Hypertensive Disorders in Pregnancy – Differential Diagnosis (Comprehensive Study Notes)

Page 1

• Scope of Discussion
  • Four main hypertensive disorders in pregnancy (see Table 1):
  – Preeclampsia (± eclampsia, HELLP)
  – Gestational hypertension
  – Chronic hypertension
  – Preeclampsia super-imposed on chronic hypertension
  • Correct diagnosis guides delivery timing, seizure prophylaxis, prognosis, future recurrence, long-term CVD risk.

• Need for Broader Differential
  • Other conditions (eg, glomerulonephritis, thrombotic microangiopathies) can mimic clinical/lab profile.

• Metadata
  • Authors/editors list; topic updated $19\,\text{May}\,2025$; literature review through $\text{Jun}\,2025$.

Page 2

• Diagnostic Criteria & Prevalence
  • Each disorder has distinct criteria (Table 1, Table 2, Algorithm 1).
  • U.S. database (≈ $4\times10^{6}$ deliveries): $11\%$ hypertension-related.
  – $4.7\%$ preeclampsia
  – $3.8\%$ gestational HTN
  – $1.7\%$ chronic HTN
  – $0.6\%$ unspecified
  • Among $\approx1.77\times10^{5}$ preeclampsia/eclampsia:
  – $47\%$ mild/unspecified
  – $37\%$ severe features/HELLP
  – $1.4\%$ eclampsia
  – $15\%$ super-imposed.

• Common Initial Labs
  • Urine protein & sediment
  • Serum creatinine
  • CBC + platelets
  • AST/ALT

Page 3

• When to Order Additional Tests
  • Based on presentation: glucose, fibrinogen, LDH, bilirubin, complement, calcium, electrolytes.

• Placental Growth Factor (PlGF)
  • NICE (UK): use PlGF-based test between $20^\text{+0}$–$36^\text{+6}$ wk to aid diagnosis.
  • Ontario HTA: adjunctive PlGF improves prediction.
  • 2023 FDA: PlGF test predicts progression to severe preeclampsia within $2$ wk for hospitalized hypertensive patients; not endorsed by ACOG/SMFM.

• BP Trajectory in Normal Pregnancy
  • Prospective $n=1000$: BP ↓ after 6 wk, nadir $16$–$20$ wk, returns to baseline by term.

Page 4

• Chronic HTN vs New Preeclampsia
  • Early pregnancy BP fall can mask chronic HTN; later return may mimic preeclampsia if no baseline readings.
  • Safest to presume preeclampsia if new HTN appears.

• Clinical Pearls
  • HTN <$20$ wk → usually chronic; rarely early preeclampsia (higher risk >$40$ yr, multifetal, pheochromocytoma).
  • Proteinuria patterns:
  – Preeclampsia often ↑ and may reach nephrotic range >3\,g/24h.
  – Chronic HTN usually <$1\,g/24h$; nephrosclerosis $1$–$2\,g/24h$ (rare in young). • Epidemiology: Preeclampsia commoner in nulliparas & age >$40$.

Page 5

• Chronic HTN ± CKD
  • New proteinuria >$20$ wk suggests super-imposed preeclampsia.
  • Serum uric acid: normal in chronic HTN, ↑ in super-imposed.
  • Exacerbation of CKD vs preeclampsia:
  – Active urine sediment, low complement, ↑ creatinine >$1.2$ mg/dL without severe HTN → CKD flare.
  • sFlt-1/PlGF ratio (early 3rd trimester) may predict preterm preeclampsia in CKD; evidence limited.

• Temporal Clues
  • 1st half gestation: worsening HTN/proteinuria → CKD.
  • 2nd half: acute HTN + severe labs → super-imposed preeclampsia.

Page 6

• Gestational HTN vs Preeclampsia
  • Gestational HTN: new HTN ≥$20$ wk, no proteinuria, no severe features (Table 3).
  • $10$–$25\%$ progress to preeclampsia; severe gestational HTN managed as preeclampsia severe.

