Update management of preeclampsia

“Toxemia of pregnancy” Eclampsia and preeclampsia were originally
attributed to “toxins” or “poisons” believed to enter the maternal
circulation—hence, the term toxemia of pregnancy.
The search for the toxins responsible for preeclampsia and eclampsia
has lasted for more than a century
Bell, M.J., 2010.

Preeclampsia is one of the most enigmatic complications of pregnancy,
and it is considered a pregnancy-specific disorder cured only by
delivery.
It has been estimated that preeclampsia complicates 2–8% of
pregnancies globally.
ACOG practice bulletin no. 202: 2019
Eclampsia complicates about 1 in 3000 (0.03%) pregnancies in the
United Kingdom and Europe. In some developing countries, the
incidence reaches 1%. and about 1% of women with pre-eclampsia in
developed countries
Hypertension accounts for 12%–25% of all antenatal admissions
(Nelson-Piercy C. Handbook of obstetric medicine. CRC press; 2020 Aug 26.)

Hypertensive disorders of pregnancy is one of the leading causes of
maternal and perinatal mortality worldwide.
16% of maternal deaths can be attributed to hypertensive disorders:
• 26% In Latin America and the Caribbean
• 9% in Africa and Asia
• maternal mortality is much lower in high-income countries than
in developing countries

preeclampsiais defined as a systolic blood pressure 140 mm Hg or
more or a diastolic blood pressure of 90 mm Hg or more, or both, on
two occasions at least 4 hours apart after 20 weeks of gestation, in a
woman with a previously normal blood pressure and frequently near
term. Although often accompanied by new-onset proteinuria,
symptoms of preeclampsia may present in the absence of proteinuria.

Gestational hypertension is defined as a systolic blood pressure 140
mm Hg or more or a diastolic blood pressure of 90 mm Hg or more, or
both, on two occasions at least 4 hours apart after 20 weeks of
gestation, in a woman with a previously normal blood pressure without
proteinuria or severe features with levels return to normal in the
postpartum period.
Gestational hypertension is considered severe when the systolic level
reaches 160 mm Hg or the diastolic level reaches 110 mm Hg.

• women diagnosed as hypertensive prior to pregnancy
• If diagnosed for the first time in the first trimester, it is likely a
chronic, pre-existing hypertension, since pregnancy-induced
hypertension (including pre-eclampsia) usually, but not invariably,
appears in the second half of pregnancy
• Diagnosis of pre-existing hypertension may, on occasion, only be
made retrospectively, i.e., 3 to 6 months after delivery when the
blood pressure has not returned to normal
(Nelson-Piercy C. Handbook of obstetric medicine. CRC press; 2020)

➢ General factors
▪ Age: Women over the age of 40 have double the risk of pre-
eclampsia
▪ body mass index greater than 30
➢ Genetic predisposition
▪ Women whose mothers had pre-eclampsia have a 20%–25% risk
of developing pre-eclampsia.
▪ In women with a sister with a history of pre-eclampsia, the risk
may be as high as 35%–40%.

➢ Obstetric factors
▪Primiparity (two- to threefold risk)
▪Multiple pregnancy (twofold risk for twins)
▪Previous pre-eclampsia (sevenfold risk)
▪Long birth interval (two- to threefold if 10 years)
▪ In vitro fertilization especially with donor eggs
▪Hydrops with a large placenta
▪Hydatidiform mole
▪Triploidy (particular association with very early-onset [before 24
weeks’ gestation] pre-eclampsia)
Although pre-eclampsia is more common in primiparous women,
it is more severe in multiparous women with higher morbidity and
mortality rates.

➢ Medical factors
▪ Pre-existing hypertension
▪ Chronic kidney disease (even without renal impairment)
▪ Diabetes (pre-existing or gestational)
▪ Antiphospholipid syndrome
▪ Systemic lupus erythematosus
▪ Sickle cell disease
(Nelson-Piercy C. Handbook of obstetric medicine. CRC press; 2020)

• The exact cause of preeclampsia remains unknown
• A fundamental task of medicine is establishing the causes of
diseases. Preeclampsia is an enigmatic and elusive disorder of
pregnancy and has been labeled the “disease of theories.”
• This condition is one of the “great obstetrical syndromes” in which
multiple and sometimes overlapping pathologic processes activate
a common pathway that leads to their clinical recognition.

