● Embryology

● Morphological Changes During Maturation of The Gametes

1. Oogenesis
→ Is the process whereby oogonia differentiate into mature oocytes.

2. Maturation of Oocytes Begins Before Birth

→ Once PGCs (Primordial Germ Cells) have arrived in the gonad of a
genetic female, they differentiate into oogonia. These cells undergo a
number of mitotic divisions, and by the end of the third month, they are
arranged in clusters surrounded by a layer of flat epithelial cells.
→ Whereas all of the oogonia in one cluster are probably derived from a
single cell, the flat epithelial cells, known as follicular cells, originate from
surface epithelium covering the ovary. The majority of oogonia continue to
divide by mitosis, but some of them arrest their cell division in prophase of
meiosis I and form primary oocytes.
→ During the next few months, oogonia increases rapidly in number, and by
the fifth month of prenatal development, the total number of germ cells in the
ovary reaches its maximum, estimated at 7 million. At this time, cell death
begins, and many oogonia as well as primary oocytes degenerate and
become atretic.
→ By the seventh month, the majority of oogonia have degenerated except
for a few near the surface. All surviving primary oocytes have entered
prophase of meiosis I, and most of them are individually surrounded by a
layer of flat follicular epithelial cells (Fig. 2.17B). A primary oocyte, together
with its surrounding flat epithelial cells, is known as a primordial follicle.

3. Maturation of Oocytes Continues at Puberty

→ Near the time of birth, all primary oocytes have started prophase of
meiosis I, but instead of proceeding into metaphase, they enter the diplotene
stage, a resting stage during prophase that is characterized by a lacy
network of chromatin (Fig. 2.17C). Primary oocytes remain arrested in
prophase and do not finish their first meiotic division before puberty is
reached. This arrested state is produced by oocyte maturation inhibitor
(OMI), a small peptide secreted by follicular cells. The total number of
primary oocytes at birth is estimated to vary from 600,000 to 800,000.
→ During childhood, most oocytes become atretic; only approximately
40,000 are present by the beginning of puberty, and fewer than 500 will be
ovulated. Some oocytes that reach maturity late in life have been dormant in
the diplotene stage of the first meiotic division for 40 years or more before
ovulation. Whether the diplotene stage is the most suitable phase to protect
the oocyte against environmental influences is unknown. The fact that the
risk of having children with chromosomal abnormalities increases with
maternal age indicates that primary oocytes are vulnerable to damage as
they age.
→ At puberty, a pool of growing follicles is established and continuously
maintained from the supply of primordial follicles. Each month, 15 to 20
follicles selected from this pool begin to mature. Some of these die, whereas
others begin to accumulate fluid in a space called the antrum, thereby
entering the antral or vesicular stage (Fig. 2.19A). Fluid continues to
accumulate such that, immediately prior to ovulation, follicles are quite
swollen and are called mature vesicular follicles or graafian follicles (Fig.
2.19B). The antral stage is the longest, whereas the mature vesicular stage
encompasses approximately 37 hours prior to ovulation.
→ As primordial follicles begin to grow, surrounding follicular cells change
from flat to cuboidal and proliferate to produce a stratified epithelium of
granulosa cells, and the unit is called a primary follicle (Fig. 2.18B,C).
Granulosa cells rest on a basement membrane separating them from
surrounding ovarian connective tissue (stromal cells) that form the theca
folliculi. Also, granulosa cells and the oocyte secretes layer of glycoproteins
on the surface of the 00- cyte, forming the zona pellucida (Fig. 2.18C). As
follicles continue to grow, cells of the theca folliculi organize into an inner
layer of secretory cells, the theca interna, and an outer fibrous capsule, the
theca externa. Also, small, fingerlike processes of the follicular cells extend
across the zona pellucida and interdigitate with microvilli of the plasma
membrane of the oocyte. These processes are important for transport of
materials from follicular cells to the oocyte.
→ As development continues, fluid-filled spaces appear between granulosa
cells. Coalescence of these spaces forms the antrum, and the follicle is
termed a vesicular or an antral follicle. Initially, the antrum is
crescent-shaped, but with time, it enlarges (Fig. 2.19). Granulosa cells
surrounding the oocyte remain intact and form the cumulus oophorus. At
maturity, the mature vesicular (graafian) follicle may be 25 mm or more in
diameter. It is surrounded by the theca interna, which is composed of cells
having characteristics of steroid secretion, rich in blood vessels, and the
theca externa, which gradually merges with the ovarian connective tissue
(Fig. 2.19).
→ With each ovarian cycle, a number of follicles begin to develop, but
usually, only one reaches full maturity. The others degenerate and become
atretic. When the secondary follicle is mature, a surge in luteinizing hormone
(LH) induces the preovulatory growth phase. Meiosis I is completed,
resulting in formation of two daughter cells of unequal size, each with 23
double-structured chromosomes (Fig. 2.20A,B). One cell, the secondary
oocyte, receives most of the cytoplasm; the other, the first polar body,
receives practically none. The first polar body lies between the zona
pellucida and the cell membrane of the secondary oocyte in the perivitelline
space (Fig. 2.20B). The cell then enters meiosis II but arrests in metaphase
 approximately 3 hours before ovulation. Meiosis II is completed only if the
oocyte is fertilized; otherwise, the cell degenerates approximately 24 hours
after ovulation. The first polar body may undergo a second division (Fig.
2.20C).

