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This month the Journal of the American Medical Association Pediatrics (JAMA Pediatrics) released an online study “Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring,” authored by Qiu et al. This study examined the issue of autism and epidural anesthesia for childbirth. The article showed a 37% increased incidence of autistic spectrum disorder (ASD) in children whose mothers received epidural anesthesia during labor. The article drew scant publicity.
Instead the key news coverage was an October 12, 2020 press release from the American Society of Anesthesiologists, the Society for Obstetric Anesthesia and Perinatology, the Society for Pediatric Anesthesia, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine, which stated “a new retrospective database study published in JAMA Pediatrics on October 12th, 2020 does not provide credible scientific evidence that labor epidurals for pain relief cause autism. . . . In the scientific literature, the finding of an association between a treatment and an outcome does not prove the treatment caused the outcome.”
The American Society of Anesthesiologists is a very reputable professional organization. I’ve been a card-carrying member of the ASA for 36 years, and I respect the Society at the highest level. The American Society of Anesthesiologists may desire to downplay the results of the JAMA Pediatrics study, but the public deserves a chance to understand what the study accomplished. The JAMA Pediatrics study was not designed to show that labor epidurals do or do not cause autism. The study was designed to assess whether labor epidural exposure for routine vaginal delivery was associated with autistic spectrum risk in the offspring. The study did find an increased incidence of autism in children of mothers who had labor epidural anesthesia, and that’s an important story.
The Center for Disease Control (CDC) states that as of the year 2020, 1 in 54 children are identified with autism spectrum disorder. The incidence of autism has increased markedly over the past decades, and the reason for this is unclear. The number of reported cases of autism increased dramatically in the 1990s and early 2000s, from less than one child per 1000 in 1996 to greater than 5 children per 1000 in 2007.
As children on the autism spectrum become adolescents and young adults, they may have difficulties developing friendships, communicating with others, or understanding what behaviors are expected in school or at work. Almost everyone in America knows a family which contains an autistic child. Many families and expectant parents fear their next child will be autistic, and would like to be aware of any behaviors or choices which increase this risks. Explanations regarding the reasons for increases in autism prevalence have been split into a) the opinion that increasing diagnosis and identification of the disorder is leading to numbers, and/or b) the opinion that the increase is due to specific environmental factors which cause autism. What those environmental factors might be is unclear. Scientific American published an excellent review of this topic in 2017.
In the United States, most laboring women are not interested in experiencing labor pain while unmedicated. Epidural anesthesia is very popular and has been shown to be safe for both the mother and for the infant.
For readers who are not healthcare providers: in administering a labor epidural anesthetic, an anesthesiologist inserts a needle into the mother’s low back, locates the tip of the needle into the epidural space adjacent to the spinal cord, and injects local anesthetic into the epidural space. The local anesthetic is usually bupivacaine or ropivacaine.
The anesthesiologist then threads a slender hollow catheter into the epidural space, to facilitate delivery of either a continuous infusion of dilute local anesthetic or intermittent injections of local anesthetic.
The duration of a labor epidural anesthetic exposure can be 8 hours or more. Beginning in the 1980s, labor epidural anesthesia became increasingly popular, rising to its current prevalence of use in the majority of vaginal childbirths. The JAMA Pediatrics study stated that, “widespread use of labor epidural anesthesia during the past few decades has significantly improved perinatal outcomes for mothers and their newborns; however, our findings raise the concern that the short duration of labor epidural anesthesia exposure may be associated with long-term neurodevelopmental disorders in offspring.”
The JAMA Pediatrics study was a retrospective longitudinal birth cohort study. The data were derived from Kaiser Southern California electronic medical records from a single medical system. A total of 147,895 singleton children were delivered vaginally in the eight years between January 1, 2008, and December 31, 2015. Seventy-four percent of these women received a labor epidural anesthetic. A screening checklist was administered to all of their children between the ages of 18 and 24 months of age to screen for developmental delays, including autistic spectrum disorder. A clinical diagnosis of autistic spectrum disorder was based on the evaluation of pediatric developmental specialists.
Autism spectrum disorders were diagnosed in 2039 children (1.9%) of the epidural anesthesia group and 485 children (1.3%) of the non-epidural anesthesia group. Children in the epidural group were 37 percent more likely to have autism than those in the unexposed group.
