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Hypospadias in males with intrauterine growth restriction due to placental insufficiency: the placental role in the embryogenesis of male external genitaliaHypospadias in Males With Intrauterine GrowthRestriction Due To Placental Insufficiency:The Placental Role in the Embryogenesis ofMale External GenitaliaYoav Yinon,1 John C.P. Kingdom,1 Leslie K. Proctor,1 Edmond N. Kelly,2 Joao L. Pippi Salle,3Diane Wherrett,4 Sarah Keating,5 Ori Nevo,6 and David Chitayat7*1Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, The Placenta Clinic, Mount Sinai Hospital, University of Toronto,Toronto, Ontario, Canada2Department of Pediatrics, Neonatal Intensive Care Unit, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada3Department of Pediatric Urology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada4Division of Endocrinology, Department of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada5Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada6Department of Obstetrics and Gynecology, Sunnybrook Health Centre, University of Toronto, Toronto, Ontario, Canada7The Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada Received 20 August 2009; Accepted 11 September 2009 Our aim was to define the association between early onset intra- uterine growth restriction (IUGR) due to placental insufficiency Yinon Y, Kingdom JCP, Proctor LK, Kelly EN, and hypospadias in males. We prospectively studied a cohort of Pippi Salle JL, Wherrett D, Keating S, Nevo O, small-for-gestational age (SGA) male infants with hypospadias Chitayat D. 2010. Hypospadias in males with managed by a multidisciplinary team over a 5-year period. Thirty SGA male infants were diagnosed with hypospadias/abnormal placental insufficiency: The placental role in genitalia after birth, and four of them were diagnosed antena- the embryogenesis of male external genitalia.
tally. Five cases occurred in the smaller pair of discordant IUGR twins, where the larger co-twin had normal male genitalia. Serialultrasounds demonstrated features of early-onset IUGR in allcases at a median gestational age of 21 weeks (range 14–31weeks).
Twenty-one (70%) pregnancies were subsequently complicated Key words: placental insufficiency; intra-uterine growth restric- by absent/reversed end-diastolic flow in the umbilical arteries indicating severe IUGR, and 17 (57%) women developed severepre-eclampsia. There were 27 (90%) live births at a mediangestational age of 31 weeks (range 27–37); 23 (77%) of the neonates had birth weights <3rd centile. All newborns hadnormal male karyotypes. In 62% (18/29) the hypospadias was Hypospadias is a common malformation in males with an incidence severe. A correlation was found between the severity of the of 0.3–0.4% [Gallentine et al., 2001; Brouwers et al., 2007]. It results IUGR and the severity of hypospadias as significantly more from an incomplete fusion of the urethral folds between the 7th and infants with severe hypospadias were less than the 3rd centilecompared to the mild–moderate hypospadias group: 94% (17/18) versus 55% (6/11), respectively (P ¼ 0.02). In conclusion, *Correspondence to:David Chitayat, Department of Obstetrics and Genecology, The Prenatal SGA male newborns with hypospadias exhibit a high rate of early Diagnosis and Medical Genetics Program, The Ontario Power Generation -onset severe IUGR due to placental insufficiency. Early placental Building, 700 University Avenue, Room 3292, Toronto, Ontario, Canada development likely influences male external genitalia formation.
Careful sonographic evaluation of the genitalia is advised when Published online 11 December 2009 in Wiley InterScience early-onset placentally mediated IUGR is found.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A 14th week of gestation. Most cases are isolated and are presumed to [Viero et al., 2004; Toal et al., 2008]. After delivery, all placentas be multifactorial traits [Calzolari et al., 1986; Baskin et al., 2001; were examined pathologically, including assignment of chorionic- Manson and Carr, 2003]. Previous epidemiologic studies found a close relationship between low birth weight and hypospadias Antenatal data were collected prospectively and included ma- [Calzolari et al., 1986; Akre et al., 1999; Weidner et al., 1999], yet ternal demographic information (age, race, parity, exposure to the underlying mechanism of this association is unclear. Hussain alcohol, tobacco, substance abuse and other teratogens, and pre- et al.  demonstrated that hypospadias was significantly more existing chronic diseases), mode of conception, first and second common in infants who were small-for-gestational age (SGA), trimester screening as well as fetal karyotype determined by am- suggesting that intra-uterine growth restriction (IUGR) rather than niocentesis, serial ultrasound findings, and obstetrical complica- the absolute birth weight is a more important risk factor for tions. Hypertensive disorders were defined according to the hypospadias. Some evidence suggests that placental insufficiency American College of Obstetricians and Gynecologist criteria may be the underlying factor, for example, hypospadias correlates [ACOG, 2002]. Delivery information was reviewed and included with low weight of the placenta [Stoll et al., 1990], and has been birth weight, gestational age at delivery, Apgar scores, head cir- observed in the smaller twin in a mono-chorionic twin pregnancy cumference and length at birth, genital findings, neonatal compli- complicated by discordant growth [Fredell et al., 1998]. These data cations, and placental histopathology.
