|Year : 2022 | Volume
| Issue : 3 | Page : 143-149
Prognostic value of carbohydrate antigen 19-9 in the urine of mothers with fetal hydronephrosis to the severity and cause of neonatal renal involvement
Razieh Sangsari1, Kayvan Mirnia1, Maryam Saeedi1, Nina Gozali Asl2, Abdol-Mohammad Kajbafzadeh3
1 Department of Pediatrics, Division of Neonatology, Faculty of Medicine, Tehran University of Medical Sciences, Children's Medical Center, Pediatric Center of Excellence, Tehran, Iran
2 Department of Pediatrics, Faculty of Medicine, Tehran University of Medical Sciences, Children's Medical Center, Pediatric Center of Excellence, Tehran, Iran
3 Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
|Date of Submission||14-Jan-2022|
|Date of Decision||24-Feb-2022|
|Date of Acceptance||23-Mar-2022|
|Date of Web Publication||06-Jul-2022|
Pediatric Urology and Regenerative Medicine Research Center, Gene, Cell and Tissue Research Institute, Children's Medical Center, Tehran University of Medical Science, Tehran
Source of Support: None, Conflict of Interest: None
Background: Hydronephrosis is the most common problem in prenatal sonography, which early detection decreases its complication and increases the survival rate of infants. Increased carbohydrate antigen 19-9 (CA19-9) tumor marker has been observed in nonmalignant conditions including hydronephrosis secondary to ureteral stones. This study aimed to determine the relationship between urinary CA19-9 in mothers with hydronephrosis fetuses with prognosis, severity, and cause of neonatal renal insufficiency. Materials and Methods: The present study is a retrospective/prospective cohort study. The CA19-9 was measured in 63 pregnant women who had a fetus with hydronephrosis in the third trimester of pregnancy. The relationship between CA19-9 and the following parameters was evaluated: causes of hydronephrosis, need for hospitalization after birth, need for surgery, treatment status, and survival. Results: In the present study, high values of CA19-9 (more than 27.8%) were able to predict severe hydronephrosis in neonates with a sensitivity of 80.6% and a specificity of 59.6%. An increase in this marker also could determine the pathological cause of hydronephrosis such as posterior urethral valves, the need for hydronephrosis surgery (P < 0.001), the need for hospitalization (P < 0.001), and the need to assisted ventilation (P = 0.001). Conclusion: The level of CA19-9 biomarker in the urine of pregnant mothers with hydronephrosis fetuses can be predictive value. Even urinary CA19-9 of mothers during the pregnancy can predict the need for the neonatal intensive care unit after delivery.
Keywords: Carbohydrate antigen 19-9, hydronephrosis, posterior urethral valves, ureteropelvic junction obstruction
|How to cite this article:|
Sangsari R, Mirnia K, Saeedi M, Asl NG, Kajbafzadeh AM. Prognostic value of carbohydrate antigen 19-9 in the urine of mothers with fetal hydronephrosis to the severity and cause of neonatal renal involvement. J Clin Neonatol 2022;11:143-9
|How to cite this URL:|
Sangsari R, Mirnia K, Saeedi M, Asl NG, Kajbafzadeh AM. Prognostic value of carbohydrate antigen 19-9 in the urine of mothers with fetal hydronephrosis to the severity and cause of neonatal renal involvement. J Clin Neonatol [serial online] 2022 [cited 2022 Nov 27];11:143-9. Available from: https://www.jcnonweb.com/text.asp?2022/11/3/143/350037
| Introduction|| |
Hydronephrosis is the most common urological finding in a pregnancy ultrasound. Fetal hydronephrosis is generally reported in 0.5%–1% of pregnancies; however, the statistics vary from 2 to 9 per 1000.,, Hydronephrosis is studied in two categories: unilateral and bilateral. It is graded based on gestational age and anterior-posterior size of the pelvis – (a) mild: 4 to <7 mm in the second trimester and 7 to <9 mm in the third trimester; (b) moderate: 7 to ≤10 mm and 9 to ≤15 mm in the second and the third trimesters, respectively; and (c) severe: >10 mm and >15 mm in the second and the third trimesters, respectively.
