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Original Investigation
October 12, 2020

Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring

Author Affiliations
  • 1Department of Anesthesiology, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 2Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena
  • 3Department of Internal Medicine, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 4Department of Pediatrics, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 5Department of Obstetrics & Gynecology, Kaiser Permanente Baldwin Park Medical Center, Baldwin Park, California
  • 6Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, North Carolina
JAMA Pediatr. 2020;174(12):1168-1175. doi:10.1001/jamapediatrics.2020.3231
Key Points

Question  Is there an association between maternal labor epidural analgesia given for vaginal delivery and risk of autism spectrum disorders in children?

Findings  In this multiethnic population-based clinical birth cohort that included 147 895 children, autism spectrum disorders were diagnosed in 1.9% of the children delivered vaginally with epidural analgesia vs 1.3% of the children delivered vaginally without the exposure, a 37% relative increase in risk that was significant after adjusting for potential confounders.

Meaning  This study suggests that exposure to epidural analgesia for vaginal delivery may be associated with increased risk of autism in children; further research is warranted to confirm the study findings and understand the potential mechanisms.

Abstract

Importance  Although the safety of labor epidural analgesia (LEA) for neonates has been well documented, the long-term health effects of LEA on offspring remain to be investigated.

Objective  To assess the association between maternal LEA exposure and risk of autism spectrum disorders (ASDs) in offspring.

Design, Setting, and Participants  Data for this retrospective longitudinal birth cohort study were derived from electronic medical records from a population-based clinical birth cohort. A total of 147 895 singleton children delivered vaginally between January 1, 2008, and December 31, 2015, in a single integrated health care system were included. Children were followed up from the age of 1 year until the first date of the following occurrences: clinical diagnosis of ASD, last date of health plan enrollment, death, or the study end date of December 31, 2018.

Exposures  Use and duration of LEA.

Main Outcomes and Measures  The main outcome was clinical diagnosis of ASD. Cox proportional hazards regression analysis was used to estimate the hazard ratio (HR) of ASD associated with LEA exposure.

Results  Among the cohort of 147 895 singleton children (74 425 boys [50.3%]; mean [SD] gestational age at delivery, 38.9 [1.5] weeks), 109 719 (74.2%) were exposed to maternal LEA. Fever during labor was observed in 13 055 mothers (11.9%) in the LEA group and 510 of 38 176 mothers (1.3%) in the non-LEA group. Autism spectrum disorders were diagnosed in 2039 children (1.9%) in the LEA group and 485 children (1.3%) in the non-LEA group. After adjusting for potential confounders, including birth year, medical center, maternal age at delivery, parity, race/ethnicity, educational level, household income, history of comorbidity, diabetes during pregnancy, smoking during pregnancy, preeclampsia or eclampsia, prepregnancy body mass index, gestational weight gain, gestational age at delivery, and birth weight, the HR associated with LEA vs non-LEA exposure was 1.37 (95% CI, 1.23-1.53). Relative to the unexposed group, the adjusted HR associated with LEA exposure of less than 4 hours was 1.33 (95% CI, 1.17-1.53), with LEA exposure of 4 to 8 hours was 1.35 (95% CI, 1.20-1.53), and with LEA exposure of more than 8 hours was 1.46 (95% CI, 1.27-1.69). Within the LEA group, there was a significant trend of ASD risk associated with increasing duration of LEA exposure after adjusting for covariates (HR for linear trend, 1.05 [95% CI, 1.01-1.09] per 4 hours). Adding fever to the model did not change the HR estimate associated with LEA exposure (adjusted HR for LEA vs non-LEA, 1.37 [95% CI, 1.22-1.53]).

Conclusions and Relevance  This study suggests that maternal LEA may be associated with increased ASD risk in children. The risk appears to not be directly associated with epidural-related maternal fever.

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    16 Comments for this article
    EXPAND ALL
    Study Design Concerns
    Kai Rabenstein, MB, BCh, BAO, MD | East Sussex Healthcare Trust, UK

    As far as I can make out, the authors of this study were attempting to control for a large number of potential confounders (the abstract mentions 15 geographic, socioeconomic and biological factors) but failed to consider the 2 most intuitively obvious: maternal (i.e. epidural decision maker's) diagnosis of ASD and family history on both parental sides. It is very well established that the genetic/heritable component in autism is very strong. This oversight renders the study findings questionable.

    CONFLICT OF INTEREST: I have an (adult) diagnosis of Asperger's and advocate for the recognition of neurodivergence among the medical profession
    Confounding Labor Variables
    Brooke Orosz, PhD |
    It is well established that labor complications and fetal distress can cause brain injury. In addition, women having long and difficult labors are more likely to request epidural anesthesia. The study authors did not look at lengh of labor, duration of ROM, incidence of fetal distress or emergency cesarean, Apgar scores, or other labor-related variables.

