Gestational Hypertension and Preeclampsia

• Defective placentation and angiogenesis: Inadequate remodeling of spiral arteries results in a high-resistance, low-flow placental circulation. Reduced placental perfusion triggers release of placental factors, including antiangiogenic molecules (soluble fms-like tyrosine kinase-1 [sFlt-1] and soluble endoglin [sEng]), which exceed pro-angiogenic factors (placental growth factor [PlGF] and vascular endothelial growth factor [VEGF]). This molecular imbalance drives endothelial dysfunction throughout maternal vasculature. Genetic and immunologic factors contribute to abnormal trophoblast invasion; women with inadequate maternal immune tolerance and placental vascular pathology are particularly susceptible.

• Endothelial dysfunction and vascular changes: Elevated sFlt-1 and sEng bind and sequester VEGF and transforming growth factor-beta, preventing their protective effects on endothelial cells. This results in increased endothelial permeability, activation of coagulation, microthrombi formation, and release of vasoactive substances (serotonin, catecholamines, prostaglandins). Endothelial injury manifests as proteinuria (glomerular endotheliosis), platelet consumption (thrombocytopenia), hemolysis (from RBC fragmentation in microvascular circulation), and hepatic inflammation (HELLP syndrome). The loss of vasodilatory prostacyclin and increased vasoconstrictive thromboxane A2 amplify vasoconstriction and hypertension.

• Systemic inflammatory cascade and oxidative stress: Preeclampsia involves a state of heightened systemic inflammation with elevated circulating cytokines (TNF-α, IL-6, IL-8), inflammatory cells, and circulating syncytiotrophoblast debris. Placental ischemia generates reactive oxygen species (ROS) and oxidative stress, overwhelming antioxidant defenses and causing lipid peroxidation. This oxidative milieu activates pattern recognition receptors (TLRs), triggering maladaptive innate immune responses. Endothelial ROS production impairs endothelial nitric oxide synthase (eNOS) function, reducing protective nitric oxide production and further promoting vasoconstriction and platelet activation.

• Immunologic and genetic factors: Inadequate maternal immune tolerance to paternal antigens, including Human Leukocyte Antigens (HLA), increases risk. Nulliparity or reduced exposure to paternal antigen (new partner) impairs immune adaptation. Genetic polymorphisms in genes encoding VEGF, eNOS, angiotensinogen, and placental factors predispose certain women. Family history of preeclampsia/hypertensive disease substantially elevates risk (2-4 fold), particularly maternal history.

• Obstetric risk factors: Primigravidity (first pregnancy) confers highest risk; parity generally reduces recurrence to 5-25% depending on whether preeclampsia occurred in prior pregnancies. Multiple gestations (twin, triplet pregnancies) substantially increase risk due to greater placental mass and relative placental insufficiency. Molar pregnancy and hydatidiform mole present unique preeclampsia risk due to abnormal trophoblastic tissue. Placental abnormalities (abruption history, infarction, circumvallate placenta) increase risk. Nulliparity and paternity changes both increase risk compared to multiparous women with same partner.

• Maternal comorbidities: Chronic hypertension (present before pregnancy or diagnosed before 20 weeks) predisposes to superimposed preeclampsia in 20-25% of affected women. Pregestational diabetes (Type 1 or Type 2) substantially elevates risk (RR 2-3). Chronic kidney disease (eGFR <60, proteinuria, or glomerulonephritis) increases risk; particularly concerning if baseline proteinuria present. Antiphospholipid syndrome (lupus anticoagulant, anticardiolipin, anti-β2 glycoprotein antibodies) and systemic lupus erythematosus confer marked increased risk (RR 2-4). Thrombophilias (Factor V Leiden, prothrombin mutation) moderately increase risk in some populations. Obesity (BMI ≥30 kg/m²), particularly class III obesity, increases risk. Advanced maternal age (>35 years) is independent risk factor.

