Anatomy, Physiology and Pathophysiology

Placenta

The placenta is the organ that links the mother's blood supply to her unborn baby's blood

supply. Food and oxygen pass through the placenta from mother to baby. Waste products can

pass from the baby back into the mother.

To support the growing baby, the placenta needs a large and constant supply of blood

from the mother. In pre-eclampsia, the placenta doesn't get enough blood. This could be because

the placenta didn't develop properly as it was forming during the first half of the pregnancy. The

problem with the placenta means the blood supply between mother and baby is disrupted.

Signals or substances from the damaged placenta affect the mother's blood vessels, causing high

blood pressure (hypertension).

At the same time, problems in the kidneys may cause important proteins that should

remain in the mother's blood to leak into her urine, resulting in protein in the urine (proteinuria).
 What causes problems with the placenta?

Although the etiology of preeclampsia is unknown, evidence supports the notion that

preeclampsia is associated with shallow cytotrophoblast invasion. Brosen et al. first described the

abnormal “shallow” cytotrophoblast invasion in placentas from women whose pregnancies are

complicated by preeclampsia. They found that cytotrophoblast invasion of the uterus is only

superficial, and the endovascular invasion does not proceed beyond the terminal portions of the

spiral arterioles. The process of trophoblast invasion is normally completed by 20 to 22 weeks of

gestation in normal pregnancy. However, in cases of preeclampsia it has been found that

cytotrophoblast invasion of the uterine spiral arterioles is often incomplete by this time and spiral

arteries fail to lose their muscular elastic components Therefore, a critical underlying lesion in

preeclampsia is the failure of extravillous trophoblasts to invade the muscular spiral arteries into

their myometrial portion and convert them to “low-resistance” capacitance vessels.

Consequently, placental hypoxia and reduced placental perfusion characterized with “low flow

and high resistance” are the central hallmarks of preeclampsia. The figure below illustrates

abnormal spiral artery remodeling that results in low flow and high resistance in cases of

preeclamptic placenta.
Definition

Pregnancy- induced hypertension is a condition in which vasopasm occurs in both small

and large arteries during pregnancy. It is unique to pregnancy and occurs in 5% - 7% of

pregnancies in the United States (Moldenhaurer and Sibai, 2003 as cited by Pilliteri 2007).

Despite years of research, the cause of the disorder is still unknown. Originally, it was called

toxemia because researchers pictured a toxin of some kind being produced by a woman in

response to foreign protein of the growing fetus, the toxin leading to the typical symptom. No

such toxin has ever been identified.

The International Society for the Study of Hypertension in Pregnancy defines

preeclampsia as hypertension of at least 140/90 mmHg on two separate occasions ≥4 hours apart

accompanied by significant proteinuria of at least 0.3 g in a 24-hour collection of urine (or >30

mg/mmol protein/creatinine ratio), arising after the 20th week of gestation in a previously

normotensive woman and resolving completely by the 6th postpartum week. Preeclampsia

complicates 2%–8% of pregnancies and occurs most commonly during the second half of

pregnancy. While overall rates of preeclampsia remain static, rates of severe preeclampsia appear

to have increased over recent decades.

Recent reports from the World Health Organization (WHO) estimate that preeclampsia is

directly responsible for 70,000 maternal deaths annually worldwide. In addition to the maternal

mortality and morbidity, preeclampsia accounts for 500,000 infant deaths annually. Preeclampsia

is a heterogeneous disorder affecting multiple organ systems. While the severity of clinical

presentation is highly variable, outcomes are usually favorable when mild preeclampsia develops

after the 36th week. The risk of adverse maternal and perinatal outcome increases significantly
when preeclampsia develops early, before 33 weeks’ gestation, or at any gestation in those with

pre-existing medical conditions.

 Preeclampsia without severe features (what used to be called "mild preeclampsia")

is characterized by the following:

o Blood pressure of 140/90 or above

o Swelling, particularly of the arms, hands, or face that is reflected in greater than

expected weight gain, which is a result of retaining fluid.

o Protein in the urine

 Preeclampsia with severe features (what used to be called "severe preeclampsia" is

characterized by:

o Blood pressure of 160/90 or higher

o A 24 hour urine collection that has more than 5 grams of protein

o Symptoms such as severe headache, changes in vision, reduced urine output,

abdominal pain, fluid in the lungs and pelvic pain

o Signs of the "HELLP" syndrome. HELLP stands for Hemolysis (damaged red

blood cells), Elevated Liver enzymes (indicating ongoing liver cell damage)

and Low Platelets (cells that help the blood to clot). It occurs in about 10% of

patients with severe preeclampsia.

