Letters
ing and respiratory risk of children with NI are needed to guide families making decisions about surgical treatment of GERD. Pragmatic clinical trials (or well-constructed observational studies) characterized by sufficient statistical power; clinically appropriate, well-defined patient variables; and comprehensive, meaningful patient outcomes have the greatest potential to identify ideal surgical candidates. These would also potentially reduce the extreme variation in surgical practice observed in our study.1 Unless prospective studies have careful patient selection, including a rigorous, standardized evaluation and preoperative management of the GERD symptoms, some infants may be enrolled for a procedure that cannot be expected to provide benefit. An additional important consideration for future studies is the inclusion of both practical and robust measures of functional impairment because the degree of functional impairment is related to overall survival, including respiratory compromise from aspiration pneumonia.2 Several prospective studies have used standardized, validated functional motor classification instruments.3 Alternatively, for infants in whom these instruments have not been validated, other clinical criteria have been used (eg, hand use, arm use) to analyze children with NI.4 Dr Hauer’s suggestion to consider confounders related to the degree of dysphagia is an important one, especially if the primary outcome of a pragmatic trial is aspiration pneumonia. Primary aspiration (eg, oral feeds or saliva) may be confused with secondary aspiration (eg, GERD). Without careful baseline and end-point measurement of the degree of dysphagia leading to primary aspiration, disentangling causes of aspiration may be impossible, leading to erroneous conclusions in a pragmatic trial. The evaluation for primary aspiration should include both clinical symptoms of aspiration (eg, choking with feeds) along with supporting diagnostic investigations if clinically appropriate. We are hopeful that the issues raised by Dr Hauer will be addressed in time. The clinical research networks exist, and the different specialties are starting to work together on other large-scale studies.5 Most importantly, the parents and caregivers of children with NI desire the best possible care for their children. We, too, are eager to see the results of these efforts significantly improve clinical practice of the treatment of GERD in children with NI. Douglas C. Barnhart, MD, MSPH Jay G. Berry, MD, MPH Rajendu Srivastava, MD, MPH
Author Affiliations: Department of Pediatrics, Primary Children’s Hospital, University of Utah, Salt Lake City (Barnhart); Department of Pediatrics, Boston Children’s Hospital, Harvard University, Boston, Massachusetts (Berry); Department of Surgery, Primary Children’s Hospital, University of Utah, Salt Lake City (Srivastava). Corresponding Author: Douglas C. Barnhart, MD, MSPH, Division of Pediatric Surgery, Primary Children’s Hospital, 100 N Mario, Ste 2600, Capecchi Drive, Salt Lake City, UT 84113 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Barnhart DC, Hall M, Mahant S, et al. Effectiveness of fundoplication at the time of gastrostomy in infants with neurological impairment. JAMA Pediatr. 2013;167(10):911-918. doi:10.1001/jamapediatrics.2013.334. jamapediatrics.com
2. Hutton JL, Cooke T, Pharoah PO. Life expectancy in children with cerebral palsy. BMJ. 1994;309(6952):431-435. 3. Rosenbaum PL, Palisano RJ, Bartlett DJ, Galuppi BE, Russell DJ. Development of the Gross Motor Function Classification System for cerebral palsy. Dev Med Child Neurol. 2008;50(4):249-253. 4. Fung EB, Samson-Fang L, Stallings VA, et al. Feeding dysfunction is associated with poor growth and health status in children with cerebral palsy. J Am Diet Assoc. 2002;102(3):361-373. 5. Narus SP, Srivastava R, Gouripeddi R, et al. Federating clinical data from six pediatric hospitals: process and initial results from the PHIS+ Consortium. AMIA Annu Symp Proc. 2011;2011:994-1003.
