Anatomy of placenta &

Pathology of
preeclampsia

The placenta (Greek,plakuos= flat cake) named on the basis of this

organs gross anatomical appearance

The placenta is a vascular organ in most mammals that unites the fetus
to the uterus of the mother. It mediates the metabolic exchanges of the
developing fetus through an intimate association of embryonic tissues
and uterine tissues and its vasculature, serving the functions of
nutrition, respiration, excretion and excretion.

Placentas have three functions: the exchange of nutrient and waste

materials between mother and fetus, the manufacture and secretion of
hormones, and the maintenance of an immunologic barrier

Placenta- remove

Developent

On the ventral surface of the embryo, a yolk sac and an allantoic sac
are formed, each with vessels and ducts connected to the future caudal
end of the embryo through the body stalk. The vessels to the allantoic
sac become the umbilical vessels and join with newly formed vessels in
the mesenchyme of the inner surface of the chorion to form the fetal
portion of the vessels to the placenta. The body stalk becomes the
umbilical cord and is covered with amnion

Fetal and maternal vascularization of the placenta is complete by the 17th to 20th
day, and nucleated fetal red blood cells can be found within the fetal vessels after
the 21st day following conception. The placenta continues to grow in thickness
and circumference until the end of the fourth month. Increased thickness of the
placenta is the result of growth in the length and size of the villi of the chorion
frondosum, with accompanying expansion of the intervillous space

The human placenta is a hemochorial placenta, which means that maternal blood
is in direct contact with fetal trophoblast. The syncytiotrophoblast invades
maternal venous sinuses relatively early and invades the spiral arterioles on the
17th or 18th day after conception. The lacunae, or lakes formed by maternal tissue
fluid and blood, form the intervillous space; throughout the rest of pregnancy and
the maternal blood circulates freely within the intervillous space.

cytotrophoblasts from anchoring villi

invade and remodel the wall of the
uterus, these epithelial cells of
ectodermal origin acquire an
adhesion receptor repertoire
characteristic of endothelial cells. We
theorize that this switch permits the
heterotypic adhesive interactions
that allow fetal and maternal cells to
cohabit in the uterine vasculature
during normal pregnancy

A placenta is an organ of round or oval shape that is relatively flat

20 cm in length / 600 gm

composed of two different surfaces, the maternal surface, facing the

towards the outside, and the fetal surface, facing towards the fetus. On
the fetal surface, we can observe the umbilical cord, the link between
the placenta and the fetus

Maternal surface

The maternal surface of the placenta is composed of the decidua, what

is known as the uterine lining during pregnancy.

There are 15-20 lobes located on the maternal surface (cotyledons),

divided by deep channels more commonly known as sulci.

Each individual lobule is divided into smaller sections containing one

villi. These villi emerges from the chorion, containing fetal capillaries,
which bathe in the intervillous space

Embeded in the decidua are maternal veins and arteries that end in the
intervillous space. They are also in continuity with the maternal
circulation.

Fetal surface

Is covered by the amnion or amniotic membrane, underlying the

amnion is the chorion which is a thicker embrane.

This structure of the placenta is continuous with the lining of the

uterine wall. Emerging from the chorion are the villi where lies a system
of fetal capillaries (blood vessels) to allow maximum contact area with
the maternal blood (also known as the intervillous space) for gas,
nutrient and waste exchange.

Also visible on the fetal surface of the placenta are the umbilical veins
and arteries that spread out from where is situated the umbilical cord.

Umbilical cord

Umbilical cord extends from the fetal surface of placenta to abdominal

surface of fetus

Length- 35 to 80 cm/ width- 2 to 3 cm

Contains 2 arteries and 1 vein that are in continuity with the fetal circulation.
These vessels are longer than the cord and tend to twist and spiral to add
strength and protect against entanglement, compression and tension

Cord itself is composed of a jelly substance known as whartons jelly, that

protects the vessels within the cord

The entire cord is covered with amnion, that continues from the fetal surface
of the placenta

Short cord.

Congenital anomalies (skeletal dysplasias, trisomy 21)

Intrauterine costraints

Twins

Excessive traction at delivery

Premture separation of the placenta

Cord rupture

Uterine inversion

Fetal distress

Low apgar

Low IQ

Long cords

Cord entanglement

True knot ((True knots usually associated with long cord and have a overall
mortality of 10%)

Excessive coiling

Fetal distress

Fetal demise

Velamentous inertion

Single umbilical artery

Placenta and preeclampsia

The importance of placenta in preeclapsia is supported by data that

suggest that

Placental tissue is necessary for development of the disease (not fetus)

Preeclampsia is always cured after delivery of the placenta

Examination of human placentas improves understanding of pathologic

changes in the uteroplacental circulation that are likely to be relevant to
preeclampsia

Gestational hypertensive disorders are more likely to develop in women

who:

Are exposed to chorionic villi for the first time

Are exposed to a superabundance of chorionic villi, as with twins or

hydatidiform mole

Have preexisting renal or cardiovascular disease

Are genetically predisposed to hypertension developing during pregnancy.