suggest that the association of low birth weight with hypospadias A diagnosis of hypospadias was based on an initial physical may be related to placental dysfunction. Since the most severe forms examination; confirmation of diagnosis and severity grading were of IUGR have their origins in the first trimester [Smith et al., 1998], done by a pediatric urologist. The severity of hypospadias was based we tested the hypothesis that severe hypospadias is associated with on the anatomical position of the urethral meatus: glandular, early-onset severe placental insufficiency.
coronal, and penile were defined as mild–moderate and penoscro-tal, scrotal and perineal were defined as severe [Boisen et al., 2005].
The evaluation of these infants included abdominal ultrasonogra-phy to define the internal genitalia, chromosome analysis, and Institutional research ethics board approval was obtained to audit extensive endocrinology work-up in cases of ambiguous genitalia, clinical outcomes and relate these to screening tests of placental which included blood testosterone level, 17-OH progesterone, FSH, LH, thyroid function tests, dehydrotestosterone, cortisol, andro- Between 2004 and 2008, 1,659 preterm male infants were born at stenedione, DHEAS, and sex hormone binding globulin levels.
Mount Sinai Hospital, 156 of them were SGA and consisted of our Some of the cases had DNA analysis of the androgen receptor and study cohort. Out of this cohort, all male infants who were diag- 7-dehydrocholesterol. All the patients had serial follow-up in the nosed with hypospadias/abnormal genitalia after birth were iden- neonatal neurodevelopmental and pediatric urology clinics.
tified. They all underwent a multidisciplinary assessment and care Descriptive statistics are presented as mean Æ 1 SD or median by a team consisting of geneticists, endocrinologists, neonatolo- (range). Fisher’s exact test was used for statistical comparison of gists, and pediatric urologists. All cases of IUGR and hypospadias categorical variables. A P-value <0.05 was considered significant.
were followed antenatally in our multidisciplinary placenta clinic,six of them were referred prior to delivery. In this clinic, we screen and follow pregnancies that are considered to be high risk because ofmedical or obstetric complications for placental dysfunction. This Thirty SGA male infants were diagnosed with hypospadias/abnor- includes first trimester screening at 10–13 weeks of gestation, mal genitalia after birth during the 5-year period. Maternal demo- maternal serum screening at 16–18 weeks, and placental ultrasound graphic data and pregnancy characteristics of these cases are shown examination with uterine artery Doppler evaluation at 19–23 in Table I. Twenty-three (77%) of these pregnancies were conceived weeks. Pregnancy-associated plasma protein-A (PAPP-A) levels spontaneously, the remainder were conceived following ovulation <0.3 multiples of the median (MoM) and alpha-fetoprotein (AFP) induction via clomiphene citrate (1), gonadotropins (3), or in vitro >2.0 MoM were considered abnormal as previously reported fertilization (3). Five were the smaller IUGR co-twin in discordant [Alkazaleh et al., 2006]. Once a diagnosis of IUGR due to placental twins (three were monochorionic-diamniotic, two dichorionic- insufficiency was made, ultrasound examinations were performed every 2 weeks from 24 weeks of gestation, and increased up to 3 per Antenatal evidence of placental dysfunction was common; low week depending on the gestational age, severity of IUGR PAPP-A levels <0.3 MoM were found in 45% and elevated AFP (determined by fetal Doppler studies, biophysical profile scores, >2.0 MoM in 71%. Both markers were abnormal in 36% of cases.
and amniotic fluid volume), and the presence/severity of pre- Abnormal uterine artery Doppler (mean pulsatility index >1.45 eclampsia. Sonographic findings indicating placental insufficiency and bilateral early diastolic notches) was found in 50% (11/22) of were recorded including absent or reversed end-diastolic flow pregnancies that had performed this test.
