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Journal of Pediatric Urology (2014) xx, 1e7

Risk factors, prevalence trend, and


clustering of hypospadias cases in Puerto
Rico
s a, Laureane Alvelo-Maldonado b,
Luis A. Avile
Seguinot c, Juan Carlos Jorge d,*
-Mojica c, Jose
Irmari Padro
a

Department of Social Sciences, School of Public Health, University of Puerto Rico, Puerto Rico
Birth Defects Prevention and Surveillance System, Department of Health of Puerto Rico, Puerto Rico
c
Department of Environmental Health, School of Public Health, University of Puerto Rico, Puerto Rico
d
Department of Anatomy and Neurobiology, School of Medicine, University of Puerto Rico,
PO Box 365067, San Juan 00936 5067, Puerto Rico
b

Received 13 September 2013; accepted 6 March 2014

KEYWORDS
Hypospadias;
Prevalence;
Risk factors;
Geographic
information systems

Abstract Objective: The aim was to determine the distribution pattern of hypospadias cases
across a well-defined geographic space.
Materials and methods: The dataset for this study was produced by the Birth Defects Prevention and Surveillance System of the Department of Health of Puerto Rico (BDSS-PR), which
linked the information of male newborns of the Puerto Rico Birth Cohort dataset (PRBC;
n Z 92,285) from 2007 to 2010. A population-based caseecontrol study was conducted to
determine prevalence trend and to estimate the potential effects of maternal age, paternal
age, birth-related variables, and health insurance status on hypospadias. Two types of
geographic information systems (GIS) methods (Anselin Local Morans I and Getis-Ord G) were
used to determine the spatial distribution of hypospadias prevalence.
Results: Birthweight (<2500 g), age of mother (40 years), and private health insurance were
associated with hypospadias as confirmed with univariate and multivariate analyses at 95% CI.
A cluster of hypospadias cases was detected in the north-central region of Puerto Rico with
both GIS methods (p  0.05).
Conclusions: The clustering of hypospadias prevalence provides an opportunity to assess the
underlying causes of the condition and their relationships with geographical space.
2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: 1 787 758 2525x1506; fax: 1 787 767 0788.
E-mail addresses: jcjorge@ymail.com, juan.jorge@upr.edu (J.C. Jorge).
http://dx.doi.org/10.1016/j.jpurol.2014.03.014
1477-5131/ 2014 Journal of Pediatric Urology Company. Published by Elsevier Ltd. All rights reserved.

Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014

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Introduction
Hypospadias is traditionally defined by the anatomical position of the urethral meatus on the ventral surface of the
penis other than close to the tip of the glans. This
anatomical variation results from incomplete fusion of the
urethral folds of the urethral spongiosum during intrauterine development and can range in position from the glans
corona up to the perineum. Aside from variations in the
localization of the urethral opening, hypospadias can also
present with atypical shape of the urethral opening, of the
glans, and of penile skin, various degrees of penile curvature, unilateral or bilateral cryptorchidism, among other
variations in genital appearance. Severe hypospadias cases
can also present with penileescrotal transposition and/or
enlarged prostatic utricle. In severe cases, clinical protocols for the management of intersexuality are commonly
deployed. Given that hypospadias is not a monolithic clinical entity, we hypothesized that hypospadias prevalence is
not uniformly distributed across space. The study of prevalence across space can provide valuable information about
plausible gene/environment interactions that may underlie
distinct distributions of cases. Moreover, the identification
of hypospadias spatial clusters, if any, can be used to
optimize the delivery of health services to manage the
condition.
An impressive body of work on the etiology of hypospadias suggests that genetic and environmental factors are
the main contributors to the high incidence of this male
congenital condition. In fact, it has been suggested that, in
the majority of cases, the etiology of this condition can be
explained by a two-hit hypothesis, whereby genetic susceptibility plus environmental exposure increases the risk
for having offspring with hypospadias [1,2]. Early epidemiologic studies on incidence rates reported an increase of
hypospadias in certain regions of the world including the
United States [3,4]. However, more recent studies do not
support such a view; for a recent review see Fisch et al. [5].
One of these early studies showed a higher incidence of
hypospadias cases in the eastern and central regions of the
United States than the western region [4]. But this study,
based on a nationwide surveillance program, the Birth Defects Monitoring Program, is limited by the fact that such a
database was not built with a random sample of US births
by representative geographic populations [5,6].
We used the Puerto Rican archipelago as a case study to
assess prevalence trend and to estimate the potential effects of maternal age, paternal age, birth-related variables, health insurance status, and the spatial distribution
pattern of hypospadias prevalence. We found that birthweight (<2500 g), age of the mother (40 years), and
private health insurance were associated with hypospadias.
In addition, clustering of confirmed hypospadias cases in
the mainland of Puerto Rico was detected.

