Recent Research in Science and Technology 2010, 2(8): 30-34

ISSN: 2076-5061
www.recent-science.com
Medical Sciences

MATERNAL RISK FACTORS ASSOCIATED WITH HYPOSPADIAS

Nerli R B1,2, Bindu S1, Guntaka A K1, Patil S M1, Neelgund S E2, Hiremath M B1
1Department

of Urology, KLE Universitys J N Medical College & KLES DR. Prabhakar Kore Hospital & MRC, Belgaum, India
590010
2PG Department of Studies in Biochemistry, Kuvempu University, Shankaraghatta, Shimoga

Abstract
Introduction: Epidemiological studies have elucidated maternal and fetal factors that are associated with an increased risk of
hypospadias .This study examined the association of hypospadias risk with several maternal reproductive and demographic
characteristics: age, parity, body mass index (BMI), nausea and vomiting of pregnancy, fertility treatments , education and
diet .
Materials and Methods: Mothers of children with hypospadias were invited to participate in this case control study.
Participating mothers completed a self administered questionnaire or a social worker administered/assisted questionnaire.
Mothers of age matched children without hypospadias acted as controls and they too similarly completed the same
questionnaire.
Results: The risk factors associated with hypospadias were maternal age, primiparity , previous fertility treatment and nausea
and vomiting of pregnancy .
Conclusions: Increased maternal age, primiparity and previous fertility treatments in mothers are associated with an increased
risk of hypospadias in male offsprings.
Keywords: Hypospadias, Maternal age, Parity, Fertility, Maternal education, Nausea and vomiting

Introduction

A detailed report by Sorensen1 and more recent

reviews by Sweet and colleagues2 and Baskin3 suggest
a multifactorial etiology of hypospadias, fitting a
polygenic model. Responsible etiologic factors may
include one or more of an environmental or other
endocrine disruptor; an endocrinopathy, enzymatic or
local tissue abnormality; and/or a manifestation of
arrested development. The characteristic defects of
hypospadias may result from one or more of the
following: (1) abnormal androgen production by the
foetal testis, (2) limited androgen sensitivity in the
target tissues of the developing external genitalia, or
(3) premature cessation of androgenic stimulation
secondary to premature involution of Leydig cells of the
foetal testis4. Other possible causes include insufficient
testosterone and/or dihydrotestosterone synthesis
(presumably defective or deficient 5-reductase
enzyme activity) and/or defective androgen receptor
quality and/or quantity. Several entities in the spectrum
of androgen resistance (androgen insensitivity
syndromes) have been elucidated at the clinical and
molecular level5,6.
Epidemiological studies have elucidated maternal
and fetal factors that are associated with an increased
risk of hypospadias. Maternal factors are advanced
maternal age, primiparity, obesity, and fertility
treatments7-9. There is less information on maternal

Corresponding Author, Email: rajendranerli@yahoo.in

and fetal factors associated with the severity of

hypospadias, rather than their effect on the overall
incidence of the condition.
This study uses data from case-control study to
examine the association of hypospadias risk with
several maternal reproductive and demographic
characteristics: age, parity, body mass index (BMI),
nausea and vomiting of pregnancy, multiple pregnancy,
fertility treatments and procedures and education.
These factors were selected because they may be
associated with maternal endocrine function and/or
with other endocrine-related outcomes.

Materials and Methods

The data for this study was collected as a part of

a case control study of hypospadias. A detailed
questionnaire was used to collect exposure information
from the mothers of cases and controls. The study
complied with all applicable regulations and was
approved by the institutional ethical committee and the
subjects gave informed consent before the study.
Recruitment of hypospadias cases and controls
Children with hypospadias without concomitant
malformations or chromosomal abnormalities admitted
to the Paediatric Urology wards for repair, formed the
study group. Mothers of these children were invited to
participate in this case control study. Participating

