Summary
Introduction
Hypospadias, one of the most common male genital birth defects, occurs in 1 out of every 200 male births in the United States and is increasing in prevalence globally.
Objective
This study aimed to characterize the combinations of birth defects that co-occur with hypospadias more often than expected by chance, while accounting for the complex clustering patterns of congenital defects.
Study Design
We analyzed cases with hypospadias and at least one additional co-occurring defect from the Texas Birth Defect Registry born between 1999 and 2014. For each combination, we calculated adjusted observed-to-expected (O/E) ratios, using Co-Occurring Defect Analysis (CODA).
Results
Among 16,442 cases with hypospadias and without known syndromes, 2,084 (12.7%) had at least one additional defect. Many of the birth defect combinations within the highest adjusted O/E ratios included cardiac, musculoskeletal, and additional urogenital defects. For example, a top combination with an adjusted O/E of 139.0 included renal agenesis and dysgenesis, reduction defects of the upper limb, and other anomalies of upper limb (including shoulder girdle). High adjusted O/E ratios were also observed in combinations that included defects outside of the urogenital developmental field. For instance, the combination with the highest O/E ratio included buphthalmos, and congenital cataract and lens anomalies (adjusted O/E ratio: 192.9). Similar results were obtained when we restricted our analyses to cases with second- or third-degree hypospadias.
Discussion
Many combinations in the top results were expected (e.g., multiple urogenital defects); however, some combinations with seemingly unrelated patterns of defects may suggest the presence of some etiologic mechanisms yet to be identified.
Conclusion
In summary, this study described patterns of co-occurring defect combinations with hypospadias that can inform further study and may provide insights for screening and diagnostic practices.
Keywords: hypospadias, birth defects, co-occurrence, epidemiology, observed-to-expected ratio
Introduction
Hypospadias is a birth defect involving the displacement of the urethral opening in the penile shaft. This defect can be accompanied by curvature of the penis (chordee), and occurs with varying degrees of severity along the ventral side of the penis. Distally-located (i.e., first degree) hypospadias is considered to be a less-severe form, with the meatus location being on the glans penis. Second- and third-degree hypospadias are considered to be more severe, and are more proximally-located, with the meatus opening located on the shaft or on the scrotum, respectively [1]. Hypospadias is one of the most commonly occurring birth defects worldwide, affecting 2.1-6.4 per 1,000 male live births, with an increasing reported prevalence over the past several decades [2]. This condition often requires surgical correction, and post-surgical complications and chronic problems can arise. These may include continued issues with urination, sexual or reproductive difficulties, and psychological or emotional distress [3 4]. Recent publications have examined maternal characteristics (e.g., nulliparity, age, body mass index) and environmental and genetic risk factors for hypospadias, but the cause is not yet understood in the majority of affected infants [5–7].
Only 12-18% of cases with hypospadias have co-occurring birth defects, which primarily are other genitourinary defects [8–10]. Despite the low proportion of these cases, the absolute number of cases with co-occurring birth defects is substantial (20.9 in 10,000 infants) due to the high overall prevalence of hypospadias [2]. The majority of hypospadias cases with co-occurring defects are not associated with a known genetic syndrome (i.e., they are nonsyndromic) [8]. In fact, there are relatively few known syndromes which include hypospadias as a feature, most of which have frequency of <1 in 10,000 [1 9]. However, it is possible that some cases with hypospadias and co-occurring defects represent syndromes that have not yet been defined.
Most previous descriptions of defects that co-occur with hypospadias have focused on how frequently individual defects co-occur and have not used analyses that account for the baseline prevalence of these defects (i.e., the expected likelihood of co-occurrence) [9 10]. Thus, patterns of two or more co-occurring defects are not well understood. These patterns of birth defect co-occurrence may provide clues about shared or overlapping etiologies; therefore, the current project sought to characterize complex patterns of defects co-occurring with hypospadias, utilizing a large, population-based dataset [11].
