Editorial Opinion
ment approaches, including Sen’s capability approach,7,8 the social return on investment model,9 and the life course model that has gained a foothold in maternal and child health research.10 In addition to better conceptual frameworks, improving measurement at a population level will take new methodological approaches. One promising model to learn from is the Life Course Metrics Project organized by the Association of Maternal & Child Health Programs.11 Adopting an investment perspective also means taking a long view on life course outcomes. Improving our understanding of how life unfolds will require a serious commitment to longitudinal, population-based data collection. For nearly 7 decades, evidence from the Framingham Heart Study and other ARTICLE INFORMATION Author Affiliations: A. J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania. Corresponding Author: Paul T. Shattuck, PhD, A. J. Drexel Autism Institute, Drexel University, 3020 Market St, Ste 560, Philadelphia, PA 19104-3734 ([email protected]).
longitudinal studies has laid the foundation for our contemporary understanding of the epidemiology and treatment of cardiovascular disease. We need a Framingham Study for autism spectrum disorders, especially to track risks and outcomes into middle and later adulthood. Finally, we need to invest in training a new generation of scholars skilled in population- and community-based approaches for improving and measuring innovation and returns on investments. It is our hope that in 10 years one of these new scholars will be in a position to write a follow-up to the article by Buescher et al titled “Return on Investments in Innovative Practices for People Affected by Autism Spectrum Disorders in the United States and United Kingdom.”
3. Roux AM, Shattuck PT, Cooper BP, Anderson KA, Wagner M, Narendorf SC. Postsecondary employment experiences among young adults with an autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2013;52(9):931-939.
Conflict of Interest Disclosures: None reported.
4. Orsmond GI, Shattuck PT, Cooper BP, Sterzing PR, Anderson KA. Social participation among young adults with an autism spectrum disorder. J Autism Dev Disord. 2013;43(11):2710-2719.
Published Online: June 9, 2014. doi:10.1001/jamapediatrics.2014.585.
5. Howlin P, Moss P. Adults with autism spectrum disorders. Can J Psychiatry. 2012;57(5):275-283.
REFERENCES 1. Buescher AVS, Cidav Z, Knapp M, Mandell DS. Costs of autism spectrum disorders in the United Kingdom and the United States [published online June 9, 2014]. JAMA Pediatr. doi:10.1001 /jamapediatrics.2014.210. 2. Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, Wagner M, Taylor JL. Postsecondary education and employment among youth with an autism spectrum disorder. Pediatrics. 2012;129(6):10421049.
9. Lawlor E, Neitzert E, Nicholls J. Measuring Value: A Guide to Social Return on Investment. London, England: New Economics Foundation; 2008. 10. US Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Bureau. Rethinking MCH: the life course model as an organizing framework: concept paper. Published November 2010. http: //mchb.hrsa.gov/lifecourse /rethinkingmchlifecourse.pdf. Accessed March 24, 2014. 11. Association of Maternal & Child Health Programs (AMCHP). The Life Course Metrics Project. http://www.amchp.org/programsandtopics /data-assessment/Pages/LifeCourseMetricsProject .aspx. Accessed March 24, 2014.
6. US Department of Education Office of Special Education Programs. Part B SPP/APR related requirements. http://www2.ed.gov/policy/speced /guid/idea/bapr/2010/e5-1820 -0624relatedrequirements.pdf. Accessed March 24, 2014. 7. Sen A. Development as Freedom. New York, NY: Knopf; 1999. 8. Shattuck PT, Roux AM, Hudson LE, Taylor JL, Maenner MJ, Trani J-F. Services for adults with an autism spectrum disorder. Can J Psychiatry. 2012;57 (5):284-291.
