Risk factors for and developmental relation of delayed oral nutrition in infants with congenital diaphragmatic hernia

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Methods : This retrospective single-center cohort study compared the clinical parameters in patients with isolated CDH born and treated at our hospital between 2006 and 2020. We evaluated clinical features significantly related to delayed oral nutrition (defined as taking ≥30 days from weaning from mechanical ventilation to weaning from tube feeding) Results : Twenty-six of the 80 cases had delayed oral nutrition. Univariate analyses showed significant differences. Multivariate analyses were performed on the three items of preterm delivery, defect size (over 50% to nearly entire defect), and ventilation for ≥9 days. We identified the latter two items as independent risk factors. The adjusted odds ratios were 4.65 (95% confidence interval, 1.27–7.03) and 6.02 (1.65–21.90), respectively. Delayed oral nutrition was related to a significantly higher probability of developmental delay at 18 months (crude odds ratio 4.16, 1.19–14.5). Conclusion: In patients with CDH, a large defect and ventilatory management over 9 days are independent risk factors for delayed oral nutrition, which is a potent predictor of developmental delay that requires active developmental care. congenital diaphragmatic hernia delayed oral nutrition tube feeding oral aversion development infant nutrition 1. Introduction Congenital diaphragmatic hernia (CDH) is a prevalent congenital disability that affects approximately 1 in 2500 to 4000 newborns [1, 2] and presents a significant challenge for surgeons and neonatologists. CDH survivors may experience neurodevelopmental, gastrointestinal, nutritional, pulmonary, and musculoskeletal issues. However, the respiratory dysfunction that is most problematic in the acute phase tends to improve in the long term. Jaillard et al. observed that growth retardation and feeding issues associated with oral aversion were the primary issues in 2-year-old CDH survivors [3]. Nonetheless, research on feeding issues in the chronic phase of CDH survivors is scarce [3–5]. Even after the respiratory status has improved during the subacute postoperative period, some patients may require extended hospitalization owing to oral nutrition difficulties or need to undergo home tube feeding after discharge. Although the cause of these feeding problems, which occur particularly during the first few months of life, is often unknown, the condition in some patients eventually improves in a short time, while in others, it does not improve for several years. In addition, although researchers have noted that this tube-dependent condition from early life can lead to complications such as infections, aspiration, and increased parental and maternal attachment insecurity, they have not thoroughly studied its negative impacts on future development [6–10]. Given the lack of research on the impact of this tube-dependent condition from early life on future development, we focused on the problem of delayed oral nutrition in the early postnatal period to identify the risk factors involved and assess the impact of this as a predictor of developmental delay at 18 months of age. 2. Methods The medical records of patients diagnosed with CDH who were born at Osaka Women’s and Children’s Hospital between January 2006 and April 2020 were retrospectively analyzed. Our study focused on patients who underwent diaphragmatic repair during the neonatal period, had isolated CDH with no identifiable genetic causes and no additional medical issues or organ abnormalities, and were discharged from the hospital. These patients were divided into two groups: those who took 30 days or more to establish oral nutrition and those who took less than 30 days. We then analyzed the risk factors for the delayed establishment of oral nutrition, which we defined as a period of 30 days or more. This index was defined as the duration between the cessation of mechanical ventilation and the cessation of tube feeding. The time period of 30 days after mechanical ventilation was set as the period when, in normal clinical practice, the patient would be expected to be in the subacute postoperative period, the respiratory status would no longer be unstable, although oxygen demand may be necessary, and nutritional intake, whether oral or tube feeding, would be stable. At our facility, patients with CDH began tube feeding while on a ventilator, and oral feeding was initiated after extubation. As a result, the total feeding volume was increased with the goal of achieving 100–120 kcal/kg/day or more until stable weight gain was finally achieved. If oral nutrition alone was not sufficient to achieve this goal, a combination of oral and tube feeding was utilized to attain complete oral nutrition. We reviewed the perioperative charts to identify factors such as sex, oligohydramnios, cesarean section, gestational age at birth, birth weight, intrauterine growth restriction, Terui’s risk stratification [ 11 ], side and size of the diaphragmatic defect, need for patch closure, duration of mechanical ventilation, duration of oxygen administration, duration of tube feeding after extubation, and duration of hospitalization. Terui’s risk stratification is a mortality predictor for CDH calculated based on the Apgar score at 1 min and the best oxygenation index within 24 hours after birth [ 11 ]. Category 1 includes neonates with neither risk factor, category 2 includes neonates with either risk factor, and category 3 includes neonates with both risk factors. Category 0 includes patients who did not require respiratory care within 24 h of birth, and category 4 includes patients who did not develop an oxygenation index due to death prior to intubation (including fetal death and stillbirth). The size of the defect was classified into categories A through D based on the intraoperative findings proposed by Tsao et al. [ 12 , 13 ]. An "A" defect is entirely surrounded by muscle, a "B" defect has a small portion ( 50%) of the chest wall devoid of diaphragmatic tissue, and a "D" defect is the complete or nearly complete absence of the entire diaphragm. These variables were binarized, and their relationship with delayed oral nutrition for 30 days or more was analyzed separately. The duration of mechanical ventilation and the duration of oxygen administration were also binarized using cutoff values. Multivariate analysis was conducted to identify the independent risk factors for delayed oral nutrition among the three variables of prolonged duration of mechanical ventilation, preterm birth, and defect size. The length of ventilation time has previously been reported as a risk factor for oral aversion [ 4 ], preterm birth represents the patient's immaturity factor, and defect size represents the severity of the disease factor. In our cohort of patients who underwent developmental testing at a corrected age of 18 months, we also analyzed the relationship between psychomotor development and delayed oral nutrition. We examined factors that have been linked to the development of CDH, including delayed oral nutrition, low birth weight, hernia on the right side, need for patch closure, need for extracorporeal membrane oxygenation (ECMO), mechanical ventilation for more than 9 days, and oxygen administration for more than 30 days [ 14 – 18 ]. Psychomotor development was assessed using the Kyoto Scale of Psychological Development (KSPD), a standardized assessment method for the Japanese population that has been shown to correlate well with the Bayley Scales, third edition [ 19 ]. A developmental quotient (DQ) value of 85 or higher, calculated using KSPD, indicates normal development, while a DQ value below 85 indicates borderline or delayed development. The KSPD consisted of three subscales: Postural-Motor, Cognitive-Adaptive, and Language-Social. The DQs of the three subscales were obtained. At our hospital, we have been administering the KSPD to all CDH patients since 2010 at the corrected age of 18 months. However, prior to that, it was administered only in cases where the pediatrician responsible for developmental follow-ups deemed it necessary. Statistical analysis The statistical analyses for this study were conducted using JMP software (version 13.0; SAS Institute Inc., Cary, NC, USA). The chi-square test, Mann–Whitney U test, and logistic regression (multivariate analysis) were utilized. Receiver operating characteristic curve (ROC) analysis was also employed to confirm the cutoff value. The cutoff values for the duration of mechanical ventilation and the duration of oxygen administration for oral nutrition, set at 30 days or more, were determined through the use of the Youden J statistic (sensitivity + specificity-1) based on the optimal operating points from the ROC curve analyses. The data are presented as median and interquartile ranges, with statistical significance defined as P < 0.05. Ethical considerations The study was approved by the Institutional Review Board of Osaka Women's and Children's Hospital (protocol no. 1489) and was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was not required owing to the retrospective study design and the use of de-identified data. The details of the study were made available on an institutional website, and individuals had the option to opt out of participation. 