Theories tried to explain preeclampsia are the following:
• Abnormal trophoblastic invasion and placental hypoxia (the most
accepted theory)
• Immunologic phenomena
• Vascular endothelial damage
• Cardiovascular maladaptation
• Inflammation and oxidative stress
• Genetic predisposition
• Coagulation abnormalities
• Dietary deficiencies or excesses
Khalil, G. and Hameed, A., 2017

It is generally accepted that abnormal placentation resulting in the
release of soluble antiangiogenic factors, coupled with increased
oxidative stress and inflammation, leads to systemic endothelial
dysfunction and the clinical manifestations of the disease.
Rana, S., Burke, S.D. and Karumanchi, S.A., 2020

Stage 1: Abnormal placentation
• During embryo implantation in early pregnancy, the extravillous
cytotrophoblast from the placenta invade and remodel the uterine
spiral arteries in the myometrium.
• This creates a high-flow, low resistance blood supply to the
maternal compartment that can adequately perfuse the placenta
and sustain the pregnancy.
• Poor cytotrophoblast invasion that leads to poor placental
implantation is the initial pathogenic event that gives rise to
preeclampsia

Stage 1: Abnormal placentation
• uteroplacental ischaemia develops whether due to poor
implantation in underlying microvascular disease or underperfusion
McElwain, C.J et al. 2020

Stage 2: Maternal response
• Normal pregnancy is associated with a systemic inflammatory
response, and this is exacerbated in pre-eclampsia. The maternal
features of preeclampsia include metabolic disturbance including
high levels of triglycerides, an exaggerated inflammatory response
with higher levels of pro-inflammatory cytokines associated with
endothelial dysfunction.
• Endothelial cell activation leads to increased capillary permeability,
increased endothelial expression of cell adhesion molecules and
pro-thrombotic factors, platelet activation and increased vascular
tone.

Stage 2: Maternal response
• In preeclampsia there is a decrease in prostacyclin synthesis and
an increase in thromboxane A2 (TXA2) synthesis. This contributes to
the platelet activation and vasoconstriction.
• These factors cause widespread microvascular damage and
dysfunction, which lead to the clinical manifestations of the
maternal syndrome such as hypertension, proteinuria and hepatic
disturbance.

Antiangiogenic factors in preeclampsia:
During normal pregnancy, vascular endothelial growth factor (VEGF)
and transforming growth factor (TGF-β1) maintain endothelial health
by interacting with their endogenous endothelial receptors.
In Preeclampsia placentally derived soluble factors include
antiangiogenic factors, such as:
▪ soluble fms-like tyrosine kinase-1 (sFlt-1)
▪ soluble endoglin (sEng).
These factors bind and neutralize the actions of proangiogenic factors,
such as vascular endothelial growth factor (VEGF) and transforming
growth factor beta.

Antiangiogenic factors in preeclampsia:
The soluble factors from the placenta can reduce the production of
important vasoactive molecules (including the vasodilator, nitric oxide)
and cause the local release of endothelially derived factors that
further exacerbate the endothelial dysfunction.
These include thromboxane and endothelin-1 (ET-1) (both induce
vasoconstriction) and proinflammatory cytokines.

➢ Blood pressure:
▪ Systolic blood pressure of 140 mm Hg or more or diastolic blood
pressure of 90 mm Hg or more on two occasions at least 4 hours
apart after 20 weeks of gestation in a woman with a previously
normal blood pressure
▪ Systolic blood pressure of 160 mm Hg or more or diastolic blood
pressure of 110 mm Hg or more. (Severe hypertension can be
confirmed within a short interval (minutes) to facilitate timely
antihypertensive therapy).

➢ Proteinuria
▪ 300 mg or more per 24 hour urine collection (or this amount
extrapolated from a timed collection) or
▪ Protein/creatinine ratio of 0.3 mg/dL or more or
▪ Dipstick reading of +2 (used only if other quantitative methods not
available)

➢ Or in the absence of proteinuria, new-onset hypertension with the
new onset of any of the following:
▪ Thrombocytopenia: Platelet count less than 100,000 per µl
▪ Renal insufficiency: Serum creatinine concentrations greater than
1.1 mg/dL or a doubling of the serum creatinine concentration in
the absence of other renal disease
▪ Impaired liver function: Elevated blood concentrations of liver
transaminases to twice normal concentration
▪ Pulmonary edema

