Meconium aspiration syndrome (MAS) is a syndrome in which the fetus inhales meconium-contaminated amniotic fluid during delivery or in utero (1), resulting in chemical inflammation, airway obstruction, and a series of systemic symptoms, with high morbidity and mortality rates (2). Severe MAS can be complicated by acute respiratory distress syndrome (ARDS), air leak syndrome, respiratory failure, persistent pulmonary hypertension (PPHN), and multiorgan functional impairment. PPHN has an important impact on severity and prognosis (3, 4).

During pregnancy, 4%–22% of women have meconium-stained amniotic fluid (MSAF) (5) and approximately 3%–12% of neonates with MSAF develop MAS (6). MSAF is rare before 34 weeks of gestation and occurs in only 2% of neonates with a gestational age <37 weeks. However, it affects 44% of neonates with a gestational age of over 42 weeks (7). The incidence of MSAF can be as high as 23%–52% when gestation is over 42 weeks (8). The mortality rate of neonates with MAS is up to 13.3% (9). The presence of meconium is related to gestational age, and the incidence of MAS increases with gestational age (10, 11), from 0.24 to 1.42 per 1,000 births between 38 and 42 weeks (12). The risk of MAS is approximately four times higher in neonates born at 42 weeks of gestation than in those born at 37 weeks. Moreover, the risk increases by 27 times when the gestational age reaches 43 weeks (5). This increase in the incidence of MAS with gestational age may be associated with the stimulation of gastrointestinal motility by vagal excitation when the fetus undergoes hypoxic stress or umbilical cord compression. Full- and post-term fetuses are more likely to expel meconium in these situations than preterm infants, and the maturity of the gastrointestinal tract in preterm infants may limit their meconium expulsion (13). Gastric motility and secretion increase with gestational age, facilitating the expulsion of meconium (14). Some studies suggest that the severity of MAS is related to the following factors, including low 5-minute Apgar score, fetal distress, fetal heart rate abnormalities, cesarean delivery and need of surfactant therapy (5, 15, 16), (33–36).

However, few studies have explored whether the clinical characteristics of patients with MAS change with gestational age. Also, few studies have discussed the risk factors for neurological injury and death in neonates with MAS. Therefore, our study retrospectively analyzed the clinical data of patients with MAS at our hospital over the past nine years. We compared the differences in the clinical characteristics of patients with MAS at different gestational ages and discussed the risk factors for neurological injury and death due to MAS.

Meconium begins to gradually form in the fetal gastrointestinal tract at 14–16 weeks of gestational age and is usually excreted within 24 h of birth (20). However, when the fetus experiences stressful conditions, such as acidosis and hypoxia, it causes a vagal response that triggers increased peristalsis of the gastrointestinal tract and relaxation of the anal sphincter, leading to the entry of the meconium into the uterine cavity and causing MSAF (8). Neonates born to mothers with MSAF are more likely to develop complications such as neonatal sepsis, seizures, and neurological damage (21). Inhalation of MSAF in utero or after birth in neonates results in the development of MAS, which occurs through pathophysiological mechanisms, including inflammation and inflammatory cascade reactions, mechanical obstruction of the airway, and PS inactivation (2). MAS is a common critical neonatal illness with complex etiologies, including fetal distress, unstable fetal heart rate, emergency cesarean delivery, low Apgar score, and intrauterine fetal growth retardation (22).

MAS accounts for 10% of neonatal respiratory failures, and the mortality rate could be as high as 20% in developing countries (23). The incidence of MAS in China is approximately 1.2–2.2%, and the mortality rate is approximately 7.0–15.0% (24). The incidence of neonatal MAS in Nepal is approximately 6.6–8.6%, with a mortality rate of 11.3% (14). According to data from a large cohort in Australia and New Zealand, the mortality rate of MAS in developed countries was 2.5% (25). In our study, the mortality rate of MAS in 2021 was decreased to 3.7%.The incidence of MAS has decreased in recent years, which may be attributed to elective induction of labor in pregnancies beyond 41 weeks, aggressive management of fetal distress, and birth asphyxia (26); however, the severity of MAS has not decreased (27).

Our study showed that differences in perinatal characteristics among the four groups were mainly found between the preterm group and the other groups. Although MAS was rare in neonates with gestational age less than 34 weeks, we still found patients less than 34 weeks with the evidence of MAS in our study. MAS mostly occurred in term infants, so the number of patients in premature group was the least. The incidence rates of intrauterine distress (56.7%, 17/30) and cesarean delivery (90.00%, 27/30) were higher in the preterm group than in the other three groups, which may be related to the adverse history of delivery and multiple maternal comorbidities in preterm mothers. The mothers of infants in the preterm group had a significantly higher incidence rate of previous cesarean deliveries, diabetes, and intrahepatic cholestasis during pregnancy than those of infants in the other three groups.