Materials and methods


The dataset for this analysis was produced by the Birth
Defects Prevention and Surveillance System of the Department of Health of Puerto Rico (BDSS-PR), which linked the
information of male newborns of the Puerto Rico Birth

L.A. Avile
s et al.
Cohort dataset (PRBC; n Z 92,285) with a dataset of
confirmed cases of hypospadias from 2007 to 2010. Initial
diagnosis of hypospadias was made by a US board-certified
physician in the birthing hospital and the birthing hospital
reported each case to BDSS-PR routinely, as required by
local and US law. A group of five BDSS-PR trained nurses in
congenital defects visited the birthing hospital and
reviewed the medical charts to confirm cases. Whenever
necessary, BDSS-PR nurses interviewed medical staff in the
birthing hospital if medical information was missing in the
charts. In addition, BDSS-PR staff contacted the parents by
phone to provide health information, genetic counseling,
and/or referral to medical services when appropriate. Case
follow-up by phone provided another opportunity to
confirm diagnosis. Given the geographical area of Puerto
Rico (9104 km2), it was possible for BDSS-PR nurses to
monitor birthing hospitals across the entire Island. Out of
hospital births and home deliveries, which represented less
than 1% of total births for the years 2009 and 2010
(Department of Health of Puerto Rico, Division of Statistical
Analysis, personal communication), are required by law to
provide birth information to the Puerto Rico Health
Department before a birth certificate can be issued to the
parents. There is a system in place where BDSS-PR is notified of births with congenital defects even when born
outside the traditional health-care system. Therefore, case
ascertainment following the established protocol identified
279 cases of hypospadias for the years 2007e10.

Caseecontrol study
We conducted a population-based caseecontrol study to
estimate the potential effects of maternal age, paternal
age, birth-related variables, and health insurance status on
hypospadias. Cases were defined as confirmed cases of
hypospadias for the years 2007e10 by BDSS-PR (n Z 279),
with or without another congenital condition. Control
subjects were defined as those male newborns with no
hypospadias and no other congenital condition according to
the PRBC dataset for the years 2007e10 (n Z 91,615).
We performed univariate analyses to estimate the
prevalence odds ratio for hypospadias for the following
variables: weeks of gestation (25e37 or 38), birthweight
(<2500 g or  2500 g), previous births (0 or 1), fathers
age (<20, 20e24, 25e29, 30e34, 35e39, 40 years),
mothers age (<20, 20e24, 25e29, 30e34, 35e39, 40),
and health insurance status (private, including pay out-ofpocket cases, vs. government) with 95% confidence interval
(CI). Age of the father and age of the mother category of 40
years or older was aggregated due to small sample size.
Eligibility for the government health insurance plan in
Puerto Rico is based on the relation of family income to
family size, which is similar to US poverty guidelines [7].
Therefore, health insurance status was used as the criterion
to provide an insight about socioeconomic status at the
household level [8], which according to the American
Community Survey Briefs, United States Census Bureau, 45%
of the population in Puerto Rico in 2010 lived under the
poverty line. A multivariate analysis to estimate the joint
prevalence odds ratio for hypospadias was performed with
those variables which their 95% CI for odds ratio did not

Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014

MODEL

Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico

include 1. Statistical analyses were performed with SPPS v.


17 (IBM).

Spatial distribution of hypospadias prevalence


The annual prevalence at birth of hypospadias for the
Puerto Rican archipelago (the islands of Puerto Rico, Vieques, and Culebra) was calculated by dividing the number
of hypospadias cases by the corresponding number of male
births for each year (2007e10). The overall 4-year prevalence at birth for hypospadias for the study period according to the mothers municipality of residence was used
to determine patterns in the spatial distribution of hypospadias prevalence. In order to statistically assess the existence of a series of neighboring municipalities with similar
or dissimilar prevalence of hypospadias beyond what would
be expected by chance, cluster analyses were conducted
using two types of geographical information systems
methods using the place of residence of the mother: (a)
Cluster and Outlier Analysis (Anselin Local Morans I), to
test for the plausible existence of clusters; and (b) GetisOrd G, to test for the plausible clustering of hot spots (high
prevalence) and cold spots (low prevalence) of hypospadias. The algorithms for cluster analyses were based on a
comparison of each individual region (municipalities within
the Puerto Rican archipelago) with its neighboring
municipalities.
Morans I value, z-score, p  0.05, and a code representing the cluster type for each prevalence per municipality were calculated, where z-scores and p-values
represent the statistical significance of the computed
index values. A positive value for Morans I indicates that a
given municipality has neighboring municipalities with a
similarly high (or similarly low) prevalence of hypospadias
which defines a spatial cluster. A negative value for Morans I indicates that a given municipality has neighboring
municipalities with dissimilar values, which defines a
spatial outlier. The output field, cluster/outlier type
(COType), distinguishes between statistically significant
cluster of high values (HH) at p  0.05, cluster of low
values (LL), outliers in which a high value is surrounded
primarily by low values (HL), and outliers in which a low
value is surrounded primarily by high values (LH).
Prevalence data were aggregated to detect hot and cold
spots. Cluster analyses were performed with ARCGIS v10
(ESRI).