Beneficial or Neutral Effect of Breastfeeding on Cognitive Outcomes in Children of Mothers With Epilepsy? Cynthia L. Harden, MD
The latest report from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study group1 on the association of breastfeeding with cognitive outcomes in children born to mothers with epilepsy taking antiepileptic drugs (AEDs) Related article page 729 is fascinating. The investigators assessed the IQ in children aged 6 years who had been exposed to AEDs in utero and used linear regression as the primary analysis. The analysis included adjustment for other known influences on IQ outcomes reported by these investigators and others, including maternal IQ, specific AED monotherapy, a standardized AED dosage, and the use of periconception folate. While these known factors remained associated with the IQ outcomes, breastfeeding was also associated: breastfed jamapediatrics.com
children had a mean IQ 4 points higher than that of nonbreastfed children, with a mean difference of 12 IQ points for the valproate sodium–exposed group (IQ of 94 for 25 children not breastfed compared with 106 for 11 children breastfed). These results must be couched in their research context, which is that 181 children were included for analysis because both breastfeeding and IQ data were available only on these, a subset of 311 births in the intent-to-treat sample (58%). However, an analysis of the sensitivity of the results to missing data showed that missing data could not explain the findings. The mean duration of breastfeeding was 7.2 months overall, and the proportion of breastfed children was similar in each nonrandomized maternal epilepsy treatment group of valproate, carbamazepine, phenytoin, or lamotrigine at 31% to 49%. JAMA Pediatrics August 2014 Volume 168, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/27/2015
699
Opinion Editorial
The group of authors has previously reported on the IQ outcomes in association with breastfeeding in this cohort at age 3 years and found no difference for the effects of breastfeeding.2 Now, at age 6 years, an age at which more detailed testing can be performed, there is a separation of IQ outcomes, with the breastfed children showing a higher IQ and, in a secondary analysis, better verbal abilities compared with nonbreastfed children. The authors put forth a detailed discussion about the much lower fraction of infant AED exposure with breastfeeding compared with the exposure in utero. So, the time course of the clinical scenario is that maximum AED exposure occurs in utero; therefore, any cognitive teratogenesis likely occurs in utero due to the greater AED exposure. Immediately after birth, there was a period of several months of breastfeeding for one-third to one-half of the evaluated group. IQ testing was then performed at age 3 years, with no difference found by the investigators’ methods,2 and at age 6 years a beneficial effect of breastfeeding was found and discussed in their present article. It is tantalizing to conceptualize this as a restorative effect because the results imply that breastfeeding in the neonatal and infantile periods, occurring just after high levels of passive AED exposure during gestation, is associated with perhaps restoring cognitive abilities closer to where they were meant to be if AED exposure had not taken place, and this subtle effect cannot be detected until testing at age 6 years. A recent study by Veiby et al3 also supports the present NEAD study1 findings regarding the dynamism of a possible effect of breastfeeding on cognitive outcomes of children exposed to AEDs in utero but not exactly the same direction and timing of an effect. In that study, mothers with epilepsy provided information on their child’s development by using a self-reported standardized scale. At age 6 months, impaired fine motor skills were reported in 11.5% of the offspring exposed to AEDs, much greater than the 4.8% reported in the nonepilepsy reference group. Breastfeeding during this period compared with stopping breastfeeding before age 6 months was associated with reduced risk of impaired fine motor skills. The beneficial effect of breastfeeding was also found in the group of 276 mothers who had epilepsy but were
ARTICLE INFORMATION Author Affiliations: Division of Epilepsy and Electroencephalography, Department of Neurology, Hofstra North Shore–Long Island Jewish School of Medicine, Hempstead, New York; Cushing Neuroscience Institute, Brain and Spine Specialists of New York, North Shore–Long Island Jewish Health System, Great Neck, New York. Corresponding Author: Cynthia L. Harden, MD, North Shore–Long Island Jewish Health System, 611 Northern Blvd, Ste 150, Great Neck, NY 11021 ([email protected]). Published Online: June 16, 2014. doi:10.1001/jamapediatrics.2014.420. 700
not taking AEDs, a finding that raises issues about confounding variables in this cohort. In any case, the benefit of at least 6 months of breastfeeding on fine motor skills was not present at the 18-month assessment, but a new potential benefit emerged: significantly fewer autistic traits were reported. Sadly, even this beneficial effect of prolonged breastfeeding was not sustained; autistic traits were more frequent in the entire maternal epilepsy AED-treated group at the 36-month assessment compared with the reference group, with no effect of breastfeeding found. The study by Veiby et al3 has more methodological limitations compared with the NEAD study.1 Two important differences are that maternal IQ was not controlled for by Veiby et al and that their outcomes were based on maternal report; the children were not individually tested by an investigator blinded to the exposure as in the NEAD study methods. However, this leaves us to question where does the truth lie? What is plausible regarding a restorative effect of breastfeeding on cognitive teratogenesis? It is difficult to completely adjust for the confounding effect of socioeconomic factors, as the NEAD study authors acknowledge. However, they valiantly tried to do so with a propensity score analysis to evaluate the probability of being breastfed based on baseline characteristics, for which socioeconomic factors are certainly key. While a much greater proportion of the nonbreastfed group was below the propensity median than the breastfed group, the investigators state that the propensity analysis does not suggest an influence of baseline characteristics on the main outcome of the study. The authors cautiously interpret their results, emphasizing the safety rather than any benefit of breastfeeding in this setting. It is up to us who study these findings and try to apply them to our practice to contain our enthusiasm that not only folate supplementation but also breastfeeding may be modifiable factors for improving cognitive outcomes in children born to mothers who must take AEDs during pregnancy. The most conservative interpretation of these results is that breastfeeding is safe for women taking these AEDs as monotherapy and should be strongly encouraged by all participants in their care, including neurologists, pediatricians, obstetricians, and allied health professionals.
