"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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Pre- and peri-pregnancy use of folic acid and multivitamins and risk of offspring autism

The findings reported by Stephen Levine and colleagues [1] observing that: "Maternal exposure to folic acid and multivitamin supplements before and during pregnancy is associated with a reduced risk of ASD [autism spectrum disorder] in the offspring compared with the offspring of mothers without such exposure" provides the blogging fodder today.

Accompanied by media headlines such as 'Taking vitamins before and during pregnancy slashes autism risk by 75%, new study shows' the Levine paper adds to the growing research literature suggesting that certain nutrients taken during critical periods of pregnancy *might* be important when it comes to offspring development (see here).

"Epidemiologic studies report inconsistent associations between maternal supplementation with multivitamins or FA [folic acid] before and during pregnancy and the risk of ASD in offspring." I'm glad the authors have mentioned that the peer-reviewed literature on folic acid in relation to offspring autism risk is not all one-way. It's something that I've been particularly interested in on this blog for some time (see here and see here for examples) in terms of countering the often simplistic view that mothers-to-be should all be loading up on folic acid for example, to offset any enhanced risk of offspring autism. Yes, folic acid is a required supplement during pregnancy when it comes to something like reducing the risk of  neural tube defects (NTDs) in offspring, but with autism in mind, the evidence is not yet so clear-cut.

Levine et al report results based on Israeli children born between 2003 and 2007 and followed-up until early 2015. Their cohort included "all children with ASD and a randomly selected one-third of all children" born during their index dates including some 45,000 participants in total. When it came to exposure patterns (exposure to folic acid and/or multi-vitamins during pregnancy), the authors relied on a prescription register that included "drug names, prescription and dispensation dates, number of pills dispensed, and ATC codes." Importantly, this meant that researchers were able to classify some important details: "vitamin supplements were classified as FA and/or multivitamin supplements, an FA supplement, and a multivitamin supplement" and the timing of their dispensation: "before pregnancy (540-271 days before childbirth) and during pregnancy (270 days before childbirth up to the date of childbirth)." This is something rather different from some other previous research attempts that have for example, tended to rely on maternal recall of pregnancy supplements.

Results: "This study of 45 300 children revealed a decreased risk of ASD in children born to mothers who used FA and/or multivitamin supplements before and/or during pregnancy compared with those who had not." Among all supplement combinations - FA and/or Multivitamin Supplements, FA Supplements, Multivitamin Supplements - there was a reduced relative risk (RR) of offspring autism compared with 'unexposed' children that was present both before pregnancy and during pregnancy supplementation and took into account various covariates such as "sex, birth year, socioeconomic status (high vs low),17 a maternal and paternal psychiatric diagnosis by childbirth (present or absent), maternal and paternal age at childbirth, and parity." The sorts of risk reduction statistics being talked about - above 50% and even approaching that 75% risk reduction - are not to be sniffed at.

Although quite a good study design, the Levine results are to be treated with some caution. Not least that the authors noted: "causality cannot be inferred from observational epidemiologic studies such as this one" so one has to be careful.

But... yet again, this is further research talking about pregnancy folic acid and offspring autism. This is an area that requires further investigation in relation to possible mechanisms (or combinations of mechanisms) [2] potentially involved. Also, whether specific groups of women taking other important medicines during pregnancy, might benefit from something like folic acid supplementation in the context of enhanced offspring risk of autism [3].

To close, a musical choice to mark the passing of Mark E Smith: Mr Pharmacist (my favourite) or the more widely known, Hit the North?

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[1] Levine SZ. et al. Association of Maternal Use of Folic Acid and Multivitamin Supplements in the Periods Before and During Pregnancy With the Risk of Autism Spectrum Disorder in Offspring. JAMA Psychiatry. 2018. Jan 3.

[2] Goodrich AJ. et al. Joint effects of prenatal air pollutant exposure and maternal folic acid supplementation on risk of autism spectrum disorder. Autism Res. 2017 Nov 9.

