Risk factors for early mortality in infants with congenital anomalies of the kidney and urinary tract: a nested cohort study

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Arantes, Marcos Burle Aguiar, Keyla C.C.M.S Cunha, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6647524/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Background To investigate predictive factors associated with neonatal mortality in infants with congenital anomalies of the kidney and urinary tract (CAKUT). Methods This study included a cohort of neonates with CAKUT born at a tertiary hospital between 1996 and 2021. Controls were matched with CAKUT cases by sex, time, and place of birth at a ratio of approximately 2:1. The covariates included in the analysis were sex, gestational age, birth weight, neonatal classification, and birth order. CAKUT was categorized into four phenotypes: urinary tract dilatation, lower urinary tract obstruction (LUTO), cystic diseases, and agenesis/hypodysplasia. The primary outcome was neonatal mortality. Survival analysis was performed using the Cox proportional hazards model. Results 857 cases and 1,755 controls were included in the analysis. The overall early mortality rate was 7.2%. After controlling for confounding factors, CAKUT cases exhibited a higher risk of early mortality than controls (hazard ratio [HR], 25.1; 95%CI, 14.0–45.2). The following covariates were independently associated with early mortality: prematurity (HR, 1.7; 95%CI, 1.2–2.5), LBW (HR, 2.4; 95%CI, 1.6–2.5), VLBW (HR, 2.9; 95%CI, 1.7–1.1), oligohydramnios (HR, 3.2; 95%CI, 2.2–4.8), cystic diseases (HR, 3.8; 95%CI, 2.3–6.4), LUTO (HR, 5.1; 95%CI, 3.0–8.5), kidney agenesis/hypodysplasia (HR, 5.1; 95%CI, 2.9–8.7), and extra-renal malformations (HR, 2.6; 95% CI, 1.7–3.9). Conclusions Our findings indicate that CAKUT was associated with an elevated early mortality rate compared with controls. Factors including prematurity, LBW, oligohydramnios, extra-renal malformations, and specific CAKUT phenotypes with kidney involvement were associated with increased mortality risk. congenital anomalies of the kidney and urinary tract neonatal mortality urinary trat dilation lower urinary tract obstruction Figures Figure 1 Figure 2 Introduction Congenital anomalies affect approximately 4% of all live births[ 1 , 2 ]. Several studies have identified CAKUT as the predominant congenital anomalies detected at birth[ 3 ], potentially accounting for more than 20% of all congenital defects[ 1 , 2 ]. The estimated prevalence of CAKUT ranges from four to 60 per 10,000 live births, depending on factors such as the sample size, diagnostic method, and population studied[ 4 ]. CAKUT have a multifactorial etiology involving genetic, epigenetic, and environmental factors[ 5 ]. Although some cases are linked to syndromes or family history, most are sporadic and isolated to the urinary tract[ 6 ]. CAKUT may originate from single-gene mutations or be caused by early transcription factors and signaling molecule disruptions, including PAX2, EYA1, BMP4, and others[ 7 – 9 ]. The spectrum of CAKUT is broad, ranging from asymptomatic to severe life-threatening conditions[ 4 ]. Early diagnosis and treatment during the prenatal period or shortly after birth, combined with improved survival rates among pediatric kidney transplant recipients, have reduced the mortality of patients with CAKUT[ 10 ]. However, CAKUT remains a cause of early mortality and the leading cause of kidney failure in young children, representing 40–50% of cases[ 11 ]. We previously investigated the risk factors of mortality in infants with CAKUT[ 12 ]. Nevertheless, data on the factors associated with neonatal death in patients with CAKUT are limited[ 13 – 15 ]. In the present study, we sought to address this knowledge gap by expanding the examination of risk factors for early mortality in infants with CAKUT, incorporating a larger sample size derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) registry, an extended temporal period, and a more comprehensive multivariate survival analysis. Materials and Methods Study design, participants, and data source This retrospective cohort study included all neonates and stillborn fetuses diagnosed with CAKUT during prenatal or postnatal care and born between 1996 and 2021 at the Hospital das Clínicas of the University Federal of Minas Gerais (HC-UFMG). The cohort included in this study was part of an ongoing case-control study designed to assess maternal risk factors for CAKUT in a birth cohort using the ECLAMC dataset[16]. The ECLAMC is an epidemiological surveillance system with hospital registrations for birth defects. HC-UFMG is a tertiary care hospital and a reference center for fetal medicine and has been a participant in the ECLAMC since 1989. All newborns with malformations were included in the database, according to the definitions provided in the ECLAMC procedure manual. Data were systematically collected and recorded, as described in detail elsewhere[17]. Ethical approval This study was approved by the Ethics Committee of our institution under the protocol 7.333.449 and followed the principles of the Declaration of Helsinki. Inclusion and exclusion criteria The inclusion criteria for the cases in this study were as follows: (1) birth weight ≥ 500 g, (2) any CAKUT phenotype, and (3) postnatal diagnosis confirmed by urinary tract imaging investigation or autopsy findings. The exclusion criteria for the case group in this study were as follows: (1) birth weight less than 500 g; (2) genital anomalies, including isolated cryptorchidism (without associated CAKUT), hypospadias, and the bladder exstrophy-epispadias complex; (3) CAKUT as a feature of chromosomal syndromes, non-chromosomal syndromes, and multiple malformations in several organs/systems; and (4) patients whose mothers did not consent to participate in ECLAMC. Healthy controls were matched with patients with CAKUT by sex, time, and place of birth at a ratio of approximately 2:1. Covariates assessment and definitions The CAKUT phenotypes were identified after comprehensive imaging workup following the protocol described elsewhere[18, 19]. Briefly, at the Fetal Medicine Division of our institution, all fetuses underwent a comprehensive US assessment to identify kidney and urinary tract anomalies, other malformations, and aneuploidy markers. Postnatally, neonates were systematically evaluated for kidney and urinary tract anomalies and followed up at the Division of Pediatric Nephrourology[20]. Cases were subdivided according to CAKUT phenotypes into four groups: (1) urinary tract dilatation (UTD), (2) lower urinary tract obstruction (LUTO), (3) cystic diseases, and (4) kidney agenesis/hypodysplasia. The UTD group mainly included ureteropelvic junction obstruction, vesicoureteral reflux, and primary megaureter; the LUTO group included cases with anatomical anomalies obstructing the urethra, mainly PUV; the cystic disease group comprised mostly of cases with multicystic dysplastic kidney; and the agenesis/hypodysplasia group comprised cases with kidney agenesis or hypodysplastic kidneys. Covariates included in the analysis were sex, gestational age (premature vs. full-term), birth weight (very low [VLBW], low [LBW], normal [NBW], and high [HBW]), neonate classification according to gestational age and birth weight (small for gestational age [SGA], appropriate for gestational age [AGA]), and large for gestational age [LGA]), birth order (firstborn or not), oligohydramnios, CAKUT phenotypes (UTD, LUTO, cystic diseases, and agenesis/hypodysplasia kidney). For survival analysis purposes, due to the relatively small sample size in some subgroups, cases were also subdivided into two categories: urinary tract dilation (UTD) and kidney anomalies (RA)[21]. Outcome The primary outcome of interest was the time to death, encompassing stillbirth and the neonatal period (initial 28 days postpartum). Statistical analysis In the descriptive analysis, nonparametric values were expressed as the median and interquartile range (IQR), whereas parametric values were presented as the mean and standard deviation, as appropriate. Survival analysis was used to assess the association between the potential risk factors and the primary outcome of interest. Survival analyses were conducted in two stages. Initially, bivariate analysis was performed using the Kaplan–Meier (KM) method. The differences between dichotomous variables were evaluated using a two-sided log-rank test. Potential factors that altered the risk of exposure in these bivariate analyses were incorporated into the multivariable model. Subsequently, the Cox regression model was applied to identify variables independently associated with the event. Inclusion in the final model was