(chorionic villi are essential)

remove

ABNORMAL DEVELOPMENT OF THE PLACENTA

IMMUNOLOGIC FACTORS

INCREASED SENSITIVITY TO ANGIOTENSIN II

GENETIC FACTORS

DIET

SYSTEMIC ENDOTHELIAL DYSFUNCTION

INFLAMMATION/INFECTION

Abnormal remodelling of the spiral

arteries

In preeclampsia, cytotrophoblast cells infiltrate the decidual portion of

the spiral arteries, but fail to penetrate the myometrial segment
The spiral arteries fail to develop into large, tortuous vascular channels
the vessels remain narrow, resulting in placental hypoperfusion

Biopsies of the uterine wall of women with this syndrome showed that invasive
cytotrophoblasts retain expression of adhesion receptors characteristic of the
progenitor population and fail to turn on receptors that promote invasion and/or
assumption of an endothelial phenotype

These defects doesnt occur in isolation

the most severely affected patients, immunolocalization on tissue sections of the placenta
showed that cytotrophoblast VEGF-A and VEGFR-1 staining decreased; however, staining for
PlGF was unaffected. Cytotrophoblast secretion of the soluble form of VEGFR-1 (sFlt-1) in vitro
also increased
hou Y, Damsky CH, Fisher SJ. Preeclampsia is associated with failure of human cytotrophoblasts to mimic a vascular
adhesion phenotype. One cause of defective endovascular invasion in this syndrome?J. Clin. Invest.1997;99:2152
2164

 In

preeclampsia

Incomplete

invasion

The

trophoblastic

magnitude of defective
trophoblastic invasion of
the spiral arteries
correlated with the severity
of the hypertensive
disorder (2000, Madazli)

Defective trophoblastic
differentiation

Defect in trophoblastic differentioation is a possible mechanism for

defective trophoblast invasion of the spiral arteries

Trophoblast differentiation during endothelial invasion involves

alteration in expression of a number of different classes of molecules

including cytokines, adhesion molecules, extracellular matrix molecules,

metalloproteinases, and the class Ib major histocompatibility complex molecule,
HLA-G

impaired placentation ischemia systemic endothelial dysfunction

Pic of lack of differentiation of

trphoblast/spiral arteries

Hypoperfusion, hypoxia, ischemia

Hypoperfusion both a cause and a consequence of abnormal placental

development

Hypoperfusion as pregnancy progresses

Pathologic examination of placentas from preeclamptic pregnancies

generally reveals placental infarcts and sclerotic narrowing of arteries
and arterioles, with characteristic diminished endovascular invasion by
cytotrophoblasts and inadequate remodeling of the uterine spiral
arterioles

Pics of placental infarct/ ischaemia

Immunology

prior exposure topaternal/fetalantigens appears to protect against

preeclampsia

higher risks of developing preeclampsia.

Nulliparous women

change partners between pregnancies

long interpregnancy intervals

use barrier contraception

conceive via intracytoplasmic sperm injection

Immunologic abnormalities, similar to those observed in organ rejection

graft versus host disease, have been observed in preeclamptic women

The extravillous trophoblast (EVT) cells express an unusual combination

of HLA class I antigens

Interaction between NK cells and EVT cells has been hypothesized to

control placental implantation

Abnormal trophoblastic invasion

Immunology

dendritic cell infiltration in decidual tissue

The

dendritic cells are initiator of antigen-specific

T-cell responses to transplantation antigens

abnormal implantation or altered maternal

immunologic response to fetal antigens.

levels of agonistic antibodies to the angiotensin AT-1 receptor.

Increased sensitivity to Angiotensin II

may be related to increased bradykinin (B2) receptor upregulation in

preeclamptic patients

Upregulation leads to heterodimerization of B2 receptors with

angiotensin II type I receptors (AT1), and thisAT1/B2heterodimer
increases responsiveness to angiotensin II in vitro

Angiotensin II is the endogenous ligand for the AT-1 receptor

increased activation of AT-1 receptor by auto-antibodies could induce

the hypertension and vascular injury observed in preeclampsia. Studies
in mice support this theory

Genetics

Primigravid w/ fHx of preeclampsia 2-5 fold higher risk than primigravid

women with no such history

The maternal contribution to development of preeclampsia can be

partially explained by imprinted genes

In a study of sisters with preeclampsia, it was demonstrated that the mother

developed preeclampsia only when thefetus/placentainherited a maternal
STOX1 missense mutation on 10q22; when thefetus/placentacarried the
imprinted paternal homolog, the preeclampsia phenotype was not expressed

Risk is 7-fold in women who have had preeclampsia in a previous

pregnancy

occurrence in spouses of men who were the product of a pregnancy

complicated by preeclampsia

Risk is in a woman who becomes pregnant by a man whose previous

partner had preeclampsia

Diet

CALCIUM SUPPLEMENTATION

there does not appear to be any benefit to routine calcium

supplementation for healthy, nulliparous women in whom baseline
dietary calcium intake is adequate.

