Childhood "neuropsychiatric morbidity" and prenatal exposure to pre-eclampsia (but not autism)

"Offspring exposed prenatally to preeclampsia have a significantly higher risk of developing a neuropsychiatric morbidity during childhood."

So said the findings reported by Kira Nahum Sacks and colleagues [1] following their analysis of a whopping "253,808 singletons... that were born between 1991 and 2014 in a single regional tertiary medical center" in Israel. Such work follows a research theme from this authorship group (see here).

Pre-eclampsia is no stranger to this blog (see here for example). It's a condition appearing during pregnancy that is characterised by "the onset of high blood pressure and often a significant amount of protein in the urine." Although most cases of pre-eclampsia are mild and some signs and symptoms treatable (see here), there are risks attached to the condition; one of the most notable being the possibility of eclampsia characterised by the onset of seizures to the mother. As you might imagine, such seizures present a risk to both mother and unborn child.

Nahum Sacks et al set out to "assess whether prenatal exposure to preeclampsia increases the risk of long-term neuropsychiatric morbidity" on the basis of "contradicting findings in the current literature." Including use of their large participant cohort, researchers took into account various other, potentially confounding factors, to look at what *might* happen in the longer term to those children who were exposed to pre-eclampsia during the nine months that made them. We are told that: "3.0% were born to mothers diagnosed with mild preeclampsia (n = 7660), 0.9% with severe preeclampsia (n = 2366) and 0.03% with eclampsia (n = 81)."

Results: it was a bit of a mixed bag of results if I'm honest. Researchers mention for example, how pre-eclampsia exposure was significantly associated with offspring obstructive sleep apnoea (OSA) and epilepsy. At least one of those outcomes - epilepsy - has previously been talked about in the peer-reviewed literature [2] as being associated with prenatal exposure to pre-eclampsia and eclampsia.

But then also there was something a little bit different in the Nahum Sacks paper: "Preeclampsia exposure [was] not associated with autism or eating disorders in offspring." This is intriguing in light of some fairly strong (and meta-analysed) links previously discussed between pre-eclampsia and autism (see here). The Dachew paper [3] that was previous fodder for this blog did caution that their meta-analysis on the topic of autism and pre-eclampsia saw evidence that many studies "did not consistently adjust for important confounding factors such as maternal obesity, parity, gestational diabetes and infection during pregnancy" and what this might mean for their overall findings. Indeed, it's a big issue for research looking at pregnancy factors as affecting offspring risk of this, that and t'other: various adverse pregnancy conditions tend to 'clump together'. This makes it all the more difficult to tie any one single factor down to any one specific risk (see here).

The Nahum Sacks findings are not to be taken lightly. The large participant group included for study add weight to the their findings. Yes, it was another observational study, and yes, there could be a 1001 other variables not controlled for that may influence the appearance of offspring neuropsychiatric morbidity. But the possibility of a link between exposure to pre-eclampsia in-utero and something like the appearance of epilepsy is something that could be worthy of a lot more study...

----------

[1] Nahum Sacks K. et al. Long-term neuropsychiatric morbidity in children exposed prenatally to preeclampsia. Early Hum Dev. 2019 Jan 31;130:96-100.

[2] Wu CS. et al. Preeclampsia and risk for epilepsy in offspring. Pediatrics. 2008 Nov;122(5):1072-8.

[3] Dachew BA. et al. Pre-eclampsia and the risk of autism-spectrum disorder in offspring: meta-analysis. Br J Psychiatry. 2018 Mar;212(3):142-147.

----------

"Are women with autism at an increased risk of adverse pregnancy outcomes?"

The paper by Heléne Sundelin and colleagues [1] provides the blogging fodder today, and research pertinent to the question: "Are women with autism at an increased risk of adverse pregnancy outcomes?" The short answer to the question is yes: "Maternal autism is associated with preterm birth, likely due to an increased frequency of medically indicated preterm births, but also with other adverse pregnancy outcomes, suggesting a need for extra surveillance during prenatal care."

It was refreshing to read the results from Sundelin et al (a research group who are no strangers to autism research) because this was a study devoted to looking at women with autism / autistic women and their pregnancy outcomes. It was distinct from other research on maternal pregnancy outcomes and offspring autism more traditionally seen in the peer-reviewed research literature and covered on this blog (see here and see here for examples).

The source material for the Sundelin study was the Swedish Medical Birth Registry (yes, one of those fantastic Scandinavian population registries again) and records of "2,198 births to 1,382 women with autism and 877,742 births to 503,846 women never diagnosed with autism." When comparing the groups across various different measures including preterm delivery ("defined as <37 completed weeks of gestation"), tobacco smoking during pregnancy and the use of various prescription medicines during pregnancy, some interesting trends were observed.