determined through a backward stepwise process, employing the likelihood ratio to evaluate the effect of omitting the variables. Variables selected for multivariable analyses were used to construct a final model after examining the interactions and proportionality assumptions. The proportional hazard assumption was assessed graphically using log-log versus time plots for each variable. Data analysis was conducted using SPSS (version 29) and STATA (version 18) statistical packages, with a two-tailed test, and statistical significance was established at P < .05. Results Study participants During the 25 years period span of the study (1996–2021), there were 61,116 births at HC-UFMG, with 956 registered cases of CAKUT in ECLAMC. Based on our exclusion criteria, 99 cases were excluded from the analysis, including isolated hypospadias (n=46), complex genital malformations (n=5), and neonates with multiple and/or chromosomal abnormalities (n=48). According to our criteria, we included 857 cases of CAKUT and 1755 controls in the analysis. The prevalence of non-syndromic CAKUT in our sample was approximately 14 per 1,000 live births. For analysis purposes, the 857 cases were stratified into four subgroups: urinary tract dilatation (UTD) (n=577), cystic diseases (n=123), LUTO (n=87), and agenesis/hypodysplasia (n=70). Baseline characteristics of the study participants and outcomes Table 1 shows the baseline clinical and demographic features of cases and controls. There were no significant differences in sex or birth order between the cases and controls. The mean birth weight was significantly lower, and the prevalence of VLBW and LBW was higher in CAKUT cases. The cases also had a significantly higher prevalence of premature birth and SGA. Among the study participants, 187 deaths occurred within the first 28 days of life, resulting in an overall mortality rate of 7.2% (187/2612). In the univariate analysis, CAKUT cases had approximately 37 times higher odds of mortality than controls (OR 37.3, 95% CI, 20.6–67.3, P < 0.001). Figure 1 illustrates the impact of the presence of CAKUT on the survival of the neonates in the first month of life. Table 1. Baseline clinical characteristics of cases and controls (n = 2,612) Controls (%) (n = 1,755) CAKUT (%) (n = 857) P-value Sex Female Male Firstborn No Yes Birth Weight (g) mean ±SD) Birth Weight classification NBW VLBW LBW HBW Gestational age Full-term Premature Fetal growth classification AGA LGA SGA 30-day Mortality No Yes 514 (29.3) 1241 (70.7) 1098 (62.7) 653 (37.3) 3037±598 1438 (81.9) 224 (12.8) 41 (2.3) 52 (3.0) 1485 (84.6) 270 (15.4) 1459 (83.1) 180 (10.3) 116 (6.6) 1743 (99.3) 12 (0.7) 252 (29.4) 605 (70.6) 516 (60.3) 340 (39.7) 2882±709 609 (71.5) 178 (20.9) 39 (4.6) 26 (3.1) 605 (70.8) 250 (29.2) 674 (79.1) 101 (11.9) 77 (9.0) 682 (79.6) 175 (20.4) 0.96 0.25 <0.001 <0.001 <0.001 0.003 <0.001 Risk factors of early mortality among cases of CAKUT (n = 857) Table 2 presents the results of the univariate survival analysis using the Kaplan-Meier method. The univariate analyses revealed that the following variables were associated with early mortality among neonates: gestational age (log-rank, 170.7, P < 0.001), birth weight (log-rank, 309.1, P < 0.001), fetal growth classification (log-rank, 43.5, P < 0.001), oligohydramnios (log-rank, 341.7, P < 0.001), CAKUT phenotypes (log-rank, 322.7, P < 0.001), kidney involvement (log-rank, 118.6, P < 0.001), and other organ involvement (log-rank, 27.2, P < 0.001). Table 2 Univariate survival analysis using the Kaplan-Meier method. Survival (%) 682 (79.6) Death (%) 175 (20.4) Mean survival time, days (95%CI) Log-Rank P-value Sex Female Male Firstborn No Yes Gestational age Full-term Premature Birth Weight NBW LBW VLBW HBW Fetal growth classification AGA LGA SGA Oligohydramnios No Yes CAKUT phenotypes LUTO Agenesis/ hypodysplasia renal Cystic diseases UTD Kidney involvement Isolated UTD Kidney anomalies Other system involvement No Yes 208 (82,5) 474 (78,3) 420 (81,4) 262 (77,1) 550 (90.9) 132 (52.8) 561 (92,1) 88 (49,4) 6 (15,4) 25 (96,2) 556 (82,5) 84 (83,2) 40 (51,9) 612 (92,4) 70 (35,9) 34 (39,1) 22 (31,4) 80 (65,0) 546 (94,6) 580 (87,3) 102 (52,8) 644 (81,6) 38 (55,9) 44 (17,5) 131 (21,7) 96 (18,6) 78 (22,9) 55 (9.1) 118 (47.2) 48 (7,9) 90 (50,6) 33 (84,6) 1 (3,8) 118 (17,5) 17 (16,8) 37 (48,1) 50 (7,6) 125 (64,1) 53 (60,9) 48 (68,6) 43 (35,0) 31 (5,4) 84 (12,7) 91 (47,2) 145 (18,4) 30 (44,1) 25,0 (23,7 - 26,4) 23,9 (23.1 – 24.9) 24.8 (23.9 – 25,8) 23.5 (22.3 – 24.8) 27.5 (26.8 – 28.1) 16.8 (15.0 – 18.5) 27,8 (27.2 – 28.4) 15,8 (13.7 – 17.8) 5,8 (2.5 – 9.0) 29,9 (29.7 – 30.0) 25,1 (24.2 – 25.8) 25,8 (23.8 – 27.7) 16,5 (13.4 – 19.6) 27,9 (27.4 – 28.5) 11,9 (9.9 – 13.8) 13,0 (10.0 – 15.9) 10,5 (7.4 – 13.6) 20,2 (17.8 – 22.5) 28,5 (28.0 – 29.0) 26,5 (25.8 – 27.2) 16,7 (14.6 – 18.7) 24.9 (24.1 – 25.6) 17.6 (14.3 – 20.9) 1.85 2.41 170.7 309.1 43.5 341.7 322.7 118.6 27.2 0.17 0.12 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 Following the adjustment by the Cox regression model, eight covariates remained independently associated with the primary outcome: prematurity (hazard ratio [HR], 1.7, 95%CI, 1.2 – 2.5, P < 0.001), LBW (HR, 2.4, 95%CI, 1.6 – 2.5, P < 0.001), VLBW (HR, 2.9, 95%CI, 1.7 – 1.1, P < 0.001), oligohydramnios (HR, 3.2E, 95%CI, 2.2 – 4.8, P < 0.001), cystic diseases (HR, 3.8, 95%CI, 2.3 – 6.4, P < 0.001), LUTO (HR, 5.1, 95%CI, 3.0 – 8.5, P < 0.001), agenesis/hypodysplasia kidney (HR, 5.1, 95%CI, 2.9 – 8.7, P < 0.001), and involvement of other organs (HR, 2.6; 95%CI, 1,7 – 3.9, P < 0.001) (Figure 2A). An additional model was evaluated, including only cases, controls, and covariates related to neonate characteristics (prematurity, birth weight, and fetal growth classification). It is noteworthy that after controlling for potential confounding covariates, neonates with CAKUT still exhibited a hazard of approximately 25 times higher for early mortality than the controls (HR, 25.1, 95%CI, 14.0 – 45.2) (Figure 2B). Discussion In this nested retrospective cohort study, we investigated the potential predictive factors associated with early mortality in a large sample of infants with CAKUT born at a tertiary hospital over a period of 25 years. Our findings indicate that the presence of CAKUT was an independent and strong factor associated with early mortality. Notably, among infants with CAKUT, prematurity, LBW, VLBW, oligohydramnios, CAKUT phenotypes with kidney involvement, and other affected organs were significant predictors of early mortality, after controlling for potential confounding factors. Our study detected one case of CAKUT among 71 live births, which was higher than the estimated general frequency of approximately 1 in 500 live births[4]. This finding can be explained by the fact that our institution is a reference center for fetal medicine and congenital anomalies. Notably, the occurrence of CAKUT increased about 37-times the odds of mortality. Even after adjusting for confounding variables, we still found that newborns with CAKUT had an HR of approximately 25 times higher for early mortality than the control group. Previous population-based studies have investigated whether the presence of any congenital birth defects is associated with mortality[22, 23]. Agha et al. [23] evaluated 45,000 children with birth defects and 45,000 matched controls born between 1979 and 1986 in Canada. The authors reported that those with birth defects had a 13 times higher mortality rate. Cardiovascular and central nervous system congenital defects were most frequently present in children who died, whereas CAKUT were detected in 12.5% of the deaths. Another cohort included 262,352 children with birth defects born in New York between 1983 and 2006[22]. The study showed that the mortality risk was 6.7 times higher in children with birth defects than in those without congenital anomalies. The authors also analyzed a selected subgroup with major birth defects and found that kidney agenesis/disgenesis was the second most important risk factor for mortality in the neonatal period (relative risk 69.5, 95%CI 64.5 - 75.2). More recently, the prevalence and impact of CAKUT were evaluated in a cohort of preterm neonates (23–33 weeks) born in the USA between 2000 and 2020 and admitted to intensive care units[24]. CAKUT comprised 2% of all infants (8093 of 409,704), and UTD was the most common diagnosis (70%). Together, all CAKUT phenotypes had an adjusted odds ratio of 3.96 (95% CI 3.70-4.24) for death or severe illness. Gonzalez et al.