3. Results Eighty patients were enrolled in this study (Table 1 ). Cases in which fetal endoscopic tracheal obstruction (FETO) was performed were not included. This cohort was divided into two groups: those who took 30 days or more to have the feeding tube removed after extubation and those who did not; moreover, binarized clinical demographics were compared. That is, univariate analysis was performed between groups with and without delay in establishing oral nutrition (Table 2 ). As presented in Table 1 , no patients were included in category 0 or 4 in Terui’s risk stratification; therefore, the data were binarized by category 1 and category 2 or 3. The cutoff values of the duration of mechanical ventilation and the duration of oxygen administration were determined by the Youden J statistic to be 9 and 37 days, respectively, and were binarized at these values. Eight findings were significantly related to the delayed oral nutrition (delayed oral nutrition vs. oral nutrition not delayed): preterm birth (42.3% vs. 11.1%, P = 0.003, crude odds ratio [OR] 5.85, 95% confidence interval (CI) 1.85–18.55), birth weight less than 2500 g (53.9% vs. 20.4%, P = 0.004, crude OR 4.57, 95% CI 1.65–12.59), Terui’s risk stratification of category 2 or 3 (66.7% vs. 23.5%, P < 0.001, crude OR 6.49, 95% CI 2.24–18.90), need for patch closure (80.8% vs. 31.5%, P < 0.001, crude OR 9.14, 95% CI 2.95–28.35), defect size of C or D (53.9% vs. 11.1%, P < 0.001, crude OR 9.33, 95% CI 2.97–29.41), mechanical ventilation for more than 9 days (84.6% vs. 33.3%, P < 0.001, crude OR 11.00, 95% CI 3.29–36.75), oxygen administration for more than 37 days (69.2% vs. 16.7%, P < 0.001, crude OR 11.25, 95% CI 3.75–33.73), and hospitalization for more than 90 days (53.9% vs. 7.4%, P < 0.001, crude OR 14.6, 95% CI 4.06–52.31). All other investigated factors were not significantly related to delayed oral nutrition. Table 1 Patient characteristics Number of patients, n 80 Sex, male, n, (%) 49 (61.3) Oligohydramnios, n (%) 15 (19.5) Cesarean section, n (%) 43 (53.0) Gestational age at birth (weeks) a 37.9 [37.0-38.7] Birth weight (g) a 2666 [2426–3042] IUGR, n (%) 11 (13.8) Terui’s risk stratification, category 0 / 1 / 2 / 3 / 4, n (%) 0 (0) / 47 (61.8) / 23 (30.3) / 6 (7.2) / 0 (0) Defect on the right side, n (%) 6 (7.4) Defect size, A / B / C / D, n (%) 21 (25.9) / 40 (49.4) / 15 (18.5) / 5 (6.2) Need for patch closure, n (%) 38 (48.8) Need for ECMO, n (%) 3 (3.7) Duration of mechanical ventilation (days) a 10 [ 6 – 16 ] Duration of oxygen administration (days) a 21 [11–51] Duration of tube feeding (days) a 33 [19–52] Duration of tube feeding after extubation (days) a 20 [ 12 – 33 ] Duration of hospitalization (days) a 57 [36–82] IUGR, intrauterine growth restriction; iNO, inhaled nitric oxide; ECMO, extracorporeal membrane oxygenation a Median [interquartile range] Table 2 Comparison of the binarized demographics between the patients with delayed oral nutrition establishment and those without. Delayed oral nutrition (n = 26) Oral nutrition not delayed (n = 54) P value Crude OR (95%CI) Sex, male, n/N, (%) 16/26, 61.5 33/54, 61.1 1 1.02 (0.39–2.66) Oligohydramnios, n/N, (%) 6/25, 24.0 9/52, 17.3 0.545 1.51 (0.47–4.84) Cesarean section, n/N, (%) 15/26, 57.7 27/54, 50.0 0.634 1.36 (0.53–3.50) Preterm birth, n/N, (%) 15/26, 42.3 6/54, 11.1 0.003* 5.85 (1.85–18.55) Birth weight less than 2500 g, n/N, (%) 14/26, 53.9 11/54, 20.4 0.004* 4.57 (1.65–12.59) IUGR, n/N, (%) 6/26, 23.1 5/54, 9.3 0.162 2.94 (0.80–10.74) Terui’s risk stratification of category 2 or 3, n/N, (%) 8/24, 66.7 12/51, 23.5 < 0.001* 6.49 (2.24–18.90) Side of hernia (right), n/N, (%) 3/26, 11.5 3/54, 5.6 0.384 2.22 (0.42–11.83) Need for patch repair, n/N, (%) 21/26, 80.8 17/54, 31.5 < 0.001* 9.14 (2.95–28.35) Defect size of C or D, n/N, (%) 14/26, 53.9 6/54, 11.1 < 0.001* 9.33 (2.97–29.41) Need for ECMO, n/N, (%) 1/26, 3.9 2/54, 3.7 1 1.04 (0.09–12.02) Mechanical ventilation for more than 9 days 22/26, 84.6 18/54, 33.3 < 0.001* 11.00 (3.29–36.75) Oxygen administration for more than 37 days 18/26, 69.2 9/54, 16.7 < 0.001* 11.25 (3.75–33.73) Hospitalization for more than 90 days, n/N, (%) 14/26, 53.9 4/54, 7.4 < 0.001* 14.6 (4.06–52.31) OR, odds ratio; IUGR, intrauterine growth restriction; ECMO, extracorporeal membrane oxygenation * Statistically significant The results of the multivariate analysis are presented in Table 3 . Two independent risk factors for delayed oral nutrition were identified: defect size of C or D (P = 0.020, adjusted OR 4.65, 95% CI 1.27–17.03) and mechanical ventilation for more than 9 days (P = 0.007, adjusted OR 6.02, 95% CI 1.665–21.90). Preterm birth was not identified as an independent risk factor for delayed oral nutrition. Table 3 Univariate and multivariate analyses of risk factors for delayed oral nutrition Univariate analysis Multivariate analysis Crude OR (95% CI) P value Adjusted OR (95% CI) P value Preterm birth 5.85 (1.85–18.55) < 0.001* 3.49 (0.88–13.80) 0.075 Defect size of C or D 9.33 (2.97–29.41) < 0.001* 4.65 (1.27–17.03) 0.020* Mechanical ventilation for more than 9 days 11.00 (3.29–36.75) < 0.001* 6.02 (1.65–21.90) 0.007* OR, odds ratio; CI, confidence interval * Statistically significant In our cohort, 51 (63.8%) patients had a developmental assessment investigated using the KSPD at a corrected age of 18 months. These 51 patients were divided into two groups, those with borderline or delayed psychomotor development and those with normal psychomotor development, and univariate analysis was performed on delayed oral nutrition and six additional items (Table 4 ). Three findings, including delayed oral nutrition, were significantly related to a borderline or delayed psychomotor development (delayed or borderline vs. normal): delayed oral nutrition (50.0% vs. 19.4%, P = 0.031, crude OR 4.16, 95% CI 1.19–14.50), mechanical ventilation for more than 9 days (65.0% vs. 35.5%, P = 0.049, crude OR 3.38, 95% CI 1.04–10.96), and oxygen administration for more than 30 days (65.0% vs. 32.3%, P = 0.042, crude OR 3.90, 95% CI 1.19–12.79). All other perinatal factors were not significantly related to borderline or delayed psychomotor development at a corrected age of 18 months. In addition, subscales of psychomotor development in these three clinical factors significantly associated with borderline or delayed psychomotor development were compared. There was a significant difference between the positive and negative groups in the cognitive-adaptive developmental quotient but not in the posture-motor or language-social developmental quotient for all three factors. Table 4 Comparison of clinical factors between patients with and without normal psychomotor development at a corrected age of 18 months Borderline or delayed PD (n = 20) Normal PD (n = 31) P value Crude OR (95%CI) Delayed oral nutrition, n, (%) 10, 50.0 6, 19.4 0.031* 4.16 (1.19–14.50) Birth weight less than 2500 g, n, (%) 10, 50.0 10, 32.3 0.249 2.10 (0.66–6.67) Side of hernia (right), n, (%) 3, 15.0 1, 3.2 0.287 5.29 (0.51–55.25) Need for patch closure, n, (%) 12, 60.0 14, 45.2 0.393 1.82 (0.58–5.70) Need for ECMO, n, (%) 2, 10.0 1, 3.2 0.553 3.33 (0.28–39.43) Mechanical ventilation for more than 9 days, (%) 13, 65.0 11, 35.5 0.049* 3.38 (1.04–10.96) Oxygen administration for more than 30 days, (%) 13, 65.0 10, 32.3 0.042* 3.90 (1.19–12.79) PD, psychomotor development; OR, odds ratio; CI, confidence interval; DQ value, developmental quotient value using Kyoto Scale of Psychological Development; ECMO, extracorporeal membrane oxygenation * Statistically significant Table 5 Comparison of PD subscales in the three clinical factors related to borderline or delayed PD at a corrected age of 18 months Delayed oral nutrition Mechanical ventilation for more than 9 days Oxygen administration for more than 30 days Positive N = 16 Negative N = 35 P value Positive N = 24 Negative N = 27 P value Positive N = 23 Negative N = 28 P value Posture-Motor 83 [66–93] 82 [73–95] 0.424 78 [66–91] 93 [76–97] 0.083 79 [58–95] 84 [75–97] 0.113 Cognitive-Adaptive 79 [66–91] 95 [77–101] 0.017* 80 [72–94] 95 [84–106] 0.005* 79 [71–101] 94 [84–101] 0.014* Language-Social 79 [64–94] 88 [74–100] 0.100 84 [72–99] 93 [73–98] 0.167 88 [69–100] 88 [73–97] 0.487 Total DQ 82 [67–92] 91 [79–99] 0.033* 82 [71–92] 93 [81–100] 0.007* 81 [68–93] 92 [82–97] 0.011* All data are expressed as the median [interquartile range]. PD, psychomotor development DQ value, Developmental quotient value using Kyoto Scale of Psychological Development * Statistically significant 4. Discussion We analyzed the risks of delayed oral nutrition after surgery in 80 patients with CDH by defining delayed oral nutrition as persistent tube feeding beyond 30 days after being taken off mechanical ventilation. Defect size of C or D and mechanical ventilation for more than 9 days were independent factors. In addition, borderline or delayed psychomotor development was significantly associated with delayed oral nutrition in the 51 patients who underwent developmental assessment at a corrected age of 18 months; furthermore, the crude OR for this association was higher than that of other previously reported factors such as the requirement for patch closure [ 15 , 18 , 20 ], ECMO [ 14 , 18 , 20 ], mechanical ventilation for more than 9 days [ 17 ], and oxygen administration for more than 30 days [ 18 ]. There have been few reports on delayed oral nutrition in patients with CDH. Muratore et al. studied 121 patients with CDH and found that 29% had oral aversion in the first year of life and reported that prolonged mechanical ventilation and the need for oxygen at discharge were risk factors [ 4 ]. However, oral aversion is poorly defined in the literature and lacks a standardized diagnostic criterion, making it difficult to make a clear diagnosis, at least in the short term [ 6 , 21 , 22 ]. Our study clearly defined the establishment of oral feeding and assessed it as a short-term outcome, one-month after ventilator weaning. This approach has the potential to predict the need for continued tube feeding at home for patients discharged immediately after diaphragmatic repair and to provide parents with relevant risk information. Interestingly, multivariate analysis identified defect size of C or D and mechanical ventilation for more than 9 days as independent risk factors, with no significant difference for preterm birth. This finding is consistent with previous reports indicating that prolonged mechanical ventilation is a risk factor for poor postoperative oral nutrition in neonatal surgery [ 4 , 21 , 23 – 25 ]. Potential causes of this phenomenon include dysphagia due to long-term intubation, aversion to oral stimulation, and respiratory status that does not allow adequate oral intake. Our study chose to use preterm birth as a representative indicator of prematurity because infants born prematurely tend to be at an increased risk of developing motor, cognitive, and behavioral disorders compared with those born at full term [ 26 , 27 ]. Rather than concluding that prematurity is not an independent factor for delayed oral nutrition in children with CDH, it would be more accurate to assume that preterm birth has no greater impact on delayed oral nutrition than the other two factors. Preterm infants are known to have feeding difficulties regardless of the underlying disease, even if preterm birth is limited to the late preterm period born at ≥ 34 weeks [ 28 ]. Preterm birth might be a risk factor in larger sample sizes or if oral nutrition was assessed earlier than 30 days after weaning from the ventilator. The independent risk factor of C or D defect size may not only be caused by the severe systemic condition of CDH affecting oral nutrition but may also involve gastroesophageal reflux (GER). Schrottenberg et al. reported on 126 patients with CDH, with 33% undergoing Nissen fundoplication at a median age of 61 days post-CDH repair and noted defect size C or D as an independent risk factor for the anti-reflux surgery [ 29 ]. In our cohort, severe GER could have contributed to delayed oral nutrition in patients with defect size C or D. We also evaluated the relationship between delayed oral nutrition and previously reported items. Bevilacqua et al. and Danzer et al. reported that