● Third Month to Birth: The Fetus and Placenta

1. Structure of The Placenta
→ By the beginning of the fourth month, the placenta has two
components: (1) a fetal portion, formed by the chorion frondosum, and (2)
a maternal portion, formed by the decidua basalis (Fig. 8.10B).
→ On the fetal side, the placenta is bordered by the chorionic plate (Fig.
8.13); on its maternal side, it is bordered by the decidua basalis, of which
the decidual plate is most intimately incorporated into the placenta. In the
junctional zone, trophoblast and decidual cells intermingle. This zone,
characterized by decidual and syncytial giant cells, is rich in amorphous
extracellular material. By this time, most cytotrophoblast cells have
degenerated. Between the chorionic and decidual plates are the
intervillous spaces, which are filled with maternal blood. They are derived
from lacunae in the syncytiotrophoblast and are lined with syncytium of
fetal origin. The villous trees grow into the intervillous blood lakes (Figs.
8.8 and 8.13).
→ During the fourth and fifth months, the decidua forms a number of
decidual septa, which project into intervillous spaces but do not reach the
chorionic plate (Fig. 8.13). These septa have a core of maternal tissue,
but their surface is covered by a layer of syncytial cells so that at all times,
a syncytial layer separates maternal blood in intervillous lakes from fetal
tissue of the villi. As a result of this septum formation, the placenta is
divided into a number of compartments, or cotyledons (Fig. 8.14).
Because the decidual septa do not reach the chorionic plate, contact
between intervillous spaces in the various cotyledons is maintained. As a
result of the continuous growth of the fetus and expansion of the uterus,
the placenta also enlarges. Its increase in surface area roughly parallels
that of the expanding uterus, and throughout pregnancy, it covers
approximately 15% to 30% of the internal surface of the uterus. The
increase in thickness of the placenta results from arborization of existing
villi and is not caused by further penetration into maternal tissues.
A. Full-Term Placenta
→ At full term, the placenta is discoid with a diameter of 15 to 25
cm, is approximately 3 cm thick, and weighs about 500 to 600 g.
At birth, it is torn from the uterine wall and, approximately 30
minutes after birth of the child, is expelled from the uterine cavity
as the afterbirth. When the placenta is viewed from the maternal
side, 15 to 20 slightly bulging areas, the cotyledons, covered by a
 thin layer of decidua basalis, are clearly recognizable (Fig. 8.14B).
Grooves between the cotyledons are formed by decidual septa.
Ihe fetal surface of the placenta is covered entirely by the
chorionic plate. A number of large arteries and veins, the chorionic
vessels, converge toward the umbilical cord (Fig. 8.14A). The
chorion, in turn, is covered by the amnion. Attachment of the
umbilical cord is usually eccentric and occasionally even marginal.
Rarely, however, does it insert into the chorionic membranes
outside the placenta (velamentous insertion).
B. Circulation of The Placenta
→ Cotyledons receive their blood through 80 to 100 spiral arteries
that pierce the decidual plate and enter the intervillous spaces at
more or less regular intervals (Fig. 8.13). Pressure in these
arteries forces the blood deep into the intervillous spaces and
bathes the numerous small villi of the villous tree in oxygenated
blood. As the pressure decreases, blood flows back from the
chorionic plate toward the decidua, where it enters the endometrial
veins (Fig. 8.13). Hence, blood from the intervillous lakes drains
back into the maternal circulation through the endometrial veins.
Collectively, the intervillous spaces of a mature placenta contain
approximately 150 mL of blood, which is replenished about three
or four times per minute. This blood moves along the chorionic
villi, which have a surface area of 4 to 14 m2. Placental exchange
does not take place in all villi, however, only in those that have
fetal vessels in intimate contact with the covering syncytial
membrane. In these villi, the syncytium often has a brush border
consisting of numerous microvilli, which greatly increases the
surface area and, consequently, the exchange rate between
maternal and fetal circulations (Fig. 8.8D).
→ The placental membrane, which separates maternal and fetal
blood, is initially composed of four layers: (1) the endothelial lining
of fetal vessels, (2) the connective tissue in the villus core, (3) the
cytotrophoblastic layer, and (4) the syncytium (Fig. 8.8C). From
The fourth month on, the placental membrane thins because the
endothelial lining of the vessels comes in intimate contact with the
syncytial membrane, greatly increasing the rate of exchange (Fig.
8.8D). Sometimes called the placental barrier, the placental
membrane is not a true barrier, as many substances pass through
it freely. Because the maternal blood in the intervillous spaces is
separated from the fetal blood by a chorionic derivative, the
human placenta is considered to be of the hemochorial type.
Normally, there is no mixing of maternal and fetal blood. However,
small numbers of fetal blood cells occasionally escape across
microscopic defects in the placental membrane.
C. Function of The Placenta
→ Main functions of the placenta are (1) exchange of metabolic
and gaseous products between maternal and fetal bloodstreams
and (2) production of hormones.
→ Exchange of Gases
Exchange of gases—such as oxygen, carbon dioxide, and carbon
monoxide—is accomplished by simple diffusion. At term, the fetus
extracts 20 to 30 mL of oxygen per minute from the maternal
circulation, and even a short-term interruption of the oxygen
supply is fatal to the fetus. Placental blood flow is critical to oxygen
supply, as the amount of oxygen reaching the fetus primarily
depends on delivery, not diffusion.
→ Exchange of Nutrients and Electrolytes
Exchange of nutrients and electrolytes, such as amino acids, free
fatty acids, carbohydrates, and vitamins, is rapid and increases as
pregnancy advances.
→ Transmission of Maternal Antibodies
Immunological competence begins to develop late in the first
trimester, by which time the fetus makes all of the components of
complement. Immunoglobulins consist almost entirely of maternal
immunoglobulin G (IgG), which begins to be transported from
mother to fetus at approximately 14 weeks. In this manner, the
fetus gains passive immunity against various infectious diseases.
Newborns begin to produce their own IgG, but adult levels are not
attained until the age of 3 years.
→ Hormone Production
By the end of the fourth month, the placenta produces
progesterone in sufficient amounts to maintain pregnancy if the
corpus luteum is removed or fails to function properly. In all
probability, all hormones are synthesized in the syncytial
trophoblast. In addition to progesterone, the placenta produces
increasing amounts of estrogenic hormones, predominantly estriol,
until just before the end of pregnancy, when a maximum level is
reached. These high levels of estrogens stimulate uterine growth
and development of the mammary glands. During the first 2
months of pregnancy, the syncytiotrophoblast also produces
human chorionic gonadotropin (hCG), which maintains the corpus
luteum. This hormone is excreted by the mother in the urine, and
in the early stages of gestation, its presence is used as an
indicator of pregnancy. Another hormone produced by the
placenta is somatomammotropin (formerly placental lactogen). It is
a growth hormone— like substance that gives the fetus priority on
maternal blood glucose and makes the mother somewhat
 diabetogenic. It also promotes breast development for milk
production.
2. Amnion and Umbilical Cord
→ The oval line of reflection between the amnion and embryonic
ectoderm (amnio-ectodermal junction) is the primitive umbilical ring. At
the fifth week of development, the following structures pass through the
ring (Fig. 8.16A,C): (1) the connecting stalk, containing the allantois and
the umbilical vessels, consisting of two arteries and one vein; (2) the yolk
stalk (Vitelline duct), accompanied by the vitelline vessels; and (3) the
canal connecting the intraembryonic and extraembryonic cavities (Fig.
8.16C). The yolk sac proper occupies a space in the chorionic cavity, that
is, the space between the amnion and chorionic plate (Fig. 8.16B).
→ During further development, the amniotic cavity enlarges rapidly at the
expense of the chorionic cavity, and the amnion begins to envelop the
connecting and yolk sac stalks, crowding them together and giving rise to
the primitive umbilical cord (Fig. 8.16B). Distally, the cord contains the
yolk sac stalk and umbilical vessels. More proximally, it contains some
intestinal loops and the remnant of the allantois (Fig. 8.16B,D). The yolk
sac, found in the chorionic cavity, is connected to the umbilical cord by its
stalk.
→ At the end of the third month, the amnion has expanded so that it
comes in contact with the chorion, obliterating the chorionic cavity (Fig.
8.10B). The yolk sac then usually shrinks and is gradually obliterated. The
abdominal cavity is temporarily too small for the rapidly developing
intestinal loops, and some of them are pushed into the extraembryonic
space in the umbilical cord. These extruding intestinal loops form a
physiological umbilical hernia (see Chapter 15). At approximately the end
of the third month, the loops are withdrawn into the body of the embryo,
and the cavity in the cord is obliterated. When the allantois and the
vitelline duct and its vessels are also obliterated, all that remains in the
cord are the umbilical vessels surrounded by Wharton jelly. This tissue,
which is rich in proteoglycans, functions as a protective layer for the blood
vessels. The walls of the arteries are muscular and contain many elastic
fibers, which contribute to a rapid constriction and contraction of the
umbilical vessels after the cord is tied off.
3. Placental Changes at The End of Pregnancy
→ At the end of pregnancy, a number of changes that occur in the
placenta may indicate reduced exchange between the two circulations.
These changes include (1) an increase in fibrous tissue in the core of the
villus, (2) thickening of basement membranes in fetal capillaries, (3)
obliterative changes in small capillaries of the villi, and (4) deposition of
fibrinoid on the surface of the villi in the junctional zone and in the
chorionic plate. Excessive fibrinoid formation frequently causes infarction
of an intervillous lake or sometimes of an entire cotyledon. The cotyledon
then assumes a whitish appearance.
→ Pada akhir kehamilan, sejumlah perubahan yang terjadi pada plasenta
dapat mengindikasikan berkurangnya pertukaran antara kedua sirkulasi.
Perubahan ini meliputi (1) peningkatan jaringan fibrosa di inti vili, (2)
penebalan membran basal di kapiler janin, (3) perubahan obliterasi pada
kapiler kecil vili, dan (4) deposisi fibrinoid pada permukaan vili di zona
 junctional dan di lempeng korionik. Pembentukan fibrinoid yang
berlebihan sering menyebabkan infark danau antarvilus atau
kadang-kadang seluruh kotiledon. Kotiledon kemudian terlihat keputihan.
4. Amniotic Fluid
→ The amniotic cavity is filled with a clear, watery fluid that is produced in
part by amniotic cells but is derived primarily from maternal blood. The
amount of fluid increases from approximately 30 mL at 10 weeks of
gestation to 450 mL at 20 weeks to 800 to 1,000 mL at 37 weeks.
→ During the early months of pregnancy, the embryo is suspended by its
umbilical cord in this fluid, which serves as a protective cushion.
→ The fluid (1) absorbs jolts, (2) prevents adherence of the embryo to the
amnion, and (3) allows for fetal movements. The volume of amniotic fluid
is replaced every 3 hours.
→ From the beginning of the fifth month, the fetus swallows its own
amniotic fluid, and it is estimated that it drinks about 400 mL a day, about
half of the total amount. Fetal urine is added daily to the amniotic fluid in
the fifth month, but this urine is mostly water because the placenta is
functioning as an exchange for metabolic wastes. During childbirth, the
amniochorionic membrane forms a hydrostatic wedge that helps to dilate
the cervical canal.
5. Fetal Membranes in Twins
→ Approximately 90% of twins are dizygotic, or fraternal, and their
incidence increases with maternal age (doubling at age 35 years) and
with fertility procedures, including ART. They result from simultaneous
shedding of two oocytes and fertilization by different spermatozoa.
Because the two zygotes have different genetic constitutions, the twins
have no more resemblance than any other brothers or sisters. They may
or may not be of different sex. The zygotes implant individually in the
uterus, and usually each develops its own placenta, amnion, and
chorionic sac (Fig. 8.18A). Sometimes, however, the two placentas are so
close together that they fuse. Similarly, the walls of the chorionic sacs
may also come into close apposition and fuse (Fig. 8.18B). Occasionally,
each dizygotic twin possesses red blood cells of two different types
(erythrocyte mosaicism), indicating that fusion of the two placentas was
so intimate that red cells were exchanged.
→ The second type of twins, which develops from a single fertilized ovum,
is monozygotic, or identical, twins. The rate for monozygotic twins is 3 to
4 per 1,000. They result from splitting of the zygote at various stages of
development. The earliest separation is believed to occur at the twocell
stage, in which case two separate zygotes develop. The blastocysts
implant separately, and each embryo has its own placenta and chorionic
sac (Fig. 8.19A). Although the arrangement of the membranes of these
twins resembles that of dizygotic twins, the two can be recognized as
partners of a monozygotic pair by their strong resemblance in blood
groups, fingerprints, sex, and external appearance, such as eye and hair
color. Splitting of the zygote usually occurs at the early blastocyst stage.
The inner cell mass splits into two separate groups of cells within the
same blastocyst cavity (Fig. 8.19B). The two embryos have a common
placenta and a common chorionic cavity but separate amniotic cavities
(Fig. 8.19B).
 → In rare cases, the separation occurs at the bilaminar germ disc stage,
just before the appearance of the primitive streak (Fig. 8.19C). This
method of splitting results in formation of two partners with a single
placenta and a common chorionic and amniotic sac. Although the twins
have a common placenta, blood supply is usually well balanced. Although
triplets are rare (about 1 per 7,600 pregnancies), birth of quadruplets,
quintuplets, and so forth is rarer. In recent years, multiple births have
occurred more frequently in mothers given gonadotropins (fertility drugs)
for ovulatory failure.
6. Parturition (Birth)
→ For the first 34 to 38 weeks of gestation, the uterine myometrium does
not respond to signals for parturition (birth). During the last 2 to 4 weeks
of pregnancy, however, this tissue undergoes a transitional phase in
preparation for the onset of labor. Ultimately, this phase ends with a
thickening of the myometrium in the upper region of the uterus and a
softening and thinning of the lower region and cervix.
→ Labor itself is divided into three stages:
(1) effacement (thinning and shortening) and dilatation of the cervix (this
stage ends when the cervix is fully dilated) → produced by uterine
contractions that force the amniotic sac against the cervical canal like a
wedge, or if the membranes have ruptured, then pressure will be exerted
by the presenting part of the fetus, usually the head.
(2) delivery of the fetus → assisted by uterine contractions, but the most
important force is provided by increased intra-abdominal pressure from
contraction of abdominal muscles.
(3) delivery of the placenta and fetal membranes → requires uterine
contractions and is aided by increasing intra-abdominal pressure. As the
uterus contracts, the upper part retracts, creating a smaller and smaller
lumen, while the lower part expands, thereby producing direction to the
force.

