Predictors of surgical complications in boys with hypospadias: data from an international registry

Introduction

Hypospadias, a congenital defect of the male external genitalia, occurs in 1 in 300 live births.1 Surgical correction is the only treatment option, with postoperative complication rates reported to range from 8% to 56%.2 3 These disparities are largely explained by variability in hypospadias phenotypes. A urethral opening at the distal end of the penis is classed as a mild hypospadias and accounts for 70% of all hypospadias cases, while an opening at the mid or proximal end of the penis is classed as severe hypospadias and accounts for the remaining 30% of cases.4 Severe forms are often found in combination with a smaller glans, less penile skin, greater curvature, and poor urethral plate quality, which are associated with more challenging surgeries and with poorer postsurgical outcomes.5 In addition, severe hypospadias may represent differences/disorders of sex development (DSD), a term used to describe a wide range of complex congenital disorders in which genetic, chromosomal, gonadal or anatomical sex is abnormal,6 resulting in atypical formation of the reproductive system. These boys often present with additional genital defects (cryptorchidism, bifid scrotum and/or micropenis) and non-genital defects.7 8

Postsurgical complications can negatively impact long-term functional, cosmetic, and psychological outcomes. Although various clinical factors, such as phenotype, age at operation, the surgeon’s experience, surgical technique and length of follow-up have all been associated with postoperative complications,9 they do not fully explain complication rates. It has been hypothesized that novel clinical factors may be associated with postsurgical complications and could therefore be used as predictive tools. Previous studies have indicated that boys with a genetically confirmed androgen receptor (AR) mutation or a co-occurring extragenital congenital malformation, are at increased risk of postsurgical complications.8 10 However, further investigation is required to confirm these associations. By characterizing this population and identifying novel predictive factors of postsurgical outcomes, alterations in both diagnosis and management can be made to optimize patient care and minimize the chances of complications occurring, thus improving short-term and long-term outcomes. As such, the aim of this study was to assess complication rate in an international cohort and identify if any clinical factors can predict surgical outcomes for boys with hypospadias.

Methods

Retrospective data were collected using the internationalDSD (I-DSD) registry based on the following inclusion criteria: XY boys raised as male, with hypospadias, born between 2000 and 2020. Data were collected on year of birth, birth weight, gestational age, biochemistry at first presentation, presence of co-occurring genital malformations (bifid scrotum, micropenis, unilateral or bilateral undescended testes), presence of co-occurring extragenital malformations, karyotype, presence of genetic mutations, number of hypospadias surgeries, type of surgical technique used, age at first surgery, number of re-do operations, presence of postsurgical complications, details of postsurgical complications and length of surgical follow-up.

Distal hypospadias were categorized by a meatal opening in the glanular and coronal regions. Mid hypospadias were categorized by a meatal opening in the subcoronal and midshaft regions. Proximal hypospadias were categorized by a meatal opening in the proximal shaft, penoscrotal, scrotal or perineal region. Using the information collected, the External Masculinization Score (EMS)11 was calculated for each boy. Biochemical results were categorized as ‘high’, ‘low’, ‘normal’ or ‘unknown’. Micropenis was defined as a phallus length below 2.5 cm at birth or 2.5 standard deviation (SD) below the average length at time of presentation. Chordee was reported as per the surgeon’s opinion with no specific definition. Single-staged procedures were defined as a repair intended to be completed in a single operation and staged procedures were defined as repairs intended to be completed in two or more operations. A re-do operation was defined as the need for any additional operation after previous hypospadias repair. Small for gestational age (SGA) was defined according to the reporting center’s local practice. A complication was defined as anything that would require medical or surgical intervention as a direct consequence of the hypospadias surgery.

Statistical analysis was performed using R Studio (V.4.2.0) and Graphpad Prism V.8.0. Logistic regressions were performed to assess whether endocrine abnormalities, disorder type, procedure type, age at first surgery, the presence of extragenital malformations, presence of genetic variants and EMS could predict the occurrence of postsurgical complications. To account for the effects of collinearity, separate logistic regressions were run for each variable (ie, the independent variable). Multivariate logistic regression was undertaken and Spearman’s correlation tests were performed to assess the correlation between numeric variables. Fisher’s exact tests were performed to further assess the association between complication rate and subgroups of clinical factors. P values <0.05 were deemed statistically significant.

All patients had to provide written consent to be included in a pseudo-anonymised format on the I-DSD Registry. Full details regarding the Standard Operating Procedures (SOP) of the I-DSD Registry can be found at: home.i-dsd.org.

Results

Of the 53 eligible centers on the I-DSD registry, 16 (30%) were able to provide data on 243 boys with an additional 25 obtained from the surgical records of one participating center (figure 1).

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Cohort characteristics

The characteristics of the cohort are summarized in table 1. At the time of the study, the median age of the cohort was 9 years old (2, 22).

Table 1

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Characteristics of study cohort

Of the 160 boys, 101 (63%) received a clinical diagnosis of non-specific 46,XY DSD. Of the remaining 59 (37%) with a specific disorder type, genetic variants were found in 33 (56%). Sixteen out of 59 (27%) boys were diagnosed based on abnormal biochemistry alone, while 10 (17%) were diagnosed through clinical observation alone. The median EMS of the cohort was 6 (2, 9), indicating a general trend of severe under masculinization.