 Eclampsia is diagnosed when a woman with preeclampsia has seizures. These

seizures usually happen in women who have severe preeclampsia, though they can

occur with preeclampsia. Eclampsia also can happen soon after a woman gives birth.

Approximately 30% to 50% of patients with eclampsia also have the HELLP

syndrome.
  Signs and Symptoms

Type Signs and Symptoms

Gestational hypertension Blood pressure is 140/90 or systolic pressure

elevated 30mmHg or diastolic pressure

elevated 15mmHg above pre-pregnancy level;

no proteinuria or edema; blood pressure returns

after delivery.

Mild preeclampsia Blood pressure of 140/90 or systolic pressure

elevated 30mmHg or diastolic pressure

elevated 15mmHg above prepregnacy level;

proteinuria of 1-2+ on a random sample;

weight gain over 2 lbs per week in second

trimester; mild edema in upper extremities or

face

Severe preeclampsia Blood pressure of 160/110; proteinuria 3-4+ on

a random sample and 5 g on a 24-hour sample;

oliguria (500ml or less in 24 hours or altered

renal function tests; elevated serum creatinine

more than 1.2 mg/dl); cerebral or visual

disturbances (headache, blurred vision);

pulmonary or cardiac involvement; extensive

peripheral edema; hepatic dysfunction;

 thrombocytopenia; epigastric pain

Eclampsia Seizure or coma accompanied by signs and

symptoms of preeclampsia

Risk Factors

Non-Modifiable

Age - While the cause of preeclampsia is unknown, a recent study shows a connection with the

age of the pregnant woman and the likelihood that she will develop preeclampsia. There is a

higher incidence woman below 20 and those above 35 years of age. The reproductive system of

women below 20 years old has not yet fully developed. In pregnant woman 35 years of age and

above, the vessels are older, they are more constricted and therefore contribute to hypertension.

While there is no universal ideal age for pregnancy, women who are closer to or over the age of

menopause are naturally less able to care for a young child. Their bodies will not produce the

appropriate nutrients during pregnancy and they are at risk for numerous complications,

including preeclampsia.

Multiple gestations - The increased placental mass in multiple pregnancies leads to increased

circulating sFlt-1 (soluble fms-like tyrosine kinase-1) levels and sFlt-1/PlGF ratios. (sFlt-1, a

tyrosine kinase protein that disables proteins that cause blood vessel growth. sFlt-1 binds and

reduces free circulating levels of the proangiogenesis factors vascular endothelial growth factor

placental growth factor. sFlt-1 therefore blunts the beneficial effects of these proangiogenic

factors on maternal endothelium with consequent maternal hypertension and proteinuria.)

Family history of preeclampsia - Studies show that there is a higher incidence of preeclampsia

in women who have relatives with history of preeclampsia as well as parents. ACVR2A (this

gene encodes a receptor that mediates functions of activins) may affect the activin A activity

which is involved in EVT (extravillous trophoblasts – specialized fetal cells that invade the

uterine implantation site) invasion in the decidua and the spiral arteries as well as remodeling of

the spiral arteries. This will now cause maternal endothelial dysfunction.

Previous history of preeclampsia - Studies show that there is a higher incidence of

preeclampsia in women who have previous history of preeclampsia. In normal pregnancy, the

shift toward a Th2 cytokine is essential. This shifting enables the maternal immune system not to

reject the fetus. In pre-eclampsia, a skewed Th1/proinflammatory type of immunity is present. It

has been proposed that in pre-eclampsia the shift toward Th2 probably does not occur, or it is

reverted in very early stages of the disease. In consequence, Th1 responses are not suppressed.

This causes an increase in IFN-gamma which affects now the endometrial vasculature

remodeling, angiogenesis at implantation sites, and maintenance of the decidual (maternal)

component of the placenta.

Modifiable

Obesity - Fat tissues produce adipokines (adipokines are cytokines produced by adipose tissue.

Cytokines are substances/proteins secreted by certain cells of the immune system and have an

effect on other cells) which are associated with oxidative stress and inflammation. The

inflammatory mediators produced by the adipose tissue can alter endothelial function.Oxidative

stress decreases availability of nitric oxide which is a free radical which plays a role in muscle

relaxation resulting in arterial vasodilation and increasing blood flow. Free radical is an
especially reactive atom or group of atoms that is produced in the body by natural biologic

processes or introduced from outside (as in tobacco smoke, toxins, or pollutants) and can damage

cells. Also, the association of obesity with preeclampsia may be due to hyperlipidaemia with

abundance of low-density lipoproteins which may predispose the women to oxidative stress and

endothelial cell dysfunction.

