EXPERT REACTION: C-section birth linked to autism and ADHD

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A review of more than 60 studies and 20 million births has found that caesarean birth is linked to a higher risk of autism spectrum disorder and attention-deficit hyperactivity disorder in kids. The international review, which includes Australian studies, shows kids have 33 per cent higher odds of developing autism spectrum disorder and 17 per cent higher odds of developing ADHD if they are born by c-section. Whether the c-section delivery was elective or emergency made almost no difference to the odds of developing these disorders. The researchers say understanding why this link might occur will be important given the increase in C-section rates.

Journal/conference: JAMA Network Open

Link to research (DOI): 10.1001/jamanetworkopen.2019.10236

Organisation/s: Karolinska Institutet, Sweden

Funder: This study was supported by the China Scholarship Council (Ms Zhang). Conflict of Interest Disclosures: Dr Sevilla-Cermeño reported receiving grants from the Alicia Koplowitz Foundation outside the submitted work. Ms Vilaplana-Pérez reported receiving grants from the Alicia Koplowitz Foundation outside the submitted work. Prof Larsson reported serving as a speaker for Eli Lilly and Shire and receiving a research grant from Shire. Prof Mataix-Cols reported receiving personal fees from UpToDate, Wolters Kluwer Health, and Elsevier outside the submitted work. Dr Fernández de la Cruz reported receiving personal fees from UpToDate, and Wolters Kluwer Health and grants from the Swedish Research Council for Health, Working Life and Welfare, and Stockholm County Council outside the submitted work. No other disclosures were reported.

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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Associate Professor Peter Baghurst is from the Faculty of Health Sciences at the University of Adelaide

It has been well established that preterm birth is strongly associated with developmental delay and with autism (Agrawal et al, Pediatrics, 2018). Since a successful vaginal birth becomes increasingly unlikely (for purely biological reasons) with increasing prematurity – thereby demanding a caesarean section - it should be no surprise at all, that autism is associated with caesarean section, whether it be performed for emergency, or for elective reasons.

In epidemiologic terms, any crude (uncorrected) association of autism with caesarean section is likely to be confounded with gestational age at birth. A correction for confounding by gestational age can be made in the statistical analysis of cohort studies – and at the design stage (by matching cases with controls) in case-control studies. While some or all of the 63 studies contributing to this analysis may have made appropriate corrections, there is no discussion of this important caveat in the main body of this paper – nor is there any mention of whether the nature or type of adjustment for gestational age was a crucial requirement in the authors’ assessment of the quality of the individual studies which they chose to include in their meta-analysis.

Given that the authors wish to convince their readers that caesarean section per se may be a causal factor of adverse outcomes like autism and ADHD, more information is needed in order to evaluate their work.

Last updated: 28 Aug 2019 4:25pm
Declared conflicts of interest:
None declared.
Associate Professor Jason Howitt, Research Director for the School of Health Sciences, Swinburne University.

This research suggests there is a modest increased in the odds of a child having autism after cesarean birth, however I believe that the findings are significantly flawed given that a number of the studies used for the analysis had incredibly high rates of autism (between 10-70%). This indicates that the data is heavily biased and not consistent with worldwide rates of autism of between 1-3% of all births. Importantly, these findings should not alter any parent’s decision on the type of delivery method for their child, nor should any mother who has an autistic child think that their birth choice could have caused autism, this is simply not true.

Last updated: 28 Aug 2019 2:27pm
Declared conflicts of interest:
None declared.
Professor Jeffrey Keelan is Deputy Director of the Women and Infants Research Foundation at the University of Western Australia

This is an interesting and well-performed metaanalysis of neurodevelopment outcomes on an impressively large number of deliveries (over 20 million) from over 60 studies performed across 19 different countries. The central findings are that caesarean section deliveries are associated with a 33% increase in risk of autism spectrum disorder (ASD) and a 17% increase in attention-deficit/hyperactivity disorder (ADHD).

