Research Article
Hypospadias, Intrauterine Growth Restriction,
and Abnormalities of the Placenta
M. Hassan Toufaily 1,2, Drucilla J. Roberts3, Marie-Noel Westgate1,2,
Anne-Therese Hunt4, and Lewis B. Holmes *1,2,5
Background: Hypospadias is more common among male infants with growth
restriction, defined as a birth weight less than the 10th centile, than in infants
with a normal birth weight. Intrauterine growth retardation (IUGR) has been
associated, also, with abnormalities of the placenta, such as maternal
vascular malperfusion. In a consecutive sample of newborn infants, the
association between hypospadias, IUGR and abnormalities of the placenta
could be analyzed. Methods: Affected infants were identified among 289,365
liveborn and stillborn infants in the Active Malformations Surveillance Program
between 1972 and 2012. The four anatomic locations of the ectopic urethral
opening, based on the recorded physical examination findings, were: (1)
glanular; (2) subcoronal; (3) penile; (4) penoscrotal. Affected infants with
associated malformations, a chromosome abnormality, teratogenic exposure,
maternal diabetes mellitus, or multiple gestations were excluded. Results:
Three hundred sixteen affected infants were identified: 52.2% glanular,
11.7% subcoronal, 27.8% penile, and 8.2% penoscrotal. The highest
frequency of IUGR (34.6%) was in the infants with the most severe
Introduction
Hypospadias is due to incomplete fusion of the urethral
folds with abnormal openings of the urethra along the
inferior aspect of the penis. It is one of the most common
congenital anomalies in males, affecting 1 in 250 live
births (Baskin et al., 2001; Holmes, 2012). The rate of
occurrence of hypospadias has been observed to be
increased in two clinical settings. First, hypospadias is
more common in very low birth-weight infants than in
term infants of normal weight (Baskin et al., 2001; Gatti
1
Active Malformations Surveillance Program, Department of Pediatric
Newborn Medicine, Brigham and Womens Hospital, Harvard Medical School,
Boston, Massachusetts
2
Medical Genetics Unit, MassGeneral Hospital for Children, Harvard Medical
School, Boston, Massachusetts
3
Department of Pathology, Massachusetts General Hospital, and Harvard
Medical School, Boston, Massachusetts
4
Hunt Consulting Associates, Chapel Hill, North Carolina
5
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts
Supported by funds provided by the Birth Defects Registry of the Massachu-
setts Department of Public Health, which is part of the National Birth Defects
Prevention Study, a project of Birth Defects and Developmental Disabilities of
the Centers for Disease Control, Atlanta.
Conflicts of Interest: None declared.
*Correspondence to: Lewis B. Holmes, Medical Genetics Unit, MassGeneral
Hospital for Children, 175 Cambridge Street, 5th Floor, Boston, MA 02114.
E-mail: holmes.lewis@mgh.harvard.edu
Published online 0 Month 2017 in Wiley Online Library (wileyonlinelibrary.com).
Doi: 10.1002/bdr2.1087
C 2017 Wiley Periodicals, Inc.
V
hypospadias (penoscrotal). The 39 reports of placenta findings showed a high
frequency of abnormalities. Conclusion: An increased rate of occurrence of
hypospadias and abnormalities of the placenta were present in infants with
intrauterine growth restriction. The postulated cause of this association is a
deficiency in the function of the placenta during weeks 10 to 14 of gestation
when normal masculinization occurs due to an increase in the level of
placental human chorionic gonadotropin and fetal testosterone. The cause of
the placental deficiency has not been established.
Birth Defects Research 00:000000, 2017.
C 2017 Wiley Periodicals, Inc.
V
Key words: hypospadias; intrauterine growth restriction; placental abnormal-
ities; vascular malperfusion; masculinization
et al., 2001; Hussain et al., 2002), as well as in infants
with poor intrauterine growth (Hashimoto et al., 2016).
Second, hypospadias and growth restriction have been
associated with abnormalities of the function of the pla-
centa (Fujimoto et al., 2008; Proctor et al., 2009; Yinon
et al., 2010; Huisma et al., 2013).
Many studies have been carried out on the causes of
hypospadias, including genetic factors and environmental
exposures. Some causes are established: chromosome
abnormalities and exposure to some anticonvulsant drugs,
such as sodium valproate (Hernandez-Diaz et al., 2012).
Thus far, commercially available molecular studies can-
not be used to identify associated genetic abnormalities
in an affected male infant. Molecular analyses in research
studies have focused on three susceptibility genes: steroid
5-alpha reductase type 2 (SRD5A2), 17-beta hydroxyste-
roid dehydrogenase (HSD17B3) and androgen receptor
(AR) gene (Sutherland et al, 1996; Manson and Carr, 2003;
Manson and Carr, 2003). For example, one study of 90 Chi-
nese males with hypospadias searched for mutations in
several genes, including SRDSA2, AR, WTI, SPY and Sox9
and identified 16 different mutations (Wang et al., 2004).
Another study identified specific polymorphisms in the
ESR1 and ESR2 genes (Ban et al., 2008). Investigators have
