Hypertensive pregnancy disorders

Hypertensive pregnancy disorders are the most common medical complication during pregnancy. There are four major types of hypertensive pregnancy disorders. The most common is gestational hypertension, also referred to as pregnancy-induced hypertension (PIH), which occurs after 20 weeks' gestation. Preeclampsia is a form of hypertensive pregnancy disorder with multiorgan involvement. It is characterized by new-onset hypertension and proteinuria after 20 weeks' gestation. Risk factors include nulliparity, a positive family history, and African-American ethnicity. Eclampsia is a severe form of preeclampsia, characterized by new-onset of eclamptic seizures (grand mal seizures). Preeclampsia may also progress to the life-threatening HELLP syndrome, which is characterized by hemolysis, elevated liver enzymes, and low platelet count.

Hypertensive pregnancy disorders are usually diagnosed in the course of regular prenatal care, which includes regular surveillance of blood pressure, weight, and urine tests. Initial treatment for all hypertensive pregnancy disorders consists of maternal and fetal monitoring until delivery is feasible. Antihypertensive treatment (e.g., labetalol, hydralazine) is indicated in severe hypertension. Magnesium sulfate is important to prevent seizures in severe preeclampsia and eclampsia. Patients with eclampsia and HELLP syndrome require immediate stabilization followed by delivery if the pregnancy is ≥ 34 weeks' gestation. Delivery is the only curative option for preeclampsia and eclampsia, which are both associated with increased maternal and fetal morbidity and mortality. HELLP syndrome has a poor fetal prognosis.

These disorders are on a spectrum from less to more severe and occur after 20 weeks' gestation.

• Gestational hypertension
  • Pregnancy-induced hypertension with onset after 20 weeks' gestation without proteinuria or end-organ dysfunction
  • Defined as a systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg on 2 separate measurements at least 4 hours apart
• Chronic hypertension: hypertension diagnosed < 20 weeks' gestation or before pregnancy
• Preeclampsia: new-onset gestational hypertension with proteinuria or end-organ dysfunction ^[1]
  • Superimposed preeclampsia: preeclampsia that occurs in a patient with chronic hypertension
  • HELLP syndrome: a life-threatening form of preeclampsia characterized by Hemolysis, Elevated Liver enzymes, and Low Platelets
  • Occurrence of new-onset hypertension, proteinuria, or end-organ dysfunction at < 20 weeks gestation is suggestive of gestational trophoblastic disease.
• Eclampsia: a severe form of preeclampsia with convulsive seizures and/or coma
• Postpartum hypertension ^[2][3]
  • Persistent hypertension after delivery that generally resolves within 12 weeks
  • If hypertension lasts > 12 weeks postpartum, a secondary cause should be considered.

Gestational hypertension can only be diagnosed if the patient was normotensive prior to 20 weeks' gestation. Otherwise, high blood pressure during pregnancy is classified as chronic hypertension.

The three primary features of PREeclampsia are Proteinuria, Rising blood pressure (hypertension), and End-organ dysfunction.

• Hypertensive pregnancy disorders occur in 6–8% of pregnancies. ^[4][5]
  • Preeclampsia: 5–7% of pregnancies ^[6]
  • Eclampsia: < 0.1% of all deliveries
  • HELLP syndrome: 0.5–0.9% of all pregnancies ^[7]

Epidemiological data refers to the US, unless otherwise specified.

• Etiology: not fully understood
• Risk factors ^[8]
  • General risk factors
    • Thrombophilia (e.g., antiphospholipid syndrome)
    • < 20 or > 40 years of age
    • African-American ethnicity
    • Diabetes mellitus or gestational diabetes
    • Chronic hypertension
    • Chronic renal disease (e.g., SLE)
    • Obesity (BMI ≥ 30)
  • Pregnancy-related risk factors
    • Nulliparity
    • Multiple gestation (e.g., twins)
    • Hydatidiform mole
    • Previous preeclampsia
    • Chromosomal anomalies or congenital structural anomalies
    • Family history

Smoking actually decreases the risk of developing preeclampsia. ^[9]