[3] Bjørk M. et al. Association of Folic Acid Supplementation During Pregnancy With the Risk of Autistic Traits in Children Exposed to Antiepileptic Drugs In Utero. JAMA Neurol. 2017 Dec 26.

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Maternal tobacco smoking and offspring ADHD risk

"The results showed that either prenatal exposure to MSDP [maternal smoking during pregnancy] or smoking cessation during first trimester was significantly associated with childhood ADHD [attention-deficit hyperactivity disorder] after adjusting for parental psychiatric history and social socioeconomic status."

and:

"With our meta-analysis, we provide evidence for an association between maternal smoking and offspring ADHD but do not solve the causality issues concerning potential confounding by other risk factors."

Those quotes were taken from the findings reported by Tianyu Dong and colleagues [1] and Lan Huang and colleagues [2] respectively, both applying the 'top of the methodological tree' analysis that is a meta-analysis to the collected data looking at whether maternal smoking during pregnancy might impact on offspring risk of a diagnosis of ADHD. Their combined answer: very possibly but...

Having previously covered the non-association between maternal smoking during pregnancy and offspring autism before on this blog (see here), the recent results from Dong and Huang highlight how tobacco smoking during pregnancy is still something to be avoided for the sake of the child(ren). The fact that Huang et al also observed something of a dose-response relationship: "The risk of ADHD was greater for children whose mothers were heavy smokers (OR: 1.75; 95% CI: 1.51-2.02) than for those mothers were light smokers (OR: 1.54; 95% CI: 1.40-1.70)" kinda adds to the strength of their argument for an *association* between smoking during pregnancy and adverse offspring developmental outcome(s).

It's true that even with such meta-analytical prowess, it's still a little difficult to say conclusively that 'smoking causes offspring ADHD'. I'm also minded to state how "different assessment tools of ADHD and a lack of objective biological measures for maternal smoking" were picked up by the authors as other reasons to be cautious about their [collected] findings. I will also direct you to other research published not-so-long-ago that did not find such a strong connection between maternal smoking during pregnancy and offspring ADHD [3] (or at least "indicating that the association between maternal smoking during pregnancy and offspring ADHD is not directly causal, but confounded by unmeasured factors.")

Still, even if maternal smoking during pregnancy represents just one of a number of factors potentially impacting on offspring risk of ADHD, it is worth reducing that risk by nudging mums-to-be (and perhaps even dads-to-be) to quit smoking for the sake of their children. This on top of the myriad of other reasons that parental tobacco smoking during conception, pregnancy and offspring childhood is something that really needs to be stamped out once and for all...

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[1] Dong T. et al. Prenatal Exposure to Maternal Smoking during Pregnancy and Attention-deficit/hyperactivity Disorder in Offspring: A Meta-analysis. Reprod Toxicol. 2017 Dec 30. pii: S0890-6238(17)30599-3.

[2] Huang L. et al. Maternal Smoking and Attention-Deficit/Hyperactivity Disorder in Offspring: A Meta-analysis. Pediatrics. 2018 Jan;141(1). pii: e20172465.

[3] Gustavson K. et al. Smoking in Pregnancy and Child ADHD. Pediatrics. 2017 Feb;139(2). pii: e20162509.

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Low birth weight and autism: rise of the population attributable risk

RIP Cheggers.

"LBW [low birth weight] accounted for 6.0% of all ASD [autism spectrum disorder] cases, 2.4% of BCD [behaviour and conduct disorder], and 6.8% of LD [learning disability] among the study population."

Those were the observations made by Sandie Ha and colleagues [1] and with it, another example of the use of the population attributable risk/fraction in the context of autism (see here for another occasion). Published in 2014 but only recently appearing on PubMed, Ha et al report results based on data from the 2011 (US) National Survey of Children’s Health, (NSCH) - a "random-digit-dial phone survey conducted between February 2011 and June 2012" - where data on birth weight and receipt or not of a diagnosis of "attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), behavior and conduct disorder (BCD) and learning disability (LD)" were available. As an aside, I've talked about the other studies arising from the NSCH program before on this blog (see here and see here for examples).

