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Naveed Hussain, MBBS*; Azhar Chaghtai, MD*; C. D. Anthony Herndon, MD‡; Victor C. Herson, MD*;
Ted S. Rosenkrantz, MD*; and Patrick H. McKenna, MD‡
ABSTRACT. Objective. There has been a major in- involved. Pediatrics 2002;109:473– 478; hypospadias, SGA,
crease in the incidence of hypospadias in infants in the intrauterine growth, temporal trend, risk factors.
1990s, but the risk factors are not known. Although there
are scattered reports in the literature regarding the asso-
ciation of low birth weight and hypospadias, this has not ABBREVIATIONS. SGA, small for gestational age; AGA, appro-
priate for gestational age; LGA, large for gestational age; NICU,
been systematically studied. The objective of this study
neonatal intensive care unit; UCHC, University of Connecticut
was to determine the association between early gestation Health Center; GA, gestational age; BW, birth weight; SEM, stan-
intrauterine growth and hypospadias. dard error of the mean; EDC, endocrine disrupter chemicals.
Methods. A retrospective review of 13 years of admis-
sions to 2 tertiary care neonatal intensive care units (NI-
T
CUs) in Connecticut (1987–2000) showed that 112 (1.66%) he development of a normal urethra in males is
of 6746 male infants had any degree of hypospadias. Of a complex process, and factors that lead to its
these, 8 were part of a genetic syndrome and were ex- abnormal development, resulting in hypospa-
cluded. A retrospective cohort analysis of these 6738 in- dias, are largely unknown.1 Hypospadias is one of
fants was performed. Infant growth parameters at birth the most common congenital anomalies in males.2
(weight, head circumference, and length) were analyzed
along with maternal risk factors known to be associated
Reports from Europe and the United States have
with changes in fetal growth, including maternal age, shown an increasing incidence of hypospadias from
race, diagnosis of preeclampsia, gestational diabetes, and 1970 to the present.3,4
maternal use of alcohol or tobacco or substance abuse The risk factors for hypospadias are not well un-
during pregnancy. derstood. An association between low birth weight
Results. The incidence of hypospadias in the NICU and hypospadias has been made,4 – 6 but a systematic
population increased 10-fold from 0.4% in 1987 to 4% in analysis of the association between hypospadias and
the first quarter of 2000. Hypospadias was significantly growth restriction has not been conducted. It is also
more common in infants who had uniformly poor intra- not clear whether the low birth weight is attributable
uterine growth (<10th percentiles) in the various param- to a lower gestational age or intrauterine growth
eters measured: birth weight, length, or head circumfer-
ence. There were no significant differences in maternal
restriction.5,6 With currently available norms for in-
age or race, nor were there differences in the use of trauterine growth to classify even the most immature
alcohol, tobacco, or street drugs by the mother. There infants into small, appropriate, or large for gesta-
were no differences between singletons and multiple- tional age (SGA, AGA, and LGA, respectively), it is
gestation births. However, the frequency of occurrence possible to delineate whether the intrauterine growth
was significantly higher among first-born infants (1.9%) was affected in early or late gestation on the basis of
compared with all other infants (0.9%). birth weight and corresponding changes in head cir-
Conclusions. The incidence of hypospadias in our cumference and length.7,8 An infant who is propor-
NICU population has increased 10-fold during the 13- tionately affected in all of its growth parameters is
year period of study. There was a significant association more likely to have incurred an insult early in ges-
of hypospadias with poor intrauterine growth. The
growth restriction was probably of early gestational
tation, whereas the infant who is disproportionately
cause as there was proportionate involvement of somatic affected, with sparing of changes in its length and
(weight and length) and brain growth (head circumfer- head circumference, is more likely to have incurred
ence). The increasing frequency of hypospadias and its an insult later in pregnancy.7,8
association with poor intrauterine growth originating in We hypothesized that hypospadias is associated
early gestation suggests that common environmental fac- with restriction in fetal growth early in pregnancy.
tor(s) that have an impact on both conditions may be The aim of this study was to describe the association
between hypospadias and intrauterine growth and
to characterize some of the risk factors that may be
From the Division of Neonatology, *Department of Pediatrics, University involved.
