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Abstract

PURPOSE:

Report urologic outcomes among newborns with spinal dysraphism managed within an expectant clean intermittent catheterization (CIC) program.

METHODS:

Newborns were followed clinically and with serial ultrasound (US). Urodynamics (UD) and dimercaptosuccinic acid (DMSA) renal scan were obtained at 3–6 months, 1 year, 3 years, then as needed. Patients with initial evaluation after 6 months were excluded.

RESULTS:

Median follow-up was 3.2 years. 11/102 began catheterization for continence (median 4.0 years) and 47/102 did not start CIC. Of these, 2/58 developed a DMSA abnormality. 44/102 began CIC early, often for elevated storage pressures and febrile urinary tract infection (UTI). Of these, 20/44 developed a DMSA abnormality including 9 who had abnormality detected prior to starting CIC. Being on CIC or starting immediately upon recognition of new hydronephrosis, reflux, elevated filling pressures, or febrile UTI was associated with lower chance of DMSA abnormalities (4/17, 24%) compared to delaying CIC (16/27, 60%) ( $p=$ 0.03).

CONCLUSIONS:

CIC can be deferred until continence in select infants with a low risk of significant DMSA abnormality. However, immediate initiation of CIC upon recognition of risk factors is recommended as this was associated with fewer DMSA abnormalities than delaying CIC. Recommendations for expectantly-managed patients include close follow-up, serial US and UD, and prompt initiation of CIC upon recognition of new hydronephrosis, reflux, elevated storage pressures, or febrile UTIs.

Keywords

Spinal dysraphism spina bifida newborn management clean intermittent catheterization expectant management DMSA abnormalities urodynamics renal outcomes urinary tract infection

1. Introduction

Patients with spinal dysraphism (SD) merit urologic care from birth to minimize renal functional loss and prevent chronic kidney disease (CKD) later in life [1, 2]. Some urologists favor proactive clean intermittent catheterization (CIC) in a majority of infants [3, 4, 5]. Others manage expectantly and intervene selectively based on clinical, radiographic, and/or urodynamic (UD) risk assessment [6, 7, 8].

The optimal management approach remains unclear [9, 10]. Proactive CIC in infants has been associated with low rates of upper urinary tract deterioration [3, 4, 11], infrequent renal functional loss [3, 12, 13], and reduced rates of augmentation cystoplasty [14, 15]. Other studies suggest that proactive CIC might prevent anatomic [16] and functional [17] bladder deterioration. However, CIC adds significantly to care burden [18], and proactive intervention may result in treatment of many patients whose kidneys are not jeopardized [19]. Recent studies suggest that CIC may not protect against urinary tract infection (UTI) [20], or prevent renal parenchymal loss [21]. In 2016, a Centers for Disease Control (CDC) working group issued a protocol which aims to standardize newborn management and allow more rigorous outcomes analysis moving forward [9].

The purpose of the current article is to report outcomes among newborns with SD managed with expectant CIC. Some patients began CIC “early,” based on problems with UTI, or in response to radiographic or UD findings. Others began later if the family sought to achieve continence for the child. It is hypothesized that (1) many children can be managed without CIC until efforts are made to achieve continence, and that if properly selected, (2) these patients will also have a low risk of renal parenchymal injury or functional loss on technetium-99m dimercaptosuccinic acid (DMSA) renal scan. It is also suspected that (3) should new hydronephrosis (HN), vesicoureteral reflux (VUR), elevated storage pressures, or interim febrile UTI be recognized during follow-up, patients who begin CIC immediately will be less likely to develop DMSA scan abnormalities compared to those in whom intervention is delayed.

2. Methods

Following institutional review board approval, infant SD patients who had initial evaluation at our center between January 2009 and October 2016 were identified via institutional registry. Retrospective review of the electronic medical record was performed. Only patients who underwent initial evaluation prior to six months of age were included. Newborn patients were managed initially without CIC. The clinical follow-up plan included a renal ultrasound (US) every 3 months in year 1, every 6 months in year 2, then annually. UD evaluation and DMSA scan were obtained at 3–6 months, 1 year, 3 years, then as needed. Informed families participated in escalation-of-care decisions.

