Preeclampsia

It contributes to both maternal and infant morbidity and mortality.

It is associated with approximately 70, 000 maternal deaths and approximately 500,000 fetal newborn deaths annually, globally.

Accounts for 6% of preterm births and 19% of medically indicated preterm birth in the US.

Worldwide, it is the second most common cause of maternal morbidity and mortality rate.

A complication of approximately 4% of pregnancies in the US.

A complex hypertensive dsease with overexpression of soluble fms-like tyrosine kinase 1, a soluble VEGF receptor that binds in neutralizes VEGF.

Characterized by abnormal trophoblast invasion, endothelial dysfunction, and vascular inflammation.

The lack of VEGF leads to maternal vascular dysfunction and organ damage.

Cardiovascular manifestations are related to increased peripheral vascular resistance, which causes hypertension, despite decreased intravascular volume.

Can be classified according to gestational age at delivery as early onset preeclampsia with delivery at 34 weeks or less, preterm preeclampsia with delivery at 37 weeks or less of gestation, and term preeclampsia with delivery at 37 weeks or greater of gestation.

Presently defined as de-novo hypertension present after 20 weeks of gestation. combined with >300 mg/day of proteinuria, other maternal organ dysfunction, such as renal insufficiency, liver involvement, neurological or hematological complications, uteroplacental dysfunction or fetal growth restriction.

Fetal manifestations include fetal growth restriction and macrosomia often seen with late onset preeclampsia.

Renal involvement is most commonly manifested as proteinuria because of glomerular endotheliosis and associated loss of podocyte  integrity.

Such renal severe lesions can result in nephrotic range proteinuria, tubular necrosis, and acute kidney injury.

Presentation is mostly asymptomatic, and diagnosis is made during routine antenatal care.

Diagnosing preeclampsia is necessary to identify women at risk for adverse outcomes and determine the best course of treatment.

Traditional definition of preeclampsia is new one onset hypertension and proteinuria at 20 weeks or more of gestation but the definition should be broadened to include other forms of maternal end-organ involvement and uteroplacental dysfunction.

Women with early onset disease of less than 34 weeks gestation are more likely than women with late onset disease at greater than 34 weeks gestation to have end-organ damage, fetal growth restriction, and a hemodynamic profile of low cardiac output, and high peripheral vascular resistance.

In women with late onset preeclampsia, who accounted for at least 70% of all women with preeclampsia, birthweight is usually normal or even increased, cardiac output may be increased, and peripheral vascular resistance is variable.

Prsentation may include: headache, visual disturbance, blindness, epigastric pain, nausea, and vomiting,

Maternal adverse outcomes occur in 10% of women with preeclampsia.

Maternal adverse outcomes occur in 15% of women with early onset disease:Life altering, life-threatening, or fatal complications.

Predisposes cardiovascular disease and may increase mortality decades after the index pregnancy.

Most cases are term or mild and transient and resolve soon following delivery.

Women with a history of preeclampsia have a twofold increased risk of ischemic heart disease and cerebrovascular disease and fourfold increased risk of developing hypertension due to endothelial dysfunction.

Cardiac output is normal, unless preeclampsia is complicated by peripartum cardiomyopathy.

The risk for latent cardiovascular disease is heightened when preeclampsia occurs early in pregnancy, results in preterm delivery, leads to small for gestational age infants.

It is a CV risk factor.

Preeclampsia and cardiovascular disease have a common denominators: obesity, diabetes, hypertension, renal disease, inflammation, autoimmune dysorders, and hypercoagulability.

Associated with a higher risk of hypertension.

Pulmonary endothelial activation, neutrophil activation, and decreased plasma oncotic pressure increase the risk of pulmonary edema in acute respiratory distress syndrome.

Severe hypertension increases the risk of hemorrhagic stroke.

The combination of hypertension and endothelial activation can result in ischemic encephalopathy in the posterior hemispheres manifested as headaches, scotomata, and seizures of eclampsia.

Patients with a history of preeclampsia in a previous pregnancy, type one or type two diabetes, and chronic hypertension are at the highest risk.

Other factors that place a person at high risk for preeclampsia include: multifetal gestation, conception by assisted reproductive technology, autoimmune disease, kidney disease, nulliparity, high prepregnancy BMI, family history of preeclampsia, and advanced maternal age of 35 years or older.

Carotid artery intima-media thickness is significantly higher in postmenopausal women who have previously had preeclampsia compared to the normotensive postmenopausal women.

