Autism risk in neonatal intensive care unit patients associated with novel heart rate patterns

Abstract

Background: Neonatal intensive care unit (NICU) patients are at increased risk for autism spectrum disorder (ASD). Autonomic nervous system aberrancy has been described in children with ASD, and we aimed to identify heart rate (HR) patterns in NICU patients associated with eventual ASD diagnosis.

Methods: This retrospective cohort study included NICU patients from 2009 to 2016 with archived HR data and follow-up beyond age 3 years. Medical records provided clinical variables and ASD diagnosis. HR data were compared in infants with and without ASD.

Results: Of the 2371 patients, 88 had ASD, and 689,016 h of data were analyzed. HR skewness (HRskw) was significantly different between ASD and control infants. Preterm infants at early postmenstrual ages (PMAs) had negative HRskw reflecting decelerations, which increased with maturation. From 34 to 42 weeks PMA, positive HRskw toward accelerations was higher in males with ASD. In 931 males with at least 4 days of HR data, overall ASD prevalence was 5%, whereas 11% in the top 5th HRskw percentile had ASD.

Conclusion: High HRskw in NICU males, perhaps representing autonomic imbalance, was associated with increased ASD risk. Further study is needed to determine whether HR analysis identifies highest-risk infants who might benefit from earlier screening and therapies.

Impact: In a large retrospective single-center cohort of NICU patients, we found that high positive skewness of heart rate toward more accelerations was significantly associated with increased risk of eventual autism spectrum disorder diagnosis in male infants but not in females. Existing literature describes differences in heart rate characteristics in children, adolescents, and adults with autism spectrum disorders, but the finding from our study in NICU infants is novel. Heart rate analysis during the NICU stay might identify, among an inherently high-risk population, those infants with especially high risk of ASD who might benefit from earlier screening and therapies.

Figure 1:. Examples of 10-minute HR segments with low, near-zero, and high skewness.

Three panels show 10 minutes of raw HR data (top) and a histogram count of all 300 HR values in the segment (bottom), with arrows in Panels A and C indicating outlier values. In Panel A, the baseline HR is 150-170 beats per minute (bpm) with a large deceleration to about 70 bpm, resulting in a low skewness value of −4.06. In Panel B, the HR gradually increases and decreases from about 150-200 bpm, with superimposed small accelerations and decelerations, resulting in a near-zero skewness value of −0.01. In Panel C, the baseline HR is about 110-120 bpm with three sharp accelerations, resulting in a high skewness value of +2.63.

Figure 2:. HR skewness in NICU patients and risk of ASD.

For 2371 NICU patients, HR skewness was measured in 10-minute segments and averaged hourly. Panel A: Mean HR skewness increases with advancing postmenstrual age from 26-34 weeks PMA, then levels off. At all PMAs, the 88 infants later diagnosed with ASD (dashed purple line) have higher mean HR skewness than infants without ASD (solid black line). The vertical dashed lines at 34 and 42 weeks PMA indicate the time frame represented in the other two panels. Panel B: From 34-42 weeks PMA, the relative density of hourly HR skewness measurements is shown for control infants (solid black line, 658,868 total hours) and for infants later diagnosed with ASD (dashed purple line, 30,148 total hours). The vertical dashed line indicates a very high HR skewness value of 1 which is further analyzed in Figure 3. Panel C: With increasing mean hourly HR skewness the relative risk (left y axis) and rate (right y axis) of ASD increases. The horizontal line at relative risk of 1 corresponds to the 4.4% rate of ASD weighted to adjust for variable amounts of data per infant between PMA 34-42 weeks.

Figure 3:. Percent of HR segments with very high HR skewness (>1) in male and female ASD infants and controls at advancing PMA.

Across a range of PMA from 26-42 weeks, percent of HR skewness values >1 is shown for control infants (black line), males with ASD (solid blue circles) and females with ASD (open red triangles). Number of male infants with ASD represented at each week PMA from 34-42 ranged from 20-45, and number of females with ASD 6-15.