Introduction
Various factors exert influence on the prognostic outcomes of preterm infants, among which the mode of delivery holds particular significance. Recent studies have demonstrated that cesarean sections performed for standard obstetrical indications are linked to improved morbidity and mortality among preterm infants. (Holzer et al., 2016; Karayel Eroglu et al., 2022). Hence, it is noteworthy that preterm infants, particularly very preterm infants (VPIs), are frequently delivered via cesarean section. There exists a well-established global consensus favoring the use of neuraxial anesthesia (NA) techniques (such as spinal anesthesia, epidural anesthesia, or combined spinal and epidural anesthesia) for cesarean sections. This preference is underpinned by compelling evidence demonstrating improved maternal outcomes (Mushambi et al., 2015; American Society of Anesthesiologists Committee on Standards and Practice Parameters., 2016), including reduced risks of short-term maternal morbidity or mortality, decreased incidence of wound infections, and alleviated postoperative pain (Chattopadhyay et al., 2014; Sayed et al., 2015).
General anesthesia (GA) stands out for its ability to provide the shortest onset time, making it a viable choice in cases of urgent medical or obstetric indications necessitating cesarean section (Palanisamy et al., 2011; Butwick et al., 2015). However, for preterm infants delivered via cesarean section, the criteria determining the selection of GA assume critical clinical significance. Anesthesiologists must carefully weigh these determinants while prioritizing the safety of both the maternal and neonates. Several studies have demonstrated that the GA group exhibits lower newborn Apgar scores and higher rates of neonatal intensive care unit (NICU) admissions compared with the NA group (Bao et al., 2022; Shi et al., 2024). While some research has explored maternal and neonatal outcomes associated with GA administration during cesarean sections (Nwafor et al., 2014; Butwick et al., 2015), there remains a notable lack of studies specifically addressing the impact of GA on the outcomes of VPIs delivered by cesarean section.
Due to the rising incidence of preterm births, SNI has emerged as a progressively concerning complication that significantly influences the prognoses of preterm infants. Correctly managing the processes of delivery and neonatal resuscitation assumes paramount importance as crucial steps in mitigating the adverse outcomes associated with SNI in preterm infants. Our research endeavors have encompassed a series of cohort studies, leveraging comprehensive databases to assess the myriad factors influencing the outcomes of VPIs. However, one critical facet of our investigations has hitherto remained unexplored: the impact of anesthesia modes on the outcomes of VPIs delivered via cesarean section. In the current study, we have undertaken an investigation to ascertain whether distinct anesthesia modalities (GA or NA) exhibit associations with neonatal adverse outcomes in VPIs.
Discussion
In this observational study, we observed an association between adverse neonatal outcomes and the use of GA in VPIs delivered by cesarean section. Specifically, GA was linked to a higher frequency of perinatal adverse outcomes, including low Apgar scores at one and 5 minutes, the need for tracheal intubation at birth, and SNI, compared to neonates delivered under NA. This association remained significant even after adjusting for potential confounding clinical factors. Additionally, a prolonged duration of GA exposure was correlated with low 5-min Apgar score in neonates.
Data from a 2015 multi-center United States survey revealed that 17.6% of women underwent cesarean sections between 24 + 0 and 36+6 weeks of gestation via GA (Butwick et al., 2015). The proportion of GA in our study was marginally lower, potentially attributable to variations in the gestational ages of the preterm infants examined and advancements in anesthesia techniques and perinatal management in recent years (Bollag et al., 2021).
