DOI: https://doi.org/10.21203/rs.3.rs-1445391/v1
Gastrointestinal perforation (GIP) among neonates is a major clinical emergency associated with high mortality, which is severe and life-threatening, especially in preterm infants. This study aimed to describe the clinical features of preterm neonatal gastrointestinal perforation and evaluate the potential prognostic factors.
A total of 191 preterm neonates with gastrointestinal perforation were included in this retrospective cohort study and assigned to survival and non-survival groups. Information containing clinical and demographic data, laboratory and imaging features, and outcomes were collected and recorded by retrospective medical records review. The independent factors associated with death risk were determined by univariate and multivariate logistic regression analyses.
The overall mortality in the study cohort was 25.1%. The median age of onset of gastric perforation was 3 days (range: 1–11 days), while the median age of onset of intestinal perforation was 7.5 days (range: 1–30 days). Abdominal distension (184 [96.3%] patients) was the most common symptom, followed by absent bowel sounds (157 [82.2%] patients), lethargy (148 [77.5%] patients), and shortness of breath (60 [59.4%] patients). Finally, three independent mortality risk factors were identified: severe acidosis (OR,7.604; 95% CI, 1.424‒51.910; p = 0.025), shock (5.131; 2.419‒11.266; p < 0.001) and coagulopathy (3.269; 1.511–7.431; p = 0.003).
Severe acidosis, shock, and coagulopathy are independently and significantly associated with an increased risk of death in preterm infants with neonatal gastrointestinal perforation. The identification of novel risk factors will facilitate the development of therapeutic strategies for preterm neonates with gastrointestinal perforation.
Gastrointestinal perforation (GIP) among neonates is a common but major clinical emergency, which carries a mortality of 20–63% and occurs in a large heterogeneous population ranging from preterm and low-birth-weight neonates to healthy term neonates[1–4]. Despite the continuous development in neonatal intensive care units and improvement of surgical and anesthetic techniques, gastrointestinal perforation is still causing significant morbidity and mortality in neonates, especially in preterm groups [1, 5, 6]. The major causes of GIP in neonates have been ascribed to preterm, low birth weight, bacterial colonization, an early and fast increase in meal volume, and intestinal ischemia according to recent studies [7–10]. Many theories have been proposed for the pathogenesis of gastrointestinal perforation; however, the etiology is still controversial. The prevention of GIP remains challenging because of the multifactorial etiology and poorly understood pathogenesis.
Several studies attempted to identify risk factors that impact the prognosis for neonates with GIP in recent years. Some studies have found that necrotizing enterocolitis (NEC), low birth weight, premature birth, intervention time, surgical procedure, location of the perforation, and sepsis were unfavorable prognostic factors [1, 2, 4, 11–16].
The etiology, the pattern of presentation, and surgical findings were suggested to be different between preterm and term infants with GIP in the study of Kara et al. Some previous studies have found that preterm birth was a common poor prognostic factor[1, 2, 12]. With the development of neonatal intensive care and the improvements in obstetrics, the premature infants’ survival rate has been rising in recent years, which increased the number of preterm infants with GIP during the neonatal periods. Therefore, it is necessary to further explore the prognostic factors of GIP in preterm infants and develop better treatment plans for these infants.
This retrospective study aimed to evaluate the etiologies, clinical findings, and potential factors affecting the outcomes of GIP in preterm neonates operated in our hospital with a large sample-sized analysis.
This study was approved by the Ethics Committee of our hospital(approval no.2021 − 329). All the patients’ guardians or parents provided written informed consent to use the clinical data of their children in our research. The study retrospectively included 191 neonates with gastrointestinal perforation who were admitted to our hospital’s neonatal intensive care unit (NICU) between April 2009 and October 2021. Patients were divided into the survival and non-survival groups according to the vital status at hospital discharge.
Inclusion criteria: (1) Gestational age is fewer than 37 weeks; (2) Age at onset ≤ 30d; (3) Gastrointestinal perforation was postoperative confirmed and diagnosed.
Exclusion criteria: (1) Patients received treatment before admission to other hospitals or transferred to other hospitals during treatment; (2) Patients complicated with major chromosomal and congenital anomalies; (3) Patients with incomplete clinical data.
The baseline clinical and biological characteristics were retrospectively collected and recorded in an electronic case report form, which includes patient demographics (gestational age, sex, birth weight, history of perinatal asphyxia, mode of delivery, age of onset), primary symptoms and signs, imaging features, preoperative laboratory findings (hemoglobin, count of leukocyte and platelet, arterial pH, C-reactive protein, concentration of sodium, and serum lactic acid), intraoperative findings (the number of ascites, the perforation sites, and perforation number), surgical intervention time (time between the onset of GIP to any surgical intervention), and complications. All included patients were followed up until in-hospital death or hospital discharge.
