Factors of poor prognosis in newborns with a prenatal diagnosis of gastroschisis in Bogota, Colombia

Objectives: To identify factors associated with poor prognoses in newborns with a prenatal diagnosis of gastroschisis in eight hospitals in Bogota, Colombia, from 2011 to 2022. Methods: A multi-center retrospective case-control study was conducted on newborns with gastroschisis in eight hospitals in Bogota, Colombia. Poor prognosis was de ﬁ ned as the presence of sepsis, intestinal complications, or death. Results: The study included 101 patients. Preterm new-borns under 32 weeks had a poor neonatal prognosis (OR 6.78 95 % CI 0.75 – 319). Oligohydramnios (OR 4.95 95 % CI 1.15 – 21.32) and staged closure with silo (OR 3.48; 95 % CI 1.10 – 10.96) were risk factors for neonatal death, and intra-abdominal bowel dilation of 20 – 25 mm was a factor for the development of intestinal complications (OR 3.22 95 % CI 1.26 – 8.23). Conclusions: Intra-abdominal bowel dilation between 20 and 25 mm was associated with intestinal complications, while oligohydramnios was associated with the risk of perinatal death, requiring increased antenatal surveillance of fetal wellbeing. Management with primary reduction when technically feasible is recommended in these infants, considering that the use of silos was associated with higher mortality.


Introduction
Gastroschisis is a congenital abdominal wall defect characterized by the herniation of the fetal intestine and, occasionally, other organs outside the abdomen into the amniotic cavity [1], it can be simple, presenting as an isolated defect, or complex, where it is associated with gastrointestinal complications such as intestinal necrosis, perforation, atresia, or volvulus, generating an increase in neonatal morbidity [2][3][4].It is the second most common abdominal congenital malformation, with a prevalence that has increased in recent years from 0.08 in the 1970s to 9.59 per 10,000 live births in 2017 [5,6].In addition, this condition carries a high rate of morbidity and mortality, with the most common complications being sepsis, necrotizing enterocolitis, intestinal stenosis, fetal growth restriction, and perinatal death [7][8][9][10].
Existing research on gastroschisis has focused primarily on the development of surgical techniques.However, recent studies have identified prenatal and postnatal risk factors associated with neonatal morbidity and mortality.For example, the mode of delivery, ultrasound markers, and prenatal monitoring practices vary significantly among healthcare providers [11][12][13][14].
Despite advances in surgical treatment, neonatal morbidity and mortality associated with gastroschisis remain high.Identifying prenatal and postnatal risk factors associated with poor prognosis is necessary to develop prevention and treatment strategies.This study reports prenatal and postnatal risk factors associated with poor prognosis in newborns with a prenatal diagnosis of gastroschisis at eight hospitals in Bogotá, Colombia, for 11 years.

Materials and methods
This retrospective multi-center case-control study included patients with a prenatal diagnosis of gastroschisis who were treated at eight hospitals in Bogotá, Colombia, from January Inclusion criteria for the study were infants with a prenatal diagnosis of gastroschisis, diagnosed by ultrasound starting in the second trimester of pregnancy to detect floating bowel loops.
Exclusion criteria were patients with a diagnosis of gastroschisis who did not complete treatment at the institution under study, patients with gastroschisis associated with aneuploidy or other fetal malformations, patients with a diagnosis of chorioamniotic infections and patients with perinatal asphyxia.
Case definition was those newborns with a prenatal diagnosis of gastroschisis who presented any complication, such as sepsis, an intestinal complication such as intestinal atresia, intestinal ischemia, necrotizing enterocolitis, and post-operative reinterventions (the presence of volvulus, stenosis, intestinal obstruction, or perforation that did not respond to medical management were indications for reintervention), or death before hospital discharge.Controls were defined as those newborns with a prenatal diagnosis of gastroschisis who did not present any of the complications mentioned above.

