2Division of Urology, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
3MD program, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
4Department of Anatomy and Neurobiology, PhD Program, School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, USA
5Biology Program, Rio Piedras Campus, University of Puerto Rico, San Juan, Puerto Rico, USA
Methods: Parents of children with hypospadias were interviewed by using a series of questionnaires (n = 128 cases). Severity was confirmed in the clinic and age of the mother was self-reported. Number of surgeries, age of child by the first and the last intervention was also assessed. Ordered logistic regression and the Brant test were employed to calculate risk between mild (Type I) and severe cases (Types II and III), and the assumption of proportional odds, respectively. The Mann-Whitney U Test was used to compare number of surgeries and age by the last repair between mild and severe cases. One-way ANOVA was employed to compare age of the child at the time of first surgery across severities (Types I - III).
Results: Women ≥ 40 years of age are 3.89 times (95% CI: 1.20-12.64) at a higher risk for having a child with the more severe forms of the condition than younger women. Repair of Type I was accomplished with 1 intervention whereas more severe cases required 1-4 (2 ± 0.5) surgical interventions. The timing for hypospadias repair of Type I cases occurred at an average age of 16.2 ± 4.88 months, of Type II cases occurred at an average age of 20.3 ± 8.15 months whereas the average age of the first hypospadias repair among Type III cases was 12.68 ± 2.52 months. Number of surgeries according to severity (p ≤ 0.0018, z-ratio = 2.91) and age difference for the timing of last repair (p ≤ 0.045, z-ratio = 1.69) were statistically different, but not the age difference for the first repair.
Conclusions: Increased maternal age is associated with the most severe forms of hypospadias. There is room for improvement for the timing of hypospadias repair according to severity.
Keywords: Hypospadias; Hypospadias repair; Hypospadias severity; Hypospadias risk; Maternal age
It is a tenet in human embryology that the etiology of most congenital conditions is due to multifactorial factors or that most conditions are idiopathic. A leading clinical embryology textbook estimates that less than a quarter of congenital conditions are produced by known factors such as chromosomal variations, mutant genes, or environmental agents . Hypospadias is not the exception; only a small proportion of cases have been linked to specific genes or environmental contaminants . The twohit hypothesis proposes that genetic susceptibility linked to environmental exposure increases hypospadias risk [5-6]. It has been long recognized that age of the mother is one of the factors that defines a high-risk pregnancy in terms of reaching a healthy full-term pregnancy but also in terms of the potentiated risk for having a child with a congenital condition . In fact, age of the mother (> 40years of age) is associated to hypospadias risk [8- 13]. In this study, we revisited the reported association between age of the mother and the risk of having a child with hypospadias, but according to severity of the condition.
Current standards of care recommend surgical repositioning of the urethral meatus between 6 and 18 months of life [14-17]. There have been a number of arguments to support such standard, some of them include: to favor positive surgical outcomes, anesthetic considerations, to favor a positive body image of the patient, and to favor sexual-and cognitive-development of the patient . The notion here is that milestones of psychosexual development are related to self-awareness of the genitals; a mental process that is believed to begin around 18 months of life . Therefore, we also aimed to determine the number and timing of hypospadias surgeries according to severity of the condition. The ultimate goal is to be able to establish an interprofessional algorithm to facilitate timely referral of hypospadias cases to pediatric urology.
All surgeries were planned as single or staged procedure at the beginning of the procedure based on the meatal position and degree of chordee. Surgeries were conducted by a single board certified pediatric urologist (MRP-B), which allowed us to complement questionnaire data with clinical record data for age of the infant by the first surgery.
Figure 1A shows that surgical repair of mild cases was accomplished with 1 intervention whereas more severe cases required 1-4 (2 + 0.5) surgical interventions. Number of
Age of the mother
(Types II and III > Type I)
> 40 years of age
1.20 – 12.64
Panel A: Surgical repair of Type 1 (mild) cases was accomplished with one intervention whereas Types II and III (severe) cases required two or more interventions.
Panel B: Age of the child (in months) at the time of the first surgical repair among Type I (white), Type II (grey), and Type III cases (black) are shown.
Panel C: Age of the child (in months) at the time of the last surgical repair among Type I (mild) cases versus Types II and III (severe) cases are shown. Data is expressed as average ±SEM; **p ≤ 0. 0018; *p ≤ 0.045. See text for details.
Although prenatal ultrasound is commonly used to determine sex of the fetus, it is not routinely used to study the anatomy of the genitals. Two echogenic lines at the tip of a blunt-ended penis can be used as the sonographic feature of hypospadias [22,23]. The echogenic lines represent the prepuce lateral folds. Another anatomical feature is the "tulip sign", which is formed by a ventrally oriented penis that is located between the scrotal folds . These features are best seen in the late second trimester of pregnancy. However, it is important to note that even during the second trimester, it is a challenge to distinguish between typical female anatomy and severe penoscrotal hypospadias with ultrasonography . Three dimensional ultrasonography is recommended to confirm diagnosis in these cases .
There is great need for prospective randomized trial studies that exclude confounding factors associated to surgery in order to unequivocally determine the ideal timing for hypospadias repair . In our experience, we found that repair of mild cases was accomplished with 1 intervention at an average age of 16.2 + 4.88 months whereas more severe cases required 1-4 (2 + 0.5) surgical interventions with an average age at the last intervention of 37 + 10.25 months. These differences were statistically significant. However, differences in the timing of the first repair were not detected as there was a wide spectrum of ages within each severity category. Timing of hypospadias repair can be affected by factors including, but not limited to, adequate penis size for surgery, parental preferences for surgery, poor adherence to treatment, among others. A deeper look into the reasons behind timing of repair is warranted. In clinical terms, it is important to bear in mind that severity of the condition can also be related to penis size, size and shape of the glans, presence and degree of penile curvature, histological quality of urethral plate, among other factors. All of these factors can also impact the best timing for hypospadias repair.
Studies show that surgical complications are minimized when hypospadias repair is done during early infancy [25,26]. Somewhat limited long-term psychosexual outcome data also supports the recommendation by American  and European  professional associations that early hypospadias repair is the best approach. Aside from the postulated psychological benefits of early repair [19,27], it has been argued that hypospadias surgery performed during adulthood does not indicate greater risk for urethroplasty complications . This is not supported by other reports [29-31]. Based on bioethical principles, it has also been argued that hypospadias repair should only occur when the patient becomes able to participate in the decision-making process . It has been difficult to assess the clinical algorithms for the management of hypospadias between institutions to establish quality indicators internationally . Therefore, defined follow up intervals for data reporting in order to better evaluate surgical approaches, timing of hypospadias repair, and objective outcome measures are still needed [18,28,34].
Ethical approval: This study received approval from the Institutional Review Board (protocol number A9000112).
Clinical trial registration: N/A
Source of support and disclaimer: This publication was supported by the National Institute on Minority Health and Health Disparities of the National Institutes of Health under Award Number 2U54MD007587. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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