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Corresponding author. Emma Children's Hospital Amsterdam UMC, University of Amsterdam, Department of Pediatric Surgery, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands. Fax: +31205669287.
Emma Children's Hospital Amsterdam UMC, University of Amsterdam, Department of Pediatric Surgery, Meibergdreef 9, Amsterdam, the NetherlandsAmsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, the NetherlandsAmsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands
Emma Children's Hospital Amsterdam UMC, University of Amsterdam, Department of Pediatric Surgery, Meibergdreef 9, Amsterdam, the NetherlandsAmsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, the NetherlandsAmsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands
Emma Children's Hospital Amsterdam UMC, University of Amsterdam, Department of Pediatric Surgery, Meibergdreef 9, Amsterdam, the NetherlandsAmsterdam Gastroenterology and Metabolism Research Institute, Amsterdam, the NetherlandsAmsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands
ARM can occur as isolated anomaly, or as part of VACTERL-association or syndromes. Additional anomalies can occur.
•
62% of the ARM patients had additional anomalies. VACTERL-association or syndromes were found in 16% and 17% respectively.
Abstract
Background
In children with anorectal malformations (ARM), additional anomalies can occur within the VACTERL-association. Routine screening is of great importance for early identification and potential treatment. However, uniformity in screening protocols is lacking and only small cohorts have been described in literature. The aim of this study was to assess and describe a unique large cohort of ARM patients who underwent VACTERL screening in the neonatal period.
Methods
A retrospective mono-center cohort study was performed. Included were all neonates born between January 2000 and December 2020 who were diagnosed with ARM and screened for additional anomalies. Full screening consisted of x-ray and ultrasound of the spine, cardiac and renal ultrasound, and physical examination for limb deformities, esophageal atresia, and ARM. Criteria for VACTERL-classification were predefined according to the EUROCAT-definitions.
Results
In total, 216 patients were included, of whom 167 (77.3%) underwent full VACTERL-screening (66% in 2000–2006 vs. 82% in 2007–2013 vs. 86% in 2014–2020). Median age at follow-up was 7.0 years (IQR 3.0–12.8). In 103/167 patients (61.7%), additional anomalies were identified. Some 35/216 patients (16.2%) fulfilled the criteria of a form of VACTERL-association. In 37/216 patients (17.1%), a genetic cause or syndrome was found.
Conclusions
The majority of ARM patients underwent full screening to detect additional anomalies (77%), which improved over time to 86%. Yet, approximately a quarter of patients was not screened, with the potential of missing important additional anomalies that might have severe consequences in the future. Forms of VACTERL-association or genetic causes were found in 16% and 17% respectively. This study emphasizes the importance of routine screening.
Anorectal malformations (ARM) are rare disorders that encompass a heterogeneous group of congenital birth defects that occur in approximately 1–3 per 5000 live births [
]. According to the Krickenbeck classification for ARM, a spectrum of malformations can be encountered ranging from relatively simple types (e.g., recto-perineal or recto-vestibular fistula) to more complex and rare types (e.g., recto-urethral fistula, cloacal anomalies or rare/regional variants such as rectal atresia) [
]. Presumably, altered spatiotemporal gene expression and multifactorial disturbances in early embryogenesis (2–4 weeks) can cause complex type ARM (e.g., recto-vesical fistula or cloacal anomaly) as well as malformations of other organ systems [
]. In 1973, the initial VATER-association was first described by Quan et al., with vertebral (V), anorectal (A), tracheo-esophageal (TE), renal and radial (R) anomalies that frequently occur simultaneously [
The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects.
In 2020, EUROCAT definitions were proposed for the diagnosis of VACTERL, describing major versus minor VACTERL features (i.e. congenital anomalies part of versus not part of the classical VACTERL-association). Subsequently, four VACTERL-subtypes (i.e. STRICT-VACTERL, VACTERL-LIKE, VACTERL-PLUS, and NO-VACTERL) were identified [
]. Still (current) studies use various VACTERL definitions (e.g. differing in minimum of additional anomalies for the diagnosis), and often do not distinguish between major and minor VACTERL features [
Does presence of a VACTERL anomaly predict an associated gynecologic anomaly in females with anorectal malformations?: a pediatric colorectal and pelvic learning consortium study.