"Women with autism were at an increased risk of preterm birth..., which after stratification, remained for moderately (32 to <37 weeks) preterm birth." Also: "Maternal autism was also linked with an increased risk of elective cesarean delivery in births to women with autism" and "Preeclampsia was more prevalent in mothers with autism."

Although not seemingly affecting many of the 'adverse' pregnancy outcomes examined, researchers also noted that rates of tobacco smoking (light and heavy use) during early pregnancy were elevated in mums with autism, alongside prescription medicine use (antiepileptics, antipsychotics, hypnotics/anxiolytics, antidepressants) being more frequently reported before and during pregnancy compared to non-autistic pregnant mums. Authors reported that "there was no increased risk of adverse pregnancy outcomes except for induction of delivery" but one has to remember that the focus was on pregnancy outcomes - "completed weeks of gestation, mode of delivery, 5-minute Apgar scores, intrauterine growth, stillbirth, and maternal complications (preeclampsia and gestational diabetes)" - and does not say anything about longer term post-pregnancy outcomes. I say this with a few potential 'issues' in mind (see here and see here and see here).

The Sundelin study is by no means perfect - a "limitation is the lack of information on life circumstances" - but does carry the research weight that comes from those extremely well-categorised Scandinavian population registries. The authors conclude that their: "results suggest a need for individual prenatal care for women with autism, weighing pros and cons for continuation of psychotropic medication, with a better understanding of the difficulties related to autism, especially regarding the communication with health care professionals." Who am I to argue with them?

----------

[1] Sundelin HE. et al. Pregnancy outcomes in women with autism: a nationwide population-based cohort study. Clin Epidemiol. 2018 Nov 30;10:1817-1826.

----------

Hypertensive disorders of pregnancy (HDP) and offspring autism and/or ADHD meta-analysed

"Pooled estimates from this systematic review and meta-analysis of 61 studies suggest that exposure to hypertensive disorders of pregnancy is associated with a small yet statistically significant increase in the odds of autism spectrum disorder and attention-deficit/hyperactivity disorder in offspring compared with no exposure."

So concluded the review and meta-analysis published by Gillian Maher and colleagues [1] that collected and analysed the current peer-reviewed research literature (up to June 2017) looking at hypertensive disorders of pregnancy (HDP) and offspring developmental outcomes. Continuing an important research theme (see here), authors observed something around "a 35% increased odds of ASD [autism spectrum disorder] compared with nonexposure" and that children were "30% more likely to have ADHD compared with unexposed offspring."

HDP according to Maher et al, covers quite a bit of diagnostic ground: "chronic hypertension (essential/secondary), white-coat hypertension, masked hypertension, transient gestational hypertension, gestational hypertension, and preeclampsia (de novo or superimposed on chronic hypertension)." The primary characteristic is "high blood pressure that either precedes pregnancy, is diagnosed within the first 20 weeks of pregnancy, or does not resolve by the 12-week postpartum checkup" [2].

There's little more to say about this area of research aside from the idea that findings "highlight the need for greater pediatric surveillance of infants exposed to HDP to allow early intervention that may improve neurodevelopmental outcome" and that more work on possible mechanism(s) need to be undertaken. On that last point the authors opine that "placental dysfunction, associated with HDP, may result in reduced placental perfusion and oxidative stress" or that: "Maternal inflammation may also play a key role." Both worthy areas for future research. The implication also, is that yet again, there may be some form of 'foetal programming' going on with regards to offspring autism that *could* be sensitive to intervention at some point...

----------

[1] Maher GM. et al. Association of Hypertensive Disorders of Pregnancy With Risk of Neurodevelopmental Disorders in Offspring: A Systematic Review and Meta-analysis. JAMA Psychiatry. 2018 Jun 6.

[2] Mammaro A. et al. Hypertensive Disorders of Pregnancy. Journal of Prenatal Medicine. 2009;3(1):1-5.

----------

Pre-eclampsia increased the risk of ASD in offspring: meta-analysed

"The finding suggests a need for early screening for ASD [autism spectrum disorder] in offspring of women with pre-eclampsia."

That was the conclusion reached in the meta-analysis published by Berihun Assefa Dachew and colleagues [1] covering the literature on pre-clampsia and offspring risk of autism or ASD.