Including data pertinent to around 81,000 children aged between 2 and 17 years of age, researchers reported that around 9% of the cohort were "born with a LBW as reported by their parent" in response to the question: "What was [sampling child’s] birth weight?" There were some interesting correlates alongside those responses regarding LBW status: "children who were female, non-Hispanic black, had single mothers, had less educated mothers, were poorer, lacked insurance, were exposed to in-home smoking, or born prematurely were more likely to have LBW compared to those with normal BW."

Insofar as 'neurobehavioural disorders' (ND) also asked about: "The weighted prevalence of parent-reported ND among children ages 2 to 17 was approximately 9.9% for ADHD, 2.3% for ASD, 4.1% for BCD, and 10.6% for LD." Yes, this was a telephone-based survey where "both exposure and outcome are based on parental reporting, and thus the information may not represent actual diagnoses" but with the size of the participant numbers included, these prevalence/frequency figures still make for important reading.

Then to the main event - the population-attributable risk percentage (PAR%) and the finding headlining this post: "LBW [low birth weight] accounted for 6.0% of all ASD [autism spectrum disorder] cases, 2.4% of BCD [behaviour and conduct disorder], and 6.8% of LD [learning disability] among the study population." The authors caution that "maternal age at delivery, gestational age, and pregnancy complications could be important confounders" and were not taken into account in their analyses and could be "potential reasons for LBW" alongside undetected "congenital anomalies or genetic disorders." Caution is required.

It's not new news that birth weight might impact on something like autism risk (see here and see here). One also has to bear in mind that something like LBW may not necessarily appear in isolation to other pregnancy or birth events (see here) so a wider research agenda perhaps needs to be followed. But the size of the PAR% talked about by Ha and colleagues is not easily ignored. Taking into account that LBW for some may very well have some 'genetic' influences, one is left asking whether those more 'social' variables linked to LBW might be to some degree 'influenced' with a corresponding effect on neurodevelopmental 'consequences' reported. I say this in the context that poverty as a variable, has already been linked to some diagnoses included in the Ha study (see here)...

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[1] Ha SU. et al. Population attributable risks of neurobehavioral disorders due to low birth weight in US children. Adv Pediatr Res. 2014;1. pii: 2.

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Antidepressant use in pregnancy and risk of offspring ADHD?

Here we go again. Antidepressant use during pregnancy comes under the spotlight yet again (see here) as per the findings reported by Takoua Boukhris and colleagues [1], this time in connection to risk of offspring diagnosis of attention-deficit hyperactivity disorder (ADHD) following gestational exposure to this class of medicines.

Drawing on data derived from the Quebec Pregnancy/Children Cohort (QPC), researchers set out to examine the "risk of ADHD associated with overall and class-specific antidepressant exposure in utero." I might add that previous data from some of the authors of the Boukhris paper on the QPC has suggested that it is "an excellent tool for the study of the risk and benefit of drug use during the perinatal period" [2].

Following nearly 150,000 live births between 1998 and 2009, researchers looked at the rates of subsequent diagnosis of ADHD alongside the pattern of medication use during pregnancy and other important variables such as "maternal history of depression/anxiety and ADHD." They concluded that: "AD [antidepressant] use during the 2nd and 3rd trimester of pregnancy, specifically tricyclics, is an independent risk factor for ADHD in children above and beyond the risk associated with maternal depression/anxiety or ADHD." Further: "SSRI [Selective serotonin reuptake inhibitors] and SNRI [Serotonin–norepinephrine reuptake inhibitors] use were not associated with increased ADHD risk."