Contractions usually begin about 10 minutes apart; then, during the

second stage of labor, they may occur <1 minute apart and last from 30 to
90 seconds. Their occurrence in pulses is essential to fetal survival, as
they are of sufficient force to compromise uteroplacental blood flow to the
fetus.

1. Prostate
→ The prostate (approximately 3 cm long, 4 cm wide, and 2 cm in
anteroposterior [AP] depth) is the largest accessory gland of the male
reproductive system. The firm, walnut-size prostate surrounds the prostatic
urethra. The glandular part makes up approximately two thirds of the prostate;
the other third is fibromuscular. The fibrous capsule of the prostate is dense and
neurovascular, incorporating the prostatic plexuses of veins and nerves.
→ All of this is surrounded by the visceral layer of the pelvic fascia, forming a
fibrous prostatic sheath that is thin anteriorly, continuous anterolaterally with the
puboprostatic ligaments, and dense posteriorly where it blends with the
rectrovesical septum.
→ The prostate has:
- a base closely related to the neck of the bladder
 - an apex that is in contact with fascia on the superior aspect of the urethral
sphincter and deep perineal muscles
- a muscular anterior surface, featuring mostly transversely oriented muscle
fibers forming a vertical, trough-like hemi sphincter (rhabdosphincter),
which is part of the urethral sphincter. The anterior surface is separated
from the pubic symphysis by retroperitoneal fat in the retropubic space
- a posterior surface that is related to the ampulla of the rectum.
- inferolateral surfaces that are related to the levator ani.
→ Although not clearly distinct anatomically, the following lobes of the prostate
are traditionally described.
- The isthmus of the prostate (commissure of prostate; historically, the
anterior lobe) lies anterior to the urethra. It is fibromuscular, the muscle
fibers representing a superior continuation of the external urethral
sphincter muscle to the neck of the bladder, and contains little, if any,
glandular tissue.
- Right and left lobes of the prostate, separated anteriorly by the isthmus
and posteriorly by a central, shallow longitudinal furrow, may each be
subdivided for descriptive purposes into four indistinct lobules defined by
their relationship to the urethra and ejaculatory ducts and-although less
apparent-by the arrangement of the ducts and connective tissue:
a. An inferoposterior (lower posterior) lobule that lies posterior to the
urethra and inferior to the ejaculatory ducts. This lobule constitutes
the aspect of the prostate palpable by digital rectal examination.
b. An inferolateral (lower lateral) lobule directly lateral to the urethra,
forming the major part of the right or left lobe.
c. A superomedial lobule, deep to the inferoposterior lobule,
surrounding the ipsilateral ejaculatory duct.
d. An anteromedial lobule, deep to the inferolateral lobule, directly
lateral to the proximal prostatic urethra.
→ The prostatic ducts (20--30) open chiefly into the prostatic sinuses that lie on
either side of the seminal colliculus on the posterior wall of the prostatic urethra
(Fig. 6.37). Prostatic fluid, a thin, milky fluid. provides approximately 20% of the
volume of semen (a mixture of secretions produced by the testes, seminal
glands, prostate, and bulbo-uretb:ral glands that provides the vehicle by which
sperms are transported) and plays a role in activating the sperms.

→ The ductus deferens, seminal glands, ejaculatory ducts, and prostate are
richly innervated by presynaptic sympathetic fibers that originate from cell bodies
in the intermediolateral cell column of the T12-L2 (or L3) spinal cord segments.
- As part of an orgasm, the sympathetic system stimulates contraction of the
internal urethral sphincter to prevent retrograde ejaculation. Simultaneously, it
stimulates rapid peristaltic like contractions of the ductus deferens, and the
combined contraction of and secretion from the seminal glands and prostate that
provide the vehicle (semen), and the expulsive force to discharge the sperms
during ejaculation. The function of the parasympathetic innervation of the internal
genital organs is unclear.

- However, parasympathetic fibers traversing the prostatic nerve plexus form the
cavernous nerves that pass to the erectile bodies of the penis, which are
responsible for producing penile erection.
 → Duktus deferens, kelenjar mani, duktus ejakulatorius, dan prostat dipersarafi
oleh serat simpatis presinaptik yang berasal dari badan sel di kolom sel
intermediolateral segmen medula spinalis T12-L2 (atau L3).
Sebagai bagian dari orgasme, sistem simpatis merangsang kontraksi sfingter
uretra internal untuk mencegah ejakulasi retrograde. Secara bersamaan,
merangsang peristaltik cepat seperti kontraksi duktus deferens, dan kontraksi
gabungan dan sekresi dari kelenjar mani dan prostat yang menyediakan
kendaraan (air mani), dan kekuatan ekspulsif untuk mengeluarkan sperma
selama ejakulasi. Fungsi persarafan parasimpatis organ genital internal tidak
jelas.
Namun, serat parasimpatis yang melintasi pleksus saraf prostat membentuk
saraf kavernosa yang berjalan ke badan ereksi penis, yang bertanggung jawab
untuk menghasilkan ereksi penis.

B. Histology
● Female Reproductive Organ
1. Ovary
→ Ovary is a small, almond-shaped structure.
→ Ovary’s thick connective tissue capsule (tunica albuginea), is covered
by a simple squamous to cuboidal mesothelium known as the germinal
epithelium (a modified mesothelium).
→ Ovary is divisible into the cortex rich in ovarian follicles and the
medulla, a highly vascular connective tissue stroma.
- The cortex, located just deep to the tunica albuginea,
houses the female germ cells, oogonia, which have
undergone a series of cell divisions to form numerous
primary oocytes.
- The medulla is a highly vascularized loose connective
tissue stroma rich in fibroblasts and estrogen-secreting
interstitial cells.
- Additionally, occasional hilar cells are present in the
medulla; these cells resemble interstitial cells of the testis,
and they manufacture a small amount of androgens.
2. Corpus Luteum and Corpus Albicans
→ Once the graafian follicle loses its oocyte, it becomes transformed into
the corpus hemorrhagicum.
→ Within a couple of days, the corpus hemorrhagicum is transformed into
the corpus luteum, a yellow glandular structure that secretes
progesterone, a hormone that suppresses LH release by inhibiting
gonadotropin releasing hormone (GnRH) and facilitates the thickening of
the uterine endometrium.
 → Additionally, estrogen (inhibitor of FSH) and relaxin (which causes the
fibrocartilage of the pubic symphysis to become more pliable) are also
released by the corpus luteum.
→ The transformation into the corpus luteum is due to both local factors
such as IGF-I (insulin-like growth factor-I) and IGF-II as well as the
hormones LH and prolactin.
→ This process involves the several steps, including:
- The breakdown of the basement membrane between the theca
interna and the granulosa cells
- Collapse and folding of the former graafian follicle upon itself
- Resorption of the blood from the corpus hemorrhagicus
- Its replacement by fibrous connective tissue.
→ Additionally, the cells of the graafian follicle also become altered, in
that theca interna cells transform into theca lutein cells and the granulosa
cells become transformed into granulosa lutein cells.
→ In case pregnancy does not occur, the corpus luteum atrophies, a
process known as luteolysis, and the absence of estrogen and
progesterone will once again permit the release of FSH and LH from the
adenohypophysis. In this case, the corpus luteum is known as the corpus
luteum of menstruation and will degenerate into the corpus albicans.