Induction or Augmentation of Labor and Autism To the Editor I read with interest the article “Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990-1998) and Education Research (19972007) Databases” by Gregory et al1 after hearing about the study through the news media. The study is a retrospective observational study exploring the association of labor induction and/or augmentation with autism spectrum disorders. There are serious flaws in the methods, data source, and conclusions of this study. Gregory et al defend their use of data from birth certificate registries by quoting a study by Vinikoor et al2 that explored the reliability of variables on the North Carolina birth certificate from a single-hospital system. Perhaps that onehospital system is excellent at accurately completing the forms? However, other authors have pointed out the significant drawbacks of using administrative databases for epidemiologic research.3 Significant variation in the accuracy of the forms between institutions is likely because the North Carolina state vital statistics website is concerned enough about the data accuracy to offer assistance in improving the accuracy and completeness of the data collected from the birth certificates.4 The biologic plausibility of exogenous oxytocin exposure is mentioned as a potential mechanism of autism spectrum disorder in the offspring of women undergoing labor induction. One important piece of data missing from the birth records is the method of labor induction because not all patients being induced receive oxytocin. Also, large databases are prone to systematic bias. The highest odds ratios stated in this study relating induction and augmentation to autism was 1.27. Such a weak association falls within the “zone of potential bias” and well below the “zone of potential interest” as described by Grimes and Schulz.5 Table 3 in the Gregory et al article shows that completion of college gives an odds ratio of approximately 1.3 for having a child with autism. This is likely a confounding factor. Or it could be that something taught in our universities may be placing the offspring of college-educated women at risk for autism spectrum disorders. Weak associations derived from administrative databases should not be newsworthy. Erroneous interpretation of such a study has the potential to cause great harm and discourage patients from undergoing labor induction or furthering their education when it is truly in their best interest. Such studies should be interpreted with caution and a healthy dose of skepticism. Michael L. Stitely, MD JAMA Pediatrics February 2014 Volume 168, Number 2
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Author Affiliation: Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. Corresponding Author: Michael L. Stitely, MD, Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Private Bag 1921, Dunedin 9054, New Zealand ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Vinikoor LC, Messer LC, Laraia BA, Kaufman JS. Reliability of variables on the North Carolina birth certificate: a comparison with directly queried values from a cohort study. Paediatr Perinat Epidemiol. 2010;24(1):102-112. 3. Grimes DA. Epidemiologic research using administrative databases: garbage in, garbage out. Obstet Gynecol. 2010;116(5):1018-1019. 4. North Carolina’s new birth certificate. http://www.pqcnc.org/node/12812. Accessed August 19, 2013. 5. Grimes DA, Schulz KF. False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol. 2012;120(4):920-927.
To the Editor In a recent epidemiological study, Gregory and colleagues1 concluded that induction or augmentation of labor during childbirth is associated with increased odds of autism in children. Unfortunately, several aspects of the design and interpretation of the findings were overlooked. We articulate them next. (1) The primary outcome (autism) is poorly defined since the specific designation for children with multiple exceptionalities was “at the discretion of school personnel” because of lack of guidelines. This raises the possibility of response misclassification likely biasing the results. (2) The exposed (labor induction/augmentation) and the unexposed (no induction/ augmented) groups are not comparable, thereby violating one of the fundamental principles of cohort study designs.2 The unexposed group included patients who delivered after spontaneous labor as well patients who delivered by repeat cesarean prior to the onset of labor. The cesarean delivery rate in North Carolina during the study years 1990 to 1998 was 22% to 23% and the repeat cesarean delivery rate was estimated to be approximately 10% of the total number of deliveries.3 Therefore, approximately 62 504 women who had repeat cesarean delivery were included in the unexposed group. This translates to a significant percentage (approximately 14%) of patients in the unexposed group who may never have been exposed to labor. Therefore, the reference group was at a clear advantage, thus having less chance for autism (selection bias). This bias would have likely led to an overestimation of the associations reported by Gregory et al. (3) The potential inclusion of more than 1 pregnancy per woman violates the statistical assumption of independence of observations, potentially leading to incorrect statistical and biologic inferences. This is very important given the heritable nature of autism.4 (4) A Cox proportional hazards regression that takes account of the changing profile of autism risks by the child’s age (at diagnosis) is more appropriate than a logistic regression model. (5) The conclusions leave room for bias due to residual confounding because several important confounders were not adjusted. (6) Our concerns regarding the heterogeneity of the primary exposure and our argument that there was no association between labor/augmentation and autism when the correct di190
agnostic criteria for autism were applied for the last 3 birth years of the study (1996-1998) have been espoused elsewhere.5 All issues considered, we believe that there is no evidence for an association between induced/augmented childbirth and autism. Anthony M. Vintzileos, MD Cande V. Ananth, PhD, MPH Author Affiliations: Department of Obstetrics and Gynecology, Winthrop University Hospital, Mineola, New York (Vintzileos); Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York (Ananth); Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New York (Ananth). Corresponding Author: Anthony M. Vintzileos, MD, Department of Obstetrics and Gynecology, Winthrop University Hospital, 259 First St, Mineola, NY 11501 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Rothman KJ, Greenland S. Cohort studies. In: Rothman KJ, Greenland S, eds. Modern Epidemiology. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins: 79-92. 3. Evans S. Trends in cesarean delivery rates for North Carolina live births. http://www.schs.state.nc.us/schs/pdf/SB_40_20120727.pdf. Accessed December 8, 2013. 4. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):e488-e495. 5. Vintzileos AM, Ananth CV. Does augmentation or induction of labor with oxytocin increase the risk for autism? Am J Obstet Gynecol. 2013;209(6):502-504.
