Complementary and Non-Coincident Increases in Heart Rate Variability and Irregularity during Fetal Development

Two distinct notions of variability have been defined to assess heart rate: deviation from a constant output (SD) and irregularity. One statistical measure of irregularity is approximate entropy, with greater irregularity corresponding to larger approximate entropy values. The specific aims of this investigation were to determine the manner in which SD and irregularity evolve during fetal development and whether this evolution is coincident or distinct. 2. Fetal heart rate was computed in 14 males and 17 females for 15 min of undisturbed recording using a fetal actocardiograph at 4 week intervals from 20 to 36 weeks gestation. 3. Mean heart rate decreased significantly with gestational ages (P < 0.05). SD increased significantly from 4.4 +/- 0.3 ms (SEM) at 20 weeks to 7.7 +/- 0.4 ms at 36 weeks (P < 0.05) and was similar between male and female fetuses (P = 0.57). Fixed approximate entropy increased significantly from 0.47 +/- 0.04 to 0.78 +/- 0.03, paralleling the change in SD (P < 0.01). Notably, normalized approximate entropy, which decorrelates SD from regularity, increased significantly with gestational age (P < 0.01) for males, while it remained relatively constant for females (P = 0.68). Approximate entropy was significantly lower at 20 weeks in males than females (P < 0.05); however, the values were similar by 28 weeks gestation. 4. Our results demonstrate that variability increases, and that irregularity increases, independently in male fetuses but not female fetuses, consistent with an increase in the coupling of emerging networks with gestational age. The present study demonstrates the complementary information obtained by analyses of both measures of variability and regularity. This reinforces a difference in gender-based development as noted in the separate context of fetal lung maturation.