• Autonomic/Sympathetic Etiologies
  • Pheochromocytoma: triad of HTN, headache, sweating + palpitations, tremor, pallor, paroxysms; may show hyperglycemia. High maternal/fetal mortality intrapartum without treatment.
  • Other neurologic causes: Guillain-Barré, paroxysmal sympathetic hyperactivity, multiple system atrophy, acute SCI.
  • Endocrine mimics: Hyperthyroidism (HTN + tachycardia), Hyperparathyroidism (HTN + hyperCa).
  • Renovascular HTN (fibromuscular dysplasia) — audible bruit; may require angioplasty 2nd tri.
  • Cushing & primary aldosteronism: see later.

Page 7

• Drug-Related HTN
  • Sympathomimetic use (cocaine, amphetamines, PCP) or withdrawal of short-acting antihypertensives (clonidine, β-blockers); tyramine with MAOI.

• HTN + Thrombocytopenia/Transaminase Elevation
  • Most = preeclampsia severe. Need to rule out HELLP, AFLP, TTP, aHUS, SLE, APS.

Page 8

• HELLP vs Preeclampsia Severe
  • HELLP defined by hemolysis, ↑ LFTs, ↓ platelets; HTN/proteinuria may be mild.
  • Debate: variant vs separate disorder; minority lack HTN/proteinuria → exclude other mimics.

• Gestational Thrombocytopenia
  • Platelets $100$–$150\,\times10^{3}/μL$ late gestation; self-limited, diagnosis of exclusion.

Page 9

• Acute Fatty Liver of Pregnancy (AFLP)
  • Overlaps with HELLP; ~$50\%$ of AFLP meet HELLP criteria (Swansea).
  • Distinctions:
  – Fibrinogen <$300\,mg/dL$ typical in AFLP; rare in HELLP absent hemorrhage.
  – AFLP often less HTN (only $26$–$70\%$) vs $80$–$100\%$ in HELLP.
  – Hypoglycemia, ↑ ammonia, prolonged $\text{PT/aPTT}$ common in AFLP.
  – Low-grade fever possible (absent in HELLP).
  • Presents 22 wk to 4 d postpartum; biopsy seldom needed.
  • Fetal link: defects in mitochondrial β-oxidation (eg, LCHAD deficiency).

Page 10

• AFLP Confirmation & Histology
  • Biopsy rarely performed; shared features with HELLP.
  • Management same initially (supportive + delivery).
  • Neonates may require metabolic evaluation.

Page 11

• Thrombotic Microangiopathies: TTP
  • TTP onset earlier: $12\%$ 1st tri, $56\%$ 2nd, $33\%$ 3rd/postpartum.
  • Labs: severe platelets ↓, MAHA, LDH >$1000$–$3000$ IU/L; mild/no LFT rise.
  • Schistocytes $2$–$5\%$ vs <$1\%$ in HELLP.
  • ADAMTS13 activity <$10\%$ diagnostic; treat immediately with plasmapheresis.

Page 12

• aHUS / Complement-Mediated TMA
  • Triggered by pregnancy; peak near term/postpartum.
  • Severe kidney injury: creatinine ≥$1.9$ mg/dL, dialysis in $71\%$ at dx.
  • LDH ≥$1832$ U/L discriminates from HELLP.
  • Liver minimally involved.
  • Treated with complement inhibitors (eculizumab, ravulizumab).

Page 13

• Systemic Lupus Erythematosus (SLE)
  • Distinguishing flare vs preeclampsia:
  – Hypocomplementemia, ↑ anti-dsDNA favor flare.
  – Proteinuria + hematuria + ↑ creatinine common in lupus nephritis; HTN less dramatic.
  – AIHA possible in SLE.

• Antiphospholipid Syndrome (APS)
  • Presents with severe preeclampsia <$34$ wk, placental insufficiency, thrombosis, livedo.
  • aPL testing reserved for additional suspicions; negative aPL excludes APS.

