Chapter 3. Congenital Genitourinary Abnormalities. William Obs

 CHAPTER 3. Congenital Genitourinary Abnormalities

BS. Nguyễn Hồng Anh

In emales, the external genitalia, gonads, and müllerian ducts each derive rom dierent primordia and in close association with the urinary tract and hindgut. Abnormal embryogenesis can lead to reproductive organs that predispose to inertility, subertility, miscarriage, or preterm delivery.

GENITOURINARY TRACT DEVELOPMENT

■ Urinary System

Between the 3rd and 5th gestational weeks, an elevation o intermediate mesoderm on each side o the etus begins to develop into the urogenital tract. Tis urogenital ridge divides into the genital ridge, destined to become the gonads, and into the nephrogenic ridge (Fig. 3-1). Each nephrogenic ridge produces a mesonephros (mesonephric kidney). Recall that evolution o the renal system passes sequentially rom the mesonephric stage to reach the permanent metanephric system (de Bakker, 2019; Upadhyay, 2014). Each nephrogenic ridge  also gives rise to a mesonephric duct, also termed wolan duct, and to a paramesonephric duct, also called müllerian duct.

Te early urinary tract develops rom the mesonephric ducts (Fig. 3-2A). Between the 4th and 5th weeks, each mesonephric duct gives rise to a ureteric bud, which grows cephalad (Fig. 3-2B). As each bud lengthens, it induces dierentiation o the metanephros, which will become the nal kidney (Fig. 3-2C) (Davidson, 2019). Te metanephros ascends to its nal position by the 9th week because o disproportionate growth o the embryo’s caudal region (Jain, 2018). Each ureteric bud also gives rise to an elongation that becomes the metanephric duct or uture ureter.

Te cloaca begins as a common opening or the embryonic urinary, genital, and alimentary tracts (Gupta, 2014). By the 7th week, it is divided by the urorectal septum to create the hindgut and the urogenital sinus (Fig. 3-2D) (Valentini, 2016). Te urogenital sinus is considered in three parts: (1) the cephalad or vesicle portion, which orms the urinary bladder; (2) the middle or pelvic portion, which creates the emale urethra; and (3) the caudal or phallic part, which gives rise to the distal vagina and to the greater vestibular (Bartholin) and paraurethral glands.

Near the end o the rst trimester, each mesonephros degenerates, and without testosterone, the mesonephric ducts regress as well. Te ureterovesical junction orms rom incorporation o the metanephric ducts into the bladder at the trigone. Abnormalities o this process lead to obstruction and vesicoureteral reux (Liaw, 2018).

■ Genital Tract

Te allopian tubes, uterus, and upper vagina derive rom the müllerian ducts (see Fig. 3-2B). Linear spatial development o these organs along the duct length is guided by several genes and notably by Hox genes (Du, 2004; Jacquinet, 2016). Tese ducts extend downward and then turn medially to meet and  use together in the midline. Te uterus is ormed by this union o the two müllerian ducts at approximately the 10th week (Fig. 3-2E) (Spencer, 2012). Fusion to create the uterus begins in the middle and then extends both caudally and cephalad.

With cellular prolieration at the upper portion, a thick wedge o tissue creates the characteristic piriorm uterine shape. At the same time, dissolution o cells at the lower pole orms the rst uterine cavity (Fig. 3-2F). As the upper wedge-shaped septum

is slowly reabsorbed, the nal uterine cavity is usually ormed

by the 20th week (oa, 1984). I the two müllerian ducts ail

to use, two separate uterine horns remain. In contrast, resorption ailure o the common tissue between them results in various degrees o persistent uterine septum.

As the distal end o the used müllerian ducts contacts the

urogenital sinus, this induces endodermal outgrowths rom the

sinus, which are termed the sinovaginal bulbs. Tese bulbs prolierate and use to orm the vaginal plate, which later resorbs to

orm the vaginal lumen. Vaginal canalization is generally completed by the 20th week (Crosby, 1962). However, the lumen

remains separated rom the urogenital sinus by the hymeneal

membrane. Tis membrane urther degenerates to leave only

the hymeneal ring.

Te close association o the mesonephric (wolan) and

paramesonephric (müllerian) ducts explains the potential to

see simultaneous abnormalities in their end organs. Nearly

hal o emales with uterovaginal malormations have associated urinary tract deects, and this association is explored

later (p. 40) (Kenney, 1984; Semmens, 1962). With müllerian anomalies, ovaries are unctionally normal but have

a higher incidence o anatomical maldescent into the pelvis

(Allen, 2012).

As discussed, the mesonephric ducts usually degenerate in

the emale. However, persistent remnants may become clinically apparent. Mesonephric, that is wolan, vestiges can persist as Gartner duct cysts. Tese are typically located in the

proximal anterolateral vaginal wall but may be ound at other

sites along the vaginal length. Most cysts are asymptomatic and

benign and usually do not require surgical excision or drainage.

Intraabdominal wolan remnants in the emale include a ew

blind tubules in the mesovarium—the epoöphoron—and similar ones adjacent to the uterus—paroöphoron (see Fig. 3-2F)

(Moore, 2020). Te epoöphoron or paroöphoron may develop

into clinically identiable benign cysts in the adult.

■ Gonads

Because o separate gonadal and müllerian derivation, women

with müllerian deects typically have unctionally normal ovaries. At approximately 4 weeks, gonads orm rom the genital

ridge, also known as the gonadal ridge. Tis ridge orms rom

the coelomic epithelium covering the medioventral surace

o the mesonephros (Smith, 2014). Recall that coelomic epithelium arises rom mesoderm and invests the body cavity’s

inner surace (Ariza, 2016). Next, strands o these epithelial

cells extend into the underlying mesenchyme as the primary

sex cords.

Another gonadal component is the primordial germ cell, the

uture oogonia. By the 6th week, primordial germ cells have migrated rom the yolk sac along the dorsal mesentery to enter

the genital ridge mesenchyme (see Fig. 3-1) (Fujimoto, 1977;

Hen, 2019). Te primordial germ cells are then incorporated

into the primary sex cords.

In the 7th week, the sexes can be distinguished. estes

are recognized during microscopic sectioning by their welldened radiating testis cords, which derived rom the primary

sex cords. Tese cords develop into the seminierous tubules

and rete testis. Te rete testis connects with small tubes arising o the mesonephric duct. Tese small tubes become the

eerent ducts that drain into the epididymis and then into

the vas deerens, which are main mesonephric duct derivatives. Ater the 8th week, gonads begin to dier grossly as

well (Shen, 2018).

In the emale embryo, the primary sex cords give rise to

the medullary cords, which persist only or a short time.

Te coelomic epithelium again prolierates into the underlying mesenchyme, and these strands are the cortical cords. By

the 16th week, the cortical cords begin to orm isolated cell

clusters called primordial ollicles. Tese ollicles contain the

oogonia, which derive rom primordial germ cells, and a single

surrounding layer o ollicular cells, derived rom the cortical

cords. Follicular cells are supporting nutrient cells.

By 8 months, the ovary has become a long, narrow, lobulated structure that is attached to the body wall by the mesovarium. Te coelomic epithelium has been separated by a band o

connective tissue—the tunica albuginea—rom the cortex. At

this stage, the cortex contains ollicles and is well dened rom

the inner medulla, which is composed o abundant blood vessels, lymphatic vessels, and nerve bers.

■ External Genitalia

Early development o the external genitalia is similar in both

sexes. By 6 weeks’ gestation, three external protuberances have

developed surrounding the cloacal membrane. Tese are the let

and right cloacal olds, which meet ventrally to orm the genital

tubercle (Fig. 3-3A). With division o the cloacal membrane

into anal and urogenital membranes in the early 7th week, the

cloacal olds become the anal and urethral olds, respectively.