ventilation time for more than 9 days and oxygen demand at 30 days of age, respectively, were related to the risk of poor neurodevelopmental outcomes at 2 years of age, which is consistent with our results [ 17 , 18 ]. Interestingly, the crude OR for delayed oral nutrition is higher than that previously reported, indicating the notable developmental impact of delayed oral nutrition. Wynn et al. first reported that the need for tube feeding at discharge was a risk factor for delayed development at 2 years of age based on the observation of 49 patients with CDH [ 30 ]. However, as the length of hospital stay of patients with CDH varies greatly and can be determined by factors other than nutritional and non-medical factors, our study set an objective cutoff of 30 days post-weaning from mechanical ventilation as a constant indicator from a more medical perspective. To better clarify the correlation between nutritional problems and developmental outcomes and provide effective interventions for high-risk patients, it is necessary to investigate the long-term developmental prognosis, including the specific abilities affected within the developmental process. Another intriguing finding concerning development is that mechanical ventilation for more than 9 days is not simply significantly related to developmental delay but is also an independent risk factor for delayed oral nutrition, which is significantly related to developmental delay (Tables 3 and 4 ). These results imply that mechanical ventilation for more than 9 days may not be an independent risk factor for developmental delay but may rather pose a risk by causing delayed oral nutrition. While we assume that prolonged mechanical ventilation would be an independent risk factor for developmental delay, statistical analyses that control for confounding factors in larger sample sizes would be necessary to reach a definitive conclusion. It is noteworthy that psychomotor development subscales related to delayed oral nutrition, mechanical ventilation for more than 9 days, and oxygen administration for more than 30 days, which were all related to developmental delay, showed significant differences only in the cognitive-adaptive developmental quotient values. In the aforementioned report by Bevilacqua et al., an analysis of 49 postoperative patients with CDH found that mechanical ventilation for more than 9 days significantly increased the risk of both cognitive and motor development at age 2 years [ 17 ]. To their point, it is possible that our examination at 18 months was too early to look at differences in language development. Focusing further on delayed oral nutrition, it is conceivable that it may have been delayed because of delayed cognitive development. It should be noted, however, that these significant differences do not establish a causal relationship between the factors and development but only suggest that it may serve as a clinical marker to predict neurodevelopmental delay. Important practices about nutritional management after diaphragmatic repair in CDH include repeating nutritional assessments until adequate weight gain is ensured and increasing nutritional intake until then, even with high-concentration milk or tube feeding. Haliburton et al. stated that 125 kcal/kg/day is needed at discharge, and Terui et al. stated that 122 kcal/kg/day is needed for catch-up growth at 2 months [ 31 , 32 ]. These amounts are higher than the nutritional requirements of infants without diseases and will require early nutritional team support in the postoperative period. If clinical best practices are to be established based on this study, one suggestion is as follows: the first step is to keep the duration of mechanical ventilation as short as possible. This may decrease the risk of oral intake delays and developmental delays. In addition, for nutritional management, the first step is diagnosing and treating any underlying medical causes leading to oral feeding difficulty [ 33 ]. Among these causes, those related to CDH may benefit from H2 blockers or prokinetic agents if GER is suspected, or respiratory support if suctioning and swallowing are not well coordinated due to tachypnea. At the same time, patients with a low risk of delayed oral nutrition should receive intensive support for oral intake for up to 30 days. High-risk patients should receive such support, and their parents should also be instructed in home tube feeding early in the postoperative period to reduce the risk of delayed discharge due to delayed feeding. In addition, active developmental care is recommended for patients with delayed oral nutrition. This study has several limitations. First, this study was a single-center retrospective study, meaning that the reported associations may not be generalizable to other populations. Although a randomized controlled trial is not feasible for our study, a well-designed prospective study should be conducted to follow these infants from birth to discharge. Second, this study did not include an evaluation of GER. Jaillard et al. pointed out that the incidence of GER varies depending on the diagnostic methods used, while Arcos-Machancoses et al. argued that GER could be diagnosed almost constantly in infants after CDH surgery [ 3 , 34 ]. Additionally, no guidelines recommend the need for a systematic, invasive evaluation of GER in asymptomatic infants with CDH [ 5 ]. As a result, some patients in our cohort were suspected of having GER and were treated with medication, but it cannot be assumed that patients who were not examined or treated did not have GER. We concluded that evaluating the relationship between GER and delayed oral nutrition is difficult. Thirdly, our cohort has too few patients on ECMO to assess its impact accurately. In Japan, the use of ECMO has declined in recent years, as reported by the CDH study groups [ 35 , 36 ]. Therefore, type II errors cannot be ruled out. Fourthly, oral stimulation was not evaluated. Oral stimulation is reported to shorten the time to establish oral nutrition in preterm infants; however, this was not evaluated in this study [ 37 ]. Patients with CDH are often deeply sedated to prevent air swallowing from the time of resuscitation immediately after birth until surgery, and it may be challenging to determine when and how to initiate procedures that stimulate the sucking reflex. Finally, a modified 18-month-old developmental examination was not performed on all cases prior to 2010, which may lead to bias concerning developmental assessment. 5. Conclusion This study highlighted the important issue of delayed oral nutrition establishment in children after CDH repair. A large diaphragmatic defect (C or D size) and ventilatory management for more than 9 days are independent risk factors for delayed oral nutrition, while preterm birth is not, suggesting that the impact of CDH severity is stronger than that of patient immaturity. Additionally, developmental delay is significantly more frequent in cases with delayed oral feeding establishment. Therefore, implementing preventive measures, including early and aggressive nutritional support and careful developmental care for the high-risk group, is recommended to mitigate problems related to delayed oral nutrition. Declarations Acknowledgments We would like to thank Editage (www.editage.com) for English language editing. Previous communication: None Competing interest The authors have no competing interests to declare that are relevant to the content of this article. Funding The authors have no relevant financial or non-financial interests to disclose. Author contributions All authors contributed to the study conception and design. Data collection and analysis were performed by all authors. The first draft of the manuscript was written by Taku Yamamichi. The draft was reviewed and edited by Noriaki Usui, and all authors commented on the second version of the manuscript. All authors read and approved the final manuscript. References Wenstrom KD, Weiner CP, Hanson JW (1991) A five-year statewide experience with congenital diaphragmatic hernia. 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J Pediatr Surg 32:1216–1220. https://doi.org/10.1016/s0022-3468(97)90685-0 D’Agostino JA, Bernbaum JC, Gerdes M et al (1995) Outcome for infants with congenital diaphragmatic hernia requiring extracorporeal membrane oxygenation: The first year. J Pediatr Surg 30:10–15. https://doi.org/10.1016/0022-3468(95)90598-7 Antiel RM, Lin N, Licht DJ et al (2017) Growth trajectory and neurodevelopmental outcome in infants with congenital diaphragmatic hernia. J Pediatr Surg 52:1944–1948. https://doi.org/10.1016/j.jpedsurg.2017.08.063 Bevilacqua F, Morini F, Zaccara A et al (2017) Does ventilatory time retain its validity in predicting neurodevelopmental outcome at two years of age in high-risk congenital diaphragmatic hernia survivors? Am J Perinatol 34:248–252. https://doi.org/10.1055/s-0036-1586120 Danzer E, Gerdes M, Bernbaum J et al (2010) Neurodevelopmental outcome of infants with congenital diaphragmatic hernia prospectively enrolled in an interdisciplinary follow-up program. J Pediatr Surg 45:1759–1766. https://doi.org/10.1016/j.jpedsurg.2010.03.011 Kono Y, Yonemoto N, Kusuda S et al (2016) Developmental assessment of VLBW infants at 18 months of age: A comparison study between KSPD and Bayley III. Brain Dev 38:377–385. https://doi.org/10.1016/j.braindev.2015.10.010 Benjamin JR, Gustafson KE, Smith PB et al (2013) Perinatal factors associated with poor neurocognitive outcome in early school age congenital diaphragmatic hernia survivors. J Pediatr Surg 48:730–737. https://doi.org/10.1016/j.jpedsurg.2012.09.026 Goldstein SA, Watkins KJ, Lowery RE et al (2022) Oral aversion in infants with congenital heart disease: A single-center retrospective cohort study. Pediatr Crit Care Med 23:e171–e179. https://doi.org/10.1097/PCC.0000000000002879 Levine A, Bachar L, Tsangen Z et al (2011) Screening criteria for diagnosis of infantile feeding disorders as a cause of poor feeding or food refusal. J Pediatr Gastroenterol Nutr 52:563–568. https://doi.org/10.1097/MPG.0b013e3181ff72d2 Einarson KD, Arthur HM (2003) Predictors of oral feeding difficulty in cardiac surgical infants. Pediatr Nurs 29:315–319 Kohr LM, Dargan M, Hague A et al (2003) The incidence of dysphagia in pediatric patients after open heart procedures with transesophageal echocardiography. Ann Thorac Surg 76:1450–1456. https://doi.org/10.1016/S0003-4975(03)00956-1 Kogon BE, Ramaswamy V, Todd K et al (2007) Feeding difficulty in newborns following congenital heart surgery. Congenit Heart Dis 2:332–337. https://doi.org/10.1111/j.1747-0803.2007.00121.x Bhutta AT, Cleves MA, Casey PH, Cradock MM, Anand KJ (2002) Cognitive and behavioral outcomes of school-aged children who were born preterm: A meta-analysis. JAMA 