In unilateral hydronephrosis, ureteropelvic junction obstruction (UPJO) is the most common cause, followed by vesicoureteral reflux, ureterovesical junction obstruction (UVJO), and less common cases such as duplication and multicystic and polycystic kidneys., In bilateral hydronephrosis, the posterior urethral valve (PUV) is the most common cause in boys and ectopic ureteral obstruction is the most common cause in girls, although bilateral reflux, UVJO, or bilateral UPJO can also be involved., To follow up infants with a history of fetal hydronephrosis, the ultrasound is performed after the first 48 h of life and before 1 month of age. In infants with the possibility of PUV and severe bilateral hydronephrosis, evaluation should be started immediately. According to the result of APD in sonography, neonatal hydronephrosis is divided into three groups: (a) mild: anterior-posterior diameter 5–10 mm, (b) moderate: 10–15 mm, and (c) severe: >15 mm.
Treatment of disorders leading to prenatal hydronephrosis varies greatly depending on the underlying cause. Many cases of fetal hydronephrosis resolve spontaneously and follow-up of the patient alone is sufficient. However, in other cases, medical or surgical treatment is needed.
Serum carbohydrate antigen 19-9 (CA19-9) is known as a valuable biomarker for pancreatic and gastrointestinal carcinoma. CA19-9 levels may also be seen in 6%–7% of patients with nondigestive malignancies. In addition, an increase in epithelial tumors has been observed. An increase in this biomarker is common in other diseases, in some cases of hydronephrosis with an unknown cause have been reported to have high serum levels of CA19-9. Increased CA19-9 has also been observed in hydronephrosis secondary to ureteral stones and a high urinary CA19-9 level is a noninvasive clinically applicable marker for differentiating between obstruction and nonobstructive dilatation in antenatal hydronephrosis.,
Although various factors can be used as predicting the prognosis of neonates with fetal hydronephrosis, this study investigated the role of urinary CA19-9 level in the mother as a noninvasive, available, and predictive diagnostic biomarker.
| Materials and Methods|| |
In this retrospective/prospective cohort study, all cases of fetal hydronephrosis referred to the Urology Department of Children's Medical Center, Tehran University of Medical Sciences (TUMS), Tehran, Iran, between years 2010 and 2018 who met the inclusion criteria were studied. Cases before 2017 were evaluated retrospectively and after that entered prospectively in the study. The maternal whose fetuses have hydronephrosis in the third trimester of pregnancy that was confirmed by perinatal ultrasound were examined by urinary marker CA19-9. The level of CA19-9 in the mother's urine and neonatal data such as demographic data and the need for surgery and/or hospitalization at birth, the type of surgery, the duration of hospitalization, the need for assisted ventilator at birth, and prophylactic antibiotics, the patient's therapeutic status, and the patient's survival status were collected in the researcher-developed questionnaire.
This study was performed according to the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of TUMS (Ethical code#: IR.TUMS.CHMC.REC.1398.047).
Inclusion and exclusion criteria
Fetuses whose hydronephrosis was confirmed by perinatal ultrasound in the third trimester of pregnancy and maternal urinary marker CA19-9 were examined in perinatal tests after ultrasound confirmation. Cases where parents were reluctant to cooperate in the study, lost to follow-up cases, and mothers or neonates with carcinoma and also neonates admitted to neonatal intensive care unit (NICU) for reasons other than hydronephrosis were excluded.
Information such as the severity of the disease based on fetal and postnatal ultrasound, the level of CA19-9 in the mother's urine, cause of neonatal hydronephrosis, the need for surgery and/or hospitalization at birth, the type of surgery, the age of the neonate at the time of surgery, the duration of hospitalization, the need for assisted ventilator at birth, the need for prophylactic antibiotics, the patient's therapeutic status, and the patient's survival status were collected in the researcher-developed questionnaire.
Our criteria for the severity of hydronephrosis were based on the grading system of hydronephrosis developed by the Society of Fetal Urology. A criterion for the normal range of CA19-9 is summarized in [Figure 1].
The information was collected through interviews with parents (in person and/or by telephone), reading the medical records, and clinical examination of patients.
To rule out other causes of increased CA19-9, all mothers who had any disease during pregnancy or infants who had an anomaly or a problem other than hydronephrosis were excluded from the study.
The urine sample of the mother was obtained after diagnosis of hydronephrosis by ultrasound during the third trimester of pregnancy. The level of CA19-9 was measured by enzyme-linked immunosorbent assay (RADIM kit, Germany). Urinary CA19-9 level more than 37 U / mL was considered high.
