Trends in Management of Fetuses with Suspected Lower Urinary Tract Obstruction (LUTO): A High-Risk Fetal and Pediatric Center Experience in a Universal-Access-to-Care System

Abstract

Introduction Neonates with lower urinary tract obstruction (LUTO) experience high morbidity and mortality associated with the development of chronic kidney disease. The prenatal detection rate for LUTO is less than 50%, with late or missed diagnosis leading to delayed management and long-term sequelae in the remainder. We aimed to explore the trends in prenatal detection and management at a high-risk fetal center and determine if similar trends of postnatal presentations were noted for the same period.

Methods Prenatal and postnatal LUTO databases from a tertiary fetal center and its associated pediatric center between 2009 and 2021 were reviewed, capturing maternal age, gestational age (GA) at diagnosis, and rates of termination of pregnancy (TOP). Time series analysis using autocorrelation was performed to investigate time trend changes for prenatally suspected and postnatally confirmed LUTO cases.

Results A total of 161 fetuses with prenatally suspected LUTO were identified, including 78 terminations. No significant time trend was found when evaluating the correlation between time periods, prenatal suspicion, and postnatal confirmation of LUTO cases (Durbin–Watson [DW] = 1.99, p = 0.3641 and DW = 2.86, p = 0.9113, respectively). GA at referral was 20.0 weeks (interquartile range [IQR] 12, 35) and 22.0 weeks (IQR 13, 37) for TOP and continued pregnancies (p < 0.0001). GA at initial ultrasound was earlier in terminated fetuses compared to continued (20.0 [IQR 12, 35] weeks vs. 22.5 [IQR 13, 39] weeks, p < 0.0001). While prenatal LUTO suspicion remained consistently higher than postnatal presentations, the rates of postnatal presentations and terminations remained stable during the study years (p = 0.7913 and 0.2338), as were GA at TOP and maternal age at diagnosis (p = 0.1710 and 0.1921).

Conclusion This study demonstrated that more severe cases of LUTO are referred earlier and are more likely to undergo TOP. No significant trend was detected between time and prenatally suspected or postnatally confirmed LUTO, highlighting the need for further studies to better delineate factors that can increase prenatal detection.

Keywords

lower urinary tract obstruction (LUTO) - fetal obstructive uropathy - trend analysis - antenatal diagnosis - pediatric urology

Introduction

Lower urinary tract obstruction (LUTO) affects 2 to 3 of every 10,000 fetuses[1] and is often associated with significant morbidity and mortality due to severe comorbidities such as pulmonary hypoplasia, renal insufficiency, and chronic kidney disease.[2] LUTO may be suspected prenatally in fetuses who exhibit the “classic” prenatal ultrasound features of megacystis, bilateral hydroureteronephrosis, oligohydramnios, and, while not entirely reliable,[3] [4] the keyhole sign.[5]

Due to the implications of a confirmed LUTO diagnosis on the child and family and the possibility of a poor prognosis,[6] 40 to 53% of prospective parents may opt to terminate the pregnancy.[6] [7] [8] Therefore, early multidisciplinary counseling to provide realistic postnatal expectations and preparation is crucial in parental guidance and decision-making regarding pregnancy management. In addition, delivery should take place in a high-risk fetal center to ensure immediate assessment by appropriate pediatric specialties equipped to manage potential complications.[9]

The severity of this condition and its implications stress the importance of obtaining an accurate and reliable prenatal diagnosis. Our previous work has explored the power of combinations of prenatal ultrasound features[3] to strengthen the prediction of LUTO. Despite advances in the accuracy of prenatal screening and technologies, detection rates are still suboptimal (33–62%).[1] [10]

To the best of our knowledge, time trends in prenatal diagnosis and postnatal presentations of LUTO have not been described. Given this diagnostic challenge, we wondered if recent progress in prenatal imaging has impacted prenatal suspicion, pregnancy management, and postnatal detection of LUTO. Therefore, the aim of this study was to assess time trends in prenatal detection of LUTO at a high-risk fetal center and to observe time trends in postnatal presentation at the corresponding tertiary pediatric center.