The big question is: what is the causal connection, if any, underpinning these findings? Due to the nature of the study, the researchers were unable to adequately adjust for the many factors which could link mode of delivery with neurodevelopmental outcomes; these include maternal age, indication for C-section, offspring sex, gestational age at delivery, pre-disposing underlying or genetic risk factors, antibiotic exposure (either during delivery or afterwards), maternal or childhood drug exposure, breast feeding practices and duration, childhood health and environmental exposures. Their data suggests that these and perhaps other confounders have a big impact on the findings. Hence, as openly acknowledged by the authors, further research is needed to dissect the impact of all of these possible factors to see if and how C-section delivery plays a causal role in neurodevelopmental and psychiatric disorders.

Last updated: 28 Aug 2019 1:11pm
Declared conflicts of interest:
None declared.
Associate Professor Alex Polyakov is a Clinical Associate Professor at the Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne and a Consultant Obstetrician, Gynaecologist and Fertility Specialist at the Royal Women's Hospital, Melbourne. He is a Medical Director of Genea Fertility Melbourne.

It is a meta-analysis which combined data from 61 studies that included more than 20 million deliveries. The authors reported a statistically significant association between caesarean delivery and autism spectrum disorders as well as ADHD. Other psychiatric disorders did not demonstrate a statistically significant association with the mode of delivery. The methods employed in meta-analysis have been criticised recently. This criticism is usually centred on the fact that a number of unrelated studies, which employed a variety of methodologies, populations and statistical analysis techniques are combined to produce a point estimate of risk. The legitimacy of such data manipulation must be questioned and its results are usually of doubtful exactitude. This can easily be demonstrated if one was to examine two largest individual studies included in the autism spectrum disorders (ADH) and ADHC meta-analysis.
 
ADH
A study by Curran et al was conducted in Sweden between 1982 and 2011 and used ICD-9 and ICD-10 to define ADH and examined 2,697314 deliveries, 28,290 children were diagnosed with ADH. This translates to a prevalence of ADH of 1.05% in this population. This is the largest study in this meta-analysis. The second-largest study was by Yip et al and was conducted in Norway and Finland between 1984 and 2004. It used ICD-8, 9 and 10 to define ADH and included 1,052,397 deliveries with 1,303 children being diagnosed with ADH. In this study, which is the second-largest included in this meta-analysis, the prevalence of ADH was 0.12%, approximately 10 times less than reported by Curran et al. This demonstrates the pitfalls of combining radically different studies to try to arrive at a meaningful conclusion.
 
ADHD
The above exercise can be repeated with the ADHD portion of the article. If the two largest studies included are examined, the prevalence of ADHD in one was 2.77%, while in the second-largest sample it was 0.2%, again a tenfold difference.
 
What can be concluded from these discrepancies in the prevalence of the two diagnoses? Firstly, even if the final results are accepted, it is almost impossible to assess their clinical significance. A 20% increase in risk has radically different meanings, depending on the prevalence of a particular outcome. For example, a 20% jump from a baseline of 3%, will translate into 3.6%, probably a clinically significant increase, that would warrant an intervention to prevent it. On the other hand, the same 20% increase, if applied to the baseline rate of 0.2%, will result in 0.24% prevalence, which may not be as clinically troublesome and may not warrant an intervention.
 
Secondly, one must question the wisdom of combining such divergent studies and expecting an accurate and unbiased estimation of risk. The old saying from computer science: 'garbage in, garbage out' seems to apply, as poor quality input will invariably produce sub-optimal output.
 
Overall, it must be stated that both caesarean section and vaginal delivery have risks for mothers and babies. These risks are not the same and there is no consensus as to which mode of delivery is better overall. The study adds another possible risk to indiscriminate utilisation of caesarean section as the preferred mode of delivery, but it must be balanced against recognised risks of alternative delivery strategies.

Last updated: 28 Aug 2019 1:10pm
Declared conflicts of interest:
None declared.

Although an interesting and controversial topic the many methodological weaknesses of this study make any conclusion very unreliable.

Firstly no realistic physiological mechanism for the weak association of autism and ADHD with mode of delivery is offered.

The studies analysed were very different (heterogeneous) and all were observational studies that do not allow for a wide variety of potential biases.

As a general rule for outcomes in observational studies to be plausibly significant the Odds Ratio (times difference) should be more than 2 and the confidence intervals should not cross one. In this study, the ASD odds ratio was only 1.33 and ADHD was only 1.17.

For all the other outcomes examined the confidence intervals crossed one meaning that there was no statistical significance.