Materials and Methods
Study Subjects
We used data from the Texas Birth Defects Registry (TBDR), 1999-2014, which includes surveillance of live births, stillbirths, and fetal deaths, to identify infants with birth defects delivered by women residing in the state of Texas. Registry staff conduct active surveillance among all hospitals and delivery centers statewide and abstract information from medical records. To be included, cases must have a chromosomal anomaly or structural birth defect diagnosed and documented in medical records within 1 year of age. For this study, data on infant and maternal characteristics (e.g., demographic information) were obtained from medical records and vital records (birth and fetal death certificates) from the Texas Department of State Health Services. Our analyses were limited to males.
Birth defects were classified as being major or minor based on definitions from the National Birth Defects Prevention Study (NBDPS) and clinicians at the Registry [12 13]. Each defect ascertained by the Registry is assigned a six-digit British Pediatric Association (BPA) code. For all major defects, these BPA codes were then categorized into 175 major defect groups based on the first four digits of the BPA codes, as previously described [13]. Cases in our analyses were male infants with first-, second-, or third-degree hypospadias or hypospadias with an unspecified location with or without chordee (BPA codes 752.600, 752.605–752.607, 752.620 752.625–752.627). Our main analyses included cases with one or more additional major birth defects. A sensitivity analysis was also performed with the case definition restricted to the subset of male infants with second- or third-degree hypospadias.
Cases with documented malformation syndromes, chromosome abnormalities, sequences, or associations (e.g., VACTERL) were identified by BPA code and by manual review of abstracted text from medical records. These syndromic cases were excluded prior to analysis. Twins and other non-singleton cases were also excluded. Infants diagnosed with cloacal exstrophy (BPA codes 751.55 & 756.79) or bladder exstrophy with imperforate anus (BPA codes 753.5 & 751.23–751.24) were also excluded because it is likely that many of these infants have undiagnosed OEIS (omphalocele, exstrophy of the cloaca, imperforate anus, and spine abnormalities) complex [14]. The protocol for this project was approved by Institutional Review Boards of the Texas Department of State Health Services and UTHealth.
Statistical Analysis
Counts and proportions of maternal and pregnancy characteristics were tabulated among male infants with hypospadias with and without co-occurring major birth defects. We also tabulated the observed count and proportion of cases with hypospadias and each other single major birth defect, for comparison to the prior literature.
Next, we used the method for assessing birth defect co-occurrence patterns proposed by Khoury et al., which involves comparing the observed number of cases with specific combinations of birth defects to the expected number [15]. The ratio is found by comparing the observed prevalence of specific birth defect combinations to the expected prevalence. Most birth defects do co-occur more frequently than expected if they were independent events, which may impact this observed to expected (O/E) ratio [15]. As such, an adjustment to the O/E ratio which accounts for this nonspecific co-occurrence is used [15]. The calculated ratio is expected to be greater than 1 if the combination of defects is occurring more often than due to chance alone.
The Co-Occurring Defect Analysis (CODA) platform [14] was used to implement large-scale calculation of these adjusted O/E ratios within RStudio version 0.99.902 and R version 3.3.1. We calculated adjusted O/E ratios for all observed defect combinations involving hypospadias and one to four co-occurring major birth defects. Birth defect combinations with <3 observed affected cases were excluded. We focused our interpretation on the 30 combinations that had the highest adjusted O/E ratios and were observed in at least 3 cases.
A Venn diagram was constructed to highlight the overlap of defects within the top 30 birth defect combinations (e.g., defect combination “A, B, and C” versus “A, B, and D” represent two combinations that both contain defects A and B). For simplicity, we limited this to five broad defect categories selected post-hoc, based on the most commonly impacted organ systems among the top 30 combinations of defects: musculoskeletal, digestive, urogenital, cardiovascular, and central nervous system. We plotted the number of the top 30 combinations that included the respective birth defects of interest. For instance, if 2 of the top 30 combinations included defects of the urogenital, musculoskeletal, and digestive systems, 2 would be indicated for the intersection of the three respective ovals.