Smoking - Inhaling tobacco smoke causes several immediate responses within the heart and its

blood vessels. Within one minute of starting to smoke, the heart rate begins to rise. This is

partially attributable to nicotine, the addictive substance in cigarettes. Nicotine stimulates the

body to produce adrenaline, making the heart beat faster. Nicotine also increases blood pressure,

which is a measure of the tension created upon the walls of the arteries by the blood. The

increase in heart rate and blood pressure means that smokers’ hearts often have to work harder

than non-smokers hearts, resulting in an increased risk of heart disease or stroke. Higher pressure

can also cause damage to organs which filter blood, such as the kidneys. However, clinical trials

on the sole use of nicotine (i.e. in the form of Nicotine Replacement Therapy; NRT) in patients

with underlying, stable coronary disease, suggest that use of therapeutic nicotine does not

increase cardiovascular risk. Smoking tobacco also results in increased exposure to carbon

monoxide (CO), a colourless, odourless gas which is produced from the incomplete burning of

combustible products. CO is the fourth most common chemical of the 4,000 different

constituents of tobacco smoke and can make up 3-5%of its volume. When levels of CO in the

blood increase the ability of the body to carry oxygen is significantly decreased. This is because

carbon monoxide attaches itself to haemoglobin (the oxygen-carrying pigment in red blood cells)

much more easily than oxygen does. This results in tissues being starved of oxygenated blood,
which causes them to suffocate and die. Smokers are also likely to experience shortness of breath

and increased heart rate as a result of carboxyhaemoglobin levels.

Low socioeconomic status - Pregnant women with low economic status have less chance to

avail of medical services. The association of low socioeconomic status and pre-eclampsia is

unclear but could be due to poor nutrition and stressful life conditions which may lead to over

reactivation of the sympathetic nervous system (Leeners et al. 2007).

Diet - Eating salty and fatty foods can lead to a high blood pressure. Fats may be deposited in the

lumen of the blood vessels causing now an increase pressure on the flow of blood. Moreover,

when there’s an increase consumption of salty foods, this can cause an increase blood volume

since sodium attracts water. This will now lead to increase blood volume hence, increasing

workload of the heart.

Pathophysiology

Growing evidence supports the concept that the placenta plays a central role in the

pathogenesis of preeclampsia and that reduced uteroplacental perfusion, which develops as a

result of abnormal cytotrophoblast invasion of spiral arterioles, triggers the cascade of events

leading to the maternal disorder. Placental ischemia leads to release of soluble placental factors,

many of which are classified as anti-angiogenic or pro-inflammatory. Once these ischemic

placental factors reach the maternal circulation, they cause widespread activation and

dysfunction of the maternal vascular endothelium that results in enhanced formation of

endothelin-1 and superoxide, increased vascular sensitivity to angiotensin II, and decreased

formation of vasodilators such as nitric oxide. These endothelial abnormalities, in turn, cause

generalized vasoconstriction throughout the body including the kidneys, which play a critical

role in the long-term regulation of arterial pressure.

 During normal pregnancy, fetally derived cytotrophoblasts invade the maternal uterine

spiral arteries, replacing their endothelium, and differentiating into an endothelial-like

phenotype. This complex and not well defined process results in a conversion of the high-

resistance, small-diameter vessels into high-capacitance, low-resistance vessels to accommodate

adequate delivery of maternal blood to the developing uteroplacental unit. In the presence of

preeclampsia, these uteroplacental arteries become fibrous causing them to narrow, which means

less blood gets the placenta. A poorly perfused placenta can lead to intrauterine growth

restrciction and fetal death in severe cases.

Angiogenic Factors

In response to placental hypoxia, the placenta is proposed to produce pathogenic factors,

which enter the maternal blood stream and are responsible for the endothelial dysfunction and

other clinical manifestations of the disorder including hypertension and proteinuria. Anti-

angiogenic and autoimmune/inflammatory factors are released.

