

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[1] Namatovu F. et al. Maternal and perinatal conditions and the risk of developing celiac disease during childhood. BMC Pediatrics. 2016;16:77.

[2] Murch S. Recent Advances in Celiac Disease. Indian J Pediatr. 2016 Jun 8.

[3] Baquero F.& Nombela C. The microbiome as a human organ. Clin Microbiol Infect. 2012 Jul;18 Suppl 4:2-4.

[4] Silano M. et al. Infant feeding and risk of developing celiac disease: a systematic review. BMJ Open. 2016 Jan 25;6(1):e009163.

[5] Mårild K. et al. Pregnancy outcome and risk of celiac disease in offspring: a nationwide case-control study. Gastroenterology. 2012 Jan;142(1):39-45.e3.

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Namatovu, F., Olsson, C., Lindkvist, M., Myléus, A., Högberg, U., Ivarsson, A., & Sandström, O. (2016). Maternal and perinatal conditions and the risk of developing celiac disease during childhood BMC Pediatrics, 16 (1) DOI: 10.1186/s12887-016-0613-y

Acute psychosis and urinary tract infection

Today I'm highlighting the paper by Krystle Graham and colleagues [1] which talked about a possible association between the presence of urinary tract infections (UTIs) in various types of psychosis. With my interest in all things biology-behaviour, remembering such posts as impulsivity and uric acid (see here), once again we have an example of how the two areas just might fit together.

The bullfighter (deceased) @Manet @Wikipedia 

So, take several groups of adult participants who were admitted "for an acute episode of DSM-IV nonaffective psychosis..., affective psychosis... or alcohol detoxification" and compare with an asymptomatic control group. Analyse for the presence of laboratory-confirmed UTI and voilà, after controlling for potentially confounding variables "UTI was almost 11 times more likely in subjects with nonaffective psychosis than controls". That and the fact that in cases of affective psychosis (major depressive disorder with psychotic features) the odds ratio for a UTI was up at nearly 9x more likely.

Coincidence I hear you cry. Well it certainly could be. But the data is strengthened by the fact that this is not the first time that this association has cropped us as per another paper by the same authors [2] covered by Dr Emily Deans over at Evolutionary Psychiatry. The fact that UTIs show more than a passing connection to behavioural and psychiatric features as per the evidence looking at delerium [3] for example should also be mentioned.

As to the reason for the association, well to quote from the NHS Choices entry on the causes of UTI: "Most urinary tract infections (UTIs) are caused by bacteria that live in the digestive system". The process of how said bacteria get from bowel to erm, nether regions is slightly more complex and could be related to hygiene practices (remember: wipe from front to back after going to the toilet) or other behaviours. One can't exclude the possibility that where psychosis occurs, such factors might come into play.

That being said, I'm also quite interested in whether there may be other reasons for the association made by Graham et al. Readers might remember back to a post I wrote recently on bacterial infections and behaviour (see here) part of which mentioned the paper by Blomström and colleagues [4] on bacterial infections requiring hospital admission and risk of later nonaffective psychosis. Given the focus on childhood in that paper, which I assume to some degree negates the possibility of sexual activity or kidney stones or a urinary catheter as being a primary cause of a bacterial infection like a UTI, one wonders if there may be something more biologically fundamental to account for the association.

Indeed, a quick trawl through the collected research literature in this area reveals some potentially relevant findings in relation, for example, to the development of psychosis after a kidney transplant [5] (open-access) and how this particular patient developed anti-NMDAR encephalitis (see here). I'm wondering whether immune suppression may be a contributing factor to the UTI - psychosis correlation, as per data on the infections favoured following something like organ transplant [6] and the degree to which UTIs are involved. That being said, a role for the immune system in psychosis is a mighty complicated subject as per other posts on this blog (see here and see here) and short of suggesting that immune function might be involved in the link with elevated rates of UTIs in cases, there's few comprehensive answers to account for the association at the current time.

Still it is an interesting area of work, also raising the question: does the treatment of UTIs have any effect on presented psychosis symptoms? Bearing in mind, the evidence so far seems a little bit contrary... [Finish post with head scratch and confused look].

Music to close. Pavement and Cut Your Hair...

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[1] Graham KL. et al. Urinary tract infections in acute psychosis. J Clin Psychiatry. 2014. Jan 21. [Epub ahead of print]

[2] Miller BJ. et al. A prevalence study of urinary tract infections in acute relapse of schizophrenia. J Clin Psychiatry. 2013 Mar;74(3):271-7.

[3] Lin RY. et al. Clinical associations of delirium in hospitalized adult patients and the role of on admission presentation. Int J Geriatr Psychiatry. 2010 Oct;25(10):1022-9.

[4] Blomström A. et al. Hospital Admission With Infection During Childhood and Risk for Psychotic Illness--A Population-based Cohort Study. Schizophr Bull. 2013 Dec 23.

[5] Zhao CZ. et al. Clinical reasoning: agitation and psychosis in a patient after renal transplantation. Neurology. 2012 Jul 31;79(5):e41-4.

[6] Galindo Sacristán P. et al. Predictive factors of infection in the first year after kidney transplantation. Transplant Proc. 2013 Dec;45(10):3620-3.

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  Graham KL, Carson CM, Ezeoke A, Buckley PF, & Miller BJ (2014). Urinary tract infections in acute psychosis. The Journal of clinical psychiatry PMID: 24499998