In the International Society for the Study of Hypertension definition above proteinuria is no longer required in the definition.

Complicates 2-8% of all pregnancies.

Pre-eclampsia is estimated to affect about 5% of deliveries while eclampsia affects about 1.4% of deliveries.

Black women are at greater risk for developing preeclampsia than other women, and experience higher rates of maternal and infant morbidity and perinatal mortality than other racial and ethnic groups.

In the US the rate of maternal death from preeclampsia is higher among black women than among white women.

Disparities in risk factors for preeclampsia include: access to early prenatal care and obstetric interventions which may account for some of the differences in prevalence and 

clinical outcomes.

The incidence of progression to a convulsive process, i.e. eclampsia, occurs in approximately 0.5% of patients with mild preeclampsia and 2-3% of those of patients with severe eclampsia, as defined by a systolic blood pressure greater than 160 mm Hg or greater, a diastolic blood pressure of 100 mm Hg or greater, nephrotic-range proteinuria of greater than 3.5 g per 24 hours, renal insufficiency, thrombocytopenia, and/or evidence of a microangiopathic hemolytic anemia, hepatocellular injury, pulmonary edema and neurologic abnormalities.

One of the main causes of maternal, fetal, and neonatal mortality, especially in countries with low-middle income.

The incidence of eclampsia in developed countries is one in 2000-3000 deliveries.

Perinatal mortality in patients with preeclampsia is twice as high as non preeclampsia pregnancies.

Eclampsia and preeclampsia account for about 12% of US maternal deaths.

Greater than one third of serious maternal morbidity and 15% of preterm births are related to preeclampsia.

Related to fetal growth restriction and preterm birth.

If untreated complications include: eclampsia, liver rupture, stroke, pulmonary edema,or kidney failure, all of which can be lethal.

liver damage is characterized by periportal inflammation  and hepatocellular damage, subscapular hematoma, and rarely hepatic failure or rupture.

Hematologic manifestations include: hemoconcentration, relative neutrophilia, microvascular thrombosid and hemolysis, platelet consumption, and disseminated intravascular coagulation.

Abruption can result from ischemia-reperfusion injury in maternal uretoplacental vessels.

Women with proteinuria have high antenatal blood pressure, deliver at early stage of gestation, and often need operative delivery.

Proteinuria is not an indicator of maternal morbidity or perinatal mortality.

Women with this condition produce excessive thromboxane.

No specific test that permits diagnosis of this disorder.

Cause is unclear but some women are genetically predisposed.

Associated with gene variations involved in thrombophilia, inflammation oxidative stress and renin angiotensin system.

Thrombophillic gene variants in F2 and F5 hve been associated consistently with preeclampsia.

Maternal gene variants and genes encoding for HLA-C interactions presispose to preeclampsia in white people, sub-Saharan Africans and Chines Han population.

Placental antiangiogenic factors ae upregulated and the maternal endothelium is disrupted in women with preeclampsia, leading to an antiangiogenic state.

Remains a leading cause of both maternal and fetal morbidity and mortality worldwide.

Typically manifests as new onset hypertension and proteinuria after 20 weeks� gestation.

Characterized by hypertension and proteinuria, occurring after 20 weeks of gestation in a previously normotensive individual.

Complications associated with preeclampsia include: preterm, birth, fetal growth, restriction, placenta, abruption, HELLP syndrome, seizures, acute kidney injury, stroke, myocardial infarction, pulmonary edema, retinal, detachment, and hepatic dysfunction, especially with onset at earlier gestational ages.

Classified as mild or severe based on blood pressure with blood pressure at least 140mm/90mm Hg for mild disease and at least 160 mm/110mm Hg for severe disease.

Blood pressure, on average, is increased in early to midpregnancy in women who later experience preeclampsia but individual blood pressure measurements are not adequate to be predictors.

Clinical diagnosis made before 37 weeks of gestation is wrong more often than it is right.

No relation to nutritional intake.

Strong risk factors: previous preeclampsia, hypertension in pregnancy, chronic kidney disease, hypertension, diabetes, autoimmune disorders and antiphospholipid syndrome.

Moderate risk factors include: first pregnancy, age 40 years or more, pregnancy interval of greater than 10 years, BMI of 35 or greater, polycystic ovarian syndrome, family history and multiple pregnancy.

Obesity is and risk factor.

The estimated risk of preeclampsia doubles for every increase of 5 to 7 in the BMI.