Analysis of 1,992 patients with anorectal malformations over the past two decades in Japan. Steering Committee of Japanese Study Group of Anorectal Anomalies.
]. Early identification of additional congenital anomalies is crucial, as these may be indicative for an underlying genetic syndrome or association and because of medical implications of the congenital abnormalities as such. In the literature, VACTERL-association was present in 5–31% of ARM patients [
]. Therefore, routine screening in the neonatal period is recommended for ARM patients, as potentially missed additional anomalies might have severe consequences later in life [
The aim of this study was therefore to assess the number of ARM patients that underwent (full) routine VACTERL screening in the neonatal period. In addition, we aimed to assess the number of patients, both simple and complex ARM types, with VACTERL-association or with additional anomalies in the VACTERL spectrum who were identified through the screening and to assess the number of patients with known genetic causes and syndromes.
2. Methods
2.1 Study design and patient population
A retrospective mono-center cohort study was performed at the pediatric surgery department of the Emma children's hospital, Amsterdam University Medical Centers (AmsterdamUMC). The AmsterdamUMC is a tertiary referral center, accredited by the national authority as a center of expertise for anorectal malformations and a member of European Reference Network (ERN) eUROGEN. This study was designed in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines [
Eligible patients were identified in 2 ways. Patients born between January 2000 and December 2018 were identified using the International Classification of Diseases (ICD)-9 code for ARM (Q42) or interventional codes for anterior and posterior sagittal anorectoplasty (335047B and 335,047, respectively). Patients born between January 2019 and December 2020 were identified from a prospective registry. Inclusion criteria were all neonates born between January 2000 and December 2020 who were diagnosed with ARM in the neonatal period (i.e. first 4 weeks of life), and screened for additional anomalies in AmsterdamUMC as soon as possible after diagnosis. Exclusion criteria were patients that did not meet the criteria for an ARM, patients of whom parents objected to the use of data, and patients without information in the medical chart about type of ARM, screening and treatment. Patients who deceased within 1 day after birth and patients who were referred to AmsterdamUMC at later age (e.g., in case of adoption or migration) were also excluded. Follow-up time was calculated from birth to last follow-up appointment.
2.2 Ethics
This study was reviewed by the medical ethical commission and was not subject to the WMO statement (ref. No. W19_293 #19.350). Written information was provided to parents or legal guardians for all identified ARM patients, including a letter of objection. In case of objection, patients were removed from the database.
2.3 Data extraction
Data on patient characteristics, type of ARM (according to Krickenbeck classification [
]), and additional anomalies (i.e. vertebral, anorectal, cardiac, trachea-esophageal, renal and limb; classification into major and minor anomalies according to EUROCAT guidelines [
]) were extracted. Furthermore, data on additional testing (i.e. spinal ultrasound and x-ray, cardiac and renal ultrasound, additional testing performed on indication, genetic counseling, genetic testing) were extracted from medical records by two independent researchers (CdB, AA) according to predefined data collection forms. In case of inconsistencies, another author (RG) was consulted for final verdict. Data validation was done by checking approximately 20% of the entered records by another author (RG). In case there were inconsistencies in more than 1% of a record, the complete record was checked.