Lateral to the urethral olds, genital swellings arise, and these

become the labioscrotal olds. Between the urethral olds, the

urogenital sinus extends onto the surace o the enlarging genital tubercle to orm the urethral groove. Late in week 7, the

urogenital membrane ruptures, exposing the cavity o the urogenital sinus to amnionic uid.

Te genital tubercle elongates to orm the phallus in males

and the clitoris in emales. Still, it is not possible to visually

dierentiate between male and emale external genitalia until

week 12. In the male etus, dihydrotestosterone (DH) orms

locally by the 5-α reduction o testosterone. DH prompts

the anogenital distance to lengthen, the phallus to enlarge,

and the labioscrotal olds to use and orm the scrotum (see

Fig. 3-3B).

In the emale etus, without DH, the anogenital distance

does not lengthen, and the labioscrotal and urethral olds do

not use (see Fig. 3-3C). Te genital tubercle bends caudally

to become the clitoris, and the urogenital sinus orms the vestibule o the vagina. Te labioscrotal olds create the labia

majora, whereas the urethral olds persist as the labia minora.

Female external genitals are dierentiated by 11 weeks,

whereas male external genital dierentiation is complete by

14 weeks.  

o dierentiate phenotypic

gender early, rst-trimester sonography relies on the angle o the

genital tubercle o a horizontal

line drawn parallel to the lumbosacral skin surace (Fig. 3-4)

(Erat, 2006). Specically, male

gender is assigned i the angle is

>30°, and emale gender i the

angle is <10°.

SEXUAL

DIFFERENTIATION

Dening gender incorporates

genetic gender, gonadal gender,

and phenotypic gender. Genetic

gender—XX or XY—is established at ertilization. However,

or the rst 6 weeks, male and

emale embryos are morphologically indistinguishable.

Gonadal gender is heralded

by the dierentiation o the primordial gonad into a testis or an

ovary. I a Y chromosome is present, the gonad begins developing

into a testis. estis development

is directed by the sex-determining

region (SRY) gene, located on the

short arm o the Y chromosome

(Sinclair, 1990). In addition,

testis development requires other

autosomal genes that include

SOX9, WT1, DAX1, WNT4, and

NR5A1(SF1) (Grinspon, 2019).

Identied mutations in these

and others are linked to disorders

o sex development, described

next.

Te importance o the SRY

gene is demonstrated in several

paradoxical conditions. For example, 46,XX phenotypic males can

result rom translocation o the Y

chromosome ragment containing

SRY to the X chromosome during

meiosis o male germ cells (Yue,

2019). Similarly, 46,XY individuals can appear phenotypically

emale i they carry a mutation in

the SRY gene (Helszer, 2013).

Last, phenotypic gender begins

at 8 weeks’ gestation. Beore this, urogenital tract development in

both sexes is homologous. Tereater, dierentiation o the internal and external genitalia to the male phenotype is dependent on

testicular unction and response. In its absence, emale dierentiation ensues irrespective o genetic gender (Table 3-1) (She, 2017).

In males, the Sertoli cells o the etal testis secrete a protein

called antimüllerian hormone (AMH), also named müllerianinhibiting substance (MIS). It acts locally as a paracrine actor

to cause müllerian duct regression (Grinspon, 2020; Mäkelä,

2019). Tus, it prevents development o the uterus, allopian

tube, and upper vagina. Sertoli cells secrete AMH beore dierentiation o Leydig cells, which synthesize testosterone. AMH

is secreted as early as 7 weeks, and müllerian duct regression is

completed by 9 to 10 weeks. Because AMH acts locally near its

site o ormation, i a testis were absent on one side, the müllerian duct on that side would persist, and the uterine horn and

allopian tube would develop on that side.

Trough stimulation initially by human chorionic gonadotropin (hCG), and later by etal pituitary luteinizing hormone

(LH), Leydig cells secrete testosterone. Tis hormone acts

directly on the wolan duct to promote development o the

vas deerens, epididymis, and seminal vesicles. estosterone also

enters etal blood and acts on the external genitalia. In these tissues, testosterone is converted to 5α-DH to cause virilization

o the external genitalia. Leydig cells also produce insulin-like

actor 3, which prompts embryonic testes to descend by acting

on the gubernaculum (Ivell, 2009).

DISORDERS OF SEX DEVELOPMENT

■ Definitions

Abnormal sex development may involve the gonads, internal

duct system, or external genitalia. Current classication o disorders o sex development (DSDs) include: (1) sex chromosome

DSDs, (2) 46,XY DSDs, and (3) 46,XX DSDs (Table 3-2)

(Hughes, 2006). Rates vary depending on included entities and

approximate 1 case in every 5000 births (Lee, 2016).

Other terms describe abnormal phenotypic ndings. First,

some DSDs have abnormal, underdeveloped gonads, that is,

gonadal dysgenesis. With this, a poorly ormed testis is called a

dysgenetic testis. A poorly ormed ovary is a streak gonad. Underdeveloped gonads ultimately ail, which creates low sex steroid

hormone levels but elevated ollicle-stimulating hormone

(FSH) and LH levels.

A second term, ambiguous genitalia, describes genitalia that

do not appear clearly male or emale. Abnormalities can include

hypospadias, undescended testes, micropenis or enlarged clitoris, labial usion, and labial mass.

Last, ovotesticular denes a rare state characterized by ovarian and testicular tissue in the same individual. It was ormerly

termed true hermaphroditism. In these cases, dierent gonad

types can be paired. Pair combinations may include a normal

testis, a normal ovary, a streak gonad, a dysgenetic testis, or an

ovotestis. In the last, both ovarian and testicular elements are

combined within the same gonad.

With ovotesticular cases, the internal ductal system structure depends on the type o ipsilateral gonad and its unction.

Specically, the amount o AMH and testosterone determines

the degree to which the internal ductal system is retained or reabsorbed (p. 35). With inadequate AMH, müllerian duct

derivatives persist. With inadequate testosterone, external genitalia are usually ambiguous and undermasculinized. Ovotesticular

development may be ound in all three o the DSD categories,

and each o these sections describes examples (see able 3-2).

■ Germ Cell Cancer

Tis cancer can develop in dysgenetic gonads o patients bearing all or part o the Y chromosome. On the Y chromosome,

the gene or testis-specic protein Y (TSPY) is one putative

cancer-predisposing gene. Other risks include disturbed gonadal

development, delayed germ cell maturation, and presence o a

gonadoblastoma (Cools, 2014). Te last is a benign tumor that

contains germ cells and immature granulosa cells (Roth, 2018).

Germ cell cancer (GCC) risk varies among DSD types, but

or some, gonadectomy may be recommended by a multispecialty DSD team (Lee, 2016). Early surgery benets those with

higher GCC risk and those in whom gonadal hormones may run

counter to preerred pubertal development or the individual’s chosen gender identity. Later surgery may benet those with

low GCC risk and in whom gonadal hormones would advance

desired pubertal development (van der Zwan, 2015).

In addition to dysgenetic gonads, undescended testes also

have higher GCC rates (Kolon, 2014). Instead o gonadectomy, orchiopexy, which translocates and xes a testis into the

scrotum, may be protective (Radmayr, 2016; Walsh, 2007).

■ Sex Chromosome DSD

Cases in this rst DSD category typically arise rom an abnormal number o sex chromosomes, that is, sex chromosome aneuploidy (SCA). Te population rate approximates 1 case per 2500

births (Howard-Bath, 2018).

