1 Departments of Andrology, 2 Public Health, 3 Paediatric Urology 4 Paediatric Endocrinology, Erasmus Medical Centre, P.O.Box 1738, 3000 DR Rotterdam 5 Department of Child Health Care, The Rotterdam Homecare Foundation, P.O.Box 21994, 3001 AZ Rotterdam, The Netherlands
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Abstract |
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Key words: birth defect registries/congenital abnormality/epidemiology/hypospadias/prevalence
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Introduction |
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Materials and methods |
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Study design and protocol
In a cross-sectional design, 7292 consecutive newborn boys were examined for hypospadias at their first visit to Child Health Care Centres (CHC) in Rotterdam, followed by verification and grading by a paediatric urologist and a paediatric endocrinologist. In the Netherlands, CHC receive notifications of all newborns within 2 days after registration in the municipal birth register. CHC invite all parents to participate in the national preventive child healthcare programme, including early detection of health risk factors, health education, and vaccination. After training in a standardized examination, CHC physicians (n = 30) examined the external genitalia of boys born in Rotterdam in the period October 1998 to October 2000, at their first visit to the CHC, before the age of 6 months. Hypospadias was defined as a displacement of the urethral meatus from the tip of the glans penis to the ventral side of the phallus, scrotum or perineum.
Of 7652 boys registered in the birth register, we report on 7292 boys (95%) who were examined by CHC physicians. To restrict potential failure to identify borderline cases, CHC physicians were instructed to refer cases if they were in doubt on the diagnosis. Moreover, cases with preputial abnormalities (e.g. cleft prepuce or inability to retract the prepuce) were also indexed in the CHC information system, as a hidden hypospadias may be present. Index cases were referred to a paediatric urologist and a paediatric endocrinologist at the Sophia Children's Hospital, Erasmus Medical Centre, Rotterdam, for verification and classification. As the classification requires ample experience, especially in cases with chordee (i.e. bending of the penis), grading was exclusively based on the examination by a paediatric urologist with extensive experience in diagnosis and surgical correction of hypospadias. The classification is based on the grading described by Duckett, following the anatomical position of the meatus (see Figure 1) (Duckett, 1998
). Moreover, the need for surgical correction was assessed.
To allow comparison with the grading of hypospadias as minor and major in other reports, we chose to conform to their criteria. In EUROCAT (the European Registration of Congenital Anomalies), hypospadias is defined as minor `when the opening of the urethra is before the coronary sulcus, glandular or first-degree' (EUROCAT Working Group, 1997), which corresponds to glandular in our grading system (Figure 1
). In the MACDP grading used by Paulozzi, the glandular forms are categorized as first-degree, which is referred to as minor, whereas second and third degree together are classified as severe (major) (Paulozzi et al., 1997
).
Hypospadias rates are presented as the number of cases per 10 000 live births, thus including females, to allow comparison with other studies. These rates are calculated using the sex ratio of male to female live births in the study period.
Statistics
Hypospadias rates are presented with 95% confidence intervals (CI). For comparison of hypospadias rates, 2-statistics are calculated, based on 2x2 cross-tabulations.
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Results |
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The frequency of hypospadias in newborn boys was 0.73% [53/7292; 95% confidence interval (CI) 0.540.92%]. As 7652 boys and 7118 girls were born alive in the study period, the sex ratio of male to female was 1.075. Based on the sex ratio, the rate among live births (males and females) was 38 per 10 000 (CI 2848). Table I shows the distribution of cases by severity. For five cases, the hypospadias grade was unknown because their parents were not willing to visit the Sophia Children's Hospital for verification, as their son had already been referred to another hospital. In these cases hypospadias was confirmed by a local paediatrician, but information on the classification was not used. The ratio of minor to major hypospadias was 0.3, on the basis of 12 minor (glandular) cases and 36 major cases (more proximal subtypes).
