Preeklamsia

01Pathophysiology

Preeclampsia is fundamentally a two-stage disease that begins in the placenta and then manifests as a systemic maternal syndrome.

In the first stage, abnormal trophoblast invasion of the uterine spiral arteries occurs during early placentation. Normally, extravillous trophoblasts remodel these arteries into low-resistance, high-flow conduits to support the growing fetus. In preeclampsia, this remodeling fails, leaving the spiral arteries constricted and unable to deliver adequate blood flow. The result is placental ischemia, which is the central initiating event.

In the second stage, the ischemic placenta releases soluble anti-angiogenic factors, most notably soluble fms-like tyrosine kinase-1 (sFlt-1). sFlt-1 binds and neutralizes pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), creating a state of widespread endothelial dysfunction. This is why preeclampsia is not merely a kidney disease or a blood pressure disease; it is a condition of systemic endothelial injury.

The damaged endothelium shifts the balance of vasoactive mediators: production of vasoconstrictors (endothelin, thromboxane A2) increases, while production of vasodilators (nitric oxide, prostacyclin) decreases. This imbalance explains the hallmark finding of systemic vasoconstriction and hypertension. The endothelial injury also increases vascular permeability, which explains the edema (facial, pulmonary) and proteinuria.

The organ-level consequences follow logically from this mechanism. In the kidney, glomerular endotheliosis (swelling of glomerular endothelial cells) reduces filtration and causes protein leakage (proteinuria) and rising creatinine. In the liver, periportal fibrin deposition and hepatocellular necrosis produce elevated AST/ALT and the subcapsular pain felt in the epigastrium or RUQ. In the brain, vasospasm, endothelial disruption, and loss of cerebrovascular autoregulation lead to headache, scotomata, and seizures (eclampsia). If severe, this can progress to posterior reversible encephalopathy syndrome (PRES) or intracerebral hemorrhage. In the hematologic system, endothelial damage triggers platelet activation and consumption (thrombocytopenia) and mechanical shearing of red blood cells (microangiopathic hemolytic anemia), which together form the basis of HELLP syndrome.

The POGI 2025 guideline emphasizes that the immune system also plays a contributory role. The placenta acts as a trigger for a maternal immune response that worsens endothelial dysfunction. This immunological component explains why nulliparity, new partner pregnancies, and donor gamete pregnancies are risk factors, because immunologic desensitization to paternal antigens has not yet occurred.

Understanding this pathway is critical for exam questions because it directly explains why delivery of the placenta is the only definitive cure. All pharmacologic treatments are temporizing measures aimed at preventing maternal complications (seizures, organ damage) while waiting for the optimal time to deliver.

02Classification and Clinical Manifestation

The clinical manifestations that define preeclampsia beyond hypertension include:

Severe features per ACOG/ISSHP/RCOG include: BP ≥160/110 on two occasions at least 4 hours apart, thrombocytopenia <100,000/uL, liver transaminases >2x upper limit of normal, creatinine >1.1 mg/dL (or doubling of baseline), pulmonary edema, new-onset neurologic symptoms, or HELLP syndrome.

An important exam pearl from the POGI guideline: the term "severe preeclampsia" is no longer recommended in clinical practice because all women with preeclampsia carry the risk of eclampsia. Instead, the guideline distinguishes between preeclampsia with and without severe features (kriteria pemberat).

03Diagnostic Workup

The diagnostic approach to preeclampsia has evolved considerably. The POGI 2025 guideline emphasizes that proteinuria is no longer a mandatory criterion for diagnosis. A woman with new-onset hypertension after 20 weeks plus any evidence of organ dysfunction (thrombocytopenia, renal insufficiency, liver injury, pulmonary edema, or cerebral/visual symptoms) meets the criteria for preeclampsia, even without proteinuria. This is a critical concept for exam purposes: approximately 10% of women with preeclampsia, and up to 50% of women with eclampsia, will not have proteinuria. So a test question presenting a pregnant woman with headache, visual changes, and elevated liver enzymes but negative dipstick still points to preeclampsia.