3. Genital Ducts
→ The genital ducts are composed of the two oviducts and the single
uterus.
a. Oviduct
→ Each oviduct (fallopian tube) is a short muscular tube leading from the
vicinity of the ovary to the uterine lumen.
→ The oviduct is subdivided into four regions:
- Infundibulum (whose fimbriae approximate the ovary)
- Ampulla
- Isthmus
- Intramural portion, which pierces the wall of the uterus.
→ The mucosa of the oviduct, composed of a simple columnar epithelium
and a vascular lamina propria, is extensively folded in the infundibulum
and ampulla, but the folding is reduced in the isthmus and intramural
portions.
→ The simple columnar epithelium is composed of two types of cells:
- Ciliated columnar cells, whose cilia beat toward the uterus to
transport the fertilized egg into the uterus for implantation
- Peg cells, which are also columnar but have no cilia.
→ Their apical region is expanded and houses the secretory product that
these cells release:
- Factors for the capacitation of spermatozoa
 - Nutrient-rich medium that nourishes the spermatozoa as well as
the fertilized ovum traveling toward the uterus.
→ The mucosa is surrounded by a thick smooth muscle coat composed
of a poorly defined inner circular and outer longitudinal layers which, via
peristaltic action, assists the cilia to propel the fertilized egg to the uterus.
The muscular coat of the oviduct is covered by a serosa, whereas its
intramural portion is embedded in the uterus and is surrounded by uterine
connective tissue.
b. Uterus
→ The uterus, a pear-shaped viscus, is divisible into a fundus, body, and
cervix.
→ During pregnancy, it is this organ that houses and supports the
developing embryo and fetus. The uterus is composed of a thick,
muscular myometrium (covered by serosa and/or adventitia) and a
spongy mucosal layer, the endometrium.
→ The endometrium, composed of an epithelially lined lamina propria,
with its superficial functional and deep basal layers, undergoes
hormonally modulated cyclic changes during the menstrual cycle.
→ The three stages of the endometrium are the:
- Follicular (proliferative) phase
- Luteal (secretory) phase
- Menstrual phase
c. Cervix of Uterus
→ The cervix is the inferior aspect of the uterus, and it protrudes into the
vagina. The lumen (canal) of the cervix is continuous with the lumen of
the uterus (superiorly) and the vaginal canal (inferiorly).
→ The wall of the cervix is thick and is composed of a dense irregular
fibroelastic connective tissue housing some smooth muscle cells and
branched cervical glands.
→ The cervical glands produce a serous secretion that lubricates the
vagina.
→ After fertilization, these glands produce a thick, viscous mucus that
impedes the entry of additional spermatozoa and microorganisms into the
uterine lumen.
→ The superior aspect of its lumen is lined by a simple columnar
epithelium whose cells secrete a mucous substance.
→ The inferior aspect of the lumen is lined by a stratified squamous
nonkeratinized epithelium that is continuous with the vaginal epithelium.
→ The thick cervical wall becomes thinner and less rigid at parturition due
to the effects of the hormone oxytocin

d. Placenta
→ During pregnancy, the uterus participates in the formation of the
placenta, a highly vascular structure that permits the exchange of various
materials between the maternal and fetal circulatory systems.
→ It must be stressed that the exchange occurs without the commingling
of the maternal and fetal bloods and that the placenta is derived from both
maternal and fetal tissues.
→ The roles of the trophoblasts and the endometrium are as follows:
- The syncytiotrophoblasts and cytotrophoblasts form the chorion,
the precursor of the chorionic plate from which the chorionic villi
will arise.
- The endometrium in contact with the chorion becomes modified to
form the decidua with its three regions:
a. Decidua basalis, the richly vascularized maternal portion of
the placenta, that induces the trophoblasts to form the
chorionic villi
b. Decidua capsularis, the tissue separating the lumen of the
uterus from the embryo and will be known as the chorion
laeve
c. Decidua parietalis, the endometrial tissue between the
uterine lumen and the myometrium.
→ Initially, the chorionic villi are slender structures and are known as
primary villi. Once they are invaded by mesenchymal cells and fetal
capillary networks, they become more substantial and their population of
cytotrophoblasts decreases because they become incorporated into the
 syncytiotrophoblasts; in this manner, the primary villi become known as
secondary villi.
→ As the placenta is forming, the decidua basalis develops large,
blood-filled vascular channels, known as lacunae, and the secondary villi
protrude into these “lakes” of maternal blood, supplied by maternal
arterioles and drained by maternal venules.
→ Secondary villi grow into these lacunae, and some of the villi contact
and fuse with the decidua basalis (anchoring villi), whereas other
secondary villi (free villi) resemble fingers that are immersed in water.
→ The fetal capillary beds of the anchoring and free villi are located
adjacent to the syncytiotrophoblasts and lie in close proximity of the
maternal blood in the lacunae.
→ Diffuse through villi:
Maternal blood → Fetal capillaries: O2 and nutrient
Fetal capillaries → Maternal blood: CO2 and waste products
→ The exchange of gases and material occurs by passing through the
placental barrier whose components are endothelial cells of fetal capillary,
basal lamina of fetal endothelium, connective tissue of secondary villus,
basal lamina of cytotrophoblasts, cytotrophoblasts, syncytiotrophoblasts.
4. Vagina
→ The vagina, an 8-9 cm long muscular sheath, extending from the cervix
of the uterus to the vestibule, is adapted for the reception of the penis
during copulation and for the passage of the fetus from the uterus during
birth.
→ The wall of the vagina is composed of three layers: the mucosa,
muscularis, and the adventitia.
→ The mucosa consists of a stratified squamous epithelium and a loose,
fibroelastic connective tissue layer, the lamina propria.
→ The muscularis is composed of a mostly longitudinally disposed
smooth muscle layer interspersed with some circularly arranged fibers. At
its external orifice, the muscularis of the vagina possesses a sphincter,
composed of circularly arrayed smooth muscle fibers.
→ The adventitia is a dense fibroelastic connective tissue that affixes the
vagina to the surrounding pelvic connective tissue.
→ Frequently, in a virgin, the external orifice of the vagina is partially
occluded by the hymen, a thin, somewhat vascular connective tissue
membrane, covered on both sides by stratified squamous epithelium.
5. Mammary Glands
→ Is a highly modified sweat glands, are identical in males and females
until the onset of puberty, when, due to hormonal influences, the female
breasts develop.
→ Technically, the mammary glands are not considered to belong in the
reproductive system, but historically they have been discussed along with
the female reproductive system and this Atlas follows that tradition.
→ In the mature female, the mammary gland is composed of numerous
individual compound glands, each of which is considered a lobe, where
each lobe is drained by a lactiferous duct that delivers milk, the secretion
of the mammary glands, onto the surface of the nipple.
→ The pigmented region of the skin surrounding the nipple, known as the
areola, is richly endowed by sweat, sebaceous, and areolar glands.
→ During pregnancy, several hormones interact to promote the
development of the secretory units of the mammary gland. Cells of the
terminal interalveolar ducts proliferate to form secretory alveoli.
→ The hormones involved in promoting this process are progesterone,
estrogen, and human chorionic mammotropin from the placenta and
lactogenic hormone (prolactin) from the acidophils of the
adenohypophysis.
→ Alveoli and terminal interalveolar ducts are surrounded by
myoepithelial cells that contract as a result of the release of oxytocin from
the neurohypophysis (in response to suckling), forcing milk out of the
breast (milk ejection reflex).
→ Milk is composed of water, proteins, lipids, and lactose. However, milk
secreted during the first few days (colostrum) is different, in that it is rich
in vitamins, minerals, lymphoid cells, and proteins, especially
immunoglobulin A, providing antibodies and immunologic support for the
neonate for the first few months of life.
→ The large, conical nipple of the breast is covered by a thin epidermis
(Ed), composed of stratified squamous keratinized epithelium. Although
the nipple possesses neither hair nor sweat glands, it is richly endowed
with sebaceous glands (SG).
→ The dense irregular collagenous connective tissue (CT) core displays
numerous longitudinally positioned lactiferous ducts that pierce the tip of
the nipple to convey milk to the outside.
→ The lactiferous ducts are surrounded by an extensive network of
smooth muscle fibers (SM) that are responsible for the erection of the
nipple, elevating it to facilitate the suckling process. The region
immediately surrounding the nipple is known as the areola (Ar).
C. Physiology
● Sel Mesenkim Amnion / Amnion Mesenchymal Cells
→ Sintesis sitokin (IL-6, IL-8, MCP-1)
- Sitokin = protein yang mengomunikasikan sinyal-sinyal dalam tubuh untuk
merespons infeksi. Dalam kondisi normal, sitokin membantu mengkoordinasikan
respons sistem kekebalan tubuh untuk menangani zat menular, seperti virus atau
bakteri.
IL = Interleukin
MCP = Monocyte chemoattractant protein-1
- Sintesis dari sitokin akan meningkat sebagai respons terhadap racun dari bakteri
dan IL-I
- Oleh karena itu, fungsi kapasitas dari sel mesenkim amnion ini adalah acuan
untuk mempertimbangkan dan mempelajari cairan amnion sebagai bukti
akumulasi mediator inflamasi terkait persalinan
● Anatomi dan Fungsi Metabolik Amnion
- Pada akhir bulan ketiga, amnion semakin membesar dan membuatnya memiliki
kontak langsung dengan bagian korion → Amnion menghabiskan tempat yang
ada pada rongga korion.
- Amnion ini terbagi ke dalam amnion plasenta dan amnion umbilical cord/tali
pusat, masing-masing menyelubungi yang di dalamnya.
- Transpor air dan larutan untuk proses homeostasis cairan amnion.
- Produksi substansi bioaktif
- Responsif secara akut dan kronis terhadap regangan mekanis (yang dapat
merubah ekspresi gen amnion) sehingga dapat memicu respons autokrin dan
parakrin untuk memproduksi matriks metaloproteinase, IL-8, dan kolagenase.
→ Matriks metalloproteinase: In summary, MMPs are multifunctional
proteases that: 1) proteolyse ECM components with subsequent release of
bioactive fragments and proteins; 2) participate in membrane shedding; 3) play
an important role in chemokine processing; and 4) alter the activity status of other
proteases.
→ Paracrine signaling: a cell targets a nearby cell (one not attached
by gap junctions). The image shows a signaling molecule produced by one cell
diffusing a short distance to a neighboring cell. Autocrine signaling: a cell
targets itself, releasing a signal that can bind to receptors on its own surface.
- Hal yang diproduksi sebagai respons dari regangan mekanis ini dapat
memodulasi perubahan sifat selaput ketika proses persalinan.
● Kolagen Interstitial
- Kolagenase interstisial atau matrix metalloproteinase-1 (MMP-1) adalah
metalloproteinase netral yang mendegradasi protein matriks ekstraseluler
termasuk kolagen tipe I, tipe III dan tipe VII.
- Kekuatan regang amnion sebagian besarnya diatur oleh interaksi kolagen fibril
dengan proteoglikan (contoh: dekorin, berfungsi meningkatkan kekuatan
jaringan). Ketika proses persalinan, terdapat perubahan komposisi (meliputi
 menurunnya jumlah dekorin dan kenaikan dari hyaluronan) sehingga timbul efek
hilangnya kekuatan regang.
- Kolagen fibril merupakan komponen utama dari matriks ekstraselular (ECM) dan
penghubung jaringan seperti tulang dan tendon, serta pada jaringan kornea.

