Fetal Autonomic Nervous sysTem Evaluation

The Autonomic Nervous System (ANS) is the main regulator of the body's homeostasis. It consists of two branches that work in balance: the sympathetic nervous system (SNS) and the parasympathetic nervous system (PNS). The SNS is responsible for the fight-or-flight response, while the PNS is responsible for the recovery response. The coordination of their actions is vital for the body's proper functioning. The two branches of the ANS develop asynchronously during fetal development, particularly from the vagus nerve (X pair of cranial nerves) within the PNS. However, its activity is severely limited by late myelination, and the tone of the SNP undergoes a first increase at around 25-32 weeks and a second increase at 37 weeks. In contrast, SNS maturation continues steadily throughout pregnancy. It has been recognized that imbalances in the development of the SNS may underlie intrauterine death, problems adapting to extrauterine life pediatric morbidity and increased risk of sudden infant death syndrome (SIDS). Altered ANS functioning has been linked to developmental pathologies in childhood, including autism spectrum disorders and other neuropsychiatric conditions, as well as adult cardiovascular and metabolic diseases. The causes of altered autonomic development are diverse, including factors related to pregnancy and pre-existing maternal pathologies. The primary causes are premature birth, abnormalities in placenta formation and development, intrauterine growth restriction (IUGR), maternal diabetes, hypothyroidism, substance abuse, and maternal mental illness.

Given this, evaluating the extent of ASN development may have significant implications not only in the obstetric and neonatal setting, but also in the long term. Sympathetic and parasympathetic tone indicators can be studied by examining Heart Rate Variability (HRV) on an electrocardiogram (ECG). Certain parameters can be detected in HRV that indicate different facets of autonomic tone, mainly the activity of the SNS (LF band), the PNS (HF band) and the sympathetic-vagal balance (LF/HF). Obtaining these parameters, however, requires the analysis of an electrocardiographic trace, which is not easy to acquire in intrauterine life.

The collaboration between the University of Pisa and the Institute of Clinical Physiology of the National Research Council of Italy (IFC-CNR) has led to the development of the FANTE method. FANTE (Fetal Autonomic Nervous Evaluation) enables the analysis of electrocardiographic traces acquired by placing electrodes on the maternal abdomen. The traces are interpreted using an algorithm developed by researchers at IFC-CNR, enabling extraction of HRV data with the same level of accuracy as fetal magnetocardiography. In sum, this method that allows accurate extraction of fetal ECGs from multichannel maternal abdominal signals. It represents a non-invasive and affordable option, which are fundamental characteristics for screening tools.

The assessment of FANTE has the potential to serve as a basis for risk stratification in populations affected by maternal or fetal disease. This tool may prove valuable for early diagnosis, allowing planning for more rigorous prenatal monitoring and comprehensive postnatal diagnosis.

Women with a singleton pregnancy attending or admitted to the Department of Obstetrics and Gynecology will be recruited between the 24th and 37th week of pregnancy. After signing the informed consent, they will be enrolled into the study.

At recruitment visit:

• Maternal anthropometric evaluation will be performed (age, body mass index (BMI), blood pressure smoking/alcohol/drug habits, medical therapies, or pathologies).
• Fetal well-being evaluation will be carried out by reviewing the reports of laboratory and ultrasound screening tests.
• The FANTE recordings will be performed using a 10-lead ECG placed on the maternal abdomen. at FANTE periodic visit:
• FANTE registrations will be performed weekly.
• Standard maternal anthropometric assessments will be conducted as part of the periodic evaluations.

At delivery:

• Mode of delivery and any complications will be assessed.
• Within 48 hours of birth, anthropometric assessment of the infant according to clinical practice (weight, abdominal and head circumference).