23.2 Hypertension & Diabetes in Pregnancy: Classification, Preeclampsia Pathogenesis and Prevention, Severe Features, Eclampsia & HELLP, Magnesium Sulfate, Gestational and Pregestational Diabetes

Why this area matters

TOS areas F and G ask you to:

• classify hypertensive disorders and their risk factors;
• differentiate their signs and severity;
• manage hypertension and its complications;
• screen early;
• manage diabetes in pregnancy and its fetal and maternal complications;
• prevent recurrence and protect long-term health.

Hypertensive disorders, especially eclampsia, are a leading cause of maternal death in the Philippines. Many eclampsia deaths follow missed blood pressure checks, unrecognized severe features or delayed magnesium sulfate. Gestational diabetes is rising with obesity in Filipino women and predicts later type 2 diabetes.

Pathogenesis and prevention of preeclampsia

• Pathogenesis:
  • in normal pregnancy, trophoblast invades and remodels the spiral arteries into wide, low-resistance vessels;
  • in preeclampsia, this remodeling is shallow and incomplete, so the placenta becomes ischemic;
  • the ischemic placenta releases antiangiogenic factors (soluble fms-like tyrosine kinase-1, sFlt-1, and soluble endoglin) and less placental growth factor (PlGF);
  • the result is widespread endothelial dysfunction: vasoconstriction, capillary leak, glomerular endotheliosis, platelet activation and microangiopathy.
• Risk factors:
  • high-risk: previous preeclampsia, chronic hypertension, pregestational diabetes, renal disease, autoimmune disease (SLE, antiphospholipid syndrome) and multiple gestation;
  • moderate-risk: nulliparity, obesity, age 35 or more, family history, a long interpregnancy interval and in vitro fertilization.
• Prevention:
  • low-dose aspirin (81 mg daily in ACOG guidance, 150 mg at night in FIGO and other guidance), started at 12 to 16 weeks, ideally before 16 weeks, and continued until 36 weeks, for women with one high-risk factor or more than one moderate-risk factor;
  • calcium supplementation for women with low dietary calcium.
• Screening: check blood pressure and urine protein at every antenatal visit, and teach the danger signs: headache, visual disturbance, epigastric pain and edema of the face and hands.

Hypertensive Disorders of Pregnancy

Hypertensive diseases complicating pregnancy are classified into four major categories based on gestational age of onset, proteinuria, and multisystem end-organ compromise.

Diagnostic Classification

1. Chronic Hypertension: Hypertension (systolic BP $\ge 140\text{ mmHg}$ or diastolic BP $\ge 90\text{ mmHg}$) that precedes pregnancy, is diagnosed before 20 weeks of gestation, or persists beyond 12 weeks postpartum.
2. Gestational Hypertension: New-onset systolic BP $\ge 140\text{ mmHg}$ or diastolic BP $\ge 90\text{ mmHg}$ diagnosed at or after 20 weeks of gestation in the absence of proteinuria or systemic end-organ signs. Blood pressure normalizes within 12 weeks postpartum.
3. Preeclampsia without Severe Features: New-onset hypertension (BP $\ge 140/90\text{ mmHg}$ on two occasions at least 4 hours apart) occurring at $\ge 20$ weeks of gestation in a previously normotensive woman, accompanied by proteinuria:
   • $\ge 300\text{ mg}$ per 24-hour urine collection, OR
   • Urine protein-to-creatinine ratio (UPCR) $\ge 0.3\text{ mg/mg}$, OR
   • Urine dipstick reading of $2+$ (used only if quantitative methods are unavailable).
4. Preeclampsia with Severe Features (PE with SF): Diagnosed in the presence of preeclampsia when ANY of the following severe features are identified (even in the absence of proteinuria):
   • Severe Hypertension: Systolic BP $\ge 160\text{ mmHg}$ or diastolic BP $\ge 110\text{ mmHg}$ on two occasions at least 4 hours apart (confirmation within minutes is enough if antihypertensive therapy has to be started sooner).
   • Thrombocytopenia: Platelet count $< 100,000/\mu\text{L}$.
   • Impaired Liver Function: Serum transaminases (AST or ALT) elevated to at least twice the upper limit of normal, or persistent severe right upper quadrant or epigastric pain unresponsive to medication and not accounted for by alternative diagnoses.
   • Renal Insufficiency: Serum creatinine $> 1.1\text{ mg/dL}$ or a doubling of serum creatinine in the absence of pre-existing renal disease.
   • Pulmonary Edema.
   • New-onset Cerebral or Visual Disturbances: Severe persistent headache refractory to analgesics, scotomata, photopsia, blurred vision, or altered mental status.
5. Eclampsia: The occurrence of new-onset grand mal (generalized tonic-clonic) seizures in a woman with preeclampsia that cannot be attributed to other neurologic conditions (such as epilepsy, intracerebral hemorrhage, or meningitis).
6. HELLP Syndrome: A severe variant of preeclampsia defined by:
   • H (Hemolysis): Microangiopathic hemolytic anemia with schistocytes on peripheral smear, elevated total bilirubin $\ge 1.2\text{ mg/dL}$, and serum lactate dehydrogenase (LDH) $> 600\text{ U/L}$.
   • EL (Elevated Liver enzymes): Serum AST or ALT $\ge 2\times$ upper limit of normal.
   • LP (Low Platelets): Platelet count $< 100,000/\mu\text{L}$. Complications include hepatic subcapsular hematoma, hepatic rupture, and DIC.