Pre-eclampsia refers to a condition/state typically occurring after about 20 weeks of pregnancy. It is characterised by a combination of symptoms including hypertension (raised blood pressure) and the presence of protein in the urine (proteinuria).

On the basis that pre-eclampsia has been mentioned as a *possible* risk factor for subsequent offspring autism diagnosis (see here), the authors set about meta-analysing the peer-reviewed research in this area covering the period up to the middle of March 2017. They eventually settled on 10 studies that suitably covered the topic; of which 5 were rated as 'good in methodological quality' and the rest, somewhere between fair and poor.

Results: most studies (7/10) reported a positive association between the presence of pre-eclampsia and offspring autism. Most studies included for meta-analysis had taken into account some potentially important confounding variables such as child gender, "maternal age and substance use during pregnancy." The overall enhanced risk of offspring autism - "pooled relative risk (RR)" - associated with intrauterine exposure to pre-eclampsia was 32% compared with non-exposed children. And with that, you can perhaps see why the authors make that call for preferential screening for autism in children exposed to pregnancy pre-eclampsia.

But one must also be a little careful with such results. Careful because studies were usually looking at one pregnancy variable and one offspring outcome. To quote the authors, studies typically "did not consistently adjust for important confounding factors such as maternal obesity, parity, gestational diabetes and infection during pregnancy" all of which have been mentioned with offspring autism risk in mind (see here and see here and see here and see here respectively). Lots of things go on during pregnancy (and indeed, before pregnancy) that *could* have a sizeable impact - alone or in combination with each other - on various offspring outcomes including risk of a diagnosis of autism.

Still the results are what they are. They invite further investigations in this area, including those relevant to the possible hows-and-whys of pre-eclampsia exposure potentially contributing to a developmental/behavioural diagnosis and what strategies might be useful to consider [2] more generally...

----------

[1] Dachew BA. et al. Pre-eclampsia and the risk of autism-spectrum disorder in offspring: meta-analysis. British Journal of Psychiatry. 2018. Jan 24.

[2] Nordqvist M. et al. Timing of probiotic milk consumption during pregnancy and effects on the incidence of preeclampsia and preterm delivery: a prospective observational cohort study in Norway. BMJ Open. 2018; 8: e018021.

----------

Pregnancy hypertension and offspring autism

"Hypertension in pregnancy was associated with ASD [autism spectrum disorder] in this population even after controlling for known confounders."

So said the findings reported by Eileen Curran and colleagues [1] who, once again (see here), relied on "data from the Millennium Cohort Study" to produce some potentially important information about how adverse pregnancy conditions may/may not impact on offspring behaviour and development.

Hypertension (a.k.a high blood pressure) during pregnancy is something to watch out for given the association with another condition: pre-eclampsia; something else that has been linked with various outcomes to offspring including autism as one possibility (see here). I might also point out that the evidence looking at pre-eclampsia and offspring autism risk is not however exactly all one-way traffic [2].

OK one needs to be a little careful with the Curran findings given that: "Mothers were asked if they experienced any illnesses during pregnancy for which they needed medical attention" where hypertension in pregnancy - "HIP" -  was one of the options. This alongside the fact that "ASD was parent-reported based on a diagnosis by a doctor or health care professional." It's not that science should disbelieve parental report (indeed, quite the contrary) but rather that when it comes to medical diagnoses such as HIP, access to medical records where facts are recorded rather than retrospectively recalled is always going to be more authoritative.

Anyhow, from the 13,000+ people who "responded to the question on health during pregnancy and ASD" researchers reported that there did seem to be something more to see when it came to the connection between HIP and autism. Such a relationship held over various different statistical models (adjusted - unadjusted, maternal age, etc.) Given also the effect of HIP on placental functions in particular, the authors suggest that their results "raises the possibility of using clinical data regarding the clinical course of pregnancy and the molecular characteristics of the placenta at birth to predict a child risk of future ASD." Big words, I'm sure you'll agree.

So, here we are again talking about 'the maternal body as environment' with autism in mind (see here). Here we are again talking about 'risk factors' for autism and particularly those linked into the nine months that made us. I know from some comments about some of my previous posts (this one for example) there is a degree of 'so what?' when it comes to this type of research and indeed, subtle shades of brow furrowing that such work is seemingly being done at all. I agree that autism research needs to broaden it's horizons quite a bit to focus more on what matters to people on the autism spectrum but I also see the value in this type of approach focused on pregnancy and even before. I say this on the basis that clues to some of the underlying biology of at least some autism may one day be gleaned from such data (indeed, some might argue it already has) and could potentially (somehow) translate into interventions supporting more traditional ones. Obviously one also needs to also bear in mind that not all autism is necessarily 'programmed' during pregnancy or before (see here).