To the Editor Autism is a major problem with apparently increasing prevalence. Accordingly, the association between labor induction/augmentation and autism reported by Gregory et al1 deserves further investigation. However, the results should be interpreted with great caution because of limitations in the study design. One of the most important limitations is that data were obtained from birth records in North Carolina that were previously “validated.” The cited validation involved assessment of agreement between selected variables in birth records and matched data from the same women enrolled in a cohort study.2 In the validation study, only 87% of the participants were successfully matched to the birth records (13% error rate). Many of the variables in the analysis by Gregory et al were actually never validated, including variables such as febrile, meconium, fetal distress, and placental abruption. Diabetes was one of the supposedly validated variables, but its κ was only 0.09. This is particularly important given that gestational diabetes has been associated with autism. More importantly, the variable induction/augmentation was never validated. This variable and the indications for induction/augmentation are often inaccurate in birth records.3,4 Confounding is another problem with the study. Labor is usually induced because of a maternal or fetal indication. Labor augmentation is an indication of labor dysfunction. Failure to adequately correct for these conditions or, even worse, a flawed attempt at correcting for a few indications casts se-
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rious doubts about any association with autism, no matter how many multivariable models are performed. Gregory et al also use terms without clear definition, such as “fetal distress,” or include overlapping categories such as induction only, augmentation only, or both. Furthermore, the analysis lumps all pregnancies at 37 weeks or greater without differentiation between term and postterm. Finally, it is a stretch to implicate oxytocin as a direct cause of autism because it does not cross the placenta.5 We are thankful that Gregory et al mention that this article should not change practice. Nonetheless, the study received wide publicity in the lay press. Given that labor induction/augmentation is frequently indicated, the repercussions can be massive. Patients are reluctant to receive oxytocin and physicians are afraid to administer it because of concerns about autism. The result is likely to be an increase in cesarean deliveries and an increase in adverse maternal and perinatal outcomes. Extreme caution, public education, and comment from national societies are needed as additional high-quality data are gathered regarding potential risk factors for autism. George R. Saade, MD Baha M. Sibai, MD Robert Silver, MD Author Affiliations: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston (Saade); Department of Obstetrics and Gynecology, University of Texas Health Sciences at Houston, Houston (Sibai); Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City (Silver). Corresponding Author: George R. Saade, MD, Department of Obstetrics and Gynecology, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Vinikoor LC, Messer LC, Laraia BA, Kaufman JS. Reliability of variables on the North Carolina birth certificate: a comparison with directly queried values from a cohort study. Paediatr Perinat Epidemiol. 2010;24(1):102-112. 3. Lydon-Rochelle MT, Holt VL, Nelson JC, et al. Accuracy of reporting maternal in-hospital diagnoses and intrapartum procedures in Washington State linked birth records. Paediatr Perinat Epidemiol. 2005;19(6):460-471. 4. Bailit JL; Ohio Perinatal Quality Collaborative. Rates of labor induction without medical indication are overestimated when derived from birth certificate data. Am J Obstet Gynecol. 2010;203(3):e1-e3. 5. Patient C, Davison JM, Charlton L, Baylis PH, Thornton S. The effect of labour and maternal oxytocin infusion on fetal plasma oxytocin concentration. Br J Obstet Gynaecol. 1999;106(12):1311-1313.
In Reply We recently published a study demonstrating an association between labor induction/augmentation and later diagnosis of autism.1 Letter writers expressed concern about overinterpretation of study findings that may inappropriately influence delivery room practice. In the article, the associated press release, and all media interviews, we relayed a very conservative message emphasizing the distinction between association and causation and clearly stated that the work did not call for any change in obstetric practice. The potential for overinterpretation of scientific research by the press jamapediatrics.com
and lay public should not preclude publication of thoughtful scientific investigation. Research is an iterative process. Initial studies highlight directions for future research, the body of evidence grows, and health drivers are clarified. We observed an adverse association between autism diagnosis and labor induction/augmentation, with statistically significant estimated odds ratios ranging from 1.15 to 1.35, depending on sex group and induction/augmentation treatment category. There is no statistically based cutoff for the size of an odds ratio required to identify an association that warrants further investigation. We did not claim to have established the basis for the association and did not conclude that either labor induction/ augmentation, or oxytocin, cause autism. In our study, we acknowledged several of the possible explanations offered by the letter writers, including (1) underlying medical or obstetric conditions that make it more likely a mother will