Results
Among 3,159,950 total male live births in Texas between 1999 and 2014, there were 16,442 male cases with hypospadias without an identified syndrome in the Texas Birth Defect Registry. The majority (>99%) of cases were live births. Maternal and pregnancy characteristics for cases with and without additional co-occurring defects are shown in Table 1. The distributions of maternal age and delivery year were similar among isolated and non-isolated cases.
Table 1.
Characteristics among non-syndromic cases with isolated and non-isolated hypospadias, Texas Birth Defects Registry, 1999-2014
| Characteristic | N (%) | |
|---|---|---|
| Isolated Hypospadias (n=14,358) |
Non-isolated Hypospadiasa (n=2,084) |
|
| Maternal Age | ||
| <20 | 1,647 (11.5%) | 262 (12.6%) |
| 20-24 | 3,599 (25.1%) | 495 (23.8%) |
| 25-29 | 4,004 (27.9%) | 581 (27.9%) |
| 30-34 | 3,247 (22.6%) | 442 (21.2%) |
| 35-39 | 1,527 (10.3%) | 244 (11.7%) |
| 40+ | 334 (2.3%) | 60 (2.9%) |
| Year of Delivery | ||
| 1999 – 2004 | 4,828 (33.6%) | 642 (30.8%) |
| 2005 – 2009 | 4,552 (31.7%) | 704 (33.8%) |
| 2010 – 2014 | 4,978 (34.7%) | 738 (35.4%) |
| Hypospadias Classification | ||
| Not Otherwise Specified (NOS) | 6,668 (46.4%) | 968 (46.4%) |
| 1st degree | 6,374 (44.4%) | 802 (38.5%) |
| 2nd degree | 949 (6.6%) | 158 (7.6%) |
| 3rd degree | 367 (2.6%) | 156 (7.5%) |
>1 additional major defect present (as classified by the first four digits of the BPA code)
Our main analyses were conducted among cases with hypospadias and at least one additional co-occurring defect (n=2,084, 12.7%). Among these cases, 38.5% (n=802) were 1st degree hypospadias cases, 7.6% (n=158) were 2nd degree hypospadias cases, 7.5% (n=156) were 3rd degree hypospadias cases, and 46.4% (n=968) were not otherwise specified (NOS) (Table 1). The proportion of total cases that had co-occurring defects for each of these groups was and 12.6%, 16.6%, 42.5%, and 14.5%, respectively. For comparison with previous literature, we tabulated the count and proportion of the 30 most common single co-occurring defects (Table 2). The most frequently observed co-occurring defects included ostium secundum type atrial septal defect (n=390, 18.5%), obstructive defects of renal pelvis and ureter (n=309, 14.7%), ventricular septal defect (n=290, 13.8%), and other specified anomalies of bladder and urethra (n=216, 10.3%) (Table 2).
Table 2.