[25] reported the outcomes of fetal CAKUT and other kidney diseases referred for prenatal evaluation at Texas Children’s Hospital Fetal Center. Of the 129 patients, 73 were discharged, 20 pregnancies were non-viable, and 36 died. The main causes of nonviable pregnancies were kidney agenesis and bilateral multicystic kidney dysplasia, whereas 75% of deaths were associated with multiple developmental anomalies. In our study, the predictors of mortality in patients with CAKUT were prematurity, LBW, VLBW, oligohydramnios, CAKUT phenotypes with kidney involvement, and malformations in other organs. These findings were similar to those of our previous study of 524 cases of CAKUT[12] and aligned with the literature. Prematurity is an independent predictor of CKD stage 2 or higher in children with CAKUT[11]. In a population-based study, Geylis et al. [26] reported that CAKUT, oligohydramnios, SGA, prematurity (< 34 weeks), and post-term delivery were independent risk factors for CKD. The detection of oligohydramnios or anhydramnios before 20 weeks of gestation is considered an important predictor of fetal and neonatal death due to pulmonary hypoplasia[27]. In fetuses with LUTO, oligohydramnios or anhydramnios have shown a sensitivity of 63% and false-positive rate of 24% as individual predictors of postnatal CKD[28]. In our analysis, in addition to the general characteristics of the neonate, such as gestational age and birth weight, the presence of kidney parenchymal involvement and extra-renal malformation associated with CAKUT also increased the mortality risk. Furthermore, infants with cystic diseases, kidney agenesis/hypodysplasia, and LUTO had higher mortality risks than those with urinary tract anomalies alone. This finding is in accordance with those of previous studies[22, 25]. Kidney agenesis/dysgenesis was associated with a high risk of neonatal mortality, whereas kidney agenesis and bilateral multicystic kidney dysplasia result in fetal death [22, 25]. A population-based epidemiological study reported poor outcomes in 284 fetuses with LUTO, including pregnancy termination (24.6%), spontaneous fetal loss (4.6%), spontaneous stillbirths (3.9%), and infant death (10.6%) [29]. Regarding extra-renal defects associated with CAKUT, a recent study evaluated 110 autopsies (90% fetal autopsies and 10% neonatal autopsies) of CAKUT cases and found that 84 cases (76.3%) showed malformations in at least one organ other than the kidney and urinary tract [30]. The strength of our study lies in the analysis of a large sample of births over a long period of 25 years. However, we are aware of the limitations of this study. First, there were some missing data in the ECLAMC records, which were typically based on case reporting forms completed at the point of care. Second, our data were obtained from a single tertiary center, which is a reference for fetal medicine. Consequently, the frequency of CAKUT and the severity of cases were higher than those in the general population. For both the reasons, our results cannot be applied to different scenarios. Third, it was not possible to investigate the mechanisms by which the risk factors contribute to mortality. Nevertheless, our study showed a significant impact of CAKUT, particularly kidney-specific anomalies, on perinatal mortality, highlighting the importance of early diagnosis and targeted management strategies. In summary, the CAKUT represents a prevalent spectrum of anomalies associated with an increased early mortality rate. CAKUT phenotypes exhibiting kidney involvement and extra-renal malformations are associated with a higher risk of early mortality. In addition, established risk factors for early mortality in the pediatric population, including prematurity, LBW, VLBW, and oligohydramnios, additionally contribute to mortality in CAKUT cases. Early prenatal detection of specific CAKUT subtypes and congenital anomalies in other organs may contribute to refined clinical risk assessment and inform decision-making processes in obstetric and neonatal care. Declarations Authors contribution: Conceptualization: Ana Cristina Simões e Silva, Eduardo Araújo Oliveira, Marcos J. Burle Aguiar; Methodology: Rodrigo Rezende Arantes, Keyla C. Cunha, Arthur A. Amaral, José Renato O. Melo, Beatriz C. Vieira, Enrico A Colosimo; Formal analysis and investigation: Enrico A Colosimo, Eduardo Araújo Oliveira, Rodrigo Rezende Arantes; Writing - original draft preparation: Rodrigo Rezende Arantes, Keyla C. Cunha, Arthur A. Amaral, José Renato O. Melo, Beatriz C. Vieira; Writing - review and editing: Ana Cristina Simões e Silva, Eduardo Araújo Oliveira, Marcos J. Burle Aguiar; Funding acquisition: Ana Cristina Simões e Silva; Supervision: Ana Cristina Simões e Silva, Eduardo Araújo Oliveira, Marcos J. Burle Aguiar Ethical Statements/ Ethical Approval: This study was approved by the Ethics Committee of our institution under the protocol 7.333.449 and followed the principles of the Declaration of Helsinki. Data availability: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Funding: This work was partially supported by Brazilian National Council of Research Development (CNPq - Grant # 304496/2023-5), Coordination of High Education Level Personnel (CAPES) and Foundation of Research of Minas Gerais (FAPEMIG). Conflict of Interest: None declared. Correspondence: Ana Cristina Simões e Silva, MD, PhD. Full Professor, Department of Pediatrics, Faculty of Medicine, UFMG. Alfredo Balena Avenue, 190, 2nd floor, room # 281, Belo Horizonte, MG, Brazil. Zip code: 30130-100. Phone: +55-31-34098073. E-mail: [email protected] References Loane M, Dolk H, Kelly A, Teljeur C, Greenlees R, Densem J, Group EW (2011) Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe. 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Pediatr Nephrol 37:613-623.10.1007/s00467-021-05254-x Vasconcelos MA, Simões e Silva AC, Gomes IR, Carvalho RA, Pinheiro SV, Colosimo EA, Yorgin P, Mak RH, Oliveira EA (2019) A clinical predictive model of chronic kidney disease in children with posterior urethral valves. Pediatr Nephrol 34:283-294.10.1007/s00467-018-4078-0 Ma Q, Li YQ, Meng QT, Yang B, Zhang HT, Shi H, Liu CY, Xiang TC, Zhao N, Rao J (2024) Maternal diseases and congenital anomalies of the kidney and urinary tract in offspring: a cohort study. World J Pediatr 20:1168-1178.10.1007/s12519-024-00822-1 Wang Y, Hu J, Druschel CM (2010) A retrospective cohort study of mortality among children with birth defects in New York State, 1983–2006. Birth Defects Res A Clin Mol Teratol 88:1023-1031.10.1002/bdra.20711 Agha MM, Williams JI, Marrett L, To T, Dodds L (2006) Determinants of survival in children with congenital abnormalities: a long-term population-based cohort study. Birth Defects Res A Clin Mol Teratol 76:46-54.10.1002/bdra.20218 Hays T, Thompson MV, Bateman DA, Sahni R, Tolia VN, Clark RH, Gharavi AG (2022) The Prevalence and Clinical Significance of Congenital Anomalies of the Kidney and Urinary Tract in Preterm Infants. JAMA Netw Open 5:e2231626.10.1001/jamanetworkopen.2022.31626 Plaud Gonzalez AM, Joseph C, Stover SR, Nassr A, Koh CJ, Angelo JR, Braun MC (2023) Fetal Nephrology: A Quaternary Care Center Experience. Kidney360 4:333-340.10.34067/KID.0004782022 Geylis M, Coreanu T, Novack V, Landau D (2023) Risk factors for childhood chronic kidney disease: a population-based study. Pediatr Nephrol 38:1569-1576.10.1007/s00467-022-05714-y Moxey-Mims M, Raju TNK (2018) Anhydramnios in the Setting of Renal Malformations: The National Institutes of Health Workshop Summary. Obstet Gynecol 131:1069-1079.10.1097/AOG.0000000000002637 Morris RK, Malin GL, Khan KS, Kilby MD (2009) Antenatal ultrasound to predict postnatal renal function in congenital lower urinary tract obstruction: systematic review of test accuracy. BJOG 116:1290-1299.10.1111/j.1471-0528.2009.02194.x Malin G, Tonks AM, Morris RK, Gardosi J, Kilby MD (2012) Congenital lower urinary tract obstruction: a population-based epidemiological study. BJOG 119:1455-1464.10.1111/j.1471-0528.2012.03476.x Aytekin EC, Sanhal CY, Toru HS (2024) Congenital anomalies of kidney and urinary tract (CAKUT) and associated extra-renal anomalies in fetal autopsies. Indian J Pathol Microbiol 67:289-296.10.4103/ijpm.ijpm_45_23 Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Major Revisions Needed 09 Jun, 2025 Reviewers agreed at journal 15 May, 2025 Reviewers invited by journal 13 May, 2025 Editor assigned by journal 13 May, 2025 First submitted to journal 12 May, 2025 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-6647524","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":456178564,"identity":"7716fe9d-bf3d-4d1a-afa2-6480e03b4452","order_by":0,"name":"Rodrigo R. Arantes","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Rodrigo","middleName":"R.","lastName":"Arantes","suffix":""},{"id":456178565,"identity":"cb81607d-6d84-4cba-9d23-ee65cbd9a7b7","order_by":1,"name":"Marcos Burle