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Discussion |
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Several authors have reported a rising trend in the occurrence of hypospadias. Dolk commented on this trend, and pinpointed the pitfalls in the interpretation of this data (Dolk, 1998). A major shortcoming of previous research is the lack of specification of the severity of hypospadias cases, whereas registries may exclude minor forms, for which criteria are not standardized. It has been suggested that the apparent increase may in fact be due to an increasing tendency to report minor cases to registries. This hypothesis could not be tested properly, as the severity was unknown in most cases reported to registries. A ratio minor/major of ~3 is generally assumed, on the basis of a large group of hypospadias cases (Paulozzi et al., 1997
). For this latter group, the hypospadias grade was specified in only ~40% of the cases. We verified the hypospadias severity among 91% of newborn boys with hypospadias and observed a minor/major rate of 0.3. As different cut-offs for minor and major are in use, we also provide the individual hypospadias subtypes. Clearly, the diagnostic criteria for hypospadias subtypes should be standardized. If our severity distribution is representative of the USA study population (Paulozzi et al., 1997
), increased reporting of glandular cases could not have explained the doubled hypospadias rate. Unfortunately, no accurate historical data are available to assess hypospadias trends over time in our study area. Our data do, however, provide a baseline for future trend studies.
The regional differences as indicated by registries (Paulozzi, 1999) should be confirmed by geographical comparisons based on systematic and standardized examination of complete birth cohorts. Recently, the results of a comparable prospective population-based study in Finland were published (Virtanen et al., 2001
). The rate of 38/10 000 in our cohort is 2.2 times higher than the rate of 17/10 000 in the Finnish birth cohort study (P = 0.002). The comparison of these two studies strongly indicates geographical differences in the prevalence of hypospadias. Moreover, the frequency distribution of subtypes appears different, with 95% (18/19) of the cases classified as glandular or coronal in contrast with 51% in our study. Interestingly, the prevalence of other related abnormalities of the male reproductive system (testicular cancer, cryptorchidism, reduced sperm count) is also different in Finland compared with other European countries (Toppari et al., 1996
), for which pathophysiological mechanisms have been suggested, but not yet confirmed.
Thus, research on causes and risk factors for hypospadias is needed. There clearly is a genetic component in the aetiology of some hypospadias cases, as illustrated by cases of familial predisposition (Bauer et al., 1981; Chambers and Malone, 1999
; Boehmer et al., 2001
). Hypospadias may be due to a defect in androgen synthesis or action due to, for example, mutations of the 5
-reductase type 2 or the androgen receptor gene (Boehmer et al., 2001
; Sultan et al., 2001b
). However, the proportion of hypospadias attributable to genetic defects in these reports was rather small. Assisted reproduction technologies may be associated with excess hypospadias. An increased hypospadias risk has been observed in male offspring after IVF and ICSI (Wennerholm et al., 2000
; Ericson and Kallen, 2001
). Several environmental factors have been associated with hypospadias, such as exposure to endocrine disrupters (Sharpe, 2001
), a maternal residence near hazardous-waste landfill sites (Dolk et al., 1998
; Elliott et al., 2001
), or a maternal vegetarian diet (North and Golding, 2000
), which may coincide with a high intake of phyto-estrogens.
Little information is available on the indications for surgical hypospadias repair, especially in mild cases. In this study, 25 and 93% of glandular and coronal cases required surgery on the basis of voiding problems or chordee, whereas surgery was needed in all more severe cases. In the total series of cases with specified grade, 79% required surgical correction. These results may affect the interpretation of hypospadias rates based on surgical records.
We demonstrate that hypospadias is one of the most frequent congenital anomalies among newborn boys. After cryptorchidism (12% at the age of 3 months) (Toppari and Kaleva, 1999), hypospadias (0.7%) is more frequent than congenital heart disease (0.5%), which is the most frequent congenital abnormality in EUROCAT. Early detection and surgical correction can prevent cosmetic and mechanical problems, and concomitant psychological complications. Awareness of this anomaly is needed to avoid misdiagnosis and to initiate timely treatment. The present study demonstrates that the national preventive child healthcare programme provides an efficient and accurate framework in the screening for hypospadias, as 88% of the potential cases identified by CHC physicians were confirmed by the expert specialists.
Summarizing, we report a 4-fold higher than expected hypospadias rate, which is not explained by a high inclusion of minor forms. This difference is probably due to underreporting in registries. The present study is only the second report on accurate prevalence data where all male newborns in an open population were systematically screened for this congenital abnormality. Comparison of the first two studies implies a substantial geographical variation in hypospadias prevalence, which should be followed by comparable studies in other countries. The minor/major ratio is 0.3, in contrast with the previously reported ratio of 3.0 based on incomplete data. Based on the high prevalence and previously suggested trends, causes of hypospadias and the geographical and temporal differences need to be explored. For accurate monitoring of hypospadias rates, complete case ascertainment including standardized classification of severity is warranted.
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Acknowledgements |
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Notes |
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References |
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Submitted on September 21, 2001; accepted on November 28, 2001.