velocities (AREDV) in the umbilical arteries; elevated head/abdo- Serial ultrasound examinations established the diagnosis of early men circumference ratio above the 95th centile for gestational age onset of growth restriction by the defined criteria at a median indicating asymmetrical IUGR [Snijders and Nicolaides, 1994]; gestational age of 21 weeks. Sonographic findings indicating pla- reduced amniotic fluid volume (amniotic fluid index <5 cm); cental dysfunction consisted of absent/reversed end-diastolic flow abnormal placental shape (small/thick) and texture; bilateral ab- in the umbilical arteries in 21 (70%) fetuses, oligohydramnios in 15 normal uterine artery Doppler, both as we have previously defined (50%) pregnancies, asymmetrical pattern of growth restriction as TABLE I. Baseline and Pregnancy Characteristics TABLE II. Obstetrical and Neonatal Outcome aOnly cases, which resulted in live birth, were included.
bAt 18, 27, and 28 weeks of gestation.
villous maturation, perivillous fibrin deposition, decidual vascul- opathy, infarction, and fetal thrombotic vasculopathy.
Postnatal genitalia findings are summarized as individual cases In four cases the genital abnormality was diagnosed antenatally (Fig. 1). In two cases a diagnosis of a female fetus was made and only after a male karyotype was found by amniocentesis, the diagnosis of abnormal genitalia was established. Chromosome analysis was performed postnatally on peripheral blood lymphocytes and all showed a normal male karyotype (46, XY). In 11, the karyotype was determined prenatally in amniocytes and confirmed after birth.
Severe proximal hypospadias occurred in 62% (18/29) of the aThree monochorionic-diamniotic and two dichorionic-diamniotic twins.
newborns and mild–moderate hypospadias was seen in 38% (11/29). Of the 18 infants with severe hypospadias, 17 (94%) were belowthe 3rd centile compared to 6 (55%) infants with mild–moderatehypospadias (P ¼ 0.02). The incidence of AREDV in the umbilical evident by head/abdomen circumference ratio above the 95th artery was similar in both groups: 67% (12/18) in the severe centile in 15 fetuses (50%), and abnormal placental shape or texture hypospadias group versus 82% (9/11) in the mild hypospadias group (P ¼ 0.7). Associated genital abnormalities included micro- The obstetrical and neonatal outcomes are summarized in Table II. Of the 30 pregnancies, 27 (90%) were live born at amedian gestational age of 31 weeks (range 27–37 weeks). Pretermdelivery at <34 weeks of gestation occurred in 28 women (93%); all TABLE III. Histopathologic Findings of the Placenta were iatrogenic by induction of labor or by cesarean section for thefollowing reasons: severe pre-eclampsia (14), severe IUGR (accompanied by pre-eclampsia in two of them), and non- reassuring fetal condition by ultrasound and/or non-stress test (9), placental abruption (2), intra-uterine fetal death (IUFD) (2), and pre-eclampsia with IUFD (1).
Mean birth weight was 970 g (range 460–2,195); 23 (77%) of the neonates were below the 3rd centile for sex and gestational age according to birth weight data for Canadian infants [Kramer et al., 2001], and the rest were below the 10th centile.
The placental histopathologic findings are summarized in Table III. Twelve (45%) had a small placenta (weight <10th centile). Findings consistent with ischemic–thrombotic placental aPlacental pathology was not available for three cases.
pathology were found in 22 (81%) cases including accelerated AMERICAN JOURNAL OF MEDICAL GENETICS PART A AMERICAN JOURNAL OF MEDICAL GENETICS PART A (regarding the possibility of partial androgen insensitivity) wasperformed. At the completion of these investigations a male genderwas assigned in all cases, and none of them had evidence ofincomplete androgen insensitivity.
Three of the cases had non-genital anomalies: the first was a patient with hydrocephalus, minor facial anomalies, and clinodac-tyly of the 5th fingers, feeding difficulties and developmental delaywho died at the age of 9 months. The second was a neonate who wasborn at 28 weeks gestation, weighed 570 g and had facial anomalies,and died 5 min after birth. The third was a patient with Ebsteinanomaly and coarctation of the aorta who died in utero at 18 weeksof gestation. In all three extensive investigations were done but nospecific diagnosis could be made. The possibility that the hypo-sdpadias was secondary to a syndrome in these three cases could notbe excluded.
