Does augmentation or induction of labor with oxytocin increase the risk for autism?




Autism spectrum disorders (ASDs) are a group of permanent developmental disabilities characterized by abnormalities in socialization, communication, and behavior. ASDs are classified under pervasive developmental disorders (PDDs) and include autistic disorder (AD), Asperger’s syndrome, and pervasive developmental disorder–not otherwise specified (PDD-NOS), which is also referred to as atypical autism.


The diagnosis of ASDs is usually made in early childhood, and the condition often leads to a compromise in the quality of life for both the affected child and the entire family. ASDs affect male more than female children on a 4:1 ratio. There has been a temporal increase in the prevalence of autism, and it is currently estimated that approximately 1 in 88 children in the United States suffer from ASDs. The rise has been attributed to increased awareness and changes in administrative classifications and definitions as well as to changes in practice patterns leading to improved diagnosis of the condition. Although a genetic predisposition to this condition has been firmly established, the exact etiology remains unknown.


Research has shown that environmental factors may play a role including perinatal risk factors. Studies have shown that preterm birth, smallness for gestational age, congenital anomalies, low Apgar scores, advanced maternal age, maternal metabolic syndrome, smoking, and exposure to betamimetic agents during pregnancy may play a role, but there is insufficient evidence to causally implicate any of these factors. In contrast, maternal hypertension, proteinuria, and preeclampsia may be protective for ASD.


Oxytocin is a neurotransmitter with important central nervous system effects regarding reproduction, social behavior, and cognitive function. Because of its possible influences in social behavior and cognitive function, oxytocin has been linked to triggers of ASDs at the molecular level, and it has been postulated that polymorphic variation at the oxytocin receptor gene may be associated with ASDs, depending on early environmental conditions. As a result, it has been hypothesized that oxytocin administration during labor may contribute to the development of ASDs by down-regulation of the fetal brain oxytocin receptors.


Given this background, it would make perfect sense to examine the clinical association between oxytocin during labor and ASDs, especially in the setting of a rising oxytocin use during labor.


Indeed, in a recent publication, Gregory et al reported for the first time an epidemiological study that examined the association between induced or augmented labor and the risk of ASDs. The authors linked 2 databases: the North Carolina Detailed Birth Records for births that occurred during the years 1990-1998 and the North Carolina Education Research data to identify children diagnosed with autism during the years 1997-2007. The authors concluded that induction or augmentation during childbirth is associated with increased odds of autism diagnosis in childhood and that the observed associations were particularly pronounced in male children. The conclusion of the study immediately gained widespread attention by news media.


Because this is an extremely important issue for obstetricians and patients, the remainder of this editorial will be focused on some important issues related to the primary exposure and interpretation of the results. We will offer an alternative interpretation of the study findings.


It has been previously hypothesized that a predisposing factor for autism may be oxytocin exposure. However, the primary exposure in the study by Gregory et al was not oxytocin exposure but “augmentation or induction of labor” as a proxy for oxytocin exposure. Because of the limitations of the data, the authors were unable to separate those patients who had exposure only to oxytocin. Prior and during the study birth years (1990-1998), an unknown mixture of agents of various dosages had been used for labor induction including amniotomy, various prostaglandins, and intracervical balloon catheters. These agents could have been used alone or in addition to oxytocin. Thus, the primary exposure is not the desired agent (oxytocin).


It is fundamental for all observational comparative studies to examine and report any known practice changes that could have influenced the results of the study. Unfortunately, there were significant changes in the criteria for diagnosing PDD-NOS (atypical autism) during the study years. The American Psychiatry Association reported that an editorial error was made in the description of the diagnostic criteria for PDD-NOS category of Autism Spectrum Disorders in the 1994 publication of the Diagnostic and Statistical Manual of Mental Disorders , fourth edition (DSM-IV). Instead of requiring “impairment in social interaction and in verbal or nonverbal communication skills,” DSM-IV stated–because of the editorial error–that the “PDD-NOS category should be used when there is a severe and pervasive impairment of reciprocal social interaction or verbal and nonverbal communication skills or when stereotyped behavior, interests, and activities are present.”


In 2000, research showed that there had been overdiagnosis of PDD-NOS in the prior years, and therefore, the wording of the criteria for PDD-NOS were revised back to the original definition in the DSM-IV, Text Revision, which was published in May 2000. Because the wrong wording of DSM-IV led to the overdiagnosis of PDD-NOS prior to year 2000, this most likely led to misclassification of ASD in the study by Gregory et al.


Because the autism diagnoses were made between 1997 and 2007, it is certain that there were overdiagnoses in the initial years of the study. This overdiagnosis of ASDs may well explain the positive associations between augmentation and/or induction and autism during the initial birth years 1990-1995. Because the median age at diagnosis of PDD-NOS in North Carolina was 55 months and the correct diagnostic criteria for PDD-NOS were applied from 2000 onward, it is expected that the correct criteria were applied only to those who were born 4-5 years earlier and onward (ie, 1996-1998). However, there were no statistically significant associations between induction/augmentation during labor and autism in years 1996-1998 in comparison to 1990 (reference year).


A careful inspection of the yearly trend of the associations between augmentation and/or induction and autism (Table 3 in Gregory et al ) reveals that there was a sudden change to nonsignificant associations during each of the 3 most recent birth years of the study (1996-1998) when the correct diagnostic criteria for autistic disorders were applied (compared to 1990).


We believe that the conclusion by Gregory et al should have been that the most recent evidence (birth years 1995-1998) indicates that when the appropriate diagnostic criteria for autistic disorders are applied, there was no increase in autism from baseline or any association between induced or augmented childbirth and autism. Therefore, based on the existing data so far, we believe that there is no evidence that oxytocin administration for labor augmentation or induction or labor augmentation or induction in general increase the risk for autism.


References



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May 13, 2017 | Posted by in GYNECOLOGY | Comments Off on Does augmentation or induction of labor with oxytocin increase the risk for autism?

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