Variables
Maternal variables: age, parity, diagnosis of gestational diabetes, hypertensive disorders during pregnancy, and body mass index (BMI).
Perinatal and neonatal variables: gestational age at delivery, mode of delivery, Apgar score at 5 min, birth weight, size of abdominal wall defect, type of surgical management, time until abdominal wall closure, days of hospitalization from birth to discharge, duration of stay in the neonatal intensive care unit (NICU), days on mechanical ventilation, need for parenteral nutrition, and the total number of days until the start of full enteral feedings.

Databases
The databases used correspond to the mandatory notification registry of congenital defects in Colombia for live births with gastroschisis and datasets from the hospitalization registry in neonatal units of the following hospitals: Hospital Universitario de La Samaritana, Hospital Universitario Clínica San Rafael, Hospital Simón Bolívar, Clínica Palermo, Clínica Universitaria Colombia, Hospital Universitario San José, Clínica Colsubsidio, and Hospital Universitario De San Ignacio during the period from January 01, 2011 to December 2022.

Bias
A multi-center study was conducted, which included patients from eight hospitals in Bogotá.This approach allowed for an increased sample size and participant diversity, potentially reducing selection bias.Additionally, it was ensured that controls came from the same source as the cases.For this purpose, databases from the mandatory notification registry of congenital defects in Colombia for live births with gastroschisis and medical records from the NICU of each institution were used.
To mitigate information bias, a review of records was conducted by two different reviewers at the time of data entry.This helped ensure that the data were accurate and complete.Furthermore, specialists at each center were trained to consider the same diagnostic ultrasound criteria.This training aimed to ensure consistency in diagnoses across the centers.

Sample size
Data from the study conducted by Fullerton et al. in North America was used to calculate the sample size.The hypothetical proportions were set with a 35 % exposure rate among controls, a 61.76 % exposure rate among cases, and an odds ratio (OR) of 3.76 for polyhydramnios leading to intestinal atresia [15].The sample size was calculated using the formula for unmatched case-control studies, considering a confidence level of 90 % and a power of 80 %.The result indicated a minimum number of 44 cases needed for the study.

Statistical analysis
The data were collected using Microsoft Excel, version 2019, and analyzed using the STATA SE 17 software.Study subjects were selected through simple random sampling from the list of patients treated during the research period.
Qualitative variables were summarized in terms of frequencies and percentages.Regarding quantitative variables, normality was assessed using the Shapiro-Wilk test.In cases where the data distribution was normal, results were presented in terms of means and standard deviations.When the distribution was not normal, results were presented in terms of median and interquartile range.
Subsequently, a bivariate analysis was conducted to assess the association between predictor variables and the adverse outcome.For normally distributed quantitative variables, the Student's t test was used.For non-normally distributed quantitative variables, the Mann-Whitney U test was applied.The Pearson chi-square test was employed for qualitative variables.Statistical significance was considered at p<0.05.Following this, a logistic regression test was performed, adjusting for the preterm birth variable to mitigate potential confounding factors.

Ethics backgrounds
The study followed the World Medical Association Declaration of Helsinki -Ethical Principles for Medical Research Involving Human Subjects [16].Our retrospective study is based on a historical database where patients' data were stored anonymized.The study was considered of no risk to patients according to Article 11 of Resolution No 008430 of 1993, of the Colombian Ministry of Health [17].The protocol was reviewed and approved by the Ethics Committees of all the participating institutions; no informed consent was required.