Discussed ully in Chapter 17 (p. 333), prenatal screening methods allow detection o aneuploidies, including SCAs

(Norton, 2016). Sonographically, a thick nuchal translucency or the presence o cystic hygromas is associated with an

increased SCA risk (American College o Obstetricians and

Gynecologists, 2020; Reiss, 2017). Cell-ree DNA present in

the maternal blood is another common aneuploidy screening tool (Fig. 16-14, p. 328) (Huang, 2018; Vogel, 2019). Its

selection solely or gender identication and without a medical indication is not recommended by the American College

o Medical Genetics and Genomics (Gregg, 2016). Still, with

cell-ree DNA use or other indications, antenatal detection o

SCAs will likely rise. Interpretation and management o ndings is discussed in Chapter 17 (p. 335). Advantageously, early

recognition o sex chromosome DSD oers an opportunity or

patient education. Decisions to end or continue pregnancies

are best guided by clinical geneticists. For continued pregnancies, prenatal diagnosis allows early postnatal interventions

(Gravholt, 2017).

Turner Syndrome

Tis develops rom de novo loss or severe structural abnormality o one X chromosome in a phenotypic emale. Most aected

etuses are spontaneously aborted. However, 1 in 2000 emale

live births are aected (Lin, 2019). In survivors with urner

syndrome, phenotype varies but nearly all aected patients have

short stature. Associated problems can include hypertension;

cardiac abnormalities, especially aortic coarctation, bicuspid

aortic valve, and Q-interval prolongation; and renal, skeletal, and otolaryngological anomalies. A webbed posterior neck

results rom cystic hygromas. Metabolic concerns are diabetes

mellitus (DM), autoimmune thyroiditis, celiac disease, and

elevated liver enzymes (Gravholt, 2019). wo streak ovaries

are typically ound, and this syndrome is the most common

orm o gonadal dysgenesis that leads to primary ovarian insu-

ciency (POI). POI is the depletion or dysunction o ovarian ollicles that leads to ailing sex hormone production. Te

uterus and vagina are normal and respond to prescribed hormones (Matthews, 2017).

Despite eventual POI, women with urner syndrome may

conceive with assisted reproductive technologies (AR) and

rarely spontaneously (Hovatta, 1999; Oktay, 2016). In gravidas with urner syndrome, cardiac morbidity stems rom

aortic dissection, aortic valve stenosis, and hypertension. For this reason, maternal–etal medicine preconceptional counseling and cardiologist evaluation is essential. For aortic dissection, risk rises as the aortic diameter increases. Te ascending

aortic size index (ASI), which is the aortic diameter divided

by body surace area, better reects risk because it accounts

or short stature. Conception should be avoided with an ASI

>2.5 cm/m2 or with an ASI o 2.0 to 2.5 cm/m2 plus comorbid aortic dissection risk actors. Tese include bicuspid aortic valve, transverse aortic arch elongation, aortic coarctation,

and hypertension (Gravholt, 2017; Silberbach, 2018). Te

American Society or Reproductive Medicine (2012) recommends against pregnancy with an ASI >2 cm. Even without

identied risk, aortic dissection can develop in pregnancy

(Carlson, 2007).

I conception is planned, preconceptional evaluation

includes echocardiography, combined computed tomography

plus cardiac magnetic resonance (CMR) imaging o the heart/

aorta, 24-hour ambulatory blood pressure monitoring, exercise

testing to reveal exercise-induced hypertension, and electrocardiogram (Gravholt, 2017). Cardiac disorders may require surveillance with serial echocardiograms.

Tis syndrome carries higher etal rates o miscarriage, preterm birth, and small-or-gestational age. Preeclampsia, gestational diabetes, and cholestasis o pregnancy are other maternal

risks (Dotters-Katz, 2016a; Grewal, 2021). Tus, baseline

serum tests ideally assess renal, liver, and thyroid unction and

screen or DM (Bouet, 2016). Tese complications and cephalopelvic disproportion account or cesarean delivery rates o

40 to 80 percent in gravidas with urner syndrome (Cadoret,

2018; Campens, 2021; Dotters-Katz, 2016a).

Klinefelter Syndrome

Tis syndrome has an estimated prevalence o 1 case per 650

newborn males etuses (Bojesen, 2003; Radicioni, 2010). With

chromosome complement o 47,XXY, these individuals tend to

be tall, undervirilized males with gynecomastia and two small,

rm testes. Tey have greatly reduced ertility rom hypogonadism due to gradual testicular ailure. Tese men are at increased

risk or mediastinal germ cell tumors, osteoporosis, hypothyroidism, DM, breast cancer, cardiovascular abnormalities, and

neurobehavioral disorders (Groth, 2013).

Aected etuses may show a thick N during rst-trimester

sonography (Gruchy, 2011). Antepartum risks include preterm

birth, cesarean delivery, small-or-gestational-age etus, and

neonatal death (Dotters-Katz, 2016b).

47,XXX and 47,XYY Karyotypes

Tese rare karyotypes are ound in 1 in 10,000 newborn

emales and 2 in 10,000 newborn males, respectively (Berglund, 2019). Sonographically, etuses with either karyotype

may show a thick N and etal-growth restriction (Gruchy,

2016). Phenotypic range is wide, but both may be taller, show

subtle acial and skeletal dysmorphisms, and display neurobehavioral problems such as autism spectrum and attentiondecit/hyperactivity disorders (Bardsley, 2013; Urbanus,

2020; Widby 2016). Hormone levels and ertility are una-

ected in most, although POI and semen abnormalities may

be seen, respectively.

Sex Chromosomal Ovotesticular DSD

In the sex chromosome DSD group, ovotesticular DSD may

arise rom a 46,XX/46,XY karyotype. Here, an ovary, testis, or

ovotestis may be paired. For others, ovotesticular DSD arises

rom a chromosomal mosaic such as 45,X/46,XY. With this

karyotype, mixed gonadal dysgenesis shows a streak gonad on

one side and either a dysgenetic testis or normal testis on the

other. For this reason, phenotypic gender varies widely.

■ 46,XY DSD

Insucient androgen exposure o a etus destined to be a male

leads to 46,XY DSD—ormerly called male pseudohermaphroditism. estes are oten present, and the uterus is generally

absent due to the normal action o AMH. Tese individuals are

usually sterile rom abnormal spermatogenesis and a small phallus that is inadequate or coitus. Described next, the etiology

o 46,XY DSD may stem rom abnormal testis development or

rom abnormal androgen production or action (see able 3-2).

Rarely, 46,XY DSD may be part o another metabolic syndrome that alters structural development, such as SmithLemli-Opitz syndrome (Neri, 1999).

46,XY Gonadal Dysgenesis

Tis spectrum o abnormal gonad underdevelopment includes

complete, partial, or mixed 46,XY gonadal dysgenesis. Tese

are dened by karyotype and by the amount o abnormal testicular tissue. Because o the potential or GCC, gonadectomy

is oten recommended (p. 36).

O these, complete gonadal dysgenesis results rom a mutation in the SRY gene or in other genes with testis-determining

eects (Hutson, 2014). Swyer syndrome reects SRY deects,

whereas Frasier and Denys-Drash syndromes have WT1 mutations. With both mutations, underdeveloped dysgenetic gonads

ail to produce androgens or AMH, which results a normal prepubertal emale phenotype and a normal müllerian system.

Partial gonadal dysgenesis denes those with gonad development intermediate between normal and dysgenetic testes.

Depending on percentages, wolan and müllerian structures

and genital ambiguity are variably expressed.

Mixed gonadal dysgenesis is one type o ovotesticular DSD.

As discussed in the last section, one gonad is streak, and the

other is a normal testis or a dysgenetic testis. Te phenotype is

wide ranging.

Last, testicular regression can ollow initial testis development

(McElreavey, 2020). Te phenotypic spectrum is broad and

depends on the timing o testis ailure.

Abnormal Androgen Production or Action

Some cases o 46,XY DSD stem rom abnormalities in: (1)

testosterone biosynthesis, (2) LH-receptor unction, (3) AMH

unction, or (4) androgen-receptor action. First, the sex-steroid

biosynthesis pathway can suer enzymatic deects that block

testosterone production. Depending on blockade timing and

degree, undervirilized males or phenotypic emales may result.