Cesarean sections can be executed under NA, encompassing spinal anesthesia and epidural anesthesia, or under GA. The selection of anesthesia mode is typically influenced by clinical indications, the anesthesiologist’s experience, and maternal preferences. NA provides the advantage of maternal consciousness during cesarean delivery and minimizes anesthetic exposure to the neonate. Additionally, NA reduces the risks of maternal aspiration and difficult airway management, commonly associated with GA (Mushambi et al., 2015). NA remains the preferred and gold standard mode of anesthesia for cesarean sections. However, specific conditions necessitate considering GA as a secondary option. These include infection at the needle insertion site, significant coagulopathy, hypovolemic shock, increased intracranial pressure due to space-occupying lesions, and scenarios where provider expertise in NA is inadequate or other critical conditions that endanger maternal-fetal life and require immediate termination (Afolabi and Lesi, 2012). Our findings indicate that maternal thrombocytopenia or coagulation disorders, and the use of antiplatelet/anticoagulation medications, are primary factors influencing the choice of GA. Pre-eclampsia continues to be a leading cause of maternal and neonatal morbidities, particularly in developing countries. The definitive treatment for pre-eclampsia involves timely termination of pregnancy, which consequently leads to a higher incidence of cesarean sections among VPIs in pre-eclamptic women (Liu et al., 2008; Nankali et al., 2012). Thrombocytopenia and coagulation disturbances, key characteristics of HELLP syndrome, often contraindicate the use of NA (Adorno et al., 2022; del-Rio-Vellosillo and Garcia-Medina, 2015). This may elucidate our finding that mothers with HELLP syndrome exhibited a higher likelihood of undergoing GA in our study. Additionally, we observed a significantly higher proportion of VPIs from emergency cesarean sections in the GA group. In scenarios such as placental abruption, placenta previa with massive bleeding, umbilical cord prolapse, or imminent fetal heart rate loss, both obstetricians and patients often favor GA due to its rapid induction and reduced cardiovascular instability (Guglielminotti et al., 2019; Ikeda et al., 2020). Previous research identified obesity as a risk factor for the selection of GA during cesarean sections (Butwick et al., 2015). Our current study corroborates this finding, noting a significantly higher maternal BMI in the GA group compared to the NA group, aligning with their results.
The choice of anesthesia during cesarean section can significantly impact neonatal outcomes (Saygı et al., 2015). Research exploring the relationship between anesthesia mode during cesarean delivery and outcomes in preterm infants has yielded varying results. One study indicated that mortality rates in preterm infants (<33 weeks’ gestational age) born to women receiving SA were higher compared to those born under GA. Conversely, another cohort study focusing on preterm infants ≤32 weeks’ gestational age found that neonates born to women receiving EA had higher Apgar scores than those from mothers who received GA (Rolbin et al., 1994; Laudenbach et al., 2009). The Apgar scoring system, a traditional and practical method for immediate neonatal assessment post-delivery, is crucial for identifying infants in need of resuscitation and predicting perinatal survival (Casey et al., 2001). In our study, the incidence of low 1-min and 5-min Apgar scores among VPIs was significantly higher, and a greater number of VPIs in the GA group required resuscitation with tracheal intubation in the delivery room. These findings indirectly reaffirm the importance of this traditional evaluation method.