That said, proteinuria evaluation remains important because it helps stratify severity and prognosis. The recommended method is the urine protein-to-creatinine ratio (uPCR) on a morning spot urine sample. The POGI guideline notes that uPCR ≥30 mg/mmol correlates well with the 24-hour collection threshold of ≥300 mg and is faster and more practical. The dipstick test (urine carik celup) has poor accuracy and should only be used as a preliminary screen in resource-limited settings; a result of ≥1+ must be confirmed.

The workup should include baseline labs for organ injury: CBC with platelet count, liver transaminases (AST/ALT), serum creatinine, LDH, and haptoglobin. These serve the dual purpose of confirming the diagnosis and detecting HELLP syndrome. When neurologic symptoms are present (severe headache unresponsive to analgesics, visual changes, altered mental status, or seizures), brain imaging with CT or MRI is indicated to evaluate for PRES, hemorrhage, or RCVS.

For fetal surveillance, the guideline recommends uterine artery Doppler (ideally at 11-14 weeks as part of first-trimester screening), serial ultrasound for estimated fetal weight, umbilical artery Doppler, middle cerebral artery PI (to detect brain-sparing), and the biophysical profile (BPP). The cerebroplacental ratio (CPR), defined as the ratio of MCA PI to umbilical artery PI, is a key integrative parameter: a CPR <1 indicates pathologic redistribution of blood flow to the brain and correlates with increased perinatal risk.

In women with pre-existing chronic hypertension, diabetes, or autoimmune disease, baseline proteinuria should be assessed before or at the first prenatal visit. This is essential because without a baseline, it becomes impossible to determine whether worsening proteinuria represents superimposed preeclampsia or progression of the underlying disease.

04Management and Treatment

Prevention

In women identified as high risk (one high-risk factor or two or more moderate-risk factors), low-dose aspirin 75-150 mg/day should be initiated between 12 and 16 weeks of gestation and continued until approximately 36 weeks. The mechanism involves selective COX-1 inhibition, which restores the thromboxane-prostacyclin balance, and COX-2 acetylation, which triggers production of aspirin-triggered lipoxins (ATL-4) with anti-inflammatory and pro-resolution properties. Aspirin also indirectly enhances endothelial NO synthase (eNOS) activity, improving vasodilation. Meta-analysis data (Roberge et al., 2017) showed a 90% reduction in early-onset preeclampsia when aspirin was started before 16 weeks. Calcium supplementation at 1.5-2 g/day is recommended for women with dietary calcium intake <600 mg/day.

Blood pressure control

The POGI 2025 guideline (aligned with ESC 2024) recommends initiating antihypertensive therapy when BP exceeds 140/90 mmHg, with a treatment target of <140/90 mmHg and diastolic not below 80 mmHg. BP below 120/70 mmHg is not recommended because of insufficient safety data. The first-line oral agent is nifedipine GITS (a dihydropyridine calcium channel blocker). Methyldopa and beta-blockers (metoprolol, bisoprolol) are alternatives. Atenolol must be avoided because of its association with impaired uteroplacental circulation and fetal growth restriction. RAAS inhibitors (ACEi and ARBs) are absolutely contraindicated in pregnancy due to fetal and neonatal toxicity.

Hypertensive emergency is defined as BP >160/100 mmHg with signs of end-organ damage. The immediate goal is to reduce MAP by 15-25% within 30 minutes, targeting systolic 140-150 and diastolic 90-100 mmHg. The first-line IV agent per the POGI guideline is nicardipine (start 5 mg/h, titrate up to 15 mg/h). Hydralazine 5 mg IV boluses and oral nifedipine 10-20 mg (repeated in 30 min if needed, max 30 mg) are alternatives. When pulmonary edema is present, nitroglycerin IV is preferred.