288:728–737. https://doi.org/10.1001/jama.288.6.728 Spittle AJ, Orton J (2014) Cerebral palsy and developmental coordination disorder in children born preterm. Semin Fetal Neonatal Med 19:84–89. https://doi.org/10.1016/j.siny.2013.11.005 Engle WA, Tomashek KM, Wallman C, Committee on Fetus and Newborn, American Academy of Pediatrics (2007) Late-preterm’ infants: A population at risk. Pediatrics 120:1390–1401. https://doi.org/10.1542/peds.2007-2952 Guglielmetti LC, Estrada AE, Phillips R et al (2020) Congenital diaphragmatic hernias: Severe defect grade predicts the need for fundoplication. Med (Baltim) 99:e23383. https://doi.org/10.1097/MD.0000000000023383 Wynn J, Aspelund G, Zygmunt A et al (2013) Developmental outcomes of children with congenital diaphragmatic hernia: A multicenter prospective study. J Pediatr Surg 48:1995–2004. https://doi.org/10.1016/j.jpedsurg.2013.02.041 Haliburton B, Chiang M, Marcon M et al (2016) Nutritional intake, energy expenditure, and growth of infants following congenital diaphragmatic hernia repair. J Pediatr Gastroenterol Nutr 62:474–478. https://doi.org/10.1097/MPG.0000000000001000 Terui K, Tazuke Y, Nagata K et al (2021) Weight gain velocity and adequate amount of nutrition for infants with congenital diaphragmatic hernia. Pediatr Surg Int 37:205–212. https://doi.org/10.1007/s00383-020-04785-y Edwards S, Davis AMG, Ernst L et al (2015) Interdisciplinary strategies for treating oral aversions in children. JPEN J Parenter Enteral Nutr 39:899–909. https://doi.org/10.1177/0148607115609311 Arcos-Machancoses JV, Ruiz Hernández C, Martin De Carpi J, Pinillos Pisón S (2018) A systematic review with meta-analysis of the prevalence of gastroesophageal reflux in congenital diaphragmatic hernia pediatric survivors. Dis Esophagus 31. https://doi.org/10.1093/dote/dox158 Lally KP, Lally PA, Van Meurs KP et al (2006) Treatment evolution in high-risk congenital diaphragmatic hernia: Ten years’ experience with diaphragmatic agenesis. Ann Surg 244:505–513. https://doi.org/10.1097/01.sla.0000239027.61651.fa Nagata K, Usui N, Kanamori Y et al (2013) The current profile and outcome of congenital diaphragmatic hernia: A nationwide survey in Japan. J Pediatr Surg 48:738–744. https://doi.org/10.1016/j.jpedsurg.2012.12.017 Greene Z, O’Donnell CPF, Walshe M (2016) Oral stimulation for promoting oral feeding in preterm infants. Cochrane Database Syst Rev 9:CD009720. https://doi.org/10.1002/14651858.CD009720.pub2 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 22 Nov, 2023 Read the published version in Pediatric Surgery International → Version 1 posted Editorial decision: Accepted 03 Nov, 2023 Reviews received at journal 03 Nov, 2023 Reviewers agreed at journal 03 Nov, 2023 Reviewers invited by journal 03 Nov, 2023 Editor assigned by journal 03 Nov, 2023 Submission checks completed at journal 03 Nov, 2023 First submitted to journal 01 Nov, 2023 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3534248","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":245586192,"identity":"cbf76816-ed64-49a3-950c-e6e15514a7ba","order_by":0,"name":"Taku Yamamichi","email":"data:image/png;base64,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","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Taku","middleName":"","lastName":"Yamamichi","suffix":""},{"id":245586193,"identity":"b10f9dae-640a-4a50-8e86-a0cc8e1f89a6","order_by":1,"name":"Yousuke Imanishi","email":"","orcid":"","institution":"Osaka University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yousuke","middleName":"","lastName":"Imanishi","suffix":""},{"id":245586194,"identity":"a6e19744-032a-49f5-80b2-ea2454494a7d","order_by":2,"name":"Takaaki Sakai","email":"","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Takaaki","middleName":"","lastName":"Sakai","suffix":""},{"id":245586195,"identity":"2a969aed-59ea-4959-987c-2c6fa85e67b4","order_by":3,"name":"Mina Yoshida","email":"","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Mina","middleName":"","lastName":"Yoshida","suffix":""},{"id":245586196,"identity":"4caaf788-3ed8-4026-a0d1-00b7449b6a33","order_by":4,"name":"Keita Takayama","email":"","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Keita","middleName":"","lastName":"Takayama","suffix":""},{"id":245586197,"identity":"73cd513a-9e4f-4d70-bfd8-1f16d208c74b","order_by":5,"name":"Naoko Uga","email":"","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Naoko","middleName":"","lastName":"Uga","suffix":""},{"id":245586198,"identity":"42c494e3-2f79-48b5-b97d-c533867118f4","order_by":6,"name":"Satoshi Umeda","email":"","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Satoshi","middleName":"","lastName":"Umeda","suffix":""},{"id":245586199,"identity":"e25a2e43-0ceb-499b-bbe0-a2484dbe62b0","order_by":7,"name":"Noriaki Usui","email":"","orcid":"","institution":"Osaka Women’s and Children’s Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Noriaki","middleName":"","lastName":"Usui","suffix":""}],"badges":[],"createdAt":"2023-11-01 11:04:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3534248/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3534248/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00383-023-05595-8","type":"published","date":"2023-11-22T15:00:35+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":47146195,"identity":"b2d37dd4-bc02-4ea0-923e-801501d471e6","added_by":"auto","created_at":"2023-11-27 15:03:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":353195,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3534248/v1/0c582e08-961b-45b3-b01e-8af526eb6829.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Risk factors for and developmental relation of delayed oral nutrition in infants with congenital diaphragmatic hernia","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eCongenital diaphragmatic hernia (CDH) is a prevalent congenital disability that affects approximately 1 in 2500 to 4000 newborns\u0026nbsp;[1, 2]\u0026nbsp;and presents a significant challenge for surgeons and neonatologists. CDH survivors may experience neurodevelopmental, gastrointestinal, nutritional, pulmonary, and musculoskeletal issues. However, the respiratory dysfunction that is most problematic in the acute phase tends to improve in the long term. Jaillard et al. observed that growth retardation and feeding issues associated with oral aversion were the primary issues in 2-year-old CDH survivors\u0026nbsp;[3]. Nonetheless, research on feeding issues in the chronic phase of CDH survivors is scarce\u0026nbsp;[3\u0026ndash;5].\u003c/p\u003e\n\u003cp\u003eEven after the respiratory status has improved during the subacute postoperative period, some patients may require extended hospitalization owing to oral nutrition difficulties or need to undergo home tube feeding after discharge. Although the cause of these feeding problems, which occur particularly during the first few months of life, is often unknown, the condition in some patients eventually improves in a short time, while in others, it does not improve for several years. In addition, although researchers have noted that this tube-dependent condition from early life can lead to complications such as infections, aspiration, and increased parental and maternal attachment insecurity, they have not thoroughly studied its negative impacts on future development\u0026nbsp;[6\u0026ndash;10].\u003c/p\u003e\n\u003cp\u003eGiven the lack of research on the impact of this tube-dependent condition from early life on future development, we focused on the problem of delayed oral nutrition in the early postnatal period to identify the risk factors involved and assess the impact of this as a predictor of developmental delay at 18 months of age.\u003c/p\u003e"},{"header":"2. Methods","content":"\u003cp\u003eThe medical records of patients diagnosed with CDH who were born at Osaka Women\u0026rsquo;s and Children\u0026rsquo;s Hospital between January 2006 and April 2020 were retrospectively analyzed. Our study focused on patients who underwent diaphragmatic repair during the neonatal period, had isolated CDH with no identifiable genetic causes and no additional medical issues or organ abnormalities, and were discharged from the hospital. These patients were divided into two groups: those who took 30 days or more to establish oral nutrition and those who took less than 30 days. We then analyzed the risk factors for the delayed establishment of oral nutrition, which we defined as a period of 30 days or more. This index was defined as the duration between the cessation of mechanical ventilation and the cessation of tube feeding. The time period of 30 days after mechanical ventilation was set as the period when, in normal clinical practice, the patient would be expected to be in the subacute postoperative period, the respiratory status would no longer be unstable, although oxygen demand may be necessary, and nutritional intake, whether oral or tube feeding, would be stable. At our facility, patients with CDH began tube feeding while on a ventilator, and oral feeding was initiated after extubation. As a result, the total feeding volume was increased with the goal of achieving 100\u0026ndash;120 kcal/kg/day or more until stable weight gain was finally achieved. If oral nutrition alone was not sufficient to achieve this goal, a combination of oral and tube feeding was utilized to attain complete oral nutrition.\u003c/p\u003e \u003cp\u003eWe reviewed the perioperative charts to identify factors such as sex, oligohydramnios, cesarean section, gestational age at birth, birth weight, intrauterine growth restriction, Terui\u0026rsquo;s risk stratification [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], side and size of the diaphragmatic defect, need for patch closure, duration of mechanical ventilation, duration of oxygen administration, duration of tube feeding after extubation, and duration of hospitalization. Terui\u0026rsquo;s risk stratification is a mortality predictor for CDH calculated based on the Apgar score at 1 min and the best oxygenation index within 24 hours after birth [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Category 1 includes neonates with neither risk factor, category 2 includes neonates with either risk factor, and category 3 includes neonates with both risk factors. Category 0 includes patients who did not require respiratory care within 24 h of birth, and category 4 includes patients who did not develop an oxygenation index due to death prior to intubation (including fetal death and stillbirth). The size of the defect was classified into categories A through D based on the intraoperative findings proposed by Tsao et al. [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. An \"A\" defect is entirely surrounded by muscle, a \"B\" defect has a small portion (\u0026lt;\u0026thinsp;50%), a \"C\" defect has a large portion (\u0026gt;\u0026thinsp;50%) of the chest wall devoid of diaphragmatic tissue, and a \"D\" defect is the complete or nearly complete absence of the entire diaphragm. These variables were binarized, and their relationship with delayed oral nutrition for 30 days or more was analyzed separately. The duration of mechanical ventilation and the duration of oxygen administration were also binarized using cutoff values.