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Science Alert: Experts Respond

Folate-autism link research questioned – Expert reaction

Posted in Science Alert: Experts Respond on May 12th, 2016.

Independent experts are unconvinced by unpublished research reporting a link between expecting mothers’ levels of folate – a vitamin pregnant women are encouraged to take – and autism in children.

pregnantPregnant women are encouraged to take the B vitamin folate, as deficiency is linked to the development of lethal or debilitating birth defects. However researchers from Johns Hopkins Bloomberg School of Public Health suggest there could be serious risks in having far too much of the same nutrient. They report that in their study of almost 1,400 mother-child pairs they found links between high levels of folate (much higher than recommended levels) at the time of birth and an increased risk of the child developing an autism spectrum disorder.

Their as yet unpublished findings will be presented May 13 at the 2016 International Meeting for Autism Research in Baltimore. A full media release reporting the study is available here.

The New Zealand Ministry of Health recommends that pregnant women consume around 600 micrograms of folate each day.

Our colleagues at the UK SMC collected the following expert commentary.

Dr Payam Rezaie, Reader in Neuropathology, The Open University and Co-editor of Researching the Autism Spectrum, said:

“The claim that excessive blood levels of folic acid and vitamin B12 in a new mother may increase the risk of the child having an autism spectrum condition is unsubstantiated. As far as I am aware this study has not been scientifically peer-reviewed, and is not  yet published. The initial findings are only now being presented at a conference later this week. Without a rigorous and independent scientific enquiry into the study, it would be irresponsible for the investigators or the media to promulgate such an assertion, based on the scant information presented in this press release – this is misleading, can cause unnecessary confusion, and is tantamount to scare-mongering.The findings should in any event be treated with extreme caution – any number of (as yet unidentified) confounding factors could have impacted on the cohort data, and these will need to be taken into account. An association, even if it exists and can be adequately verified through independent scientific scrutiny, does not necessarily imply causation. Maintaining an adequate intake of essential nutrients, including folic acid and vitamin B12, is crucial during pregnancy to avoid serious birth defects and harm to the unborn child. Expert medical advice should always be sought when planning for pregnancy, and followed up during the course of pregnancy and after birth, to prioritise the health of both mother and child.”

Dr. Channa Jayasena, Senior Clinical Lecturer in Reproductive Endocrinology, Imperial College London, said:

“This was a large observational study conducted by a top US hospital, which was performed in over 1000 women and their children over several years, including over 100 identified cases of ASD. However, it is really important to remember that the scientific evidence has not yet undergone scientific peer review to check its quality (which will happen when published in a journal), and we have just been given access to the study’s ‘headline’. The claim that excessive levels of folate and vitamin B12 are linked to ASD is bound to frighten many mums and dads to be. However as with any observational study, it is crucial to remember a correlation between ASD and high levels of folate and vitamin B12 does not prove causation  since there may something else about the families with high folate and vitamin B12 (economic, social or another biological factor) causing ASD rather than the vitamin levels themselves. Furthermore, we need to remember that taking folate before and during pregnancy is recommended by the NHS because it is has immensely positive effects on the developing brain, by preventing severe brain and spinal cord defects in babies. It is also important to highlight that the taking regular amounts of multivitamins (containing folic acid and B12) actually lowered the risk of ASD in this study, so it gives us no reason to think that taking the recommended dose of pregnancy vitamins is unsafe. It is unclear how very high levels of these vitamins could increase the risk of ASD, but it certainly needs further studies to investigate further. For this reason, it is important that their data gets released to the scientific community without delay.

Dr Maralyn Druce, Clinical Reader in Endocrine Medicine, Barts and the London School of Medicine, said:

“Investigation of a relationship between folate and autism has been long debated, with over 40 papers on the subject to date with conflicting results some showing the direct opposite to this one.

“As this is a preliminary abstract presented at a conference we are missing the precise details of the group’s research. However when case-control studies of this type demonstrate an association, it is difficult to make meaningful conclusions.

“It is important not to confuse an association with proof of causation – the folate level may be a confounder or simply an unrelated marker.