Materials and Methods

Study Design, Population, and Variables

Following a retrospective chart review (REB #22-0036-C) at a tertiary high-risk fetal center (Mount Sinai Hospital, Toronto, Canada) and associated pediatric hospital (Hospital for Sick Children, Toronto, Canada), pregnancies with prenatally suspected and postnatally confirmed LUTO diagnoses between 2009 and 2021 were collected. These high-risk centers cover pre- and postnatal referrals, respectively, for the Greater Toronto Area with a population of 7,281,694 residents (approximately 65,500 births in 2021).[11] [12] Patients with external follow-up and delivery outside our center or those with incomplete data were excluded from postnatal analysis.

Variables assessed included maternal age at presentation, fetal sex, gestational age (GA) at termination of pregnancy (TOP), number of TOP, prenatally suspected and postnatally confirmed LUTO diagnoses, perinatal deaths, autopsy results, and time of initial postnatal presentation. A prenatally suspected LUTO diagnosis was considered if the fetus presented with a combination of two or more of the following ultrasound features: megacystis, oligo- or anhydramnios, bilateral hydronephrosis and/or hydroureters, the keyhole sign, or bladder wall thickening.

Postnatal LUTO diagnosis was confirmed via voiding cystourethrography or during cystoscopy. The collected pre- and postnatal data are independent and not every patient was seen in both institutions due to external follow-ups, postnatal referrals from different institutions, or relocation of patients with transfer to different institutions.

Study Outcomes

The primary outcome included time trend analyses to assess the correlation between time periods, prenatally suspected and postnatally confirmed or newly diagnosed LUTO cases, respectively. All patients with prenatal suspicion of LUTO and all patients with postnatal diagnosis of LUTO were included in the time trend analysis irrespective if they had available postnatal data or the diagnosis was suspected prenatally.

Secondary outcomes included maternal age at presentation, GA at pre- and postnatal presentation, number of TOP, GA at TOP, and pre- and postnatal mortality. Patients with prenatal suspicion of LUTO but unavailable postnatal data were excluded from the secondary outcome analysis.

Statistical Analysis

Linear regression and time series analysis were performed with R-Studio (Version 2022.02.1 Build 461, package lmtest) to assess the population changes and time trends. The data set was analyzed for autocorrelation via Durbin–Watson (DW) test. Briefly, the DW test ranges from 0 to 4, whereby values close to 0 indicate positive and values close to 4 indicate negative autocorrelation. Secondary outcome data was evaluated for Gaussian distribution via normality tests (D'Agostino and Pearson and Shapiro–Wilk). Subsequently, unpaired t-test, Mann–Whitney U test, Kruskal–Wallis test (post hoc: Dunn's test), analysis of variance (post hoc: Tukey test), and chi-square tests for trends were performed as appropriate. Data is presented as median ± interquartile range (IQR). p-Values below 0.05 were considered statistically significant and calculated in R or GraphPad Prism version 9.5.0 for Mac OS (GraphPad Software, San Diego, California, United States, www.graphpad.com), respectively.

Results

During the 13-year study period, a total of 161 fetuses were assessed prenatally with suspected LUTO at the fetal center of which 102 had a confirmed LUTO diagnosis postnatally ([Table 1]). A total of 149 patients presented to the pediatric center and received a LUTO diagnosis, including 41 patients prenatally seen at the fetal referral center and 66 cases without a prenatal LUTO diagnosis.