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Medical Management of Severe Preeclampsia and Eclampsia

Definitive treatment of preeclampsia is delivery of the fetus and placenta. Medical stabilization with antihypertensive therapy and seizure prophylaxis must occur prior to delivery.

Acute Antihypertensive Therapy for Severe Hypertension (BP $\ge 160/110\text{ mmHg}$)

The goal of therapy is to lower blood pressure into the safe range (systolic 140-150 mmHg, diastolic 90-100 mmHg) to prevent maternal stroke and abruption while preserving uteroplacental perfusion:

• IV Labetalol (Combined $\alpha/\beta$-blocker): First-line agent. Initial dose 20 mg IV bolus over 2 minutes. If BP remains $\ge 160/110\text{ mmHg}$ after 10 to 20 minutes, administer 40 mg, then 80 mg every 10 to 20 minutes to a maximum cumulative dose of 220 mg. Contraindicated in maternal asthma, severe sinus bradycardia, or uncompensated heart failure.
• IV Hydralazine (Direct arteriolar vasodilator): Initial dose 5 to 10 mg IV bolus over 2 minutes. Repeat with 5 to 10 mg IV after 20 to 30 minutes if needed (maximum cumulative dose 20-30 mg). Risk of reflex tachycardia and precipitous maternal hypotension.
• Oral Nifedipine (Immediate-release dihydropyridine calcium channel blocker): 10 to 20 mg orally (swallowed, never administered sublingually due to risk of sudden fatal hypotension). Repeat in 20 minutes if needed, then 10 to 20 mg every 2 to 6 hours.
• Strict Contraindication: Angiotensin-Converting Enzyme Inhibitors (ACEi) and Angiotensin Receptor Blockers (ARBs) are teratogenic and fetotoxic (causing oligohydramnios, fetal renal dysgenesis, skull hypoplasia, and neonatal death).

Magnesium Sulfate ($\text{MgSO}_4$) Seizure Prophylaxis

Magnesium sulfate is the drug of choice for preventing eclamptic convulsions in preeclampsia with severe features and for arresting active eclamptic seizures (superior to phenytoin and diazepam). It acts as a central NMDA receptor antagonist and cerebral vasodilator.

• Administration Regimens:
  • Zuspan Intravenous Regimen: Loading dose of 4 g IV in 100 mL $D_5W$ infused over 15 to 20 minutes, followed by a continuous maintenance infusion of 1 to 2 g/hour IV.
  • Pritchard Intramuscular Regimen: Loading dose of 4 g IV plus 10 g deep IM (5 g in each buttock with 1 mL 2% lidocaine), followed by 5 g IM in alternating buttocks every 4 hours.
• Monitoring for Hypermagnesemic Toxicity: Magnesium is excreted exclusively by the kidneys. Clinical monitoring must be performed every hour:
  1. Patellar Reflexes (Deep Tendon Reflexes): The therapeutic serum level is about 4 to 7 mEq/L (4.8 to 8.4 mg/dL). Loss of patellar reflexes is the earliest clinical sign of toxicity, appearing at about 7 to 10 mEq/L.
  2. Respiratory Rate: Respiratory depression ($< 12\text{ breaths/min}$) and then respiratory paralysis appear at about 10 to 13 mEq/L.
  3. Urine Output: Must remain $\ge 30\text{ mL/hr}$ (or $\ge 100\text{ mL/4 hours}$). If oliguria develops, magnesium rapidly accumulates, precipitating toxicity.
  4. Cardiac Toxicity: Conduction changes appear above about 15 mEq/L, and cardiac arrest at about 25 mEq/L or more.
• Antidote for Toxicity: Immediately discontinue the $\text{MgSO}_4$ infusion. Administer 10 mL of 10% Calcium Gluconate (1.0 g) IV push slowly over 3 to 5 minutes.