Page 14

• Management Reference
  • Separate UpToDate topics for APS obstetric care; aPL positivity without syndrome also addressed.

Page 15

• Mimics of Headache / Abdominal Pain
  • Migraine phases; no lab abnormalities.
  • GI causes: GERD, PUD, viral gastroenteritis.
  • Surgical abdomen: appendicitis, cholecystitis, pancreatitis.
  • Infections (HSV, sepsis) may mimic HELLP but with fever & no HTN.
  • Thrombocytopenia absent in these disorders.

Page 16

• Pulmonary Embolism
  • Dyspnea, pleuritic chest pain, characteristic imaging findings; consider in differential.

Page 17

• Key Summary Points
  • Always default to preeclampsia assumption for new HTN.
  • HTN + low platelets/↑ LFTs → think severe preeclampsia/HELLP first; but differentiate AFLP, TTP, aHUS, SLE, APS.
  • Detailed history/physical + labs essential to rule out medical/surgical mimics.

Page 18

• Graphic – Diagnostic Criteria
  • Gestational HTN: BP ≥$140/90$ ×$2$ ≥$4$ h apart after $20$ wk; no proteinuria/end-organ signs.
  • Preeclampsia: same BP plus proteinuria ≥$300$ mg/24h (or PCR ≥$0.3$).
  • Severe features:
  – BP ≥$160/110$
  – Platelets <$1\times10^{5}/μL$ – LFTs ≥$2×$ normal or severe RUQ pain – Creatinine >$1.1$ mg/dL or double baseline
  – Pulmonary edema
  – Neuro/visual symptoms.
  • Eclampsia = seizures.
  • Chronic HTN defined pre-20 wk or persisting >$12$ wk postpartum.

Page 19

• Super-imposed Preeclampsia Severe – same severe criteria applied atop chronic HTN.

Page 21

• Comparison Table Key Numbers
  • HELLP: HTN $82$–$88\%$, proteinuria $≈100\%$, platelets ↓ all cases.
  • Gestational HTN: no proteinuria/LFT changes.
  • Chronic HTN: variable proteinuria.

Page 23

• Algorithm Highlights
  • BP ≥$140/90$ (×$2$, ≥$4$ h apart); if ≥$160/110$ confirm quickly.
  • Onset <$20$ wk → chronic HTN unless mole/hydrops.
  • Evaluate proteinuria, severe symptoms.
  • Consider atypical causes if labs extreme or presentation early.

Page 24

• Differential List Embedded in Algorithm
  • APS, AFLP, TTP, HUS.
  • History/lab magnitude/spectrum & extra-preeclampsia signs key.

Page 25

• Detailed Severe Feature Definitions
  • Reiterates BP, CNS, hepatic, platelet, renal, pulmonary criteria (see above).

Page 26–27

• Cushing Syndrome Signs
  • Hyperandrogenism: hirsutism, acne, amenorrhea.
  • Metabolic: weight gain, central obesity, impaired glucose.
  • Skin/MSK: violaceous striae, muscle weakness, ↓ BMD.
  • CV: HTN, edema, ASCVD.
  • Neuropsych: depression, cognition deficits.
  • Other: fatigue, immunosuppression.

Page 28–30

• Frequency Tables (Imitators)
  • HELLP vs AFLP vs TTP vs HUS vs SLE—percentages of HTN, proteinuria, fever, jaundice, CNS, plus lab severities (platelets, LDH, creatinine, DIC, hypoglycemia, ADAMTS13).