VEGF and the placental growth factor (PlGF), besides their role in angiogenesis are also

important in the maintenance of proper endothelial cell function and health.

sFlt-1 is a circulating soluble receptor for both VEGF and PlGF, which when increased

in maternal plasma leads to less circulating free VEGF and free PlGF, thus preventing their

availability to stimulate angiogenesis and maintain endothelial integrity. In the kidney this

inactivation of free VEGF is believed to cause endotheliosis and proteinuria (Wang et al., 2009)

While sFlt-1 production appears to be regulated by the hypoxia inducible factor-1, other

factors such as tumor necrosis factor (TNF)-α and the agonistic autoantibody to the angiotensin

II type I receptor (AT1-AA) also appear to be involved.

 Endothelin
There is growing evidence to suggest an important role for endothelin-1 (ET-1) in the

pathophysiology of preeclampsia.

ET-1 was identified as a potent endothelium-derived vasoconstrictor, the most potent

vasoconstrictor known. Much of the research on endothelin-1 has focused on the role of the

endothelin type A (ETA) receptor in the vascular smooth muscle and how they serve as important

regulators of ET-1 dependent vasoconstriction and cellular proliferation.

Nitric oxide
Studies have suggested an important role for nitric oxide (NO) in modulating arterial

pressure under various physiological and pathophysiological conditions. NO production is

elevated in normal pregnancy and these increments appear to play an important role in the

vasodilatation that occurs in pregnancy . On the other hand, placental ischemia has been reported

to result in endothelial dysfunction and reduced NO production.

Manifestations

 Rapid weight gain. A weight gain over 2 pounds per week in the 2nd trimester and one pound

per week in 3rd trimester indicates abnormal fluid retention in the interstitial spaces. The

abnormal fluid retention [edema (starts in the upper part of the body)] is due to protein loss

(proteinuria – presence of protein in the urine) and lowered glomerular filtration rate and

increased permeability of glomeruli membranes thereby increasing the tubular reabsorption of

sodium. Sodium retains fluid thus, increase in bodily fluid causing rapid weight gain.
 Reduced urine output/Olguria or no urine output. The decrease glomerular filtration rate

increases tubular reabsorption of Na which in turn causes water retention leading to decreased

urine outpu/ oliguria.

 Dizziness. Associated with headache.

 Epigastric pain, excessive vomiting and nausea as a result of pancreatic and hepatic ischemia,

and abdominal edema.

 Vision changes (blurred vision, seeing spots), dizziness, severe headache hyperreflexia.

These changes could be associated with cerebral edema.

 Thrombocytopenia Coagulopathy. In preeclampsia, endothelial injury causes platelets

aggregation.

 Hypertension.Accommodation to normal pregnancy includes a decrease in both systolic and

diastolic BP as a result of a decrease in systemic vascular resistance primarily secondary to

vasodilation. Relaxin, which is released from the ovaries under the influence of human chorionic

gonadotrophin, upregulates nitric oxide synthase, the enzyme that generates Nitric oxide from

arginine, via the endothelial endothelin B receptor. In preeclampsia, derangement of endothelial-

derived vasoactive factors results in predominance of substances that are vasoconstrictors

(endothelin, thromboxane A2) over vasodilators (Nitric oxide, prostacyclin), hence hypertension.

 Proteinuria. Vasospasm in the kidney increases blood flow resistance causing ischemia to the

kidneys. This leads to increased permeability of the glomerular membrane, allowing the serum

protein albumin and globulin to escape into the urine.

 Increase AST, ALT and LD.Due to the effects of hypoxia in the liver will cause necrosis and

degeneration of hepatocytes and thus would increase AST, ALT and lactate dehydrogenase

levels. In preeclampsia there is releasing of different mediators from liver and blood vessel
endothelium (fibronectin, thrombomodulin, endothelin-l, thromboxane), which causes

vasoconstriction and liver hypoxia. Hypoxia increases the level of ALT, respectively

Complications

If preeclampsia is left untreated, it can:

 Progress to eclampsia, a much more serious pregnancy condition that results in seizures

and other more serious consequences for you and your baby

 Cause HELLP syndrome, another more serious condition that can result in complications

including liver damage without prompt treatment

 Preterm delivery

 Intrauterine growth restriction (IUGR)

 Abruptio placenta

In the first weeks of gestation, physiological hypoxia promotes trophoblast proliferation. Next,
these trophoblasts differentiate into an invasive phenotype acquiring chemokine receptors (e.g.
CCR1), cell adhesion molecules (αVβ3, α1β1, VE-cadherin, VCAM-1, PECAM-1), and the
ability to secrete metalloproteinases (MMPs 1, 2, 3, 7, 9 and 14). The invasive cytotrophoblast
then migrates, preceding the formation of the placental villi and becoming the extravillous
cytotrophoblast, whereby it participates in the remodeling of the uterine spiral arteries. The early
antecedents to pre-eclamptic disease include maintaining the proliferative phenotype of the
trophoblast, preventing its differentiation into an invasive phenotype, or blocking its capacity to
migrate. These are further promoted by the persistence of low oxygen tensions and the presence
of TGF-β1, TGF-β3 and IFN-γ. Green arrows and lines describe progressive events and
stimulatory or promoting factors; and red lines describe inhibitory factors.