be induced/ augmented; (2) events of labor and delivery that are associated with induction or augmentation; or (3) drugs and methods used in induction/augmentation. Letters raised possible pathways for the introduction of bias. First, some mothers delivering via cesarean do not have an equal likelihood of being exposed to induction/ augmentation. To evaluate this concern, we reran model 6 excluding births delivered via cesarean. Second, as described in the article’s limitations, the data set did not link siblings, leading us to treat correlated observations as independent. We reran model 6 restricting the sample to firstborns. Third, we did not distinguish among term births. We refit model 6 with categories for less than 34, 35 to 36, 37 to 39, and 40 weeks’ or greater gestational age. The first 2 follow-up analyses showed somewhat attenuated odds ratios, but the pattern of adverse associations remained. The additional gestational age categories did not substantively alter the originally reported odds. A fourth cited source of bias was the change in diagnostic criteria for autism between Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision). Note that the confidence intervals on the odds ratios for 1996 to 1998 are not statistically significant. In addition, the overestimation to which the letter writers refer is only for pervasive developmental disorder not otherwise specified and not for autism spectrum disorder overall. Nevertheless, we limited the analysis to only 1996 to 1998; however, the much smaller sample size introduced instability in coefficient estimates on many variables. We argue that further research is warranted. We note that a child’s autism diagnosis in the North Carolina Education Research Data Center is determined by prior clinical diagnosis and further evaluation by a school psychologist that includes standard individualized testing. Because for some study years school personnel were allowed to only report the primary exceptionality designation, even if a child had multiple designations, we may not have captured all autism cases in the North Carolina Education Research Data Center. However, autism prevalence in our study was consistent with that reported nationally and in North Carolina. Letter writers raised data quality issues with the detailed birth record. Studies have shown that inaccuracy in birth JAMA Pediatrics February 2014 Volume 168, Number 2
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records2-6 typically stems from underreporting such that birth certificate information can usually be trusted to “rule in” but not “rule out” a particular risk factor (ie, it is specific but not sensitive). This is true for studies cited by the letter writers. For a falsely elevated odds ratio, it must be the case that underreporting of induction/augmentation is systematically occurring among women who are less likely to have autistic children. However, we do not have reason to believe that the underreporting of the induction/augmentation exposure is anything but randomly distributed. In addition, while we do not wish to impugn oxytocin, recent research indicates that oxytocin crosses the human placenta in both directions.7 We note the importance of further research to address data quality issues in our article and further note that almost all epidemiological studies are subject to some degree of response and exposure misclassification. In summary, there are clear benefits to labor induction and augmentation, particularly among women with medical and obstetric conditions that increase the risk for stillbirth or neonatal morbidity. As stated earlier and in our article, the findings of this study should not change current obstetric practice. Finally, as we did in the article, we emphasize the preliminary nature of the results but also the need for further research. Marie Lynn Miranda, PhD Rebecca Anthopolos, MA Simon G. Gregory, PhD
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Author Affiliations: Department of Pediatrics, University of Michigan, Ann Arbor (Miranda); Children’s Environmental Health Initiative, School of Natural Resources and Environment, University of Michigan, Ann Arbor (Miranda, Anthopolos); Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina (Gregory); Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina (Gregory). Corresponding Author: Marie Lynn Miranda, PhD, School of Natural Resources and Environment, University of Michigan, 440 Church St, 2046 Dana Bldg, Ann Arbor, MI 48109 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Bailit JL; Ohio Perinatal Quality Collaborative. Rates of labor induction without medical indication are overestimated when derived from birth certificate data. Am J Obstet Gynecol. 2010;203(3):e1-e3. 3. Piper JM, Mitchel EF Jr, Snowden M, Hall C, Adams M, Taylor P. Validation of 1989 Tennessee birth certificates using maternal and newborn hospital records. Am J Epidemiol. 1993;137(7):758-768. 4. Lydon-Rochelle MT, Holt VL, Nelson JC, et al. Accuracy of reporting maternal in-hospital diagnoses and intrapartum procedures in Washington State linked birth records. Paediatr Perinat Epidemiol. 2005;19(6):460-471. 5. Parrish KM, Holt VL, Connell FA, Williams B, LoGerfo JP. Variations in the accuracy of obstetric procedures and diagnoses on birth records in Washington State, 1989. Am J Epidemiol. 1993;138(2):119-127. 6. Kahn EB, Berg CJ, Callaghan WM. Cesarean delivery among women with low-risk pregnancies: a comparison of birth certificates and hospital discharge data. Obstet Gynecol. 2009;113(1):33-40. 7. Malek A, Blann E, Mattison DR. Human placental transport of oxytocin. J Matern Fetal Med. 1996;5(5):245-255.