Finally, the question of how HIP or other related pregnancy factors might impact on offspring behaviour and development still needs answering. Yes, there is the concept of 'inflammation' creeping into this question [3], made all the more plausible by the fact that mothers body has to alter during pregnancy to accommodate that foreign body known as a foetus together with its placenta. Combined with the already known about idea that HIP can seemingly impact on the flow of nutrients through the placenta (made all the more convincing as a consequence of findings linking the inter-pregnancy interval to autism) and there are a few research avenues potentially ripe for further investigation.

----------

[1] Curran EA. et al. Hypertension in pregnancy and autism spectrum disorder in a British cohort: Long term consequences for mother and child. Pregnancy Hypertension: An International Journal of Women's Cardiovascular Health. 2016; 6: 153.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] LaMarca BD. et al. Inflammatory cytokines in the pathophysiology of hypertension during preeclampsia. Curr Hypertens Rep. 2007 Dec;9(6):480-5.

----------

Eileen A. Curran, Ali S. Khashan, Gerard W. O’Keeffe, & Louise C. Kenny (2016). 35 Hypertension in pregnancy and autism spectrum disorder in a British cohort regnancy Hypertension: An International Journal of Women's Cardiovascular Health., 6

Induced labour and autism (again)

"In this nationwide sample of live births we observed no association between induction of labor and offspring ASD [autism spectrum disorder] within sibling comparison. Our findings suggest that concern for ASD should not factor into the clinical decision about whether to induce labor."

So said the findings reported by Anna Sara Oberg and colleagues [1] supposedly providing some reassurance to mums-to-be and other groups around the likelihood of offspring autism when birth or labour has to be induced. Based on the analysis of one of those oh-so important Scandinavian health registries, researchers followed all the live births recorded in Sweden between 1992 and 2005 looking for signs that labour was induced. As per some media discussion of the study: "Methods to induce labor include rupturing of membranes, mechanical or pharmacological ripening of the cervix, and administration of oxytocin, either used alone or in combination." They also followed the cohort, numbering above a million offspring, looking for recorded diagnoses of ASD in children and, taking into account "a wide range of measured confounders" examined whether induced labour might elevate the risk of offspring ASD.

The headlines suggesting 'no link' between induced labour and offspring autism don't however actually tell the full story of these findings. When taking into account the full cohort - "1 362 950 births"- there did seem to be a slight increased risk of offspring autism associated with labour induction. This association persisted "after adjustment for measured potential confounders" albeit to an even lesser degree. The 'no link' headlines seemed to have focused on further analysis where siblings, one who was induced, one who was not, were compared with regards to autism rates: "thus accounting for all environmental and genetic factors shared by siblings, labor induction was no longer associated with offspring ASD."

I've talked about labour induction and autism risk before on this blog (see here) based on findings [2] that Oberg et al were knowledgeable about and that had reported something of an increased risk based on the analysis of over half a million births in a part of the United States. Personally, I do think there is a little more to see in this area than has hitherto been uncovered. The reasons for induction is something to focus on as per the observations that issues such as pre-eclampsia and gestational diabetes are mentioned and the body of research linking such factors to offspring autism risk (see here and see here for examples). That induction also might mean use of oxytocin (the cuddle hormone!) is something else that perhaps require further investigations too. Without trying to scaremonger, I do wonder whether further thought might be needed based on the findings reported by Leffa and colleagues [3] with oxytocin in mind.

The take-away message: induced labour is pretty unlikely to 'cause' offspring autism but beware of sweeping generalisations and media headlines...

----------

[1] Oberg AS. et al. Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders. JAMA Pediatr. 2016. 25 July.

[2] Gregory SG. et al. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013 Oct;167(10):959-66.

[3] Leffa DD. et al. DNA damage after chronic oxytocin administration in rats: a safety yellow light? Metab Brain Dis. 2016 Aug 3.

----------

Oberg, A., D’Onofrio, B., Rickert, M., Hernandez-Diaz, S., Ecker, J., Almqvist, C., Larsson, H., Lichtenstein, P., & Bateman, B. (2016). Association of Labor Induction With Offspring Risk of Autism Spectrum Disorders JAMA Pediatrics DOI: 10.1001/jamapediatrics.2016.0965

Pre-eclampsia exposure and autism

A few weeks back, the paper from Cheryl Walker and colleagues [1] reporting that: "Children with ASD [autism spectrum disorder] were twice as likely to have been exposed in utero to preeclampsia as controls with TD [typical development]" provided some column inches in certain media quarters.