“It is also not clear if and how the researchers accounted for other confounding factors such as social class.

“Importantly, women who are pregnant or thinking of getting pregnant should not look at this result and think it is safer to stop taking folic acid – we know that supplementation has reduced serious birth defects.”

Dr Erica Watson, Lister Research Prize Fellow, University Lecturer in Reproductive Biology, University of Cambridge, said:

“There is a wealth of reliable data indicating the importance of mothers taking folate supplements during pregnancy to reduce the risk of neural tube defects in their babies and so it would be extremely irresponsible to rush into condemning folate. In the context of the recent controversy regarding autism and vaccines, of which there is now an undeniably vast amount of data disproving a relationship, we must be very careful in the claims that are made between autism and folate. The data must be overwhelmingly strong for action to be taken and the data must be more than correlative.  If a causal relationship is found, then it is important that the range of folate levels required for a healthy pregnancy is further defined. It is clear that not enough folate can increase the risk of severe congenital malformations and so supplementation is necessary to decrease this risk. But what is the upper limit? Why are some mothers at more risk than others? Clearly, there is also a genetic component to this story that needs to be explored further.”

Dr Nathalie McDermott, Paediatrician, Centre for International Child Health, Imperial College London, said:

“We don’t routinely monitor pregnant women’s B12 or folate levels unless they were previously known to have a deficiency  (which generally would only be the case if they were known to have pernicious anaemia (B12 deficiency) or had had a previous child with a neural tube defect (folate)).

“The results of this study should be heeded with caution until it has been peer reviewed and subsequent studies corroborate the findings. Women should continue to take the normal recommended amount of folic acid supplementation if they are looking to become pregnant or are in the early stages of pregnancy. The normal recommended amount of folic acid is 400 micrograms daily, which is the amount contained in standard vitamin preparations targeted for pregnancy. If there is confusion over different vitamin preparations, women should discuss with their pharmacist before taking the supplement. Some pregnant women are prescribed higher amounts of folic acid by their doctor as they are known to have a folic acid deficiency or have previously had a baby with a neural tube defect, they should continue taking what they have been prescribed, but if they are concerned should discuss further with their doctor before stopping any supplements. The risk of neural tube defects (such as spina bifida)is a proven consequence of folate deficiency in early pregnancy. The risk of not taking supplements based on the current available evidence is greater than of taking them and pregnant women should be advised to continue the standard recommended supplementation unless advised otherwise by their doctor.”

Prof Dorothy Bishop, Professor of Developmental Neuropsychology, said:

“Unfortunately, large datasets with many variables do lend themselves to generating spurious findings, because they allow opportunities for doing many different exploratory analyses, and then selectively reporting the ones that come out as statistically significant. I would be very surprised if this finding replicated in another sample, and I think it would be irresponsible of the authors to release this finding without first trying to replicate it.”

Dr Max Davie, Mental Health lead, Royal College of Paediatrics and Child Health, said:

“If the study had shown a causal link between excess ingestion of folate and B12, this would be an extraordinary finding. It would therefore require extraordinary evidence.

“However, this study only shows an association, which may be due to chance, reverse causation, or a common unknown factor causing both an increase in ASD diagnosis, and B12/ folate levels.

“The study might appear to be large and well-powered, and it is hard to comment without the data, but I would estimate that you are talking about the difference between (roughly) 104 out of 1250 ‘low folate’ women having children with ASD, versus 3 out of 140 women with ‘high’ folate, when one would expect 1 diagnosis in for this number. So you are essentially talking about 2 extra diagnoses, which in a complex spectrum condition like ASD is impossible to interpret as anything other than chance.  The figure of 17.6 for having both high folate and B12 is literally meaningless.

“So even on the basis of their data, which has not been peer-reviewed, the authors are going way out on a limb in drawing casual connections here, and are being quite irresponsible in undermining decades of public health work to increase the numbers of women taking folate before and during pregnancy, in order to prevent potentially devastating neurological conditions.”