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ing and respiratory risk of children with NI are needed to guide families making decisions about surgical treatment of GERD. Pragmatic clinical trials (or well-constructed observational studies) characterized by sufficient statistical power; clinically appropriate, well-defined patient variables; and comprehensive, meaningful patient outcomes have the greatest potential to identify ideal surgical candidates. These would also potentially reduce the extreme variation in surgical practice observed in our study.1 Unless prospective studies have careful patient selection, including a rigorous, standardized evaluation and preoperative management of the GERD symptoms, some infants may be enrolled for a procedure that cannot be expected to provide benefit. An additional important consideration for future studies is the inclusion of both practical and robust measures of functional impairment because the degree of functional impairment is related to overall survival, including respiratory compromise from aspiration pneumonia.2 Several prospective studies have used standardized, validated functional motor classification instruments.3 Alternatively, for infants in whom these instruments have not been validated, other clinical criteria have been used (eg, hand use, arm use) to analyze children with NI.4 Dr Hauer’s suggestion to consider confounders related to the degree of dysphagia is an important one, especially if the primary outcome of a pragmatic trial is aspiration pneumonia. Primary aspiration (eg, oral feeds or saliva) may be confused with secondary aspiration (eg, GERD). Without careful baseline and end-point measurement of the degree of dysphagia leading to primary aspiration, disentangling causes of aspiration may be impossible, leading to erroneous conclusions in a pragmatic trial. The evaluation for primary aspiration should include both clinical symptoms of aspiration (eg, choking with feeds) along with supporting diagnostic investigations if clinically appropriate. We are hopeful that the issues raised by Dr Hauer will be addressed in time. The clinical research networks exist, and the different specialties are starting to work together on other large-scale studies.5 Most importantly, the parents and caregivers of children with NI desire the best possible care for their children. We, too, are eager to see the results of these efforts significantly improve clinical practice of the treatment of GERD in children with NI. Douglas C. Barnhart, MD, MSPH Jay G. Berry, MD, MPH Rajendu Srivastava, MD, MPH
Author Affiliations: Department of Pediatrics, Primary Children’s Hospital, University of Utah, Salt Lake City (Barnhart); Department of Pediatrics, Boston Children’s Hospital, Harvard University, Boston, Massachusetts (Berry); Department of Surgery, Primary Children’s Hospital, University of Utah, Salt Lake City (Srivastava). Corresponding Author: Douglas C. Barnhart, MD, MSPH, Division of Pediatric Surgery, Primary Children’s Hospital, 100 N Mario, Ste 2600, Capecchi Drive, Salt Lake City, UT 84113 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Barnhart DC, Hall M, Mahant S, et al. Effectiveness of fundoplication at the time of gastrostomy in infants with neurological impairment. JAMA Pediatr. 2013;167(10):911-918. doi:10.1001/jamapediatrics.2013.334. jamapediatrics.com
2. Hutton JL, Cooke T, Pharoah PO. Life expectancy in children with cerebral palsy. BMJ. 1994;309(6952):431-435. 3. Rosenbaum PL, Palisano RJ, Bartlett DJ, Galuppi BE, Russell DJ. Development of the Gross Motor Function Classification System for cerebral palsy. Dev Med Child Neurol. 2008;50(4):249-253. 4. Fung EB, Samson-Fang L, Stallings VA, et al. Feeding dysfunction is associated with poor growth and health status in children with cerebral palsy. J Am Diet Assoc. 2002;102(3):361-373. 5. Narus SP, Srivastava R, Gouripeddi R, et al. Federating clinical data from six pediatric hospitals: process and initial results from the PHIS+ Consortium. AMIA Annu Symp Proc. 2011;2011:994-1003.
Induction or Augmentation of Labor and Autism To the Editor I read with interest the article “Association of Autism With Induced or Augmented Childbirth in North Carolina Birth Record (1990-1998) and Education Research (19972007) Databases” by Gregory et al1 after hearing about the study through the news media. The study is a retrospective observational study exploring the association of labor induction and/or augmentation with autism spectrum disorders. There are serious flaws in the methods, data source, and conclusions of this study. Gregory et al defend their use of data from birth certificate registries by quoting a study by Vinikoor et al2 that explored the reliability of variables on the North Carolina birth certificate from a single-hospital system. Perhaps that onehospital system is excellent at accurately completing the forms? However, other authors have pointed out the significant drawbacks of using administrative databases for epidemiologic research.3 Significant variation in the accuracy of the forms between institutions is likely because the North Carolina state vital statistics website is concerned enough about the data accuracy to offer assistance in improving the accuracy and completeness of the data collected from the birth certificates.4 The biologic plausibility of exogenous oxytocin exposure is mentioned as a potential mechanism of autism spectrum disorder in the offspring of women undergoing labor induction. One important piece of data missing from the birth records is the method of labor induction because not all patients being induced receive oxytocin. Also, large databases are prone to systematic bias. The highest odds ratios stated in this study relating induction and augmentation to autism was 1.27. Such a weak association falls within the “zone of potential bias” and well below the “zone of potential interest” as described by Grimes and Schulz.5 Table 3 in the Gregory et al article shows that completion of college gives an odds ratio of approximately 1.3 for having a child with autism. This is likely a confounding factor. Or it could be that something taught in our universities may be placing the offspring of college-educated women at risk for autism spectrum disorders. Weak associations derived from administrative databases should not be newsworthy. Erroneous interpretation of such a study has the potential to cause great harm and discourage patients from undergoing labor induction or furthering their education when it is truly in their best interest. Such studies should be interpreted with caution and a healthy dose of skepticism. Michael L. Stitely, MD JAMA Pediatrics February 2014 Volume 168, Number 2
Copyright 2014 American Medical Association. All rights reserved.