How dare you insult Hero's Duty, you little guttersnipe!

Although not the first time that pre-eclampsia - a hypertensive state characterised by proteinuria occurring during pregnancy and potentially affected by/affecting the placenta - has been mentioned in the autism research literature [2] (open-access), the value-added bit to the Walker paper was the use of participants/data included in the CHARGE study. As an aside, CHARGE has been mentioned a few times on this blog (see here for example).

The Walker study looked at maternal self-reports and details "abstracted from medical records" of "Preeclampsia and placental insufficiency" in their cohort comprising some 500 children diagnosed with an ASD and nearly 200 diagnosed with developmental delay (DD) compared against 350 asymptomatic controls. Compared against those TD children, those with autism were more frequently reported to have been exposed to pre-eclampsia during gestation. Further, some relationship between pre-eclampsia severity and autism risk was also observed. The authors also noted: "Placental insufficiency appeared responsible for the increase in DD risk associated with severe preeclampsia."

Whilst appreciating that not nearly a week goes by without scientific research linking something or other to a higher risk of autism and the subsequent possibility of 'correlation burnout', these are interesting results. Pregnancy hypertension - high blood pressure - as part of pre-eclampsia is an important factor driving various adverse effects/events which can impact on both developing foetus and mother (e.g. placental abruption). Maternal hypertension as part of the condition called metabolic syndrome has previously been linked to an increased risk of offspring autism [3] (see here for my take on the study) as well as being a potential stand-alone factor [4].

The link between pre-eclampsia and placental insufficiency (where the placenta does not deliver the optimal amount of oxygen or nutrients to the baby) is also a potentially intriguing point with autism in mind. Regular readers might remember some of my previous discussions on the Barker (foetal programming) hypothesis proposed by the late David Barker, and the idea that nutrition in-utero might have some pretty profound consequences for offspring later life health. Although hesitant to say that issues mediated by placental function are directly linked to autism, there is a growing appreciation that the placenta may be a further point of inquiry when it comes to offspring neurodevelopmental functions. Take for example other work by Walker and colleagues related to trophoblast inclusions in relation to autism [5] (see here for my previous discussion on this research) as one example. Perhaps more speculatively is the suggestion that a short interpregnancy interval (IPI) might also increase the risk of offspring autism [6] and what this could also mean from a 'depletion of micronutrients' point of view potentially similar to a placental insufficiency scenario.

What is becoming clearer from this and other research on the 'nine months that made us' in relation to autism or other neurodevelopmental diagnoses, is that further efforts are required to tease apart various factors. So:

(a) What are the process by which adverse pregnancy conditions impact on offspring outcomes? Do we already have research precedents as per the paper by van Gelder and colleagues [7] talking about "physiological changes early in pregnancy that manifest in gestational hypertension and pre-eclampsia may play a role in the aetiology of major birth defects, including congenital heart defects and hypospadias". Both congential heart defects and hypospadias have been previously mentioned in the autism research literature (see here and see here respectively).

 and

(b) Linked to the previous question(s), who is more likely to be at risk of such issues, and what intervention(s) might mean for offspring and mother alike?

Music: Dolly sings Jolene at Glastonbury 2014.

----------

[1] Walker CK. et al. Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA Pediatrics. 2014. 8 December.

[2] Gardener H. et al. Prenatal risk factors for autism: comprehensive meta-analysis. Br J Psychiatry. 2009 Jul;195(1):7-14.

[3] Krakowiak P. et al. Maternal metabolic conditions and risk for autism and other neurodevelopmental disorders. Pediatrics. 2012 May;129(5):e1121-8.

[4] Polo-Kantola P. et al. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr. 2014 Feb;164(2):358-65.

[5] Walker CK. et al. Trophoblast Inclusions Are Significantly Increased in the Placentas of Children in Families at Risk for Autism. Biological Psychiatry. 2013; 74: 204-211.

[6] Gunnes N. et al. Interpregnancy interval and risk of autistic disorder. Epidemiology. 2013 Nov;24(6):906-12.

[7] van Gelder M. et al. Maternal hypertensive disorders, antihypertensive medication use, and the risk of birth defects: a case-control study. BJOG. 2014 Nov 14. doi: 10.1111/1471-0528.13138.

----------

Walker CK, Krakowiak P, Baker A, Hansen RL, Ozonoff S, & Hertz-Picciotto I (2014). Preeclampsia, Placental Insufficiency, and Autism Spectrum Disorder or Developmental Delay. JAMA pediatrics PMID: 25485869