● Amniotic Fluid
→ Warna: pada keadaan normal adalah tidak berwarna atau jernih
→ Amniotic fluid that's tinted brown or green means the fetus has passed meconium
(their first poop) in your uterus.Meconium in amniotic fluid can cause complications if the
fetus breathes it in. In severe cases, the fetus may develop meconium aspiration
syndrome and need immediate treatment after birth.
● Letak: terkumpul dalam rongga amnion
● Jumlahnya meningkat seiring berjalannya kehamilan, tetapi, pada kurang lebih minggu
ke-34 atau menuju bulan ke-9 kehamilan volume dari cairan amnion akan mulai
menurun
● Fungsi:
- Peredam guncangan
- Mencegah embrio menempel ke amnion
- Memungkinkan pergerakan janin.
● Volume rata-rata: 1000 ml / 1 liter (pada saat aterm)
- Volume ini dapat bervariasi apabila terdapat abnormalitas
- Volume diganti setiap 3 jam
- Dari awal bulan kelima, janin menelan cairan amnionnya sendiri (sekitar 400 mL
per hari)

D. Clinical Science

1. Abortus
● Patogenesis
→ Sebagian besar abortus spontan terjadi setelah kematian janin yang kemudian diikuti
dengan perdarahan ke dalam desidua basalis.
→ Selanjutnya, terjadi perubahan nekrotik pada daerah implantasi dan infiltrasi sel-sel
peradangan akut.
→ Buah kehamilan yang terlepas seluruhnya (atau sebagian) diinterpretasikan sebagai
benda asing di dalam rongga uterus. Sehingga dapat menyebabkan kontraksi uterus,
perdarahan, juga ekspulsi.
→ Kematian embrio biasanya terjadi paling lama 2 minggu sebelum perdarahan pada
abortus spontan, oleh karena itu pengobatan untuk mempertahankan janin tidak dapat
dilakukan jika telah terjadi perdarahan dalam jumlah banyak (karena abortus sudah tidak
dapat dihindari pada tahap ini).
→ Hasil konsepsi biasanya dikeluarkan dengan lengkap pada usia kehamilan sebelum
minggu ke-10. Meskipun demikian, hal ini tidak selalu terjadi dan intrauterin harus selalu
dipastikan bersih dari sisa kehamilan.
 → Hasil konsepsi yang dikeluarkan secara lengkap sebelum minggu ke 10 ini dapat
terjadi karena sebelum minggu ke-10, vili korialis belum menanamkan diri dengan erat
ke dalam desidua sehingga telur masih dapat mudah terlepas keseluruhannya.
→ Sedangkan antara minggu ke-10 hingga ke-12, korion telah tumbuh dengan cepat
dan hubungan vili korialis dengan desidua makin erat sehingga seringkali sisa korion
(plasenta) akan tertinggal jika terjadi abortus.
→ Terdapat abortus dalam bentuk istimewa, seperti:
a. Telur kosong (blighted ovum) → Yang terbentuk hanyalah kantong amnion berisi
cairan amnion tanpa adanya janin. Hal ini terjadi ketika telur yang dibuahi
menempel ke dinding uterus tetapi embrio tidak berkembang.
b. Mola kruenta → Telur yang dibungkus oleh darah kental. Terbentuk apabila
abortus terjadi secara perlahan (lambat laun) sehingga darah sempat membeku
antara desidua dan korion. Bila darah beku ini sudah seperti daging, maka mola
kruenta dapat disebut sebagai mola karnosa.
c. Mola tuberosa → Telur yang terdapat benjolan, disebabkan oleh hematom di
antara bagian amnion dan korion.
→ Embrio yang mengalami kematian pada usia masih sangat muda, dapat diabsorbsi
oleh rahim dan pada akhirnya menghilang.
→ Pada kondisi lain, janin dapat menjadi kering dan mengalami mumifikasi hingga
menyerupai kertas perkamen (fetus papyraceus). Keadaan ini lebih banyak ditemukan
pada kehamilan kembar (disebut vanishing twin).
Fetus papyraceus is a rare condition which describes a mummified fetus in a
multiple gestation pregnancy in which one fetus dies and becomes
flattened between the membranes of the other fetus and uterine wall. We
report a case of fetus papyraceus diagnosed during labor as a result of arrested
descent.
→ Bila kematian janin terjadi ketika janin sudah agak besar, maka janin tersebut dapat
mengalami maserasi.

2. Obstetrical Hemorrhage
→ In addition to hypertension and infection, obstetrical hemorrhage remains
among the infamous triad of maternal death causes.
→ Of more than 7000 pregnancy-related maternal deaths in the United States
from 2006 to 2015, hemorrhage was a direct cause in 11 percent (Creanga, 2015, 2017;
Petersen, 2019).
→ Hemorrhage is also the single most important cause of maternal death
worldwide (Goffman, 2016; Oladapo, 2016).
→ Notably, perhaps a third of severe cases of hemorrhage are likely preventable
(Lepine, 2020).
→ These statistics have prompted several organizations to develop programs to
prevent hemorrhage-related maternal morbidity. In the United States, one example is the
Alliance for Innovation on Maternal Health (AIM) (2015), with its intent to standardize
recognition, response, and reporting of obstetrical hemorrhage.
● General Considerations
A. Mechanisms of Normal Hemostasis
→ Near term, an incredible amount of blood—at least 600 mL/min—flows
through the spiral arteries and into the intervillous space (Pates, 2010).
Averaging 120 in number, the spiral arteries lack a muscular layer
because of their remodeling by trophoblasts and thereby form a
low-pressure system. With placental separation, vessels at the
implantation site are avulsed.
→ Hemostasis is achieved first by myometrial contraction, which directly
compresses the arteries. Compression is followed by clotting and
eventually by obliteration of vessel lumens. If, after delivery, the
myometrium contracts vigorously, substantial hemorrhage from the
placental implantation site is unlikely. Importantly, an intact coagulation
system is not necessary for postpartum hemostasis unless there are
lacerations in the uterus, birth canal, or perineum. However, fatal
postpartum hemorrhage can result from uterine atony despite normal
coagulation.