➢ Or in the absence of proteinuria, new-onset hypertension with the
new onset of any of the following:
▪ New-onset headache unresponsive to medication and not
accounted for by alternative diagnoses or visual symptoms

➢ Assessment of Blood pressure:
• Auscultatory method
• Automated device
• Home blood pressure monitoring
• Ambulatory blood pressure monitoring

➢ Assessment of Blood pressure:

➢ Assessment of Proteinuria:
• Before the Task Force on Hypertension in 2013, proteinuria was an
essential part of the diagnosis of preeclampsia.
• The amount of protein was previously related to the severity of
the disease. >5 g.
• After the publication of the new guidelines, limited data are
available on whether preeclampsia with or without proteinuria
will have different outcomes.

• Urine dipsticks
Based on the current available data, the accuracy of dipstick
urinalysis in pregnancy with 1+ threshold for predicting
proteinuria of 300 mg/day is poor with a positive likelihood ratio
of 3.48 (95% CI, 1.66e7.27), a negative likelihood ratio of 0.6 (95%
CI, 0.45e0.8), sensitivity of 59% (95% CI, 37%e79%), and specificity
of 28% (95% CI, 18% to 41%.
Waugh, J.J et al., 2004.

• Urine dipsticks
.

• 24-hour urine collection
300 mg or more per 24 hour urine collection (or this amount
extrapolated from a timed collection) is considered positive
The reference standard for measuring urinary protein excretion is
a 24-hour urine collection
Not practical for women need rapid diagnosis

• Protein/creatinine ratio
A value of of 0.3 mg/dL or more is considered positive

➢ Warning symptoms of preeclampsia: (signs precedes symptoms)
• Persistent headache
• Blurring of vision and flashing lights
• Epigastric Pain
• right upper quadrant pain
• Nausea and vomiting
• Rapidly increasing swelling of face, fingers or legs
• Rapid weight gain

➢ Warning symptoms of preeclampsia: (signs precedes symptoms)

➢ Investigations:
• 24-hour urinary protein excretion >0.3 g
• Protein creatinine ratio ; albumin creatinine ratio (
• Complete blood count CBC
• Prolonged clotting times (if concomitant DIC in HELLP syndrome)
• Renal fuvction test ; creatinine
• Liver function tests, particularly raised transaminases

➢ Investigations:
• Reduced fetal growth and oligohydramnios
• Abnormal uterine artery Doppler (bilateral notches and increased
resistance ; pulsatility index at 24 weeks predict pre-eclampsia)
• Abnormal umbilical artery Doppler (reduced, absent or reversed
end diastolic flow indicating fetal compromise)
• Low placental growth factor (PlGF) (reduced in pre-eclampsia and
predictive of delivery for pre-eclampsia within 2 weeks)

Bartal MF, Lindheimer MD & Sibai BM. 2022

➢ Antepartum management:
• Maternal evaluation at the initial evaluation, a complete blood
count with platelet estimate, serum creatinine, LDH, AST, ALT, and
testing for proteinuria should be obtained in parallel with a
comprehensive clinical maternal and fetal evaluation.
• Fetal evaluation should include ultrasonographic evaluation for
estimated fetal weight and amount of amniotic fluid, as well as
fetal antepartum testing.
• Subsequent management will depend on the results of the
evaluation and gestational age.
• The decision to deliver must balance the maternal and fetal risks.

➢ Antepartum management:
• Continued observation is appropriate for a woman with a preterm
fetus if she has gestational hypertension or preeclampsia without
severe features.

Expectant Management
Delivery
Preeclampsia
Outpatient
Inpatient

➢ Conditions Precluding Expectant Management:
• Maternal
1. Uncontrolled severe-range blood pressures (persistent systolic
blood pressure 160 mm Hg or more or diastolic blood pressure
110 mm Hg or more not responsive to antihypertensive
medication .
2. Persistent headaches, refractory to treatment .
3. Epigastric pain or right upper pain unresponsive to repeat
analgesics
4. Visual disturbances, motor deficit or altered sensorium.
5. Stroke
6. Myocardial infarction

• Maternal
7. HELLP syndrome
8. New or worsening renal dysfunction (serum creatinine greater
than 1.1 mg/dL or twice baseline)
9. Pulmonary edema
10. Eclampsia
11. Suspected acute placental abruption or vaginal bleeding in the
absence of placenta previa

• Fetal:
1. Abnormal fetal testing
2. Fetal death
3. Fetus without expectation for survival at the time of maternal
diagnosis (eg, lethal anomaly, extreme prematurity)
4. Persistent reversed end-diastolic flow in the umbilical artery

➢ Inpatient Versus Outpatient management:
Ambulatory management at home is an option only for women with
gestational hypertension or preeclampsia without severe features
and requires frequent fetal and maternal evaluation.
Hospitalization is appropriate for women with severe features and
for women in whom adherence to frequent monitoring is a concern.