Page 31–36

• Abdominal Pain Etiologies (Table 6 A-E)
  • Epigastric: MI, pancreatitis, PUD, GERD, gastritis, dyspepsia, gastroparesis.
  • RUQ: biliary colic, cholecystitis, cholangitis, SOD dysfunction, hepatitis, Fitz-Hugh-Curtis, liver abscess, Budd-Chiari, PVT.
  • LUQ: splenic causes (megaly, infarct, abscess, rupture).
  • Lower abdomen: appendicitis, diverticulitis, nephrolithiasis, pyelonephritis, cystitis, urinary retention, colitis, testicular torsion.
  • Pelvic (female): ectopic, PID, ovarian torsion/ruptured cyst, endometriosis, endometritis, fibroids, OHSS, ovarian cancer, mittelschmerz.

Page 37–38

• Pelvic Pain Detailed Features
  • Highlights presentation, lateralization, key differentiators for each gynecologic cause.

Page 39

• Contributor Disclosures – no financial conflicts.

Hypertensive disorders in pregnancy primarily include preeclampsia ($\pm$ eclampsia, HELLP), gestational hypertension, chronic hypertension, and preeclampsia superimposed on chronic hypertension. Accurate diagnosis is crucial for guiding management, prognosis, and long-term risk. Other conditions like glomerulonephritis or thrombotic microangiopathies can mimic these disorders.

Approximately $11\%$ of pregnancies in the U.S. involve hypertension, with preeclampsia accounting for about $4.7\%$ and gestational hypertension $3.8\%$. Initial lab work typically includes urine protein/sediment, serum creatinine, CBC+platelets, and AST/ALT. Placental Growth Factor (PlGF) tests can aid diagnosis and predict severe preeclampsia in some settings but are not universally endorsed.

Key Diagnostic Distinctions:

• Gestational Hypertension: New hypertension (BP $\ge140/90$ mmHg) after $20$ weeks, without proteinuria or severe features. About $10$–$25\%$ progress to preeclampsia.

• Preeclampsia: Gestational hypertension plus new-onset proteinuria ($\ge300$ mg/24h or PCR $\ge0.3$). Severe features include BP $\ge160/110$ mmHg, platelets <1\times10^5/\mu\text{L}, elevated liver enzymes ($\ge2\times$ normal), creatinine >1.1 mg/dL, pulmonary edema, or neuro/visual symptoms. Eclampsia is defined by seizures.

• Chronic Hypertension: Hypertension present before pregnancy or developing before $20$ weeks' gestation, or persisting beyond $12$ weeks postpartum.

• Preeclampsia Superimposed on Chronic Hypertension: New-onset proteinuria after $20$ weeks in a patient with chronic hypertension, or worsening hypertension/proteinuria with new severe features. Serum uric acid is often elevated.

Differential Diagnoses/Mimics:

• HELLP Syndrome: Characterized by Hemolysis, Elevated Liver enzymes, and Low Platelets. Hypertension and proteinuria may be mild or absent.

• Acute Fatty Liver of Pregnancy (AFLP): Overlaps with HELLP, but often presents with less severe hypertension, hypoglycemia, hyperammonemia, prolonged coagulation times, and low fibrinogen.

• Thrombotic Microangiopathies (TTP, aHUS): TTP presents with severe thrombocytopenia, microangiopathic hemolytic anemia (MAHA), high LDH, and often very low ADAMTS13 activity. aHUS involves severe kidney injury and high LDH.

• Systemic Lupus Erythematosus (SLE) Flare: Distinguished from preeclampsia by hypocomplementemia and elevated anti-dsDNA antibodies.

• Antiphospholipid Syndrome (APS): Often associated with severe preeclampsia before $34$ weeks and placental insufficiency; require specific antibody testing.

• Other conditions: Pheochromocytoma (hypertension, headache, sweating, palpitations), drug-related hypertension, and various abdominal pain/headache etiologies (e.g., migraine, GI issues, surgical conditions, infections). These generally lack the specific lab abnormalities of hypertensive disorders of pregnancy.

In cases of new hypertension during pregnancy, especially with low platelets or elevated liver enzymes, severe preeclampsia/HELLP should be the initial assumption, but a thorough history, physical exam, and comprehensive labs are essential to rule out other medical or surgical mimics.