Results
From a total of 135 neonates with a prenatal diagnosis of gastroschisis included in the database, 44 cases and 44 controls were randomly selected for a total of 88 subjects in follow-up.The mean maternal age in the overall population was 22.6 (SD 4.77), and it was similar in both case and control groups.A total of 4 (5 %) subjects were diagnosed with gestational diabetes, with a higher proportion in the control group (7 %) than in the case group (2 %).Other notable maternal variables include BMI, with a normal BMI observed in most of the general population (53 %) and similar distributions in both case and control groups.Table 1 shows the general characteristics of the population.
Concerning ultrasound variables, a high proportion of subjects with fetal growth restriction was found in the case group (47.7 %) compared to the control group (40.9 %).Similarly, oligohydramnios and intestinal dilation of 20-25 mm or >25 mm were more frequently observed in the case group.
Regarding perinatal and neonatal variables, 53.41 % of the population had a gestational age between 34 and 36.6 weeks; the majority underwent cesarean section (96.59 %), and the average birth weight was 2,216 (SD 477.3), lower in the case group compared to controls 2,112 (SD 479) and 2,320 (SD 457) respectively.
On the other hand, variables strongly associated with poor prognosis factors in patients with gastroschisis were the presence of polyhydramnios with an OR of 4.30 (CI 0.39-216.55),gestational age less than 32 weeks with an OR of 6.78 (95 % CI 0.75-319.35,p=0.04), and intestinal dilation less than 20 mm was associated with a significantly reduced risk of poor prognosis OR 0.33 (95 % 0.12-0.89,p=0.008).Logistic regression adjusting for preterm birth revealed persistence and an increase in the association measures between poor prognosis factors and oligohydramnios, polyhydramnios, and dilation >20 mm, as shown in Table 3.
Additionally, in the associations of variables with intestinal complications and death, oligohydramnios OR 4.95 (95 % CI 1.15-21.32,p=0.04) and late closure with silo OR=3.48 (95 % CI 1.10-10.96,p=0.03) were significantly associated with a higher risk of death.Regarding intestinal complications, dilation of intestinal loops less than 20 mm was significantly associated with a lower risk of intestinal complications OR=0.20 (95 % CI 0.06-0.66p=0.08).In contrast, dilation of intestinal loops from 20 to 25 mm was significantly associated with a higher risk of intestinal complications OR=3.22 (95 % CI 1.26-9.23 p=0.018).

Discussion
Despite comprehensive multidisciplinary management in referral centers, patients with a prenatal diagnosis of gastroschisis can exhibit severe intestinal complications, such as bowel atresia, volvulus, intestinal perforations, bowel necrosis, enterocolitis, and even mortality, leading to significant short-term morbidity and perinatal mortality [18].Therefore, pinpointing risk factors for poor perinatal prognosis is paramount and requires targeted research efforts.

Main results
Our study has identified prenatal ultrasonographic evidence of IABD between 20 and 25 mm as prognostically unfavorable for intestinal complications.Moreover, oligohydramnios emerged as a precursor for perinatal mortality.In terms of postnatal surgical intervention, staged reductions using a silo were correlated with increased mortality risks.

Strengths and limitations
One of the main strengths lies in our sample's multi-center origin, enhancing our findings' representativeness and allowing for more robust generalizations.In addition, the sample size provides a solid foundation for statistical analysis, enhancing the reliability of our results.The rigorous data collection and randomness of the sample ensure the reliability of our data and help minimize potential biases in our research.
Regarding the limitations of our study, is that we cannot assert definitive associations due to the lack of statistical significance in some of our results.Nevertheless, our study is a valuable first step in this research field.The current limitations can serve as a basis for future studies to delve into aspects that we have not been able to address conclusively.
The retrospective nature of this study, coupled with the reliance on clinical records for data collection, represents inherent limitations; considering that not all data on the variable of the size of the abdominal wall defect were found.In the case of fetal growth restriction, no record of the calculation formula for estimating prenatal fetal weight was found, given that abdominal circumference is less sensitive in cases of abdominal wall defects.However, the presence of the condition was confirmed with neonatal weight, which reduced this bias.
In summary, our strengths support the quality and credibility of our study, while our weaknesses point out areas for future research and improvement.