2.4 Routine screening protocol
Since 2017, a clinical care pathway was implemented in the AmsterdamUMC including a routine screening protocol for additional anomalies in children with ARM. Complete routine screening according to AmsterdamUMC protocol (as depicted in Fig. 1) for additional anomalies in children with ARM consisted of urogenital tract ultrasound, spinal x-ray and ultrasound assessed by a pediatric radiologist (R, V), cardiac ultrasound assessed by a pediatric cardiologist (C), and physical examination done by a pediatric surgeon, neonatologist, pediatrician, or clinical geneticist to assess limb deformities (L), as well as anomalies in the genital and anoperineal area (A). Furthermore, presence of potentially associated esophageal atresia (TE) was clinically assessed (i.e. physical examination). In case anomalies were suspected during clinical assessment, additional imaging studies were undertaken to confirm or rule out the suspected diagnosis. Genetic counseling was performed by a clinical geneticist at the treating physician's discretion and consisted of thorough examination of medical history family history and physical examination. Additional genetic testing was done at the clinical geneticist's discretion. Genetic testing was mostly done by karyotyping, array analysis, Sanger sequencing or next generation sequencing. Variants of unknown significance were not considered causative.
Fig. 1Overview of AmsterdamUMC routine protocol for ARM patients within 4 weeks after birth. ∗for all ARM patients, thorough physical examination is required, including inspection of the spine and/or back (V), genital and anoperineal region (A), cardiac sounds (C), thoracic examination for identification of esophageal atresia (TE), and inspection of lower and upper extremities (L).
]. While spine and spinal cord anomalies often occur simultaneously in patients with ARM, an ultrasound of the spinal cord was not considered compulsory, as these were not considered as major anomalies outside the VACTERL-association. Subsequently, in this study, all patients that underwent x-ray of the spine, cardiac and renal ultrasound and physical assessment of potential TE presence or limb deformities were categorized into VACTERL subtypes as defined below. In case of uncertainties regarding classification of additional anomalies, an expert panel consisting of a pediatric cardiologist, pediatric urologist, pediatric neurologist, pediatric geneticist (with expertise in syndromic anomalies), and pediatric surgeon were consulted.
2.5 ARM and VACTERL definitions
Patients were classified according to their type of ARM using the Krickenbeck classification with major clinical groups and rare or regional variants [
STRICT-VACTERL: 3 or more major anomalies (in different organ systems) without other anomalies outside of the VACTERL-association.
-
VACTERL-LIKE: less than 3 major anomalies plus minor anomalies adding up to 3 or more anomalies.
-
VACTERL-PLUS: patients who fulfilled the strict-VACTERL or the VACTERL-like group, with additional anomalies outside of the VACTERL-association.
-
NO-VACTERL: less than 3 anomalies.
2.6 Outcomes
Primary outcome was the proportion of ARM patients who underwent full routine screening according to AmsterdamUMC protocol of the total included ARM patients.
Secondary outcomes were the number of ARM patients with additional anomalies according to the type of ARM, the number of ARM patients with a VACTERL-association (STRICT-VACTERL, VACTERL-LIKE, VACTERL-PLUS, or NO-VACTERL) or any other known genetic cause or syndrome (confirmed by clinical assessment and/or a pathogenic result upon genetic testing) of all screened patients, and the number of patients without any additional anomaly at all.
2.7 Statistical analyses
Statistical analysis was conducted using IBM SPSS Statistics for Windows, Version 26 (IBM Corp., Armonk, N.Y., USA). Descriptive statistics were used for analysis of baseline characteristics. These were reported as proportions and percentages for binary or categorical variables, and as mean with standard deviation (SD) or as median with interquartile range (IQR) for continuous variables as appropriate. To evaluate changes over time in screening, patients were categorized into 3 time periods (i.e. period 1: 2000–2006, period 2: 2007–2013, period 3: 2014–2020). To compare screening percentages over time, Chi-square for trend was used. A p-value of <0.05 was considered statistically significant. No other comparisons or quantitative syntheses were performed because ofbecause of small numbers and large heterogeneity. Missing or unknown data were described. In case of missing data in clinical assessment (physical examination) of ‘TE’ or ‘L’ associated anomalies, it was classified as ‘no anomalies’ as these anomalies are usually never missed clinically.