According to previous studies, we defined GIP as the destruction of the integrity of the digestive tract. Preterm born was defined as birth before 37 weeks gestation, respectively. NEC The severity of thrombocytopenia was defined as mild (100–150×109/L), moderate (50–100×109/L), and severe (< 50×109/L))[17], [18]. Severe acidosis was defined as arterial blood pH༜7.05 in this study, while hyponatremia was defined as the concentration of serum sodium (Na+) was less than 130 mEq/L [18][19]. Shock and sepsis were diagnosed based on the Pediatric Sepsis Consensus (PSC) criteria while fever was defined as an axillary temperature was no less than 37.3°C. According to previous literature, coagulopathy was defined as platelet count < 1×105/mm3or activated prothrombin time > 60 sec or INR > 1.5, as well as the high PCT level was diagnosed with age-specific cut-off values[18]. Infants with suspected NEC (stage I), moderate NEC (stage II), or severe NEC (stage III) were categorized according to Bell’s classification standard[19]. In this study, confirmed NEC was defined as NEC stage II and III. Spontaneous intestinal perforation (SIP) was diagnosed by the fellow criteria: (1) no clinical evidence of NEC; (2) isolated intestinal perforation confirmed by surgery and/or pathological examination (without surrounding ischemia, inflammation, pneumatosis, or necrosis); (3) no intestinal anomalies, such as intestinal atresia, volvulus, imperforate anus or traumatic perforations[9, 20–22]. Gastrointestinal(GI) anomalies were also confirmed by surgery and/or pathological examination.
Descriptive statistics were analyzed by SPSS software version 25.0 (SPSS, Chicago, IL, USA.), with probability levels of 0.05 considered statistically significant. Categorical variables were described by frequency rates and percentages and compared by use of the Fisher exact test or χ2 test. A Shapiro-Wilk test was used for the baseline variable to estimate whether the continuous data followed a normal distribution. Based on the Shapiro–Wilk test’s results, continuous variables were expressed as mean ± standard deviation (SD) if they were normally distributed or median (interquartile range [IQR]) if they were not. Comparisons were determined thanks to the Mann-Whitney U test or Student’s t-test for continuous variables as appropriate. The association of potential predictors and unfavorable outcomes was explored by univariate and multivariate logistic regression. Multivariate logistic regression models were derived based on the incorporated baseline variables, which were considered clinically relevant or showed a univariate relationship with outcome. Given the number of events available, the variables for inclusion were carefully selected to make sure the parsimony of the final models.
A total of 191 preterm neonates had surgically diagnosed neonatal gastrointestinal perforation between April 2009 and October 2021. As shown in Table 1, the overall mortality rate of the whole cohort was 25.1%. The median age of onset of gastric perforation was 3 days (range: 1–11 days), while the median age of onset of intestinal perforation was 7.5 days (range: 1–30 days), respectively. Among the total population, abdominal distension was the most frequent presentation at admission, which was followed by absent bowel sounds, lethargy, and shortness of breath. There were no significant differences in clinical presentation between the two groups. The detailed demographic and clinical characteristics in the derivation and test cohorts were described in Table 1.
|
Total (n = 191) |
Survivors (n = 143) |
Non-survivors (n = 48) |
p value |
|
|---|---|---|---|---|
|
Male gender, n (%) |
99(51.8) |
77(53.8) |
22(45.8) |
0.336 |
|
GA (wk)a |
34 [32, 35] |
34 [32, 35] |
34 [33, 35] |
0.754 |
|
BW (g)a |
2000 [1670, 2340] |
2000 [1735, 2310] |
2000 [1635, 2385] |
0.594 |
|
LBW, n (%) |
157 (82.2) |
118 (82.5) |
39 (81.2) |
1 |
|
Cesarean section, n (%) |
146 (76.4) |
112 (78.3) |
34 (70.8) |
0.389 |
|
Primegravidity, n (%) |
63 (33.0) |
45 (31.5) |
18 (37.5) |
0.554 |
|
Primipara, n (%) |
93 (61.6) |
64 (57.7) |
29 (72.5) |
0.143 |
|
Feeding before onset, n (%) |
130 (71.0) |
97 (70.3) |
33 (73.3) |
0.84 |
|
History of perinatal asphyxia, n (%) |
91 (47.6) |
68 (47.6) |
23 (47.9) |
1 |
|
Age of onset (d)b |
5 [2, 8.5] |
5 [2, 9] |
5 [2, 6.25] |
0.185 |
|
Symptom, n (%) |
||||
|
Abdominal distension |
184 (96.3) |
138 (96.5) |
46 (95.8) |
1 |
|
Lethargy |
148 (77.5) |
111 (77.6) |
37 (77.1) |
1 |
|
Shortness of breath |
87 (45.5) |
68 (47.6) |
19 (39.6) |
0.428 |
|
Cyanosis |
87 (45.5) |
68 (47.6) |
19 (39.6) |
0.428 |
|
Vomiting |
54 (28.3) |
39 (27.3) |
15 (31.2) |
0.731 |
|
Feeding intolerance |
41 (21.5) |
32 (22.4) |
9 (18.8) |
0.744 |
|
Fever |
25 (13.1) |
16 (11.2) |
9 (18.8) |
0.273 |
|
Bloody stool |
45 (23.6) |
36 (25.2) |
9 (18.8) |
0.477 |
|
Signs, n (%) |
||||
|
Absent bowel sounds |
157 (82.2) |
116 (81.1) |
41 (85.4) |
0.649 |
|
Prominent abdominal veins |
74 (38.7) |
52 (36.4) |
22 (45.8) |
0.32 |
|
Abdominal erythema |
47 (24.6) |
32 (22.4) |
15 (31.2) |
0.298 |
| Abbreviations: IQR, interquartile range; GA, Gestational age; LBW, Low Birth weight. | ||||
| aMean and standard deviation. | ||||
| bMedian and interquartile range. | ||||
As shown in Table 2, leukopenia, elevated serum lactic acid, thrombocytopenia, and acidosis were statistically associated with severe sequelae, while the other laboratory findings were not. Pneumoperitoneum (95%) was the most frequent finding during preoperative radiological evaluations, but there was no statistical difference.
