Contemporary Understanding of the Central Autonomic Nervous System in Fetal-Neonatal Transition

Autonomic Nervous System in the fetus, during Labor and Transition

The central autonomic nervous system (cANS) has critical multi-level roles in supporting the successful transition of the fetus to the extrauterine world through its coordinated effects on the circulatory, cardiovascular, respiratory, and neurological systems. In 2018, Dr. Adre du Plessis and I authored a review article titled, “The critical role of the central autonomic nervous system in fetal-neonatal transition” for Seminars in Pediatric Neurology.[1] This review article described the complex role of the cANS in both normal and complicated fetal-neonatal transition in preterm and term children, and how a malfunctioning cANS can lead to brain injury and long-term health conditions including neuropsychiatric and cardiovascular disease.[1,2]

The study of heart rate variability (HRV) as a way to evaluate the developing cANS, including both the sympathetic and parasympathetic divisions, has continued to advance in recent years. New studies have provided additional understanding of the developing cANS in the fetus as well as the preterm and term neonate. Others have explored the use of new technologies to better understand the maternal and fetal-neonatal cANS.

The development of a child’s cANS begins long before birth. The proper function and maturation of the cANS is critical to supporting successful fetal-neonatal transition.[1] Evaluation of fetal heart rate response by changes in HRV during labor may indicate the health and maturational state of the fetal cANS. Cardiotocography (CTG) is a widely used clinical method to evaluate the fetal heart rate and uterine contractions during labor. While this tool does not allow for the level of continuous heart rate data required for advanced quantitative HRV analysis, it enables a clinical understanding of fetal HRV which can indicate fetal well-being and tolerance of labor. Absent or minimal HRV on the cardiotocogram may signal failing function of the fetal cANS and lead to changes in labor management and delivery. For example, maternal infections, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), can exert effects on the maternal cANS, but also in the fetus. In a case-control study of pregnant patients during labor who were either seropositive or seronegative for SARS-CoV-2, Farhan and colleagues found that cardiotocography was abnormal in 60% of cases with coronavirus disease 2019 (COVID-19; SARS-CoV-2 positive) with increased rates of fetal tachycardia and reduced fetal HRV, compared to cases without infection.[3]

HRV response may vary during labor due to the different maturational state of the cANS in fetuses being delivered at preterm versus term.[1] A recent study of fetal cANS during active labor with uterine contractions found that term fetuses had greater parasympathetic mediated changes in heart rate response, while preterm fetuses had greater sympathetic mediated changes in heart rate response.[4]

Music can be calming to the cANS of patients of all ages, including the fetus. In a study by Massimello and colleagues of pregnant patients at 32 to 38 gestational weeks, a music stimulus played by headphones on the maternal abdomen was associated with an increase in fetal HRV, mediated by parasympathetic activation, without a change in the baseline fetal heart rate.[5] This study displayed the ability to activate the parasympathetic nervous system in the fetus through music stimulation. This finding at least raises the possibility of music as a potential therapy for certain maternal-fetal conditions associated with impaired cANS development.

New technologies to Monitor HRV in Pregnancy

Smartwatch technology enables continuous monitoring of the wearers heart rate and respiratory rate, and can detect sleep and activity levels. This may allow for long-term home monitoring of women during pregnancy, potentially providing information about stress and HRV changes. In a longitudinal cohort study in Finland that included a four-week time interval before and during national stay-at-home orders for COVID-19, smartwatch data was used to analyze whether pandemic restrictions impacted maternal daily patterns and well-being through evaluation of HRV metrics.[6] Overall, the study found that pregnant patients coped well with the changes in their lifestyle induced by the COVID-19 restrictions. However, there was a change in HRV, subjective stress levels, sleep, and physical activity.[6] With improving technology, research utilization of smartwatch acquired HRV may enable a better understanding of HRV throughout pregnancy and this may correlate with fetal cANS development. Importantly, ambulatory monitoring of fetal HRV can enable an evaluation of fetal well-being and understanding of the development and maturation of the cANS throughout gestation.

An additional area of expanding research is in the use of noninvasive fetal electrocardiography to improve the ability to monitor pregnancies out of the hospital. In a recent systematic review of 11 studies utilizing noninvasive fetal electrocardiography, successful HRV signal acquisition ranged from 48.6% to 95.0%, with good quality signal achieved in the second trimester, but with reduced quality in the early third trimester due to the fetal vernix.[7] In all studies, the electrocardiogram required proper placement by a healthcare provider and could not be placed by the patient, however the device was well received by the pregnant patients.[7]

In the future, wearable home-monitoring devices to capture fetal HRV may allow for continuous assessment of the fetus and the developing cANS. Combining techniques to monitor maternal HRV and fetal HRV may yield exciting data on how the two influence each other throughout gestation and prepare the fetus for the complicated task of fetal-neonatal transition.

cANS Development in Preterm and Term-born Infants

The development of the cANS may differ between preterm neonates compared to the corrected age-matched fetus.[2] The extrauterine environment of the neonatal intensive care unit (NICU) is drastically different from the relatively calm intrauterine milieu. In a prospective longitudinal cohort study of cANS maturation in 100 infants born preterm, Mulkey et. al. found that the rate of cANS maturation from birth to NICU discharge was similar for infants born at ≤29 weeks, 30–33 weeks, or at ≥34 weeks gestation.[8] The infants born most preterm had the lowest sympathetic and parasympathetic tone at birth, but all groups displayed a positive maturational trajectory for both divisions of the cANS throughout the NICU hospitalization.[8] This study showed that the cANS can mature similarly across a range of birth gestational ages even in the NICU environment. The cohort of preterm-born infants included in this study, however, had relatively low prematurity-related systemic morbidity, which may be why cANS development in them was not significantly impacted by greater exposure to prematurity.[8]

It also appears that prematurity-related medical morbidities may have a greater effect on cANS development than early gestational age. Schlatterer et. al. compared cANS development by HRV analysis among children born preterm in a community NICU with low prematurity-related morbidity to those cared for at a high-morbidity regional referral NICU[9] and found that prematurity-related medical morbidities had a greater impact on cANS development compared to early gestational age.[9]

Finally, while not a prematurity-related morbidity, complex congenital heart disease is associated with decreased autonomic tone at birth which may be important for postnatal intensive care management.[10] Infants with complex congenital heart disease may have difficulty with fetal-neonatal transition not only because of their underlying cardiac malformation, but owing to reduced cANS tone.[10]

Conclusion

Advancing technologies including smart wearable devices may offer the ability for continuous cANS monitoring throughout the lifetime, beginning in the womb. Future work is needed to utilize HRV data and explore therapies with the potential to prevent cANS dysfunction and ideally allow for therapies to better support cANS health and thus health of the individual in both the prenatal and postnatal periods.[1,2] Environmental exposures and maternal physical and mental health conditions can affect fetal cANS development that can manifest as changes in offspring neurobehavior, neurodevelopment, and neuropsychological function.[11,12] Since our 2018 publication,[1] there have been important advances in our understanding of the cANS in the fetus and newborn. However, there is far more to learn. The field will benefit from the ongoing research and development of real-time HRV monitoring and therapeutics to support cANS development in high-risk pregnancies.