Activation of select immune system cells alters secretion of cytokine profiles that lead to the
maternal syndrome of pre-eclampsia. Initially these adverse events cause persistent placental
hypoxia then inadequate placentation, etc. The pathological cytokine profiles may be due to an
alteration in immune system regulation, or an inadequate fetal allorecognition, or to
inflammatory triggers present during implantation.

Although much research into mechanism of preeclampsia has taken place, its exact

pathogenesis remains uncertain. Preeclampsia is thought to result from an abnormal placenta, the

removal of which ends the disease in most cases. During normal pregnancy, the placenta

undergoes process of vascularization to allow for blood flow between the mother and fetus

abnormal development of the placenta leads to poor placental perfusion. The placenta of women

with preeclampsia is abnormal and characterized by poor trophoblastic invasion. It is thought

that this results in oxidative stress, hypoxia, and release of factors that promote endothelial

dysfunction, inflammation, and other possible reactions (Eiland, et al,.2012) (Mustafa, et al

,.2012).

The clinical manifestations of preeclampsia are associated with general endothelial

dysfunction, including vasoconstriction and end-organ ischemia Implicit in this generalized

endothelial dysfunction may be an imbalance of angiogenic and anti-angiogenic factors (Al-

Jameil, et al,. 2014).

Both circulating and placental levels of soluble fms-like tyrosine kinase-1 (sFlt-1) are higher

in women with preeclampsia than in women with normal pregnancy (Mustafa, et al ,.2012).

sFlt-1 is an anti-angiogenic protein that antagonizes vascular endothelial growth factor (VEGF)

and placental growth factor (PIGF), both of which are proangiogenic factors. Soluble endoglin
(sEng) has also been shown to be elevated in women with preeclampsia and has anti-angiogenic

properties, much like sFlt-1 does.

Both sFlt-1 and sEng are upregulated in all pregnant women to some extent, supporting the idea

that hypertensive disease in pregnancy is a normal pregnancy adaptation gone awry. As natural

killer cells are intimately involved in placentation and as placentation involves a degree of

maternal immune tolerance for a foreign placenta which requires maternal resources for its

support, it is not surprising that the maternal immune system might respond more negatively to

the arrival of some placentae under certain circumstances, such as a placenta which is more

invasive than normal. Initial maternal rejection of the placental cytotrophoblasts may be the

cause of the inadequately remodeled spiral arteries in those cases of pre-eclampsia associated

with shallow implantation, leading to downstream hypoxia and the appearance of maternal

symptoms in response to up regulated sFlt-1 and sEng.

Oxidative stress is thought to play an important part in the pathogenesis of pre-eclampsia. The

main source of reactive oxygen species (ROS) is the enzyme xanthine oxidase (XO) and this

enzyme mainly occurs in the liver. One hypothesis is that the increased purine catabolism from

placental hypoxia results in increased ROS production in the maternal liver and release into the

maternal circulation causing endothelial cell damage (McMaster, et al,. 2008).

Abnormalities in the maternal immune system and insufficiency of gestational immune

tolerance seem to play major roles in pre-eclampsia. One of the main differences found in pre-

eclampsia is a shift toward Th1 responses and the production of IFN-γ. The origin of IFN-γ is not

clearly identified and could be the natural killer cells of the uterus, the placental dendritic cells

modulating responses of T helper cells, alterations in synthesis of or response to regulatory

molecules, or changes in the function of regulatory T cells in pregnancy aberrant immune

responses promoting pre-eclampsia may also be 10 due to an altered fetal all recognition or to

inflammatory triggers. It has been documented that fetal cells such as fetal erythroblasts as well

as cell-free fetal DNA are increased in the maternal circulation in women who develop

preeclampsia. These findings have given rise to the hypothesis that pre-eclampsia is a disease

process by which a placental lesion such as hypoxia allows increased fetal material into maternal

circulation that leads to an immune response and endothelial damage ultimately resulting in

preeclampsia and eclampsia (Laresgoiti, etal,. 2010).