Aguiar","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Marcos","middleName":"Burle","lastName":"Aguiar","suffix":""},{"id":456178566,"identity":"8bcec7d9-31e9-4b22-98f0-42ee786de45b","order_by":2,"name":"Keyla C.C.M.S Cunha","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Keyla","middleName":"C.C.M.S","lastName":"Cunha","suffix":""},{"id":456178567,"identity":"25226121-ddfa-4ddf-a4d4-4bb0fcd1187b","order_by":3,"name":"Arthur Aguiar Amaral","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Arthur","middleName":"Aguiar","lastName":"Amaral","suffix":""},{"id":456178568,"identity":"a99ca3c9-0a96-4a11-8d85-97af65b2df76","order_by":4,"name":"José Renato O. Melo","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"José","middleName":"Renato O.","lastName":"Melo","suffix":""},{"id":456178569,"identity":"9715221c-628d-44cc-8699-ec5644181fc0","order_by":5,"name":"Beatriz Chaves C. Vieira","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Beatriz","middleName":"Chaves C.","lastName":"Vieira","suffix":""},{"id":456178570,"identity":"99e0766f-fe57-4536-a5de-a27386644474","order_by":6,"name":"Enrico A. Colosimo","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Enrico","middleName":"A.","lastName":"Colosimo","suffix":""},{"id":456178571,"identity":"36cf47f0-f1f2-40e1-9aed-dc2ca865c883","order_by":7,"name":"Eduardo A. Oliveira","email":"","orcid":"","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":false,"prefix":"","firstName":"Eduardo","middleName":"A.","lastName":"Oliveira","suffix":""},{"id":456178572,"identity":"bf44ef12-9663-4ebf-80bf-41e9adaa4e80","order_by":8,"name":"Ana Cristina Simões e Silva","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYLCChAIGBn4JMFNChkgtBgwMkjMYGBuAWniItAaoxeAGWAsDYS387ccff3hgcFje+Hbz8Uc3aix4GNgPH92AT4vEmRwziQSDw4bb7hxLbM45BnQYT1raDbzW3OBhA/oljXHbjRzD5hw2oBYJHjO8WuRvsD/+ANRiv3kGSMs/IrQAfW0AdJhN4gYJoJbcNiK0GEL8YpM840Za4uzcPgkeNkJ+kTt+/PHHHxUStv0zkg98zvlWJ8fPfvgYfu9jADbSlI+CUTAKRsEowAYAlEVGLkOcL4IAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-9222-3882","institution":"UFMG: Universidade Federal de Minas Gerais","correspondingAuthor":true,"prefix":"","firstName":"Ana","middleName":"Cristina Simões e","lastName":"Silva","suffix":""}],"badges":[],"createdAt":"2025-05-12 14:21:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6647524/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6647524/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":83018860,"identity":"89c504a9-375f-4fbc-b7a9-b6cbcc8149d1","added_by":"auto","created_at":"2025-05-19 07:03:23","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":24764,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan–Meier curves showing the probability of neonatal survival in neonates with CAKUT compared to controls (A); and among infants with CAKUT according to the gestational age (B); the presence of oligoidramnios (C); and the CAKUT phenotypes (D), n = 857. Legend: UTD, urinary tract dilation; LUTO, lower urinary tract obstruction.\u003c/p\u003e","description":"","filename":"Onlinefloatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-6647524/v1/9a46e26458ba34eef0a53280.png"},{"id":83018871,"identity":"8a1d0f84-dc99-40a9-ba2f-ca8f05c012b9","added_by":"auto","created_at":"2025-05-19 07:03:24","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":4134392,"visible":true,"origin":"","legend":"\u003cp\u003eAdjusted hazard ratio of the risk of death in infants with CAKUT. Panel (A) includes only newborns with CAKUT; panel (B) includes newborns with CAKUT and controls. Reference category (red squares), gray squares (non-significant), and blue squares (P \u0026lt; 0.001) (n = 857). Legend: NBW, normal body weight; LBW, low birth weight; VLBW, very low birth weight; HBW, high birth weight; AGA, adequate for gestational age; LGA, large for gestational age; SGA, small for gestational age; UTD, urinary tract dilation; LUTO, lower urinary tract obstruction.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6647524/v1/9e3de85e6f3b846fed65b0ad.jpg"},{"id":83019949,"identity":"0d7065a8-968e-4cb8-8f02-bf49356e4f4e","added_by":"auto","created_at":"2025-05-19 07:11:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4834679,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6647524/v1/7a7a88e3-61b6-4c1d-a148-d3b95feb102c.pdf"}],"financialInterests":"","formattedTitle":"Risk factors for early mortality in infants with congenital anomalies of the kidney and urinary tract: a nested cohort study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCongenital anomalies affect approximately 4% of all live births[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Several studies have identified CAKUT as the predominant congenital anomalies detected at birth[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], potentially accounting for more than 20% of all congenital defects[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The estimated prevalence of CAKUT ranges from four to 60 per 10,000 live births, depending on factors such as the sample size, diagnostic method, and population studied[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCAKUT have a multifactorial etiology involving genetic, epigenetic, and environmental factors[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Although some cases are linked to syndromes or family history, most are sporadic and isolated to the urinary tract[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. CAKUT may originate from single-gene mutations or be caused by early transcription factors and signaling molecule disruptions, including PAX2, EYA1, BMP4, and others[\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The spectrum of CAKUT is broad, ranging from asymptomatic to severe life-threatening conditions[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Early diagnosis and treatment during the prenatal period or shortly after birth, combined with improved survival rates among pediatric kidney transplant recipients, have reduced the mortality of patients with CAKUT[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, CAKUT remains a cause of early mortality and the leading cause of kidney failure in young children, representing 40\u0026ndash;50% of cases[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe previously investigated the risk factors of mortality in infants with CAKUT[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Nevertheless, data on the factors associated with neonatal death in patients with CAKUT are limited[\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the present study, we sought to address this knowledge gap by expanding the examination of risk factors for early mortality in infants with CAKUT, incorporating a larger sample size derived from the Latin American Collaborative Study of Congenital Malformations (ECLAMC) registry, an extended temporal period, and a more comprehensive multivariate survival analysis.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design, participants, and data source\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis retrospective cohort study included all neonates and stillborn fetuses diagnosed with CAKUT during prenatal or postnatal care and born between 1996 and 2021 at the Hospital das Clínicas of the University Federal of Minas Gerais (HC-UFMG). \u0026nbsp;The cohort included in this study was part of an ongoing case-control study designed to assess maternal risk factors for CAKUT in a birth cohort using the ECLAMC dataset[16]. The ECLAMC is an epidemiological surveillance system with hospital registrations for birth defects. HC-UFMG is a tertiary care hospital and a reference center for fetal medicine and has been a participant in the ECLAMC since 1989. All newborns with malformations were included in the database, according to the definitions provided in the ECLAMC procedure manual. Data were systematically collected and recorded, as described in detail elsewhere[17].