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Author Affiliation: Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin, New Zealand. Corresponding Author: Michael L. Stitely, MD, Department of Women’s and Children’s Health, Dunedin School of Medicine, University of Otago, Private Bag 1921, Dunedin 9054, New Zealand ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Vinikoor LC, Messer LC, Laraia BA, Kaufman JS. Reliability of variables on the North Carolina birth certificate: a comparison with directly queried values from a cohort study. Paediatr Perinat Epidemiol. 2010;24(1):102-112. 3. Grimes DA. Epidemiologic research using administrative databases: garbage in, garbage out. Obstet Gynecol. 2010;116(5):1018-1019. 4. North Carolina’s new birth certificate. http://www.pqcnc.org/node/12812. Accessed August 19, 2013. 5. Grimes DA, Schulz KF. False alarms and pseudo-epidemics: the limitations of observational epidemiology. Obstet Gynecol. 2012;120(4):920-927.
To the Editor In a recent epidemiological study, Gregory and colleagues1 concluded that induction or augmentation of labor during childbirth is associated with increased odds of autism in children. Unfortunately, several aspects of the design and interpretation of the findings were overlooked. We articulate them next. (1) The primary outcome (autism) is poorly defined since the specific designation for children with multiple exceptionalities was “at the discretion of school personnel” because of lack of guidelines. This raises the possibility of response misclassification likely biasing the results. (2) The exposed (labor induction/augmentation) and the unexposed (no induction/ augmented) groups are not comparable, thereby violating one of the fundamental principles of cohort study designs.2 The unexposed group included patients who delivered after spontaneous labor as well patients who delivered by repeat cesarean prior to the onset of labor. The cesarean delivery rate in North Carolina during the study years 1990 to 1998 was 22% to 23% and the repeat cesarean delivery rate was estimated to be approximately 10% of the total number of deliveries.3 Therefore, approximately 62 504 women who had repeat cesarean delivery were included in the unexposed group. This translates to a significant percentage (approximately 14%) of patients in the unexposed group who may never have been exposed to labor. Therefore, the reference group was at a clear advantage, thus having less chance for autism (selection bias). This bias would have likely led to an overestimation of the associations reported by Gregory et al. (3) The potential inclusion of more than 1 pregnancy per woman violates the statistical assumption of independence of observations, potentially leading to incorrect statistical and biologic inferences. This is very important given the heritable nature of autism.4 (4) A Cox proportional hazards regression that takes account of the changing profile of autism risks by the child’s age (at diagnosis) is more appropriate than a logistic regression model. (5) The conclusions leave room for bias due to residual confounding because several important confounders were not adjusted. (6) Our concerns regarding the heterogeneity of the primary exposure and our argument that there was no association between labor/augmentation and autism when the correct di190
agnostic criteria for autism were applied for the last 3 birth years of the study (1996-1998) have been espoused elsewhere.5 All issues considered, we believe that there is no evidence for an association between induced/augmented childbirth and autism. Anthony M. Vintzileos, MD Cande V. Ananth, PhD, MPH Author Affiliations: Department of Obstetrics and Gynecology, Winthrop University Hospital, Mineola, New York (Vintzileos); Department of Obstetrics and Gynecology, College of Physicians and Surgeons, Columbia University, New York (Ananth); Department of Epidemiology, Joseph L. Mailman School of Public Health, Columbia University, New York (Ananth). Corresponding Author: Anthony M. Vintzileos, MD, Department of Obstetrics and Gynecology, Winthrop University Hospital, 259 First St, Mineola, NY 11501 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Rothman KJ, Greenland S. Cohort studies. In: Rothman KJ, Greenland S, eds. Modern Epidemiology. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins: 79-92. 3. Evans S. Trends in cesarean delivery rates for North Carolina live births. http://www.schs.state.nc.us/schs/pdf/SB_40_20120727.pdf. Accessed December 8, 2013. 4. Ozonoff S, Young GS, Carter A, et al. Recurrence risk for autism spectrum disorders: a Baby Siblings Research Consortium study. Pediatrics. 2011;128(3):e488-e495. 5. Vintzileos AM, Ananth CV. Does augmentation or induction of labor with oxytocin increase the risk for autism? Am J Obstet Gynecol. 2013;209(6):502-504.