The 30 most frequently observed single co-occurring defects among male infants with non-isolated hypospadias (n = 2,084), Texas Birth Defect Registry, 1999-2014
| Defect | No. of individual cases | Case proportiona |
|---|---|---|
| Ostium secundum type atrial septal defect | 378 | 18.1% |
| Obstructive defects of renal pelvis and ureter | 309 | 14.8% |
| Ventricular septal defect | 290 | 13.9% |
| Other specified anomalies of bladder and urethra | 216 | 10.4% |
| Polydactyly | 108 | 5.2% |
| Atresia and stenosis of urethra and bladder neck | 100 | 4.8% |
| Other anomalies of aorta | 98 | 4.7% |
| Other deformities of feet | 96 | 4.6% |
| Other specified anomalies of ureter | 85 | 4.1% |
| Atresia and stenosis of large intestine, rectum and anal canal | 79 | 3.8% |
| Microcephalus | 73 | 3.5% |
| Congenital hypertrophic pyloric stenosis | 70 | 3.4% |
| Cleft lip +/− cleft palate | 60 | 2.9% |
| Renal agenesis and dysgenesis | 56 | 2.7% |
| Syndactyly | 52 | 2.5% |
| Other specified anomalies of kidney | 51 | 2.4% |
| Varus (inward) deformities of feet | 51 | 2.4% |
| Anomalies of great veins | 49 | 2.4% |
| Anomalies of the pulmonary artery | 49 | 2.4% |
| Reduction deformities of brain | 47 | 2.3% |
| Anomalies of spine | 46 | 2.2% |
| Other specified anomalies of the heart | 46 | 2.2% |
| Anomalies of the pulmonary valve | 45 | 2.2% |
| Transposition of great vessels | 39 | 1.9% |
| Congenital hydrocephalus | 37 | 1.8% |
| Coarctation of aorta | 37 | 1.8% |
| Teratology of Fallot | 34 | 1.6% |
| Other anomalies of lower limb | 34 | 1.6% |
| Anomalies of diaphragm | 34 | 1.6% |
| Other anomalies of ribs and sternum | 32 | 1.5% |
Among non-isolated cases of hypospadias
We calculated adjusted O/E ratios for 601 observed combinations involving hypospadias and one, two, three, or four co-occurring defects, and focused on the 30 combinations with the highest adjusted O/E ratios (Table 3). Hypospadias, bupthalmos, and congenital cataract and lens anomalies made up the combination with the highest O/E ratio (adjusted O/E ratio: 192.9) meaning the prevalence of this combination was almost 200-fold higher than would be expected if the occurrence of these defects were independent. The next four top combinations (adjusted O/E ratios: 139.0 to 109.1), featured hypospadias co-occurring with several urogenital (e.g., renal agenesis and dysgenesis, cystic kidney disease,), central nervous system (e.g., reduction deformities of the brain, other anomalies of spinal cord), cardiac (e.g., ostium secundum type atrial septal defect, anomalies of great veins), and musculoskeletal defects (e.g., anomalies of the ribs and sternum, anomalies of spine) (Table 3). The range of the remaining top 30 adjusted O/E ratios was 71.2 to 29.4. Many of the top 30 combinations involved defects in the urogenital (17 combinations, 56.7%), cardiac (16 combinations, 53.3%), and musculoskeletal (12 combinations, 40.0%) systems. Sensitivity analysis restricted to cases with second- or third-degree hypospadias (n = 314) identified similar defect combinations and relative rankings as in the main analyses.
Table 3.
Top 30 combinations of co-occurring defects among male infants with non-isolated hypospadias (n = 2,084), ranked by adjusted observed-to-expected (O/E) ratio, Texas Birth Defect Registry (TBDR), 1999-2014a
| Cases (n) with combination of co-occurring defects | Adjusted (O/E) Ratio | |
|---|---|---|
| Buphthalmos; Congenital cataract and lens anomalies | 3 | 192.9 |
| Renal agenesis and dysgenesis; Reduction defects of upper limb; Other anomalies of upper limb including shoulder girdle | 3 | 139.0 |
| Ostium secundum type atrial septal defect; Anomalies of great veins; Obstructive defects of renal pelvis and ureter; Renal agenesis and dysgenesis | 3 | 137.0 |
| Atresia and stenosis of large intestine, rectum and anal canal; Cystic kidney disease; Other anomalies of ribs and sternum | 3 | 127.6 |
| Ostium secundum type atrial septal defect; Anomalies of great veins; Other specified anomalies of bladder and urethra; Obstructive defects of renal pelvis and ureter | 3 | 109.1 |
| Atresia and stenosis of large intestine, rectum and anal canal; Renal agenesis and dysgenesis; Other anomalies of ribs and sternum | 3 | 71.2 |