    If perinatal rather than genetic factors really do play a significant  role in autism, difficult labor is a much more plausible mechanism than the tiny traces of epidural drugs that enter the bloodstream and pass to the baby.
    CONFLICT OF INTEREST: None Reported
    Yes, There Are Likely Unmeasured Confounders
    B Segal, MD, MHCM | Wake Forest School of Medicine
    I agree with Dr. Rabenstein that there may be unmeasured confounders, and this study must be viewed as hypothesis-generating. One approach in ASD studies with other associations to try to control for parental genetics has been to use sibling controls. I think that approach would be useful in exploring this association further as well.
    CONFLICT OF INTEREST: Coauthor on the study in question
    Potential for Patient Harm
    Robert Lennon, MD, JD | Penn State College of Medicine
    You suggest that a correlation between maternal exposure to labor epidural analgesia (LEA) and an increased prevalence of autistic spectrum disorder (ASD) diagnosis in those exposed is concerning “for the safety and long-term health” of children born to mothers who choose LEA. But the paper overlooks the single most obvious covariate – the presence of ASD in the mothers. ASD has a strong genetic component [1] and persons with ASD have high pain sensitivity [2]. Therefore, laboring mothers with ASD can be expected to desire LEA and have a greater prevalence of ASD among their offspring than laboring mothers without ASD. Far from being a headline-making finding, the findings under these circumstances would be fully expected and do not suggest greater risk of ASD from LEA. At most they confirm that observational studies of ASD should control for its genetic component and avoid causal claims or implications.

    References
    1. Genetic links to autism. Psychologist (London, England : 1988). 2009;22(6):474-474.
    2. Gu X, Zhou TJ, Anagnostou E, et al. Heightened brain response to pain anticipation in high-functioning adults with autism spectrum disorder. The European journal of neuroscience. 2018;47(6):592-601. doi:10.1111/ejn.13598
    3. 12 news outlets according to the article's altimetric tracker. https://summon.altmetric.com/details/92233039/news
    CONFLICT OF INTEREST: None Reported
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    High degree of loss-to-follow up in study claiming association between epidural during labor and autism spectrum disorder
    Trond Nordseth, MD PhD | Associate Professor, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
    In this publication, Qiu and co-workers demonstrated an association between epidural during labor and a later diagnosis of autism specter disorder (ASD).

    The primary outcome was an ICD-9 diagnosis code of 299.x being given at two separate visits during follow-up in the Kaiser Permanente (KSPC) hospital system. The authors have not reported how many of the study participants were in fact assessed for the primary outcome.

    Thus, children being diagnosed with ASD outside the KSPC system may not have been registered. In addition, children not enrolled as KSPC members by 1 year of age were not assessed
    with respect to the outcome. According to the numbers at risk table in Figure 2, there was a considerable loss to follow-up (LTFU) during the study period. By 4 years of age, where most diagnoses had been made, 52 206 children (35%) from the initial cohort was LTFU. In the study, follow-up ended when one of the following occurred: “diagnosis of ASD, last date of continuous KPSC plan membership, death of the child .. or study end date”. It seems the main reason for LTFU was discontinuation of KSPC membership.

    If the rates of LTFU were different between the epidural and non-epidural group, for reason related to the outcome, this may cause biased effect estimates. In Cox regression, the reason for censoring should be independent of the outcome (i.e. the censoring should be "non-informative"). Adjusting for possible confounders is less helpful if the primary outcome was measured differently among participants.
    CONFLICT OF INTEREST: None Reported
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    Interpretation and impact of the results
    Tea Dakic, MD, MSc Bioethics | Clinical Center of Montenegro
    The key conclusion of this study is that that exposure to labor epidural analgesia (LEA) for vaginal delivery may be associated with 37% relative increase in risk of autism in children, in comparison to the children delivered vaginally without the exposure. While I am highly respectful of the efforts the authors made to devise a stringent methodology, I am worried about the interpretation of the results and the impact they may have.
    My concern is twofold.