Further points on hypertensive disorders:

• Treat urgently: severe-range BP of 160/110 or more that persists for 15 minutes must be treated within 30 to 60 minutes to prevent stroke.
• Chronic hypertension: keep BP below 140/90. Use labetalol, nifedipine or methyldopa, and avoid ACE inhibitors and ARBs.
• Managing an eclamptic seizure:
  • protect the airway;
  • turn the patient to the left side;
  • give oxygen;
  • give magnesium sulfate (not diazepam);
  • control blood pressure;
  • deliver once she is stable.
• Recurrent seizures: give a further 2 g of magnesium sulfate IV.
• Postpartum: continue magnesium sulfate for 24 hours after delivery or after the last seizure. Preeclampsia and eclampsia can first appear up to 6 weeks postpartum.
• Timing of delivery:
  • gestational hypertension or preeclampsia without severe features: at 37 weeks;
  • preeclampsia with severe features: at 34 weeks or after maternal stabilization (with steroids if preterm). Deliver at once for eclampsia, HELLP with complications, pulmonary edema, abruption or a nonreassuring fetal status.
  • Preeclampsia itself is not an indication for cesarean.
• Long-term risk: women with preeclampsia have a higher lifelong risk of chronic hypertension, ischemic heart disease and stroke, so their BP and cardiovascular risk should be monitored after pregnancy.

Gestational Diabetes Mellitus (GDM)

Gestational diabetes is carbohydrate intolerance resulting in hyperglycemia with onset or first recognition during pregnancy.

• Pathophysiology: Placental secretion of diabetogenic hormones—primarily Human Placental Lactogen (hPL), along with progesterone, cortisol, and prolactin—induces maternal peripheral insulin resistance starting in the late second trimester. This spares glucose for transplacental transfer to the fetus. In GDM, maternal pancreatic $\beta$-cells fail to mount a compensatory hyperinsulinemic response.
• Diagnostic Screening: Administered universally between 24 and 28 weeks of gestation using the IADPSG / WHO One-Step 75-gram Oral Glucose Tolerance Test (OGTT):
  • Fasting plasma glucose: $\ge 92\text{ mg/dL}$ ($5.1\text{ mmol/L}$)
  • 1-hour plasma glucose: $\ge 180\text{ mg/dL}$ ($10.0\text{ mmol/L}$)
  • 2-hour plasma glucose: $\ge 153\text{ mg/dL}$ ($8.5\text{ mmol/L}$)
  • A single abnormal value establishes the diagnosis of GDM.
• Maternal and Fetal Risks:
  • Fetal Complications: Maternal hyperglycemia triggers fetal hyperglycemia and subsequent fetal hyperinsulinemia (Pedersen hypothesis). Insulin acts as a major fetal anabolic hormone, driving fetal macrosomia (birth weight $> 4,000\text{ g}$ or $> 4,500\text{ g}$), asymmetric septal cardiac hypertrophy, polyhydramnios, and organomegaly. Neonatal risks include birth trauma (shoulder dystocia, clavicular fracture, Erb's palsy), neonatal hypoglycemia (abrupt cessation of maternal glucose supply while fetal hyperinsulinemia persists after cord clamping), hypocalcemia, polycythemia, hyperbilirubinemia, and Neonatal Respiratory Distress Syndrome (hyperinsulinism impairs surfactant production by inhibiting type II pneumocyte maturation).
  • Absence of Structural Congenital Anomalies: Isolated GDM develops during the second and third trimesters after organogenesis is complete, and thus does NOT increase the risk of congenital structural anomalies (unlike pregestational diabetes, which is linked to caudal regression syndrome and ventricular septal defects).
• Management: First-line therapy is Medical Nutrition Therapy (MNT) and moderate physical activity. If fasting glucose remains $\ge 95\text{ mg/dL}$ or 2-hour postprandial glucose remains $\ge 120\text{ mg/dL}$, pharmacotherapy is initiated with Insulin (the gold standard, as it does not cross the placenta).

Pregestational diabetes and long-term follow-up

• Preconception care:
  • aim for HbA1c below 6.5% before conception, because high glucose during organogenesis causes anomalies and miscarriage;
  • give folic acid;
  • screen for retinopathy and nephropathy.
• Anomalies of pregestational diabetes:
  • cardiac defects (transposition of the great arteries, VSD);
  • neural tube defects;
  • renal anomalies;
  • caudal regression syndrome, rare but characteristic.
• Other risks:
  • stillbirth;
  • polyhydramnios;
  • preeclampsia;
  • diabetic ketoacidosis, which develops at lower glucose levels in pregnancy;
  • worsening retinopathy.
• Insulin is the preferred drug. Requirements rise through pregnancy, then fall sharply after the placenta is delivered.
• Labor and delivery:
  • control glucose during labor to prevent neonatal hypoglycemia;
  • feed the newborn early and check glucose;
  • watch for hypocalcemia, polycythemia, jaundice and respiratory distress.
• Timing of delivery: well-controlled gestational diabetes on diet alone is delivered at about 39 to 40 weeks. Medication-treated or pregestational diabetes is usually delivered at 39 weeks, or earlier if control is poor or there are complications.
• After gestational diabetes:
  • stop insulin and check glucose;
  • do a 75 g OGTT at 4 to 12 weeks postpartum;
  • screen for diabetes every 1 to 3 years for life, because about half of women develop type 2 diabetes within a decade or two;
  • encourage breastfeeding, weight control and exercise, which lower this risk;
  • screen early in the next pregnancy.