In contrast to these central enzymatic deects, peripheral deects

can be causative. Namely, abnormal action o 5α-reductase

type 2 enzyme impairs conversion o testosterone to DH and

blunts virilization.

Second, hCG/LH receptor abnormalities within the testes

can lead to Leydig cell hypoplasia and decreased testosterone

production. In contrast, disorders o AMH and AMH receptors result in persistent müllerian duct syndrome (PMDS).

Tese patients appear as males but have a persistent uterus and

allopian tubes due to ailed AMH action.

Last, the androgen receptor may be deective and result in

androgen-insensitivity syndrome (AIS). Resistance to androgens may be incomplete and result in varying degrees o virilization and genital ambiguity. Milder orms may lead to poorly

virilized men with severe male-actor inertility.

Tose with complete androgen-insensitivity syndrome

(CAIS) are phenotypically normal emales. Girls oten present

at puberty with primary amenorrhea. External genitalia appear

normal; pubic and axillary hair are scant or absent; the vagina

is markedly shortened; and the uterus and allopian tubes are

absent. However, these individuals develop breasts during

puberty due to conversion o androgen to estrogen. estes

may be palpable in the labia or groin or may lie intraabdominally. raditionally, testes are removed. However, women with

AIS have a low risk o GCC, and retention until ater puberty

allows hormone-mediated breast and bone mass development.

Despite hormone replacement ater ultimate gonadectomy,

many individuals describe hormone-related mood imbalance.

New cancer-surveillance protocols may allow gonad retention

(Cools, 2017; Weidler, 2019).

■ 46,XX DSD

Tis DSD group may stem rom abnormal ovarian development or rom excess androgen exposure.

Abnormal Ovarian Development

Disorders o ovarian development in those with a 46,XX complement include: (1) gonadal dysgenesis, (2) testicular DSD,

and (3) ovotesticular DSD.

With 46,XX gonadal dysgenesis, similar to urner syndrome,

streak gonads develop. Tese lead to hypogonadism, prepubertal normal emale genitalia, and normal müllerian structures.

However, other urner stigmata are absent.

With 46,XX testicular DSD, several genetic mutations lead

to testis-like ormation. Most commonly, deects stem rom

SRY translocation onto one paternal X chromosome. Less

oten, other genes with testis-determining eects are activated.

Regardless, AMH prompts müllerian system regression, and

androgens promote wolan system development and external

genitalia masculinization. Spermatogenesis, however, is absent

because needed genes on the long arm o the Y chromosome are

lacking. Tese persons are not usually diagnosed until puberty

or during inertility evaluation.

With 46,XX ovotesticular DSD, individuals possess a unilateral ovotestis with a contralateral ovary or testis, or bilateral

ovotestes. An overexpression o SOX genes, which are testis

promoting, or decient ovarian promoting genes are implicated

(Grinspon, 2019). Phenotypic ndings depend on the degree

o androgen exposure.

Androgen Excess

Discordance between emale gonadal sex and phenotypically

masculine external genitalia may also result rom excessive

etal androgen exposure. Te prior term was emale pseudohermaphroditism. In aected individuals, the ovaries and

emale internal ductal structures such as the uterus, cervix,

and upper vagina develop. Tus, patients are potentially ertile. Te external genitalia, however, are variably virilized

depending on the amount and timing o androgen exposure.

Te embryonic clitoris, labioscrotal olds, and urogenital

sinus are commonly aected by elevated androgen levels. Virilization may range rom modest clitoromegaly to posterior

labial usion and a phallus with a penile urethra. Degrees o

virilization can be described by the Prader score, which ranges

rom 0 or a normal-appearing emale to 5 or a normal, virilized male. Te external genitalia score is another and similarly ranges rom 0 to 12, respectively (Ahmed, 2000; van der

Straaten, 2020).

Fetal, placental, or maternal sources can provide the excessive androgen levels. Maternally derived androgen excess may

come rom virilizing ovarian tumors such as luteoma and Sertoli-Leydig cell tumor or rom virilizing adrenal tumors. Fortunately, these neoplasms inrequently cause etal eects because

o the placental syncytiotrophoblast’s tremendous ability to

convert C19 steroids—androstenedione and testosterone—

into estradiol via the enzyme aromatase (Chap. 5, p. 101). As

another source, drugs such as testosterone, danazol, and other

androgen derivatives may virilize.

O etal sources, exposure can arise rom etal congenital

adrenal hyperplasia (CAH). Tis stems rom a etal enzyme

deciency in the steroidogenic pathway and leads to androgen

accumulation. Most cases have a 21-hydroxylase deciency.

Rarely, others involve decient 3β-hydroxysteroid dehydrogenase, 17α-hydroxylase, cholesterol side-chain cleavage enzyme,

P450 oxidoreductase, or 11β-hydroxylase (El-Maouche, 2017;

Narasimhan, 2019). CAH is a requent cause o virilization,

and its approximate incidence in the United States is 1 case in

18,000 live births (Chan, 2013; Pearce, 2016).

With CAH, phenotypes depend on the enzyme deect’s

location in the steroidogenic pathway and its severity (Miller,

2011). Classically, decient enzymes block corticosteroid

production, which eeds back to raise adrenocorticotropic

hormone (ACH) levels. Tis prompts increased levels o precursors, which detour into pathways that generate androgens.

With severe deciency, aected newborns also have blocked

aldosterone production that leads to lie-threatening salt wasting. Tis is typied by hyponatremia, hyperkalemia, metabolic

acidosis, and hypovolemia (Bizzarri, 2016). Other mutations

may prompt etal virilization alone (Auchus, 2015).

Te mildest abnormalities present later and are described

as “nonclassic,” “late-onset,” or “adult-onset” CAH. In these

patients, adrenal axis activation at puberty increases steroidogenesis and unmasks mild enzymatic deciency. Excess androgen

provides negative eedback to gonadotropin-releasing hormone

(GnRH) receptors in the hypothalamus. Tese patients oten

have hirsutism, acne, and anovulation. Tus, late-onset CAH

may mimic polycystic ovarian syndrome (McCann-Crosby,

2014).

In some instances, CAH can be diagnosed antenatally. Early

maternal dexamethasone therapy can dampen androgen excess

to minimize virilization (Chap. 19, p. 369). Cell-ree DNA can

identiy etal gonadal gender. I Y-chromosome cell-ree DNA

is identied, androgens will not harm the male etus and maternal dexamethasone treatment can be stopped (ardy-Guidollet,

2014).

O rare placental sources, placental aromatase deciency

rom a etal CYP19 gene mutation causes accumulation o

placental androgen and underproduction o placental estrogens (Chap. 5, p. 102) (Jones, 2007). Consequently, both the

mother and the 46,XX etus are virilized.

■ Gender Assignment

Delivery o a newborn with a DSD is a potential medical emergency and can also create possible long-lasting psychosexual

and social ramications or the individual and amily. Ideally,

once the aected neonate is stable, parents are encouraged to

hold the child. Te newborn is reerred to as “your baby,”

and suggested terms include “phallus,” “gonads,” “olds,” and

“urogenital sinus” to reerence underdeveloped structures. An

obstetrician explains that the genitalia are incompletely ormed

and emphasizes the situation’s seriousness and need or rapid

consultation and laboratory testing.

Because similar or identical phenotypes may have several

etiologies, identication o a specic DSD may require several

diagnostic tools (McCann-Crosby, 2015). Relevant historical

questions seek prior obstetrical outcomes, medication inventory, consanguinity, germane antenatal testing and sonography

results, and amily history o genetic or structural anomalies.