\u003c/p\u003e \u003cp\u003eMultivariate analysis was conducted to identify the independent risk factors for delayed oral nutrition among the three variables of prolonged duration of mechanical ventilation, preterm birth, and defect size. The length of ventilation time has previously been reported as a risk factor for oral aversion [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], preterm birth represents the patient's immaturity factor, and defect size represents the severity of the disease factor.\u003c/p\u003e \u003cp\u003eIn our cohort of patients who underwent developmental testing at a corrected age of 18 months, we also analyzed the relationship between psychomotor development and delayed oral nutrition. We examined factors that have been linked to the development of CDH, including delayed oral nutrition, low birth weight, hernia on the right side, need for patch closure, need for extracorporeal membrane oxygenation (ECMO), mechanical ventilation for more than 9 days, and oxygen administration for more than 30 days [\u003cspan additionalcitationids=\"CR15 CR16 CR17\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003ePsychomotor development was assessed using the Kyoto Scale of Psychological Development (KSPD), a standardized assessment method for the Japanese population that has been shown to correlate well with the Bayley Scales, third edition [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. A developmental quotient (DQ) value of 85 or higher, calculated using KSPD, indicates normal development, while a DQ value below 85 indicates borderline or delayed development. The KSPD consisted of three subscales: Postural-Motor, Cognitive-Adaptive, and Language-Social. The DQs of the three subscales were obtained. At our hospital, we have been administering the KSPD to all CDH patients since 2010 at the corrected age of 18 months. However, prior to that, it was administered only in cases where the pediatrician responsible for developmental follow-ups deemed it necessary.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical analysis\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe statistical analyses for this study were conducted using JMP software (version 13.0; SAS Institute Inc., Cary, NC, USA). The chi-square test, Mann\u0026ndash;Whitney U test, and logistic regression (multivariate analysis) were utilized. Receiver operating characteristic curve (ROC) analysis was also employed to confirm the cutoff value. The cutoff values for the duration of mechanical ventilation and the duration of oxygen administration for oral nutrition, set at 30 days or more, were determined through the use of the Youden J statistic (sensitivity\u0026thinsp;+\u0026thinsp;specificity-1) based on the optimal operating points from the ROC curve analyses. The data are presented as median and interquartile ranges, with statistical significance defined as P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003cp\u003e \u003cb\u003eEthical considerations\u003c/b\u003e \u003c/p\u003e \u003cp\u003e The study was approved by the Institutional Review Board of Osaka Women's and Children's Hospital (protocol no. 1489) and was conducted in accordance with the principles of the Declaration of Helsinki. Informed consent was not required owing to the retrospective study design and the use of de-identified data. The details of the study were made available on an institutional website, and individuals had the option to opt out of participation.\u003c/p\u003e"},{"header":"3. Results","content":"\u003cp\u003eEighty patients were enrolled in this study (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Cases in which fetal endoscopic tracheal obstruction (FETO) was performed were not included. This cohort was divided into two groups: those who took 30 days or more to have the feeding tube removed after extubation and those who did not; moreover, binarized clinical demographics were compared. That is, univariate analysis was performed between groups with and without delay in establishing oral nutrition (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). As presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, no patients were included in category 0 or 4 in Terui\u0026rsquo;s risk stratification; therefore, the data were binarized by category 1 and category 2 or 3. The cutoff values of the duration of mechanical ventilation and the duration of oxygen administration were determined by the Youden J statistic to be 9 and 37 days, respectively, and were binarized at these values. Eight findings were significantly related to the delayed oral nutrition (delayed oral nutrition vs. oral nutrition not delayed): preterm birth (42.3% vs. 11.1%, P\u0026thinsp;=\u0026thinsp;0.003, crude odds ratio [OR] 5.85, 95% confidence interval (CI) 1.85\u0026ndash;18.55), birth weight less than 2500 g (53.9% vs. 20.4%, P\u0026thinsp;=\u0026thinsp;0.004, crude OR 4.57, 95% CI 1.65\u0026ndash;12.59), Terui\u0026rsquo;s risk stratification of category 2 or 3 (66.7% vs. 23.5%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, crude OR 6.49, 95% CI 2.24\u0026ndash;18.90), need for patch closure (80.8% vs. 31.5%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, crude OR 9.14, 95% CI 2.95\u0026ndash;28.35), defect size of C or D (53.9% vs. 11.1%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, crude OR 9.33, 95% CI 2.97\u0026ndash;29.41), mechanical ventilation for more than 9 days (84.6% vs. 33.3%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, crude OR 11.00, 95% CI 3.29\u0026ndash;36.75), oxygen administration for more than 37 days (69.2% vs. 16.7%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, crude OR 11.25, 95% CI 3.75\u0026ndash;33.73), and hospitalization for more than 90 days (53.9% vs. 7.4%, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, crude OR 14.6, 95% CI 4.06\u0026ndash;52.31). All other investigated factors were not significantly related to delayed oral nutrition.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePatient characteristics\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of patients, n\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, male, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (61.3)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOligohydramnios, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15 (19.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean section, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e43 (53.0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGestational age at birth (weeks)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37.9 [37.0-38.7]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight (g)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2666 [2426\u0026ndash;3042]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIUGR, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (13.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTerui\u0026rsquo;s risk stratification, category 0 / 1 / 2 / 3 / 4, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0 (0) / 47 (61.8) / 23 (30.3) / 6 (7.2) / 0 (0)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDefect on the right side, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (7.4)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDefect size, A / B / C / D, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (25.9) / 40 (49.4) / 15 (18.5) / 5 (6.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed for patch closure, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e38 (48.8)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed for ECMO, n (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (3.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of mechanical ventilation (days)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 [\u003cspan additionalcitationids=\"CR7 CR8 CR9 CR10 CR11 CR12 CR13 CR14 CR15\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of oxygen administration (days)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 [11\u0026ndash;51]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of tube feeding (days)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 [19\u0026ndash;52]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of tube feeding after extubation (days)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 [\u003cspan additionalcitationids=\"CR13 CR14 CR15 CR16 CR17 CR18 CR19 CR20 CR21 CR22 CR23 CR24 CR25 CR26 CR27 CR28 CR29 CR30 CR31 CR32\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDuration of hospitalization (days)\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 [36\u0026ndash;82]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003eIUGR, intrauterine growth restriction; iNO, inhaled nitric oxide; ECMO, extracorporeal membrane oxygenation\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e \u003cp\u003ea Median [interquartile range]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the binarized demographics between the patients with delayed oral nutrition establishment and those without.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDelayed oral nutrition\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;26)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOral nutrition not delayed\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;54)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCrude OR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex, male, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16/26, 61.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33/54, 61.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.02 (0.39\u0026ndash;2.66)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOligohydramnios, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/25, 24.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/52, 17.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.545\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.51 (0.47\u0026ndash;4.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCesarean section, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15/26, 57.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27/54, 50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.634\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.36 (0.53\u0026ndash;3.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreterm birth, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15/26, 42.