As per the convoluted research history talking about pregnancy antidepressant 'exposure' and possible risk of offspring autism, there are certain caveats and issues worth mentioning. Antidepressant use during pregnancy is not something to be taken lightly as per any calls to 'restrict use' during the special nine months that make us. Such medicines serve an important purpose in controlling some potentially important clinical symptoms; said symptoms do not just dissipate during the special time called pregnancy as per other clinical examples with other labels (see here).  It's also worth pointing out that such observational studies looking at medication use and offspring outcomes are just that - observational. As per the tenet 'correlation is not the same as causation', one has to be a little careful with such data...

That all being said, I do find the Boukhris results to be intriguing on the basis that this is not the first time that an *association* has been talked about in the peer-reviewed science domain [3] and on more than one occasion [4]. Further investigations are perhaps required into the possible mechanism(s) involved in any such relationship between medicine and offspring development, and indeed, whether such connections could potentially invite new intervention options for labels like ADHD? I'm also more than a little interested in the 'medication type' angle to the Boukhris observations not necessarily being the same as that put forward in relation to offspring risk of autism.

And just before you go, it's worth highlighting the findings reported by Viktorin and colleagues [5] looking at pregnancy antidepressant use and intellectual (learning) disability: "After adjustment for confounding factors... the current study did not find evidence of an association between ID and maternal antidepressant medication use during pregnancy."

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[1] Boukhris T. et al. Antidepressant Use in Pregnancy and the Risk of Attention Deficit with or without Hyperactivity Disorder in Children. Paediatr Perinat Epidemiol. 2017 Jun 22.

[2] Bérard A. & Sheehy O. The Quebec Pregnancy Cohort – Prevalence of Medication Use during Gestation and Pregnancy Outcomes. Croy A, ed. PLoS ONE. 2014;9(4):e93870.

[3] Man KKC. et al. Prenatal antidepressant use and risk of attention-deficit/hyperactivity disorder in offspring: population based cohort study. BMJ. 2017 May 31;357:j2350.

[4] Clements CC. et al. Prenatal antidepressant exposure is associated with risk for attention-deficit hyperactivity disorder but not autism spectrum disorder in a large health system. Mol Psychiatry. 2015 Jun;20(6):727-34.

[5] Viktorin A. et al. Association of Antidepressant Medication Use During Pregnancy With Intellectual Disability in Offspring. JAMA Psychiatry. 2017 Jul 12.

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Assisted reproductive technology and risk of offspring autism meta-analysed

"Our study indicated that the use of ART [assisted reproductive technology] may [be] associated with higher risk of ASD [autism spectrum disorder] in the offspring. However, further prospective, large, and high-quality studies are still required."

So said the results of the meta-analysis published by Liang Lui and colleagues [1] (open-access) surveying the peer-reviewed research literature - "11 records (3 cohort studies and 8 case-control studies)" - between 2006 and 2015. ART covers a variety of techniques "to achieve pregnancy and live birth" most notably including IVF (in vitro fertilisation) and artificial insemination. Some, but not all, of the studies included for review suggested an *association* between ART use and enhanced risk of offspring autism particularly in "European and Asian populations." The authors were however unable to tease apart which specific ART(s) might be associated with a higher risk than others.

This is not the first time that this topic has been covered on this blog (see here). On that previous occasion I intimated that the source of any risk from ART on offspring autism was not yet identified and, in some cases, other birth factors might exert some effect. In short, it's more complicated than paper titles can transmit.

Does my opinion change as a result of these meta-analysed findings? Well, not really. I appreciate the findings reported by Lui and colleagues but I still think other birth factors might come into play outside of just ART exerting a primary effect. Not least is the possibility that issues affecting fertility in the first place might be particularly relevant among other confounders. I echo the sentiments of the authors that more research might be required in this area but with the various stresses and strains being placed on autism research resources these days, I'm not inclined to suggest that this area should necessarily be top of this list of priorities. Sorry.