    Firstly, it is known that autism spectrum disorders are highly genetic. Studies suggest that autism is the neuropsychiatric disorder most affected
    by genetic factors, with about 90% of variance is attributable to genetic factors. When it comes to testing the hypothesis that some non-genetic factor significantly increases the risks of autism, the size ratio of the case-controls could play a significant role. The fact that case-control ratio of this study is 4:1 may cause lower reliability of the results, negatively affect the study precision, and weaken the hypothesis. Since the statistical power of a study reduces as the group sizes become more unequal, and since the LEA-group takes up for roughly three quarters of the cases, there is a great possibility that the intangible genetic confounders did not show up enough have the to have a detectable effect in the much smaller non-LEA group.
    Secondly, even if we reserve the genetic variations that may have been overlooked, there is still the issue of the ethical interpretation and communication of research results. The authors did fairly disclose the limitations of the study, by declaring that some important aspects of LEA exposure or additives such as opioids have not been assessed. They further affirmed that their findings should not be interpreted as a demonstration of a causal link between LEA exposure and subsequent development of autism spectrum disorders. Yet, that does not prevent misleading reinterpretations of the study in the media, which is already producing sensational titles, such as “Epidurals During Childbirth Tied to Autism Risk”, and affecting the public opinions and attitudes. It is my concern that the way the authors arrayed the results in the conclusion may avert both physicians from recommending and patients from deciding in favor of epidurals, the most common and very safe type of anesthetic used for pain relief during labor, on the basis of questionable data.

    While I acknowledge that no study is fully reflective of the objective reality, I fear that the numbers this one produced may give way to misconceptions, affect the general discourse on autism and cause bias in future decision-making regarding labor pain relief.
    CONFLICT OF INTEREST: None Reported
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    Come Off It!
    Mark Pickin, MB ChB | York
    Give me one logical and scientifically plausible mechanism that could lead an epidural to cause autism. Yes, maybe children who are going to develop autism somehow are associated with mothers who require epidurals, but that is not causative although it may be an avenue for research...but unlikely.
    CONFLICT OF INTEREST: None Reported
    Asking as a non-scientist
    Bernie Folan | Private
    This is the best example of the importance of post-publication open comments I've seen.

    Sadly looking at pick-up by news outlets and their headlines is super depressing.

    Should this have got through peer review? I'm not a scientist but work in scholarly communication.

    It seems hugely irresponsible for newspapers to be pushing this message out there having read the comments here about unexplored factors. If the reviewers and other readers feel it is ok, I guess there is nothing to be done about the general public receiving information that may lead to erroneous and
    damaging conclusions.

    I am the mother of an autistic son who very much chose to have epidural, and would again. My son also had his umbilical cord wrapped tightly around his neck and has an autistic father. Should I feel guilty I didn't endure the pain? (Rhetorical question).
    CONFLICT OF INTEREST: None Reported
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    Association of Epidural Labor Analgesia with Autism Spectrum Disorders
    Grace Lim, MD, MSc | University of Pittsburgh
    In a recent study, Qiu et al. reported epidural labor analgesia (ELA) is associated with a 37% increased autism spectrum disorder (ASD) risk in children (1). However we wish to highlight critical study design flaws and the authors’ misleading conclusions.

    First, no plausible biologic mechanism was established a priori. Based on findings of a monkey study (2), the authors state that “standard doses of local anesthetics produce neurotoxic effects and alter neurobehavioral development.” However, local anesthetic doses in this animal study (0.5% bupivacaine, 0.6 mg/kg bolus, infusion over 20 minutes) are not standard in modern clinical obstetric anesthesia
    practice (3). They state local anesthetics’ low molecular weight allows easy placental transfer. However, ELA-based local anesthetics e.g., bupivacaine, have high protein binding and a pKa value that results in a low fetal/maternal plasma concentration ratio (4). They cite three human studies suggesting anesthesia exposure is linked to ASD, but this assertion is not supported by data in these studies. One study did not differentiate any effect of ELA from oxytocin, and all 3 studies failed to account for confounder bias. Therefore, this description is, at best, misleading and, at worst, erroneous.

    Second, confounder adjustment was incomplete, with confounding by indication a major concern. Maternal and intrapartum factors which may influence likelihood of ELA request and ASD risk, include a parental history of ASD5, induction of labor, labor dystocia, and fetal hypoxia or malposition. Further, considering the small effects found in the analysis (i.e. overall unadjusted absolute risk difference of 0.06% increase in the odds of ASD with ELA; lower 95% confidence interval limit of linear trend of hazard ratio = 1.01), in the presence of residual confounders, these intervals would likely reach or overlap the null.

    Most importantly, the authors did not discuss the clinical implications of their findings. ELA is recognized as the most effective method of providing labor analgesia. It also allows epidural anesthesia for an unplanned cesarean delivery, which avoids any maternal or neonatal complications from general anesthesia exposure. Failing to counterbalance the small, albeit unlikely, effect of ELA on ASD against these important benefits may cause undue stress, anxiety, and harm to expectant mothers. We hope that the editors and authors more seriously consider the implications of these findings on expectant mothers and providers who have to allay mothers’ fears about epidural-associated ASD.