➢ Management of mild cases with no evidence of pre-eclampsia:
managed as outpatients. National Institute for Care and Excellence
(NICE) recommends that admission is not mandatory for pre-
eclampsia and that individual risk assessment regarding place of care
is appropriate
(Nelson-Piercy C.; 2020 & NICE guidelines 2019)

➢ Management of pre-eclampsia:
• Monitoring for pre-eclampsia:
1.Regular checks of serum creatinine, haemoglobin, platelet count
(and if thrombocytopenia is present and platelet count <100 ×
109/L, a coagulation screen and liver function.
2. Regular urinalysis, and if proteinuria (≥1+) is detected, PCR or
ACR.
3.Uterine artery Doppler blood flow examination at 20–24 weeks’
gestation, looking particularly for the presence of a prediastolic
‘notch’ or a persistent high-resistance waveform is predictive of
subsequent pre-eclampsia, FGR and placental abruption.

4. NICE recommends offering PlGF-based testing if pre-eclampsia
is suspected at <35 weeks and commercial tests are now
available.

• Treatment of hypertension:
Treatment of pre-existing hypertension in pregnancy reduces the
risk of severe hypertension
Good control of blood pressure is important, and decreases the
complications; maternal (e.g. in HELLP syndrome or another crisis)
or fetal (e.g. with severe growth restriction).

Drug treatment:

Drug treatment:
o First-line drug : Labetalol
Labetalol, a combined α- and β-adrenergic blocker, is the
recommended first-line drug. initial regimen of labetalol at 200
mg orally every 12 hours and dose may be increased up to 800
mg orally every 8–12 hours as needed (maximum 2,400 mg/ d).
few side effects, two to four times daily and should be avoided in
women with asthma.
Parenteral labetalol can be used in the intrapartum management
of acute severe hypertension

Drug treatment:
o Second-line drugs: Nifedipine
Calcium antagonists (e.g. slow-release nifedipine or amlodipine)
can be used alone or in conjunction with labetalol in women who
fail to respond to monotherapy or to replace labetalol in women
who are unable to tolerate it or in whom it is contraindicated.
Side effects include headache, facial flushing and oedema, and
may necessitate withdrawal in some patients.

Drug treatment:
o Third-line drugs : Methyldopa
Methyldopa has been used for many years without any reports of
serious adverse effects on the fetus or on children.
side effects include depression, sedation and postural
hypotension. liver function test abnormalities, and hemolytic
anemia necessitate a change to an alternative drug.

Drug treatment:
o Fourth-line drugs:
α-adrenergic blockers (e.g. doxazosin) which are safe and well
tolerated and other vasodilators such as oral hydralazine.

Drug treatment:
o Other drugs:
Diuretics: avoided in pregnancy, cause further depletion of a
reduced intravascular volume only for heart failure, pulmonary
oedema and idiopathic intracranial hypertension
β-Blockers: used in cardiac disease, migraine prophylaxis and
thyrotoxicosis rather than for hypertension. May affect fetal
growth when used in large doses, may cause neonatal
hypotension and hypoglycemia others. β-Blockers should not be
given to women with a history of asthma.

Drug treatment:
o Other drugs:
Angiotensin-converting enzyme inhibitors
should not be used in pregnancy because they are teratogenic,
increasing the risk of cardiovascular and neurological
malformations.

➢ Intrapartum Management:
• Prevention of seizures
• Control of hypertension

Magnesium Sulfate
▪ A strong evidence prove that the efficacy of magnesium
sulfate to prevent seizures in women with preeclampsia with
severe features and eclampsia.
▪ Reduced the risk of eclampsia (RR, 0.41; 95% CI, 0.29– 0.58).
▪ Reduced the risk of placental abruption (RR, 0.64; 95% CI,
0.50–0.83).
▪ Reduced the risk of maternal mortality (RR, 0.54; 95% CI, 0.26–
1.10).