• Overview: Multiple maternal, fetal, and placental factors are involved in placental hypoperfusion, which leads to maternal hypertension and other consequences.
  • Uterine spiral arteries normally develop into high-capacity blood vessels. This process is defective in patients with preeclampsia, which leads to hypoperfusion of the placenta and fetus (see “Placenta” for more information on normal placenta formation).
  • Arterial hypertension with systemic vasoconstriction causes placental hypoperfusion → release of vasoactive substances → ↑ maternal blood pressure to ensure sufficient blood supply of the fetus
  • Systemic endothelial dysfunction causes placental hypoperfusion → ↑ placental release of factors → endothelial lesions that lead to microthrombosis
  • Abnormal placental (or trophoblast) implantation or development in the uterus
• Consequences of vasoconstriction and microthrombosis
  • Organ ischemia and damage
    • Preeclampsia: multiorgan involvement (primarily renal)
    • Eclampsia: predominantly cerebral involvement
    • HELLP syndrome: severe systemic inflammation with multiorgan hemorrhage and necrosis (particularly liver involvement)
  • Chronic hypoperfusion of the placenta → insufficiency of the uteroplacental unit and fetal growth restriction

Gestational hypertension

• Asymptomatic hypertension
• Nonspecific symptoms (e.g., morning headaches, fatigue, dizziness) can occur.

Preeclampsia ^[6]

• Onset: ∼ 90% occur after 34 weeks' of gestation.

Preeclampsia without severe features

• Usually asymptomatic
• Nonspecific symptoms may include:
  • Headaches
  • Visual disturbances
  • RUQ or epigastric pain
  • Rapid development of edema
• Hypertension
• Proteinuria

Preeclampsia with severe features ^[12]

• Severe hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 110 mmHg)
• Proteinuria, oliguria
• Headache
• Visual disturbances (e.g., blurred vision, scotoma)
• RUQ or epigastric pain
• Pulmonary edema
• Cerebral symptoms (e.g., altered mental status, nausea, vomiting, hyperreflexia, clonus)

HELLP syndrome ^[13]

• Onset: most commonly > 27 weeks' gestation (∼ 30% occur postpartum)
• Preeclampsia usually present (∼ 85%)
• Nonspecific symptoms: nausea, vomiting, diarrhea
• RUQ pain (liver capsule pain; liver hematoma)
• Rapid clinical deterioration (DIC, pulmonary edema, acute renal failure, stroke, abruptio placentae)

Eclampsia

• Onset: The majority of cases occur intrapartum and postpartum.
• Most often associated with severe preeclampsia
• Eclamptic seizures: generalized tonic-clonic seizures (usually self-limited) ^[5]

Deterioration with headaches, RUQ pain, hyperreflexia, and visual changes are warning signs of a potential eclamptic seizure.

Prenatal screening for hypertensive pregnancy disorders

Early detection to prevent maternal and fetal complications.

• Maternal blood pressure
• Maternal weight
• Maternal urine status (urine dipstick)
• See “Prenatal care” for more details.

Initial workup ^[14]

• Blood pressure measurement: To diagnose PIH, blood pressure must be elevated on at least 2 occasions that are at least 4 hours apart
  • Hypertension ≥ 140/90 mmHg
  • Severe hypertension: systolic BP ≥ 160 mmHg or diastolic BP ≥ 110 mmHg
• Urine tests
  • 24-hour urine collection (gold standard): proteinuria ≥ 300 mg/24 h
  • Urine dipstick: > 1+ protein
  • Urine protein/creatinine ratio ≥ 0.3 mg/dL
• Laboratory analysis
  • CBC (RBC, platelets)
  • Liver function tests (transaminases)
  • Kidney function tests (creatinine)
  • Peripheral smear and coagulation studies are indicated if HELLP syndrome is suspected (i.e., thrombocytopenia and/or liver function impairment are present).

Fetal assessment

• Ultrasound can assess the following:
  • Fetal growth in relation to gestational age
  • Placental implantation and amount of amniotic fluid
• Obstetric Doppler ultrasound
  • Noninvasive method for monitoring placental and fetal blood flow ^[15]
  • Used to evaluate the uterine arteries, umbilical arteries, umbilical vein, fetal middle cerebral arteries, fetal aorta, and heart
    • Increased resistance in the uterine arteries with an abnormal flow pattern
    • Bilateral notches (i.e., early diastolic indentation) of the uterine artery flow profile are associated with uteroplacental dysfunction and preeclampsia.
• Cardiotocography (CTG): used to monitor fetal heart rate and uterine contractions (also called electronic fetal monitor)

Differential diagnosis of eclampsia

Seizure disorders during pregnancy

• Epilepsy
• Encephalitis
• Metabolic disorders (e.g., hypoglycemia, hyponatremia)
• Hemorrhagic stroke
• Ischemic stroke
• Withdrawal syndromes