    Sincerely,
    Grace Lim MD MS
    Alexander J Butwick MBBS, FRCA, MS

    1- University of Pittsburgh School of Medicine
    2- Stanford University School of Medicine


    References

    1. Qiu C, Lin JC, Shi JM, et al. Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring. JAMA Pediatr. 2020.
    2. Golub MS, Germann SL. Perinatal bupivacaine and infant behavior in rhesus monkeys. Neurotoxicol Teratol. 1998;20(1):29-41.
    3. Lim G, Facco FL, Nathan N, Waters JH, Wong CA, Eltzschig HK. A Review of the Impact of Obstetric Anesthesia on Maternal and Neonatal Outcomes. Anesthesiology. 2018;129(1):192-215.
    4. Santos AC, Pedersen H. Local anesthetics in obstetrics. Cambridge, MA: Blackwell Scientific; 1989.
    CONFLICT OF INTEREST: None Reported
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    Could there be a possible link between labor epidural analgesia and genetic risk for ASD?
    Daimei Sasayama, M.D., Ph.D. | Shinshu University School of Medicine
    This study showed an association between the labor epidural analgesia (LEA) of the mother and autism spectrum disorder (ASD) diagnosis of the child. As the authors have mentioned in their article, this study does not demonstrate a causal relationship between LEA exposure and subsequent development of ASD. We agree that several major limitations prevent us from concluding that maternal LEA exposure is directly tied to the increased risk of ASD in children.

    One of the limitations to note in this study is the difference in the characteristics between mothers who were exposed to LEA and those who were
    not. The authors have raised several possible confounding factors related with maternal characteristics such as educational level, smoking, and race/ethnicity. These characteristics differed significantly between those exposed to LEA and those who were not. Although factors that were examined in this study were included as covariates to adjust for potential confounding, we believe that there were many other possible confounders that were not included in their analyses. One of the unassessed but relevant characteristics of the mother is the pain sensitivity. It is highly likely that those who choose LEA have higher sensitivity to pain.

    Some studies have demonstrated that sensitivity to pain differ between children with and without ASD.1,2 Furthermore, brain response to pain anticipation is reported to be heightened in high-functioning adults with ASD.3 Such evidence suggests that ASD traits in mothers may make mothers more prone to choose LEA. Given the high heritability of ASD, ASD traits in mothers are likely to contribute to higher chances of the children developing ASD. Therefore, this study generates a hypothesis that pain aversion behavior may be linked to genetic liability to ASD. If this hypothesis is true, then the relationship between maternal LEA and child ASD may be a spurious association caused by the third factor, i.e., the genetic predisposition to ASD.

    We believe that there are many other unnoticed confounding factors which could possibly cause an apparent association between maternal LEA and child ASD. Therefore, we should not jump to the conclusion that a causal relationship exists between maternal LEA and child ASD diagnosis. Nevertheless, the association reported here is robust, and thus further investigation is warranted to elucidate the true reason underlying this association.

    References
    1. Allely CS. Pain sensitivity and observer perception of pain in individuals with autistic spectrum disorder. ScientificWorldJournal. 2013;2013:916178.
    2. Tordjman S, Anderson GM, Botbol M, et al. Pain reactivity and plasma beta-endorphin in children and adolescents with autistic disorder. PLoS One. 2009;4(8):e5289.
    3. Gu X, Zhou TJ, Anagnostou E, et al. Heightened brain response to pain anticipation in high-functioning adults with autism spectrum disorder. Eur J Neurosci. 2018;47(6):592-601.
    CONFLICT OF INTEREST: None Reported
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    Crucial confounders must be taken into account in examining the association between epidural analgesia and autism spectrum disoרגקר
    Lena Sagi-Dain, MD | Obstetrics and Gynecology, Carmel Medical Center, Haifa, Israel
    Lena Sagi-Dain, Martha Dirnfeld, Shlomi Sagi.

    We have read with great interest the impressive paper of Qiu C. et al., comparing the risk for autism spectrum disorder (ASD) between 109,719 children born to women exposed to labor epidural analgesia (LEA) and 38,176 children unexposed to LEA (1). As ASD is a complex multifactorial disorder, inflicting severe psychological and economic consequences on the affected families, exploration of potential factors associated with this disorder is crucial, in order to define its direct causes and potentially to decrease its incidence. After adjusting for numerous confounders, the authors demonstrated a significant association between
    LEA and ASD – hazard ratio 1.37 (95% confidence interval 1.23-1.53), and showed that longer duration of epidural exposure was associated with greater ASD risk. The authors suggested that this association might be related to adverse effects of LEA on maternal and fetal physiology.