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[1] Liu L. et al. Association between assisted reproductive technology and the risk of autism spectrum disorders in the offspring: a meta-analysis. Sci Rep. 2017 Apr 7;7:46207.

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Liu L, Gao J, He X, Cai Y, Wang L, & Fan X (2017). Association between assisted reproductive technology and the risk of autism spectrum disorders in the offspring: a meta-analysis. Scientific reports, 7 PMID: 28387368

ALSPAC says no to cat ownership - psychosis risk hypothesis but...

"While pregnant women should continue to avoid handling soiled cat litter, given possible T. gondii exposure, our study strongly indicates that cat ownership in pregnancy or early childhood does not confer an increased risk of later adolescent PEs [psychotic experiences]."

So said the findings reported by Francesca Solmi and colleagues [1] (open-access) who brought a smile to any reader of the title of their paper: "Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort." For those who might not be aware of the hypothesis, cat ownership has been previously linked to 'adverse' psychological outcomes (see here) tied into some peer-reviewed evidence on one possible environmental factor linked to psychosis and conditions manifesting psychosis: Toxoplasma gondii.

ALSPAC - Avon Longitudinal Study of Parents and Children - brought it's quite significant scientific prowess to bear on the question of whether "cat ownership in pregnancy and childhood (ages 4 and 10 years) was associated with psychotic experiences (PEs) in early (age 13, N = 6705) and late (age 18, N = 4676) adolescence, rated from semi-structured interviews." Having a cat in the house was not the only question asked by Solmi et al as the presence of other pets were also investigated: "dogs, rabbits, rodents, birds (all waves), and tortoises and fish (from 21 months)." PEs were assessed at approximate ages of 13 and 18 years old via responses to the "psychotic-like symptoms interview (PLIKSi), a semi-structured interviewer-rated screening assessment for PEs." Various other variables were also factored into the examination of any effect or not.

Results: well, as per the opening sentence to this post, cat ownership did not seem to be related to later PEs. The potential caveat being that in some of their analyses there did seem to be a possible association - "Owning a cat at age 4 years was associated with higher odds of having PEs at age 13 years in univariable models" - but the significance of this association disappeared when adjustments for other potentially confounding variables were made. Obviously this kind of study can't control for every single potentially confounding variable but they did at least try.

Why the disparity between these results and the previous ones suggestive of a possible connection between childhood cat ownership and later adverse psychological health? Well, an important point is made by Solmi and colleagues: "Our study was based on PEs in early and late adolescence, unlike other studies which were based on a clinical diagnosis of schizophrenia." In other words. psychotic experiences might be part and parcel of schizophrenia but not necessarily all that schizophrenia encompasses and not necessarily just enough to merit a diagnosis of schizophrenia. They do also go on to highlight how the previous report on the association may also not have included the range of potentially confounding variables that were included and controlled for in the current study as another possibility for the differences reported. Having said that [2]...

Does the T. gondii - schizophrenia hypothesis fall as a result of the Solmi results? Probably not. Solmi et al hint that even though cat ownership probably isn't related to PEs, they do not totally debunk the idea that there may be a connection. They did not for example, look for the presence of contact with T. gondii in this particular study (others have) as per serological examination of participants. I say this bearing in mind that not every moggy is necessarily infected with T. gondii or anything else. Sweeping generalisations on all cats are not required.

Music to close, and containing the lyric 'Caringosity killed the Kerouac cat', a chirpy little number from a band with quite a contentious name...

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[1] Solmi F. et al. Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychol Med. 2017 Feb 22:1-9.

[2] Fuller Torrey E. et al. The antecedents of psychoses: a case-control study of selected risk factors. Schizophr Res. 2000 Nov 30;46(1):17-23.

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Solmi F, Hayes JF, Lewis G, & Kirkbride JB (2017). Curiosity killed the cat: no evidence of an association between cat ownership and psychotic symptoms at ages 13 and 18 years in a UK general population cohort. Psychological medicine, 1-9 PMID: 28222824