"In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis"

The title heading this post - "In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis" - comes from the findings published by Annemette Halvorsen and colleagues [1] on a topic that has been of some research interest for quite a few years (see here and see here for example).

SSRIs denote a class of medicines called the selective serotonin reuptake inhibitors, principally used to treat/manage various types of depression. Although in quite a few cases a lifesaver, such medicines also come with a risk-benefit profile (same as all medicines), a risk-benefit profile that also extends to their use during important times such as pregnancy. Minus any scaremongering sentiments, for quite a while now, there has been some interest in whether SSRI use during pregnancy *might* have some important implications for offspring health and development [2]. Such *associations* whilst potentially important, need of course to be balanced with the reasons why SSRIs are used, and how for example, depression is not typically something that magically disappears as and when a woman becomes pregnant...

The Halvorsen paper represents a "systematic review and meta-analysis" of the pertinent research literature examining whether "in utero exposure to selective serotonin reuptake inhibitors (SSRIs) is associated with increased risk of developing mental- or behavioral disorders." Such a 'boiling down'  of the research literature was, we are told, "conducted in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline" and specifically covered in connection to various childhood developmental labels such as attention-deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD).

Based on their analysis of the available data - "20 studies were included in the review and results from 18 of these were meta-analyzed" - researchers observed "a statistically significant positive association between in utero exposure to SSRIs and mental- or behavioral disorders such as autism spectrum disorder..., attention-deficit/hyperactivity disorder... and mental retardation." I say that with the suggestion that intellectual (learning) disability might be a more appropriate description for that last label mentioned. The authors caution however that their results do not necessarily mean that prenatal SSRI exposure *causes* something like autism or ADHD: "these associations do not necessarily reflect a causal relationship since the results included in this meta-analysis are likely affected by residual confounding by indication, which is likely to account for some (or all) of the positive association."

So what to make of this research? Well 'it's complicated' is the long-and-short of it. Minus any sweeping generalisations I'll take you back to some other research (see here) that did try and disentangle the 'causality' side of this area of study (whether underlying maternal depression or antidepressant use was the most important variable). The findings reported by Rai et al [3] did [cautiously] talk about how "children exposed to antidepressants during pregnancy seemed to be at a higher risk of autism, particularly autism without intellectual disability, than children of mothers with psychiatric disorders who were not treated with antidepressants during pregnancy." Other research however has observed something rather different (see here). Y'see, it's complicated.

So all I can really say is that more research is required, and if in doubt, talk to your prescribing physician.

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[1] Halvorsen A. et al. In Utero Exposure to SSRIs and Development of Mental Disorders: A Systematic Review and Meta-analysis. Acta Psychiatr Scand. 2019 Apr 2.

[2] Pedersen LH. et al. Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. BMJ. 2009;339:b3569.

[3] Rai D. et al. Antidepressants during pregnancy and autism in offspring: population based cohort study. BMJ. 2017;358:j2811.

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On the link between academic achievement and drug abuse: stay in school kids!

"These results provide empirical support for efforts to improve academic achievement as a means to reduce risk of drug abuse."

So said the findings reported by Kenneth Kendler and colleagues [1] who aimed to answer the research question: "To what extent is the known association between poor academic achievement and risk of drug abuse influenced by causal processes?" This follows a scheme of other research from authors on this topic [2].

I'll admit to being slightly outside of my research comfort zone with the topic under investigation and methods used by Kendler et al. I'm aware of the observation that higher academic achievement *might* reduce the risk of drug abuse but I'm not particularly au fait with the scientific literature looking at this relationship. No mind, the Kendler paper is another example of good value for [scientific] money insofar as authors reporting on the use of two different methodologies - "using instrumental variable and co-relative analysis designs" - to try and answer the 'causal' question. Sweden was the research starting point, and some rather impressive study cohort figures: "instrumental variable analysis included 934 462 participants (478 341 males and 456 121 females" followed for nearly 20 years and: "Co-relative analyses were conducted in pairs of cousins (263 222 pairs), full siblings (154 295), and monozygotic twins (1623) discordant for AA [academic achievement]." Alongside looking at academic achievement as a function of month of birth, they also had access to data on a history of drug abuse as per: "Drug abuse registration in national medical, criminal, or pharmacy registries."

The combined results suggested that there is a "significant association observed between AA at 16 years of age and risk of DA [drug abuse] into middle adulthood" and that the link "may be causal". They stress how keeping kids/young adults in school and learning and (hopefully) achieving could provide some important protection against the development of drug abuse. Accepting that drug abuse often has wider implications and effects than for just individuals, I don't doubt that the message 'stay in school' might also impact more extensively too.