3. Results
3.1 Participants
In total, 351 patients were identified of whom 6 objected to participation. After medical record reviewing, 129 patients were excluded (Fig. 2., including reasons). Consequently, 216 patients were included (n = 82 in period 1, n = 55 in period 2, n = 79 in period 3), comprising 106 female (49.1%) and 110 male (50.9%) patients with a median age of 7.0 years (IQR 3.0–12.8) at latest follow-up. Ten different ARM types were identified of which recto-perineal fistula occurred most often, encompassing 44/106 female patients (41.5%) and 52/110 male patients (47.3%). A complete overview of identified ARM types is shown in Table 1. In total, 6 patients (2.8%) died during the study period. Three patients died because ofbecause of respiratory insufficiency (at age 2, respectively 3 days, and 3 months) and 1 because ofbecause of abdominal compartment syndrome (at age 16 years). In 2 patients, the cause of death was not mentioned in the available medical record.
Fig. 2Flowchart for in- and exclusion of participants. N = number.
In total, 167/216 ARM patients (77.3%) were fully screened for additional anomalies, within the VACTERL-association spectrum, according to AmsterdamUMC protocol. Over the 3 time periods, percentage of full VACTERL screening increased (65.9% vs. 81.8% vs. 86.1%, p-trend = 0.02). Vertebral screening (spinal x-ray and spinal cord ultrasound) was performed in 192/216 patients (88.9%). Over the 3 time periods, percentage of vertebral screening remained similar (89.0% vs. 87.3% vs. 89.9%, p-trend = 0.901). Cardiac screening (cardiac ultrasound) was performed in 180/216 patients (83.3%). Over the 3 time periods, percentage of cardiac screening increased (76.1% vs. 90.9% vs. 94.9%, p-trend<0.001). Renal screening (urogenital ultrasound) was performed in 209/216 patients (96.8%). Over the 3 time periods, percentage of renal screening remained similar (96.3% vs. 94.5% vs. 98.7%, p-trend = 0.513). A complete overview on screening requiring additional imaging studies per ARM type is shown in Table 2.
Table 2Screening requiring additional imaging studies according to type of ARM.
Additional anomalies were identified both in patients with simple ARM types, as well as in patients with more complex ARM types. In total, additional anomalies were identified in 103/167 patients (61.7%) that underwent full screening (Table 3a–e). Vertebral anomalies were identified in 58/192 patients (30.2%) that underwent additional imaging studies. Cardiac anomalies were identified in 61/180 patients (33.9%) that underwent additional imaging studies. Tracheo-esophageal anomalies were identified in 17/216 patients (7.9%). Renal anomalies were identified in 30/209 patients (14.3%). Limb anomalies were identified in 18/216 patients (8.3%). Overall, for every type of anomaly, the percentage of diagnosed patient remained similar over the 3 time periods (for all p-trend >0.05, data not shown). An overview of identified additional anomalies according to ARM type is shown in Table 3(a-e). No additional anomalies were identified in 64/167 patients (38.3%) that underwent full screening.
Table 3a-eAdditional anomalies according to type of ARM.
Type of ARM
Vertebral anomalies
None
minor
major
n (%)
n (%)
n (%)
a. Vertebral anomalies according to type of ARM
Recto-perineal fistula, n = 96 missing, n = 14
70 (85.4)
2 (2.4)
10 (12.2)
Recto-vestibular fistula, n = 43 missing, n = 2
31 (75.6)
5 (12.2)
5 (12.2)
Recto-urethral fistula, n = 36 missing, n = 1
18 (51.4)
7 (20.0)
10 (28.6)
Recto-vesical fistula, n = 6 missing, n = 1
1 (20.0)
1 (20.0)
3 (60.0)
Cloaca, n = 13 missing, n = 1
5 (41.7)
3 (25.0)
4 (33.3)
Anal stenosis, n = 3 missing, n = 2
0
0
1 (100.0)
Imperforate anus without fistula, n = 12 missing, n = 1
9 (81.8)
1 (9.1)
1 (9.1)
Rare/regional fistula, n = 6 missing, n = 2
0
1 (25.0)
3 (75.0)
Type of fistula unknown, n = 1 missing, n = 0