Prof David Smith, Emeritus Professor of Pharmacology, University of Oxford and Founding Director of Oxford Project to Investigate Memory and Ageing (OPTIMA) and Founding Director of MRC Anatomical Neuropharmacology Unity, said:

“This report is from a conference and we have insufficient details to judge its validity. It is not consistent with several previous reports, notably Norwegian and Dutch studies on much larger cohorts of mothers and children where no increased risk was found; indeed, in the latter studies a slightly decreased risk of autism was found in children from mothers who took folic acid supplements in pregnancy. The novelty of the study is that the blood levels of folate and B12 were measured at, or close to, the time of birth rather than early in pregnancy and so would reflect exposure of the child late in foetal life. The major weakness of the report is that no mention was made of possible confounding factors, such as social class, which have a major impact on supplement use and which may influence autism risk. Note that the folate levels were very high and would only occur in a small minority of European women since in Europe, in contrast to America, there is no mandatory fortification of foods with folic acid.”

Dr Justin Williams, Senior Clinical Lecturer in Child & Adolescent Psychiatry, University of Aberdeen, said:

“These findings appear to reflect a simple correlation and we know that correlation is not causation. Often, in studies where there appears to be a relationship between prenatal exposure and subsequent problems with behavioural development, it is actually because the mother has genes which affect her behaviour, which she then pass on to her child. We know that autism is a highly genetic condition, and mothers who carry autism genes are more likely to be anxious and have more diligent personalities. Therefore, during pregnancy, it seems probable that they will be more likely to take vitamin supplements.”

Ian Dale, Head of Research at the National Autistic Society, said:

“This research, which has not been reviewed by experts, claims that pregnant women who take too much folate are at an increased risk of giving birth to an autistic child. However, until there have been adequate reviews of the study, we cannot know whether these bold findings are accurate or can be applied more widely.

“Folate is a crucial vitamin for pregnant women, which has known effects on the developing foetus. But we would urge that the results of this study are analysed thoughtfully, and that people do not worry unnecessarily nor base any decisions on this research.”

Prof Tamsin Ford, Professor of Child and Adolescent Psychiatry, University of Exeter, said:

“It is difficult to tell without seeing the important detail one would expect to see in a paper, as this research has not yet reached that stage, but I worry that this finding is a correlation at best that could have been detected by chance or explained by confounders – and at the moment this press release appears to be based solely on a presentation at a conference so hasn’t been scrutinised by other experts as would normally happen. It is really important that such findings are peer reviewed and replicated. Correlation does not imply causation so even if others detected the same relationship, it would not necessarily mean that the cause of the autism spectrum difficulties was high blood folate or B12.

“When it comes to any supplements, pregnant women should discuss them with their GP or midwife – low levels of folate in pregnancy have been associated with spina bifida or similar difficulties and I worry that some women may suffer alarm and distress at hearing about this report, and that this may result in some pregnant women from stopping supplements that are really important for them.”

“If I was present at the press briefing then I would be asking:

  • What else did they account for in their analysis – age of mother and Social Economic Status might be particularly pertinent here?
  • How did they measure autism spectrum?
  • I am struck by relatively how small their sample of mothers and children were – if recruited over 5 years but only 1391 – (I suspect constrained by those who had blood available but speculating) so the question arises, how representative are these mothers of those in Boston (and elsewhere) and indeed of those in the original cohort, how were they selected and how might any differences between those who were included in the analysis and those who were not, bias the study or mean that the findings were not broadly generalizable?
  • The prevalence of Autism spectrum conditions varies depending on how you measure it – but mostly in children, people report about 1-2% – so that is 14-28 children in this sample; even 5% which seems hugely unlikely would be 70 – combined with 1/10 (so around 140) mums with high folate – and then they adjust for other variables – some rather small cells here. So how precise are their estimates i.e. what is the 95% confidence interval (or the range in which the estimate would lie if the study were repeated lots of times on 95% of tests) as I would suspect it is wide
  • How many statistical tests did they run? 1 out of 20 would be statistically significant at p=0.05 by chance (that is in fact what p=0.05 means)”

Dr Jenny Myers, NIHR Clinician Scientist and Senior Lecturer/Consultant Obstetrician, University of Manchester, said:

Q: What are the absolute risks of autism, so how much of an absolute increase would this have?