And minus any sweeping generalisations, the findings presented by Mochrie and colleagues [3] offer at least one clinical direction where efforts might need to be especially focused...

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[1] Kendler KS. et al. Academic Achievement and Drug Abuse Risk Assessed Using Instrumental Variable Analysis and Co-relative Designs. JAMA Psychiatry. 2018. Sept 5.

[2] Kendler KS. et al. Social and economic consequences of alcohol use disorder: a longitudinal cohort and co-relative analysis. Psychol Med. 2017 Apr;47(5):925-935.

[3] Mochrie KD. et al. ADHD, depression, and substance abuse risk among beginning college students. J Am Coll Health. 2018 Sep 26:1-5.

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Meteorological factors and autism?

If I had a pound (inflation adjusted y'know) for every time the words 'correlation does not equal causation' were used with autism and related conditions in mind, my piggy bank would probably be rather full by now. Indeed such is the application of this term when referring to the wide (very wide) variety of associations made between this, that and t'other, that a backlash has seemingly emerged to counter its usage as per this Slate article.

Cool, clear water @ Wikipedia 

Of course that's not to say that correlation does not imply causation. Recently for example, a study appeared  in the very well respected New England Journal of Medicine (NEJM) by Franz Messerli* which concluded: "Chocolate consumption enhances cognitive function, which is a sine qua non for winning the Nobel Prize, and it closely correlates with the number of Nobel laureates in each country".

Whilst still wondering whether this is some kind of spoof article (apparently it's not) this study encapsulates everything about the notion of correlation ≠ causation given the multitude of other factors which might possibly influence citizens of a particular country winning the distinguished Nobel Prize. I am willing to concede however, should more 'direct' prospective evidence emerge, that eating chocolate might be part and parcel of Nobel Prize winning.

With this same logic I was intrigued to read the recent paper by Sophie St Hilaire and colleagues** (open-access) which based on an ecological study of autism concluded that precipitation and drinking water source might be associated with autism. Drinking water you say? Y'mean similar to the fish and pharmaceutics research and the Brick chlorination by-products paper? Well, similar at least.

In brief:

• Based on data derived from the study by Waldman and colleagues*** which concluded a possible link between annual precipitation and autism prevalence rates in the Western United States, the source of drinking water was analysed with respect to autism rates.
• The percentage of surface drinking water was thrown into the statistical mix as was population density, farming land, SES, risk of neurological disorder from air pollution, suicide rates and meteorological data.
• When analysing all this data, the authors concluded that precipitation was linked to autism rates but the source of drinking water was an important factor too.
• In among the other correlations, rates of autism also correlated with the suicide rate and negatively correlated with the unemployment rate.

There are some other interesting factoids to take from the authors findings and conclusions. Surface sources of drinking water potentially implying some role for environmental contamination was a primary association. More than that however, the authors seemed to rule out any significant association with contaminated run-off water derived for example from pesticide use and indeed urban pollution and autism rates. They leave the door open to air pollution as a possible factor and indeed pharmaceutical contamination of water sources; bearing in mind they did not test the drug residues in water hypothesis.

The negative correlation between autism rates and unemployment (as in high prevalence of autism being linked to low unemployment rates) goes back to other research in this area. That being said, I'm reminded about more recent investigation which seem to imply an opposite trend (high prevalence of autism linked to lower SES) so once again we have to be careful not to generalise too much.

There's no doubt that this is an interesting study despite the reliance on population facts and figures and our old friend correlation. Accepting another old adage on 'lies, damn lies and statistics' (see here****), there are some useful components from the St Hilaire study ripe for further testing. Not least the continuing theme that environment may very much be a part of the increase in reported cases of autism.

To finish, bird is the word (or did you not know?).

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* Messerli FH. Chocolate consumption, cognitive function, and Nobel Laureates. NEJM. October 2012.

** St Hilaire S. et al. An ecological study on childhood autism. Int J Health Geographics. 2012; 11: 44.

*** Waldman M. et al. Autism prevalence and precipitation rates in California, Oregon, and Washington counties. Arch Pediatr Adolesc Med. 2008; 162: 1026-1034.

**** Bartell SM. & Lewandowski TA. Administrative censoring in ecological analyses of autism and a Bayesian solution. J Environ Public Health. 2011; 2011: 202783.

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Sophie St Hilaire, Victor Ezike, Henrik Stryhn, & Michael A Thomas (2012). An ecological study on childhood autism International Journal of Health Geographics