    As LEA is the most effective and most commonly used therapy for pain relief during labor and delivery (2), the observed association between LEA and ASD is at least worrisome. However, and quite surprisingly, several obvious obstetric and neonatal parameters recorded at any delivery and associated with ASD were not reported and adjusted for. These basic data include presence of fetal distress, induction of labor, delivery mode (with an emphasis on urgent cesarean deliveries and vacuum extractions), antepartum and postpartum hemorrhage, neonatal Apgar score, as well as the need for hospitalization in neonatal intensive care unit (3,4). Furthermore, numerous additional factors linked to ASD were not mentioned, such as paternal age, maternal periconceptional folic acid intake, or antidepressant exposure (3,5).

    Labor process is often associated with severe or intolerable pain, which has several adverse consequences in addition to potential emotional distress and suffering. These effects include maternal hyperventilation, neurohumoral responses adversely affecting placental perfusion and fetal oxygenation, and increased risk for postpartum depression and psychological trauma (2). The article of Qiu C. et al., not referring to several crucial confounders, might expose the parturients to an unnecessary distress, cause them to refuse LEA and by this to increase the maternal suffering, as well as adverse physiologic effects of labor pain.
    Inclusion of major obstetric confounders in logistic regression analysis might eliminate the statistically significant association between LEA and ASD, and lead to dramatic changes in authors' conclusions.


    References:
    1. Qiu C, Lin JC, Shi JM, et al. Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring. JAMA Pediatr. 2020;Oct 12:e203231. doi: 10.1001/jamapediatrics.2020.3231.
    2. Grant GI. Pharmacologic management of pain during labor and delivery. In: UpToDate, Post, TW (Ed), UpToDate, Crowley M, 2020.
    3. Wang C, Geng H, Liu W, Zhang G. Prenatal, perinatal, and postnatal factors associated with autism: A meta-analysis. Medicine.2017;96(18):e6696. doi: 10.1097/MD.0000000000006696.
    4. Polo-Kantola P, Lampi KM, Hinkka-Yli-Salomäki S, Gissler M, Brown AS, Sourander A. Obstetric risk factors and autism spectrum disorders in Finland. J Pediatr. 2014;164(2):358-65. doi: 10.1016/j.jpeds.2013.09.044.
    5. Sørensen MJ, Grønborg TK, Christensen J, et al. Antidepressant exposure in pregnancy and risk of autism spectrum disorders. Clin Epidemiol. 2013;15;5:449-59. doi: 10.2147/CLEP.S53009. PMID: 24255601.
    CONFLICT OF INTEREST: None Reported
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    Epidural analgesia, autism spectrum disorders, and the potential to worsen racial/ethnic disparities
    Paloma Toledo, MD, MPH | Northwestern University
    We read with interest the article by Qui et al., which evaluated the association between epidural analgesia during labor and risk of autism spectrum disorders (ASD).1 We, as members of the Society for Obstetric Anesthesia and Perinatology Diversity and Inclusivity Task Force are concerned that the results of this study could result in a worsening of existing racial/ethnic disparities in the use of neuraxial labor analgesia.

    Labor is one of the most painful events a woman will experience in her lifetime. Neuraxial labor analgesia is the most effective way to manage labor pain, yet minority women are less
    likely to utilize epidural analgesia for pain control due to concerns about the procedure and inaccurate understanding of the associated risks.2 Untreated pain is of great public health concern, as severe acute postpartum pain may result in the development of both chronic pain and postpartum depression,3 two conditions which disproportionally affect minority women.

    We feel that it is biologically implausible that epidural analgesia is causative for autism spectrum disorders. While there are several methodological issues that result from the retrospective nature of the study, it is important to note in addition to how significantly different the two cohorts were, several important confounding factors which likely have a greater effect on the development of ASD than the use of neuraxial labor analgesia that were not available in the dataset, namely, paternal information and other environmental factors.4

    While the results from this study are exploratory in nature, our concern is that their dissemination without highlighting the study’s limitations may result in a false belief that epidural analgesia is causative for ASD. This misinformation may have unintended consequences, akin to when parents avoided vaccinating their children for fear of causing ASD; yet in this case, the result may be that the burden of pain may be increasingly shouldered by minority women, as they will avoid using labor epidurals. It is imperative that providers educate their patients about labor pain management using linguistically-concordant and culturally-tailored information. Unfortunately, correction of misinformation about controversial issues may fail to change beliefs, especially among those who are likely to hold those misconceptions.5 Thus, anesthesiologists should be prepared to openly address patient concerns about ASD, discussing its complex etiology and at the same time, assuring patients of the safety of neuraxial labor analgesia.