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/54, 11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.003*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.85 (1.85\u0026ndash;18.55)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight less than 2500 g, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14/26, 53.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11/54, 20.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.004*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.57 (1.65\u0026ndash;12.59)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIUGR, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6/26, 23.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5/54, 9.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.94 (0.80\u0026ndash;10.74)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTerui\u0026rsquo;s risk stratification of category 2 or 3, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8/24, 66.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12/51, 23.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.49 (2.24\u0026ndash;18.90)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSide of hernia (right), n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3/26, 11.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3/54, 5.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.22 (0.42\u0026ndash;11.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed for patch repair, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21/26, 80.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17/54, 31.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.14 (2.95\u0026ndash;28.35)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDefect size of C or D, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14/26, 53.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6/54, 11.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e9.33 (2.97\u0026ndash;29.41)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed for ECMO, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1/26, 3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2/54, 3.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.04 (0.09\u0026ndash;12.02)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation for more than 9 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e22/26, 84.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18/54, 33.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.00 (3.29\u0026ndash;36.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygen administration for more than 37 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18/26, 69.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9/54, 16.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e11.25 (3.75\u0026ndash;33.73)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHospitalization for more than 90 days, n/N, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14/26, 53.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4/54, 7.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e14.6 (4.06\u0026ndash;52.31)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eOR, odds ratio; IUGR, intrauterine growth restriction; ECMO, extracorporeal membrane oxygenation\u003c/p\u003e \u003cp\u003e* Statistically significant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results of the multivariate analysis are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Two independent risk factors for delayed oral nutrition were identified: defect size of C or D (P\u0026thinsp;=\u0026thinsp;0.020, adjusted OR 4.65, 95% CI 1.27\u0026ndash;17.03) and mechanical ventilation for more than 9 days (P\u0026thinsp;=\u0026thinsp;0.007, adjusted OR 6.02, 95% CI 1.665\u0026ndash;21.90). Preterm birth was not identified as an independent risk factor for delayed oral nutrition.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eUnivariate and multivariate analyses of risk factors for delayed oral nutrition\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eUnivariate analysis\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eMultivariate analysis\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCrude OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePreterm birth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.85 (1.85\u0026ndash;18.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.49 (0.88\u0026ndash;13.80)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDefect size of C or D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.33 (2.97\u0026ndash;29.41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.65 (1.27\u0026ndash;17.03)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.020*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation for more than 9 days\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11.00 (3.29\u0026ndash;36.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.02 (1.65\u0026ndash;21.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.007*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003eOR, odds ratio; CI, confidence interval\u003c/p\u003e \u003cp\u003e* Statistically significant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eIn our cohort, 51 (63.8%) patients had a developmental assessment investigated using the KSPD at a corrected age of 18 months. These 51 patients were divided into two groups, those with borderline or delayed psychomotor development and those with normal psychomotor development, and univariate analysis was performed on delayed oral nutrition and six additional items (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Three findings, including delayed oral nutrition, were significantly related to a borderline or delayed psychomotor development (delayed or borderline vs. normal): delayed oral nutrition (50.0% vs. 19.4%, P\u0026thinsp;=\u0026thinsp;0.031, crude OR 4.16, 95% CI 1.19\u0026ndash;14.50), mechanical ventilation for more than 9 days (65.0% vs. 35.5%, P\u0026thinsp;=\u0026thinsp;0.049, crude OR 3.38, 95% CI 1.04\u0026ndash;10.96), and oxygen administration for more than 30 days (65.0% vs. 32.3%, P\u0026thinsp;=\u0026thinsp;0.042, crude OR 3.90, 95% CI 1.19\u0026ndash;12.79). All other perinatal factors were not significantly related to borderline or delayed psychomotor development at a corrected age of 18 months. In addition, subscales of psychomotor development in these three clinical factors significantly associated with borderline or delayed psychomotor development were compared. There was a significant difference between the positive and negative groups in the cognitive-adaptive developmental quotient but not in the posture-motor or language-social developmental quotient for all three factors.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of clinical factors between patients with and without normal psychomotor development at a corrected age of 18 months\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBorderline or delayed PD\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;20)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNormal PD\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;31)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eCrude OR (95%CI)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelayed oral nutrition, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10, 50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6, 19.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.031*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.16 (1.19\u0026ndash;14.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBirth weight less than 2500 g, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10, 50.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10, 32.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2.10 (0.66\u0026ndash;6.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSide of hernia (right), n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3, 15.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1, 3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.287\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.29 (0.51\u0026ndash;55.25)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed for patch closure, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12, 60.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e14, 45.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.393\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.82 (0.58\u0026ndash;5.70)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeed for ECMO, n, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2, 10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1, 3.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.33 (0.28\u0026ndash;39.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation for more than 9 days, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13, 65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11, 35.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.049*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.38 (1.04\u0026ndash;10.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxygen administration for more than 30 days, (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13, 65.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10, 32.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.042*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e3.90 (1.19\u0026ndash;12.