Introduction

Caesarean section (CS) is a well-known and potentially life-saving surgical procedure. The global rate of deliveries by CS has increased from 12.1% in 2000 to 21.1% of deliveries in 2015 (1). It is estimated that 9-19% of CSs can be justified by medical indications (2, 3), and the World Health Organization currently recommends CS for up to 15% of deliveries(4). Yet, national frequencies varies greatly and range from 0.6% in South Sudan (1) to 55-65% in Brazil (5).
Recently, increasing evidence has shown that birth delivery mode has an impact on child health (6). CS is associated to early complications such as birth asphyxia, respiratory disturbances (7), soft tissue injury (8), and to neurological and psychological complications such as autism spectrum disorders (9), ADHD (10), psychosis (11), anxiety, depression, and sleep disturbances (12). Notable CS-associated late-term complications for the child includes implications of the immune system: systemic connective tissue disorders, juvenile arthritis (13), inflammatory bowel disease, immune deficiencies, asthma (14, 15), sepsis (16), type 1 diabetes (14), celiac disease (17), and autoimmune diseases (12).
Compared to infants delivered vaginally, a delivery by CS is thought to alter the short-term immune response in new-borns by variation of bacterial colonization of the intestinal tract, due to lack of exposure to the vaginal and anal microbiota during delivery (18, 19). Further, the level of foetal stress during CS is lower compared to vaginal delivery (VD), as both the initiation of birth and the contractions during VD may trigger many biological effects (20). Pre-labour CS, i.e. CS before the onset of labour, are more often associated with several of the above mentioned complications compared with in-labour CS (7, 11, 13, 14, 17), suggesting that important endocrine, physiological and biochemical processes in the infant are initiated by labour. Most biomarker studies reported regarding CS versus VD have excluded cases with in-labour CS, thus the studies cannot explain if the differences found are due to the surgery or the lack of labour.
Infant males are known to be more fragile due to yet unknown biological mechanisms (21); they are more often prematurely spontaneously aborted (22), born premature or late, stillborn, have a higher infant mortality, and are also more often delivered by CS (23).
Accordingly, we aimed to explore the delivery mode’s effects on the immune system and brain per se of the infants, by measuring inflammatory, stress, growth, and neurotrophic biomarkers in more than 7000 neonatal dried blood spot samples (DBSS). Further, we wanted to elucidate potential gender- and gestational age-dependent differences of the biomarker levels.