Demographic, clinical, radiographic and UD data were extracted from the electronic health record, and organized by clinical encounter in a REDCap (research electronic data capture system) [22] to create a longitudinal dataset. HN grading was done based on the Society for Fetal Urology (SFU) system [23]. Early CIC is defined as initiation of catheterization prior to efforts to achieve urinary continence with CIC. Febrile UTI is defined as a febrile illness (temperature over 38.5 degrees Celsius) with positive urine culture (greater than 50,000 colony forming units of pathogenic bacteria) from a catheterized specimen. Elevated storage pressure is defined as end fill pressure (EFP) $>$ 40 cm H ${}_{2}$ O or detrusor leak point pressure (DLPP) $>$ 40 cm H ${}_{2}$ O. End fill pressure (EFP) is defined as the maximum detrusor pressure measured in cm H ${}_{2}$ O – excluding any detrusor contractions – measured during filling cystometery. If an organized detrusor contraction with leakage occurs, EFP is defined as the pressure immediately prior to contraction. If no organized detrusor contraction or leakage occurs, EFP is defined as the pressure at estimated bladder capacity for age or volume causing patient discomfort. DMSA abnormality is defined as (i) a new focal cortical defect or (ii) differential renal function less than 40%, identified either on an initial study in infancy or upon interval DMSA evaluation. Focal defects were identified visually by a radiologist or urologist reviewing the DMSA as areas of decreased peripheral uptake with volume loss and/or concavity. To account for transient DMSA abnormalities caused by pyelonephritis, studies were delayed for a minimum of 3 months following a febrile UTI event. Outcomes of interest include febrile UTIs, DMSA abnormalities, elevated storage pressures, and early CIC.

Results are described using total proportion with outcome and survival curve analysis with cumulative incidence. Proportions are compared by Fisher’s exact test. Log rank test and cox proportional hazard analysis is used to compare longitudinal data between groups.

Table 1
Characteristics of cohort

	Total	Early CIC	No Early CIC
Demographic	N $=$ 102	N $=$ 44	N $=$ 58
Gender
Female	49 (48%)	25 (57%)	24 (44%)
Diagnosis
Spina bifida	93 (91%)	41 (93%)	52 (90%)
Caudal regression	6 (6%)	2 (5%)	4 (7%)
Lipomeningocele	3 (3%)	1 (2%)	2 (3%)
Neurologic lesion level
Thoracic	3 (3%)	2 (5%)	1 (2%)
High lumbar (L1–L2)	6 (6%)	4 (9%)	2 (3%)
Low lumbar (L3–L5)	39 (38%)	17 (39%)	22 (38%)
Lumbar (Unknown)	31 (30%)	13 (30%)	18 (31%)
Sacral	17 (17%)	6 (14%)	11 (19%)
Unknown	6 (6%)	2 (5%)	4 (7%)
Shunt status ${}^{1}$
VP shunt	78/96 (81%)	37/42 (88%)	43/54 (80%)
CIC status from birth
CIC from birth	6 (6%)	6 (14%)	0 (0%)
Diaper drainage from birth	96 (94%)	38 (86%)	58 (100%)

${}^{1}$ Among 96 patients with spina bifida or lipomeningocele,

3. Results

One hundred and two patients were followed for a median duration of 3.2 years (interquartile range [IQR] 1.9–5.0 yrs). Patient characteristics are shown in Table 1. Spina bifida was the most common dysraphism (91%) and lumbar lesions (75%) were most common overall. The majority of the spina bifida and lipomengocele patients (78/96, 81%) had a ventriculoperitoneal shunt. Forty-nine patients were female.

3.1 CIC outcomes

Early CIC was started in 44/102 patients at a median age of 1.2 years (IQR 0.5–3.0 years) and characteristics by group is shown in Table 1. The only significant difference between those started on early CIC and those not started on early CIC was number on CIC since birth ( $p=$ 0.005, Fisher’s exact test) Table 2 summarizes findings which prompted early CIC, with elevated storage pressures and recurrent febrile UTIs being most common. There were 6 patients in whom early CIC was initiated in the neonatal period. Anticholinergic therapy was initiated within 9 months of beginning catheterization in 41/44 patients (93%) managed with early CIC. Two patients managed with early CIC did not begin anticholinergic therapy (family preference). Another could not be catheterized per urethra and underwent reconstructive surgery (augmentation cystoplasty with Monti catheterizable channel). 4 patients underwent vesicostomy at a median age of 1.8 years (range 0.6–2.9 years) and all were managed with CIC prior to vesicostomy.