    Sincerely,
    Paloma Toledo, MD, MPH, Carlos Delgado, MD, and Ron George, MD, FRCPC

    References

    1. Qui C, Lin JC, Shi JM, et al. Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring. JAMA Pediatr.
    2. Toledo P, Sun J, Peralta F, Grobman WA, Wong CA, Hasnain-Wynia R. A qualitative analysis of parturients' perspectives on neuraxial labor analgesia. Int J Obstet Anesth. 2013;22(2):119-123.
    3. Eisenach JC, Pan PH, Smiley R, Lavand'homme P, Landau R, Houle TT. Severity of acute pain after childbirth, but not type of delivery, predicts persistent pain and postpartum depression. Pain. 2008;140(1):87-94.
    4. Bai D, Yip BHK, Windham GC, et al. Association of Genetic and Environmental Factors With Autism in a 5-Country Cohort. JAMA Psychiatry. 2019.
    5. Nyhan B, Reifler J, Richey S, Freed GL. Effective messages in vaccine promotion: a randomized trial. Pediatrics. 2014;133(4):e835-842.
    CONFLICT OF INTEREST: None Reported
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    Association of Exposure to Labor Anesthesia and Neonatal Brain Development
    Marisa Spann, PhD, MPH | Columbia University Irving Medical Center
    Qiu et al. found that a longer duration of epidural analgesia exposure during vaginal labor and delivery was associated with an increased risk of ASD in offspring.1 These findings and the FDA’s warning of potential neurotoxicity of anesthesia, indicate that more work is required to characterize the short to long-term effects of analgesia exposure on development, as it may be a better option for pain management than anesthesia.2 Qiu et al. provide an extension of the narrowing focus on the adverse developmental effects of cesarean delivery, which is highly confounded by exposure to analgesics and anesthetics. Despite convincing evidence from pre-clinical studies1 and the FDA’s indication that third trimester exposure to analgesia may have detrimental effects on the fetus, only one study has considered the effect of perinatal analgesia on brain development.3 Using MRI, this study showed that perinatal exposure to epidural or spinal analgesia during labor and delivery, regardless of delivery type , was associated with greater volumes in the frontal and occipital lobes and right posterior cingulate. Longer duration of exposure was associated with greater occipital lobe volumes, suggesting a regional sensitivity to dose.4 Compared to Qiu et al., this sample was more homogenous on maternal demographic, pregnancy histories, and infant birth characteristics. These results support the validity of the Qiu et al. findings, suggesting that associations of perinatal epidural analgesia exposure with later development of ASD is likely due to the effects of analgesia exposure on brain development. Qiu et al., adds to our understanding of the long-term effects of epidural analgesia during vaginal labor and delivery on psychiatric outcomes of offspring, complementing earlier reports associating epidural analgesia exposure with learning disabilities5 and anesthetic exposure soon after delivery with poor muscle tone and neurological disturbances.6 These findings necessitate identifying brain systems vulnerable to analgesia and anesthesia exposure and comparing their neurotoxic safety profiles of specific agents, so as to reduce the risk of neurodevelopmental disorders. Combining pre-clinical models, epidemiological studies and translational neuroimaging studies has the potential to identify the mechanisms of neurotoxicity associated with perinatal analgesia and anesthetic exposure and how they mediate developmental disorders.

    References
    1. Qiu C, Lin JC, Shi JM, et al. Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring. JAMA Pediatr. Oct 2020
    2. Administration UFaD. FDA drug safety communication : FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women; 2016.
    3. Spann MN, Serino D, Bansal R, et al. Morphological features of the neonatal brain following exposure to regional anesthesia during labor and delivery. Magn Reson Imaging. Feb 2015;33(2):213-21. doi:10.1016/j.mri.2014.08.033
    4. Spann MN, Bansal R, Rosen T, Peterson BS. Exposure to Regional Anesthesia during Labor and Delivery and Its Effect on Neonatal Brain Morphology. Neuropsychopharmacology. DEC 2013 2013;38:S152-S153.
    5. Flick RP, Lee K, Hofer RE, et al. Neuraxial labor analgesia for vaginal delivery and its effects on childhood learning disabilities. Anesth Analg. Jun 2011;112(6):1424-31.
    6. Sepkoski CM, Lester BM, Ostheimer GW, Brazelton TB. The effects of maternal epidural anesthesia on neonatal behavior during the first month. Dev Med Child Neurol. Dec 1992;34(12):1072
    CONFLICT OF INTEREST: None Reported
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    Unmeasured confounding and collider bias concerns
    Tiffany Fitzpatrick, PhD MPH | Yale School of Public Health
    Co-author: Adele Carty, PhD Candidate, MSc | Dalla Lana School of Public Health, University of Toronto

    We read with great interest the article by Qiu et al. showing an association between labor epidural analgesia and increased risk of autism spectrum disorders (ASDs) in offspring. Several leading medical societies/associations have released a joint statement recognizing the potential for this article to cause anxiety among pregnant women – reassuring that epidural analgesia is the standard of care for labor pain relief, and existing evidence supports its role in improving maternal and neonatal outcomes. As this commentary also notes, correlation does not
    imply causation. We would like to highlight several methodological considerations which further limit the causal implications of this article.

