Hypospadias, which is caused by incomplete development of the urethra, is one of the most common congenital anomalies in male infants, with an estimated prevalence of 64.7 cases per 10 000 male live births in the USA [1]. Hypospadias can have different degrees of clinical severity, as defined by the location of the urethral opening [2]. Estimates of the prevalence of hypospadias vary across and within different geographical settings globally. The extent to which artifactual differences (eg, differences in clinical practice, registry ascertainment, or case definitions) contribute to the observed prevalence differences is unknown. Moreover, there have been reports of increases in the prevalence of hypospadias in many countries, especially in the last decades of the 20th century [2–9]. However, a number of countries have also reported that the prevalence has not increased in recent decades [3,7,9–17].

To better understand prevalence trends in recent years across the world, we evaluated hypospadias data in 27 birth defect surveillance programs participating in the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR).

Among 27 programs participating in the ICBDSR, the total prevalence of hypospadias was 20.9 per 10 000 births during 1980–2010, although it varied greatly by geographical region.

The international total prevalence of hypospadias increased during the entire study period, with significant increases from 2000 to 2010. When we restricted to programs among the main subgroup, the rates of increase were similar, although the time trend was significant over more years. The increasing trends were also consistent for most of the study period across all degrees of clinical severity of hypospadias.

Our international total prevalence estimates of hypospadias were similar to those from previous studies, with many previous reported estimates from individual ICBDSR programs, including the USA [5], Australia [2], Germany [21], Northern Netherlands [21], Hungary [21], Malta [21], Spain [21], and Tuscany [21]. For Latin American countries, our results were consistent with previous estimates from Argentina [22] and Mexico [23]. In fact, all Latin American programs had a relatively low prevalence that fell within the lowest quartile of all participating programs. As the magnitude of the difference was quite large and consistent across programs in Latin American countries, it is possible that the difference between Latin American countries and other countries may reflect true prevalence differences, perhaps related to differences in both genetic and nongenetic hypospadias risk factors.

As previously reported, programs in the USA and northern Europe had higher prevalence estimates [23]. There have been reports of increases in the prevalence of hypospadias in many countries, particularly during the late 1960s until around the early 1990s in the USA and Europe (reviewed in the work of Agopian [24]). Our results for the period from 1980 to early 1990s seem consistent with these reported increases.

However, this increase was reported to stabilize or even decrease in more recent years in many, though not all, studies [3,7,21], whereas we detected an increase throughout this time. For example, separate reports from Washington State, USA (1987–2002 births) [17], New York State, USA (1983–1995 births) [13], Scotland (1988–1997 births) [11], Italy (2001–2004 births) [14], Finland (1970–1994 births) [12], and Europe (1980–1999 births from the EUROCAT network) [7] did not indicate increases in the prevalence in more recent years. Furthermore, individual reports from Spain (1996–2002 births) [16], Northern England (19932000 births) [10], and Japan (1985–1997 births) [15] suggested that the prevalence may have been decreasing in recent years. As expected, among the countries represented in our study (ie, Finland, Italy, Spain, and other European regions), much of the corresponding data within these same time windows appeared to be similar in our data (ie, not increasing). However, our results among all programs indicated an increase in the total prevalence during recent years. This difference was probably related to the inclusion of a very large number of programs throughout a long (and in many instances, more recent) analysis period (1980–2010), as well as our use of joinpoint regression. However, it is noteworthy that these increases were not observed during the entire period for each program, and it is important to remember that our findings were most influenced by the programs with larger sample sizes.

Although our study likely reflects a better estimate of global trends than smaller studies, it is likely that some of the observed prevalence increases in our study were artifactual, and reflect changes over time in how cases with hypospadias were identified and documented at the medical facility and/or were ascertained by the surveillance system (eg, underascertainment in earlier years). While quality metrics for systematic assessment of birth defect surveillance have recently been proposed [25], many programs have not yet reported on these metrics [26,27]. Some ICBDSR systems implemented systematic surveillance changes during the study period (Supplementary Table 1), including a stronger focus on ascertaining less severe hypospadias cases in more recent years [21] and improvements in data collection over time.

Nevertheless, we still observed increasing prevalence time trends in the main subgroup, which represented 47.0% of total births across all ICBDSR programs. The data from these programs may have been less subject to bias compared with those from other sites, and these trends within this subgroup were similar to the trends observed in the full analytic group. This consistency suggests that much of the increasing trends in the prevalence of hypospadias may represent a true (nonartifactual) increase. However, consistent trends were not seen across every program.

It has been proposed that the observed prevalence increase might reflect increases in exposure to hypospadias risk factors overtime [9]. However, given the broad range of potentially relevant environmental and occupational exposures that could be responsible for the observed increase, as well as issues related to exposure dosage, timing, and other factors, it has been challenging to identify the main culprits. It is also possible that changes over time in the distribution of other parental factors associated with hypospadias risk (eg, parity, body mass index, maternal age, and fertility treatments) may have influenced the prevalence over time, but data were not available to assess this possibility in our analyses [24]. Further study of potential hypospadias risk factors, including genetic factors, endocrine disruptors, and other maternal and paternal exposures and characteristics may shed light on this possibility.

This study had some known limitations. First, it lacked uniformity in data collection across programs, which may have led to heterogeneity among cases across programs. Initiatives related to standardizing these methodologies across programs would be helpful to future work. Second, as individual-level data were not available, we could not adjust for differences in the distributions of hypospadias risk factors across countries, and this unmeasured confounding may also have partially accounted for the differences in hypospadias prevalence across programs. Third, the joinpoint regression modeled the data based on an assumption of linear trends across subperiods, although it did not account for completely nonlinear (eg, exponential) trends. Nevertheless, this statistical approach had more flexibility than a traditional assessment of a continuous prevalence estimate under the assumption of a linear change over an entire study period, which would not have been able to agnostically identify changes limited to study subperiods. We also did not have data related to co-occurring congenital malformations (~88.5% of hypospadias is expected to be isolated in European countries [21]) or on hypospadias treatment; while we had data on hypospadias severity for some programs, these data were not available for the majority of programs.

Despite these limitations, this study has several important strengths. We analyzed data from surveillance programs across the world, representing one of the largest case samples among published studies. Further, our data allowed us to look at trends over a 31-yr period. We also investigated the trends by differing degrees of severity and considered differences in characteristics of surveillance programs.

Our results suggest that the international total prevalence of hypospadias increased during 1980–2010 and that these trends were probably not entirely artifactual. Considering these trends, it seems clear that further surveillance around hypospadias is critical.