Results
As in other countries, hypospadias is the most common
urogenital tract condition in Puerto Rico. For the time
period 2007e10, we found that hypospadias prevalence
remained relatively constant with an average prevalence of
30.2/10,000 male live births (Fig. 1A). Analysis by comorbidity showed that 251 out of 279 hypospadias cases did not
have another congenital condition, whereas 14 cases had
one additional condition and 14 cases had two or more
additional congenital conditions (Fig. 1B). Those cases with
one comorbidity were associated with cardiovascular
(n Z 6), musculoskeletal (n Z 3), central nervous system
(n Z 1), oral (n Z 1), eyes and ears (n Z 1),

Figure 1 Profile of hypospadias prevalence for the Puerto


Rican archipelago, 2007e10. (A) Hypospadias prevalence per
10,000 male live births is shown for years 2007e10. The dotted
line indicates the average hypospadias prevalence for this time
period. (B) Most of hypospadias cases are isolated (90%),
whereas 5% exhibit one comorbid congenital condition and 5%
exhibit two or more congenital conditions (see text for
details).

chromosomalegenetic (n Z 1), or genital ambiguity (n Z 1)


conditions.

Caseecontrol study
Table 1 shows that there is an increased odds ratio of having
a newborn with hypospadias according to gestational age
(25e37 weeks), birthweight (<2500 g), age of the mother
(40 years), age of father (30e34 years), and health insurance status (private insurance). A positive linear correlation for parental age was noted (Pearson correlation
coefficient Z 0.69; p < 0.01). Therefore, the age of the
father was not included in our multivariate logistic regression analysis as it showed the lowest OR value between
these two variables and it did not meet the assumption of
absence of multicollinearity. Similarly, a positive linear
correlation between gestational age and birthweight was
noted (Pearson correlation coefficient Z 0.78; p < 0.001).
Therefore, gestational age was not included in our multivariate logistic regression analysis as it showed the lowest
OR value between these two variables and it did not meet
the assumption of absence of multicollinearity.
Multivariate analyses confirmed statistical significance
as follows: birthweight less than 2500 g, OR Z 3.84 (95% CI
2.99e4.95); age of the mother of 40 years, OR Z 2.63
(95% CI 1.19e5.81); and private health insurance,
OR Z 1.41 (95% CI 1.07e1.86).

Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014

MODEL

L.A. Avile
s et al.
Table 1

Risk factors for hypospadias in Puerto Rico.

Total
Gestational age
25e37 weeks
38e44 weeks
Birthweight
<2500 g
>2500 g
Prior births
0
1
Paternal age
<20
20e24
25e29
30e34
35e39
40e44
45
Maternal age
<20
20e24
25e29
30e34
35e39
40
Health insurance
Government
Private

Hypospadias

Controls

Total

Prevalencea

279
275
140
135
279
90
189
279
273
6
268
19
77
60
64
25
15
8
279
46
80
73
54
16
10
279
169
110

91,615
90,948
34,074
56,874
91,576
10,166
81,410
91,601
90,701
900
88,479
6481
23,804
24,334
17,858
9566
4005
2431
91,586
16,231
29,511
23,453
14,716
6265
1410
91,383
62,551
28,832

91,894
91,239
34,214
56,384
91,855
10,256
81,599
91,880
90,974
906
88,747
6500
23,881
24,394
17,922
9591
4020
2439
91,865
16,277
29,591
23,526
14,770
6281
1420
91,662
62,720
28,942

30.36
30.14
40.92
23.77
30.37
87.75
23.16

OR

95% CI

1.73
1

1.36e2.19b

3.81

2.96e4.90b

30.01
66.23

1
2.22

0.98e4.99

29.23
32.24
24.60
35.71
26.07
37.31
32.80

1.19
1.31
1
1.45
1.06
1.52
1.33

0.71e2.00
0.94e1.84

28.26
27.04
31.03
36.56
25.47
70.42

1.11
1.06
1.22
1.44
1
2.77

0.63e1.96
0.62e1.82
0.71e2.10
0.82e2.51

27.12
38.01

1
1.41

1.02e2.07b
0.66e1.70
0.86e2.68
0.64e2.80

1.26e6.13b

1.11e1.80b

OR Z odds ratio.
a
Per 10,000 male live births.
b
Significant at 95% confidence interval (CI).