Signs o maternal hyperandrogenism are sought. Neonatal

physical examination evaluates: (1) ability to palpate gonads

in the labioscrotal or inguinal regions, (2) ability to palpate

uterus during rectal examination, (3) phallus size, (4) other syndromic eatures, and (5) genitalia pigmentation, which derives

rom increased melanocyte-stimulating hormone levels that can

accompany ACH secretion. Te newborn metabolic condition is assessed, and hyperkalemia, hyponatremia, and hypoglycemia may indicate CAH. Other neonatal tests include genetic

studies, hormone measurements, imaging, and in some cases

endoscopic, laparoscopic, and gonadal biopsy. Sonography or

magnetic resonance (MR) imaging can help identiy müllerian/

wolan structures, gonad location, and associated malormations such as renal anomalies.

BLADDER AND PERINEAL ABNORMALITIES

During embryo ormation, a bilaminar cloacal membrane lies

at the caudal end o the germinal disc and orms the inraumbilical abdominal wall. Normally, an ingrowth o mesoderm

between the ectodermal and endodermal layers leads to ormation o the lower abdominal musculature and pelvic bones.

Without this reinorcement, the cloacal membrane may prematurely rupture. Depending on the inraumbilical deect’s

extent, cloacal exstrophy, bladder exstrophy, or epispadias may

result, and all are rare.

Cloacal exstrophy, also known as the omphalocele, bladder

exstrophy, imperorate anus, spina bida (OEIS) complex,

aects approximately 1 in 300,000 live births (Keppler-Noreuil,

2007; Woo, 2010). With bladder exstrophy, the bladder lies

outside the abdomen, is open, drains directly into amnionic

uid, and thus does not ll. Sonography in the rst trimester

may show a thin-walled, lower-abdominal cystic structure and

a thick N (Mallmann, 2014; onni, 2011). During secondtrimester scans, ndings are a midline, inraumbilical, anteriorabdominal-wall deect, ailure to see the bladder, and associated

OEIS deects (Ben-Neriah, 2007). Prenatal karyotyping is recommended. Delivery route is usually dictated by the associated

spina bida deect. Postnatal repair is complex, and individuals

may struggle with urinary and ecal incontinence and the challenges o neonatal gender assignment (Woo, 2010).

With bladder exstrophy, associated ndings oten include

abnormal external genitalia and a widened symphysis pubis. At

the same time, however, the uterus, allopian tubes, and ovaries

are typically normal except or occasional müllerian duct usion

deects. Although oten not identied in aected etuses, sonographic indicators are inability to see the bladder, solid mass

between the umbilical arteries, low umbilical insertion into the

abdomen, divergent pubic rami, normal amnionic uid volume,

and in males, a small penis with anteriorly displaced scrotum

(Mallmann, 2019). Te dierential diagnosis includes bladder

exstrophy or agenesis, bilateral ectopic ureters, patent urachus,

cloacal exstrophy, and simple nonvisualization o the bladder.

MR imaging may be a helpul adjunct (Goldman, 2013). Fetal

karyotyping is considered i genitalia are ambiguous. For an

aected etus, the prenatal course is typically routine, and cesarean delivery is reserved or obstetrical indications.

For a gravida with bladder exstrophy hersel, pregnancy is

associated with greater risk or antepartum pyelonephritis, urinary retention, ureteral obstruction, pelvic organ prolapse, miscarriage, preterm birth, and breech presentation. Te American

Urological Association has published management guidelines

or pregnancy (Eswara, 2016). Due to the extensive adhesions

rom prior repair and altered anatomy typically encountered,

some recommend planned early cesarean delivery at a tertiary

center (Deans, 2012; Greenwell, 2003). Dy and coworkers

(2015) described using paramedian abdominal wall and vertical uterine incisions.

Epispadias without bladder exstrophy is rare and develops in

association with other anomalies such as a widened, patulous

urethra; absent or bid clitoris; nonused labial olds; and attened mons pubis. Vertebral abnormalities and pubic symphysis diathesis are also common.

Clitoral anomalies are rare. One is clitoral duplication or

bid clitoris, which usually develops in association with bladder

exstrophy or epispadias. With emale phallic urethra, the urethra

opens at the clitoral tip. Last, clitoromegaly noted at birth suggests etal exposure to excessive androgens (p. 38). Without

a DSD, idiopathic congenital clitoromegaly in emales born

extremely premature is rare but well-recognized, and observation is recommended (Williams, 2013).

As noted, the hymen marks the embryological boundary

between structures derived rom the müllerian and urogenital

sinus. Hymeneal anomalies include imperorate, microperorate,

cribriorm (sievelike), navicular (boat-shaped), and septate

hymens. Tey result rom ailure o the inerior end o the vaginal plate—the hymeneal membrane—to canalize. Rarely, with

an imperorate hymen, secretions may markedly accumulate in

the etal uterus and vagina, that is, hydrometrocolpos (HMC).

Most cases o HMC are asymptomatic and resolve postnatally

as mucus is reabsorbed and estrogen levels decline. Rarely, perinatal urinary tract obstruction results rom mass eect and is

relieved with cruciate incision o the hymen (Grimstad, 2019).

Fetal HMC sonographically appears as a cystic mass behind

the bladder. Te dierential diagnosis includes reproductive tract outlet obstruction o the hymen, vagina, or cervix;

ureterocele; megacystis; ovarian, urachal, or mesenteric cyst;

anterior meningocele; bowel or bladder duplications; and urogenital sinus or cloacal dysgenesis. Rare associated syndromes

are McKusick-Kauman, Ellis-van Creveld, or Bardet-Biedl

syndromes (Garcia Rodriguez, 2018).

MÜLLERIAN ABNORMALITIES

Four principal abnormalities arise rom deective müllerian

duct embryological steps: (1) agenesis o both ducts, either

ocally or along the entire duct length; (2) unilateral maturation o one müllerian duct with incomplete or absent development o the opposite side; (3) absent or aulty midline usion o

the ducts; or (4) deective canalization. Various classications

have been proposed, and Table 3-3 shows the one rom the

American Fertility Society (1988). Tis classication system is

the most widely used, although several others have been created

(Grimbizis, 2013, 2016; Ludwin, 2018b).

A müllerian anomaly is suspected i a vaginal septum, blindending vagina, or duplicated cervix is ound. Amenorrhea may

be an initial complaint or those with agenesis o a müllerian

component. In those with outlet obstruction but unctioning

endometrium, pelvic pain may arise rom occult blood that

accumulates and distends the vagina, uterus, or allopian tubes

(Kapczuk, 2018; Patel, 2016). Endometriosis and its associated

dysmenorrhea, dyspareunia, and chronic pain are also requent

with outlet obstruction (Matalliotakis, 2017).

■ Comorbid Renal Anomalies

Renal anomalies most requently accompany unicornuate

uterus, uterine didelphys, and anomalies with an ipsilateral

obstructive vaginal septum. Less oten, partial bicornuate, and

partial septate uteri are associated (Heinonen, 2018). When

müllerian anomalies are identied, the urinary system can

be evaluated with sonography, MR imaging, or intravenous

pyelography (Hall-Craggs, 2013). Te last two are advantageous because ureteral anatomy can be aected too. An absent

unilateral kidney is the most common nding. On the other

hand, i renal agenesis is ound rst, reproductive-tract imaging

in early puberty may help identiy müllerian anomalies early

(Friedman, 2018).

■ Müllerian Agenesis (Class I)

Class I segmental deects are caused by müllerian hypoplasia

or agenesis as shown in Figure 3-5 (American Fertility Society, 1988). Tese developmental deects can aect the vagina,

cervix, uterus, or allopian tubes and may be isolated or may

coexist with other müllerian anomalies.

■ Vaginal Abnormalities

O these, vaginal agenesis is the most proound and may be

isolated or associated with other müllerian anomalies. One

example is the Mayer-Rokitansky-Küster-Hauser (MRKH)

syndrome, in which upper vaginal agenesis is typically associated with uterine hypoplasia or agenesis. Less oten, this syndrome also displays additional abnormalities and is known by

the acronym MURCS (müllerian duct aplasia, renal aplasia,

and cervicothoracic somite dysplasia) (Rall, 2015).