Differential diagnosis of HELLP syndrome

Causes of thrombocytopenia and liver impairment during pregnancy

• Thrombotic microangiopathy (TTP, HUS)
• Fulminant viral hepatitis

Acute fatty liver of pregnancy

• Definition: : a rare disease most common in the third trimester; characterized by extensive fatty infiltration of the liver, which can result in acute liver failure
• Epidemiology: 1–3:10,000 cases ^[16]
• Etiology: unknown
• Pathophysiology: dysfunction of fatty acid β-oxidation
• Clinical features
  • Sudden onset of jaundice
  • RUQ pain, nausea, and vomiting
  • Coagulopathy with an increased risk of disseminated intravascular coagulation (DIC)
  • Hypoalbuminemia; → ascites ^[17]
• Diagnostics
  • Laboratory analysis
    • ↑ AST, ↑ ALT
    • ↓ Platelets, ↑ WBC
    • Hypoglycemia
    • Liver synthesis parameters: ↓ clotting factors , ↓ cholinesterase
  • Imaging: rule out other diagnoses (e.g., liver hematoma)
  • Liver biopsy: confirms the diagnosis but biopsy during pregnancy is associated with a high risk of complications for mother and fetus and should be avoided ^[16]
• Treatment: immediate delivery ^[18]
• Complications
  • Acute liver failure
  • Acute renal failure
  • Encephalopathy
  • Fetal and maternal death (∼ 10%)

Intrahepatic cholestasis of pregnancy

• Definition: a rare disease most common in the third trimester that presents with pruritus, jaundice, and an elevation in serum bile acid concentrations
• Epidemiology: occurs in 0.1–0.2% of pregnancies
• Etiology: multifactorial ^[19]
• Clinical features
  • Jaundice
  • Pruritus
• Diagnostics ^[20]
  • ↑ Total serum bile acid levels > 10 micromol/L
  • ↑ ALP
  • ↑ ALT, AST
  • ↑ Direct bilirubin
  • Normal γ-GT
  • Hepatitis serology (to rule out viral hepatitis)
  • Antismooth muscle and antimitochondrial antibodies (to rule out autoimmune liver disease)
• Treatment
  • First-line medication: ursodeoxycholic acid PO
  • Cholestyramine PO: may cause a deficiency in fat-soluble vitamins and lead to related adverse effects
  • Delivery at 36–37 weeks' gestation; or at the time of diagnosis if diagnosed at term (fully reversible postpartum)
• Complications
  • Fetal growth restriction
  • Increased fetal mortality
  • Premature labor; and increased preterm birth rates
  • Recurrence in following pregnancies (40–60%)

Early initiation of therapy with ursodeoxycholic acid reduces the risk of preterm birth and stillbirth.

The differential diagnoses listed here are not exhaustive.

Gestational hypertension and preeclampsia without severe features ^[5]

• Initial antepartum evaluation: Assess the maternal and fetal status and the necessity for hospitalization and delivery.
  • Laboratory analysis: CBC, platelet count, serum creatinine, liver enzyme levels
  • Urine protein test
  • Monitor for symptoms of severe preeclampsia
  • Fetal ultrasound (estimate fetal weight and amniotic fluid volume)
  • Nonstress test (NST)
  • Biophysical profiling if NST is nonreactive
• Hospitalization and delivery indicated if: ^[12]
  • Pregnancy ≥ 37 0/7 weeks' gestation
  • Suspected placental abruption
  • Pregnancy ≥ 34 0/7 weeks' gestation plus one of the following:
    • Labor or rupture of membranes
    • Fetal weight < 5^thpercentile
    • Oligohydramnios
    • Abnormal maternal or fetal test results
• In all other cases, continue outpatient monitoring ^[5]
  • Maternal monitoring: (1–2 x/week): blood pressure, urine dipsticks, blood analysis (platelet count, liver enzymes, renal function)
  • Fetal monitoring: ultrasound every 3 weeks and NST 1–2 x/week
  • Patient education
    • Recognize signs of severe preeclampsia or fetal distress (e.g., reduced fetal movement, vaginal bleeding).
    • Avoid physical exertion .
  • Antihypertensive drug therapy for severe hypertension (systolic BP ≥ 160 mmHg or diastolic BP ≥ 110 mmHg)
    • Hydralazine
    • Labetalol
    • Methyldopa
    • Nifedipine

ACE inhibitors and angiotensin-receptor blockers (ARB) are contraindicated during pregnancy due to their teratogenic effect.

Preeclampsia without severe features can progress to preeclampsia with severe features within days, and thus should be closely monitored.