The current treatment for MAS is supportive and includes oxygen therapy, mechanical ventilation, and intravenous rehydration. In recent years, the use of PS, iNO, high-frequency mechanical ventilation, and ECMO has made saving more patients with MAS possible (28). In this study, 28 (9.52%) patients received combined PPHN, and 23 were treated with iNO (82.14%, 23/28). iNO affects vascular smooth muscle, causing pulmonary vasodilation in the region of pulmonary ventilation, and reduces ventilation-perfusion mismatch to improve oxygenation (29). iNO therapy reduces ECMO requirements and mortality in patients with hypoxic respiratory failure and PPHN (28). Patients with severe MAS and respiratory failure can be treated with ECMO. Studies have shown that up to 35% of infants require ECMO due to MAS and that the survival rate of patients with MAS can exceed 94% after treatment with ECMO (30). ECMO in neonates was only recently introduced in our center; therefore, only one child with MAS was successfully treated with ECMO in this study. The use of ECMO is limited in developing countries; therefore, our data may provide a reference for regions where ECMO is not yet available. Antibiotics were used in 89.8% (264/294) of the patients in our study, which was similar to the study from the USA (92%, 6906/7518) (23). In clinical practice, it is difficult to completely eliminate intrauterine infection at the beginning of MAS, and secondary infection may occur later, so the proportion of antibiotics use was usually high.

A study found that antibiotic use in patients with MAS did not significantly reduce the risk of mortality, length of hospital stay, or incidence of sepsis (31). Kelly et al. found that antibiotics did not reduce the risk of sepsis in patients with MAS (32). Therefore, more clinical evidence is needed to determine the effectiveness of antibiotics in MAS treatment.

Symptoms in patients with MAS range from mild shortness of breath to severe respiratory distress and various serious complications, such as pulmonary hypertension, sepsis, pulmonary hemorrhage, and neurological damage. In this study, respiratory failure, neurological injury, and metabolic acidosis were the top three complications. The differences in the incidence of neurological injury among patients with different gestational ages were statistically significant. Early-term infants had the highest incidence rate of neurological injury, and the difference was statistically significant compared with that in late-term infants. Preterm and early-term infants were more likely to have neurological injuries such as intracranial hemorrhage. Pneumothorax is an important indicator of MAS severity. In a cohort study including 1,061 patients with MAS, pneumothorax was present in 42% of the patients who died (25). The incidence of pneumothorax in our study was 18.37% (54/294), and 19.37% (4/23) of the patients who died of MAS had a pneumothorax. The difference in the incidence of pneumothorax between patients of different gestational ages was statistically significant, and the incidence of pneumothorax was highest in the late-term group.

This study also investigated independent risk factors for neurological injury and death in patients with MAS. We found that the risk factors for neurological injury included low 1-min Apgar scores, low gestational age, metabolic acidosis, and respiratory failure. MAS is a complex disease associated with neurological injury (33), and HIE reportedly increases mortality rate in patients with MAS (14, 34). Neonates with a lower gestational age have less tolerance for hypoxia and are more likely to develop neurological injuries. Hypoxemia is often observed in patients with MAS. The low 1-minute Apgar score observed in them suggests severe perinatal hypoxemia with secondary respiratory depression and metabolic acidosis, leading to pulmonary vasoconstriction and reduced pulmonary blood flow, which aggravate hypoxemia and metabolic acidosis, creating a spiral effect of pulmonary hypertension in MAS (7). Optimizing the timing of delivery could improve neurological outcomes. Blood gas analysis in this study showed the first results within 2 h after birth.

This study found that respiratory failure, metabolic acidosis, and sepsis were risk factors for mortality in patients with MAS. Respiratory failure is an independent risk factor for death and neurological injury. Correction of respiratory failure should be considered during treatment. Optimizing respiratory support methods, early use of PS and iNO, timely drainage of tension pneumothorax, and use of ECMO for those who meet these guidelines are essential. In this study, 15.6% (46/294) of patients with sepsis were diagnosed, and the mortality rate was 21.7% (10/46). Two children who died of sepsis had positive blood cultures for Listeria. Although Listeria infection is relatively rare in neonates, it can cause serious complications, such as central nervous system infection, acute respiratory distress syndrome, and death. Therefore, attention should be paid to bacterial infections in the perinatal period (35, 36).

Although many studies have shown that the incidence of MAS increases with gestational age, few have discussed the differences in the clinical characteristics of patients with MAS at different gestational ages. This study retrospectively analyzed the clinical data of 294 children with MAS over nine years to compare the similarities and differences in clinical characteristics among different gestational ages and identify the risk factors for neurological injury and death in patients with MAS; this study could serve as a reference for future diagnosis and treatment of patients with MAS at different gestational ages.

This study has some limitations. First, only single-center data from our hospital were included, and the number of patients in some groups was low; therefore, multicenter studies with larger sample sizes are required in the future. Second, this study only analyzed the clinical characteristics of the patients during hospitalization; the patients could have been followed up after discharge to monitor their prognosis. Moreover, because of the potential for poor outcome, the best approach for managing MAS is prevention. In this study, we only focus on the clinical characteristics of neonates with MAS, while in the future study, we will pay more attention to the risk factors of MAS and the treatment methods such as labor induction in reducing the risk of MAS.

In conclusion, the incidence of MAS has decreased in recent years, but the mortality rates fluctuate. There was no significant difference in treatment among neonates with MAS at different gestational ages. The incidence rate of pneumothorax was highest in late-term infants and that of neurological injury was highest in early-term infants. Low 1-min Apgar score, low gestational age, metabolic acidosis, and respiratory failure were independent risk factors for neurological injury in patients with MAS. Respiratory failure, metabolic acidosis, and sepsis were independent risk factors for death in children with MAS. Neonates with MAS should be closely monitored, adequately examined, and given timely supportive treatment. Moreover, patients with risk factors should be managed promptly to reduce the incidence of neurological injuries and mortality.