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e \u003cp\u003ePD, psychomotor development; OR, odds ratio; CI, confidence interval; DQ value, developmental quotient value using Kyoto Scale of Psychological Development; ECMO, extracorporeal membrane oxygenation\u003c/p\u003e \u003cp\u003e* Statistically significant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of PD subscales in the three clinical factors related to borderline or delayed PD at a corrected age of 18 months\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"10\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c4\" namest=\"c2\"\u003e \u003cp\u003eDelayed oral nutrition\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003eMechanical ventilation\u003c/p\u003e \u003cp\u003efor more than 9 days\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c10\" namest=\"c8\"\u003e \u003cp\u003eOxygen administration\u003c/p\u003e \u003cp\u003efor more than 30 days\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;16\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;35\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;24\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;27\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003ePositive\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;23\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003eNegative\u003c/p\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;28\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePosture-Motor\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 [66\u0026ndash;93]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e82 [73\u0026ndash;95]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.424\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e78 [66\u0026ndash;91]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93 [76\u0026ndash;97]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.083\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e79 [58\u0026ndash;95]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e84 [75\u0026ndash;97]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.113\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCognitive-Adaptive\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 [66\u0026ndash;91]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95 [77\u0026ndash;101]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.017*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e80 [72\u0026ndash;94]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95 [84\u0026ndash;106]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.005*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e79 [71\u0026ndash;101]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e94 [84\u0026ndash;101]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.014*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLanguage-Social\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e79 [64\u0026ndash;94]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 [74\u0026ndash;100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.100\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e84 [72\u0026ndash;99]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93 [73\u0026ndash;98]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e88 [69\u0026ndash;100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e88 [73\u0026ndash;97]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.487\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal DQ\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e82 [67\u0026ndash;92]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e91 [79\u0026ndash;99]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.033*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82 [71\u0026ndash;92]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e93 [81\u0026ndash;100]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.007*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e81 [68\u0026ndash;93]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e92 [82\u0026ndash;97]\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0.011*\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"10\" nameend=\"c10\" namest=\"c1\"\u003e \u003cp\u003eAll data are expressed as the median [interquartile range]. PD, psychomotor development\u003c/p\u003e \u003cp\u003eDQ value, Developmental quotient value using Kyoto Scale of Psychological Development\u003c/p\u003e \u003cp\u003e* Statistically significant\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eWe analyzed the risks of delayed oral nutrition after surgery in 80 patients with CDH by defining delayed oral nutrition as persistent tube feeding beyond 30 days after being taken off mechanical ventilation. Defect size of C or D and mechanical ventilation for more than 9 days were independent factors. In addition, borderline or delayed psychomotor development was significantly associated with delayed oral nutrition in the 51 patients who underwent developmental assessment at a corrected age of 18 months; furthermore, the crude OR for this association was higher than that of other previously reported factors such as the requirement for patch closure [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], ECMO [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], mechanical ventilation for more than 9 days [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], and oxygen administration for more than 30 days [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere have been few reports on delayed oral nutrition in patients with CDH. Muratore et al. studied 121 patients with CDH and found that 29% had oral aversion in the first year of life and reported that prolonged mechanical ventilation and the need for oxygen at discharge were risk factors [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, oral aversion is poorly defined in the literature and lacks a standardized diagnostic criterion, making it difficult to make a clear diagnosis, at least in the short term [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Our study clearly defined the establishment of oral feeding and assessed it as a short-term outcome, one-month after ventilator weaning. This approach has the potential to predict the need for continued tube feeding at home for patients discharged immediately after diaphragmatic repair and to provide parents with relevant risk information.\u003c/p\u003e \u003cp\u003eInterestingly, multivariate analysis identified defect size of C or D and mechanical ventilation for more than 9 days as independent risk factors, with no significant difference for preterm birth. This finding is consistent with previous reports indicating that prolonged mechanical ventilation is a risk factor for poor postoperative oral nutrition in neonatal surgery [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR24\" citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Potential causes of this phenomenon include dysphagia due to long-term intubation, aversion to oral stimulation, and respiratory status that does not allow adequate oral intake.\u003c/p\u003e \u003cp\u003eOur study chose to use preterm birth as a representative indicator of prematurity because infants born prematurely tend to be at an increased risk of developing motor, cognitive, and behavioral disorders compared with those born at full term [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Rather than concluding that prematurity is not an independent factor for delayed oral nutrition in children with CDH, it would be more accurate to assume that preterm birth has no greater impact on delayed oral nutrition than the other two factors. Preterm infants are known to have feeding difficulties regardless of the underlying disease, even if preterm birth is limited to the late preterm period born at \u0026ge;\u0026thinsp;34 weeks [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Preterm birth might be a risk factor in larger sample sizes or if oral nutrition was assessed earlier than 30 days after weaning from the ventilator.\u003c/p\u003e \u003cp\u003eThe independent risk factor of C or D defect size may not only be caused by the severe systemic condition of CDH affecting oral nutrition but may also involve gastroesophageal reflux (GER). Schrottenberg et al. reported on 126 patients with CDH, with 33% undergoing Nissen fundoplication at a median age of 61 days post-CDH repair and noted defect size C or D as an independent risk factor for the anti-reflux surgery [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In our cohort, severe GER could have contributed to delayed oral nutrition in patients with defect size C or D.\u003c/p\u003e \u003cp\u003eWe also evaluated the relationship between delayed oral nutrition and previously reported items. Bevilacqua et al. and Danzer et al. reported that ventilation time for more than 9 days and oxygen demand at 30 days of age, respectively, were related to the risk of poor neurodevelopmental outcomes at 2 years of age, which is consistent with our results [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Interestingly, the crude OR for delayed oral nutrition is higher than that previously reported, indicating the notable developmental impact of delayed oral nutrition. Wynn et al. first reported that the need for tube feeding at discharge was a risk factor for delayed development at 2 years of age based on the observation of 49 patients with CDH [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. However, as the length of hospital stay of patients with CDH varies greatly and can be determined by factors other than nutritional and non-medical factors, our study set an objective cutoff of 30 days post-weaning from mechanical ventilation as a constant indicator from a more medical perspective. To better clarify the correlation between nutritional problems and developmental outcomes and provide effective interventions for high-risk patients, it is necessary to investigate the long-term developmental prognosis, including the specific abilities affected within the developmental process.\u003c/p\u003e \u003cp\u003eAnother intriguing finding concerning development is that mechanical ventilation for more than 9 days is not simply significantly related to developmental delay but is also an independent risk factor for delayed oral nutrition, which is significantly related to developmental delay (Tables\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and \u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). These results imply that mechanical ventilation for more than 9 days may not be an independent risk factor for developmental delay but may rather pose a risk by causing delayed oral nutrition. While we assume that prolonged mechanical ventilation would be an independent risk factor for developmental delay, statistical analyses that control for confounding factors in larger sample sizes would be necessary to reach a definitive conclusion.\u003c/p\u003e \u003cp\u003eIt is noteworthy that psychomotor development subscales related to delayed oral nutrition, mechanical ventilation for more than 9 days, and oxygen administration for more than 30 days, which were all related to developmental delay, showed significant differences only in the cognitive-adaptive developmental quotient values. In the aforementioned report by Bevilacqua et al., an analysis of 49 postoperative patients with CDH found that mechanical ventilation for more than 9 days significantly increased the risk of both cognitive and motor development at age 2 years [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. To their point, it is possible that our examination at 18 months was too early to look at differences in language development. Focusing further on delayed oral nutrition, it is conceivable that it may have been delayed because of delayed cognitive development. It should be noted, however, that these significant differences do not establish a causal relationship between the factors and development but only suggest that it may serve as a clinical marker to predict neurodevelopmental delay.