Conflict of Interest Disclosures: Dr Harden reported serving as a speaker for UCB Pharma, GlaxoSmithKline, and Lundbeck; consulting for Upsher-Smith; obtaining grant support from the National Institute of Neurological Disorders and Stroke; and receiving royalties from Up-to-Date and John Wiley & Sons, Inc. REFERENCES 1. Meador KJ, Baker GA, Browning N, et al; Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group. Breastfeeding in children of women taking antiepileptic drugs: cognitive
outcomes at age 6 years [published online June 16, 2014]. JAMA Intern Med. doi:10.1001 /jamapediatrics.2014.118. 2. Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010; 75(22):1954-1960. 3. Veiby G, Engelsen BA, Gilhus NE. Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. JAMA Neurol. 2013;70(11):1367-1374.
JAMA Pediatrics August 2014 Volume 168, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/27/2015
jamapediatrics.com
ment approaches, including Sen’s capability approach,7,8 the social return on investment model,9 and the life course model that has gained a foothold in maternal and child health research.10 In addition to better conceptual frameworks, improving measurement at a population level will take new methodological approaches. One promising model to learn from is the Life Course Metrics Project organized by the Association of Maternal & Child Health Programs.11 Adopting an investment perspective also means taking a long view on life course outcomes. Improving our understanding of how life unfolds will require a serious commitment to longitudinal, population-based data collection. For nearly 7 decades, evidence from the Framingham Heart Study and other ARTICLE INFORMATION Author Affiliations: A. J. Drexel Autism Institute, Drexel University, Philadelphia, Pennsylvania. Corresponding Author: Paul T. Shattuck, PhD, A. J. Drexel Autism Institute, Drexel University, 3020 Market St, Ste 560, Philadelphia, PA 19104-3734 ([email protected]).
longitudinal studies has laid the foundation for our contemporary understanding of the epidemiology and treatment of cardiovascular disease. We need a Framingham Study for autism spectrum disorders, especially to track risks and outcomes into middle and later adulthood. Finally, we need to invest in training a new generation of scholars skilled in population- and community-based approaches for improving and measuring innovation and returns on investments. It is our hope that in 10 years one of these new scholars will be in a position to write a follow-up to the article by Buescher et al titled “Return on Investments in Innovative Practices for People Affected by Autism Spectrum Disorders in the United States and United Kingdom.”
3. Roux AM, Shattuck PT, Cooper BP, Anderson KA, Wagner M, Narendorf SC. Postsecondary employment experiences among young adults with an autism spectrum disorder. J Am Acad Child Adolesc Psychiatry. 2013;52(9):931-939.
Conflict of Interest Disclosures: None reported.
4. Orsmond GI, Shattuck PT, Cooper BP, Sterzing PR, Anderson KA. Social participation among young adults with an autism spectrum disorder. J Autism Dev Disord. 2013;43(11):2710-2719.
Published Online: June 9, 2014. doi:10.1001/jamapediatrics.2014.585.
5. Howlin P, Moss P. Adults with autism spectrum disorders. Can J Psychiatry. 2012;57(5):275-283.
REFERENCES 1. Buescher AVS, Cidav Z, Knapp M, Mandell DS. Costs of autism spectrum disorders in the United Kingdom and the United States [published online June 9, 2014]. JAMA Pediatr. doi:10.1001 /jamapediatrics.2014.210. 2. Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, Wagner M, Taylor JL. Postsecondary education and employment among youth with an autism spectrum disorder. Pediatrics. 2012;129(6):10421049.