Based on the study of Kajbafzadeh et al., and considering the error of 5% and the power = 95%, the sample size for selecting women with fetal hydronephrosis was estimated to be 50.
Data were entered into SPSS statistical software (version 23.0 for Windows; IBM SPSS Statistics, Armonk, NY, USA). Frequency and percentages were calculated for qualitative variables and the mean, range, and standard deviation were calculated for quantitative variables. t-test or analysis of variance test was used to compare quantitative variables and Chi-square test was used to compare qualitative variables. The correlation between quantitative variables was evaluated by the Pearson correlation test. To determine the diagnostic value of the marker in predicting the outcome of the disease, the analysis of the area under the receiver operator characteristic curve (AUC) was used. The cutoff point, the sensitivity, and the specificity of the marker were determined to evaluate the predictive value of the CA19-9. The significance level was considered P < 0.05.
| Results|| |
In the present study, a total of 63 infants were evaluated. The mean age of the children was 49.5 ± 15.18 months (range: 30–108 months). None of the patients required dialysis. The basic clinical information of the patients is shown in [Table 1].
|Table 1: The basic clinical information of the children with hydronephrosis|
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The mean level of CA19-9 in maternal urine was 164.71 ± 282.28 U/ml which was in the wide range of <0.6 to more than 1000 U/ml. The relationship between the level of CA19-9 in the mother's urine during pregnancy and the clinical variables of the children is presented in [Table 2].
|Table 2: The relationship between the level of tumor marker carbohydrate antigen 19-9 in the mother's urine during pregnancy and the clinical variables of the children|
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The level of the CA19-9 in the mother's urine during pregnancy was correlated with hydronephrosis severity on fetal ultrasound (P = 0.008), hydronephrosis severity on neonatal ultrasound (P = 0.017), hospitalization after birth (P < 0.001), the need for assisted ventilation (P = 0.001), the cause of hydronephrosis (P < 0.001), and need for reconstructive surgery (P < 0.001).
Based on the analysis of the AUC, the assessment of maternal urinary CA19-9 level had a high diagnostic value in predicting the presence of PUV in infants (AUC = 0.966, confidence interval [CI] 95% = 0.921–1.000). The best cutoff point for this issue was 396, which leads to PUV diagnosis with 100% sensitivity and 93.1% specificity [Figure 2]a. Furthermore, maternal urinary CA19-9 level had a high diagnostic value in predicting hospitalization in children (AUC = 0.789, CI 95% = 0.636–0.942), with the best cutoff point of 70.3, which predicts hospitalization with 76.5% sensitivity and 71.7% specificity [Figure 2]b. This marker also has a predicting value for the need for surgery in children (AUC = 0.755, CI 95% = 0.638–0.873), with the best cutting point equal to 32.6, a sensitivity of 80.6%, and a specificity of 59.4% [Figure 2]c. Evaluation of urinary CA19-9 level in mother had a high predicting value in the severity of hydronephrosis in neonate (AUC = 0.774, CI 95% = 0.660–0.888) with the cutoff point of 27.8, sensitivity of 6. 80%, and specificity 59.4% [Figure 2]d.
|Figure 2: Sensitivity and specificity of CA 19-9 Maternal urine during pregnancy to predict (a) posterior urethral valves, (b) hospitalization, (c) need for surgery, and (d) the severity of hydronephrosis in infants|
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| Discussion|| |
CA19-9 has a prognostic value as a biomarker in a variety of gastrointestinal or pancreatic cancers., Increased concentration of this marker in nontumor conditions such as diabetes mellitus, hepatobiliary complications, and also in benign urinary disorders such as urinary tract obstruction and hydronephrosis has been shown.,,, In addition, based on the available evidence, this marker seems to be widely used as a prognostic marker in predicting complications such as obstructive tubulopathies.
In summary, in the present study, the increase in CA19-9 levels in the mother's urine was associated with the severity of hydronephrosis in both the fetus and the newborn (based on ultrasound evidence). In this regard, high values of this marker (more than 27.8) with a sensitivity of 80.6% and a specificity of 59.4% were able to predict severe hydronephrosis in the infant. In addition to determining the severity of hydronephrosis, we found that increasing this marker (with different cutoff points) has a high prognostic value to determine the pathological cause of the lesion (essentially following PUV), the need for surgery to repair the lesion, and the need to hospitalize patients at birth.