|
Total (n = 191) |
Survivors (n = 143) |
Non-survivors (n = 48) |
p value |
|
|---|---|---|---|---|
|
Laboratory findings |
||||
|
WBC count, 109cells/La |
6.83 [3.53, 11.57] |
7.29 [3.85, 12.85] |
4.69 [2.65, 9.47] |
0.009 |
|
< 5*109cells/L |
72 (37.7) |
47 (32.9) |
25 (52.1) |
0.027 |
|
Hb, g/La |
138 [115, 163.5] |
136 [113, 163] |
147 [130, 168.75] |
0.096 |
|
PLT count, 109cells/Lb |
190 [117, 261] |
201 [127.5, 276] |
168.5 [96, 204.75] |
0.028 |
|
Thrombocytopenia |
70 (36.6) |
50 (35.0) |
20 (41.7) |
0.509 |
|
CRP༞8mg/L, n(%) |
120 (62.8) |
92 (64.3) |
28 (58.3) |
0.567 |
|
pHa |
7.3 [7.23, 7.37] |
7.31 [7.23, 7.38] |
7.28 [7.14, 7.34] |
0.048 |
|
pH༜7.05, n (%) |
10 (5.3) |
3 (2.1) |
7 (14.9) |
0.003 |
|
Lac, mmol/Lb |
1.5 [1, 2.7] |
1.4 [0.9, 2.2] |
2.1 [1.2, 4.10] |
0.005 |
|
Lac༞5mmol/L, n (%) |
17 (8.9) |
8 (5.6) |
9 (18.8) |
0.013 |
|
SC, mEq/La |
136 [134, 139] |
137 [134, 139] |
135.9 [133.2, 137.6] |
0.18 |
|
Hyponatremia, n(%) |
18 (9.4) |
12 (8.4) |
6 (12.5) |
0.577 |
|
Imaging features |
||||
|
Pneumoperitoneum, n(%) |
178(93.2) |
134(93.7) |
44(91.7) |
0.877 |
| Abbreviations: WBC, White blood cell; Hb, Haemoglobin; PLT, Platelet; CRP, C-reactive protein; PCT, procalcitonin; Lac, lactic acid; SC, Sodium concentration. | ||||
| aMean and standard deviation. | ||||
| bMedian and interquartile range. | ||||
As depicted in Table 3, gastric perforation has a higher mortality rate than intestinal perforation (29.5% vs. 22.5%), but statistically significant difference was not found between the two groups (p = 0.359). 50 of 191 cases were diagnosed with multiple perforations (2 or more), and 36 of them were from the intestines as well as 14 of them were from the stomach. The number of ascites and the incidences of multiple perforations in the survival group were lower than those in the non-survival group, but there was no significant difference either(p = 0.507), which was same in the situation of surgical intervention time (p = 0.637).