Nerli R B et al./Rec Res Sci Tech 2 (2010) 30-34

mothers completed either a self administered

questionnaire or a social worker administered/assisted
questionnaire. A study coordinator was available at that
time to answer any questions the mothers had about
the questionnaire, but was otherwise uninvolved in its
administration. For each hypospadias case, two
children of similar age without hypospadias or known
malformations were randomly selected from the
paediatric ward. The mothers of these children also
completed the same questionnaire.
Similarly mothers admitted for delivery in the
maternity wards and gave birth to male neonates with
hypospadias without concomitant malformations,
identified by the Paediatric Urologist formed the second
group of the study. The mothers were examined so as
to calculate the BMI. The mothers were similarly
administered the questionnaire. For each neonate with
hypospadias, two other neonates of similar age and
birth weight without hypospadias or known
malformations were randomly selected from the
maternity/neonatal ward. The mothers of these
neonates also completed the same questionnaire.

questionnaire provided two or more choices of

response. We assessed contraceptive use at
conception by listing seven types of contraception:
combined oral contraceptives, minipills, injections,
implants, intrauterine device (IUD), and other methods
such as condom and natural methods. We ascertained
history of complications such as high blood pressure
with yes/no questions. In the question, regarding
nausea during pregnancy, we asked those who stated
that they had been nauseous to specify the trimester of
nausea, and permitted them to specify more than one
trimester. We assessed meat and fish consumption by
asking whether meat/fish had been consumed at least
once a week.
Statistical analyses
We performed analyses using descriptive
statistics and Students t-test to compare risk factors.

Results

During the study period Aug 2008 to Dec 2009, 7

children were born with hypospadias in our hospital, an
incidence of 0.33% of all male live births. The maternal
reproductive and demographic risk factors are as
shown in Table 1. The risk factors associated with
hypospadias were maternal age, primiparity, previous
fertility treatment and nausea and vomiting of
pregnancy.

Collection of exposure data

Each mother completed a questionnaire that
included questions about her gynaecologic and
reproductive history, her health and diet before and
during the index pregnancy, and parental demographic,
physical and social characteristics and characteristics
of the case/control child . For most questions, the
Table 1
Maternal age (yrs)
BMI
Primiparity
Fertility Treatment
PIH (Pregnancy induced
hypertension)
NVP (Nausea , vomiting of
pregnancy)
Education
Consanguineous marriage

Hypospadias (n=7)
27.143.20 *
26.241.159
6 (85.7%) *
0.570.53 *
0.0

Controls (n=14)
23.43.15
25.870.07
4 (28.5%)
0.0
0.0

0.710.48 *

0.0

0.0

0.0

During the same period 23 children with

hypospadias underwent repair. The maternal

reproductive and demographic risk factors during the

index pregnancy were as shown in Table 2.
Table 2

Maternal age during Index

Pregnancy
Primiparity during Index pregnancy
Fertility Treatment
PIH
NVP
Education
Consanguineous marriage

Hypospadias (n=23)
29.753.6*

Controls (n=46) P
24.212.46

12 (52.17%) *

11 (23.91)

0.430.50 *
0.0
0.650.48*
0.0

0.170.38
0.0
0.300.46
0.0

Nerli R B et al./Rec Res Sci Tech 2 (2010) 30-34

The risk factors in this group were the same i.e.

maternal age at the time of index pregnancy,
primiparity during index pregnancy, fertility treatment
during index pregnancy and NVP of pregnancy.
Maternal education was not a relevant risk factor as the
mothers in both the group were educated atleast upto
high school level and were well versed in reading and
writing. None the mothers in both the groups had
consanguineous marriage and none experienced or
reported pregnancy induced hypertension .There was
no relevant data in relation to use of contraceptive pills
in any group of mothers. Similarly there was no
difference in meat/fish consumption in the mothers of
both the groups. The number of mothers consuming
only vegetarian diet and non vegetarian diet were
similar in both the groups.

