Title:
General anesthesia at time of preterm cesarean delivery and childhood neurodevelopmental and perinatal outcomes

Authors/Institutions:
Lindsay Speros Robbins, MD, MPH^1,2, Christina T Blanchard, MS¹, Fred J Biasini, PhD³, Mark J Powell, MD⁴, Brian M Casey, MD^1,2, Alan T Tita, MD, PhD^1,2, Lorie M Harper, MD, MSCI^1,2

¹Center for Women’s Reproductive Health, University of Alabama at Birmingham, ²Department of Obstetrics and Gynecology, University of Alabama at Birmingham, ³Department of Psychology, University of Alabama at Birmingham, ⁴Department of Anesthesiology, University of Alabama at Birmingham

Objective:
In 2016, the FDA expressed concern that general anesthesia or sedation exposure in pregnancy or before 3 years of age may impact pediatric neurodevelopment and called for further research examining the impact of anesthesia, including single, short exposures. We examine the impact of general anesthesia (GA) during cesarean delivery (CD) on neurodevelopment at two years of age among infants born preterm.

Study Design: 
Secondary analysis of a multicenter RCT assessing magnesium for prevention of cerebral palsy in preterm infants. Women were included if they delivered a singleton, non-anomalous infant <37wks by CD. The exposure of interest was general anesthesia. The primary outcome was mild to moderate developmental delay at 24 mos by Bayley Scales of Infant Development II (BSID). Secondary outcomes were BSID subdomains, periventricular leukomalacia, seizures, abnormal tone, hypotension, ventilator need, duration of oxygen use, and use of visual aids. Chi square, Fisher Exact, student’s t-test, Wilcoxon Rank Sum tests, and multivariable logistic regression models were performed.

Results:
Of 557 women, 119 (21%) received GA. Women receiving GA were more likely to be unmarried, non-white, delivering more preterm (28.6 vs 29.7 wks, p<0.01), undergoing CD for fetal distress (49% vs 36%, p=0.01), and in preterm labor >4cm (11% vs 3%, p<0.01). Betamethasone and magnesium exposure were similar between groups, as was substance use. Mild to moderate developmental delay was not increased in those exposed to GA (Table). When BSID subdomains were analyzed individually, nominal increases in mild and moderate mental delay among infants exposed to GA did not persist after controlling for significant variables, including gestational age at delivery. Secondary outcomes did not differ significantly between groups.

Conclusion:
General anesthesia at time of CD does not appear to increase the risk of neurodevelopmental delay at two years in infants born preterm. Future studies should evaluate the impact of longer or multiple anesthetic exposures on neurodevelopment among all infants.

Table 1. Demographic, pregnancy, and delivery characteristics

*Includes failed induction, abnormal presentation, prior cesarean, abruption/previa, preeclampsia/hypertension, and other
¹Missing 52: General anesthesia (n=99), Regional anesthesia (n=406)
²Missing 1: General anesthesia (n=119), Regional anesthesia (n=437)

Table 2: Childhood neurodevelopmental and perinatal outcomes

*Backward selection model used with entry at p<0.25, ^†Age corrected for prematurity. Adjusted for ¹GA at delivery, reason for CD, education,
GA at randomization, ²GA at delivery, reason for CD,  married, ³GA at delivery, reason for CD, married, GA at randomization, ⁴GA at delivery,
reason for CD, ⁵GA at delivery, reason for CD, race, education, GA at randomization, ⁶missing 15: General anesthesia (n=116), Regional
anesthesia (n=426), ⁷GA at delivery, reason for CD, GA at randomization, ⁸GA at delivery, reason for CD, education

References:

• FDA Drug Safety Communication: FDA review results in new warnings about using general anesthetics and sedation drugs in young children and pregnant women. https://www.fda.gov/drugs/drugsafety/ucm532356.htm. December 14, 2016. Accessed February 2019.
• FDA Drug Safety Communication: FDA approves label changes for use of general anesthetic and sedation drugs in young children. https://www.fda.gov/Drugs/DrugSafety/ucm554634.htm. April 24, 2017. Accessed February 2019.
• De Tina A, A Palanisamy. General Anesthesia During the Third Trimester: Any Link to Neurocognitive Outcomes? Anesthesiology Clin 2013;35:69-80.
• Sprung J, et al. Anesthesia for Cesarean Delivery and Learning Disabilities in a Population-based Birth Cohort. Anesthesiology 2009;2(11):302-310.