Table 2
Reasons for starting CIC

Febrile UTI	21/44 (48%)
Non febrile UTI	4/44 (9%)
Hydronephrosis ${}^{1}$	10/44 (23%)
Vesicoureteral reflux	15/44 (34%)
Urodynamic findings ${}^{2}$	26/44 (59%)
DMSA abnormality	9/44 (20%)

Note: many patients had more than one reason. ${}^{1}$ Median SFU grade was 2 (IQR 1–2), 6 had bilateral hydronephrosis. ${}^{2}$ Median EFP was 45 cm H2O (IQR 40–50).

58/102 patients did not start early CIC. In 11/58, CIC was started for the singular purpose of continence at a median age of 4.0 years (range 3.4–4.8 years). The remaining 47 patients did not start CIC within 2.2 year median follow-up (IQR 1.2–3.6 years).

3.2 DMSA outcomes

DMSA abnormalities were found in 22/102 patients (22%) at a median age of 1.0 years (IQR 0.6–2.0 years). Abnormalities were detected on initial DMSA scan in 8 patients, 2 ${}^{\rm nd}$ in 11, 3 ${}^{\rm rd}$ in 2, and 6 ${}^{\rm th}$ in 1. Previous VUR (HR 5.9, 95% CI 2.3–14.9, $p<$ 0.001), febrile UTI (HR 3.8, 95% CI 1.4–10.1, $p=$ 0.007), and elevated storage pressures (HR 3.9, 95% CI 1.6–9.7, $p=$ 0.004) were all independently associated with subsequent abnormal DMSA by multivariable cox proportional hazard analysis. Of note, 5 patients had DMSA abnormalities recognized on a study performed within 6 months of a documented febrile UTI event without interval evaluation. No patient had an abnormal serum Cr value during study follow up.

Figure 1.

Clinical progress in patients who may have benefitted from earlier CIC.

Among 44 patients in whom early CIC was initiated, 20 (45%) were found to have a DMSA abnormality. In 9/20, the DMSA abnormality was recognized prior to initiation of early CIC (Fig. 1) at a median age of 8.9 months (range 1.5–37.9 months). In all 9 of these patients, at least one of the following had been documented prior to abnormal scan: VUR (4/9), febrile UTI (4/9), and/or elevated storage pressure (4/9). In 11/20, DMSA abnormality was recognized after initiation of early CIC.

Among patients who (a) either had yet to start CIC at study completion (N $=$ 47) or (b) began CIC in an attempt to achieve continence (N $=$ 11), 2/58 (3%) were found to have a DMSA abnormality. Of these 2 patients, 1 had a pelvic kidney without focal scarring, 35% ipsilateral differential function, and no UTI history. The other expired due to an autopsy-proven non-urologic cause at 8 months of age (before CIC could be initiated at next clinic visit). Patients who were not managed with early CIC (2/58, 3%) had a significantly-lower rate of DMSA abnormalities compared to those managed with early CIC or vesicostomy (20/44, 45%) ( $p<$ 0.001).

3.3 Effect of delaying CIC in patients at-risk for renal injury

All 44 patients in whom early CIC was initiated were recognized to have one or more of the following: new HN, VUR, elevated storage pressures, or interim febrile UTI. Seventeen of these 44 patients were either already catheterizing or began immediately upon initial recognition of one or more of the above findings at a median age of 1.0 years (IQR 0.3–1.4 years). 27/44 patients did not start CIC immediately when one or more of these findings was recognized. In these patients, a median delay of 1.2 years (IQR 0.3–2.6 years) was observed from recognition said findings to CIC start at a median age of 2.3 years (IQR 0.6–3.2). Four of the 17 patients (24%) who began CIC prior to or promptly upon initial recognition of new HN, VUR, elevated storage pressure or interim febrile UTI, were found to have a DMSA abnormality compared to 16/27 patients (60%) in whom CIC initiation was delayed ( $p=$ 0.03). Within the latter group, DMSA abnormalities were present prior to initiation of CIC in 9/16 patients while none of the 4 promptly-managed patients had abnormalities before intervention ( $p=$ 0.09)

Table 3
Total proportion and estimated cumulative incidence of outcomes of interest