There is a dose response relationship between obesity class and preeclampsia.

Much higher risk for women who have donated a kidney.

Risk factor predict for preeclampsia only 30% of the time.

Seizures can manifest as one or more generalized convulsions, which may be associated with or without coma.

Best medication to prevent seizures is magnesium sulfate.

The protective effects of magnesium are attributed to calcium channel blockade and vasodilation.

With HELLP syndrome associated with a higher maternal risk than preeclampsia without the HELLP syndrome.

7% of cases of severe preeclampsia occur in the second trimester.

In the second trimester associated with a high rate of abruptio placenta (22%), HELLP syndrome (17%), eclampsia (17%) and DIC (8%).

Elevated plasma homocysteine levels in early pregnancy can increase the risk of developing severe preeclampsia by threefold.

Literature supports delivery within 72 hours in severe preeclampsia.

Immediate cesarean delivery confers no benefit to patients with severe preeclampsia over vaginal delivery.

Resolution of preeclampsia is initiated with delivery, but maternal and organ complications may worsen in the postpartum, and particularly during the first three days.

Earlier planned birth minimizes maternal risks, but it may increase the risk for the newborn, particularly at preterm gestational ages.

Characterized by systemic endothelial dysfunction.

Only known cure is delivery of the placenta.

Often culminates in delivery of a very preterm infant with substantial increase in risk of neonatal death.

Life threatening complications include seizures, cerebral hemorrhage. disseminated intravascular hemorrhage, and renal failure.

Decreased urinary placental growth factor at mid pregnancy is associated with early development of preeclampsia.

May be associated with increased risk of renal disease, cardiovascular disease for several years after pregnancy.

Children born to mothers with pre-eclampsia have increased risk of bronchopulmonary dysplasia, and cerebral palsy, caused by preterm birth and small for gestational age.

Decreases health related quality of life,

Increases the risk of post-partum depression.

Associated with increased risk of microalbuminuria up to 5 years after preeclampsia associated pregnancy.

When associated with a woman�s first pregnancy the patient is at an increased risk of kidney biopsy later in life.

When associated with a first pregnancy predicts for increased risk of ischemic heart disease, stroke, hypertension, stroke and death from cardiovascular disease.

May be associated with posterior reversible encephalopathy syndrome.

Among women with preeclampsia in only one of two or three pregnancies the risk of ESRD was increased if the episode occurred in the second or third pregnancy, respectively, indicating that women with severe preeclampsia with the first pregnancy are less likely to become pregnant again than women without preeclampsia.

The risk of ESRD is greater in women with more than one preeclampsia pregnancy than in those with only one episode.

Women who have preeclampsia have twice the risk of stroke and 4 times the risk of hypertension later in life, compared with women who do not develop preeclampsia.

Combination of late first-trimester uterine artery Doppler US, placental growth factor, and pregnancy associated plasma protein-A in maternal blood predicts early-onset preeclampsia with a sensitivity of 934% and a specificity of 95% in some studies.

First-trimester uterine artery Doppler US predicts for early-onset preeclampsia with a specificity of 92%.

Low dietary calcium and low serum calcium levels are associated.

Calcium supplements in women with low calcium intake reduces preeclampsia risk.

Calcium supplementation is recommended in the second half of pregnancy for women with low dietary calcium.

Studies show that low-dose calcium supplementation is noninferior to high-dose calcium supplementation with respect to the risk of preeclampsia (Dwarikanath, P).

Dietary supplementation with vitamin C and vitamin E or magnesium does not reduce risk.

Vitamin D deficiency is associated with increased risk

L-arginine, a nitric oxide precursor, with other antioxidants reduces the risk.

A diet rich in fruits, vegetable oils reduces risk.

Women at increased risk of preeclampsia should take low-dose aspirin to reduce the likelihood of developing preeclampsia as well as preterm birth and intrauterine growth restriction (US Preventive Services Task Force).

Low-dose aspirin, reduce the incidence of preterm preeclampsia by 62%.

Aspirin inactivates the cyclooxygenase-1 enzyme, suppressing the production of prostaglandins and thromboxane.

Aspirin results in inhibition of oxidative stress and inflammation and platelet aggregation, as well as promotes trophoblast invasion, spiral arteries remodeling, and the development of chorionic villi, a phenomenon that mainly occurs during the first trimester of pregnancy and is completed by 20 weeks of gestation.

The prevention of preeclampsia with aspirin is most effective when aspirin is initiated between 11 weeks 0 days and 16 weeks 6 days of gestation.