0
0
1 (100.0)
Total, n = 216missing, n = 24 (11.1%)
134 (69.8)
20 (10.4)
38 (19.8)
Type of ARM
Cardiac anomalies
None
minor
major
n (%)
n (%)
n (%)
b. Cardiac anomalies according to type of ARM
Recto-perineal fistula, n = 96 missing, n = 15
62 (76.5)
0
19 (23.5)
Recto-vestibular fistula, n = 43 missing, n = 8
20 (57.1)
1 (2.9)
14 (40.0)
Recto-urethral fistula, n = 36 missing, n = 3
20 (60.6)
0
13 (39.4)
Recto-vesical fistula, n = 6 missing, n = 1
4 (80.0)
0
1 (20.0)
Cloaca, n = 13 missing, n = 3
5 (50.0)
1 (10.0)
4 (40.0)
Anal stenosis, n = 3 missing, n = 2
1 (100.0)
0
0
Imperforate anus without fistula, n = 12 missing, n = 2
4 (40.0)
0
6 (60.0)
Rare/regional fistula, n = 6 missing, n = 2
3 (75.0)
0
1 (25.0)
Type of fistula unknown, n = 1 missing, n = 0
0
0
1 (100.0)
Total, n = 216missing, n = 36 (16.7%)
119 (66.1)
2 (1.1)
59 (32.8)
Type of ARM
Tracheo-esophageal anomalies
None
minor
major
n (%)
n (%)
n (%)
c. Tracheo-esophageal anomalies according to type of ARM
Recto-perineal fistula, n = 96
91 (94.8)
0
5 (5.2)
Recto-vestibular fistula, n = 43
39 (90.7)
0
4 (9.3)
Recto-urethral fistula, n = 36
32 (88.9)
0
4 (11.1)
Recto-vesical fistula, n = 6
6 (100.0)
0
0
Cloaca, n = 13
11 (84.6)
0
2 (15.4)
Anal stenosis, n = 3
3 (100.0)
0
0
Imperforate anus without fistula, n = 12
11 (91.7)
0
1 (8.3)
Rare/regional fistula, n = 6
5 (83.3)
0
1 (16.7)
Type of fistula unknown, n = 1
1 (100.0)
0
0
Total, n = 216missing, n = 0
199 (92.1)
0
17 (7.9)
Type of ARM
Renal anomalies
none
minor
major
n (%)
n (%)
n (%)
d. Renal anomalies according to type of ARM
Recto-perineal fistula, n = 96 missing, n = 5
83 (91.2)
3 (3.3)
5 (5.5)
Recto-vestibular fistula, n = 43 missing, n = 0
37 (86.0)
0
6 (14.0)
Recto-urethral fistula, n = 36 missing, n = 0
29 (80.6)
3 (8.3)
4 (11.1)
Recto-vesical fistula, n = 6 missing, n = 0
4 (66.7)
1 (16.7)
1 (16.7)
Cloaca, n = 13 missing, n = 0
10 (76.9)
0
3 (23.1)
Anal stenosis, n = 3 missing, n = 1
2 (100.0)
0
0
Imperforate anus without fistula, n = 12 missing, n = 0
In total, 112/216 patients (51.9%) underwent consultation by a clinical geneticist. The percentage of patients who underwent a genetic consultation increased from 18% in 2000 to 88% in 2020 (Chi-square for trend p < 0.001). In 176/216 patients (81.5%) a diagnosis of an underlying genetic or syndromic condition could be made or could be categorized according to VACTERL classification. Regarding VACTERL classification, 139/176 patients (80.0%) could be classified into 1 of the VACTERL groups. Some 22/176 patients (12.5%) were classified into the STRICT-VACTERL group, 9/176 patients (5.1%) into the VACTERL-LIKE group, 4/176 patients (2.3%) into the VACTERL-PLUS group, and 104/176 patients (59.0%) into the NO-VACTERL group. In 37/176 patients (21.0%), their phenotype could be explained by identified genetic or syndromic disorders and were therefore excluded from VACTERL classification. In these 37 patients, the following syndromes were mostly identified: Cat-eye syndrome (n = 6, 16.2%), caudal regression syndrome (n = 6, 16.2%), Down syndrome (n = 6, 16.2%), Currarino syndrome (n = 4, 10.8%), Townes-Brocks syndrome (n = 3, 8.1%), cri-du-chat syndrome (n = 2, 5.4%), and Moebius syndrome (n = 1, 2.7%), Jacobson syndrome (n = 1, 2.7%), Kabuki syndrome (n = 1, 2.7%), Crouzon syndrome (n = 1, 2.7%), CHARGE syndrome (n = 1, 2.7%), Pallister-Hall syndrome (n = 1, 2.7%), Pallister-Killian syndrome (n = 1, 2.7%), 8p deletion syndrome (n = 1, 2.7%), 9q34 duplication syndrome (n = 1, 2.7%), and Xq22.3 duplication syndrome (n = 1, 2.7%). The number of patients diagnosed with genetic aberrations did not change over time (Chi-square for trend 0.930). A complete overview of prevalence of VACTERL classification according to ARM type is shown in Table 4. In addition, an overview of incidence of VACTERL classification according to year of birth can be found in Supplementary Table 1.