| Reduction deformities of brain; Anomalies of spine; Other anomalies of ribs and sternum | 3 | 70.2 |
| Microphthalmos; Coloboma and other anomalies of anterior segments | 4 | 68.8 |
| Ventricular septal defect; Other anomalies of aorta; Anomalies of great veins; Anomalies of spine | 3 | 59.8 |
| Other specified anomalies of spinal cord; Atresia and stenosis of large intestine, rectum and anal canal; Other specified anomalies of ureter | 3 | 59.1 |
| Other specified anomalies of spinal cord; Atresia and stenosis of large intestine, rectum and anal canal; Anomalies of spine | 3 | 55.3 |
| Anomalies of great veins; Anomalies of spine; Renal agenesis and dysgenesis | 3 | 48.4 |
| Ventricular septal defect; Other anomalies of aorta; Anomalies of great veins; Anomalies of peripheral vascular system | 3 | 47.0 |
| Other specified anomalies of ureter; Anomalies of spine; Other anomalies of ribs and sternum | 3 | 45.8 |
| Ostium secundum type atrial septal defect; Other specified anomalies of bladder and urethra; Obstructive defects of renal pelvis and ureter; Other specified anomalies of ureter | 3 | 44.8 |
| Microphthalmos; Congenital anomalies of posterior segment | 4 | 44.4 |
| Anomalies of great veins; Obstructive defects of renal pelvis and ureter; Other specified anomalies of bladder and urethra | 3 | 39.6 |
| Ostium secundum type atrial septal defect; Endocardial cushion defects; Congenital mitral stenosis | 3 | 38.6 |
| Anomalies of great veins; Other specified anomalies of ureter; anomalies of spine | 3 | 37.7 |
| Tracheoesophageal (T-E) fistula esophageal atresia and stenosis; Obstructive defects of renal pelvis and ureter; Other specified anomalies of ureter | 3 | 36.7 |
| Anomalies of great veins; Anomalies of spine; Other anomalies of ribs and sternum | 3 | 35.8 |
| Ostium secundum type atrial septal defect; Other anomalies of aorta; Anomalies of great veins; Anomalies of peripheral vascular system | 3 | 35.6 |
| Tetralogy of Fallot; Anomalies of pulmonary valve; Anomalies of pulmonary artery | 3 | 34.2 |
| Cystic kidney disease; Other specified anomalies of ureter; Other specified anomalies of bladder and urethra | 3 | 34.0 |
| Ventricular septal defect; Congenital stenosis of aortic valve; Congenital mitral stenosis; Other anomalies of aorta | 3 | 32.2 |
| Anomalies of great veins; Renal agenesis and dysgenesis; Obstructive defects of renal pelvis and ureter | 3 | 31.0b |
| Obstructive defects of renal pelvis and ureter Other specified anomalies of ureter; Other anomalies of ribs and sternum | 4 | 30.7 |
| Obstructive defects of renal pelvis and ureter; Anomalies of spine; Other anomalies of ribs and sternum | 4 | 30.2 |
| Ventricular septal defect; Other anomalies of aorta; Anomalies of great veins; Obstructive defects of renal pelvis and ureter | 4 | 29.6 |
| Other specified anomalies of brain; Other specified anomalies of the heart; Other anomalies of aorta | 3 | 29.5 |
| Ventricular septal defect; Anomalies of great veins; Anomalies of spine | 5 | 29.4b |
Combinations with <3 cases available in the dataset were excluded.
Combination is represented in a higher-order combination within the 30 largest adjusted O-E ratios (e.g., combinations with defects A and B versus defects A, B, and C).
Five organ systems commonly observed among the top combinations were used to construct a Venn diagram (Figure 1): defects of the musculoskeletal, digestive, urogenital, cardiovascular, and central nervous system. The diagram indicates the number of birth defect combinations among our top 30 combinations that included defects within these five systems (e.g., number of top combinations with both cardiovascular and musculoskeletal defects). For example, 16 (53.3%) of the top combinations involved cardiovascular defects, and 8 (26.7%) of these combinations also involved co-occurring urogenital defects. Few combinations had no co-occurring defect in any of these five organ systems (3/30 combinations). In 13 (43.3%) of the top combinations, two of these systems (e.g., cardiovascular and musculoskeletal) were represented, and 4 (13.3%) combinations involved defects in three of these systems.