There may be a benefit for preeclampsia prevention in some high-risk

populations, particularly those who eat a low calcium diet

Calium for preeclampsia prevention

A multicentre trial conducted in the USA, 1996 to identify risk

factors for the development of preeclampsia in nulliparous women
,comparing calcium supplementation to a placebo Calcium
A total of 4589 women from five centers was studied
supplementation had no effect on the risks posed by body mass index
and blood pressure

Vitamin D supplements

conflicting results

observational studies--association between vitamin D deficiency and an

risk of preeclampsia and early onset severe preeclampsia

A prospective cohort study of women at high risk for preeclampsia did not
find an association

Vitamins C and E, Fish oilno high quality evidence that it is not

effective

Systemic endothelial dysfunction

evidence supporting generalized endothelial dysfunction

Impaired flow-mediated vasodilation and impaired acetylcholine mediated

vasorelaxation .

endothelial-derived vasodilators--nitric oxide +prostacyclin

vasoconstrictors, such as endothelins and thromboxanes

Enhanced vascular reactivity to angiotensin

placentation requires angiogenesis vascular network O2 +nutrients to

the fetus

Balance needed between proangiogenic (VEGF, PlGF) and antiangiogenic

factors (sFlt-1)

Factors are elaborated by the developing placenta

antiangiogenic factors results in the systemic endothelial dysfunction

characteristic of preeclampsia

sFlt-1Soluble fmslike tyrosine kinase 1 (sFlt-1 or sVEGFR-1) is a

naturally occurring, circulating antagonist to vascular endothelial
growth factor (VEGF)

VEGF is an endothelial specific mitogen

VEGF activities are mediated primarily by interaction with two highaffinity receptor tyrosine kinases,

VEGFR-1 (fms-like tyrosine kinase-1 [Flt-1])

VEGFR-2 (kinase-insert domain region[KDR]/Flk-1)

Placental growth factor (PlGF) also binds VEGF receptors

sFlt-1 antagonizes the proangiogenic biologic activity of circulating

VEGF and PlGF by binding to them

placental expression and secretion of sFlt-1 appear to play a central

role in the pathogenesis of preeclampsia

Eng is a coreceptor for transforming growth factor (TGF)-beta

A novel placenta-derived soluble form of Eng, referred to as soluble

endoglin (sEng), is an anti-angiogenic protein that appears to be
another important mediator of preeclampsia

sEng is elevated in the sera of preeclamptic women two to three

months before the onset of clinical signs of preeclampsia, correlates
with disease severity, and falls after delivery.

multivariate analysis indicated that each angiogenic factors were

significantly associated with preeclampsia and composite measure
that incorporated all three angiogenic molecules was more strongly
predictive of preeclampsia than the individual biomarkers.

Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM, Epstein FH, Romero R, Thadhani R, Karumanchi
SA: Soluble endoglin and other circulating antiangiogenic factors in preeclampsia.N Engl J Med355:992
1005,2006

Jamaica

A total of 103 participants (50pre-eclampsia, 53 controls) were recruited

from the University Hospital of the West Indies (UHWI). Blood samples were
collected in the fasting state a commercially available kit supplied by Oxford
Biomedical Research Inc. (MI, USA) was used to measure plasma levels of
NO.

In the Jamaican population, NO production increases inpre-eclampsiabut is

not related to the height of the BP.

J Obstet Gynaecol.2007 May;27(4):383-7. Booking blood pressures and plasma nitrite in Jamaican
women withpre-eclampsia. Levy N,Bramwell G,Wierenga A,Fletcher H,McFarlane-Anderson N.

Inflammation/infection

Circulating syncytiotrophoblast debris may contribute to maternal

inflammation

Trophoblastic debris and the microparticles shed during normal

pregnancy are proinflammatory

microparticles carry anti-angiogenic proteins such as sFlt1 and sEng

A systematic review and metaanalysis of observational studies that

examined the relationship between maternal infection and
preeclampsia

risk of preeclampsia in

UTI (pooled OR 1.57; 95% CI 1.45-1.70)

periodontal disease (pooled OR 1.76; 95% CI 1.43-2.18).

conclusion

For example, increased circulating levels of soluble VEGFR-1 and

reduced levels of PlGF predict the subsequent development of
preeclampsia (124,125). By building on these types of studies, prenatal
tests of placental function will eventually become as common as those
tests already in place to assess the health of other important organs.
Along the way we will also learn a great deal about possible therapeutic
strategies for preventing and/or treating pregnancy complications.