Discussion

Hypospadias occurs as a result of abnormal

urethral closure from 8 to 14 weeks after conception
and is one of the most common birth defects with a
prevalence of 3 5 per 1000 births10. Conversion of
testosterone to dihydrotestosterone and proper
androgen receptor signalling are critical to normal
urethral closure. One factor that is known to interfere
with this process is oestrogen 11. Thus it has been
hypothesized that increased maternal oestrogen levels
may be associated with increased hypospadias risk
12,13.
Maternal primiparity, age 35 years or older and
BMI > 26 are factors known to be associated with
increased risk of hypospadias among offspring,
especially when present in combination. Two
studies14,15 have examined the combination of maternal
age and parity , and both these studies have shown
twofold to threefold higher risks of hypospadias among
older primiparous women , as compared to younger,
multiparous women. Carmichael et al 8 have suggested
that BMI may further modify the increased risk. Carlson
et al16 have reported that advanced maternal age was
associated with increased severity of hypospadias in
their population. Several explanations have been
postulated for the finding of increased incidence and
severity of hypospadias with increasing maternal age.
Older mothers would potentially have longer exposure
to endocrine disruptors than younger mothers and thus
a greater risk of hypospadias17. A population based
study has noted an increase in organochlorine
pesticide concentration in adipose tissue that
correlated to increasing age. The main exposure
source for these environmental toxins was suggested
to be dietary, particularly fish and other animal
products18. Organochlorine pesticides have well
documented estrogenic effects19. A case control study
has demonstrated an increase in cytogenetic damage

that correlates with increasing age in women with

occupational exposure to pesticides 20. Our study too
revealed that the age of the mothers of children with
hypospadias was significantly more than mothers of
children without hypospadias.
The specific association of maternal age, parity
and BMI either individually or in combination, with
maternal hormone levels seems to be somewhat
unclear. One study which has utilised samples from the
collaborative perinatal study , found that free oestradiol
levels during early pregnancy were higher in womens
first pregnancies than during their second pregnancies
21 .Results stratified by pre-pregnancy weight indicated
that levels were particularly high among women who
were experiencing their first pregnancy and had prepregnancy weight >125 lbs.
Maternal sub-fertility has been proposed to
contribute to higher risks of hypospadias observed
among older and primiparous women22. Multiple births
and fertility treatments, specifically intracytoplasmic
sperm injection, are associated with increased risk of
hypospadias 23 .Several studies 8,24 have shown
association of multiple birth with increased risk in
univariable analyses , but with reduced risk in subjects
with birth weight 2500 g. This finding supports the
hypothesis that the association of hypospadias with
multiple birth stems from its association with growth
retardation 25. Multiple gestation is associated with
elevated oestradiol during early pregnancy, but also
with elevated levels of other hormones such as
testosterone, progesterone and HCG 26.
Nausea in early pregnancy is believed to be
caused by the early surge of pregnancy hormones,
particularly HCG; the onset and peak of nausea and
vomiting in early pregnancy parallel the HCG curve27.
First trimester nausea is considered to be a sign of a
healthy pregnancy, because it is associated with lower
risks of miscarriage and premature birth28,29. In contrast,
the absence of nausea may reflect potential problems
with the pregnancy and is associated with low HCG
levels27,29. Akre et al 30 showed absence of nausea
during early pregnancy was associated with increased
risk of hypospadias, which lends support to the
hypothesis that abnormally low HCG levels resulting
from placental insufficiency in early pregnancy may be
involved in the etiology of hypospadias8. Carmichael et
al 8 reported a similar negative association between
early nausea and hypospadias.
Several studies have found associations between
hypospadias risk and preterm birth and low birth
weight25,31. Disturbance of placental function early in
pregnancy is a key mechanism underlying both
preterm birth/low birth weight and the improper closure
of the urethra, because the placenta is the main
product of pregnancy hormones in early pregnancy and
is thus instrumental in the differentiation and

Nerli R B et al./Rec Res Sci Tech 2 (2010) 30-34

development of the fetal organs 31-33. Hypospadias risk

is associated with gestational hypertension , which in
turn is associated with preeclampsia and placental
dysfunction32 .This provides further support for the
notion that placental dysfunction is involved in the
etiology of hypospadias .
Our study does have its limitations in that the
collected data is based on self report in the
questionnaire. Our data on previous fertility treatments,
NVP and PIH lacked several details to make a
meaningful conclusion. Most Indian women are
vegetarians and even among the mothers having
nonvegetarian diet, the amount of meat/fish
consumption is variable and does not give adequate
statistical information. We also lacked several factors
that might play a role in the etiology of hypospadias
such as genetic susceptibility; paternal semen quality
and exposure to environmental toxins .We have also
not made a comparison of severity of hypospadias and
risk factors.

9.
10.

11.

12.

13.

14.

Conclusions

The results of our study show that increased

maternal age, primiparity, NVP and previous fertility
treatment were associated with increased risk of
hypospadias on univariate analysis.

15.

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