Research indicated that the impact of drugs related to GA on the developing brain was mediated through both morphological alterations and molecular mechanisms (Vutskits and Xie, 2016). Groundbreaking studies, particularly within the scope of fetal alcohol syndrome, had elucidated that exposure to substances functioning as pharmacological antagonists of the NMDA-type glutamate receptor (NMDAR) or as positive allosteric modulators of the type A GABA receptor (GABAAR)-mediated neurotransmission, precipitated rapid cellular demise during specific developmental periods in the immature rodent brain, contingent on the brain region (Ikonomidou, C. et al., 1999; Ikonomidou, C. et al., 2000). Preliminary investigations had uncovered GA prompt region-specific temporal alterations in the expression of brain-derived neurotrophic factor (BDNF), with the subsequent modifications in the activity of downstream signaling pathways posited to trigger the initiation of apoptotic sequences (Yon, J. H., et al., 2005; Popic, J. et al., 2012). In recent years, the potential neurotoxic effects of GA on the developing brain have garnered increased attention. Animal studies suggest that exposure to GA agents in utero can induce apoptosis and developmental neural degeneration in the fetal brain (Palanisamy, 2012). Notably, the most critical period for anesthetic-induced neurodegeneration is approximated to be around the 26th week of gestation in humans (Clancy et al., 2007). Given the heightened susceptibility of VPIs to maternally administered drugs, due to immature enzyme systems, an incomplete blood-brain barrier, and limited serum protein availability for drug binding, it is crucial to assess both early neonatal outcomes and the long-term effects of anesthetic exposure. Various anesthetic agents can have a broad spectrum of impacts on newborns. Consequently, our study also examined the well-defined adverse outcomes associated with long-term survival and quality of life in VPIs, including SNI, BPD, NEC, and ROP. IVH is a prevalent type of brain injury in preterm infants, often leading to complications such as PVL (Ballabh, 2010; Su et al., 2016). Studies indicate an increased incidence of severe IVH with decreasing gestational age and birth weight (Zhao et al., 2022). Additionally, low Apgar scores are well-established risk factors for IVH (Coskun et al., 2017; Zea-Vera et al., 2019). This could explain the higher prevalence of SNI observed in VPIs from the GA group compared to those from the NA group in our study.
Few studies have explored the association between the interval from anesthesia induction to birth and perinatal outcomes during GA, yielding mixed results. Kate Swanson’s research indicated that a longer interval time (exceeding 4 min) from the initiation of general endotracheal anesthesia to cesarean delivery correlates with a higher frequency of perinatal complications. In bivariable analysis, a 5-min Apgar score of less than 7 was more prevalent in groups with an interval time exceeding 4 min. However, this association did not remain significant in multivariable analysis (Swanson et al., 2021). Hu L and colleagues reported that extending the interval from anesthesia induction to delivery, within certain limits, does not significantly effect fetal outcomes in full-term cesarean deliveries (Hu et al., 2017). However, these studies focused solely on full-term deliveries. In contrast, our current study observed that a longer interval from skin incision to delivery during GA was associated with lower 5-min Apgar scores in preterm deliveries. This finding suggests that, in addition to large molecule drugs like non-depolarizing muscle relaxants, other GA-related drugs may also cross the placental barrier and effect the fetus. Common obstetric general anesthesia agents, such as propofol and ketamine, are associated with increased risks of tachycardia, hypertension, and respiratory adverse events in infants, including cough and laryngospasm (Hayes et al., 2020). Recent studies suggest the feasibility of using opioids at the time of maternal anesthesia induction (Caissie et al., 2022). However, concerns about neonatal respiratory depression risk often leads anesthesiologists to avoid these drugs during induction. Prolonged skin incision-to-delivery intervals under GA may result in increased fetal exposure to anesthetic drugs, potentially elevating the risk of fetal respiratory depression. Minimizing exposure duration to GA could therefore offer clinical benefits for VPIs.
This study has several limitations. First, we were unable to evaluate certain factors, notably the interval from the decision to perform a cesarean section to the delivery of the neonate, a critical determinant of neonatal outcomes. This is partly because prolonged delivery times in emergency situations often involve logistical challenges, such as transporting the patient to the operating room (Wong et al., 2017; Temesgen et al., 2020). Second, despite our efforts to adjust for relevant confounders, residual confounding biases may still exist. This limitation stems from the retrospective nature of our study, wherein data were occasionally recorded inconsistently or inaccurately in medical records.
In conclusion, our study suggests that for VPIs delivered via cesarean section, GA is associated with lower Apgar scores, increased need for tracheal intubation resuscitation, and adverse neurological outcomes. Prolonged exposure to GA may contribute to neonatal postnatal depression. While these findings do not negate the utility of GA in cesarean sections for VPIs, they underscore the importance of specific precautions. These include minimizing the duration of fetal delivery and ensuring adequate preparation for neonatal resuscitation when GA is selected for cesarean sections in VPIs.