In our study, the total mortality of preterm neonates with gastrointestinal perforation was 25.1%, which was similar to previous studies[1, 11, 15, 22–24]. With the development of intensive care measures, operative techniques, and anesthesiology procedures during the neonatal period, the survival rate of premature infants has been increasing, however, gastrointestinal perforation still leads to high neonatal mortality, especially in premature groups[1, 11, 22]. Compared with full-term infants, preterm infants are physiologically and metabolically immature. Therefore, their condition may change more rapidly and the prognosis may be worse than the term-born neonates. As early detection, diagnosis, and access to treatment can improve the infants’ survival, it is necessary to determine the major risk factors in high-risk infants for early intervention.
The symptoms of gastrointestinal perforations during the initial stages are usually non-specific. In our study, abdominal distension was the most common presentation at admission, followed closely by absent bowel sounds, lethargy, and shortness of breath, which is consistent with previous studies. However, these symptoms and signs had no significant indication of the severity of the disease.
In our study, the median age of onset of gastric perforation was 3 days (range: 1–11 days) and the median age of onset of intestinal perforation was 7.5 days (range: 1–30 days). Saracli et al.’s study has reported that NGP generally occurs between 2 and 7 days after birth, which was in line with our study. It’s also reported that the majority of perforated-NEC onset occurs between 2 and 8 weeks following birth, as well as SIP mainly occurs within 10 days after birth. In Calisti et al.’s previous study, the mean age of intestinal perforation in neonates was about 10 days, which is later than the onset age in our study . We speculate that this is due to the higher proportion of intestinal structural abnormalities (such as intestinal atresia, malrotation, volvulus, etc.) in our cohort.
Our study confirmed that severe acidosis (arterial blood pH༜7.05) was associated with an unfavorable outcome of death, which is consistent with the previous finding. Acidosis is a well-known indicator of high mortality. In this study, ten neonates developed severe acidosis and seven of them died. As far as we’ve known, changes in pH can influence vascular tone (i.e., intracellular acidosis is associated with vasodilation). Vasovagal reactions without effective treatment probably led to irreversible shock and even death. Second, acidosis causes damage to cardiomyocytes through altered cellular Ca2 + fluxes as well as by modifying the functional properties of myofilament proteins, which in turn affects myocardial contractility. The decline in cardiac contractility causes a circulatory disturbance, reduces gastrointestinal mucosal perfusion, which hinders the repair of perforations. In our study, elevated lactic acid is another important independent risk factor of mortality of GIP. This has been reported in our previous study .
We observed that shock was a risk factor for in-hospital mortality in patients with GIP. In a shock state, blood flow is redistributed and shunted preferentially to the brain and heart at the gradual expense of peripheral vascular beds. Decreased blood perfusion leads to insufficient oxygen delivery of intestinal mucosa, resulting in tissue hypoxia, which is associated with increased enterocyte damage and integrity loss. The destruction of the digestive tract barrier leads to bacterial translocation, which leads to severe sepsis and multiple organ dysfunction.
Our study also confirmed that coagulopathy was associated with mortality of GIP, which has not been reported in previous studies. This result is consistent with our previous study. It is well known that blood coagulation plays a major role in the process of protecting the damaged tissue and vessel following repair. In the meanwhile, dysfunctional coagulation may also lead to bleeding in patients with blood coagulation disorders or undergoing surgery. On the one hand, it hinders the repair of the perforation site, on the other hand, the increase of bleeding leads to the decrease of blood perfusion, which further aggravates the damage of gastrointestinal mucosa.
Leukopenia has been reported to be a poor prognostic factor in previous studies, although it has not been confirmed in our study[24, 31]. The decisive diagnostic value of leukopenia in neonatal infectious diseases is still controversial. It’s suggested in a previous cohort study focusing on WBC counts in febrile neonates that any WBC count threshold was not recommended to identify bacterial infections for the modest discriminatory power in identifying neonates with bacterial infections and the substantial overlap among groups.
Surgical intervention time (time from symptoms and surgical intervention) was reported to be a risk factor for postoperative death, which is contrary to our present study[11, 24, 33]. Our results are consistent with a previous study in another hand , which warrants some further thoughts.
There are two main advantages to this study. Firstly, to the best of our knowledge, this is the largest sample size study on the risk factors of GIP in preterm neonates. Secondly, we collected available data from all aspects and comprehensively evaluated its relationship with death.
Our study also has several limitations. First, the present study has the inherent limitations of a retrospective, single-center investigation. Our data were collected retrospectively, which may produce a population bias. The findings reported here will require verification in a prospective, multicenter trial. Secondly, considering that our hospital is the largest tertiary referral center for children in southwest China, the neonates in this cohort are relatively seriously ill and most of them were referred from other hospitals, which means the prehospital treatment regimens cannot be accurately collected, such as the history of indomethacin, paracetamol, etc. Finally, confounding factors, such as the welfare systems, medical environment, and socio-behavioral factors, may also need to be considered.