of Connecticut Health Center, Farmington, Connecticut; and ‡Division of
Urology, Department of Surgery, Connecticut Children’s Medical Center,
Hartford, Connecticut. METHODS
This study was presented, in part, as a platform presentation at the Society We undertook a retrospective cohort study of a total of 6746
for Pediatric Research Meeting; May 12–16, 2000; Boston, MA. male admissions to the neonatal intensive care units (NICUs) at
Received for publication Sep 29, 2000; accepted Aug 23, 2001. University of Connecticut Health Center (UCHC; 3157) and the
Reprint requests to (N.H.) University of Connecticut School of Medicine, Connecticut Children’s Medical Center (3589) between January
Farmington, CT 06030-2948. E-mail: hussain@nso1.uchc.edu 1987 and April 2000. These NICUs take care of infants from the
PEDIATRICS (ISSN 0031 4005). Copyright © 2002 by the American Acad- central and northern regions of the state of Connecticut. It is
emy of Pediatrics. important to note that the reason for NICU admission was not
ARTICLES 475
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was seen in 23% of the infants. The BW percentile of this is not clear, but with the increase in incidence of
infants with anterior hypospadias was 24 ⫾ 4 centile hypospadias that has been noted, the increase in
(mean ⫾ SEM) and those with posterior hypospadias severity is not unexpected and strengthens the argu-
was 13 ⫾ 7 centile (mean ⫾ SEM); however, because ment that external factors may be involved.
of relatively small numbers, a relationship of severity The causes for poor intrauterine growth are many.
of hypospadias to severity of growth restriction A myriad of factors, from genetic to placental to
could not be made definitively. Of note were 4 in- maternal conditions and environmental changes,
fants with severe symmetric growth retardation have been studied. Some of these factors, such as
whose hypospadias was so severe that gender as- maternal preeclampsia,17 gestational diabetes, and
signment initially was not possible at birth. Only the use of alcohol or tobacco or substance abuse by
after investigations for ambiguous genitalia were the mother,4,18 were investigated in our study and
completed was it confirmed that these were male were not found to be important in relation to the
infants with severe hypospadias. Cryptorchidism occurrence of hypospadias in the infant. A higher
was present as a related diagnosis with hypospadias incidence of hypospadias was seen in first-born in-
in 27% of infants. fants in our study. Although this has been noted in a
previous report,19 no explanation has been forthcom-
DISCUSSION ing. It is known that first-born infants are more likely
We found a trend of increasing incidence of hypo- to have growth restriction,20 and the relationship to
spadias between January 1987 and April 2000 in a hypospadias may be linked to this observation. Ad-
selected population of infants who were admitted to vanced maternal age was found to be a risk factor by
tertiary-level NICUs in Connecticut. This 10-fold in- Fisch et al.21 In our study, there was a similar trend,
crease was not explained by changes in referral pat- but no significant relationship could be demon-
terns or criteria for diagnosis in these centers and strated.
probably reflects a true overall increase in incidence. There is controversy regarding the pathogenesis of
These data agree with the trends suggested by Pau- hypospadias.1,22,23 Heinonen et al24 and Kallen and
lozzi et al3 and, more recently, by Riley et al,12 but colleagues4,13 explored various maternal risk factors,
the magnitude of change is much greater. It is ex- but no definite conclusions were drawn. Many are of
tremely difficult to obtain retrospective population- the opinion that it is unlikely that genetic factors play
based data on the true state or nationwide incidence a role.25–28 Recent evidence from animal29,30 and hu-
of hypospadias because congenital defect registries man studies31,32 has suggested a relationship of male
do not usually track this malformation. We believe genital abnormalities with environmental factors.
that the current report reinforces the need for pro- Hypospadias is more commonly seen in infants of
spective tracking of the incidence of hypospadias at infertile couples who conceived by in vitro fertiliza-
the state and national levels. tion33 or other assisted reproductive techniques.34
A significant association between hypospadias Fertility drugs have been suspected, but a recent
and intrauterine growth restriction is demonstrated meta-analysis failed to show an effect.35 Anti-andro-
in this report. This association with low BW has been gen compounds have been implicated36; especially
suggested6,13,14 but has not previously been well the environmental anti-androgens or “endocrine dis-
characterized. A recent report reaffirmed the associ- rupter chemicals” (EDCs) have been implicated in
ation and speculated on factors involved in critical causing male genital abnormalities, including hypo-
periods early in gestation.15 It is widely known that spadias in humans,37,38 and there seems to be in-
factors that inhibit intrauterine growth of the infant creasing evidence for this from animal studies.39 – 41
cause a proportionate decrease in somatic (weight Conversely, in case reports of overdosage with me-
and length) and brain (head circumference) growth if droxyprogesterone in early pregnancy, there seemed
these factors are active early in gestation.7,8 If growth to be no adverse effects on the fetus.42 However, it is
inhibition is caused by nutritional and other factors important to bear in mind that the exposure of the
in the second and third trimesters of gestation, then EDCs, albeit in low concentrations, is continual and
there is relative sparing of brain growth (head cir- starts from conception through the most critical pe-
cumference) with a predominant effect on weight riods of early embryogenesis. Moreover, the pres-
initially and changes in length occurring after a more ence of a combination of these agents may have more
prolonged insult.7,8 In our analyses of intrauterine than an additive effect.