Figure 1.
Venn diagram of the top 30 birth defect combinations, where counts represent the number of the top 30 combinations that include the indicated defects (e.g., 6 of the top 30 combinations include urogenital and cardiovascular defects) in cases with hypospadias, Texas Birth Defect Registry, 1999-2014
Discussion
We report on patterns of co-occurrence of additional defects among infants with hypospadias. Many of the top identified combinations included other urogenital defects, which are thought to occur within the same developmental field as these male genital defects (e.g., renal and bladder defects). Developmental field defects were first described by Opitz as anomalies which manifest due to disturbances in the development of complex structures in the embryo [16]. These structures are thought to be linked in a “spatial, temporal and hierarchal manner” [16], and the etiologies of defects in the same developmental field are unknown and likely related and complex [17].
In 7 (23.3%) of the top 30 combinations, either renal agenesis, renal dysgenesis or cystic kidney disease was present. These renal malformations may be occurring with hypospadias, in at least a portion of subjects, as a result of errors occurring due to shared etiologic origins during development. Incidentally, renal agenesis, specifically, is observed more frequently in males than females (7:1) [18]. However, in some cases, the combination of these renal defects and hypospadias may additionally suggest the presence of a specific complex called congenital anomalies of the kidneys and urinary tract (CAKUT), which includes cystic kidney defects and renal agenesis, as well as hypospadias and other urogenital defects [19 20] CAKUT arises due to genetic mutations that affect multi-functional transcription factors and other proteins which disrupt the differentiation of the intermediate mesoderm and endotherm, leading to multiple defects within the urogenital system [21]. It is also possible that some combinations with renal anomalies may reflect unrecognized malformation patterns (e.g., syndromes or complexes), particularly for combinations in which renal anomalies were reported in combination with defects outside the expected developmental field (e.g., upper limb defects).
Several of the top combinations were at least partially suggestive of other known syndromes or complexes and may, therefore, represent syndromic cases without a documented syndromic diagnosis within the first year of life [13]. Specifically, 3 of the 30 top combinations included hypospadias and heart defects in combination with renal, bladder, spinal, and/or anal defects. This constellation of defects is suggestive of VACTERL association (vertebral defects, anal atresia, cardiac defects, tracheo-esophageal fistula, renal anomalies, and limb abnormalities). Genital defects, including hypospadias, are occasionally observed among cases with VACTERL. One study reported that 21.7% of male infants with VACTERL had a genitourinary defect present and 13.0% of male infants with VACTERL had hypospadias specifically [22]. However, these defects are not necessarily considered hallmark VACTERL features [22].
Congenital heart defects were present in over half of the top results (17/30 combinations), which is similar to reported frequencies among studies describing individual birth defects co-occurring with hypospadias [8]. Although cardiac defects (1% of total births per year in the United States) and hypospadias are both among the most common birth defects in the general population, the likelihood of co-occurrence due to chance alone was accounted for in our analyses by the computation of the adjusted O/E ratio [2 13 15 23]. This particular clustering may have a shared genetic etiology which has been suggested by other work [24]. A recent animal model experiment has provided evidence suggesting that mutations in various genes that contribute to the development of structural kidney and related defects (e.g., urinary tract) may also be involved for the development of congenital heart defects [24]. Specifically, 29% of 135 mouse model lineages with congenital heart defect-causing mutations had both cardiac and renal defects [24]. In fact, routine pre-operative imaging on 77 human patients with cardiac defects requiring surgical intervention revealed similar frequencies of renal anomalies (including many that were undiagnosed and identified during retrospective clinical review) [24]. These findings suggest that there may be some overlapping etiology involved for certain combinations observed in our data, such as those which included renal anomalies in combination with hypospadias and congenital heart defects.