Magnesium Sulfate
▪ United States regimen : (intravenous administration of a 4–6 g
loading dose over 20–30 minutes, followed by a maintenance
dose of 1–2 g/hour).
▪ For women requiring cesarean delivery (before onset of labor),
the infusion should ideally begin before surgery and continue
during surgery, as well as for 24 hours afterwards.
▪ For women who deliver vaginally, the infusion should continue
for 24 hours after delivery.

Magnesium Sulfate
▪ In case of difficulties with establishing venous access,
magnesium sulfate can be administered by intramuscular (IM)
injection, 10 g initially as a loading dose , followed by 5 g every
4 hours.

Magnesium Sulfate
▪ Monitoring by:
1. Urine output ( avoided in renal impairment or reduced loading
dose)
2. Respiratory rate
3. Tendon reflexes

Magnesium Sulfate
▪ Toxicity:

• Control of hypertension:
Although parenteral antihypertensive therapy may be needed
initially for acute control of blood pressure, oral medications can be
used as expectant management is continued.
Oral labetalol and calcium channel blockers are commonly used
If the maximum dose is inadequate to achieve the desired blood
pressure goal, or the dosage is limited by adverse effect, then
short-acting oral nifedipine can be added gradually

• Control of hypertension:

➢ Mode of Delivery :
• The mode of delivery in women with gestational hypertension or
preeclampsia (with or without severe features) should be
determined by routine obstetric considerations.
• The decision to perform cesarean delivery should be
individualized, based on anticipated probability of vaginal
delivery and on the nature and progression of preeclampsia
disease state.

➢ Low dose aspirin:
• The rationale for the use of low-dose aspirin is that it inhibits
platelet cyclooxygenase and therefore TXA2 synthesis.
• NICE recommends aspirin 75–150 mg in women at increased risk
of pre-eclampsia.
• aspirin should be started before 12 weeks’ gestation and be
continued throughout pregnancy. There is some evidence that the
reduction in risk of pre-eclampsia is greater if the aspirin is taken
later in the day (at bedtime)

➢ Low dose aspirin:
Rolnik DL, et al. 2017

➢ Calcium and vitamin D:
• Meta-analysis of 13 randomized trials comparing at least 1 g daily
of calcium during pregnancy with placebo showed a greater than
50% reduction in the risk of pre-eclampsia.
• The World Health Organization recommends calcium 1.5–2 g daily
for pregnant women with low dietary calcium intake.
• Low maternal serum 25(OH)D (25-hydroxyvitamin D)
concentrations increase pre-eclampsia risk, and vitamin D
supplementation lowers this risk.

➢ Other drugs:
• Low Molecular weight Heparin
• Proton pump inhibitors.
• Pravastatin
• metformin

➢ Other drugs:
Cruz-Lemini, M., et al 2021.

➢ Other drugs:
Tong S, et al. 2020

There has been an increasing amount of literature studying the
relationship between ART and pregnancy and perinatal outcomes over
the past decade, but there is also a lack of clinical practice guidelines
for women who conceived through ART.
Cryopreservation has led to the rise of frozen embryo transfer (FET),
which expands the scope of treatment and decreases the risk of
ovarian hyperstimulation syndrome

While ART continues to benefit many couples around the world, it may
be associated with adverse outcomes, including hypertensive
disorders of pregnancy.
Several metanalyses was done to find relationship between ART and
hypertensive disorders ( Quin et al 2015 Chich et al 2021)
There is strong relationship but further studies with randomized
controlled trials are needed.

➢ Frozen transfer
In recent studies , there is increased risk of hypertensive disorders in
frozen embryo transfer compared to fresh transfer (Maheshwari et al
2018)
Programmed cycles with absence of corpus luteum were associated
with higher risk (Hoynk et al 2019)

➢ Frozen transfer
In an attempt to explain the mechanism(s) underlying the increased
risk of preeclampsia after FET, some hypotheses were formulated:
• Vitrification and warming process might affect the developing
trophoblast, resulting in abnormal Placentation.
• Estradiol rise
• Epigenetic changes by vitrification.
• Protocol used (absence or presence of Corpus luteum)

Update management of preeclampsia

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