B. Definition and Incidence

→ Historically, postpartum hemorrhage has been defined as blood losses
≥500 mL after the third stage of labor. This is problematic because almost
half of all women delivered vaginally shed that amount of blood or more
when losses are carefully measured. Moreover, approximately 5 percent
of women delivering vaginally lose >1000 mL of blood (Fig. 42-1)
(Pritchard, 1962). Almost a third of women undergoing cesarean delivery
have blood loss >1000 mL. The American College of Obstetricians and
Gynecologists (2019a) now defines postpartum hemorrhage as
cumulative blood loss >1000 mL or blood loss accompanied by signs and
symptoms of hypovolemia.
→ In a Maternal-Fetal Network Units study of more than 115,000
deliveries, the incidence of hemorrhage with vaginal delivery was 5.3
percent, and it was 10.5 percent for cesarean delivery (Yee, 2019).
Importantly, hemorrhage is underreported. From the National Hospital
Discharge Summary database, the reported postpartum hemorrhage
incidence between 2001 and 2005 was only 2.6 percent (Berg, 2009).

C. Blood Loss Assessment

→ At delivery, visual estimation is often used as a qualitative measure of
blood loss. However, this method is more likely to underestimate the
actual blood loss when volumes are high and to overestimate it when
volumes are low (Al Kadri, 2011; Natrella, 2018). Thus, estimated blood
loss that is considered greater than “average” should alert the provider.
Instead, different methods can be used as quantitative measures. First,
gravimetric measurement weighs blood-soaked items and subtracts
pre-use dry weights. Another evolving tool uses a tablet-device camera
and colorimetric analysis to calculate blood loss (Spies, 2020; Venkatesh,
2020). The American College of Obstetricians and Gynecologists (2019b)
recognizes the use of quantitative methods to help identify severe
hemorrhage.
→ Intrapartum, quantitative measurement is more accurate than visual
estimation, but the effectiveness of these methods on clinical outcomes
has not been demonstrated. A Cochrane Review of three trials found no
differences between subjective and objective methods when comparing
outcomes that included need for transfusion, plasma expanders, or
uterotonics (Diaz, 2018).
→ Postpartum, retrospective estimation also can be informative. The
blood volume of a pregnant woman with normal pregnancy-induced
hypervolemia usually rises by 50 percent. However, individual increases
range from 30 to 60 percent, that is, 1500 to 2000 mL for an
average-sized woman (Pritchard, 1965). The equation to calculate blood
volume is shown in Table 42-1. It is axiomatic that a normal pregnant
woman tolerates, without any decrease in postpartum hematocrit, blood
loss at delivery that approaches the volume of blood that was added
during pregnancy. Thus, if blood loss is less than the pregnancy-added
volume, the hematocrit remains the same acutely and during the first
several days postpartum. It then rises as nonpregnant plasma volume
levels return during the next week or so. Whenever the postpartum
hematocrit is lower than one obtained on admission for delivery, blood
loss can be estimated as the sum of the calculated pregnancy-added
volume plus 500 mL for each 3-volume-percent decline of the hematocrit.
→ For research and clinical care initiatives, excessive blood loss has
been estimated by several methods (Coviello, 2019; Saoud, 2019). Tita
and colleagues (2012) used a 6-volume-percent drop in the postpartum
hematocrit to define clinically significant blood loss with vaginal delivery.
This decline easily signifies a >1000-mL blood loss in the average-sized
woman. They documented this amount in a fourth of women. Another
marker used to estimate hemorrhage incidence is the transfusion rate. In
the study by Tita just cited, more than 6 percent of women who delivered
vaginally underwent blood transfusion. In a study of more than 66,000
women delivered at Parkland Hospital, 2.3 percent overall were given
blood transfusions for hypovolemia (Hernandez, 2012). Half of these
women had undergone cesarean delivery. Importantly, for those
transfused, these investigators calculated blood loss to average
approximately 3500 mL! The need for blood transfusion is now followed
as a severe maternal morbidity (SMM) indicator. The heightened
awareness of SMM is outlined in Chapter 1 (p. 5). Transfusions represent
 more than 80 percent of total SMM rates. The incidence of massive
transfusion for postpartum hemorrhage has been reported to be from 25
to 65 per 100,000 births (Green, 2016; Ramler, 2019). However, defining
healthcare quality using transfusion as an SMM metric is problematic.
First, this metric is solely derived from administrative billing codes.
Second, transfusion rates may be skewed based on the hospital’s
case-mix (Bailit, 2013). This can distort values for regional referral centers
that care for women at high risk for hemorrhage, such as those with
placenta accreta spectrum.

D. Risk Factors
→ Hemorrhage can manifest at any time during pregnancy, delivery, or
the puerperium. Contributions to maternal death from some of these
causes of are shown in Figure 42-2. The Joint Commission (2019)
requires accredited delivery services to employ tools that evaluate
maternal hemorrhage risk on admission to labor and delivery and
postpartum. Several methods are available, and the American College of
Obstetricians and Gynecologists’ (2019b) scoring tool stratifies risk using
several obstetrical factors listed in Table 42-2. Unfortunately, these
scoring systems only modestly predict hemorrhage (Chu, 2020). Kawakita
and colleagues (2019) examined three commonly referenced tools and
found moderate performance in identifying women at risk during cesarean
delivery. In contrast, the Association of Women’s Health, Obstetric and
Neonatal Nurses (AWHONN) risk assessment tool was predictive of those
at high risk (Colalillo, 2021).

E. Timing of Hemorrhage
→ Obstetrical hemorrhage is traditionally classified as antepartum—such
as with placenta previa or placental abruption, or as
postpartum—commonly caused by uterine atony or genital tract
lacerations. In individual women, however, these terms are nonspecific,
and it is reasonable to specify the cause and gestational age as
descriptors. With antepartum hemorrhage, timing may give a clue to its
cause. Many aspects of bleeding during the first half of pregnancy from
abortion or ectopic pregnancy are covered in Chapters 11 and 12.
Discussions that follow concern pregnancies with a viable-size fetus. In
these cases, rapid assessment should always consider the deleterious
fetal effects of maternal hemorrhage. During active labor, slight vaginal
bleeding is common. This “bloody show” is the consequence of cervical
effacement and dilation and concurrent tearing of small vessels. However,
with uterine bleeding above the cervix, placental abruption, placenta
previa, and vasa previa must be considered. The first two are presented
in Chapter 43 and vasa previa is discussed in Chapter 6 (p. 115). In some
women, especially those with a placenta previa, cervical varicosities may
bleed (O’Brien, 2013).
→ Near term in many women, the source of uterine bleeding is not
identified, bleeding ceases, and no apparent anatomical cause is found at
delivery. In most of these cases, bleeding likely originated from a slight
marginal placental separation. Despite this, any pregnancy with
antepartum bleeding remains at higher risk for an adverse outcome even
though bleeding has stopped and placenta previa has been excluded
sonographically.
→ Bleeding after midpregnancy is associated with several adverse
outcomes. The Canadian Perinatal Network described 806 women with
hemorrhage between 22 and 28 weeks’ gestation (Sabourin, 2012).
Placental abruption (32 percent), previa (21 percent), and cervical
bleeding (6.6 percent) were the most frequent causes identified. In a third,
no cause was found. Of all women, 44 percent were delivered before 29
weeks’ gestation. In more than 68,000 women in Scotland, the incidence
of antepartum hemorrhage after the first trimester was 11 percent
(Bhandari, 2014). These women were at significantly higher risk for
preterm birth, labor induction, and postpartum hemorrhage. With
postpartum hemorrhage, the source in most cases can and should be
determined. Frequent causes are uterine atony with placental site
bleeding, genital tract trauma, or both. Postpartum hemorrhage is usually
obvious. Important exceptions are unrecognized intrauterine and
intravaginal blood accumulation and uterine rupture with intraperitoneal or
retroperitoneal bleeding. Another consideration is an expanding vulvar or
vaginal hematoma (p. 740). Initial evaluation includes attempts to
differentiate uterine atony from genital tract lacerations. For this, risk
factors are sought, the lower genital tract is examined, and uterine tone is
assessed. Atony is identified by a boggy, soft uterus during bimanual
examination and by expression of clots and hemorrhage during uterine
massage.
→ Persistent bleeding despite a firm, well-contracted uterus suggests that
hemorrhage most likely is from lacerations. Bright red blood further
suggests arterial bleeding. To confirm that lacerations are a source of
bleeding, careful inspection of the vagina, cervix, and uterus is essential.
Examination is easier if regional analgesia is employed. Transfer from a
labor and delivery room to an operative suite also may be prudent. If there
are no lower genital tract lacerations and the uterus is contracted, yet
supracervical bleeding persists, manual exploration of the uterus is done
to exclude a uterine tear (Kaplanoglu, 2016). This also is completed
routinely after internal podalic version or breech extraction. Some perform
this after successful vaginal birth after cesarean, and this is our practice.
Late postpartum hemorrhage describes bleeding after the first 24 hours.
Found in up to 1 percent of women, one risk factor is postpartum
 hemorrhage at the time of delivery (Fein, 2021). Delayed hemorrhage
may be serious and is discussed in Chapter 36 (p. 637).