To the Editor Autism is a major problem with apparently increasing prevalence. Accordingly, the association between labor induction/augmentation and autism reported by Gregory et al1 deserves further investigation. However, the results should be interpreted with great caution because of limitations in the study design. One of the most important limitations is that data were obtained from birth records in North Carolina that were previously “validated.” The cited validation involved assessment of agreement between selected variables in birth records and matched data from the same women enrolled in a cohort study.2 In the validation study, only 87% of the participants were successfully matched to the birth records (13% error rate). Many of the variables in the analysis by Gregory et al were actually never validated, including variables such as febrile, meconium, fetal distress, and placental abruption. Diabetes was one of the supposedly validated variables, but its κ was only 0.09. This is particularly important given that gestational diabetes has been associated with autism. More importantly, the variable induction/augmentation was never validated. This variable and the indications for induction/augmentation are often inaccurate in birth records.3,4 Confounding is another problem with the study. Labor is usually induced because of a maternal or fetal indication. Labor augmentation is an indication of labor dysfunction. Failure to adequately correct for these conditions or, even worse, a flawed attempt at correcting for a few indications casts se-
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rious doubts about any association with autism, no matter how many multivariable models are performed. Gregory et al also use terms without clear definition, such as “fetal distress,” or include overlapping categories such as induction only, augmentation only, or both. Furthermore, the analysis lumps all pregnancies at 37 weeks or greater without differentiation between term and postterm. Finally, it is a stretch to implicate oxytocin as a direct cause of autism because it does not cross the placenta.5 We are thankful that Gregory et al mention that this article should not change practice. Nonetheless, the study received wide publicity in the lay press. Given that labor induction/augmentation is frequently indicated, the repercussions can be massive. Patients are reluctant to receive oxytocin and physicians are afraid to administer it because of concerns about autism. The result is likely to be an increase in cesarean deliveries and an increase in adverse maternal and perinatal outcomes. Extreme caution, public education, and comment from national societies are needed as additional high-quality data are gathered regarding potential risk factors for autism. George R. Saade, MD Baha M. Sibai, MD Robert Silver, MD Author Affiliations: Department of Obstetrics and Gynecology, The University of Texas Medical Branch, Galveston (Saade); Department of Obstetrics and Gynecology, University of Texas Health Sciences at Houston, Houston (Sibai); Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City (Silver). Corresponding Author: George R. Saade, MD, Department of Obstetrics and Gynecology, The University of Texas Medical Branch, 301 University Blvd, Galveston, TX 77555 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Vinikoor LC, Messer LC, Laraia BA, Kaufman JS. Reliability of variables on the North Carolina birth certificate: a comparison with directly queried values from a cohort study. Paediatr Perinat Epidemiol. 2010;24(1):102-112. 3. Lydon-Rochelle MT, Holt VL, Nelson JC, et al. Accuracy of reporting maternal in-hospital diagnoses and intrapartum procedures in Washington State linked birth records. Paediatr Perinat Epidemiol. 2005;19(6):460-471. 4. Bailit JL; Ohio Perinatal Quality Collaborative. Rates of labor induction without medical indication are overestimated when derived from birth certificate data. Am J Obstet Gynecol. 2010;203(3):e1-e3. 5. Patient C, Davison JM, Charlton L, Baylis PH, Thornton S. The effect of labour and maternal oxytocin infusion on fetal plasma oxytocin concentration. Br J Obstet Gynaecol. 1999;106(12):1311-1313.
In Reply We recently published a study demonstrating an association between labor induction/augmentation and later diagnosis of autism.1 Letter writers expressed concern about overinterpretation of study findings that may inappropriately influence delivery room practice. In the article, the associated press release, and all media interviews, we relayed a very conservative message emphasizing the distinction between association and causation and clearly stated that the work did not call for any change in obstetric practice. The potential for overinterpretation of scientific research by the press jamapediatrics.com
and lay public should not preclude publication of thoughtful scientific investigation. Research is an iterative process. Initial studies highlight directions for future research, the body of evidence grows, and health drivers are clarified. We observed an adverse association between autism diagnosis and labor induction/augmentation, with statistically significant estimated odds ratios ranging from 1.15 to 1.35, depending on sex group and induction/augmentation treatment category. There is no statistically based cutoff for the size of an odds ratio required to identify an association that warrants further investigation. We did not claim to have established the basis for the association and did not conclude that either labor induction/ augmentation, or oxytocin, cause autism. In our study, we acknowledged several of the possible explanations offered by the letter writers, including (1) underlying medical or obstetric conditions that make it more likely a mother will be induced/ augmented; (2) events of labor and delivery that are associated with induction or augmentation; or (3) drugs and methods used in induction/augmentation. Letters raised possible