With a labor epidural anesthetic exposure of less than 4 hours, compared to the non-epidural group, the Hazard Ratio was 1.33 (95%CI, 1.17-1.53), a 33% greater incidence. With a labor epidural anesthetic exposure of 4 to 8 hours, the Hazard Ratio was 1.35 (95%CI, 1.20-1.53), a 35% greater incidence, and with a labor epidural anesthetic exposure of more than 8 hours the Hazard Ratio was 1.46 (95%CI, 1.27-1.69), a 46% greater incidence. Thus there was a trend of increased autism risk associated with increasing duration of labor epidural anesthetic exposure.
The authors wrote, “the risk was increased with increasing duration of exposure to labor epidural anesthesia. Potential mechanisms showing an association between labor epidural anesthesia and risk of autism spectrum disorder are largely unknown and require further studies. Although labor epidural anesthesia can effectively block labor pain and pain related hormonal release and changes, we speculate that its (i.e. labor epidural anesthesia) commencement may represent the beginning of a novel maternal and fetal physiology, a new homeostasis, and a dynamic biochemical equilibrium, which encompass the principles of physiology, endocrinology, immunology, pharmacology and toxicology, epigenetics, and psychology. Some mechanisms are transient, but others may be persistent and may affect major body systems. . . . Owing to their low molecular weight, all local anesthetics given epidurally can cross the placenta and be redistributed into the maternal and fetal circulation, and thereby may subject both the mother and fetus to the risk of toxic effects.”
The JAMA Pediatrics authors concluded, “exposure to labor epidural anesthesia was associated with a 37% increased risk of autism spectrum disorder in children after adjusting for potential confounders. Longer duration of epidural exposure was associated with greater autism spectrum disorder risk. . . . This study suggests that maternal labor epidural anesthesia may be associated with increased autism spectrum disease risk in children.”
The paper stated that, “In the United States, more than 70% of women receive some form of a neuraxial procedure (i.e. epidural or spinal anesthetic) during labor. Although the effectiveness of neuraxial anesthesia for labor pain management and the safety of neuraxial anesthesia for the fetus and newborns during the perinatal period have been well documented, the long-term effects of neuraxial anesthesia on the offspring are largely unknown. Limited toxicology and animal studies have shown that standard clinical doses of local anesthetics can produce neurotoxic effects and alter normal behavioral development in rhesus monkeys.”
In the conclusions to the JAMA Pediatrics study the authors wrote, “Our findings are intriguing and bring a concern for the safety and long-term health of offspring regarding the short term epidural use for labor pain. . . . 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.”
The JAMA Pediatrics study has certain strengths, including its large size, and a single integrated health care delivery system for both the collection of data and the standardized screening for autistic spectrum disorder. The study has the limitation of being a retrospective examination of prerecorded medical record data. The authors admit in their paper: “our findings should be interpreted with caution given the wide varieties of labor epidural anesthesia practice and cannot be interpreted as a demonstration of a causal link between labor epidural anesthesia exposure and subsequent development of autistic spectrum disorder.”
Recall that the American Society of Anesthesiologists, the Society for Obstetric Anesthesia and Perinatology, the Society for Pediatric Anesthesia, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine released their joint statement that said, “’Association Between Epidural Analgesia During Labor and Risk of Autism Spectrum Disorders in Offspring,’ a new retrospective database study published in JAMA Pediatrics on October 12th, 2020 does not provide credible scientific evidence that labor epidurals for pain relief cause autism.”
Please note: “Credible scientific evidence” of cause and effect could only come from a prospective, randomized, double-blinded, placebo-controlled trial of women treated with or without labor epidural anesthesia. That study will never be done, because it would require pregnant women to enroll in a trial in which half of the mothers would receive a local anesthetic epidural anesthetic and half of the mothers would receive placebo epidurals. Then their physicians would prospectively collect data on the two groups, followed by screening their singleton birth children for autistic spectrum disorders. Such a study could provide scientific evidence whether labor epidurals do or do not cause autism—but no one is going to be able to do that study in the United States. Going forward, the best evidence we’re likely to get are future multiple repeat retrospective studies, such as this current JAMA Pediatrics publication, to ascertain whether there is “a statistical association” between labor epidural anesthesia and the occurrence of autistic children. Repeat studies will be published. Stay tuned. In the meantime, labor pain will continue, and physician anesthesiologists will continue to place labor epidurals in the majority of laboring women to blunt the agony of childbirth pain.
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