Table 4Prevalence of VACTERL-type (according to EUROCAT classification) according to type of ARM.
Patients in whom their phenotype could be explained by genetic or syndromic disorders diagnosed by genetic testing and therefore excluded from VACTERL classification.
STRICT-VACTERL
VACTERL-LIKE
VACTERL-PLUS
NO-VACTERL
n (%)
n (%)
n (%)
n (%)
n (%)
Recto-perineal fistula, n = 96 missing, n = 20 (20.8%)
14 (14.6)
5 (5.2)
2 (2.1)
1 (1.0)
54 (56.3)
Recto-vestibular fistula, n = 43 missing, n = 9 (20.9%)
4 (9.3)
4 (9.3)
2 (4.7)
1 (2.3)
23 (53.5)
Recto-urethral fistula, n = 36 missing, n = 3 (8.3%)
7 (19.4)
6 (16.7)
1 (2.8)
1 (2.8)
18 (50.0)
Recto-vesical fistula, n = 6 missing, n = 2 (33.3%)
0
2 (33.3)
1 (16.7)
0
1 (16.7)
Cloaca, n = 13 missing, n = 1 (7.7%)
3 (23.1)
1 (7.7)
3 (23.1)
1 (7.7)
4 (30.8)
Anal stenosis, n = 3 missing, n = 2 (66.7%)
1 (33.3)
0
0
0
0
Imperforate anus without fistula, n = 12 missing, n = 1 (8.3%)
6 (50.0)
1 (8.3)
0
0
4 (33.3)
Rare/regional fistula, n = 6 missing, n = 2 (33.3%)
2 (33.3)
2 (33.3)
0
0
0
Type of fistula unknown, n = 1 missing, n = 0
0
1 (100.0)
0
0
0
Total, n = 216missing, n = 40 (18.5%)
37 (17.1)
22 (10.2)
9 (4.2)
4 (1.9)
104 (48.1)
n = number.
a Patients in whom their phenotype could be explained by genetic or syndromic disorders diagnosed by genetic testing and therefore excluded from VACTERL classification.
In our cohort of 216 ARM patients, 77% of the patients underwent full screening to identify potential associated anomalies according to AmsterdamUMC screening protocol. Over time, screening percentages were significantly improved. Additional anomalies were present in 62% of the patients that underwent full screening, with vertebral and cardiac most commonly. Twenty percent of the patients fulfilled the criteria for STRICT-VACTERL, VACTERL-LIKE, or VACTERL-PLUS. Additional anomalies were identified in both patients with simple ARM types, as well as in patients with more complex ARM types. Genetic causes or syndromic anomalies were diagnosed in 21% of the patients.