Of the 160 boys included in the study, 100% had one or more genital malformation. Of the 160 boys, 30 (19%), 34 (21%), 58 (36%) and 25 (16%) had 1, 2, 3 and 4 additional genital malformations present, respectively. The remaining 13 (8%) has ≥2 additional genital malformations; due to missing data, the exact number was unknown. One hundred and thirty-nine (87%) patients had chordee, 101 (63%) presented with micropenis, 74 (46%) had undescended testes and 57 (36%) had a bifid scrotum. Of those with undescended testes, 46 (62%) had bilateral undescended testes and 28 (38%) had unilateral undescended testes.

In terms of extragenital malformations, 63 (39%) presented with at least one additional extragenital malformation, most commonly SGA (figure 2).

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Figure 2

Frequency of complication according to additional extragenital malformation. CHD, congenital heart defect; CNS, central nervous system; ENT, ear nose and throat; GI, gastrointestinal; MS, musculoskeletal; SGA, small for gestational age.

Discussion

The complication rate of 64% observed in this cohort is high and exceeds that of 56% previously reported in boys with proximal hypospadias.2 Prior to the former study by Long et al, lower complication rates for proximal repairs were often reported, ranging from 13% to 23%.13 14 As nearly half of complications seen in this cohort arose 2 years after first hypospadias repair, it is possible that past studies lacked adequate follow-up periods, partially accounting for the comparatively high rates seen in the current study. Long-term prospective studies regarding complications in hypospadias are required to truly determine complication rates over time.

As previously described, additional genital malformations may be associated with poor surgical outcomes, likely secondary to smaller glans, less penile skin, greater degrees of chordee, and poor urethral plate quality.8 In this study, 87% of boys presented with chordee, which has been associated with a 55% increase in complication rates.15 Additionally, as 63% of the boys presented with micropenis, tissue availability and glans quality would likely be suboptimal in many cases, requiring the utilization of more complex surgical methods during hypospadias correction. Indeed, as the data for this study were obtained from the I-DSD Registry, inherently, this cohort may be at a greater risk of complications due to the suboptimal anatomy associated with severe undermasculinization and DSD. Due to the retrospective nature of this study, however, it was not possible to collect detailed information on the quality of the urethral plate, angle of penile curvature or glans width. We would recommend that these should be introduced as aspects of standard data collection during hypospadias repairs. In addition, more detailed standard data collection regarding the precise type of surgical procedure would be useful for any future studies into complication rates.

Within this study cohort, median age at first surgery was older than the 6‒18 months recommended by the American Academy of Paediatrics (AAP) and the European Association of Urology (EAU).16 17 This may be due to characteristics associated with DSD postponing hypospadias surgery. For example, malformations such as undescended testes may be corrected first (via orchidopexy) due to the risk of malignancy or functional impairment. Furthermore, due to high rates of SGA and micropenis, it is possible that some hypospadias surgeries were postponed in order to permit penile growth and reduce anesthetic risk.

SGA was the most prevalent extragenital malformation in this cohort and was seen in 23% of all boys, which may therefore contribute to the high rates of complications observed. A recent study has reported higher hypospadias reoperation rates in boys with SGA.18 That said, in our cohort, SGA alone was not sufficient to predict postsurgical complication rates as a single risk factor. This again confirms that several mechanisms may lead to complications.

No single clinical factor or combination of risk factors was significantly associated with postsurgical complication rates in this cohort. It was previously reported that boys with hypospadias and an identified AR variant were more likely to require additional operations than those with no identified AR variant.10 In our study, however, while there was a high complication rate, the presence of additional extragenital malformations, or a genetic diagnosis were not associated with risk of complication. Previous studies have excluded patients with genetic variants in their analysis, which may explain differences in reported complication rates.18 It is plausible that the high rates of extragenital malformations within the current cohort prevented an association being observed and that discrepancies in the results obtained from this study may be due to variations in genetic and biochemical testing internationally. It is possible that severe forms of hypospadias, such as those which may be reported by specialists in the care of DSD, may be part of a more complex syndrome that affects systems out-with the urogenital system, highlighting the need for multidisciplinary care in hypospadias and other DSD conditions.19

This study has several strengths. It is one of the largest of its type, offering valuable insight into the characteristics and complication risks of a rare group of individuals with hypospadias. Additionally, the use of international data allows the results gathered to be applied on a global basis, demonstrating the benefits of using networks such as the I-DSD Registry. Due to the rarity and heterogeneity of these conditions, data collected from single centers are typically limited and only applicable to a specific region. This study could therefore offer a guide for the creation of international management protocols. One limitation of this study is the variations in genetic and biochemical testing observed between clinics. Similarly, clinical definitions will differ internationally, for example, in how SGA is classified. Definition and classification variations may therefore alter result interpretation.

In conclusion, boys with proximal hypospadias in the I-DSD Registry have high rates of additional comorbidities and a high risk of postoperative complications. No clinical factors alone or in combination were significantly associated with complication rates. High complication rates with no observable cause suggest the involvement of other factors which need investigation. Further studies are needed to identify novel clinical factors which may be associated with complication rates in this complex group.