\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eEthical approval\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of our institution under the protocol 7.333.449 and followed the principles of the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInclusion and exclusion criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe inclusion criteria for the cases in this study were as follows: (1) birth weight ≥ 500 g, (2) any CAKUT phenotype, and (3) postnatal diagnosis confirmed by urinary tract imaging investigation or autopsy findings. The exclusion criteria for the case group in this study were as follows: (1) birth weight less than 500 g; (2) genital anomalies, including isolated cryptorchidism (without associated CAKUT), hypospadias, and the bladder exstrophy-epispadias complex; (3) CAKUT as a feature of chromosomal syndromes, non-chromosomal syndromes, and multiple malformations in several organs/systems; and (4) patients whose mothers did not consent to participate in ECLAMC. Healthy controls were matched with patients with CAKUT by sex, time, and place of birth at a ratio of approximately 2:1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eCovariates assessment and definitions\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CAKUT phenotypes were identified after comprehensive imaging workup following the protocol described elsewhere[18, 19]. Briefly, at the Fetal Medicine Division of our institution, all fetuses underwent a comprehensive US assessment to identify kidney and urinary tract anomalies, other malformations, and aneuploidy markers. Postnatally, neonates were systematically evaluated for kidney and urinary tract anomalies and followed up at the Division of Pediatric Nephrourology[20]. Cases were subdivided according to CAKUT phenotypes into four groups: (1) urinary tract dilatation (UTD), (2) lower urinary tract obstruction (LUTO), (3) cystic diseases, and (4) kidney agenesis/hypodysplasia. The UTD group mainly included ureteropelvic junction obstruction, vesicoureteral reflux, and primary megaureter; the LUTO group included cases with anatomical anomalies obstructing the urethra, mainly PUV; the cystic disease group comprised mostly of cases with multicystic dysplastic kidney; and the agenesis/hypodysplasia group comprised cases with kidney agenesis or hypodysplastic kidneys.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCovariates included in the analysis were sex, gestational age (premature vs. full-term), birth weight (very low [VLBW], low [LBW], normal [NBW], and high [HBW]), neonate classification according to gestational age and birth weight (small for gestational age [SGA], appropriate for gestational age [AGA]), and large for gestational age [LGA]), birth order (firstborn or not), oligohydramnios, CAKUT phenotypes (UTD, LUTO, cystic diseases, and agenesis/hypodysplasia kidney). For survival analysis purposes, due to the relatively small sample size in some subgroups, cases were also subdivided into two categories: urinary tract dilation (UTD) and kidney anomalies (RA)[21].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOutcome\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome of interest was the time to death, encompassing stillbirth and the neonatal period (initial 28 days postpartum).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStatistical analysis\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn the descriptive analysis, nonparametric values were expressed as the median and interquartile range (IQR), whereas parametric values were presented as the mean and standard deviation, as appropriate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSurvival analysis was used to assess the association between the potential risk factors and the primary outcome of interest. Survival analyses were conducted in two stages. Initially, bivariate analysis was performed using the Kaplan–Meier (KM) method. The differences between dichotomous variables were evaluated using a two-sided log-rank test. Potential factors that altered the risk of exposure in these bivariate analyses were incorporated into the multivariable model. Subsequently, the Cox regression model was applied to identify variables independently associated with the event. Inclusion in the final model was determined through a backward stepwise process, employing the likelihood ratio to evaluate the effect of omitting the variables. Variables selected for multivariable analyses were used to construct a final model after examining the interactions and proportionality assumptions. The proportional hazard assumption was assessed graphically using log-log versus time plots for each variable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eData analysis was conducted using SPSS (version 29) and STATA (version 18) statistical packages, with a two-tailed test, and statistical significance was established at P \u0026lt; .05.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy participants\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the 25 years period span of the study (1996\u0026ndash;2021), there were 61,116 births at HC-UFMG, with 956 registered cases of CAKUT in ECLAMC. Based on our exclusion criteria, 99 cases were excluded from the analysis, including isolated hypospadias (n=46), complex genital malformations (n=5), and neonates with multiple and/or chromosomal abnormalities (n=48). According to our criteria, we included 857 cases of CAKUT and 1755 controls in the analysis. The prevalence of non-syndromic CAKUT in our sample was approximately 14 per 1,000 live births. For analysis purposes, the 857 cases were stratified into four subgroups: urinary tract dilatation (UTD) (n=577), cystic diseases (n=123), LUTO (n=87), and agenesis/hypodysplasia (n=70).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eBaseline characteristics of the study participants and outcomes\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 1 shows the baseline clinical and demographic features of cases and controls. There were no significant differences in sex or birth order between the cases and controls. The mean birth weight was significantly lower, and the prevalence of VLBW and LBW was higher in CAKUT cases. The cases also had a significantly higher prevalence of premature birth and SGA. Among the study participants, 187 deaths occurred within the first 28 days of life, resulting in an overall mortality rate of 7.2% (187/2612). In the univariate analysis, CAKUT cases had approximately 37 times higher odds of mortality than controls (OR 37.3, 95% CI, 20.6\u0026ndash;67.3, P \u0026lt; 0.001). Figure 1 illustrates the impact of the presence of CAKUT on the survival of the neonates in the first month of life.\u003c/p\u003e\n\u003cp\u003eTable 1. Baseline clinical characteristics of cases and controls (n = 2,612)\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"612\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 262px;\"\u003e\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eControls (%)\u003c/p\u003e\n \u003cp\u003e(n = 1,755)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003eCAKUT (%)\u003c/p\u003e\n \u003cp\u003e(n = 857)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003eP-value\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 262px;\"\u003e\n \u003cp\u003eSex\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Male\u003c/p\u003e\n \u003cp\u003eFirstborn\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003eBirth Weight (g) mean \u0026plusmn;SD)\u003c/p\u003e\n \u003cp\u003eBirth Weight classification\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; NBW\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; VLBW\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;LBW\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; HBW\u003c/p\u003e\n \u003cp\u003eGestational age\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Full-term\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Premature\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFetal growth classification \u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;AGA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;LGA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;SGA\u003c/p\u003e\n \u003cp\u003e30-day Mortality\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e514 (29.3)\u003c/p\u003e\n \u003cp\u003e1241 (70.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1098 (62.7)\u003c/p\u003e\n \u003cp\u003e653 (37.3)\u003c/p\u003e\n \u003cp\u003e3037\u0026plusmn;598\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1438 (81.9)\u003c/p\u003e\n \u003cp\u003e224 (12.8)\u003c/p\u003e\n \u003cp\u003e41 (2.3)\u003c/p\u003e\n \u003cp\u003e52 (3.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1485 (84.6)\u003c/p\u003e\n \u003cp\u003e270 (15.4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1459 (83.1)\u003c/p\u003e\n \u003cp\u003e180 (10.3)\u003c/p\u003e\n \u003cp\u003e116 (6.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1743 (99.3)\u003c/p\u003e\n \u003cp\u003e12 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 109px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e252 (29.4)\u003c/p\u003e\n \u003cp\u003e605 (70.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e516 (60.3)\u003c/p\u003e\n \u003cp\u003e340 (39.7)\u003c/p\u003e\n \u003cp\u003e2882\u0026plusmn;709\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e609 (71.5)\u003c/p\u003e\n \u003cp\u003e178 (20.9)\u003c/p\u003e\n \u003cp\u003e39 (4.6)\u003c/p\u003e\n \u003cp\u003e26 (3.1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e605 (70.8)\u003c/p\u003e\n \u003cp\u003e250 (29.