Te obstetrical signicance o vaginal anomalies depends

greatly on the degree o obstruction. Complete vaginal agenesis, unless corrected surgically, precludes pregnancy by vaginal

intercourse. With MRKH syndrome, a unctional vagina can be

created, but uterine agenesis proscribes childbearing. In these

women, however, ova can be retrieved or in vitro ertilization

(IVF) and carriage by a surrogate mother (Reichman, 2010).

Uterine transplantation is experimental but holds promise or

these women (Johannesson, 2021; Jones, 2019).

O other vaginal anomalies, congenital septa may orm longitudinally or transversely, and each can arise rom a usion

or resorption deect. A longitudinal septum divides the vagina

into right and let portions. It may be complete and extend the entire vaginal length. A partial septum usually orms high in the

vagina but may develop at lower levels. Tese septa are oten

associated with other müllerian anomalies (Haddad, 1997).

During examination, the provider can usually guide a speculum up along one side o the septum. Similarly, in labor, a

complete longitudinal vaginal septum usually does not cause

dystocia because the etus can descend through one vaginal

side, which dilates suciently. An incomplete distal longitudinal septum, however, may interere with descent, and

antepartum resection is preerred (Homan, 2020). Rarely, a

woman with an incomplete distal longitudinal septum instead

presents in labor. During second-stage labor, this septum usually becomes attenuated by pressure rom the etal head. Ater

ensuring adequate analgesia, the attachment o the septum to

the posterior vaginal wall is isolated between two clamps, transected, and ligated. Following placenta delivery, the superior

attachment is similarly isolated between clamps and transected,

while careully avoiding urethral injury.

A transverse septum poses an obstruction o variable thickness. It may develop at any depth within the vagina, but most

lie in the lower third (Williams, 2014). Septa may or may not

be perorate, and thus obstruction or inertility is possible.

In labor, perorate strictures may be mistaken or the upper

limit o the vaginal vault, and the septal opening is misidenti-

ed as an undilated cervix (Kumar, 2014). I encountered during labor, and ater the cervix has dilated completely, the head

impinges on the septum and causes it to bulge downward. I

the septum does not spontaneously yield, slightly stretching its

opening usually leads to urther dilation. Occasionally cruciate incisions that avoid the urethra and rectum are required

to permit delivery (Blanton, 2003; Levin, 1963). For a thick

transverse septum, cesarean delivery may be necessary.

■ Cervical Abnormalities

Developmental abnormalities o the cervix include partial or

complete agenesis, duplication, or a longitudinal dividing septum. Complete agenesis is incompatible with pregnancy. IVF

with gestational surrogacy or with transmyometrial embryo

transer are options (Al-Jaroudi, 2011; Xu, 2009). Instead,

surgical correction by uterovaginal anastomosis successully

relieves outlet obstruction, but subsequent pregnancy and live

birth rates are low (Mikos, 2020). Signicant complications

including deaths have accompanied such corrective surgery.

Some experts recommend hysterectomy or complete cervical agenesis and reserve reconstruction attempts or careully

selected patients with cervical dysgenesis (Roberts, 2011; Rock,

2010). 

Uterine Abnormalities

From a large variety, a ew o the more common congenital

uterine malormations are shown in able 3-3. Assessing an

accurate population prevalence is dicult because the best

diagnostic techniques are invasive. Te prevalence ound with

imaging ranges rom 0.4 to 10 percent, and rates in women

with recurrent miscarriage are signicantly higher (Byrne,

2000; Dreisler, 2014; Saravelos, 2008). In a general population, the most requent nding is arcuate uterus, ollowed in

descending order by septate, bicornuate, didelphic, and unicornuate classes (Chan, 2011b).

As a group, these anomalies pose greater risk or miscarriage, malpresentation, preterm birth, and poor etal growth

(Chan, 2011a; Hua, 2011; Reichman, 2009). Vaginal delivery is the preerred delivery route when easible. Te cervix o

the pregnancy-containing uterus or horn will typically dilate

suciently. Similarly, any proximal longitudinal septum will

stretch to permit etal descent.

Müllerian uterine anomalies may be discovered rst during pelvic examination, cesarean delivery, tubal sterilization,

or inertility evaluation. Depending on clinical presentation,

sonography, hysterosalpingography (HSG), MR imaging, laparoscopy, and hysteroscopy may also be diagnostic. Each has

limitations and thus may be combined to completely dene

anatomy.

I a müllerian anomaly is suspected, two-dimensional

transvaginal sonography (2-D VS) is initially perormed in

most clinical settings. For this indication, the pooled accuracy

or 2-D VS is 90 to 92 percent (Pellerito, 1992). Treedimensional (3-D) VS is more accurate than 2-D VS

because it provides uterine images rom virtually any angle.

Te diagnostic accuracy o 3-D VS approaches 97 percent

(Vaz, 2017). Tus, coronal images can be constructed, and

these are essential in evaluating both internal and external

uterine contours. Both 2-D and 3-D VS are suitable or use

in pregnancy (Fig. 3-6).

Several studies reported good concordance between 3-D

VS and MR imaging o müllerian uterine anomalies (Deutch,

2008; Graupera, 2015). MR imaging is oten preerred or

complex anatomy, especially cases or which corrective surgery

is planned. MR imaging provides clear delineation o both the

internal and external uterine anatomy and has a reported accuracy o up to 100 percent or müllerian anomaly evaluation

(Bermejo, 2010; Pellerito, 1992). Moreover, secondary diagnoses such as renal or skeletal anomalies can be concurrently

evaluated. MR imaging without contrast is sae in pregnancy.

Saline inusion sonography (SIS) is a technique that instills

uid into the uterine cavity to distend and dene cavity shape.

It improves delineation o internal uterine morphology. However, SIS is contraindicated in pregnancy. It requires a patent

endometrial cavity.

In women undergoing ertility evaluation, HSG is usually

selected or uterine cavity and tubal patency assessment. It is contraindicated during pregnancy. HSG poorly denes the external

uterine contour and can delineate only patent cavities. Described

next, remember that some unicornuate rudimentary horns lack

a cavity. Also, outlet obstructions will preclude dye lling. For

inertility, hysteroscopy and/or laparoscopy plus chromotubation

may help conrm or treat uterine cavity or tubal pathologies.

Tese also screen or endometriosis, which oten coexists with

both inertility and müllerian anomalies (American Society or

Reproductive Medicine, 2015). In pregnancy, laparoscopy is

rarely used to diagnose müllerian deects, and hysteroscopy is

contraindicated.

Unicornuate Uterus (Class II)

General population estimates cite an incidence o 1 case in

4000 women (Reichman, 2009). In class II-D orms, only one

uterine horn is present (see Fig. 3-5). Instead, an underdeveloped rudimentary horn may be present. Te rudiment may or

may not communicate with the dominant horn and may or

may not contain an endometrium-lined cavity. With noncommunicating types, the rudiment may lie near the uterus or may

lie anywhere along the embryological migration path o the

paramesonephros. Tis starts at the back and sweeps orward

along the broad ligament.

Tis anomaly may be detected during ertility evaluation

by HSG, but alse-negative examinations stem rom noncavitary or noncommunicating horns ailing to ll with dye. I this

anomaly is suspected, 3-D VS raises diagnostic accuracy, but

again MR imaging may be preerred to dene endometrium

(Fukunaga, 2017). Importantly, 40 percent o aected women

will have renal anomalies (Fedele, 1996).