Interpretation
In the realm of prenatal diagnostics, IABD has emerged as a pivotal marker for assessing the risk of complex conditions.Our observations indicate that fetuses with IABD measurements of 20-25 mm are at a considerably higher risk for intestinal complications, with an OR of 3.22 (95 % CI 1.26-8.23),a finding consistent with Nitzsche et al., who identified a cutoff point of 18 mm as a predictor for complex gastroschisis [19].This aligns with the systematic analysis by D'Antonio et al., which found an association between IABD and bowel atresia, with an OR of 5.48 (95 % CI 3.1-9.8)[20], and is further corroborated by a comprehensive review that predicts higher IABD in fetuses with complex gastroschisis, with a risk ratio (RR) of 3.01 (95 % CI 2.22-4.07)[21].Meanwhile, an IABD of less than 20 mm has been identified as a protective factor, associated with improved neonatal outcomes and fewer intestinal complications (OR 0.20; 95 % CI 0.06-0.6).Consequently, the termination of pregnancy in fetuses with intestinal dilatations less than 20 mm would not be recommended, in accordance with guidelines from the Fetal Medicine Foundation [22].
As for oligohydramnios, a study of 101 patients with gastroschisis suggested that oligohydramnios was not a statistically significant predictor for complex gastroschisis [23].
Similarly, the research presented by Johnston et al., indicated that oligohydramnios does not appear to worsen the prognosis for neonates with gastroschisis [24].However, in contrast to these findings, our study found that oligohydramnios is indeed a poor prognostic risk factor, associated with a higher rate of neonatal death (OR 4.95; 95 % CI 1.15-21.32,p=0.04).This discrepancy in findings highlights the complexity of prenatal prognostication in gastroschisis and underscores the need for further research.It may also point to the potential influence of other confounding variables that were not accounted for in previous studies, or it might suggest variability in the impact of oligohydramnios on neonatal outcomes across different populations.
The optimal gestational age for delivering fetuses with gastroschisis has been controversial.Prat et al., in 2017, advocated allowing gestation to proceed as close to term as possible except in fetuses with bowel loop deterioration or other fetal or maternal causes indicating the need for delivery [25].This stance is akin to the recommendations of the Fetal Medicine Foundation, which advises ending the pregnancy at 38 weeks or earlier if there is evidence of poor growth, fetal hypoxia, or dilatation of the intra-abdominal bowel [22].Sparks et al. recommends delivery at 37 weeks, considering that, beyond that gestational age, mortality increases with expectant management (RR 1.90; 95 % CI 1.73-2.08)at 39 weeks [26].Our findings highlight improved neonatal outcomes for full-term births, which acted as a protective factor against adverse neonatal prognosis (OR 0.77; 95 % CI 0.28-2.14),death (OR 0.54; 95 % CI 0.14-2.11),and intestinal complications (OR 0.77; 95 % CI 0.28-2.14),even though the results did not reach statistical significance.
In terms of surgical management, our findings indicate that primary closure with suturing is associated with lower mortality and improved neonatal prognosis compared to delayed closure with a silo (OR 0.31; 95 % CI 0.10-0.96)compared to delayed closure using a silo (OR 3.48; 95 % CI 1.10-10.96).This is in line with literature suggesting that primary reduction is associated with fewer days on mechanical ventilation, without affecting the type or duration of ventilation or oxygen requirements [3].Additionally, Tauriainen et al. underscore that complications from silo correlate with adverse outcomes, highlighting the risks of managing gastroschisis with silo [14].

Conclusions
The prenatal and postnatal factors influencing gastroschisis outcomes has illuminated several significant prognostic markers.IABD exceeding 20 mm and the presence of oligohydramnios were found to unfavorably impact intestinal complications and perinatal mortality, respectively.Surgical management outcomes revealed that primary closure with suturing has an advantage over delayed closure using a silo, 1, 2011 to December 2022.The hospitals included in this study were Hospital Universitario De La Samaritana, Hospital Universitario Clínica San Rafael, Hospital Simón Bolívar, Clínica Palermo, Clínica Universitaria Colombia, Clínica Pediátrica Colombia, Clínica Colsubsidio 94 y Hospital Universitario De San Ignacio.These hospitals are reference centers for the management patients with prenatal diagnosis of congenital malformations in Colombia.The research team collected and carefully evaluated the information from medical records and the Colombian mandatory congenital defects notification registry.

Table  :
Poor prognosis factors.

Table  :
Association of maternal, prenatal, and neonatal variables with poor prognosis in patients with gastroschisis, adjusted for preterm birth.