Women at risk for preeclampsia can be evaluated with trimester screening for maternal factors, uterine artery pulsatility index, mean arterial pressure, and serum pregnancy associated plasma protein A.

Aspirin is the drug of choice in prevention, showing a moderate benefit.

Evidence supports the use of exercise, aspirin, calcium, and labor induction as effective preventive strategies.

Exercise reduces the risk of preeclampsia without adverse fetal effects and should be achieved by undertaking at least 140 minutes per week of moderate intensity exercise, sufficient to raise the heart rate and allow speaking but not singing.

Aspirin reduces the risk of preeclampsia in the dose dependent manner, and lowers the rate of serious material complications, preterm birth, delivery of small for gestational age infants and fetal or newborn death in women at increased risk for preeclampsia.

In the ASPRE trial, first trimester screening of high risk women who received aspirin found that the risk of preterm preeclampsia was reduced by more than 60%.

Aspirin prophylaxis against preeclampsia is associated with a small increase in antepartum and postpartum bleeding, as well as neonatal bleeding in rare cases.

Calcium supplementation during pregnancy reduces the risk of preeclampsia t term or preterm gestational age.

Women at increased risk of preeclampsia include those with an earlier episode, diabetes, hypertension, kidney disease, or an autoimmune disease.

Preeclampsia significantly associated with non-critical heart defects in offspring, and preeclampsia with onset before 34 weeks is associated with critical heart defects: the absolute risk of congenital heart defects, however is low.

USPSTF recommends that women with high-risk disease take low-dose aspirin daily between weeks 12 and 28 of pregnancy.

USPSTF found that the use of low-dose aspirin in women at increased risk of preeclampsia have a 2 to 5% reduction in absolute risk for preeclampsia, and a 2 to 4% decrease for preterm birth, and a 1-5% decline in intrauterine growth restriction.

USPSTF reported that the preventive use of aspirin in high-risk patients does not increase the risk of placental abruption, postpartum hemorrhage, fetal intracranial bleeding, or perinatal mortality (Henderson JT et al).

Once it develops, the only effective treatment is delivery.

A trial of nulliparous woman show that labor induction at 39 weeks to 39 weeks four days of gestation compared with expectant care, reduces the risk of gestational hypertension and preeclampsia.

Late postpartum eclampsia accounts for 14% of eclampsia cases.

Late postpartum eclampsia manifests between 48 hours and four weeks following delivery.

The most common presenting symptom in late postpartum eclampsia is headache, occurring in about 70% of cases.

For women is having increased risk of preeclampsia no program of maternal and fetal surveillance as shown to reduce maternal or perinatal risk.

These women are encouraged to self monitor for symptoms of preeclampsia: headache, reduced fetal movement, self monitoring  blood pressure, increased frequency of antenatal care visit, self monitoring for proteinuria, monthly laboratory testing for thrombocytopenia,, elevated creatinine or aminotransferase levels or angiogenic imbalance, and third trimester fetal assessment with ultrasound, pulse pulsatility indexes of the umbilical and middle cerebral arteries.

Initiation of birth is recommended at an early gestational age of less than 24 weeks, when the risk of maternal complications and fetal mortality are high, and any gestational age when serious maternal or fetal complications are noted, and at term gestational age of 37 weeks even in the absence of complications, to minimize the risk for the mother without increasing the risk for the newborn.

Expectant management of preeclampsia is considered preference to initiation of birth from fetal viability to 36 weeks six days of gestation period, if medical care is readily available.

Presently, no disease modifying therapy is available for established preeclampsia.

Severe hypertension is associated with maternal and perinatal adverse outcomes and warrants antihypertensive therapy with agents nodedipine, parenteral labetalol or parenteral hydralazine.

Treatment for chronic or gestational hypertension that is non severe is recommended, as well.

Preeclampsia may first develop in the postpartum, when the risk of associated maternal complications and death is highest.

Postpartum preeclampsia results from redistribution of extravascular fluid and may require rehospitalization.

Preeclampsia in the postpartum period is associated with the increased mental health problems.

In a metanalysis of 22 studies involving 99,415 women with preeclampsia: 15% subsequently had gestational hypertension and 15% had preeclampsia during a subsequent pregnancy.

The recurrence rate may be as high is 50% if prior preeclampsia was of early onset or associated with complications.

4-8% of women will have at least one episode of preeclampsia during their lifetime.