“The absolute rates of autism are difficult to be precise about but likely 6-14 per 1000. That means there will have been approximately 20 cases in this cohort (at 14/1000). Even if it is a particularly high risk cohort with a doubled prevalence, there will only be 40 children affected. 10% of the women in the study had a folate level above the threshold investigated which equates to 140 women – the number of children affected in this group will therefore be 4-8 in the high folate group – not exactly big numbers. Similar for the B12 which was high in around 84 women – around 7-8 children. Therefore, it’s really important that people recognise the relatively small size of the study and that the findings could easily have occurred by chance. The confidence intervals are very wide. Although there was a significant effect of supplementation taken 3-4 times per week, the increased risk was not significant for women taking supplements every day – most likely highlighting that the sample was quite small.

Q: Would someone have to take more than the recommended amounts of supplements in order to reach these levels of B12 and folate?

“Most excess folate and B12 is excreted through the kidneys, high dose supplements will increase the levels considerably. NORMAL diet would not.”

Q: Is it common for women to produce/absorb high levels of B12/folate?

“Levels will be high if they take high dose supplements.”

Q: Should women stop taking supplements? Are there certain supplements that are safe?

“Normal dietary supplements should still be recommended for use (400micro grams at the beginning of pregnancy to reduce the risk of neural tube defects).”

Q: Do women in the UK get tested for folate and B12 levels?

“Not routinely.”

Q: Is there a mechanism by which folate might be linked to autism?

“Not that I am aware of. It would be a good question for the investigators.”

Q: Is this just correlation at best? Are there obvious confounders that could be linked to this?

“There are likely to be lots of other confounders – it is not clear what other risk factors have been taken into account. Women may have had poor diets and be from poorer backgrounds therefore been advised to take supplements for example. It may be the other risk factors which made them more likely to be given dietary supplements are more relevant. There could be lots of other relevant environmental or biological factors which are important in this group. Given the small numbers it will not have been possible to make multiple adjustments to account for all of these factors.

Q: The folate and B12 levels were measured after birth – is there a cumulative effect of taking supplements or do they get broken down quickly in the body? Presumably if the latter then these women would need to continue taking the supplements after birth in order for there to be an effect?

“If the increased risk of autism really is associated with increased levels of vitamins then the crucial thing surely is the concentration in the baby at birth? Have they measured this?”

Dr Ian Johnson, Nutrition Researcher and Emeritus Fellow, Institute of Food Research, said:

“This is a very interesting observation obtained from a reasonably large study, but it needs to be treated with considerable caution because the protective effect of folate supplementation against neural tube defects is very well established.  In contrast, this is a preliminary report from a single study. Judging from the press release, no direct association between autism and maternal vitamin intake from foods or supplements has been established. The observed correlation between blood folate and vitamin B12 levels and risk of autism, for which incidentally no indication of statistical significance is given in the press release, could reflect high intakes, or possibly some previously unobserved metabolic abnormality, or perhaps a combination of the two. Nevertheless I think further research to explore this issue is certainly justified.

Prof Richard Anderson, spokesperson for the Royal College of Obstetricians and Gynaecologists (RCOG) and Head of Obstetrics and Gynaecology, University of Edinburgh, said:

“There is strong scientific evidence showing that folic acid reduces the number of pregnancies affected by neural tube defects, such as spina bifida. The RCOG, with health authorities around the world, recommends that women take folic acid when trying to conceive and in early pregnancy. In this new study women taking low doses of folic acid supplements were less likely to have a child with autism, but those with very high levels of folic acid in their blood were more likely to have a child with autism. The authors of the study acknowledge the well-established health benefits of folic acid supplementation, and do not suggest that women stop taking folic acid supplements.

“The results of this small study should be treated with caution as any mechanism linking folic acid with autism remains unknown. However it highlights that women should take the recommended daily intake, but not exceed it. The causes of autism remain an important area of research.