Table 1 Summary of basic characteristics in each year from 2009 to 2021

Referral year	2009	2010	2011	2012	2013	2014	2015	2016	2017	2018	2019	2020	2021	p-Value
Total prenatal LUTO suspicion (confirmed LUTO)	10 (5)	8 (6)	10 (7)	16 (10)	13 (8)	11 (8)	8 (7)	12 (9)	10 (7)	15 (8)	19 (8)	12 (6)	17 (13)	0.7913
Postnatal data unavailable	4	2	3	4	4	1	−	2	3	4	7	4	3
Correct prenatal diagnosis (%)	50.0	75.0	70.0	62.5	61.5	72.7	87.5	75.0	70.0	53.4	42.1	50.0	76.5	0.4913
TOPs (confirmed LUTO)	6 (2)	3 (2)	1 (0)	8 (3)	7 (4)	5 (2)	4 (4)	7 (6)	5 (3)	8 (4)	12 (5)	8 (3)	4 (2)	0.2338
TOPs (%)	60.0	37.5	10.0	50.0	53.8	45.5	50.0	58.4	50.0	53.4	63.2	66.7	23.5
Perinatal deaths: IUFD, stillbirths, neonatal/infant death (confirmed LUTO)	3 (2)	2 (1)	3 (1)	3 (2)	2 (1)	1 (1)	2 (1)	2 (0)	1 (0)	4 (1)	4 (1)	2 (2)	1 (1)	0.9802
Other postnatal diagnosis	1	0	0	2	1	2	1	1	0	3	4	2	1	0.8760
Maternal age (y)	33.5 (IQR 21, 40)	33.0 (IQR 27, 36)	32.0 (IQR 21, 35)	28.5 (IQR 21, 36)	28.0 (IQR 18, 41)	30.0 (IQR 24, 37)	31.0 (IQR 19, 36)	31.0 (IQR 21, 36)	31.0 (IQR 21, 39)	29.5 (IQR 22, 41)	30.0 (IQR 24, 37)	29.0 (IQR 24, 37)	33.0 (IQR 26, 40)	0.1921
GA initial visit (wk)	16.0 (IQR 12, 27)	21.0 (IQR 16,34)	20.0 (IQR 15, 34)	20.5 (IQR 13, 36)	20.0 (IQR 13, 33)	20.0 (IQR 13, 36)	20.0 (IQR 17, 23)	20.0 (IQR 12, 33)	22.5 (IQR 18, 34)	20.0 (IQR 13, 35)	21.0 (IQR 13, 29)	17.5 (IQR 13, 37)	21.0 (IQR 13, 36)	0.5605
GA TOP (wk)	22.5 (IQR 19, 37)	29.0	22.0	21.0 (IQR 19, 23)	22.5 (IQR 20, 27)	25.0 (IQR 19, 31)	16.5 (IQR 15, 21)	18.0 (IQR 15, 22)	21.0 (IQR 14, 22)	21.5 (IQR 16, 29)	23.0 (IQR 19, 29)	21.5 (IQR 16, 23)	20.5 (IQR 15, 27)	0.1710
Autopsies	6	0	1	4	4	3	2	5	2	3	5	6	4	0.7682
Postnatal presentations (no prenatal diagnosis)	7 (5)	6 (4)	8 (4)	11 (3)	7 (1)	16 (9)	8 (4)	15 (4)	12 (7)	11 (7)	12 (5)	17 (7)	19 (6)	0.7913
Age at postnatal presentation (d)	232.0 (IQR 2, 1039)	50.5 (IQR 1, 2702)	3.5 (IQR 0, 503)	8.0 (IQR 0, 1198)	11.0 (IQR 1, 86)	15.5 (IQR 1, 2195)	17.5 (IQR 0, 2790)	12.0 (IQR 0, 2938)	27.0 (IQR 2, 4623)	39.0 (IQR 0, 4752)	14.0 (IQR 1, 3460)	18.0 (IQR 0, 3783)	3.0 (IQR 0, 4144)	0.6904

Abbreviations: GA, gestational age; IQR, interquartile range; IUFD, intrauterine fetal demise; LUTO, lower urinary tract obstruction; TOP, termination of pregnancy.