Main Horn. Pregnancies developing in the main horn carry

signicant obstetrical risks. Tese include rst- and secondtrimester miscarriage, malpresentation, etal-growth restriction,

etal demise, prematurely ruptured membranes, and preterm

delivery (Chan, 2011a; Hua, 2011; Reichman, 2009). Tese

risks theoretically stem rom abnormal uterine blood ow, cervical insuciency, and diminished cavity size and muscle mass

(Donderwinkel, 1992). Te main unicornuate horn is indeed

smaller than normal uterine lengths o 7- to 8-cm (Hawkins,

2013). One small study o 140 nulligravidas ound a median

uterine length o 5 cm (Li, 2019). Tose with lengths rom the

internal os to undus <4.5 cm prior to pregnancy had higher

preterm labor rates during subsequent pregnancy compared

with longer hemiuteri. Tus, a heightened awareness o potential complications is prudent. However, specic surveillance or

poor etal growth or preterm labor is mainly guided by prior

pregnancy outcomes.

Rudimentary Horn. Ectopic pregnancy, correctly termed

a cornual pregnancy, can develop within a remnant (Arleo,

2014). Tis risk includes noncommunicating cavitary rudiments, or which transperitoneal sperm migration permits

ovum ertilization and pregnancy (Nahum, 2004). Although

less common than other unicornuate pregnancy complications, rupture can create lie-threatening hemorrhage. Convergence o uterine and ovarian branches near the pregnancy

and the commonly associated placenta accreta spectrum

(PAS) explain this risk.

In a report o 70 such pregnancies, Rolen and associates

(1966) ound that most rudimentary uterine horn pregnancies

ruptured prior to 20 weeks’ gestation. Nahum (2002) reviewed

the literature rom 1900 to 1999 and identied 588 rudimentary horn pregnancies. Hal had uterine rupture, and 80 percent did so beore the third trimester. O the total 588, the

neonatal survival rate was only 6 percent.

First-trimester sonography allows an earlier diagnosis and

rudiment excision beore rupture. Te main horn shows an

empty endometrium continuous with the cervical canal, and the

interstitial portion o a allopian tube is seen only on one side.

Te rudimentary horn pregnancy displays: (1) no continuity

between the cervical canal and gestational sac, (2) myometrium

surrounding the gestation, (3) PAS-associated hypervascularity

surrounding the gestational sac, and (4) a vascular pedicle connecting the main horn and the sac’s surrounding myometrium

(Mavrelos, 2007; sarir, 2005). I necessary, 3-D VS is an

appropriate adjunct (olani, 2018). As seen in Figure 3-6, the

connecting pedicle can be broad and vascular.

reatment is surgical and removes the rudimentary horn

and in situ pregnancy. Te ipsilateral allopian tube is also

excised to avert uture ectopic pregnancies (Dove, 2017;

Worley, 2008). Steps include sequential division o the

uteroovarian ligament, mesosalpinx, round ligament, and pedicle to the main horn. Ideally, the ovary is spared, but large

pregnancies with a short uteroovarian ligament may prompt

adnexectomy. Surgical route is dictated by pregnancy size and

laparoscopic capabilities.

In nonpregnant women, most unicornuate uteri are asymptomatic. Tose with a noncommunicating cavitary rudiment

may present with outlet obstruction symptoms at puberty. In

this instance, comorbid endometriosis can club mbria and

obstruct tubal egress o blood. In all cases, prophylactic excision o a cavitary rudiment is recommended to avoid pregnancy

in an inadequately sized horn (Fedele, 2005; Rackow, 2007;

Schneiderman, 2018). Data regarding subsequent pregnancy

ater excision are scarce. In one series o eight women, all had a

preterm cesarean delivery (Pados, 2014).

Uterine Didelphys (Class III)

Tis anomaly arises rom incomplete usion that results in

two entirely separate hemiuteri, two cervices, and usually

two vaginas or a longitudinal vaginal septum (see Fig. 3-5).

Uterine didelphys may be isolated or part o a rare triad

with an obstructed hemivagina and ipsilateral renal agenesis

(OHVIRA), also known as Herlyn-Werner-Wunderlich syndrome (ong, 2014). Rarely diagnosed antenatally, it is considered in a etus with renal agenesis and a cystic pelvic mass,

which reects hydrometrocolpos (p. 40) (una, 2019). Fetal

MR imaging aids diagnosis.

Uterine didelphys is suspected on pelvic examination by

identication o a longitudinal vaginal septum and two cervices. During HSG or ertility evaluation, contrast shows

two separate endocervical canals. Tese open into separate

noncommunicating usiorm endometrial cavities that each

ends with a solitary allopian tube. In women without ertility issues, 2- or 3-D VS is a logical initial imaging tool,

and separate divergent uterine horns with a large intervening

undal clet are seen. Endometrial cavities and two cervices

are uniormly separate. MR imaging can clariy cases lacking

classic ndings.

Adverse obstetrical outcomes associated with uterine didelphys are similar to but less requent than those seen with unicornuate uterus. Increased risks include miscarriage, preterm

birth, and malpresentation (Chan, 2011a; Hua, 2011).

Metroplasty or either uterine didelphys or bicornuate

uterus involves resection o intervening myometrium and undal recombination (Alborzi, 2015). Tese rarely perormed

surgeries are chosen or highly selected patients with otherwise

unexplained recurrent miscarriage at later gestational ages.

Ater metroplasty, scheduled delivery prior to labor is prudent

to avoid uterine rupture (Ayhan, 1992).

Bicornuate Uterus (Class IV)

Tis usion anomaly results in two hemiuteri. As shown in

Figure 3-5, the central myometrium runs either partially or

completely to the cervix. A complete bicornuate uterus may

extend to the internal cervical os and have a single cervix

(bicornuate unicollis) or reach the external os (bicornuate

bicollis). As with uterine didelphys, a coexistent longitudinal

vaginal septum is common Radiological discrimination o a bicornuate uterus rom a

septate uterus can be challenging, and dening criteria vary.

Tis distinction, however, is important because septate uterus

can be treated with hysteroscopic septal resection. HSG or 2-D

VS may initially suggest an anomaly, but urther distinction is

provided by 3-D VS or MR imaging. With these, the intercornual angle, undal contour, and a straight line drawn between

the imaged tubal ostia serve as dening thresholds (Fig. 3-7).

Bicornuate uterus carries increased risks or miscarriage,

preterm birth, and malpresentation (Chan, 2011a; Mastrolia,

2017). As discussed in the prior section, rare surgical correction

by metroplasty is reserved or highly selected cases.

Septate Uterus (Class V)

With this anomaly, a resorption deect leads to a persistent

complete or partial longitudinal uterine septum (see Fig. 3-5). In the rare Robert uterus, an asymmetric longitudinal septum

creates a sequestered noncommunicating hemicavity that acts

similar to a rudimentary horn (Ludwin, 2018a).

Many septate uteri are identied during evaluation o

inertility or recurrent pregnancy loss. Although an abnormality may be identied with HSG or 2-D VS, typically

3-D VS or MR imaging is required to dierentiate septate

and bicornuate uteri. Experts still debate diagnostic criteria

(see Fig. 3-7).

Septate anomalies can be associated with increased risks or

adverse pregnancy outcomes that include miscarriage, preterm

delivery, and malpresentation (Chan, 2011a; Ghi, 2012). In

those with recurrent pregnancy loss, hysteroscopic septal resection may improve birth rates (American Society or Reproductive Medicine, 2016; Corroenne, 2018; Valle, 2013). During a

subsequent labor, those with prior septal resection, especially i

complicated by uterine peroration, carry a small risk or uterine rupture (Homer, 2000; Sentilhes, 2005).

Arcuate Uterus (Class VI)

Tis malormation is a mild deviation rom the normally developed uterus (see Fig. 3-7). Most consider this anomaly benign,

but some have ound excessive second-trimester losses, preterm

labor, and malpresentation (Chan, 2011a; Mucowski, 2010;

Prior, 2018; Woeler, 2001).