    Foremost, evidence supports the development of ASDs as being a function of the interaction between environmental and genetic factors, with strong familial heritability. Despite the authors’ ability to identify families, they neglected to control for the potential biologic effect (i.e., heritability) of these factors in their analysis, raising serious concern regarding residual confounding. We appreciate the authors have presented E-values to provide insight into the potential impact of residual confounding; however, it is not unlikely that the above unmeasured confounders would have greater independent associations with both epidural analgesia and ASDs than suggested. We argue that a sibling-matched sensitivity analysis be considered to mitigate risks of unmeasured confounding to provide a more valid estimate.

    Given the authors have restricted their study cohort to live, singleton births, we also have concerns regarding the potential for collider bias. For example, for this bias to occur, two assumptions need to hold: 1) epidural analgesia use is associated with stillbirths; and 2) a common cause is present for stillbirths and ASDs. To aid in reducing the potential risk of this bias, it is recommended that authors adjust their analysis for common causes of stillbirths and ASDs, such as antenatal complications (i.e., asphyxia, placental abruption, etc.); factors that the authors neglected to control for in their analysis.

    We further caution that, although the identification of maternal epidural analgesia use is well captured in health administration data and unlikely subjected to reporting biases, the same cannot be said for diagnosis of ASDs. Critically, higher ASD prevalence is associated with more advantaged socioeconomic status (SES). In this article, mothers receiving epidural analgesia had higher levels of education and median household income – proxies for SES. Surprisingly, the authors excluded children not enrolled as health plan members by 1-year of age, potentially removing individuals most susceptible to underreporting of ASDs. Thus, the outcome of ASDs included in this article is likely differentially underreported.

    Research, such as that by Qiu et al., is needed to advance our understanding of ASDs; however, we caution that these findings should not be used to inform clinical decisions for maternal pain management during labor. While the association between epidural analgesia and ASDs is noteworthy, it’s lack of causation is undisputedly important. While we limit our discussion to methodological considerations, we note the sensationalist headlines following this article are particularly troubling and place unnecessary stress on mothers delivering during a global pandemic.
    CONFLICT OF INTEREST: None Reported
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    Responses to the 14 varying comments and Views
    Chunyuan Qiu, MD, MS | Kaiser Permanente Southern California
    We appreciate and welcome all views from the 14 comments. This is a scientific research paper that reported our findings in an area that has not been studied previously. We hope our research will inspire more research in this unexplored principle to ensure the safety for our patients.
    We appreciated Dr. Spann’s comment. Thank you for providing additional evidence toward this occurrence and including your own original research. Your finding of greater volumes in the frontal lobe, occipital lobe, and right posterior cingulate after neuraxial exposure and its associated duration effect is unsettling but further points towards the same
    phenomenon. We hope your past important works and our current findings will inspire more research to understand the long-term safety of LEA and effects of regional anesthetics on neonatal brain morphology.
    We appreciate Dr. Folan’s and Dr. Pickin’s view, and we did not make any causal conclusion and the study does have many limitations.1 Considering the low incidence of ASD, the additional risk associated with LEA, if any, is still small. Labor epidural has a proven benefit to mothers and fetus in the near term. We do not recommend any practice changes simply based on our single retrospective study alone. No mothers should feel guilty for choosing an epidural for labor with what we know today. Our study is an important step forward by pointing out the fact that more research in this area is urgently needed. Our study should be considered as a new driving force toward future better and safer perinatal care.
    We appreciated the comments of Dr. Fitzpatrick. We did not make recommendations to change clinical practice, rather we encourage more research in this area. We agree that sibling-matched design is better, however, our cohort will not allow us to find enough mothers who had discordant exposure on epidural use. We respectfully disagree on the comment on collier bias in our study as stillbirths were not included, and our results remained after excluding pre-term birth. The purpose of only including children enrolled as KPSC member by age 1 was to ensure that all children included will have equal opportunity to be screened for ASD since screening for ASD at their well-bay check-up visits did not occur before age 1.
    We appreciate Dr. Rabenstein’s, Dr. Lennon’s comments and varying view. In our earlier birth cohort study derived from the same integrated health care system using the same method which included 3388 children diagnosed with ASD. We only identified 25 mothers and 121 older siblings that had a documented ASD diagnosis.2 Adjustment for mothers or older siblings with ASD did not explain away the associations we found between maternal diabetes and risk of ASD in children. Unfortunately, we don’t have information on fathers. Given the heterogeneity of ASD, we doubt that the association we found between LEA and risk of ASD was purely genetics. Future studies are warranted as we stated.
    Reply continued on next comment.

