Labor epidural analgesia (LEA) is potentially associated with increased risk for autism spectrum disorder (ASD) in offspring, according to a study findings published in JAMA Pediatrics.1 Just  24 hours after the study was published, multiple organizations for obstetricians, pediatricians, and anesthesiologists posted a joint statement that insists the study does not provide credible scientific evidence to support its conclusion.2

The original authors note that “our study has several limitations, and our findings should be interpreted with caution given the wide varieties of LEA practice and cannot be interpreted as a demonstration of a causal link between LEA exposure and subsequent development of ASD.”1

The 5 organizations who published the joint statement in opposition of the study findings, The Society for Obstetric Anesthesia and Perinatology (SOAP), the American Society of Anesthesiologists, the Society for Pediatric Anesthesia, the American College of Obstetricians and Gynecologists (ACOG), and the Society for Maternal-Fetal Medicine (SMFM), indicate that the “flawed” study should not be cause for concern among pregnant women considering pain management options for labor.2

Understanding the Original Study

Researchers analyzed 147,895 singleton births at Kaiser Permanente Southern California hospitals from January 1, 2008 to December 31, 2015. Mothers reported their complete labor and delivery record, income, gestational weight gain, pregnancy BMI, race and ethnicity, and smoking status; these covariates were evenly distributed between the LEA and non-LEA cohorts.  The mean gestational age at delivery was 38.9 weeks (SD, 1.5); 74,425 (50.3%) boys and 73,470 (49.7%) girls were born to 119,973 unique mothers, and 109,719 (74.2%) infants were exposed to maternal LEA.


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In the LEA group, 2039 children (1.9%) were diagnosed with ASD compared with 485 children (1.3%) in the non-exposed group. Among children in the cohort exposed to LEA, 1.6% of children who had exposure for less than 4 hours, 1.8% of children who had exposure for 4 to 8 hours, and 2.2% of children who had exposure for more than 8 hours were eventually diagnosed with ASD, respectively. After adjusting for covariates, the hazard ratio (HR) for less than 4 hours of LEA exposure was 1.33; for 4 to 8 hours, the HR was 1.35; and for LEA exposure of more than 8 hours, the HR was 1.46. Mothers in the LEA group were more likely to have a fever compared with non-LEA mothers (11.9% vs 1.3%). Researchers concluded that fever after LEA was not associated with ASD risk after adjusting for the same covariates considered in the primary analysis (adjusted HR, 1.03).

The study authors calculated that LEA exposure was associated with a 37% increase in ASD risk for offspring after adjusting for confounders and that duration of exposure plays a role in risk level (33% increase for less than 4 hours of exposure, 35% increase for 4 to 8 hours of exposure, and 46% increase for more than 8 hours of exposure).

Researchers stated that the large and diverse study population, well-documented exposures and outcomes, and the ability to control for multiple confounding factors were strengths of this study. However, the study authors noted that they may not have captured all necessary covariates and called for more research to confirm their findings.

“Potential uncontrolled confounders may explain the association that we observed,” the study authors concluded. “These confounders may include factors both antecedent and subsequent to the peripartum period, such as paternal history, genetic predisposition, viral or bacterial infection, and exposure to other environmental toxins.”

For a comprehensive review of the full study, click here.

Backlash: Correlation Does Not Imply Causation

In the immediate aftermath of the original study’s publication, medical organizations worked together to publish a joint statement aimed at reassuring pregnant women that there is no causal relationship between LEA and ASD.

“These five medical societies that represent more than 100,000 physicians want to assure the public that an association between a mother’s use of epidural analgesia during childbirth, and her infant’s risk of developing autism does not imply causation,” the statement says. “In the scientific literature, the finding of an association between a treatment and an outcome does not prove the treatment caused the outcome.”

Ruth Landau, MD, President of SOAP and Virginia Apgar Professor of Anesthesiology, described neuraxial analgesia as the “gold standard” for labor pain management in the joint statement and stated clinicians should not stop providing LEA. “If anything, epidurals improve maternal and neonatal outcomes,” she said.

The medical organizations noted that annually, millions of women who choose LEA for pain relief give birth without complications. The statement argues that mechanisms like maternal fever, which the original study authors hypothesize could be a factor in the association they found between LEA and ASD, is not a plausible reason and was not confirmed in the study authors’ analysis.

The organizations stated they will continue to support research and education about the safety of LEA for both mothers and children, but, currently, there is no evidence to suggest that “these very low levels of drug exposure can cause any harm to an infant’s brain.”

How Should Clinicians Respond?

ACOG’s Vice President of Practice Activities, Christopher M. Zahn, MD, released a statement advocating for providers not to alter their current practice in light of the study findings.3

“Current clinical practice guidance recognizes that there are many medical indications for analgesia and anesthesia during labor and delivery and that in the absence of a medical contraindication, maternal request is a sufficient medical indication for pain relief during labor,” Dr Zahn said. “Obstetricians, anesthesiologists, and other clinicians providing care to patients during labor and delivery should not change practice due to this study, which has severe limitations.”

If patients ask were to ask about the study findings during a visit, Lisa Shulman, MD, a member of the American Academy of Pediatrics Council on Children with Disabilities Autism Subcommittee, advises clinicians to have a discussion about prenatal care and managing childbirth with their patient. In a conversation with the Clinical Advisor, she emphasized that the original study found an association between LEA and ASD, but not a causal link.

“The bottom line message for families when they ask about this study is that the use of epidurals during childbirth has improved outcomes for mothers and babies,” Dr Shulman said. “This study adds to our knowledge of another potential risk factor for ASD, but should not be used as the reason a mother decides against pain relief during childbirth. Families should talk with their healthcare providers about how to manage childbirth, and about the importance of prenatal care in contributing to a healthy baby and healthy mother.”

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. Published online October 12, 2020. doi:10.1001/jamapediatrics.2020.3231
  2. Labor epidurals do not cause Autism; safe for mothers and infants, say anesthesiology, obstetrics, and pediatric medical societies. Washington, DC: The American College of Obstetricians and Gynecologists; October 13, 2020. Accessed October 15, 2020. https://www.acog.org/news/news-releases/2020/10/labor-epidurals-do-not-cause-autism-safe-for-mothers-and-infants
  3. ACOG statement on flawed study suggesting association between epidural analgesia during labor and risk of Autism Spectrum Disorders in offspring. Washington, DC: The American College of Obstetricians and Gynecologists; October 13, 2020. Accessed October 15, 2020 https://www.acog.org/news/news-releases/2020/10/acog-statement-on-study-suggesting-association-between-epidural-analgesia-during-labor-and-risk-of-autism-spectrum-disorders-in-offspring