Our cohort included five sets of discordant twins, in which the IUGR twin had hypospadias and the healthy co-twin had normalmale genitalia (Table III, cases 15–19). Three of these twins weremonochorionic-diamniotic and all were complicated with severepre-eclampsia. Interestingly, the severity of the hypospadias ap-peared to be milder in the IUGR twins: four of the five IUGR twinshad mild hypospadias, whereas only 7 of the 25 IUGR singletonshad mild hypospadias.
This study describes the association between hypospadias and earlyonset IUGR in 30 fetuses over a 5-year-time period in a single center.
This cohort of patients is unique as all had antenatal follow-upshowing early onset of IUGR with sonographic findings indicatingsevere placental dysfunction in most of these pregnancies. More-over, our cohort represents the more extreme cases of IUGR as mostof the fetuses (77%) were below the 3rd centile. The nature andseverity of the underlying placental disease was substantiated bypostnatal histopathologic examination of the placentas by a peri-natal pathologist. Nearly half had chorion regression (small pla-centas with eccentric cords) [Proctor et al., 2009] and most hadsome evidence of ischemic–thrombotic injury to the gas-exchang-ing placental villi. Of these infants, 62% had severe hypospadias and11 had ambiguous genitalia. All these infants had normal malekaryotypes, and none had evidence of an underlying genetic causefor hypospadias.
The association between low birth weight and hypospadias has been described before [Calzolari et al., 1986; Akre et al., 1999;Weidner et al., 1999], and two previous studies have reported on theassociation between IUGR and hypospadias [Hussain et al., 2002;Fujimoto et al., 2008]. However, in these studies a diagnosis of FIG. 1. Ultrasound image at 28 weeks of gestation of an IUGR fetus IUGR was inferred due to a postnatal diagnosis of SGA infant at with AEDV demonstrating micropenis, hypospadias (a), and bifid birth. Our study progresses the findings of these earlier reports by scrotum (b); postnatal examination confirmed the antenataldiagnosis (c). [Color figure can be viewed in the online issue, which establishing a clear link both to severely impaired fetal growth and is available at www.interscience.wiley.com.] to an underlying diagnosis of severe placental dysfunction. Fetalgrowth restriction can result from a variety of intrinsic or extrinsic penis (8), bifid scrotum (9), penoscrotal transposition (6), severe insults, yet all our cases had sonographic findings indicating chordee (11), and cryptorchidism (14).
placental dysfunction as the cause of growth restriction.
In 11 infants the hypospadias was so severe that the gender could Hussain et al. showed a 3.83% incidence of hypospadias among not be determined. All were investigated by our Multidisciplinary SGA male infants compared to 1.27% among AGA infants [Hussain Urogenital Team, and DNA analysis of the androgen receptor gene et al., 2002]. Recently, Fujimoto et al. reported on a series of 104 AMERICAN JOURNAL OF MEDICAL GENETICS PART A extremely low birth weight (<1,500 g) male infants, and 16 (15.3%) female external genitalia. An alternative explanation is that one or of them having hypospadias [Fujimoto et al., 2008]. Our study more of the growing array of genes controlling early fate decisions in design is not able to determine the true incidence of hypospadias placentation [Rawn and Cross, 2008] either directly or indirectly among IUGR fetuses due to the inherent selection bias in our affects the formation of the male external genitalia.
tertiary clinical practice. However, since during the study period, A large proportion (62%) of the infants in our study had severe 156 IUGR male infants less than 37 weeks of gestation were hypospadias compared to only 6% in the Fredell et al. cohort of delivered at our hospital, the rough estimate for the incidence of 2,500 boys with hypospadias [Fredell et al., 2002] and 23% in hypospadias in IUGR fetuses is 19% (30/156) compared to a Hussain’s study, which included SGA infants with hypospadias background incidence of 0.3% [Gallentine et al., 2001; Brouwers [Hussain et al., 2002]. This may reflect the early onset as well as the et al., 2007]. Therefore, it is likely that severe placental dysfunction severity of the placental dysfunction in our cohort of patients, in is causally associated with disruption of normal male external view of the fact that our center is a tertiary facility involved in the genital development. During the study period no case of term more severe cases of IUGR. Unlike previous studies, which did not IUGR with hypospadias was identified, indicating that this associa- show a correlation between the severity of hypospadias and the tion is more common among the severe cases of growth restriction, severity of growth restriction [Hussain et al., 2002; Fujimoto et al., 2008], our data do support such relationship as significantly more In the Fujimoto et al.  study, 16 male infants with infants with severe hypospadias were below the 3rd centile com- hypospadias and birth weight below 1,500 g were compared to pared to the ones with mild–moderate hypospadias.