pathways for the introduction of bias. First, some mothers delivering via cesarean do not have an equal likelihood of being exposed to induction/ augmentation. To evaluate this concern, we reran model 6 excluding births delivered via cesarean. Second, as described in the article’s limitations, the data set did not link siblings, leading us to treat correlated observations as independent. We reran model 6 restricting the sample to firstborns. Third, we did not distinguish among term births. We refit model 6 with categories for less than 34, 35 to 36, 37 to 39, and 40 weeks’ or greater gestational age. The first 2 follow-up analyses showed somewhat attenuated odds ratios, but the pattern of adverse associations remained. The additional gestational age categories did not substantively alter the originally reported odds. A fourth cited source of bias was the change in diagnostic criteria for autism between Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) and Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition, Text Revision). Note that the confidence intervals on the odds ratios for 1996 to 1998 are not statistically significant. In addition, the overestimation to which the letter writers refer is only for pervasive developmental disorder not otherwise specified and not for autism spectrum disorder overall. Nevertheless, we limited the analysis to only 1996 to 1998; however, the much smaller sample size introduced instability in coefficient estimates on many variables. We argue that further research is warranted. We note that a child’s autism diagnosis in the North Carolina Education Research Data Center is determined by prior clinical diagnosis and further evaluation by a school psychologist that includes standard individualized testing. Because for some study years school personnel were allowed to only report the primary exceptionality designation, even if a child had multiple designations, we may not have captured all autism cases in the North Carolina Education Research Data Center. However, autism prevalence in our study was consistent with that reported nationally and in North Carolina. Letter writers raised data quality issues with the detailed birth record. Studies have shown that inaccuracy in birth JAMA Pediatrics February 2014 Volume 168, Number 2
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records2-6 typically stems from underreporting such that birth certificate information can usually be trusted to “rule in” but not “rule out” a particular risk factor (ie, it is specific but not sensitive). This is true for studies cited by the letter writers. For a falsely elevated odds ratio, it must be the case that underreporting of induction/augmentation is systematically occurring among women who are less likely to have autistic children. However, we do not have reason to believe that the underreporting of the induction/augmentation exposure is anything but randomly distributed. In addition, while we do not wish to impugn oxytocin, recent research indicates that oxytocin crosses the human placenta in both directions.7 We note the importance of further research to address data quality issues in our article and further note that almost all epidemiological studies are subject to some degree of response and exposure misclassification. In summary, there are clear benefits to labor induction and augmentation, particularly among women with medical and obstetric conditions that increase the risk for stillbirth or neonatal morbidity. As stated earlier and in our article, the findings of this study should not change current obstetric practice. Finally, as we did in the article, we emphasize the preliminary nature of the results but also the need for further research. Marie Lynn Miranda, PhD Rebecca Anthopolos, MA Simon G. Gregory, PhD
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Author Affiliations: Department of Pediatrics, University of Michigan, Ann Arbor (Miranda); Children’s Environmental Health Initiative, School of Natural Resources and Environment, University of Michigan, Ann Arbor (Miranda, Anthopolos); Center for Human Genetics, Department of Medicine, Duke University Medical Center, Durham, North Carolina (Gregory); Duke Institute of Molecular Physiology, Duke University Medical Center, Durham, North Carolina (Gregory). Corresponding Author: Marie Lynn Miranda, PhD, School of Natural Resources and Environment, University of Michigan, 440 Church St, 2046 Dana Bldg, Ann Arbor, MI 48109 ([email protected]). Conflict of Interest Disclosures: None reported. 1. Gregory SG, Anthopolos R, Osgood CE, Grotegut CA, Miranda ML. Association of autism with induced or augmented childbirth in North Carolina Birth Record (1990-1998) and Education Research (1997-2007) databases. JAMA Pediatr. 2013;167(10):959-966. 2. Bailit JL; Ohio Perinatal Quality Collaborative. Rates of labor induction without medical indication are overestimated when derived from birth certificate data. Am J Obstet Gynecol. 2010;203(3):e1-e3. 3. Piper JM, Mitchel EF Jr, Snowden M, Hall C, Adams M, Taylor P. Validation of 1989 Tennessee birth certificates using maternal and newborn hospital records. Am J Epidemiol. 1993;137(7):758-768. 4. Lydon-Rochelle MT, Holt VL, Nelson JC, et al. Accuracy of reporting maternal in-hospital diagnoses and intrapartum procedures in Washington State linked birth records. Paediatr Perinat Epidemiol. 2005;19(6):460-471. 5. Parrish KM, Holt VL, Connell FA, Williams B, LoGerfo JP. Variations in the accuracy of obstetric procedures and diagnoses on birth records in Washington State, 1989. Am J Epidemiol. 1993;138(2):119-127. 6. Kahn EB, Berg CJ, Callaghan WM. Cesarean delivery among women with low-risk pregnancies: a comparison of birth certificates and hospital discharge data. Obstet Gynecol. 2009;113(1):33-40. 7. Malek A, Blann E, Mattison DR. Human placental transport of oxytocin. J Matern Fetal Med. 1996;5(5):245-255.
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