In our study, full screening for additional anomalies was lacking in 23% of the included patients. Compared to previous similar cohort studies, this number is relatively low as other authors reported incomplete screening in 40–89% [
]. These studies often do not have a routine screening protocol on sight. Because of our screening protocol, the number of fully screened patients is high and improved over time to 86% in 2014–2020. This can be explained by natural improvement over time, increase of cardiac and genetic screening over time (increase of vertebral and renal screening was not expected because already high in period 1), and active implementation of the screening. In addition, screening percentages may have increased because ofbecause of the incorporation of spinal cord ultrasound in our screening protocol, because spinal cord anomalies are often seen in ARM patients, unlike the screening protocol in other centers [
]. Still, in our study population, almost a quarter of patients is not fully screened for additional anomalies. This could partially be explained by the retrospective character of this study, in combination with the long period of time from which the patients were included (since the year 2000). Consequently, screening may be performed, while results were not stored or noted in the (paper) medical record of the patient, before digitalization in the year 2016. Therefore, the actual number of patients with full screening might even be higher. Also, non-compliance to the screening protocol may be a reason. Implementing standard screening for all additional anomalies in the VACTERL spectrum has developed over the years, and the request for additional imaging studies may have been less common in the past. Moreover, in the next couple of years we aim to increase the percentage of fully screened patients to 100%. Promoting factors within our centers might be the incorporation of a monthly multidisciplinary team meeting since 2018, dedicated physicians from all disciplines and extra education.
In this study, additional anomalies were identified in both patients with relatively simple ARM types (i.e. recto-perineal or recto-vestibular fistula), as well as in patients with more complex ARM types (e.g., recto-urethral fistula, cloaca, and rare/regional variants). Previous studies investigated whether additional anomalies were more frequently present in complex ARM types with the aim to minimize or abandon routine screening in patients with more simple ARM types. They found that in patients with more complex ARM types, additional anomalies were more often identified [
Analysis of 1,992 patients with anorectal malformations over the past two decades in Japan. Steering Committee of Japanese Study Group of Anorectal Anomalies.
]. Our study could not reproduce this, as even in children with more simple ARM types, major vertebral and cardiac anomalies were identified in 12–40%. This could be explained by the thorough screening that was performed in patients with complex as well as more simple types of ARM. In our opinion, and in accordance with a previous study, routine screening is necessary for all ARM patients to early detect potential (life-threatening) anomalies and thus improve short- and long-term (functional) outcomes [
]. In addition, routine screening is of great importance to prevent missing additional anomalies with potential severe consequences in the future. For example, missed vertebral anomalies (e.g., butterfly corpora or scoliosis) might lead to chronic back pain or growth deformities at later age, and children with ventricle septum defect (VSD) require endocarditis prophylaxis and follow-up with a pediatric cardiologist. Furthermore, children with unilateral renal agenesis require yearly follow-up by a pediatric urologist or pediatric nephrologist to assess the presence of vesico-urethral reflux, and children with tethered spinal cord (TSC) require neurological consultation as TSC might be associated with walking disorders and bladder dysfunction [
Twenty percent of included ARM patients could be classified as STRICT-VACTERL, VACTERL-LIKE, or VACTERL-PLUS (13%, 5%, and 2%, respectively), according to the EUROCAT definitions [
]. Notably, the highest percentage of the patients (13%) could be classified as STRICT-VACTERL, which is assumed to be the most severe type of VACTERL-association, resulting in potential poorer outcomes compared to patients in the VACTERL-LIKE group because ofbecause of the severity of associated anomalies. Unfortunately, literature regarding VACTERL classification according to EUROCAT guidelines is scarce. However, various studies implemented other VACTERL classifications, resulting in large heterogeneity in the use of VACTERL definition. For example, studies used different requirements (i.e. 2 or 3 major anomalies) for a VACTERL diagnosis. This resulted in a range of 5–31% prevalence of VACTERL-association in ARM patients, which is in line with our results [
Does presence of a VACTERL anomaly predict an associated gynecologic anomaly in females with anorectal malformations?: a pediatric colorectal and pelvic learning consortium study.
]. This range of prevalence demonstrates that the use of VACTERL definitions according to the EUROCAT study is of great importance to improve reproducibility and uniformity.