• Demographic and lifestyle factors: Race/ethnicity: African American and Hispanic women have higher incidence and more severe disease. Low socioeconomic status and limited prenatal care access increase risk. Maternal stress and short interpregnancy interval (<1 year) are associated factors. Smoking paradoxically appears protective (though not recommended). Dietary factors: Low calcium intake and vitamin D deficiency are epidemiologically associated.

• Cardinal symptoms—early preeclampsia: Most women with mild-moderate preeclampsia remain asymptomatic and are identified through screening blood pressure monitoring and urinalysis. When present, symptoms include headache (often frontal, persistent, unresponsive to analgesics), upper abdominal/right upper quadrant pain (from hepatic congestion and capsular distension), visual disturbances (blurred vision, scotomata, photopsia from retinal arteriolar vasospasm), and malaise/nausea. Edema of face, hands, or sacrum may develop but is nonspecific. Dyspnea suggests pulmonary edema (severe preeclampsia).

• Symptoms of severe preeclampsia: Severe headache (often described as "worst headache of life"), epigastric pain (ominous sign suggesting hepatic involvement), visual symptoms progressing (scotomata, amaurosis), altered mental status/confusion, seizures (eclampsia), and respiratory distress from pulmonary edema. Fetal symptoms: Decreased fetal movement (indicating fetal compromise). Postpartum presentation: Preeclampsia develops in ~25% of cases postpartum (typically within 48 hours), sometimes called postpartum preeclampsia; eclamptic seizures may occur days postpartum.

• Physical examination findings: Hypertension (≥140/90 mmHg or increase ≥30 mmHg systolic/≥15 mmHg diastolic from baseline; note that BP increases gradually in normal pregnancy, so relative changes matter). Generalized edema (face, hands, sacrum), though edema alone non-diagnostic. Retinal findings on fundoscopy including arteriolar narrowing, hemorrhages, cotton-wool spots, and papilledema (from hypertensive encephalopathy). Right upper quadrant tenderness and hepatomegaly (from hepatic congestion). Hyperreflexia and clonus (≥2 beats indicates severity; ≥3 beats at high risk for eclampsia). Pulmonary crackles (pulmonary edema), decreased oxygen saturation. Altered sensorium or lethargy. Laboratory stigmata: Thrombocytopenia apparent on CBC; hemolysis may cause jaundice. Acute kidney injury evident from elevated creatinine.

• Blood pressure measurement and classification: Gestational hypertension = BP ≥140/90 mmHg (confirmed on two occasions ≥4 hours apart) OR single reading ≥160/110 mmHg after 20 weeks gestation in previously normotensive woman, WITHOUT proteinuria or other end-organ dysfunction. Preeclampsia without severe features = hypertension + proteinuria ≥0.3 g/24 hours (or urine protein-to-creatinine ratio [UPCR] ≥0.3 g/g, or ≥1+ on dipstick if 24-hour urine unavailable) OR hypertension + one or more clinical/laboratory findings of end-organ dysfunction WITHOUT meeting severe feature thresholds. Preeclampsia with severe features = hypertension PLUS at least one of the following severe features. Note: In 2013, ACOG eliminated the requirement for proteinuria in diagnosis, allowing "preeclampsia without proteinuria" if other end-organ findings present.

• Severe features of preeclampsia (one or more required for diagnosis of severe preeclampsia):
• Maternal symptoms: Persistent headache, visual disturbances, epigastric pain, pulmonary edema, altered mental status
• Hypertension: Systolic BP ≥160 mmHg and/or diastolic BP ≥110 mmHg on two occasions ≥15 minutes apart (at rest) at delivery center
• Laboratory abnormalities: Platelet count <100,000/μL, Serum creatinine >1.1 mg/dL (or doubling if chronic kidney disease), Liver transaminases ≥2× upper limit normal, LDH >600 IU/L, Brain natriuretic peptide (BNP) elevation (≥100 pg/mL suggests volume overload)
• Imaging: Pulmonary edema on chest X-ray, Placental abnormalities on ultrasound (infarction, abruption), Fetal growth restriction (estimated fetal weight <10th percentile) or oligohydramnios (AFI <5 cm)

• Proteinuria quantification: 24-hour urine protein ≥0.3 g is gold standard; urine protein-to-creatinine ratio (UPCR) ≥0.3 g/g is acceptable; spot urine dipstick ≥1+ is suggestive but less accurate. Note that absence of proteinuria does NOT exclude preeclampsia in 2013 diagnostic criteria; other end-organ features sufficient.