“The RCOG recommends that all women take 400 micrograms of folic acid daily while they are trying to conceive, and until their 12th week of pregnancy, with higher doses only recommended for certain groups of women such as those with diabetes. We are also calling for a food fortification policy with mandatory fortification of bread or flour with folic acid as a public health measure to prevent folate deficiency and to improve the lives of both mothers and babies. This will reach women most at risk due to poor dietary habits or socioeconomic status, in addition to those women who may not have planned their pregnancy.”

Prof Jonathan Green, Professor of Child and Adolescent Psychiatry, University of Manchester, said:

“There are many epidemiologically based association claimed made of this sort – increasingly so in autism at the moment. Without details of the analysis, or any theory of action this looks like low grade evidence and, if not peer-reviewed, seems irresponsible.”

Prof Chris Jarrold, Professor of Cognitive Development, School of Experimental Psychology, University of Bristol, said:

“This could be unduly alarmist, not least because this is a conference presentation that has yet to be fully peer reviewed.  From the limited evidence provided one needs to be very careful at this stage about giving it too much weight.  The researchers rightly note that their ‘findings warrant additional investigation’.

“The researchers state that they have controlled for ‘pertinent covariates’.  It would be important to confirm that this includes controlling for socio-economic status.  This is a predominantly low-income sample, and because autism diagnosis is somewhat subjective (i.e., based on clinical impression rather than a definitive genetic test) there is evidence that people from higher socio-economic status groups can more easily access the services needed to obtain a diagnosis (particularly when that diagnosis then incurs significant costs for local educational or health provision).  This is a potential issue here, because one would expect supplement use to also relate to social class in the same direction.

“The sample appears to be unusual in that the incidence of autism is surprisingly high, with 107 of 1,391 individuals receiving a diagnosis.  This 7.7% rate is noticeably higher than the 1 in 68 baseline incidence that the press release quotes (1.5%).  Unless folate and B12 levels are unusually high in this whole sample of mothers, this discrepancy needs explaining.

“In addition, even with 107 individuals with autism in the sample, it would be important to know how many mothers had atypically high folate and/or high B12 levels.  If there are relatively few mothers in these groups, then even a large percentage change in incidence could, in fact, be driven by a relatively small difference in the absolute numbers of individuals with autism in each subgroup.”

Dr Rosa Hoekstra, Lecturer in Psychology, King’s College London’s Institute of Psychiatry, Psychology and Neuroscience (IoPPN), said:

“As with the recent press release based on a conference presentation on autism and pesticides I think the press should be careful giving major attention to this piece of work. At present we simply don’t have the level of detail required to fully evaluate the merits and draw-backs of the study. The authors also helpfully highlight the need for caution themselves, indicating their findings ‘should be interpreted with caution and should be further confirmed in other independent cohorts’.

“Just to add: it’s not the authors’ fault that this information is lacking from the abstract: there is a strict word limit in abstract submissions, so they simply can’t include all these details. But unfortunately this also means we have to fare on little information. I would encourage the journalists to ask for these additional details. If at this stage it is impossible to receive these details then journalists may want to wait publicising these findings until the work is published in full in a peer-reviewed academic journal.

“Lastly, I think the authors have done a pretty good job trying to write a nuanced message, also highlighting that B12 and folate are essential nutrients for maternal and foetal health. Any journalist writing about this study should make sure to include this important nuance in their piece.”

“Here are a couple of questions or comments journalists may want to put forward during the press briefing:

  • The abstract indicates the study included 1391 mother-child pairs, including 107 children with ASD and 1284 typically developing children. The authors have removed children with ADHD, ID (without autism) and other developmental disabilities from their analyses. It would be interesting to know why: did they also investigate the possible link between folate and B12 with these other disorders? If so, is the effect reported specific to autism or also seen for other developmental disorders and disabilities?
  • The information provided does not make clear how the authors accounted for possible confounding variables, and which confounders they included in their analyses. Important possible confounders include: child’s gender (higher autism risk in boys), perinatal complications (associated with a higher autism risk); maternal prepregnancy obesity and maternal diabetes (factors previously associated with increased autism risk in the same study cohort (Li, Fallin, et al., Pediatrics, 2016); maternal age (high maternal age associated with increased autism risk in child). To be able to interpret the study’s findings these details are needed.
  • The authors seem to have focused specifically on extremely high levels of folate and B12, defined as >59 nmol/L for folate and >600 pmol/L for B12. What is unclear from the information provided is why they chose this definition. It would be useful to know if the association was dose-dependent (i.e. the more extreme the folate and B12 levels, the higher the autism risk), or was only observed for the group above this (seemingly arbitrary) cut-off. If the result is only observed for this extreme group the findings are more likely to be spurious.”

Dr James Cusack, Research Director, Autistica, said:

“Although this finding is striking, it is vital to remember that this research is at a very early stage.  In fact, this information has simply come from a single poster at a conference.  It is far too early to say whether this finding is correct and so families should not be overly concerned.

“It is of course important to understand whether there are any environmental factors which increase the likelihood of autism.  As the authors of this poster themselves suggest, to actually understand whether there is a link between increased folate and autism, we need far more data from other cohorts, more in-depth peer review, and further data analysis.

“To put this result in context, we have had an array of proposed environmental factors associated with autism over the years.  For example, early research suggested anti-depressant use in mothers increased the likelihood of autism, but careful statistical analyses, and control of confounding factors, disproved this theory.

“It’s exceptionally important that when we talk about autism research findings, we consider the evidence carefully and proportionately.  Autism researchers should be well aware of this, following the false link between MMR and autism and the huge societal issues this has led to.”

Dr Ginny Russell, Senior Research Fellow, Child Health Group, University of Exeter Medical School, said:

“Studies are frequently published about ‘causes’ of autism. Often, like this one, they are based on correlations which do not prove causality and have not been replicated. In this case, the study in question is not yet peer reviewed or published. I would urge caution when interpreting these results: more evidence is needed to support the findings before jumping to hasty conclusions.”

Prof Andrew Sherman, Professor of Obstetrics, King’s College London, said:

“This research does not suggest any harmful effects of recommended folate supplements taken in early pregnancy which are beneficial. Women should continue to take these. There is no rationale mechanism for this finding, but it needs further evaluation as this a very provisional observation.”

A spokesperson for the British Pregnancy Advisory Service said:

“Folic acid supplementation in early pregnancy has been proven to dramatically reduce the risk of neural tube defects (NTDs) such as spina bifida, which causes life-long disability, and anencephaly, a fatal condition where the baby’s brain and skull do not form properly. The neural tube closes very early in pregnancy, before many women may even know they are pregnant. Rates of NTDs in the UK remain higher than elsewhere in Europe, with around 1,000 pregnancies estimated to be affected every year. The overwhelming majority of these cases end in the painful decision to terminate what is often a much wanted pregnancy. We would absolutely advise women who are planning pregnancies to continue to take folic acid supplements, with the current recommendation to continue with these up until the 12th week of pregnancy.”

For info:

The World Health Organisation recommends red blood cell folate levels should be above 906 nmol/L in women of reproductive age to achieve the greatest reduction in NTDs. Analysis of blood samples from the National Diet and Nutrition Survey published in 2015 found among UK women of reproductive age the median level was 535 nmol/L and the mean 614 nmol/L (Scotland mean 563, Northern Ireland mean 512, Wales mean 611)

 

Declared interests

Dr Rezaie: “None”

Dr Jayasena: “None”

Prof Bishop: “I have no conflict of interest.”

Dr Johnson: “No grants and no commercial affiliations”

Prof Jarrold: “I’m a Governor of the Venturers’ Academy school for individuals with autism:

http://merchantsacademy.org/venturers-academy-our-new-school/

Dr Hoekstra: “I am a member of the International Society for Autism Research that organises IMFAR (the meeting where these findings will be presented). However, I am not attending this edition of IMFAR and have no involvement in this particular study.”

Others: None received

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