9. Lawlor E, Neitzert E, Nicholls J. Measuring Value: A Guide to Social Return on Investment. London, England: New Economics Foundation; 2008. 10. US Department of Health and Human Services, Health Resources and Services Administration, Maternal and Child Health Bureau. Rethinking MCH: the life course model as an organizing framework: concept paper. Published November 2010. http: //mchb.hrsa.gov/lifecourse /rethinkingmchlifecourse.pdf. Accessed March 24, 2014. 11. Association of Maternal & Child Health Programs (AMCHP). The Life Course Metrics Project. http://www.amchp.org/programsandtopics /data-assessment/Pages/LifeCourseMetricsProject .aspx. Accessed March 24, 2014.
6. US Department of Education Office of Special Education Programs. Part B SPP/APR related requirements. http://www2.ed.gov/policy/speced /guid/idea/bapr/2010/e5-1820 -0624relatedrequirements.pdf. Accessed March 24, 2014. 7. Sen A. Development as Freedom. New York, NY: Knopf; 1999. 8. Shattuck PT, Roux AM, Hudson LE, Taylor JL, Maenner MJ, Trani J-F. Services for adults with an autism spectrum disorder. Can J Psychiatry. 2012;57 (5):284-291.
Beneficial or Neutral Effect of Breastfeeding on Cognitive Outcomes in Children of Mothers With Epilepsy? Cynthia L. Harden, MD
The latest report from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study group1 on the association of breastfeeding with cognitive outcomes in children born to mothers with epilepsy taking antiepileptic drugs (AEDs) Related article page 729 is fascinating. The investigators assessed the IQ in children aged 6 years who had been exposed to AEDs in utero and used linear regression as the primary analysis. The analysis included adjustment for other known influences on IQ outcomes reported by these investigators and others, including maternal IQ, specific AED monotherapy, a standardized AED dosage, and the use of periconception folate. While these known factors remained associated with the IQ outcomes, breastfeeding was also associated: breastfed jamapediatrics.com
children had a mean IQ 4 points higher than that of nonbreastfed children, with a mean difference of 12 IQ points for the valproate sodium–exposed group (IQ of 94 for 25 children not breastfed compared with 106 for 11 children breastfed). These results must be couched in their research context, which is that 181 children were included for analysis because both breastfeeding and IQ data were available only on these, a subset of 311 births in the intent-to-treat sample (58%). However, an analysis of the sensitivity of the results to missing data showed that missing data could not explain the findings. The mean duration of breastfeeding was 7.2 months overall, and the proportion of breastfed children was similar in each nonrandomized maternal epilepsy treatment group of valproate, carbamazepine, phenytoin, or lamotrigine at 31% to 49%. JAMA Pediatrics August 2014 Volume 168, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/27/2015
699
Opinion Editorial
The group of authors has previously reported on the IQ outcomes in association with breastfeeding in this cohort at age 3 years and found no difference for the effects of breastfeeding.2 Now, at age 6 years, an age at which more detailed testing can be performed, there is a separation of IQ outcomes, with the breastfed children showing a higher IQ and, in a secondary analysis, better verbal abilities compared with nonbreastfed children. The authors put forth a detailed discussion about the much lower fraction of infant AED exposure with breastfeeding compared with the exposure in utero. So, the time course of the clinical scenario is that maximum AED exposure occurs in utero; therefore, any cognitive teratogenesis likely occurs in utero due to the greater AED exposure. Immediately after birth, there was a period of several months of breastfeeding for one-third to one-half of the evaluated group. IQ testing was then performed at age 3 years, with no difference found by the investigators’ methods,2 and at age 6 years a beneficial effect of breastfeeding was found and discussed in their present article. It is tantalizing to conceptualize this as a restorative effect because the results imply that breastfeeding in the neonatal and infantile periods, occurring just after high levels of passive AED exposure during gestation, is associated with perhaps restoring cognitive abilities closer to where they were meant to be if AED exposure had not taken place, and this subtle effect cannot be detected until testing at age 6 years. A recent study by Veiby et al3 also supports the present NEAD study1 findings regarding the dynamism of a possible effect of breastfeeding on cognitive outcomes of children exposed to AEDs in utero but not exactly the same direction and timing of an effect. In that study, mothers with epilepsy provided information on their child’s development by using a self-reported standardized scale. At age 6 months, impaired fine motor skills were reported in 11.5% of the offspring exposed to AEDs, much greater than the 4.8% reported in the nonepilepsy reference group. Breastfeeding during this period compared with stopping breastfeeding before age 6 months was associated with reduced risk of impaired fine motor skills. The beneficial effect of breastfeeding was also found in the group of 276 mothers who had epilepsy but were