Linear regression analysis showed a significant correlation between the study years and prenatally suspected LUTO cases (correlation coefficient: 0.56; p = 0.05; R ²= 0.25, [Table 2]). However, time trend analysis revealed no signs of autocorrelation, indicating that there is no future time trend to be expected toward more prenatally suspected LUTO pregnancies referred to our center ([Supplementary Figs. S1] and [S2]). Among the 149 postnatally confirmed LUTO fetuses, a positive correlation between time period and patients diagnosed per year showed statistical significance (correlation coefficient: 0.77; p = 0.002; R ²= 0.55). In keeping with the prenatal data, no autocorrelation for the postnatal data could be detected (DW = 2.85, p-value = 0.91, [Supplementary Fig. S1]).

Table 2 Univariate linear regression for total prenatally suspected and postnatally confirmed LUTO diagnoses

Univariate linear regression (association to total prenatally suspected LUTO diagnoses)
	F -value	R 2	p -Value
Total prenatally suspected LUTO diagnoses	4.967	0.311	0.048
Univariate linear regression (association to total postnatal LUTO diagnoses)
	F -value	R 2	p -Value
Total postnatal LUTO diagnoses	15.82	0.589	0.002

Abbreviation: LUTO, lower urinary tract obstruction.

Parents opted for pregnancy termination in 78 of 161 (48.4%) of prenatally suspected LUTO pregnancies. Again, no significant time trend could be observed (p = 0.1525). Of the 83 ongoing pregnancies, 13 (16%) resulted in fetal death, 13 (16%) in neonatal death (< 28 days of life), and 4 (5%) in infant death (> 28 days of life). From all suspected LUTO pregnancies, 102 neonates (63.4%) had a LUTO diagnosis confirmed postnatally, without any significant differences during the study period (p = 0.4913) and 15 babies received other diagnoses, including cloacal dysgenesis (n = 2), urethrovaginal fistula (n = 1), urethral diverticulum (n = 2), limb-body-wall defect (n = 1), VACTERL association (n = 1), duplication of the penile urethra (n = 1), bilateral multicystic dysplastic kidney (n = 1), transient hydronephrosis (n = 1), right renal agenesis without reliably identified urethral orifice (suspicious of bladder outlet obstruction, no final confirmation, n = 1), hypoplasia of genital erectile tissue (distal urethral obstruction was not identified, n = 1), polycystic kidneys (n = 1), enlarged bladder (no obstruction identified, n = 1), or a horseshoe kidney (n = 1). We were unable to determine the postnatal diagnosis in 44 patients due to unavailable postnatal diagnosis, unavailable postnatal data, or external follow-up. Prenatal detection rates ranged between 42.1% in 2019 and 87.5% in 2015 ([Table 1] and [Fig. 1]).

Fig. 1 Overview of the number of terminated pregnancies, prenatally suspected and postnatally confirmed lower urinary tract obstruction (LUTO) patients from 2009 to 2021.

Pregnancies opting for termination presented significantly earlier compared to those that had continued (20.0 weeks of gestation, IQR = 12, 35 vs. 22.0 weeks, IQR = 13, 37, respectively; p < 0.0001) and underwent initial ultrasounds at an earlier GA (p < 0.0001). Maternal ages for fetuses with a prenatally suspected LUTO diagnosis, GA at initial prenatal visit, number of TOP, GA at TOP, and age at postnatal presentation did not change significantly over time (p = 0.1921, p = 0.5605, p = 0.2338, p = 0.1710, and p = 0.6904).

Discussion

Our study shows variations in annual prevalence of prenatally suspected and postnatally diagnosed patients with LUTO, yet no significant time trends over the last 13 years. These results are consistent with data of a previous population-based study in the United Kingdom that found no differences in the prevalence of LUTO between 1995 and 2007, although the results in that study were limited by detection rates lower than 50%.[10] Moreover, there is a risk of possible underestimation of LUTO incidence due to consistently high termination rates and mortality rates among this population.[1] [10] [13] This was also reflected in our cohort that demonstrated consistently greater rates of prenatally suspected LUTO than postnatally confirmed diagnoses due to high rates of pregnancy termination.