Seizure prophylaxis

Magnesium sulfate is the drug of choice for preventing and treating eclamptic seizures. Its mechanism involves calcium antagonism and NMDA receptor blockade. The standard regimen (Zuspan protocol) is a loading dose of 4-6 g IV over 15-20 minutes, followed by a maintenance infusion of 1-2 g/h. Monitoring during magnesium infusion is essential: check patellar reflexes (loss of reflexes is the earliest sign of toxicity), respiratory rate (must remain >12/min), and urine output (must remain >25-30 mL/h). The antidote for magnesium toxicity is calcium gluconate 1 g IV. This is a frequently tested concept.

Delivery Timing

The POGI guideline is very clear: delivery is the only way to halt and reverse the pathologic process of preeclampsia. On preterm cases with severe features, the decision to deliver balances the risk to the mother against fetal prematurity, but maternal safety always takes priority.

05Differential Diagnosis and Distractors

The most common exam trap in this differential is distinguishing preeclampsia from gestational hypertension. Both present with new-onset hypertension after 20 weeks. The key is looking for end-organ damage (even in the absence of proteinuria): elevated liver enzymes, low platelets, creatinine rise, neurologic symptoms, or pulmonary edema. The other high-yield distractor is HELLP syndrome presenting without significant hypertension, which can fool students into searching for another cause of thrombocytopenia and hemolysis.

06Traps and High-Yield Pearls

The single most common way students lose points on preeclampsia questions is by requiring proteinuria to make the diagnosis. This is outdated. Per current ACOG, ISSHP, and POGI 2025 guidelines, preeclampsia can be diagnosed based on new-onset hypertension after 20 weeks plus any evidence of end-organ dysfunction, even with completely negative urine studies. About 10% of women with systemic features of preeclampsia (thrombocytopenia, liver injury, neurologic symptoms) will have no proteinuria. Furthermore, up to 50% of eclampsia cases present without proteinuria. If the vignette gives you a pregnant woman with headache, blurred vision, and platelets of 80,000 but a normal urine dipstick, the answer is still preeclampsia.

Another major trap involves drug contraindications. Exam writers love testing whether students reflexively prescribe ACE inhibitors or ARBs for hypertension without checking for pregnancy. These agents are absolutely contraindicated throughout pregnancy because of fetal renal toxicity (oligohydramnios, renal dysgenesis, pulmonary hypoplasia, neonatal anuria). Similarly, atenolol should not be used because of its association with fetal growth restriction from reduced uteroplacental perfusion. The safe choices are nifedipine, methyldopa, and other beta-blockers like metoprolol.

A third frequently tested trap is magnesium sulfate toxicity. Students are expected to know the monitoring sequence: loss of patellar reflexes (first sign, occurs at serum Mg 8-12 mg/dL) precedes respiratory depression (Mg >12 mg/dL), which precedes cardiac arrest (Mg >15-20 mg/dL). If the question describes a patient on MgSO4 who has lost her deep tendon reflexes, the immediate next step is to stop the infusion, not to increase the dose. The antidote is IV calcium gluconate.

Regarding delivery timing, the core principle is that preeclampsia with severe features at or beyond 34 weeks mandates delivery. Expectant management is only considered before 34 weeks, and only if the mother and fetus are stable. If the vignette describes worsening labs, uncontrollable BP, or signs of fetal distress at any gestational age, the answer is delivery. The "only cure is delivery" concept is the single most tested pearl for this diagnosis.

Finally, watch for the vignette that presents a woman with chronic hypertension whose BP worsens with new proteinuria or new organ dysfunction after 20 weeks. This is superimposed preeclampsia, not simply worsening chronic hypertension. The distinction matters because superimposed preeclampsia carries the same risk of eclampsia and requires magnesium sulfate prophylaxis and earlier delivery planning. The POGI guideline recommends that all women with chronic hypertension, diabetes, or autoimmune disease have baseline proteinuria measured before or at the first prenatal visit, precisely to enable this distinction later in pregnancy.