Cesarean Delivery

As noted in the above sections, cesarean delivery rates are

increased with müllerian uterine anomalies. Data regarding

subsequent trial o labor ater cesarean (OLAC) are ew

and show evidence both or and against its success and saety

(Erez, 2007; Ravasia, 1999). Failed OLAC attempts or the

risk o rupture may stem rom smaller than normal cavity size,

abnormal propagation o myometrial action potentials, and a

weaker cesarean scar due to congenitally altered vascular anatomy (Altwerger, 2015). Other actors that support or disavor

OLAC are similar to those or women with normal-shaped

uteri and are outlined in Chapter 31.

In those without prior cesarean delivery, external cephalic

version (ECV) is reasonable to avoid primary cesarean delivery

or malpresentation. A smaller uterine cavity or an obstructing midline partition may limit etal turning. Tese are added

to the traditional list o actors that should be reviewed when

assessing a potential ECV candidate (Chap. 28, p. 528).

At times, a müllerian anomaly may not be diagnosed until

cesarean delivery, and additional inormation should be methodically sought. Prior to hysterotomy closure, the cavity is manually

explored to dene the length o any cavity partition. I a rudimentary horn is ound, the main cavity is also digitally explored

or a communication. However, this may be missed due to its

narrow caliber.

Ater closure, the undus is examined. Te external contour

is delineated to dierentiate bicornuate rom didelphys types. I

only one adnexum is ound, a unicornuate uterus is suspected.

In this case, i an obvious rudiment is not attached to the main

horn, the surgeon should trace the embryological migratory

path o the paramesonephric duct starting at the patient’s back

and sweeping orward. I ound, the rudiment may be removed

or at minimum its accompanying allopian tube should be

ligated to prevent later ectopic pregnancy.

With any müllerian anomaly, both renal ossae are examined

intraoperatively to conrm kidneys. Postoperative radiologic

assessment o the urinary collecting anatomy is reasonable.

Treatment with Cerclage

Uterine anomalies are one risk or cervical insuciency (Althuisius, 2001; Berghella, 1999; Mastrolia, 2018). Some women

with uterine anomalies and repetitive pregnancy loss ater the

rst trimester may benet rom cervical cerclage (Golan, 1992;

Yassaee, 2011). Others with partial cervical atresia or hypoplasia

also may benet (Ludmir, 1991; Song, 2015). For women with

a uterine anomaly, candidacy or cervical length sonographic

screening or or cerclage placement is determined by the same

criteria used or women without a uterine deect (American

College o Obstetricians and Gynecologists, 2021; Society or

Maternal–Fetal Medicine, 2016). Tese topics are discussed in

Chapters 45 (p. 794) and 11 (p. 205), respectively.

■ Diethylstilbestrolrelated

Abnormalities (Class VII)

In the 1960s, a synthetic nonsteroidal estrogen—diethylstilbestrol (DES)—was used to treat threatened abortion, preterm

labor, preeclampsia, and diabetes. It was remarkably ineective. Moreover, women exposed as etuses carry increased risks

or vaginal clear cell adenocarcinoma, cervical intraepithelial

neoplasia, and vaginal adenosis (Hatch, 2001; Herbst, 1971;

Robboy, 1984). Women exposed in utero can also show a cervix

or vagina with a transverse septum, circumerential ridge, or cervical collar. Uteri are potentially smaller or have a -shaped cavity

(see Fig. 3-5) (Kauman, 1984). Women exposed as etuses are

now postreproductive, but they did suer risks or inertility and

adverse pregnancy outcome (Kauman, 2000; Palmer, 2001).

■ Fallopian Tube Abnormalities

Te allopian tubes develop rom the unpaired distal ends o

the müllerian ducts. Congenital anomalies include accessory

ostia, complete or segmental tubal agenesis, and several embryonic cystic remnants. Te most common is a small, benign cyst

attached by a pedicle to the distal end o the allopian tube—

the hydatid o Morgagni. In other cases, benign paratubal cysts

may be o mesonephric or mesothelial origin. Last, in utero

exposure to DES is associated with various tubal abnormalities

(DeCherney, 1981).

UTERINE FLEXION

Moderate exion o the pregnant uterus is typically inconsequential, but exaggerated exion may pose unique complications.

Antefexion describes orward angling o the uterine undus in

the sagittal plane relative to the cervix. In extreme cases, the

undus later in pregnancy alls orward to lie below the lower

margin o the symphysis. Abdominal wall laxity is contributory. Tis uterine position can prevent proper transmission o

labor contractions but is usually corrected by repositioning and

application o an abdominal binder. 

Retrofexion describes uterine undal angling posteriorly in

the sagittal plane. A growing retroexed uterus undus will

occasionally become trapped in the hollow o the sacrum

(Fig. 3-8). Symptoms include pelvic pressure or pain plus

voiding dysunction or retention. During bimanual pelvic

examination, the cervix will be anterior and behind the symphysis pubis, whereas the uterus is wedged in the deep pelvis. Sonography or MR imaging can aid diagnosis (Gardner,

2013; Grossenburg, 2011).

With continued uterine growth, the incarcerated uterus can

spontaneously resolve over 1 to 2 weeks. A knee-chest position

assumed by the patient several times daily may assist resolution

(Hooker, 2009). An indwelling urinary catheter or intermittent

sel-catheterization resolves retention. Persistent cases require

manual repositioning. For this, ater bladder catheterization, the

uterus can usually be pushed out o the pelvis when the woman

is placed in a knee-chest position. Oten, this is best accomplished by digital pressure applied through the rectum or vagina.

Intravenous sedation or spinal analgesia aids comort and allows

sucient dislodging orces (Hire, 2019). Aterward, insertion

o a sot, space-lling pessary or a ew weeks usually prevents

recurrence (Gibbons, 1969).

For rare resistant cases, advancing a colonoscope or colonoscopic insuation can dislodge the undus (Newell, 2014;

Seubert, 1999). Upward round ligament traction during laparoscopy also has been described (Lettieri, 1994).

Rarely, sacculation may orm as an extensive lower uterine

segment dilation due to persistent uterine entrapment. Clinically, the elongated vagina extends above the level o the deeply

descended etal head. Te Foley catheter is requently palpated

above the level o the umbilicus! In these extreme cases, sonography and MR imaging help dene anatomy (Gottschalk,

2008; Lee, 2008). o avoid uterine rupture, cesarean delivery is

necessary when sacculation is marked. Spearing (1978) recommended extending the abdominal incision above the umbilicus

and delivering the entire uterus rom the abdomen beore hysterotomy. Correct anatomical relationships are ideally restored

to help prevent inadvertent incisions into and through the

vagina and bladder (Fig. 3-9). (Singh, 2007; Uma, 2002).

Uterine torsion is another rare acquired anomaly. During

pregnancy, the uterus commonly rotates gently to the maternal

right. Rotation exceeding 180 degrees creates torsion, and most

cases stem rom uterine leiomyomas, müllerian anomalies, etal

malpresentation, pelvic adhesions, or laxity o the abdominal

wall or uterine ligaments. In one review o 212 cases, associated

symptoms were obstructed labor, intestinal or urinary complaints abdominal pain, uterine hypertonus, vaginal bleeding, or hypotension (Jensen, 1992).

In some women, torsion can be conrmed preoperatively

with MR imaging, which shows a twisted vagina that appears

X-shaped rather than its normal H-shape (Nicholson, 1995).

Flipped placenta location and abnormal umbilical Doppler

ndings have been described sonographically (Rood, 2014).

However, uterine torsion is usually ound at the time o cesarean delivery, and the severely rotated uterus should be repositioned anatomically beore hysterotomy. In some cases, an

inability to reposition or a ailure to recognize the torsion

may lead to a posterior hysterotomy incision (Albayrak, 2011;

Karavani, 2017). Rotation o 90 degrees risks uterine vessel laceration (Berger, 2020).