62 controls whose birth weight was less than 1,500 g but did not have Another indication for an association between IUGR and hy- hypospadias. The patients with hypospadias demonstrated a sig- pospadias comes from monozygotic twins. A study of 18 twin pairs nificantly higher placenta-to-fetal ratio associated with placental in which one twin had hypospadias and one did not, found that in infarction compared to controls [Fujimoto et al., 2008]. Moreover, 16 pairs, the healthy co-twin weighed at birth 500 g more than the placental histopathologic findings in the hypospadias cases revealed twin with hypospadias [Fredell et al., 1998]. In our study five of the severe degenerative changes, infarction, and calcification, similar to cases were twins (three monochrionic and two dichorionic with the findings in our study. However, the prevalence of pregnancy- unknown zygosity), in which the IUGR twin was the one with induced hypertension in their study was significantly lower in the hypospadias. Since monozygotic twins share the same intrauterine hypospadias group than in controls (14.2% vs. 26%, respectively), environment and genotype as well as the same placenta, the whereas 57% of the pregnancies in our series were complicated by discordance for the hypospadias is difficult to explain. Conditions, severe pre-eclampsia, as expected in the presence of severe placental for which monozygotic twins are discordant, are usually multifac- dysfunction. Similarly, in a large population-based case-control torial or the result of a new dominant mutation that affected one of study hypospadias was shown to be associated with severe pre- the twins or discordance for a chromosome abnormality, which was eclampsia with an odds ratio of 2.1 [Akre et al., 1999]. The ruled out in our cases. However, these data support the hypothesis association between pre-eclampsia and hypospadias reflects abnor- that fetal growth and risk of hypospadias are strongly associated and may indicate an epigenetic phenomena as the cause of the associa- The most severe forms of placenta-mediated IUGR originate in the early part of the first trimester, around weeks 7–8, when the male Since there is substantial evidence for increased risk of external genitalia are forming. This has been supported by studies hypospadias/ambiguous genitalia in IUGR male fetuses, in patients showing that low maternal circulating levels of PAPP-A at 8–14 with early placental dysfunction an US study directed to the fetal weeks of gestation are significantly predictive of IUGR, and more so genitalia should be considered, and if amniocentesis is done when measured prior to 13 weeks [Smith et al., 2002, 2006; Dugoff correlation between the fetal phenotypic sex and chromosome sex et al., 2004]. However, the underlying mechanism of the association should be determined. A discrepancy between the two should be between hypospadias and placental insufficiency is unclear. The discussed among the specialists involved in the investigation and development of the human male urethra, which occurs between 7 treatment of babies with ambiguous genitalia and presented to the and 14 weeks of gestation, is the result of androgen action on the women/couples in view of the above findings. This will allow the external genitalia. Lack of testosterone, 5-alpha reductase deficien- women/parents to make an informed decision regarding the preg- cy, complete or incomplete androgen receptor insensitivity, and nancy and to prepare them for the delivery and the postnatal steroidogenic enzyme deficiencies are known to result in ambigu- investigation and treatment required. An attempt should be made ous genitalia. The earlier the disruption, the more severe the to obtain a piece of cord and cord blood to allow in depth postnatal hypospadias [Main et al., 2006]. Since fetal testosterone secretion investigation since obtaining sufficient amount of blood for DNA is under the influence of placental hCG during the first 14 weeks of extraction, in these cases, may be difficult.
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Helmut Erich SEGNER Born 10th September 1954 in Tauberbischofsheim, GermanyNationality: GermanProfessional address:Centre for Fish and WildlifeUniversity BernPostbox 8466CH-3001 BernTel. +41-31 631 2441/2465, Fax +41-31 631 2611, Email: firstname.lastname@example.org ACADEMIC AND PROFESSIONAL QUALIFICATIONS Habilitation in Zoology, University Karlsruhe: “Morphology, biochemistryand environme