|
Total (n = 191) |
Survivors (n = 143) |
Non-survivors (n = 48) |
p value |
|
|---|---|---|---|---|
|
Surgical intervention time, h |
0.637 |
|||
|
≤ 4 hours, n(%) |
122 |
93 |
29 |
|
|
4–12 hours, n(%) |
50 |
35 |
15 |
|
|
༞ 24 hours, n(%) |
19 |
15 |
4 |
|
|
Perforation site, n(%) |
0.359 |
|||
|
Stomach |
71 (37.2) |
50 (35.0) |
21 (43.8) |
|
|
Intestinal |
120 (62.8) |
93 (65.0) |
27 (56.2) |
|
|
Amount of ascites (ml)a |
0.507 |
|||
|
༜100, n(%) |
137 (70.2) |
105 (71.9) |
32 (65.2) |
|
|
≥ 100, n(%) |
54 (29.8) |
38 (28.1) |
16 (34.8) |
|
|
Multiple perforations, n(%) |
50 (26.2) |
37 (25.9) |
13 (27.1) |
1 |
Among the 71 premature neonates with gastric perforation, 25 of them were confirmed with congenital absence of gastric musculature after surgery, and 6 cases were combined with congenital GI malformations that could cause distal obstruction, including Merkel's diverticulum(three), annular pancreas(two), and intestinal atresia(one). In the population of 120 neonates with intestinal perforation, 61 of their primary causes were NEC, as well as 36 neonates were diagnosed with SIP. Twenty-three neonates were associated with GI anomalies, including Merkel's diverticulum perforation(five), intestinal atresia(five), acute perforated appendicitis(four), Hirschsprung disease(three), volvulus(two), imperforate anus(two), malrotation(one), and intestinal stenosis(one).
Among all complications, pneumonia was the most frequently observed one which was followed by sepsis and coagulopathy. In the meanwhile, NEC, shock, and coagulopathy were more frequent in the non-survival group and there were significant differences in the latter two indexes (all p༜0.05), which is illustrated in Table 4.
|
Total (n = 191) |
Survivors (n = 143) |
Non-survivors (n = 48) |
p value |
||||||
|---|---|---|---|---|---|---|---|---|---|
|
Complications, n(%) |
|||||||||
|
Sepsis |
134 (70.2) |
95 (66.4) |
39 (81.2) |
0.079 |
|||||
|
Pneumonia |
165 (86.4) |
124 (86.7) |
41 (85.4) |
1 |
|||||
|
Respiratory failure |
62 (32.5) |
43 (30.1) |
19 (39.6) |
0.298 |
|||||
|
Shock |
65 (34.0) |
34 (23.8) |
31 (64.6) |
< 0.001 |
|||||
|
Coagulopathy |
96 (50.3) |
60 (42.0) |
36 (75.0) |
< 0.001 |
|||||
|
NEC |
91 (47.6) |
67 (46.9) |
24 (50.0) |
0.833 |
|||||
| Abbreviations: NEC, necrotizing enterocolitis. | |||||||||
In univariable analysis, patients with leukopenia (leukocyte < 5×109/L), decreased platelet count, severe acidosis (pH < 7.05), elevated lactic acid (serum lactic acid > 5mmol/L), shock, and coagulopathy had higher odds of poor prognosis than others. The above significant variables were included in the multivariable logistic regression model of all 191 subjects, which showed that pH < 7.05, shock, and coagulopathy were associated with increased odds of death (Table 5).
|
Univariable OR (95% CI) |
p value |
Multivariable OR (95% CI) |
p value |
|
|---|---|---|---|---|
|
WBC count < 5*109 cells/L |
2.220 (1.143–4.344) |
0.019 |
||
|
Plt count, 10⁹cells/L |
0.996 (0.993–0.999) |
0.025 |
||
|
pH < 7.05 |
8.050 (2.134–38.682) |
0.003 |
7.604 (1.424–51.910) |
0.025 |
|
Lactate > 5mmol/L |
3.894 (1.401–11.032) |
0.009 |
||
|
Shock |
5.846 (2.924–12.065) |
< 0.001 |
5.131 (2.419–11.266) |
< 0.001 |
|
Coagulopathy |
4.150 (2.043–8.938) |
< 0.001 |
3.269 (1.511–7.431) |
0.003 |
| Abbreviations: CI, confidence interval; OR, odd ratio; WBC, white blood cell. | ||||
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[25]. 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[22]. 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 [26]. 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[27]. 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)[28]. 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[29]. 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 [30].
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[30]. 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[32].
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 [31], 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.
In conclusion, gastrointestinal perforation is a major neonatal emergency, which is life-threatening and especially severe in preterm infants. In our study, the factors affecting the prognosis of preterm GIP patients were severe acidosis (arterial blood pH < 7.05), shock, and coagulopathy. It is hoped that early diagnosis and timely intervention can improve the prognosis.
Interest
None.
Acknowledgments
We thank our patients for entrusting us with their care and for giving us the opportunity to learn and understand their disease and hopefully help others who may suffer from this disease in the future. And we thank all participants and staff of this study and the physicians for their work.
Funding
This study is supported by the Foundation for Science & Technology Research Project of Chongqing(CSTC 2018jcyjAX0230) and the Science-Health Joint Medical Scientific Research Project of Chongqing [No.2019ZDXM021].
Data Availability Statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.