growth parameters, we found that there was a con- Because a cause-effect relationship has not been
sistent involvement of growth parameters, ie, demonstrated between known factors for poor
weight, length, and head circumference, in infants growth and hypospadias, we speculate involvement
with hypospadias, and this finding is highly sugges- of other unknown factors. A common theme that
tive of an effect in early gestation on growth—per- may perhaps interrelate the incidence of growth re-
haps early enough to affect adversely urethral devel- striction and hypospadias is the report that some
opment. environmental factors, especially “endocrine dis-
There was a higher incidence (35%) of the more rupters,” have been shown to be associated with
severe forms of hypospadias, ie, mid- and posterior, both growth restriction and hypospadias. Heindel
in our study. This represents a notable increase in the et al39 showed that contaminated groundwater can
severity of hypospadias compared with a previous cause both growth restriction and reproductive
study, which reported that only approximately 13% abnormalities in mice. Gray et al40,41 demonstrated
of the cases were of the severe type.16 The reason for similar effects with some well-known EDCs with
ARTICLES 477
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38. Kristensen P, Irgens LM, Andersen A, Bye AS, Sundheim L. Birth sexual differentiation of rodents. Toxicol Ind Health. 1996;12:515–531
defects among offspring of Norwegian farmers, 1967–1991. Epidemiol- 42. Yovich JL, Turner SR, Draper R. Medroxyprogesterone acetate therapy
ogy. 1997;8:537–544 in early pregnancy has no apparent fetal effects. Teratology. 1988;38:
39. Heindel JJ, Chapin RE, George J, et al. Assessment of the reproductive 135–144
toxicity of a complex mixture of 25 groundwater contaminants in mice 43. Key TJ, Bull D, Ansell P, et al. A case-control study of cryptorchidism
and rats. Fundam Appl Toxicol. 1995;25:9 –19 and maternal hormone concentrations in early pregnancy. Br J Cancer.
40. Gray LE, Wolf C, Lambright C, et al. Administration of potentially 1996;73:698 –701
antiandrogenic pesticides (procymidone, linuron, iprodione, chlozoli- 44. Greig RA, Sennefelder G. PCB concentrations in winter flounder from
nate, p,p⬘-DDE, and ketoconazole) and toxic substances (dibutyl- and Long Island Sound, 1984 –1986. Bull Environ Contam Toxicol. 1987;39:
diethylhexyl phthalate, PCB 169, and ethane dimethane sulphonate) 863– 868
during sexual differentiation produces diverse profiles of reproductive 45. Greig RA, Sennefelder G. Metals and PCB concentrations in mussels
malformations in the male rat. Toxicol Ind Health. 1999;15:94 –118 from Long Island Sound. Bull Environ Contam Toxicol. 1985;35:331–334
41. Gray LE, Kelce WR. Latent effects of pesticides and toxic substances on 46. Dolk H. Rise in prevalence of hypospadias. Lancet. 1998;351:770
IMPACT OF RESEARCH
“The main aim of health research is to improve the health of people. Yet the
performance of researchers tends to be measured by the scientific quality of their
research rather than by its impact on health. This is unsatisfactory, even nonsen-
sical, so a committee on the Royal Netherlands Academy of Arts and Sciences is
trying to devise a way of measuring the social impact of applied health research.
Its first report was discussed at a recent meeting in Amsterdam,1 and the Academy
now plans to experiment with methods of measuring social impact.”
REFERENCE
1. Health Sciences Subcommittee of the Medical Committee of the Royal Netherlands Academy of Arts and Sciences.
The Societal Impact of Applied Health Research: Towards a Quality Assessment System. Amsterdam, the Netherlands:
KNAW; 2001. www.knaw.nl/cg
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