proposed that studies of the molecular abnormalities asso-
ciated with isolated hypospadias focus on allelic variants
in genes which control androgen action and metabolism
(Manson and Carr, 2003).
2 HYPOSPADIAS, IUGR, AND PLACENTA ABNORMALITIES
Epidemiologic studies have assessed the relationship of
several environmental exposures. Some studies have estab-
lished associations, such as exposure during pregnancy to
antiandrogenic compounds (Baskin et al., 2001); the
mother being a vegetarian (North and Golding, 2000) or
having pre-eclampsia (Yinon et al., 2010) or hypertension
(Agopian et al., 2016); abnormalities of a fathers sperm
and testes (Sweet et al., 1974); conception with in vitro
fertilization (Silver et al., 1999); multiple gestations (Fre-
dell et al., 2002).
We have assessed the association of hypospadias with
intrauterine growth retardation (IUGR) and the presence
of abnormalities in the placentas of affected infants. This
association was assessed among the infants with hypospa-
dias who were identified by the Active Malformations Sur-
veillance Program, conducted over 41 years (19722012)
at the Boston Lying-In Hospital, which later became part
of Brigham and Womens Hospital. An additional hypo-
thesis tested was whether the frequency of IUGR was
higher among the infants with the more severe types of
hypospadias.
Materials and Methods
Infants with isolated hypospadias were identified at birth
by the staff of the Active Malformations Surveillance
Program. This project was carried out 6 days a week,
including holidays, from February 16, 1972 until October
1, 2012, except for the period January 1, 1975 through
December 31, 1978, when the program was interrupted
due to the loss of office space (Holmes, 2012). The defini-
tion of a malformation used was a structural abnormality
with surgical, medical, or cosmetic importance. The details
of the methodology used and the demographic characteris-
tics of the population surveyed are provided (above) in
the description of the Research Setting.
The severity of the hypospadias was based on the find-
ings recorded by the examining pediatricians and the con-
sulting urologists, if that consultation occurred before the
newborn infant and his mother were discharged from the
birth hospital. The four categories (Fig. 1) used were: (1)
distal or glanular hypospadias with the urethral meatus at
the lower edge of the penile glans or at the corona; (2)
subcoronal hypospadias with the location just below the
glans; (3) penile hypospadias with the meatus being
located on the shaft of the penis; (4) perineoscrotal (or
penoscrotal) with the urethral opening on the perineum
and below the shaft of the penis (Fig. 1).
The births were classified as liveborn, stillborn, or elec-
tive terminations. Spontaneous abortions (before 20 weeks
gestational age) were not included.
All male infants born with isolated hypospadias were
identified. The infants excluded from this analysis were
those with a chromosome abnormality; infants of mothers
with insulin-dependent diabetes mellitus; hypospadias as
FIGURE 1. Diagram of location of ectopic opening of urethra in the different
types of hypospadias: glanular (A), penile (B), penoscrotal (C), and perineal
(D). From Holmes LB, Common malformations, Oxford University Press, NY,
2012, Page 139, Figure 14.1.
part of a malformation syndrome; infants exposed to a ter-
atogenic medication, such as sodium valproate; and
affected infants in pregnancies with multiple gestations.
The race of each infant was established by asking the
mother to select a racial designation for her infant from a
printed list of possibilities.
The definition used for IUGR was a birth weight less
than 10th percentile for gestational age. To determine the
growth percentile of each affected infant, the Okens refer-
ence percentiles (Oken et al., 2003) were used. The weight
and gestational age at birth were used to establish the
fetal growth percentile for each affected newborn infant.
Infants were considered to have IUGR or to be small for
gestational age (SGA) if their birth weight was below the
10th centile; normal, if they are between 10th and 90th cen-
tile; and large for gestational age, if they were over the
90th centile.
The placentas of the affected infants were dissected
and analyzed by the perinatal pathologists at the Brigham
and Womens Hospital. The placenta reports available
were reviewed by an experienced perinatal pathologist
(D.J.R.) and the findings were divided into five categories:
maternal vascular malperfusion (MVM), inflammatory
lesions (INF), fetal vascular malperfusion (FVM), anatomi-
cal abnormalities, and other conditions, such as meconium
pigment in macrophages in the membranes (Fig. 2). MVM
was diagnosed when there were at least two of the follow-
ing findings: placental eight less than the 10th percentile
for gestational age, two or more placental infarcts, distal
villous hypoplasia, decidual vasculopathy, atherosis, mater-
nal floor infarct, or massive perivillous fibrin inflammatory
response, chronic villitis, plasma cell deciduitis, or chronic
BIRTH DEFECTS RESEARCH 00:0000 (2017) 3