F. Appreciation of Estimated Blood Loss

→ As discussed, visual blood loss estimates are often inaccurate,
especially with excessive bleeding. Instead of sudden and massive
hemorrhage, postpartum bleeding is frequently steady. If bleeding from
atony or laceration persists, it may appear to be only moderate at any
given instant but may continue until serious hypovolemia develops. In
some cases, after placental separation, blood may not escape vaginally
but instead may collect within the uterine cavity, which can become
distended by 1000 mL or more of blood. Moreover, postpartum uterine
massage will be ineffective if applied to a roll of abdominal fat mistaken
for the uterus. All of these factors can lead to an underappreciation of the
magnitude of hemorrhage over time. The effects of hemorrhage depend
mainly on the maternal nonpregnant blood volume and the corresponding
degree of pregnancy-induced hypervolemia. Small women—even those
with appropriate pregnancy induced hypervolemia—do not tolerate more
than seemingly average blood loss. Some gravidas may be particularly
susceptible to hemorrhage because their blood volume expansion is less
than expected. An example is women with severe preeclampsia or
eclampsia, who are more vulnerable to hemorrhage because they
frequently do not have a normal blood volume accrual. Specifically,
Zeeman and associates (2009) documented a mean increase above
nonpregnant volume of only 10 percent in eclamptic women (Chap. 40, p.
693). Another example is the moderate to severe curtailing of
pregnancy-induced volume expansion in women with chronic renal
insufficiency (Chap. 56, p. 1004). When excessive hemorrhage is
suspected in these high-risk women, crystalloid and blood are promptly
administered for suspected hypovolemia. A treacherous feature of
postpartum hemorrhage is the failure of the pulse and blood pressure to
undergo more than moderate alterations until large amounts of blood
have been lost. The normotensive woman initially may actually become
somewhat hypertensive from catecholamine release in response to
hemorrhage. Importantly, women with preeclampsia may become
“normotensive” despite remarkable hypovolemia. Accordingly,
hypovolemia may not be recognized until very late.

→ Cari terkait after delivery coagulant untuk follow-up postpartum delivery

Changes in the coagulation status of the blood contribute to a 10-fold
increased risk of venous thromboembolic disease seen in pregnancy,
which rises to 25-fold in the postpartum period. The widely accepted
assumption that the hypercoagulable state of pregnancy resolves at six
weeks postnatal is based on little scientific evidence. Individual
parameters show considerable variation in their recovery to pre pregnancy
levels after childbirth, with some such as factor VIII and von
Willebrand factor falling to baseline levels within 72 hours
postpartum but others, such as the reduction in protein S, taking
several weeks to recover. The cumulative effects of these is not known
but could be assessed using a global test of haemostatic function such
as thromboelastography (TEG). This technique evaluates the
viscoelastic properties of blood during coagulation and fibrinolysis. It is
able to provide information relating to the cumulative effect of several
components of coagulation at a given time point and, unlike conventional
clotting tests, can be performed on whole blood, thus incorporating the
contribution of platelets to coagulation.
Normal pregnancy is accompanied by increased concentrations of
factors VII, VIII, X and von Willebrand factor and by pronounced
increases in fibrinogen. Factors II, V and IX are relatively unchanged.
Free protein S, the active, unbound form, is decreased during
pregnancy. Plasminogen activator inhibitor type 1 (PAI-1) levels are
increased fivefold. Levels of PAI-2, produced by the placenta, increase
dramatically during the third trimester. Markers of thrombin generation
such as prothrombin F1 + 2 and thrombin-antithrombin (TAT) complexes
are also increased. These changes, which may not completely return to
baseline until more than 8 weeks postpartum, begin with conception
and result in the hypercoagulable state of pregnancy.
The hypercoagulability of pregnancy has likely evolved to protect
women from hemorrhage at the time of miscarriage or childbirth.
Indeed, in the developing world, the leading cause of maternal death is
still hemorrhage, but in Western Europe and the United States, where
hemorrhage is successfully treated or prevented, the leading cause of
maternal death is thromboembolic disease.

→ Hubungan preeklamsia dan hemostasis

Preeclampsia and eclampsia appear to be a state of increased
coagulopathy as evidenced by an increase in fibrin formation,
activation of the fibrinolytic system, platelet activation and a decrease
in platelet count. Routine tests used to assess decompensated
disseminated intravascular coagulopathy are of limited value in the
preeclamptic and eclamptic population. More sophisticated tests such as
determinations of antithrombin III, thrombin-antithrombin III complex,
D-dimer, factor VIII antigen/activity ratio, and beta-thromboglobulin,
however, show a compensated coagulopathy in the preeclamptic patient.
 These hemostatic changes, probably the result of endothelial damage,
are implicated in the pathogenesis of this disease. A better
understanding about the abnormalities of hemostasis and coagulation in
the preeclamptic and eclamptic patient may allow the clinician to provide
improved management and possibly peripartum therapy.

● Uterine Atony
A. Third-stage Labor Management
→ The most frequent cause of obstetrical hemorrhage is failure of the
uterus after delivery to contract sufficiently and arrest bleeding from
vessels at the placental implantation site (Yee, 2019).
→ That said, some bleeding is inevitable during third-stage labor as
the placenta begins to separate. Blood from the implantation site may
escape into the vagina immediately—the Duncan mechanism of
placental separation, or it remains concealed behind the placenta
and membranes until the placenta is delivered—the Schultze
mechanism. Placental descent is signified by a slack umbilical cord.
After signs of placental separation, the uterus should be massaged
if it is not contracted firmly. Importantly, separation and delivery of
the placenta by cord traction, especially when the uterus is atonic,
may cause uterine inversion.
→ Following placental delivery, the fundus is always palpated to
confirm that the uterus is well contracted. If it is not firm, vigorous
fundal massage usually prevents postpartum hemorrhage from atony
(Hofmeyr, 2013). Concurrent administration of a uterotonic agent,
discussed in the next sections, is another recommended preventive
measure.
B. Risk Factors
→ In many women with known risks, uterine atony can at least be
anticipated. However, as discussed earlier, risk-based scoring systems
have limited value. In one study, up to half of women with atony after
cesarean delivery had no risk factors (Rouse, 2006). The magnitude of
risk for atony imposed by each of the factors shown in Table 42-2 varies
considerably between reports. Primiparity and high parity are two
factors (Driessen, 2011). In one study, the incidence of postpartum
hemorrhage rose from 0.3% in women of low parity to 1.9% with
parity of four or greater. It was 2.7% with parity of seven or greater
(Babinszki, 1999). The overdistended uterus is prone to hypotonia
after delivery, and thus women with a large fetus, multiple fetuses, or
hydramnios carry greater risk (Blitz, 2019). Labor abnormalities
predispose to atony and include hyper- or hypotonic labor. Similarly, labor
induction or augmentation with either prostaglandins or oxytocin is
more likely to be followed by atony (Driessen, 2011). The frequency of
hemorrhage increases with third-stage labor lasting >20 minutes
(Frolova, 2016). Last, the woman who has had a prior postpartum
hemorrhage is at risk for recurrence

C. Evaluation and Management

→ To improve immediate postpartum care, clinical safety bundles
provide a standardized response. In principle, all of these programs
suggest notifying unit personnel, activating resources, and standardizing
management. With immediate postpartum hemorrhage, careful
inspection aims to exclude birth canal laceration. In some cases,
bleeding is caused by retained placental fragments, and placental
inspection after delivery should be routine. If a defect is seen, the
uterus should be manually explored and the fragment removed.
Occasionally, retention of a succenturiate lobe may cause postpartum
hemorrhage. During examination for lacerations and causes of atony, the
uterus is massaged and uterotonic agents are administered.

→ Manual Removal of the Placenta

If heavy bleeding persists after delivery of the newborn but while the
placenta remains partially or totally attached, then manual placental
removal is indicated (Cummings, 2016; Frolova, 2016). For this,
adequate analgesia is mandatory, and aseptic surgical technique is used.
As illustrated, the fingertips of one hand, with fingers approximated, are
insinuated between the uterine wall and placenta. A sweeping forward
motion in this plane will peel the placenta off its uterine attachment. After
its removal, trailing membranes are carefully teased free from the decidua
using ring forceps as needed. Another method to clear membranes is to
wipe out the uterine cavity with a gauze-wrapped hand. Bierer forceps
guided by ultrasound to remove retained placenta also has been
described (Siegel, 2020). Some administer a single dose of intravenous
antibiotics after manual uterine exploration, however, one systematic
review of observational studies found no benefits (Chibueze, 2015). The
American College of Obstetricians and Gynecologists (2020b) concluded
that data neither support nor refute this practice. The World Health
Organization (WHO) (2015) recommends ampicillin or cefazolin
antimicrobial prophylaxis after manual placenta removal. At Parkland
Hospital, we routinely provide a single dose of cefazolin after manual
exploration.