	Proportion	1 year cumulative	3 year cumulative	5 year cumulative
		incidence (95% CI)	incidence (95% CI)	incidence (95% CI)
Febrile UTI	42/102 (41%)	23% (15–32%)	40% (31–52%)	57% (42–72%)
EFP $>$ than 40 centimeters water	36/102 (35%)	13% (8–21%)	34% (24–45%)	42% (31–55%)
DMSA abnormality	22/102 (22%)	11% (6–19%)	23% (15–34%)	29% (19–43%)
CIC started before continence desired ${}^{1}$	44/102 (43%)	17% (12–26%)	35% (26–45%)	49% (38–61%)

UTI $=$ urinary tract infection; VUR $=$ vesicoureteral reflux; EFP $=$ end fill pressure; CI $=$ confidence interval; CIC $=$ clean intermittent catheterization; ${}^{1}$ CIC for continence was modeled as competing risk for cumulative incidence calculations for this outcome.

3.4 Cumulative incidence estimates

Table 3 lists total proportion and estimated cumulative incidences of outcomes of interest (febrile UTI, elevated storage pressures, DMSA abnormality, early CIC). The failure curves are shown in Fig. 2. An estimated 29% (95% CI: 19–43%) of patients will develop a DMSA abnormality by 5 years of age and 49% (95% CI: 38–61%) of patients will start early CIC.

Figure 2.

Failure curves for outcomes of interest.

4. Discussion

This study reports outcomes among children with SD who were managed within an expectant CIC program. It was hypothesized that in select patients, CIC might be deferred until efforts to achieve continence with low risk of DMSA abnormality. Indeed, it was observed that around 60% of children were managed without early CIC, and only two of these patients had an abnormal DMSA (one had a pelvic kidney with no focal defect and the other expired from a non-urologic cause before CIC was initiated). Therefore, these findings are congruent with previous studies demonstrating safety of expectant management in select newborns [6, 7, 8], and stratification of low-risk patients appears to have been accurate within this program. These findings are important because CIC is the only medical factor associated with parenting stress in mothers of children with spina bifida [18].

Early CIC was instituted in a minority of patients (43%) due to identification of risk factors. As expected, these children had a significantly-higher rate of abnormal DMSA findings (45%) which is also congruent with previous work [7]. In 9 patients – all with previously-recognized VUR, febrile UTI or elevated storage pressures – a DMSA abnormality was recognized before early CIC was initiated. Therefore, about 10% of patients in this cohort may have potentially benefitted from earlier initiation of CIC, which may have prevented DMSA abnormalities in some.

Some patients in this cohort began CIC immediately upon recognition of new HN, VUR, elevated storage pressures, or interim febrile UTI during follow-up. In others, intervention was delayed (likely secondary to provider practice variation, family preferences, etc.), allowing serendipitous comparison. Already being on CIC or beginning immediately upon recognition of new HN, VUR, elevated storage pressures, or interim febrile UTI was associated with lower chance of DMSA abnormalities (4/17, 24%) compared to delaying initiation of CIC (16/27, 60%) ( $p=$ 0.03). Therefore, prompt initiation of CIC upon recognition of any of the aforementioned findings may prevent subsequent DMSA abnormalities, though further study along these lines is needed. Lastly, development of DMSA abnormalities after initiation of catheterization was common among patients managed with early CIC (11/20, 55%), and 4 patients on CIC underwent subsequent vesicostomy. These findings suggest that at-risk patients who have begun a catheterization program need continued follow-up and can still develop upper tract changes including DMSA abnormalities.

4.1 Renal outcomes

Direct comparison of renal outcomes to the existing literature is difficult due to variability among protocols and inconsistency with respect to how renal outcome measures are defined [10]. Woo et al., in a cohort of 83 expectantly-managed patients (N $=$ 83) and others who began CIC from birth (N $=$ 17), reported scarring or functional discrepancy in 43% overall (median age at DMSA 9 years) and found CIC from birth to be independently associated with subsequent DMSA abnormality [21]. Wide reported nuclear scan abnormalities (defined by focal scarring) in 5/41 patients (12%) overall at 11-year median follow-up [5]. Of note, DMSA abnormalities appeared to be morefrequent among patients who began CIC from birth (4/23 patients, 17.4%) compared those in whom intervention was delayed (1/15 patients, 6.7%), though treatment compliance within the former group was questioned [5]. Most studies report nuclear scan abnormalities in 15–25% of children with SD [24, 25, 26, 27], though cohorts vary widely with respect to utilization of CIC, age of evaluation, and duration of follow-up. In the present study, DMSA abnormalities were observed in 22% patients overall. The cohort is also the youngest among those mentioned, and DMSA abnormalities are known to accumulate with increasing age [21, 28]. Lastly, multivariate analysis was congruent with previous studies associating VUR [7, 12, 13, 21, 25, 26, 27], history of febrile UTI [7, 25, 26, 27], and impaired bladder compliance [5, 8] with upper tract deterioration and/or parenchymal loss on nuclear renal scan.