In 21% of the patients, their phenotype could be explained by a genetic cause or underlying syndrome, which is comparable to numbers described in previous studies (range 10–24%) [
]. However, not all patients were routinely assessed by a clinical geneticist, nor did they undergo routine genetic testing. Therefore, the true prevalence of genetic causes or syndromes might be underestimated. Over the past decades, genetic testing methods have become widely accessible and insights have changed tremendously. In AmsterdamUMC, routine assessment by a clinical geneticist is currently incorporated in the standard care pathway for all ARM patients. In this study, this is demonstrated by an increase of genetic consultation over time. Interestingly, the number of patients diagnosed with genetic aberrations did not increase over time. This may be because ofbecause of low prevalence of genetic disorders, small numbers in this study, and statistical uncertainty. Furthermore, it might be that, because ofbecause of the development of genetic testing, diagnosis of genetic aberrations in patients born in period 1 was made at later age compared to patients born in period 3. It is of great importance to early identify potential underlying causes which might benefit the patient, but also to be able to adequately inform parents about the chance of recurrence in future offspring and inform them about the possibilities of prenatal diagnosis.
Interestingly, according to the EUROCAT study, spinal cord anomalies are not classified as a major anomaly outside the VACTERL [
]. Therefore, further research is necessary to investigate definitions of major and minor features, and to assess whether or not other additional anomalies should be added to the VACTERL-association diagnosis (e.g., spinal dysraphisms, gynecological anomalies).
This study should be interpreted in the light of some strengths and limitations. First, this a unique large cohort of patients from the past 21 years with an extremely rare disease to assess the number of patients who underwent full screening for additional anomalies, and classify them according to VACTERL-association diagnosis and genetic causes and syndromes. Second, the incorporation of a multidisciplinary team to consult in case of uncertainties on classification of additional anomalies improved quality of the categorization and assessment of the encountered anomalies in this study. Third, we are the first to incorporate the criteria for VACTERL-association as mentioned by the key paper of EUROCAT, which improves reproducibility and uniformity. However, in this study, all limb anomalies were assessed and, in contrast to the EUROCAT study, no difference was made between lower or upper extremity anomalies. Furthermore, limb x-ray was not routinely incorporated but only performed on indication (after thorough clinical assessment by the treating physician). Therefore, unnecessary exposure to radiation in young children is prevented, decreasing the risk of radiation induced malignancies on the long term [
]. As with all studies of retrospective nature, this study is prone to several limitations, of which most importantly information and registration bias, especially because ofbecause of the large timeframe in which the study was executed. In addition, patients might be missed because ofbecause of wrong use of the ICD-9 codes. Selection bias might be present, but is reduced to a minimum because ofbecause of our inclusion methods (i.e. ICD codes and prospective registration).
In conclusion, this study showed that 77% of the ARM patients underwent full screening to early detect and possibly treat additional anomalies. In 62% of the patients, additional anomalies were identified (most often cardiac and vertebral anomalies), in both patients with simple and complex ARM types. The minority of patients (20%) could be classified into a type of VACTERL-association, while genetic causes were found in 21% of the patients. Additional anomalies were present not only in complex type, but also in simple type ARM. Therefore, without screening additional anomalies could be missed, with potentially serious implications for (functional) outcomes in patients. This emphasizes that routine screening (including genetic screening) of all ARM patients regardless of type of ARM is important.
Conflicts of interest
The authors declare that they have no competing interests.
Funding
No funding was received.
Acknowledgments
Not applicable.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
The VATER association. Vertebral defects, Anal atresia, T-E fistula with esophageal atresia, Radial and Renal dysplasia: a spectrum of associated defects.
Does presence of a VACTERL anomaly predict an associated gynecologic anomaly in females with anorectal malformations?: a pediatric colorectal and pelvic learning consortium study.
Analysis of 1,992 patients with anorectal malformations over the past two decades in Japan. Steering Committee of Japanese Study Group of Anorectal Anomalies.
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