Hypertensive Moms Need Love: Hydralazine, Methyldopa, Nifedipine, Labetalol

Preeclampsia with severe features

Indications for delivery

• Pregnancy is ≥ 34 0/7 weeks' gestation.
• Pregnancy is < 34 0/7 weeks' gestation with maternal or fetal instability.
  • Immediate delivery after stabilization (IV magnesium sulfate prophylaxis, antihypertensive drugs, corticosteroids ) if one of the following is present:
    • Pulmonary edema
    • Eclampsia (cerebral symptoms)
    • Disseminated intravascular coagulation (DIC)
    • Placental abruption
    • Severe, uncontrollable hypertension
    • Nonreassuring signs of fetal distress
    • Fetal demise
  • Delivery 24–48 hours after corticosteroid administration and initial stabilization if one of the following is present:
    • Labor or premature rupture of membranes
    • HELLP syndrome
    • Fetal growth restriction (< 5^thpercentile)
    • Severe oligohydramnios
    • Umbilical cord artery doppler showing reversed end-diastolic flow
    • New-onset or worsening renal impairment
• Procedure: Vaginal delivery should be conducted if possible, but often cesarean delivery is needed for younger gestational age, immature cervix, or poor maternal or fetal condition.

Delivery is the only cure for preeclampsia.

Expectant management

Indicated if pregnancy < 34 weeks and mother and fetus are stable

• Monitor in facilities with maternal and neonatal ICU: ^[12]
  • Daily maternal monitoring: vital signs, laboratory tests, monitor symptoms of severe preeclampsia, contractions, rupture of membranes, vaginal bleeding
  • Daily fetal nonstress test and kick count, twice-weekly BPP, ultrasound every two weeks
• Magnesium sulfate infusion for prophylaxis of eclampsia
• Oral antihypertensive treatment of severe hypertension; (see “Treatment” for “Gestational hypertension and preeclampsia without severe features” above)
• Corticosteroids for fetal lung maturity
• Diuretics for pulmonary edema

Eclampsia

• Stabilization
  • Airway management
  • Supplemental oxygenation
  • Anticonvulsive therapy
    • Magnesium sulfate IV (first-line); Calcium gluconate IV can be used if early signs of magnesium toxicity (e.g., decreased deep tendon reflexes) develop.
    • Alternative or supportive: lorazepam or diazepam IV if unresponsive to magnesium sulfate
  • Position patient on left lateral decubitus position to prevent placental hypoperfusion through compression of the inferior vena cava and reduce the risk of aspiration in the mother.
• Expectant management in patients < 34 weeks' gestation to allow time for corticosteroid administration can be considered in select cases, but the safety and benefits of this approach have not been confirmed (see “Expectant management” of “Preeclampsia with severe features” above)
• Delivery: once the mother is stable and seizures have stopped

Delivery is the only cure for eclampsia.

HELLP syndrome ^[21]

• Stabilization
  • IV fluids
  • Blood transfusions
  • Antihypertensive agents (labetalol, hydralazine)
  • Magnesium sulfate
  • High dose glucocorticoids ^[22][23]
• Delivery: if ≥ 34 weeks' gestation or at any gestational age with deteriorating maternal or fetal status

• Maternal complications
  • Placental abruption
  • DIC
    • Injury to placenta → tissue factor release → unregulated activation of the coagulation cascade
    • ∼ 20% of patients with HELLP syndrome develop DIC.
  • Cerebral hemorrhage, ischemic stroke
  • Acute respiratory distress syndrome (ARDS)
  • Acute renal failure
  • Hepatic subcapsular hematoma
    • Complication of severe preeclampsia and HELLP syndrome
    • Severe hypotension may occur due to rupture of hematoma.
  • Aspiration pneumonia
  • Retinal detachment
  • Long-term: increased risk for cardiovascular disease, diabetes mellitus, and chronic kidney disease ^[24]
  • Maternal death ^[25]
• Fetal complications: occur due to insufficient placental perfusion
  • Fetal growth restriction
  • Preterm birth
  • Seizure-induced fetal hypoxia
  • Fetal death

Ischemic stroke, cerebral hemorrhage, and ARDS are the most common causes of death in patients with preeclampsia.

References:^[26]

We list the most important complications. The selection is not exhaustive.

The prognosis of hypertensive pregnancy disorders depends on the severity of the condition and the complications that occur. In the majority of cases, the conditions resolve within hours or days after delivery.

• Recurrence rate in following pregnancies
  • Preeclampsia: 10–20% ^[27]
  • Eclampsia: 1–2% ^[28]
  • HELLP syndrome: 3–5% ^[29]
• Maternal mortality
  • Eclampsia: 5–10%
  • HELLP syndrome: 1–3.5% ^[30]
• Fetal mortality
  • Eclampsia: 5–11% ^[31]
  • HELLP syndrome: up to 24%

Prophylactic low-dose ASA PO from 12–14 weeks' gestation for patients with a high risk of developing preeclampsia ^[32]