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e674 (79.1)\u003c/p\u003e\n \u003cp\u003e101 (11.9)\u003c/p\u003e\n \u003cp\u003e77 (9.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e682 (79.6)\u003c/p\u003e\n \u003cp\u003e175 (20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 128px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.96\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u0026nbsp;\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRisk factors of early mortality among cases of CAKUT (n = 857)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Table 2 presents the results of the univariate survival analysis using the Kaplan-Meier method. The univariate analyses revealed that the following variables were associated with early mortality among neonates: gestational age (log-rank, 170.7, P \u0026lt; 0.001), birth weight (log-rank, 309.1, P \u0026lt; 0.001), fetal growth classification (log-rank, 43.5, P \u0026lt; 0.001), oligohydramnios (log-rank, 341.7, P \u0026lt; 0.001), CAKUT phenotypes (log-rank, 322.7, P \u0026lt; 0.001), kidney involvement (log-rank, 118.6, P \u0026lt; 0.001), and other organ involvement (log-rank, 27.2, P \u0026lt; 0.001).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2\u003c/strong\u003e Univariate survival analysis using the Kaplan-Meier method.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"876\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003eSurvival (%)\u003c/p\u003e\n \u003cp\u003e682 \u0026nbsp;(79.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003eDeath (%)\u003c/p\u003e\n \u003cp\u003e175 \u0026nbsp;(20.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eMean survival time, days \u0026nbsp;(95%CI)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003eLog-Rank\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eP-value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Female\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Male\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eFirstborn\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Yes\u003c/p\u003e\n \u003cp\u003eGestational age\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Full-term\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Premature\u003c/p\u003e\n \u003cp\u003eBirth Weight\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;NBW\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;LBW\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;VLBW\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;HBW\u003c/p\u003e\n \u003cp\u003eFetal growth classification\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; AGA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; LGA\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; SGA\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eOligohydramnios\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u003c/p\u003e\n \u003cp\u003eCAKUT phenotypes\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; LUTO\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Agenesis/ hypodysplasia renal\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Cystic diseases\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; UTD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Kidney involvement\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Isolated UTD\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Kidney anomalies\u003c/p\u003e\n \u003cp\u003eOther system involvement\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; No\u003c/p\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Yes\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 94px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e208 (82,5)\u003c/p\u003e\n \u003cp\u003e474 (78,3)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e420 (81,4)\u003c/p\u003e\n \u003cp\u003e262 (77,1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e550 (90.9)\u003c/p\u003e\n \u003cp\u003e132 (52.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e561 (92,1)\u003c/p\u003e\n \u003cp\u003e88 (49,4)\u003c/p\u003e\n \u003cp\u003e6 (15,4)\u003c/p\u003e\n \u003cp\u003e25 (96,2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e556 (82,5)\u003c/p\u003e\n \u003cp\u003e84 (83,2)\u003c/p\u003e\n \u003cp\u003e40 (51,9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e612 (92,4)\u003c/p\u003e\n \u003cp\u003e70 (35,9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34 (39,1)\u003c/p\u003e\n \u003cp\u003e22 (31,4)\u003c/p\u003e\n \u003cp\u003e80 (65,0)\u003c/p\u003e\n \u003cp\u003e546 (94,6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e580 (87,3)\u003c/p\u003e\n \u003cp\u003e102 (52,8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e644 (81,6)\u003c/p\u003e\n \u003cp\u003e38 (55,9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e44 (17,5)\u003c/p\u003e\n \u003cp\u003e131 (21,7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e96 (18,6)\u003c/p\u003e\n \u003cp\u003e78 (22,9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e55 (9.1)\u003c/p\u003e\n \u003cp\u003e118 (47.2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e48 (7,9)\u003c/p\u003e\n \u003cp\u003e90 (50,6)\u003c/p\u003e\n \u003cp\u003e33 (84,6)\u003c/p\u003e\n \u003cp\u003e1 (3,8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e118 (17,5)\u003c/p\u003e\n \u003cp\u003e17 (16,8)\u003c/p\u003e\n \u003cp\u003e37 (48,1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e50 (7,6)\u003c/p\u003e\n \u003cp\u003e125 (64,1)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e53 (60,9)\u003c/p\u003e\n \u003cp\u003e48 (68,6)\u003c/p\u003e\n \u003cp\u003e43 (35,0)\u003c/p\u003e\n \u003cp\u003e31 (5,4)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e84 (12,7)\u003c/p\u003e\n \u003cp\u003e91 (47,2)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e145 (18,4)\u003c/p\u003e\n \u003cp\u003e30 (44,1)\u003c/p\u003e\u0026nbsp;\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 246px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25,0 (23,7 - 26,4)\u003c/p\u003e\n \u003cp\u003e23,9 (23.1 \u0026ndash; 24.9)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24.8 (23.9 \u0026ndash; 25,8)\u003c/p\u003e\n \u003cp\u003e23.5 (22.3 \u0026ndash; 24.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27.5 (26.8 \u0026ndash; 28.1)\u003c/p\u003e\n \u003cp\u003e16.8 (15.0 \u0026ndash; 18.5)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27,8 (27.2 \u0026ndash; 28.4)\u003c/p\u003e\n \u003cp\u003e15,8 (13.7 \u0026ndash; 17.8)\u003c/p\u003e\n \u003cp\u003e5,8 (2.5 \u0026ndash; 9.0)\u003c/p\u003e\n \u003cp\u003e29,9 (29.7 \u0026ndash; 30.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25,1 (24.2 \u0026ndash; 25.8)\u003c/p\u003e\n \u003cp\u003e25,8 (23.8 \u0026ndash; 27.7)\u003c/p\u003e\n \u003cp\u003e16,5 (13.4 \u0026ndash; 19.6)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27,9 (27.4 \u0026ndash; 28.5)\u003c/p\u003e\n \u003cp\u003e11,9 (9.9 \u0026ndash; 13.8)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e13,0 (10.0 \u0026ndash; 15.9)\u003c/p\u003e\n \u003cp\u003e10,5 (7.4 \u0026ndash; 13.6)\u003c/p\u003e\n \u003cp\u003e20,2 (17.8 \u0026ndash; 22.5)\u003c/p\u003e\n \u003cp\u003e28,5 (28.0 \u0026ndash; 29.0)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e26,5 (25.8 \u0026ndash; 27.2)\u003c/p\u003e\n \u003cp\u003e16,7 (14.6 \u0026ndash; 18.7)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e24.9 (24.1 \u0026ndash; 25.6)\u003c/p\u003e\n \u003cp\u003e17.6 (14.3 \u0026ndash; 20.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 101px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e1.85\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e2.41\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e170.7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e309.1\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e43.5\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e341.7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e322.7\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e118.6\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e27.2\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.12\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\u0026nbsp;\u0026nbsp;\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eFollowing the adjustment by the Cox regression model, eight covariates remained independently associated with the primary outcome: prematurity (hazard ratio [HR], 1.7, 95%CI, 1.2 \u0026ndash; 2.5, P \u0026lt; 0.001), LBW (HR, 2.4, 95%CI, 1.6 \u0026ndash; 2.5, P \u0026lt; 0.001), VLBW (HR, 2.9, 95%CI, 1.7 \u0026ndash; 1.1, P \u0026lt; 0.001), oligohydramnios (HR, 3.2E, 95%CI, 2.2 \u0026ndash; 4.8, P \u0026lt; 0.001), cystic diseases (HR, 3.8, 95%CI, 2.3 \u0026ndash; 6.4, P \u0026lt; 0.001), LUTO (HR, 5.1, 95%CI, 3.0 \u0026ndash; 8.5, P \u0026lt; 0.001), agenesis/hypodysplasia kidney (HR, 5.1, 95%CI, 2.9 \u0026ndash; 8.7, P \u0026lt; 0.001), and involvement of other organs (HR, 2.6; 95%CI, 1,7 \u0026ndash; 3.9, P \u0026lt; 0.001) (Figure 2A). An additional model was evaluated, including only cases, controls, and covariates related to neonate characteristics (prematurity, birth weight, and fetal growth classification). It is noteworthy that after controlling for potential confounding covariates, neonates with CAKUT still exhibited a hazard of approximately 25 times higher for early mortality than the controls (HR, 25.1, 95%CI, 14.0 \u0026ndash; 45.2) (Figure 2B).