→ Uterotonic Agents
Several compounds can be used to prompt the postpartum uterus to
contract. One of these is routinely selected and given to prevent
postpartum bleeding. Choices for prophylaxis include oxytocin (Pitocin);
the ergots, namely ergonovine (Ergotrate) and methylergonovine
(Methergine); or misoprostol (Cytotec) (Chap. 27, p. 507). The WHO
(2018) recommends oxytocin for first-line use for prophylaxis. For
administration, 20 units of oxytocin in 1000 mL of crystalloid solution is
effective and given intravenously (IV) at 10 mL/min for a dose of 200
mU/min. Higher concentrations are minimally more efficient (Tita, 2012). A
summary of oxytocin administration regimens is found in the Practice
Brief of the Association of Women’s Health Objective and Neonatal
Nurses—AWHONN (2014). In those without IV access, oxytocin may be
given intramuscularly (IM). Adnan and colleagues (2018) found the IV
route to more effectively prevent severe hemorrhage compared with IM
administration. Oxytocin is never given as an undiluted bolus dose
because serious hypotension or cardiac arrhythmias can develop. Most
agents for prevention of atony are also used to treat it. For atony, IV
oxytocin is continued or may be initiated if not selected initially. It is
considered first-line treatment by the WHO (2012). If bleeding and atony
are refractory, an agent from a different group can be added (American
College of Obstetricians and Gynecologists, 2019a).
Ergot alkaloids have been used for centuries to treat uterine atony. If
atony persists despite oxytocin and other preventive measures, ergot
derivatives can be used for second-line treatment. Given parenterally,
these drugs rapidly stimulate tetanic uterine contractions and act for
approximately 45 minutes (Schimmer, 2011). A common regimen is 0.2
mg of either drug given IM. Methergine can be repeated at 2- to 4-hour
intervals as needed. A caveat is that ergot agents, especially given IV,
may cause dangerous hypertension, especially in women with
preeclampsia. Severe hypertension is also seen with concomitant use of
protease inhibitors given for human immunodeficiency viral (HIV)
infection. These adverse effects notwithstanding, it is speculative whether
ergot derivatives offer superior therapeutic effects compared with
oxytocin. Other second-line agents for atony have included the E- and
F-series prostaglandins. Carboprost tromethamine (Hemabate) is the
15-methyl derivative of prostaglandin F2α . It is approved for uterine atony
treatment in a dose of 250 μg (0.25 mg) given IM. This dose can be
repeated if necessary, at 15- to 90-minute intervals up to a maximum of
eight doses. Observational data indicate an 88-percent success rate
(Oleen, 1990). Carboprost causes side effects in approximately 20
percent of women. These include, in descending order of frequency,
diarrhea, hypertension, vomiting, fever, flushing, and tachycardia. Another
pharmacological effect is pulmonary airway and vascular constriction.
Thus, carboprost should not be used for asthmatic women or those with
pulmonary hypertension, including women those with suspected amnionic
fluid embolism (p. 745). It has also been reported to cause arterial oxygen
desaturation that averaged 10 percent (Hankins, 1988). We have
occasionally encountered severe hypertension with carboprost given to
women with preeclampsia. Other relative contraindications to carboprost
include renal, liver, and cardiac disease (American College of
Obstetricians and Gynecologists, 2019a). Misoprostol is a synthetic
prostaglandin E1 analogue. In a Cochrane review, Mousa and associates
(2014) reported no added benefits for misoprostol use for treatment
compared with oxytocin or ergonovine. If misoprostol is used to treat
atony, the American College of Obstetricians and Gynecologists (2019a)
recommends a dose of 600 to 1000 µg rectally, orally, or sublingually.
Dinoprostone (Cervidil, Prepidil) is prostaglandin E2 . It may also be used
off label for atony treatment and is given as a 20-mg suppository per
rectum or per vagina every 2 hours. It typically causes diarrhea, which is
problematic for the rectal route, whereas vigorous vaginal bleeding may
preclude its use per vagina. Hypotension, which is commonly
encountered with hemorrhage, is considered a contraindication by some.
For this reason, this agent is not deployed for hemorrhage management
at Parkland Hospital. IV prostaglandin E2—sulprostone—is used in
Europe, but it is not available in the United States.

→ Tranexamic Acid
This antifibrinolytic agent has been evaluated to treat postpartum
hemorrhage. In the randomized WOMAN trial of gravidas with
hemorrhage following vaginal birth or during cesarean delivery, mortality
rates from obstetrical hemorrhage were 1.2 percent in those given a 1-g
IV tranexamic acid dose plus traditional care for bleeding. This rate was
significantly lower than the 1.7-percent death rate in women given
traditional care alone (WOMAN Trial Collaborators, 2017). Another study
of women with hemorrhage following vaginal birth found that rates of
progression to severe PPH, of transfusion, and of peripartum
hysterectomy were lower in the TXA group compared with the
traditional-care group (Ducloy-Bouthors, 2011). Use of tranexamic acid in
hemorrhage is discussed further in Chapter 44 (p. 773).

→ Bleeding Unresponsive to Uterotonic Agents

If bleeding persists after initial measures for atony, the following
management steps are performed immediately and simultaneously:

1. Begin bimanual uterine compression, which is easily done and controls

most cases of continuing hemorrhage (Fig. 42-4). This technique is not
simply fundal massage. The posterior uterine wall is massaged by one
hand on the abdomen, while the other hand is made into a fist and placed
into the vagina. This fist kneads the anterior uterine wall through the
anterior vaginal wall, and the uterus is compressed between the two
hands.
2. Mobilize the emergent-care obstetrical team and call for whole blood or
packed red cells.
3. Request urgent help from the anesthesia team.
4. Secure at least two large-bore IV catheters so that crystalloid with
oxytocin can be continued simultaneously with blood products. Insert a
Foley catheter for continuous urine output monitoring.
5. Begin volume resuscitation with rapid IV crystalloid infusion (p. 734).
6. With sedation, analgesia, or anesthesia established and now with
optimal exposure, once again manually explore the uterine cavity for
retained placental fragments and for uterine abnormalities, including
lacerations or rupture.
7. Thoroughly inspect the cervix and vagina again for lacerations that may
have escaped attention.
8. Administer blood transfusions if the woman is still unstable or if
bleeding persists (Chap. 44, p. 771).
At this juncture, after causes other than atony have been excluded and
after hypovolemia is reversed, several other measures are considered if
bleeding continues (Merriam, 2020). Their use depends on several factors
such as parity, desire for sterilization, and experience with each method.

→ Balloon Tamponade and Surgical Procedures

For this, the tip of a 24F to 30F Foley catheter with a 30-mL balloon is
guided into the uterine cavity and filled with 60 to 80 mL of saline.
The open tip permits continuous drainage of blood from the uterus.
We have experienced balloon rupture when more than 50 mL was
instilled into the balloon, thus a 34F Foley with a 60-ml balloon can be
used. If bleeding subsides, the catheter is typically removed after 12
to 24 hours. Similar devices for tamponade include
SengstakenBlakemore, Rusch, and ebb balloons and condom catheters
(Antony, 2017; Kondoh, 2019).
→ Antibiotic prophylaxis using cefazolin, 1 gram every 8 hours until
removal, has recently been suggested to reduce risk of postpartum
endometritis (Martingano, 2020). Instead, specially constructed
intrauterine balloons are available to treat hemorrhage from uterine atony
and other causes. A Bakri Postpartum Balloon or BT-Cath may be
inserted and inflated to tamponade the endometrial cavity and stop
bleeding (Fig. 42-5). Insertion requires two or three team members. The
first performs abdominal sonography during the procedure. The second
places the deflated balloon into the uterus and stabilizes it. The third
member instills fluid to inflate the balloon, rapidly infusing at least 150 mL
followed by further installation over a few minutes for a total of 300 to 500
mL to arrest hemorrhage. It is reasonable to remove the balloon after
approximately 12 hours (Einerson, 2017).
In small studies evaluating uterine balloons for all causes, the
success rate approximated 85 percent (Kaya, 2016; Said Ali, 2021;
Vintejoux, 2015). From their review, Suarez and associates (2020) used
balloon tamponade in 4729 women and reported a similar success rate.
At least one case of uterine rupture with a balloon has been reported
(Ngyuen, 2018). Combinations of balloon tamponade and uterine
compression sutures also have been described (Diemert, 2012; Yoong,
2012). Failure of uterotonic agents and tamponade requires more
invasive methods. These include uterine compression sutures, major
pelvic vessel ligation, angiographic embolization, and hysterectomy.
These are discussed in detail in Chapters 44 (p. 778). Peripartum
hysterectomy is illustrated in Chapter 30 (p. 560).