    Sincerely,
    Chunyuan Qiu MD, MS
    Anny H. Xiang Ph. D.
    Vimal Desai MD

    1 Qiu C, Lin JC, Shi JM, et al. Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring. JAMA Pediatr. 2020;174(12):1168–1175. doi:10.1001/jamapediatrics.2020.3231

    2 Xiang AH, Wang X, Martinez MP, Walthall JC, Curry ES, Page K, Buchanan TA, Coleman KJ, Getahun D. Association of maternal diabetes with autism in offspring. JAMA. 2015 Apr 14;313(14):1425-34. doi: 10.1001/jama.2015.2707. Erratum in: JAMA. 2017 Feb 7;317(5):538. PMID: 25871668.
    CONFLICT OF INTEREST: None Reported
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    Response to 14 comments and views (part 2)
    Chunyuan Qiu, MD, MS | Kaiser Permanente Southern California
    Continued…
    We appreciate your comments and different views, Dr. Lim and Dr. Butwick. Your concerns about biological plausibility, confounders and clinical implications will be addressed in the upcoming correspondence. I am sure that you agree, no known biological plausibility does not mean one does not exist, as exampled by Barry Marshall whose discovery of the biological association of H. Pylori and gastric ulcer disease was initially doubted. Furthermore, we provided fair explanation.1
    Thank you, Dr. Sasayama for the hypothesis about pain sensitivity as well. Pain is unpleasant sensory and emotional experience, which is subjective in nature and influenced via
    many factors. I hope that you agree that pain and a pain sensitivity study itself warrants its own field of research in connection to ASD. Assessing pain sensitivity as a potential mechanism is interesting to pursue.
    We appreciated Dr. Nowrasteh’s comments. The purpose of only including children enrolled as KPSC member by age 1 was to ensure that all children included will have equal opportunity to be screened for ASD, since screening for ASD at their well-bay check-up visits did not occur before age 1. The purpose of censoring when they discontinue KPSC membership was also to minimize ascertainment bias. The cohort included children born in 2015 with last follow-up in 2018, thus the subjects did not reach the age of 4 in our study design. As one of the largest integrated healthcare systems, we are known for stable membership over time.
    We appreciate Dr. Orosz’s, Dr. Dakic’s and Dr. Toledo’s points especially fresh from the bioethical point of view. We did not include all potential covariates and confounders in this study. We have stated that “potential uncontrolled confounders may explain the association that we observed” and encourage more research in this area.1 However, length of labor was not linked to ASD outcomes.2 Our study was an epidemiological study showing associations after adjusting for a handful of known confounders. We do not have genetic data. Also, no cesarean deliveries were included but when birth defects were excluded the association remained, as to answer Dr. Sagi-Dan’s comment. As you correctly pointed out, we fairly stated the limitations of our study, but misinterpretations of our study are our concerns as well. For example, a joint statement misquoted our finding on fever “while the authors speculate about mechanisms (like maternal fever) that could explain a link between epidural pain relief and autism, none of these are plausible or confirmed in the analysis.”3 Our analysis reported the following: “we did not find that ERMF was associated with a risk of ASD.”1

    Sincerely,
    Chunyuan Qiu MD, MS
    Anny H. Xiang Ph. D.
    Vimal Desai MD
    1Qiu C, Lin JC, Shi JM, et al. Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring. JAMA Pediatr. 2020;174(12):1168–1175. doi:10.1001/jamapediatrics.2020.3231
    2 Smallwood M, Sareen A, Baker E, Hannusch R, Kwessi E, Williams T. Increased risk of autism development in children whose mothers experienced birth complications or received labor and delivery drugs. ASN Neuro. 2016;8(4):1759091416659742. doi:10.1177/1759091416659742
    3 The American College of Obstetricians and Gynecologists. Labor Epidurals Do Not Cause Autism; Safe for Mothers and Infants, Say Anesthesiology, Obstetrics, and Pediatric Medical Societies. Accessed December 16, 2020. https://www.acog.org/news/news-releases/2020/10/labor-epidurals-do-not-cause-autism-safe-for-mothers-and-infants
    CONFLICT OF INTEREST: None Reported
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