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this nested retrospective cohort study, we investigated the potential predictive factors associated with early mortality in a large sample of infants with CAKUT born at a tertiary hospital over a period of 25 years. Our findings indicate that the presence of CAKUT was an independent and strong factor associated with early mortality. Notably, among infants with CAKUT, prematurity, LBW, VLBW, oligohydramnios, CAKUT phenotypes with kidney involvement, and other affected organs were significant predictors of early mortality, after controlling for potential confounding factors.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur study detected one case of CAKUT among 71 live births, which was higher than the estimated general frequency of approximately 1 in 500 live births[4]. This finding can be explained by the fact that our institution is a reference center for fetal medicine and congenital anomalies. Notably, the occurrence of CAKUT increased about 37-times the odds of mortality. Even after adjusting for confounding variables, we still found that newborns with CAKUT had an HR of approximately 25 times higher for early mortality than the control group. Previous population-based studies have investigated whether the presence of any congenital birth defects is associated with mortality[22, 23]. Agha et al. [23] evaluated 45,000 children with birth defects and 45,000 matched controls born between 1979 and 1986 in Canada. \u0026nbsp;The authors reported that those with birth defects had a 13 times higher mortality rate. \u0026nbsp;Cardiovascular and central nervous system congenital defects were most frequently present in children who died, whereas CAKUT were detected in 12.5% of the deaths. Another cohort included 262,352 children with birth defects born in New York between 1983 and 2006[22]. The study showed that the mortality risk was 6.7 times higher in children with birth defects than in those without congenital anomalies. The authors also analyzed a selected subgroup with major birth defects and found that kidney agenesis/disgenesis was the second most important risk factor for mortality in the neonatal period (relative risk 69.5, 95%CI 64.5 - 75.2). \u0026nbsp;More recently, the prevalence and impact of CAKUT were evaluated in a cohort of preterm neonates (23–33 weeks) born in the USA between 2000 and 2020 and admitted to intensive care units[24]. CAKUT comprised 2% of all infants (8093 of 409,704), and UTD was the most common diagnosis (70%). Together, all CAKUT phenotypes had an adjusted odds ratio of 3.96 (95% CI 3.70-4.24) for death or severe illness. Gonzalez et al.[25] reported the outcomes of fetal CAKUT and other kidney diseases referred for prenatal evaluation at Texas Children’s Hospital Fetal Center. Of the 129 patients, 73 were discharged, 20 pregnancies were non-viable, and 36 died. The main causes of nonviable pregnancies were kidney agenesis and bilateral multicystic kidney dysplasia, whereas 75% of deaths were associated with multiple developmental anomalies.\u003c/p\u003e\n\u003cp\u003eIn our study, the predictors of mortality in patients with CAKUT were prematurity, LBW, VLBW, oligohydramnios, CAKUT phenotypes with kidney involvement, and malformations in other organs. These findings were similar to those of our previous study of 524 cases of CAKUT[12] and aligned with the literature. Prematurity is an independent predictor of CKD stage 2 or higher in children with CAKUT[11]. \u0026nbsp;In a population-based study, Geylis et al. [26] reported that CAKUT, oligohydramnios, SGA, prematurity (\u0026lt; 34 weeks), and post-term delivery were independent risk factors for CKD. The detection of oligohydramnios or anhydramnios before 20 weeks of gestation is considered an important predictor of fetal and neonatal death due to pulmonary hypoplasia[27]. In fetuses with LUTO, oligohydramnios or anhydramnios have shown a sensitivity of 63% and false-positive rate of 24% as individual predictors of postnatal CKD[28]. In our analysis, in addition to the general characteristics of the neonate, such as gestational age and birth weight, the presence of kidney parenchymal involvement and extra-renal malformation associated with CAKUT also increased the mortality risk. Furthermore, infants with cystic diseases, kidney agenesis/hypodysplasia, and LUTO had higher mortality risks than those with urinary tract anomalies alone. \u0026nbsp;This finding is in accordance with those of previous studies[22, 25]. Kidney agenesis/dysgenesis was associated with a high risk of neonatal mortality, whereas kidney agenesis and bilateral multicystic kidney dysplasia result in fetal death [22, 25]. \u0026nbsp;A population-based epidemiological study reported poor outcomes in 284 fetuses with LUTO, including pregnancy termination (24.6%), spontaneous fetal loss (4.6%), spontaneous stillbirths (3.9%), and infant death (10.6%) [29]. \u0026nbsp;Regarding extra-renal defects associated with CAKUT, a recent study evaluated 110 autopsies (90% fetal autopsies and 10% neonatal autopsies) of CAKUT cases and found that 84 cases (76.3%) showed malformations in at least one organ other than the kidney and urinary tract [30]. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe strength of our study lies in the analysis of a large sample of births over a long period of 25 years. However, we are aware of the limitations of this study. First, there were some missing data in the ECLAMC records, which were typically based on case reporting forms completed at the point of care. Second, our data were obtained from a single tertiary center, which is a reference for fetal medicine. Consequently, the frequency of CAKUT and the severity of cases were higher than those in the general population. For both the reasons, our results cannot be applied to different scenarios. Third, it was not possible to investigate the mechanisms by which the risk factors contribute to mortality. Nevertheless, our study showed a significant impact of CAKUT, particularly kidney-specific anomalies, on perinatal mortality, highlighting the importance of early diagnosis and targeted management strategies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn summary, the CAKUT represents a prevalent spectrum of anomalies associated with an increased early mortality rate. CAKUT phenotypes exhibiting kidney involvement and extra-renal malformations\u0026nbsp;are associated with a higher risk of early mortality.\u0026nbsp;In addition, established risk factors for early mortality in the pediatric population, including prematurity, LBW, VLBW, and oligohydramnios, additionally contribute to mortality in CAKUT cases. Early prenatal detection of specific CAKUT subtypes and congenital anomalies in other organs may contribute to refined clinical risk assessment and inform decision-making processes in obstetric and neonatal care.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthors contribution:\u0026nbsp;\u003c/strong\u003eConceptualization: Ana Cristina Sim\u0026otilde;es e Silva, Eduardo Ara\u0026uacute;jo Oliveira, Marcos J. Burle Aguiar; Methodology: Rodrigo Rezende Arantes, Keyla C. Cunha, Arthur A. Amaral, Jos\u0026eacute; Renato O. Melo, Beatriz C. Vieira, Enrico A Colosimo; Formal analysis and investigation: Enrico A Colosimo, Eduardo Ara\u0026uacute;jo Oliveira, Rodrigo Rezende Arantes; Writing - original draft preparation: Rodrigo Rezende Arantes, Keyla C. Cunha, Arthur A. Amaral, Jos\u0026eacute; Renato O. Melo, Beatriz C. Vieira; Writing - review and editing: Ana Cristina Sim\u0026otilde;es e Silva, Eduardo Ara\u0026uacute;jo Oliveira, Marcos J. Burle Aguiar; Funding acquisition: Ana Cristina Sim\u0026otilde;es e Silva; Supervision: Ana Cristina Sim\u0026otilde;es e Silva, Eduardo Ara\u0026uacute;jo Oliveira, Marcos J. Burle Aguiar\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical Statements/ Ethical Approval:\u003c/strong\u003e This study was approved by the Ethics Committee of our institution under the protocol 7.333.449 and followed the principles of the Declaration of Helsinki.