More bias was introduced by examining multiple outcomes and conducting many sub-analyses without allowing for the multiple analyses that may have randomly found chance associations. This is sometimes called by the derogatory name 'data dredging'.

There were also multiple unadjusted confounders e.g. age.

At best observational studies are 'hypothesis generators' and require prospective unbiased studies to confirm or deny the hypothesis generated in this study.

The many weaknesses in this study and the statistically small effect for just two of the many outcomes mean that no clinical conclusions can be drawn from these data.

Genetic causes are now being confirmed for many of these neurodevelopmental disorders and they are unaffected by obstetric management.

Last updated: 28 Aug 2019 1:10pm
Declared conflicts of interest:
None declared.
Gino Pecoraro OAM is Associate Professor of Obstetrics and Gynaecology at the University of Queensland and President of the National Association of Specialist Obstetricians and Gynaecologists (NASOG). He is also a practising obstetrician and gynaecologist in private practice in Brisbane.

A controversial new study has been released looking specifically at adverse effects associated with a baby being born by cesarean section when compared with babies delivered vaginally either unassisted or assisted by either forceps or vacuum. 

In a review sure to further inflame already heated discussions around the world about when a baby should be delivered by cesarean section, authors have reported a statistical association between babies born by cesarean section and autism spectrum disorder, as well as attention-deficit/hyperactivity disorder.

The authors conclude an increased association is present independent of whether a Caesar was undertaken as an elective or emergency procedure or indeed even if it was the result of an 'unnecessary' cesarean section.

Although the study was a composite of over 67 individual studies looking at more than 20 million babies born in 19 countries from as far back as 1966, it has a number of significant limitations making conclusions other than 'more research is needed' impossible to be made.

Important shortfalls of this study are that no uniform definition of 'unnecessary' cesarean section was used and the internationally recognised diagnostic criteria for autism spectrum disorder and ADHD have changed (leading generally to increased diagnosis of affected children) making comparisons across different time periods and countries, difficult and potentially invalid.

In addition, during the study period, other variables have significantly changed including the age of both mother and father which have been implicated in other studies as both increasing the risk of needing delivery by cesarean section and of diagnosis of autism spectrum disorder in the children produced.

Other variables which are known to lead to increased rates of cesarean section including maternal weight, rates of diabetes and other illness affecting pregnancy as well as changing societal expectations for when cesarean section rather than difficult operative vaginal delivery is acceptable.

This study is certainly interesting and begs further prospective research be undertaken to try and answer the question of whether delivery by cesarean section increases the burden of mental health issues in children. Ultimately, this study does not answer this question, but merely comes up with the correct recommendation that 'further research is required'.

Before undergoing any treatment, particularly elective treatment, it is important that doctors make patients aware of the options they have and their potential risks and benefits.

While interesting and a starting point for further research and conversation, I cannot at this time say with any confidence, that this study will substantially alter obstetric practice, particularly in emergency situations.

Last updated: 28 Aug 2019 1:09pm
Declared conflicts of interest:
None declared.
Associate Professor Helen Leonard is Head of Child Disability at The Telethon Kids Institute, and is a researcher at The University of Western Australia

In recent decades there has been a marked increase in the diagnosis of neurodevelopmental disorders, particularly autism. Over a similar time period, there has been an increase in delivery by Caesarean section.

This paper reports a meta-analysis of studies undertaken to investigate whether there is any association between Caesarean section and increased risk of a neurodevelopmental or psychiatric disorder. Further to the screening of nearly 7000 articles the authors identified 61 studies involving 20 million deliveries which met their inclusion criteria.

Their analysis demonstrated that delivery by Caesarean section was associated with a modestly increased risk for autism spectrum disorders as well as for attention-deficit/hyperactivity disorder.

The authors claimed that a strength of their study was the wide range of conditions included. However study sample sizes were much smaller for intellectual disability and other neuropsychiatric disorders such as obsessive-compulsive and tic disorders so, although increased risks were seen, the results were much less precise.

As has previously been shown, the risk for autism did not vary according to the type of Caesarean section, emergency or elective.

Furthermore, the authors acknowledged the lack of adjustment for confounders in many of the included studies making it impossible to determine whether any increased risk was associated with the indication for Caesarean section rather than with the procedure itself.

Last updated: 28 Aug 2019 1:08pm
Declared conflicts of interest:
None declared.

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