FIGURE 2. Placental pathology. Panel showing examples of the categories of placental pathology scored in this manuscript. A: FVM. Image of an old thrombus in
an umbilical artery (hematoxylin and eosin stain; original magnification, 340). B: MVM. Image of a hypertensive type placental infarct (hematoxylin and eosin
stain; original magnification, 320). C: Inflammatory pathology. Image shows two chorionic villi with villitis of unknown etiology. Note increased mononuclear cells
in the villous stroma and paucity of villous vessels (hematoxylin and eosin stain; original magnification, 3400). D: Anatomical pathology. Photograph of a placenta
with a membranous insertion of the umbilical cord.

chorioamnionitis. FVM was defined as the presence of
any fetal thromboembolic phenomenon including avascu-
lar villi, villous stromal karyorrhexis, or fetal vascular
thrombi. Anatomical abnormalities included marginal or
membranous cord insertion, membranous vessels (with a
normal cord insertion), villous maturational arrest,
hypercoiled or flat umbilical cords, or long umbilical
cords. The other category included diagnoses, such as
subchorionic fibrin, accreta and intervillous thrombus
(Salafia et al., 1992; Benirschke, 1994; Heifetz, 1996;
Roberts and Post, 2008; Tantbirojn et al., 2009; Chan
and Baergen, 2012).
Examination of the placenta was an option for the
obstetrician who had delivered the infant, and, as a result,
the placentas of all infants with hypospadias were not
examined.
Infants with malformations were subdivided into those
whose mothers had always planned to deliver at this hos-
pital (maternal nontransfers) and those who had planned
to deliver at another hospital, but transferred their care
4 HYPOSPADIAS, IUGR, AND PLACENTA ABNORMALITIES

anatomical abnormalities (n 5 11) identified were meco-

TABLE 1. Correlation of Birth Weight percentile with presence of hypospadias nium pigment in macrophages in the membranes, subchor-
ionic fibrin, accreta, and intervillous thrombus and one
Expected frequency
membranous vessel and one hypercoiled umbilical cord.
Expected Frequency if no association
Centile grouping proportion in sample with centile grouping
Discussion
<10th centile .1 42 26 This analysis of the findings in 316 newborn infants with
10th90th centile .8 184 209 isolated hypospadias confirmed that there was a signifi-
>90th centile .1 35 26 cant increase in the frequency of hypospadias in infants
who were SGA. In addition, the frequency of infants being
Goodness of fit test comparing observed to expected, X2 5 15.7,
p 5 0.0004 SGA correlated with the severity of the hypospadias.
One strength of this study was that it evaluated a con-
secutive sample of affected male newborns over a long
after the prenatal detection of a malformation in the fetus period of time. However, a weakness of this study is the
(maternal transfers). This study focused on the infants of fact that the findings in the examination of the placenta
nontransfer mothers. were available in only 12.3% (39/316) of the infants with
hypospadias. This occurred because the obstetricians had
Results the option of requesting an examination of the placenta
Three hundred sixteen affected male infants with isolated after each delivery. In addition, because these findings
hypospadias were identified during the study period: 165 were from a Malformations Surveillance Program, there
(52.2%) had glanular hypospadias; 37 (11.7%, subcoro- was no study-based physical examination of either the
nal); 88 (27.8%), penile and 26 (8.2%), penoscrotal hypo- infants or their placentas. Likewise, the affected infants
spadias. There was a significant (p 5 0.0004) increase in did not have additional diagnostic studies to identify asso-
frequency of hypospadias in the infants who were SGA ciated molecular abnormalities.
(Table 1). In addition, the presence of IUGR or SGA birth The hypothesis for the cause of the hypospadias in
weight correlated with the severity of the degree of hypo- association with growth restriction is based on limited
spadias (r 5 .90; p 5 0.10) (Table 2). The highest percent- information. The rise in the fetal level of testosterone
age of IUGR (34.6%) occurred in the nine infants with the between weeks 11 and 14 of gestation is associated with
most severe degree of hypospadias, penoscrotal or peri- the normal maturation and closure of the urethra in the
neoscrotal hypospadias. male fetus. Fetal testosterone secretion is under the influ-
The racial distribution was: 211 (66.8%) infants were ence of placental human chorionic gonadotropin (hCG)
White; 38 (12%) infants were Black; 10 (3.2%) were of during the first 14 weeks of gestation (Brouwers et al.,
mixed race; 25 (7.9%) were Hispanic; 12 (3.8%) were 2007). Studies of 54 normal male fetuses showed that
Asian; 1 (0.37%) was American Indian; and 19 (6.0%) were fetal testosterone levels declined between 11 and 19
of unknown race. None of the infants with isolated hypospa- weeks of gestation in parallel with the decline in hCG
dias identified was either stillborn or in a pregnancy that (Fowler et al., 2009). Theoretically, the dysfunction of the
had been terminated because of fetal anomalies. placenta reduces the level of hCG, which in turn causes
The placenta reports showed a high frequency of MVM, the deficient masculinization of the urethra of the male
INF, FVM, and anatomical abnormalities (Table 3). The fetus.