The prenatal detection rate in this study was higher (63.4%) than previously reported rates between 33 and 62%[1] [10] and was above 70% in half of the observed years. With regard to decreasing fertility rates in Toronto between 2012 and 2021 (41.6 to 33.8 in 1,000 females of reproductive age),[11] the stable but still low prenatal detection rates and postnatal presentations suggest an improvement of prenatal detection due to raised awareness and improved interdisciplinary collaboration leading to more referrals and increased likelihood of anomaly detection. In addition, this can be attributed to the centralization in the health care system of Ontario, allowing universal access to highly specialized and qualified high-risk centers. This is of particular importance, especially in rare congenital diseases such as LUTO.[14] [15] Despite the implications of a postnatal false-positive diagnosis, prophylactic prenatal counseling and closer postnatal monitoring outweigh the risk of a missed LUTO diagnosis and long-term sequelae attributed to delayed management.

However, it is possible that prenatal detection based on ultrasound findings and basic urine analysis has reached their peak and cannot be further improved by solely utilizing these tools. Hence, standardization and utilization of diagnostic scores (e.g., for prenatal differentiation between LUTO and underlying pathologies[16] or the Z-score[17]) and artificial intelligence-based tools such as the Toronto Nomogram[4] or convolutional neural network models[18] can be a valuable addition to assist in prenatal diagnostics in order to further improve detection rates.[19]

In addition, cases of late-onset or atypical presentation of LUTO might not be detected at mid-trimester ultrasound screening increasing the risk of a missed diagnosis. Thus, initiation of routine third trimester screening could potentially contribute to increased detection of these cases.

In the present study, LUTO affected mainly male fetuses and a suspected LUTO diagnosis led to constantly high termination rates of nearly 50% during the observation period, confirming previously published data.[3] [8] Pregnancies opting for termination were diagnosed earlier, suggesting the presence of more severe ultrasound findings and a poorer potential prognosis.[13] [20]

Even in those that did not terminate the pregnancy, the mortality rate was as high as 36% which can be ranked to the lower end of the scale according to previously reported rates of 23% up to 75 to 90%.[6] [21] [22] [23]

There are several limitations that should be considered when interpreting this study.

The prenatal detection rate was calculated based on all suspected LUTO fetuses including those with unavailable postnatal data. Given the lack of confirmation for some of these cases, our findings might under- or overestimate the true detection rate and should be interpreted carefully (87% after exclusion of these 44 fetuses). In addition, numbers of prenatally suspected LUTO and postnatal presentations are incongruent due to external follow-ups of patients or transfer to other institutions which may have an impact on the secondary outcome of this study; however, for time trend analysis all suspected LUTO patients were included.

Despite these limitations, this study highlights that there have not been time trend changes in prenatal suspicion and postnatal presentation during the 13-year study period. However, in the light of declining birth rates in the referral area, the stable detection rates and postnatal presentations indicate that any differences in outcomes can be attributed to the raised awareness, growing evidence, lower threshold for diagnosis, and management of LUTO diagnoses. Furthermore, our data confirm that early severe findings are associated with earlier presentation and a higher likelihood of pregnancy termination.

Conclusion

This study adds knowledge to the body of evidence about LUTO and shows there are no time trend changes of prenatal suspicion and postnatal presentation during the 13-year study period. Given the stagnating prenatal detection rates and long-term sequelae associated with a missed diagnosis, these results highlight the need for further improvement of pre- and postnatal management. Our results underline the need for further studies to better delineate factors that can increase prenatal detection rates to decrease the rate of undetected LUTO cases. Longer follow-up data with higher patient numbers are required to validate these findings and assess long-term trends for this condition.

Conflict of Interest

None declared.

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Publikationsverlauf

Eingereicht: 08. Mai 2023

Angenommen: 04. Juli 2023

Artikel online veröffentlicht:
22. August 2023