Similar results have been obtained in some studies on the prognostic role of CA19-9 in predicting the severity and consequences of hydronephrosis in neonates.,, In the study of Aybek et al., serum and urinary levels of CA19-9 in 54 patients with benign hydronephrosis and 23 patients as a control group were evaluated. CA19-9 showed a higher value in hydronephrosis patients compared to the control group. It has been revealed that increased serum CA-9-19 concentration in hydronephrosis patients is associated with urinary tract infections, bilateral hydronephrosis, proteinuria, the severity of duct obstruction, and degree of hydronephrosis in patients. On the other hand, there was a relationship between serum levels of CA19-9 and renal failure in patients. Furthermore, changes in serum and urinary CA19-9 were reported as a suitable criterion for the diagnosis of hydronephrosis and its malignancy in the early stages of the disease.,
In a similar study, the prognostic role of CA19-9 in the urine of mothers with fetuses with hydronephrosis due to PUV was studied. In this study, the level of CA19-9 in the urine of 20 pregnant women with healthy fetus and 20 pregnant women with fetuses with PUV and hydronephrosis were evaluated. In addition, the level of CA19-9 of the first neonatal urine was measured. They showed the prognostic role of CA19-9 in the urine of mothers with fetuses with PUV hydronephrosis. There was also a significant relationship between the level of CA19-9 in the mother's urine and the neonate's first urine.
In a study by Özkuvancı et al., it was found that a level higher than a cutoff point of 55.5 units of CA19-9 in urine will be able to predict and differentiate obstructive hydronephrosis from nonobstructive with a sensitivity of 75% and a specificity of 66%. However, in this study, the evaluation of the marker level in the neonate's urine was used to determine the pathological cause of hydronephrosis rather than its severity or consequences.
In another study by Akbaş et al., neonates with severe hydronephrosis had higher maternal urinary CA19-9 levels than neonates in the control group. However, the difference between the incidence of mild/moderate hydronephrosis with the control group was not significant; therefore, similar to our study, the increase in this marker predicted the severity of hydronephrosis. However, in the abovementioned study, it was shown that CA19-9 levels in maternal blood could not have a prognostic value for the severity of neonatal hydronephrosis.
The advantage of the present study was the predicting value of the maternal urine CA19-9 level in the severity of neonatal hydronephrosis, the need for surgery, the need for hospitalization at birth and the need to assisted ventilation. Then can even predict the need to be admitted to the NICU after delivery. In addition, the increase in urinary levels of this marker in the mother was able to predict the cause of hydronephrosis, and in this regard, the background of PUV was associated with higher levels of CA19-9 in the mother's urine.
There were limitations in this study, including lack of assessment of CA19-9 level in neonatal urine (with sufficient sample size) or other urinary biomarkers and also using relatively limited sample size. Besides, some patients did not have fetal and neonatal information, including ultrasound results, or did not cooperate properly to provide evidence, which led to their exclusion from the study.
| Conclusion|| |
Evaluation of the level of CA19-9 biomarker in the urine of pregnant mothers of infants with fetal hydronephrosis can predict the severity of hydronephrosis and its consequences include the need for hospitalization at birth and the need for surgery to treat this complication. Even urinary CA19-9 of mothers during the pregnancy can predict the need for NICU admission after delivery. Much higher levels of this marker are also predictable in underlying PUV-induced hydronephrosis. Therefore, along with other diagnostic features and markers regarding the severity of obstructive European disease and the incidence of neonatal hydronephrosis, this marker can also be used with high accuracy and reliability in predicting the severity of the lesion and its consequences.
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Tehran University of Medical Sciences (TUMS) (Ethical code#: IR.TUMS.IKHC.REC.1398.047).
We would like to thank all parents of neonates, the nephrology department staff of Children's Medical Center, and all those who cooperated in the study process.
What is already known
Urinary CA19-9 of fetus needs for defining the severity of hydronephrosis and the need for NICU admission after delivery.
What this study adds
Urinary CA19-9 of pregnant mothers of infants with fetal hydronephrosis can predict in which hospital with what level of care the baby should be delivered.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]