TABLE 2. Relationship between Hypospadias and IUGR

Weight between 10th

SGAa and 90th centile Large for Data not
Type of hypospadias Total IUGR Normal gestational ageb available

Glanular 165 (52.2%) 15 (9.1%) 83 (50.3%) 25 (15.2%) 42 (25.5%)

Subcoronal 37 (11.7%) 3 (8.1%) 26 (70.3%) 5 (13.5%) 3 (8.1%)

Penile 88 (27.8%) 15 (17%) 62 (70.4%) 5 (5.7%) 6 (6.8%)

Penoscrotal 26 (8.2%) 9 (34.6%) 13 (50%) 0 (0%) 4 (15.4%)

Total 316 42 (13.3%) 184 (58.2%) 35 (11.1%) 55 (17.4%)
a th
Birth weight less than 10 centile in birth weight, definition of IUGR.
b
Birth weight greater than 90th centile of normal
BIRTH DEFECTS RESEARCH 00:0000 (2017) 5

Other examples are the twintwin transfusion syndrome

TABLE 3. Abnormalities Identified in the Placentas (Hoyme et al., 1982) and the association of fetal renal tubu-
lar dysgenesis and associated abnormalities of the placenta
Type of hypospadias
(Taweevisit and Thorner, 2010; Linn et al., 2013). The find-
Abnormalities Glanular Subcoronal Penile Penoscrotal Total ings reported in the placenta of the latter condition have
f
been described with the term maternal floor infarction in
MVM 0 2 6 3 11 (29.7%)
association with massive perivillous fibrin deposition. This
INF 1 1 3 1 6 (16.2%)
condition, which results in intrauterine fetal demise, has
FVM 0 0 0 1 1 (2.7%) been reported in three consecutive pregnancies of one
Anatomical 1a 1c 5c 4c 11 (29.7%) woman with the same partner (Linn et al., 2013).
changes In addition, mesenchymal dysplasia of the placenta is
present in approximately 20% of infants with Beckwith-
Other 1b 2d 2b,e 3b 8 (21.6)
Wiedemann syndrome (BWS) (Hmida et al., 2008). Abnor-
Total 3 6 16 12 37
malities of the placenta have also been observed to be risk
a
Hypercoiled umbilical cord. factors for several adverse perinatal outcomes. For exam-
b
Meconium pigment in macrophages in the membranes. ple, a small placenta (less than 10 cm diameter) and a low
c
Marginal or membranous cord. maternal pregnancy-associated plasma protein-A (PAPP-A)
d
Subchorionic fibrin (1); accreta (1). have been found to be a predicator of IUGR, preterm
e
Intervillous thrombus. delivery and stillbirth (Proctor et al., 2009). Velamentous
and marginal cord insertions have been associated with
This association of hypospadias, IUGR and placental adverse perinatal outcomes, such as placenta previa and
deficiency has been evaluated in one prospective case placental abruption (Ebbing et al., 2013).
series to identify the associated maternal and fetal find- In summary, we found that hypospadias was associated
ings. Yinon et al. (2010) and Proctor et al. (2009) des- with intrauterine growth restriction and placental patholo-
cribed the findings in 30 male infants with hypospadias gies. The findings showed that the more severe the hypo-
who had been identified prospectively during pregnancy spadias the stronger this association is. We hypothesize
as being growth restricted. They assessed the findings in that placental dysfunction between 10 and 14 weeks
prenatal screening by ultrasound, the histo-pathologic gestational age leads to decreased testosterone and thus
findings in the placenta, the anatomic findings in the increased incidence of hypospadias. More studies on pla-
infants, and the status of the infants at birth. The common cental causes of IUGR and its association with androgen
abnormalities identified included: low PAPP-A levels and metabolism and urogenital development are needed.
elevated AFP levels in maternal serum; signs of placental
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