Spatial distribution of hypospadias prevalence


The Puerto Rican Archipelago is divided into 78 municipalities, which include the mainland of Puerto Rico with a
population of 3,725,778, the island municipality of Vieques
with a population of 9,301, and the island municipality of
Culebra with a population of 1818. Therefore, the population of mainland Puerto Rico constitutes 99.7% of the total
population of the archipelago [9]. Fig. 2A shows those
municipalities below the average value of hypospadias
prevalence and those above the average value of hypospadias prevalence for the years 2007e10. Cluster and
outlier analysis (Anselin Local Morans I) detected six
contiguous municipalities in the north-central region of the
Island (from west to east: Vega Baja, Vega Alta, Dorado,
Toa Baja, Catan
o, and Bayamo
n) with a similar high prevalence of hypospadias (Fig. 2B, shown in black). Therefore,
this cluster of municipalities is statistically different from
the rest of the mainland with regard to hypospadias prevalence (p  0.05). Two municipalities (from north to south:
San Sebastia
n and Maricao) were identified as spatial outliers for hypospadias prevalence where a high value is surrounded by low values (HL). Three municipalities (from
north to south: Ceiba, San Lorenzo, and Naguabo) were
identified as having low values (LL) for hypospadias

prevalence. By using a second geographical information


system, Getis-Ord G analysis, clustering of a hot spot (high
hypospadias prevalence) in the north-central region was
confirmed (Fig. 2C).

Discussion
The prevalence of hypospadias in Puerto Rico has remained
relatively constant during the years 2007e10. The calculated prevalence was 30.2/10,000 male live births for this
time period. This low prevalence allows us to interpret the
odds ratio as a measure of risk. We found that 90% of these
cases did not exhibit comorbid congenital conditions.
Birthweight (<2500 g), age of the mother (40 years), and
private health insurance were found to be risk factors for
having a newborn with hypospadias. A cluster of hypospadias cases was detected in the north-central region of the
mainland. Given the protocol for case ascertainment in the
Island, the clustering of cases cannot be a statistical artifact related to a regional bias in the medical competency of
the health professionals related to the surveillance system.
Health-care provider density does not explain the clustering of cases either, as the highest densities for providers
(San Juan, Mayague
z, and Ponce metropolitan municipalities) fell outside the hot spot for hypospadias prevalence.

Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014

MODEL

Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico

Figure 2 Spatial distribution of hypospadias prevalence for the Puerto Rican archipelago, 2007e10. (A) Municipalities below the
average value of hypospadias prevalence are shown in white whereas municipalities above the average value of hypospadias
prevalence are shown in gray and black. Puerto Rico is the largest island of the Puerto Rican archipelago followed by the island
municipality of Vieques. Culebra is the smallest island municipality of this archipelago within the Caribbean region. North cardinal
point applies to (AeC). Geographic scale (size in km) and legend for hypospadias prevalence are shown (see text for details). (B) Six
contiguous municipalities in the north-central region of the mainland with the highest prevalence of hypospadias are shown in
black. Two municipalities identified as spatial outliers (High Low) are shown in the darkest gray tone. Three municipalities identified as spatial outliers (Low Low) are shown in the lightest gray tone. Geographic scale (size in km) and legend for Anselin Local
Morans I values are shown (see text for details). (C) Cold spots for low hypospadias prevalence are shown in white or hatched lines.
Hot spots for high hypospadias prevalence are shown in black. Municipalities between cold and hot spots are shown in gray tones.
Geographic scale (size in km) and legend for GetiseOrd G values are shown (see text for details).

Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014

MODEL

6
The prevalence and epidemiologic profile of hypospadias in Puerto Rico further supports the notion that cases
are not particularly different from other regions of the
world. Our study is also consistent with most recent
studies, which report stable or declining prevalence of
hypospadias [5,10e15]. Australia [16] and Denmark [17]
are noted as exceptions. We found an association between hypospadias and low birthweight, as has been
shown particularly for severe hypospadias [18e20]. But the
strong association between birthweight and gestational
age in our sample, and the lack of information on severity
for low birthweight cases, does not allow us to determine
which of the two is the proxy variable that underlies
hypospadias cases. Nevertheless, in agreement with
recent studies, we also found that gestational age is
associated with hypospadias [20,21]. Strong evidence for
early delivery as a risk factor for congenital urogenital
conditions is provided by Jensen et al. [20], suggesting
that prenatal factors that affect relative fetal growth restriction can also produce hypospadias. However, it is
important to note that global growth deficits among
hypospadiac boys do not seem to persist through infancy
[22]. Other reports have shown that younger [23] or older
[24] paternal age is associated with increased hypospadias
risk. In our sample, we found a strong positive linear correlation between maternal and paternal age, which confounds the plausible contribution of each as a risk factor
for the condition. According to several studies, older
maternal age has been identified as a risk factor for
hypospadias [10,25,26], but it has been difficult to
pinpoint the relevance of this association with hypospadias
etiology. For instance, is age associated with underlying
genetic defects associated with aging or with subfertility?
We did not conduct analyses for multiple births (n Z 6) or
gestational diabetes mellitus (n Z 6) due to the small
number of cases in the sample.
We found that private health insurance is associated
with the condition. Our multivariate logistic regression
analysis indicates that the effect of health insurance status
persists after controlling for age of mother. Therefore, it
will be advantageous for further lines of inquiry to determine social class differences following a social theorybased model beyond traditional socioeconomic status
measures [27,28]. In this context, it will be important for
future studies to inquire about the use of assisted reproductive technologies among women with private health
insurance. In addition, further analyses by type and place
of employment may reveal patterns of significant population mobility on a daily basis, which adds to the complexity
of plausible environmental factors associated with the
condition.
Our study indicates that hypospadias prevalence according to the mothers residence is not distributed uniformly across the island of Puerto Rico as identified with
prevalence values. The cluster of hypospadias cases in the
north-central region of Puerto Rico was detected by using
two separate approaches: Morans Global I and Getis-Ord
G. The first one identifies statistically significant spatial
clusters and spatial outliers, while the second one detects
locations with high or low prevalence (hot and cold spots,
respectively). While Anselin Local Morans I analysis
identified six contiguous municipalities in the north-

L.A. Avile
s et al.
central region of Puerto Rico with high hypospadias prevalence, Getis-Ord G identified a gradient pattern across
the mainland from north to south with the hot spot in the
north-central region as well. Getis-Ord G is based on
inferential statistics where results of the analysis are
interpreted within the context of the null hypothesis,
which states that there is no spatial clustering of feature
values. But if the z-score is positive or negative, it indicates that high values or low values are clustered in the
study area, respectively. The use of Global Morans I becomes particularly important when both high and low
values produce clusters as these may cancel each other
out because Global Morans I provides a spatial autocorrelation analysis which identifies the spatial distribution of
high values when surrounded by low values, and vice
versa. In this study, the spatial autocorrelation refers to
the relationship of computed I values with neighboring
municipalities. Taken together, both GIS methods do not
require data filtering and both methods assume complete
spatial randomness; that is, values are randomly distributed among the features in the dataset which assumes
random spatial processes at work. In our case, the total
number of hypospadias cases and the total number of male
live births without a congenital condition per municipality
per year were submitted to built-in analytical algorithms
of each method without making assumptions about frequency of cases nor space. The fact that both methods
detected spatial clustering of hypospadias provides strong
evidence that such spatial distribution was not produced
by an artifact introduced by the number of hypospadias
cases nor from the geographical units that were used in
the analyses.
According to four local and federal government reports
(data not shown), the following environmental contaminants are found in discrete regions of the island: chlorinated pesticides, polychlorinated biphenyls, phthalates,
and dioxins; all of which have been associated with hypospadias [29]. It is of interest for future studies to determine
whether there is a correlation between the spatial distribution of these contaminants and hypospadias clusters according to severity of the condition.
It remains as a tenet in the field that most hypospadias
cases are idiopathic. In spite of great research efforts, it is
plausible that the etiology of the condition has remained
elusive because studies that screen for risk factors are not
conducted according to severity [19]; for a recent review
see Ref. [30]. Therefore, it remains as a challenge for
future studies to determine the distribution of hypospadias
prevalence for the Puerto Rican archipelago according to
severity type.

Conclusion
The clustering of hypospadias prevalence provides an opportunity to assess the underlying causes of the condition
and their relationships with geographical space.

Conflict of interest
None.

Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014

MODEL

Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico

Funding
None.

Ethical approval
This study was approved by the Institutional Review Board
(IRB) Committee.

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Please cite this article in press as: Avile


s LA, et al., Risk factors, prevalence trend, and clustering of hypospadias cases in Puerto Rico,
Journal of Pediatric Urology (2014), http://dx.doi.org/10.1016/j.jpurol.2014.03.014