4.2 Urodynamic findings

Detrusor storage pressure over 40 cm H ${}_{2}$ O is thought to confer upper tract risk in patients with SD. [29]. One-third of patients in this study developed EFP $>$ 40 cm H ${}_{2}$ O – predominantly in the first 2 years of life. It has been hypothesized that as many as 35% of bladders change (usually for worse) on serial UD evaluation up to age 2, often with stabilization thereafter [1]. Congruent with this, the estimated cumulative incidence of EFP $>$ 40 cm H ${}_{2}$ O rose sharply from 1–3 years with less increase from 3–5 years. While frequent UD evaluation may be prudent before age 3, more selective utilization thereafter may be reasonable. Lastly, some experts estimate upper tract risk based on the presence or absence of detrusor sphincter dyssynergia (DSD) [4, 14, 30]. Given the frequent artifact that occurs when squirming, crying infants undergo cystometrogram, we found accurate assessment of DSD to be difficult in practice.

4.3 Limitations

This study is limited by retrospective nature and lack of a control group. While the schedule for follow-up and diagnostic evaluation outlined in the methods section was generally followed, not all patients obtained imaging at the planned time. Our description of renal outcomes included only DMSA results, a study with inherent limitations including technical variability and subjective interpretation. Difficulty in distinguishing congenital dysplasia and transient pyelonephritic lesions may have contributed to overestimation of the incidence of acquired renal injury in this series. However, there were no patients who had an abnormal DMSA who then had a subsequent normal DMSA. While there were no patients with abnormal serum Cr values in this cohort, more precise measures of glomerular filtration rate were not routinely performed. Another limitation was that CIC was not started in all patients who had an indication, as can be gleaned from the text. Additionally, a discrete cutoff for elevated filling pressures ( $>$ 40 cm H ${}_{2}$ O) was used, when in reality, upper tract risk likely exists on a continuum. Analysis for this criterion may have failed to include some patients with appreciable upper tract risk with pressure values just below this threshold. Also, the occurrence of interim febrile UTI was recorded as a binary (yes/no) variable within the longitudinal dataset. Therefore, if a patient experienced multiple febrile UTIs between any two follow-up visits, only a single instance was captured for analysis (potentially underestimating the true incidence of febrile UTI). A prospective comparative multicenter trial which compares proactive and expectant newborn management according to long-term renal outcomes would be ideal. The recently-initiated CDC collaboration [9] may offer some insights along these lines.

5. Conclusions

In a select group of newborn patients with SD, CIC can be deferred until efforts to achieve continence with a low risk of developing a significant DMSA abnormality. Conversely, identifying and protecting patients at high risk for renal injury is important but remains challenging. Many severely-affected patients developed new DMSA abnormalities and/or underwent vesicostomy despite CIC. Upon recognition of new HN, VUR, elevated storage pressures, or febrile UTIs, immediate compared to delayed initiation of CIC may decrease chance of subsequent DMSA abnormality. About 10% of patients in this program could have potentially benefitted had CIC been started immediately upon recognition of these factors. Recommendations for expectantly-managed patients include close clinical follow-up, serial renal US and UD evaluation, and prompt initiation of CIC upon recognition of new HN, VUR, elevated storage pressures or febrile UTI.

Footnotes

Conflict of interest

The authors have no conflict of interest to report.

Abbreviationss

SD – spinal dysraphism

CKD – chronic kidney disease

CIC – clean intermittent catheterization

UD – urodynamic

HN – hydronephrosis

US – ultrasound

VUR – vesicoureteral reflux

DMSA – (technetium-99m) dimercaptosuccinic acid

UTI – urinary tract infection

CDC – Centers for Disease Control

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Expectant use of CIC in newborns with spinal dysraphism: Report of clinical outcomes