• Laboratory studies—comprehensive panel:
• Complete Blood Count (CBC): Platelet count (<100,000/μL indicates HELLP syndrome component; <50,000 severe), hematocrit elevation (hemoconcentration from intravascular depletion), schistocytes on blood smear (microangiopathic hemolytic anemia [MAHA])
• Comprehensive Metabolic Panel (CMP): Serum creatinine (>1.1 mg/dL or doubling), BUN (elevation indicates prerenal azotemia), electrolytes (hyponatremia from SIADH if eclampsia), liver transaminases (AST/ALT >2× ULN), total/direct bilirubin (>1.2 mg/dL in HELLP)
• Coagulation studies: PT/INR, aPTT, fibrinogen (<100 mg/dL in severe HELLP), D-dimer (elevated from consumption); thrombocytopenia with normal PT/aPTT/fibrinogen differentiates from DIC
• LDH (>600 IU/L, often markedly elevated in HELLP)
• 24-hour urine protein or UPCR (quantify proteinuria severity)
• Serum angiogenic biomarkers: sFlt-1/PlGF ratio >85 has high negative predictive value for ruling out preeclampsia in next 1-4 weeks (emerging test, not yet standard of care); useful in equivocal cases

• Imaging studies:
• Fetal ultrasound: Estimated fetal weight (FGR <10th percentile indicates fetal compromise), amniotic fluid volume (oligohydramnios AFI <5 cm or MVA <2 cm), umbilical artery Doppler (increased pulsatility index or reversal of end-diastolic flow indicates severe placental insufficiency), middle cerebral artery (MCA) Doppler (redistribution to brain), cerebroplacental ratio (decreased)
• Maternal chest X-ray: If dyspnea/respiratory distress present (assess for pulmonary edema; bilateral infiltrates)
• Maternal echocardiography: Reserved for persistent pulmonary edema or hemodynamic instability; may show systolic/diastolic dysfunction, diastolic dysfunction with normal EF (restrictive pattern from hypertrophy and fibrosis)

• Diagnostic criteria summary (2013 ACOG):
• Gestational hypertension alone: New hypertension ≥20 weeks, NO proteinuria, NO end-organ dysfunction
• Preeclampsia (without severe features): Hypertension + proteinuria ≥0.3 g/24h OR hypertension + ONE milder end-organ sign (mild thrombocytopenia 100-149K, mild renal insufficiency creatinine 1.1-1.5, mild liver enzyme elevation, no severe symptoms)
• Preeclampsia with severe features: Hypertension + at least ONE severe maternal symptom OR ONE severe laboratory/imaging finding
• Eclampsia: Seizure activity (generalized tonic-clonic) in patient with preeclampsia; seizure unattributable to other causes

Management depends critically on gestational age, severity, maternal condition, and fetal status; delivery is definitive therapy (only cure is termination of pregnancy), timing of which represents central treatment decision

• Preeclampsia without severe features at term (≥37 weeks): Delivery recommended via induced vaginal delivery or cesarean delivery (indication-dependent). Blood pressure management with goal <160/110 mmHg to prevent maternal complications; antihypertensives (first-line: labetalol 200-400 mg PO TID or nifedipine XL 30 mg daily; can add second-line agent if needed) as outlined below. Antenatal corticosteroids NOT indicated at term. Magnesium sulfate NOT routinely given unless severe features develop. Close monitoring for conversion to severe preeclampsia during labor.