Reduction deformities of the brain (e.g., agenesis of the corpus callosum) and other specified anomalies of the brain (e.g., Dandy-Walker variant) were present in the top combinations as well. There have been some reports of an increased frequency of certain craniofacial and neurodevelopmental defects among infants with hypospadias, although it is unclear what the developmental connection with hypospadias might be [9 11 25]. There are few known syndromes that fit well with these observed combinations of defects. However, two top combinations included cases with microphthalmia, coloboma, congenital anomalies of the posterior segment, and hypospadias. This pattern seemed potentially suggestive of undiagnosed Lenz micropthalmia syndrome, an X-linked recessive disorder primarily affecting males, which features microphthalmia and coloboma as hallmark features, with 77% of individuals also exhibiting hypospadias or another urogenital defect [26]. However, it seemed interesting that the top combinations that included hypospadias in combination with eye defects did not include defects in other organ systems. Thus, if these combinations are confirmed in independent samples, they represent an important phenotypic subgroup for further investigation.
Considering the etiologic complexity of most birth defects, further characterization of many of the identified patterns would be informative. Clinical case studies might be particularly helpful in investigating potential genetic and/or environmental etiologies of hypospadias and the presented combinations. The results discussed here, in combination with future work, will also hopefully provide insight and help to inform diagnostic and counseling practices in treatment of infants with hypospadias. For example, pending confirmation of patterns in future work, screening for some of the defects in the top combinations may be worth considering for some patients (e.g., those with select defects of the eye or brain or with multiple VACTERL features).
Strengths and Limitations
Similar to other analyses of birth defect registries, our analyses were limited to the available secondary data, which may have led to under or over-reporting of certain defects. In the TBDR, classification of hypospadias severity is dependent on the description in medical records. For some cases, these records do not provide sufficient information to make a definitive distinction of severity. Previous work has demonstrated some hypospadias cases may have been subject to more or less scrutiny from clinicians based on the severity and location of other co-occurring defects (e.g. other urogenital defects) [10]. We cannot rule out the possibility of misclassification, particularly for mild hypospadias. However, we conducted a sensitivity analysis to address the possibility of differences in defect co-occurrence patterns among infants with second- or third-degree hypospadias specifically, as compared to all infants with hypospadias. Results were similar to our main findings; however, first-degree and unspecified hypospadias cases constituted the majority of our full analytic sample, which is consistent with the distribution among other populations [2]. The number of cases with second- and third-degree hypospadias in our data was small, and a larger sample size (e.g., with sufficient numbers to restrict to third-degree hypospadias specifically) may be helpful for informing clinical practice relevant to screening and counseling among infants with hypospadias. We also cannot exclude the possibility of under-ascertainment of some malformation syndromes, chromosome abnormalities, sequences, or associations (e.g., VACTERL).
This study included several major strengths. One such strength was the use of a large population-based sample, which limited the potential for selection bias that may have been present in a clinical population. The large sample also allowed for agnostic assessment of a large number of high-order combinations of defects. Additionally, we were able to implement an analytic approach that accounted for the tendency of birth defects to cluster non-specifically.
Conclusions
We identified several combinations with high adjusted O/E ratios that did not seem likely to be explained by known syndromes, and that extended outside of the developmental field associated with hypospadias. Our description of patterns of defects co-occurring with hypospadias provides a foundation for better understanding hypospadias among infants with other birth defects.
Supplementary Material
Acknowledgments
Funding Information: This project was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health & Human Development (1R01HD093660-01A1) and in part by Title V Maternal and Child Health Block Grant with the Texas Department of State Health Services. The project sponsors had no active involvement in the project.
Footnotes
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Ethical Approval: This project was approved by Institutional Review Board of the Texas Department of State Health Services.
Conflicts of Interest Statement: None.
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