ARTICLE INFORMATION Author Affiliations: Division of Epilepsy and Electroencephalography, Department of Neurology, Hofstra North Shore–Long Island Jewish School of Medicine, Hempstead, New York; Cushing Neuroscience Institute, Brain and Spine Specialists of New York, North Shore–Long Island Jewish Health System, Great Neck, New York. Corresponding Author: Cynthia L. Harden, MD, North Shore–Long Island Jewish Health System, 611 Northern Blvd, Ste 150, Great Neck, NY 11021 ([email protected]). Published Online: June 16, 2014. doi:10.1001/jamapediatrics.2014.420. 700
not taking AEDs, a finding that raises issues about confounding variables in this cohort. In any case, the benefit of at least 6 months of breastfeeding on fine motor skills was not present at the 18-month assessment, but a new potential benefit emerged: significantly fewer autistic traits were reported. Sadly, even this beneficial effect of prolonged breastfeeding was not sustained; autistic traits were more frequent in the entire maternal epilepsy AED-treated group at the 36-month assessment compared with the reference group, with no effect of breastfeeding found. The study by Veiby et al3 has more methodological limitations compared with the NEAD study.1 Two important differences are that maternal IQ was not controlled for by Veiby et al and that their outcomes were based on maternal report; the children were not individually tested by an investigator blinded to the exposure as in the NEAD study methods. However, this leaves us to question where does the truth lie? What is plausible regarding a restorative effect of breastfeeding on cognitive teratogenesis? It is difficult to completely adjust for the confounding effect of socioeconomic factors, as the NEAD study authors acknowledge. However, they valiantly tried to do so with a propensity score analysis to evaluate the probability of being breastfed based on baseline characteristics, for which socioeconomic factors are certainly key. While a much greater proportion of the nonbreastfed group was below the propensity median than the breastfed group, the investigators state that the propensity analysis does not suggest an influence of baseline characteristics on the main outcome of the study. The authors cautiously interpret their results, emphasizing the safety rather than any benefit of breastfeeding in this setting. It is up to us who study these findings and try to apply them to our practice to contain our enthusiasm that not only folate supplementation but also breastfeeding may be modifiable factors for improving cognitive outcomes in children born to mothers who must take AEDs during pregnancy. The most conservative interpretation of these results is that breastfeeding is safe for women taking these AEDs as monotherapy and should be strongly encouraged by all participants in their care, including neurologists, pediatricians, obstetricians, and allied health professionals.
Conflict of Interest Disclosures: Dr Harden reported serving as a speaker for UCB Pharma, GlaxoSmithKline, and Lundbeck; consulting for Upsher-Smith; obtaining grant support from the National Institute of Neurological Disorders and Stroke; and receiving royalties from Up-to-Date and John Wiley & Sons, Inc. REFERENCES 1. Meador KJ, Baker GA, Browning N, et al; Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group. Breastfeeding in children of women taking antiepileptic drugs: cognitive
outcomes at age 6 years [published online June 16, 2014]. JAMA Intern Med. doi:10.1001 /jamapediatrics.2014.118. 2. Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Effects of breastfeeding in children of women taking antiepileptic drugs. Neurology. 2010; 75(22):1954-1960. 3. Veiby G, Engelsen BA, Gilhus NE. Early child development and exposure to antiepileptic drugs prenatally and through breastfeeding: a prospective cohort study on children of women with epilepsy. JAMA Neurol. 2013;70(11):1367-1374.
JAMA Pediatrics August 2014 Volume 168, Number 8
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a Penn State Milton S Hershey Med Ctr User on 05/27/2015
jamapediatrics.com