• Preeclampsia without severe features at preterm (<37 weeks), expectant management: Goal is to prolong pregnancy to improve fetal maturity while minimizing maternal risk. Hospitalization recommended for initial assessment, though outpatient management (frequently) with close surveillance acceptable if reliable follow-up. Antenatal corticosteroids (betamethasone 12 mg IM ×2 doses 24 hours apart OR dexamethasone 6 mg IM ×4 doses 12 hours apart) administered to promote fetal lung maturity and reduce

Maternal emergencies (act immediately)

• Eclampsia: generalized tonic-clonic seizure from cerebral vasospasm, endothelial leak, and loss of autoregulation. Heralded by persistent headache, visual scotomata, and hyperreflexia with clonus, but may occur without warning and up to several weeks postpartum. Management per ACOG Practice Bulletin 222 is airway protection, left lateral positioning, and magnesium sulfate — not benzodiazepines or phenytoin as first line.
• Hemorrhagic stroke / hypertensive encephalopathy: the leading cause of death in preeclampsia; driven by severe-range systolic pressure breaching cerebral autoregulation. Sudden severe headache with focal deficit demands emergent imaging and rapid antihypertensive therapy.
• Posterior reversible encephalopathy syndrome (PRES): vasogenic edema of the parieto-occipital white matter on MRI; presents with cortical blindness, confusion, or seizure and typically reverses with BP control and delivery.
• HELLP syndrome: microangiopathic hemolysis, transaminitis, and platelet consumption from endothelial injury; schistocytes, elevated LDH, and falling platelets. May progress to DIC or hepatic subcapsular hematoma with rupture — sudden RUQ/shoulder pain with hypotension is a surgical emergency.
• Pulmonary edema: low oncotic pressure plus capillary leak plus diastolic dysfunction; worsened by aggressive IV fluids. Hypoxemia and crackles.
• Placental abruption: painful vaginal bleeding, tetanic uterus, nonreassuring fetal tracing.
• Acute kidney injury: glomerular endotheliosis plus renal hypoperfusion; oliguria with rising creatinine.

Treatment-related

• Magnesium toxicity: sequential loss of deep tendon reflexes → respiratory depression → cardiac arrest; risk rises with renal impairment. Monitor reflexes, respirations, urine output; antidote is calcium gluconate 1 g IV.
• Antihypertensive overshoot: hydralazine causes reflex tachycardia and maternal hypotension with fetal distress; labetalol may cause neonatal bradycardia and is avoided in asthma or heart block.
• ACE inhibitors/ARBs are contraindicated — fetal renal dysgenesis, oligohydramnios, skull hypoplasia.

• Magnesium sulfate is an anticonvulsant, not an antihypertensive: it prevents and treats eclamptic seizures but does not lower blood pressure. The classic distractor is choosing magnesium to control severe-range hypertension, or choosing lorazepam/phenytoin for an eclamptic seizure — ACOG designates magnesium as the agent of choice for both prophylaxis and treatment.
• Severe-range BP (≥160/110) is a hypertensive emergency in pregnancy: the single best next step is prompt IV therapy — labetalol, hydralazine, or oral immediate-release nifedipine — targeting treatment within the first hour to prevent maternal stroke.
• Delivery is the only cure; magnesium, antihypertensives, and corticosteroids buy time, they do not treat the disease. The placenta, not the fetus, is the pathologic organ.
• Loss of the patellar reflex is the first sign of magnesium toxicity, preceding respiratory depression and cardiac arrest; the antidote is calcium gluconate. Reduce dosing and monitor closely with renal impairment.
• Low-dose aspirin prophylaxis is recommended by USPSTF and ACOG for women at high risk (prior preeclampsia, chronic hypertension, pregestational diabetes, CKD, autoimmune disease, multifetal gestation), begun in the late first trimester — ideally before 16 weeks. Mechanism: preferential inhibition of platelet thromboxane A2 over endothelial prostacyclin.
• Hypertension before 20 weeks is chronic hypertension — unless there is a snowstorm uterus and markedly elevated hCG, in which case suspect molar pregnancy, the classic exception and a favorite association.
• Epigastric or RUQ pain with a falling platelet count is HELLP until proven otherwise; a sudden drop in blood pressure with shoulder pain suggests hepatic subcapsular hematoma rupture.
• Proteinuria is not required for the diagnosis, and eclampsia can present postpartum in a woman who was normotensive at discharge — both are high-yield traps.