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e This work was partially supported by Brazilian National Council of Research Development (CNPq - Grant # 304496/2023-5), Coordination of High Education Level Personnel (CAPES) and Foundation of Research of Minas Gerais (FAPEMIG).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest:\u0026nbsp;\u003c/strong\u003eNone declared.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence:\u0026nbsp;\u003c/strong\u003eAna Cristina Sim\u0026otilde;es e Silva, MD, PhD.\u003c/p\u003e\n\u003cp\u003eFull Professor, Department of Pediatrics, Faculty of Medicine, UFMG.\u003c/p\u003e\n\u003cp\u003eAlfredo Balena Avenue, 190, 2nd floor, room # 281, Belo Horizonte, MG, Brazil. Zip code: 30130-100. Phone: +55-31-34098073. E-mail: [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLoane M, Dolk H, Kelly A, Teljeur C, Greenlees R, Densem J, Group EW (2011) Paper 4: EUROCAT statistical monitoring: identification and investigation of ten year trends of congenital anomalies in Europe. Birth Defects Res A Clin Mol Teratol 91 Suppl 1:S31-43.10.1002/bdra.20778\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMonier I, Hachem S, Goffinet F, Martinez-Marin A, Khoshnood B, Lelong N (2024) Population-based surveillance of congenital anomalies over 40 years (1981\u0026ndash;2020): Results from the Paris Registry of Congenital Malformations (remaPAR). 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Pediatr Nephrol 39:1065-1075.10.1007/s00467-023-06137-z\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoato RT, Aguiar MB, Mak RH, Colosimo EA, Simoes e Silva AC, Oliveira EA (2023) Maternal risk factors for congenital anomalies of the kidney and urinary tract: A case-control study. J Pediatr Urol 19:199 e191-199 e111.10.1016/j.jpurol.2022.11.025\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCastilla EE, Orioli IM (2004) ECLAMC: the Latin-American collaborative study of congenital malformations. Community Genet 7:76-94.10.1159/000080776\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBouzada MC, Oliveira EA, Pereira AK, Leite HV, Rodrigues AM, Fagundes LA, Goncalves RP, Parreiras R (2004) Diagnostic accuracy of postnatal renal pelvic diameter as a predictor of uropathy: a prospective study. 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Pediatr Nephrol 34:283-294.10.1007/s00467-018-4078-0\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa Q, Li YQ, Meng QT, Yang B, Zhang HT, Shi H, Liu CY, Xiang TC, Zhao N, Rao J (2024) Maternal diseases and congenital anomalies of the kidney and urinary tract in offspring: a cohort study. World J Pediatr 20:1168-1178.10.1007/s12519-024-00822-1\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang Y, Hu J, Druschel CM (2010) A retrospective cohort study of mortality among children with birth defects in New York State, 1983\u0026ndash;2006. Birth Defects Res A Clin Mol Teratol 88:1023-1031.10.1002/bdra.20711\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAgha MM, Williams JI, Marrett L, To T, Dodds L (2006) Determinants of survival in children with congenital abnormalities: a long-term population-based cohort study. Birth Defects Res A Clin Mol Teratol 76:46-54.10.1002/bdra.20218\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHays T, Thompson MV, Bateman DA, Sahni R, Tolia VN, Clark RH, Gharavi AG (2022) The Prevalence and Clinical Significance of Congenital Anomalies of the Kidney and Urinary Tract in Preterm Infants. JAMA Netw Open 5:e2231626.10.1001/jamanetworkopen.2022.31626\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePlaud Gonzalez AM, Joseph C, Stover SR, Nassr A, Koh CJ, Angelo JR, Braun MC (2023) Fetal Nephrology: A Quaternary Care Center Experience. Kidney360 4:333-340.10.34067/KID.0004782022\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGeylis M, Coreanu T, Novack V, Landau D (2023) Risk factors for childhood chronic kidney disease: a population-based study. Pediatr Nephrol 38:1569-1576.10.1007/s00467-022-05714-y\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoxey-Mims M, Raju TNK (2018) Anhydramnios in the Setting of Renal Malformations: The National Institutes of Health Workshop Summary. Obstet Gynecol 131:1069-1079.10.1097/AOG.0000000000002637\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorris RK, Malin GL, Khan KS, Kilby MD (2009) Antenatal ultrasound to predict postnatal renal function in congenital lower urinary tract obstruction: systematic review of test accuracy. BJOG 116:1290-1299.10.1111/j.1471-0528.2009.02194.x\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMalin G, Tonks AM, Morris RK, Gardosi J, Kilby MD (2012) Congenital lower urinary tract obstruction: a population-based epidemiological study. BJOG 119:1455-1464.10.1111/j.1471-0528.2012.03476.x\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAytekin EC, Sanhal CY, Toru HS (2024) Congenital anomalies of kidney and urinary tract (CAKUT) and associated extra-renal anomalies in fetal autopsies. Indian J Pathol Microbiol 67:289-296.10.4103/ijpm.ijpm_45_23\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"congenital anomalies of the kidney and urinary tract, neonatal mortality, urinary trat dilation, lower urinary tract obstruction","lastPublishedDoi":"10.21203/rs.3.rs-6647524/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6647524/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eTo investigate predictive factors associated with neonatal mortality in infants with congenital anomalies of the kidney and urinary tract (CAKUT).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis study included a cohort of neonates with CAKUT born at a tertiary hospital between 1996 and 2021. Controls were matched with CAKUT cases by sex, time, and place of birth at a ratio of approximately 2:1. The covariates included in the analysis were sex, gestational age, birth weight, neonatal classification, and birth order. CAKUT was categorized into four phenotypes: urinary tract dilatation, lower urinary tract obstruction (LUTO), cystic diseases, and agenesis/hypodysplasia. The primary outcome was neonatal mortality. Survival analysis was performed using the Cox proportional hazards model.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003e857 cases and 1,755 controls were included in the analysis. The overall early mortality rate was 7.2%. After controlling for confounding factors, CAKUT cases exhibited a higher risk of early mortality than controls (hazard ratio [HR], 25.1; 95%CI, 14.0\u0026ndash;45.2). The following covariates were independently associated with early mortality: prematurity (HR, 1.7; 95%CI, 1.2\u0026ndash;2.5), LBW (HR, 2.4; 95%CI, 1.6\u0026ndash;2.5), VLBW (HR, 2.9; 95%CI, 1.7\u0026ndash;1.1), oligohydramnios (HR, 3.2; 95%CI, 2.2\u0026ndash;4.8), cystic diseases (HR, 3.8; 95%CI, 2.3\u0026ndash;6.4), LUTO (HR, 5.1; 95%CI, 3.0\u0026ndash;8.5), kidney agenesis/hypodysplasia (HR, 5.1; 95%CI, 2.9\u0026ndash;8.7), and extra-renal malformations (HR, 2.6; 95% CI, 1.7\u0026ndash;3.9).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusions\u003c/b\u003e\u003c/p\u003e \u003cp\u003eOur findings indicate that CAKUT was associated with an elevated early mortality rate compared with controls. Factors including prematurity, LBW, oligohydramnios, extra-renal malformations, and specific CAKUT phenotypes with kidney involvement were associated with increased mortality risk.\u003c/p\u003e","manuscriptTitle":"Risk factors for early mortality in infants with congenital anomalies of the kidney and urinary tract: a nested cohort study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-19 07:03:19","doi":"10.21203/rs.3.rs-6647524/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revisions Needed","date":"2025-06-09T11:42:50+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-05-15T20:19:56+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-13T21:50:29+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-13T15:13:45+00:00","index":"","fulltext":""},{"type":"submitted","content":"Pediatric Nephrology","date":"2025-05-12T10:18:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"pediatric-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pnep","sideBox":"Learn more about [Pediatric Nephrology](http://link.springer.com/journal/467)","snPcode":"467","submissionUrl":"https://www.editorialmanager.com/pnep/default2.aspx","title":"Pediatric Nephrology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"71d19c68-d85d-40e7-b6e3-576c2e4d8b2b","owner":[],"postedDate":"May 19th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-07-22T07:22:50+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-19 07:03:19","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6647524","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6647524","identity":"rs-6647524","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}