\u003c/p\u003e \u003cp\u003eImportant practices about nutritional management after diaphragmatic repair in CDH include repeating nutritional assessments until adequate weight gain is ensured and increasing nutritional intake until then, even with high-concentration milk or tube feeding. Haliburton et al. stated that 125 kcal/kg/day is needed at discharge, and Terui et al. stated that 122 kcal/kg/day is needed for catch-up growth at 2 months [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. These amounts are higher than the nutritional requirements of infants without diseases and will require early nutritional team support in the postoperative period. If clinical best practices are to be established based on this study, one suggestion is as follows: the first step is to keep the duration of mechanical ventilation as short as possible. This may decrease the risk of oral intake delays and developmental delays. In addition, for nutritional management, the first step is diagnosing and treating any underlying medical causes leading to oral feeding difficulty [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Among these causes, those related to CDH may benefit from H2 blockers or prokinetic agents if GER is suspected, or respiratory support if suctioning and swallowing are not well coordinated due to tachypnea. At the same time, patients with a low risk of delayed oral nutrition should receive intensive support for oral intake for up to 30 days. High-risk patients should receive such support, and their parents should also be instructed in home tube feeding early in the postoperative period to reduce the risk of delayed discharge due to delayed feeding. In addition, active developmental care is recommended for patients with delayed oral nutrition.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, this study was a single-center retrospective study, meaning that the reported associations may not be generalizable to other populations. Although a randomized controlled trial is not feasible for our study, a well-designed prospective study should be conducted to follow these infants from birth to discharge. Second, this study did not include an evaluation of GER. Jaillard et al. pointed out that the incidence of GER varies depending on the diagnostic methods used, while Arcos-Machancoses et al. argued that GER could be diagnosed almost constantly in infants after CDH surgery [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Additionally, no guidelines recommend the need for a systematic, invasive evaluation of GER in asymptomatic infants with CDH [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. As a result, some patients in our cohort were suspected of having GER and were treated with medication, but it cannot be assumed that patients who were not examined or treated did not have GER. We concluded that evaluating the relationship between GER and delayed oral nutrition is difficult. Thirdly, our cohort has too few patients on ECMO to assess its impact accurately. In Japan, the use of ECMO has declined in recent years, as reported by the CDH study groups [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Therefore, type II errors cannot be ruled out. Fourthly, oral stimulation was not evaluated. Oral stimulation is reported to shorten the time to establish oral nutrition in preterm infants; however, this was not evaluated in this study [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Patients with CDH are often deeply sedated to prevent air swallowing from the time of resuscitation immediately after birth until surgery, and it may be challenging to determine when and how to initiate procedures that stimulate the sucking reflex. Finally, a modified 18-month-old developmental examination was not performed on all cases prior to 2010, which may lead to bias concerning developmental assessment.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eThis study highlighted the important issue of delayed oral nutrition establishment in children after CDH repair. A large diaphragmatic defect (C or D size) and ventilatory management for more than 9 days are independent risk factors for delayed oral nutrition, while preterm birth is not, suggesting that the impact of CDH severity is stronger than that of patient immaturity. Additionally, developmental delay is significantly more frequent in cases with delayed oral feeding establishment. Therefore, implementing preventive measures, including early and aggressive nutritional support and careful developmental care for the high-risk group, is recommended to mitigate problems related to delayed oral nutrition.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank Editage (www.editage.com) for English language editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003ePrevious communication:\u0026nbsp;\u003c/u\u003e\u003c/strong\u003eNone\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eCompeting interest\u003c/u\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cu\u003eFunding\u003c/u\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Data collection and analysis were performed by all authors. The first draft of the manuscript was written by Taku Yamamichi. The draft was reviewed and edited by Noriaki Usui, and all authors commented on the second version of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWenstrom KD, Weiner CP, Hanson JW (1991) A five-year statewide experience with congenital diaphragmatic hernia. Am J Obstet Gynecol 165:838\u0026ndash;842. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/0002-9378(91)90425-Q\u003c/span\u003e\u003cspan address=\"10.1016/0002-9378(91)90425-Q\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLangham MR, Kays DW, Ledbetter DJ et al (1996) Congenital diaphragmatic hernia: Epidemiology and outcome. Clin Perinatol 23:671\u0026ndash;688. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/s0095-5108(18)30201-x\u003c/span\u003e\u003cspan address=\"10.1016/s0095-5108(18)30201-x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJaillard SM, Pierrat V, Dubois A et al (2003) Outcome at 2 years of infants with congenital diaphragmatic hernia: A population-based study. 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Ann Surg 244:505\u0026ndash;513. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/01.sla.0000239027.61651.fa\u003c/span\u003e\u003cspan address=\"10.1097/01.sla.0000239027.61651.fa\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNagata K, Usui N, Kanamori Y et al (2013) The current profile and outcome of congenital diaphragmatic hernia: A nationwide survey in Japan. J Pediatr Surg 48:738\u0026ndash;744. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpedsurg.2012.12.017\u003c/span\u003e\u003cspan address=\"10.1016/j.jpedsurg.2012.12.017\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGreene Z, O\u0026rsquo;Donnell CPF, Walshe M (2016) Oral stimulation for promoting oral feeding in preterm infants. Cochrane Database Syst Rev 9:CD009720. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/14651858.CD009720.pub2\u003c/span\u003e\u003cspan address=\"10.1002/14651858.CD009720.pub2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"congenital diaphragmatic hernia, delayed oral nutrition, tube feeding, oral aversion, development, infant nutrition","lastPublishedDoi":"10.21203/rs.3.rs-3534248/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3534248/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003ePurpose\u003c/strong\u003e: To identify risk factors for delayed oral nutrition in infants with a congenital diaphragmatic hernia (CDH) and its impact on developmental delay at 18 months of age.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: This retrospective single-center cohort study compared the clinical parameters in patients with isolated CDH born and treated at our hospital between 2006 and 2020. We evaluated clinical features significantly related to delayed oral nutrition (defined as taking ≥30 days from weaning from mechanical ventilation to weaning from tube feeding)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Twenty-six of the 80 cases had delayed oral nutrition. Univariate analyses showed significant differences. Multivariate analyses were performed on the three items of preterm delivery, defect size (over 50% to nearly entire defect), and ventilation for ≥9 days. We identified the latter two items as independent risk factors. The adjusted odds ratios were 4.65 (95% confidence interval, 1.27–7.03) and 6.02 (1.65–21.90), respectively. Delayed oral nutrition was related to a significantly higher probability of developmental delay at 18 months (crude odds ratio 4.16, 1.19–14.5).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e In patients with CDH, a large defect and ventilatory management over 9 days are independent risk factors for delayed oral nutrition, which is a potent predictor of developmental delay that requires active developmental care.\u003c/p\u003e","manuscriptTitle":"Risk factors for and developmental relation of delayed oral nutrition in infants with congenital diaphragmatic hernia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-11-06 10:28:32","doi":"10.21203/rs.3.rs-3534248/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2023-11-03T15:44:59+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2023-11-03T15:44:31+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"214417cc-123c-4578-bbd2-bb9abc982b4f","date":"2023-11-03T15:43:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2023-11-03T15:33:54+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2023-11-03T15:33:12+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2023-11-03T12:12:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Surgery International","date":"2023-11-01T10:52:14+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-surgery-international","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pesi","sideBox":"Learn more about [Pediatric Surgery International](http://link.springer.com/journal/383)","snPcode":"383","submissionUrl":"https://submission.nature.com/new-submission/383/3","title":"Pediatric Surgery International","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"94522449-06f5-4dae-979f-6854fb3d5aa2","owner":[],"postedDate":"November 6th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-11-27T15:02:10+00:00","versionOfRecord":{"articleIdentity":"rs-3534248","link":"https://doi.org/10.1007/s00383-023-05595-8","journal":{"identity":"pediatric-surgery-international","isVorOnly":false,"title":"Pediatric Surgery International"},"publishedOn":"2023-11-22 15:00:35","publishedOnDateReadable":"November 22nd, 2023"},"versionCreatedAt":"2023-11-06 10:28:32","video":"","vorDoi":"10.1007/s00383-023-05595-8","vorDoiUrl":"https://doi.org/10.1007/s00383-023-05595-8","workflowStages":[]},"version":"v1","identity":"rs-3534248","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3534248","identity":"rs-3534248","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}