Hypertensive, Hepatic & Metabolic Disorders of Pregnancy

Hypertensive disorders of pregnancy

Definitions. Hypertension in pregnancy is BP ≥140/90 on two readings at least 4 hours apart. Timing and associated findings separate the categories.

End-organ criteria. Without proteinuria, preeclampsia is diagnosed when new hypertension comes with platelets below 100,000/μL, creatinine above 1.1 mg/dL (or doubling), transaminases at least twice normal, pulmonary edema, or new cerebral or visual symptoms.

Preeclampsia before 20 weeks points to a hydatidiform mole, whose excess trophoblast (large-for-dates uterus, very high hCG) drives early disease.

Pathogenesis of preeclampsia

Failed spiral artery remodeling. In normal pregnancy, extravillous cytotrophoblast invades the maternal spiral arteries and replaces their smooth muscle and endothelium, converting them into wide, low-resistance channels that flood the intervillous space. In preeclampsia the invasion is shallow, the arteries stay narrow and muscular, and the placenta becomes ischemic. Placental ischemia is the root of both the maternal syndrome and fetal growth restriction.

Antiangiogenic imbalance. The stressed placenta releases soluble fms-like tyrosine kinase-1 (sFlt-1), a decoy receptor that traps VEGF and placental growth factor (PlGF), and soluble endoglin, which blocks TGF-β signaling. Serum sFlt-1 rises and free PlGF falls, so the sFlt-1/PlGF ratio climbs. Deprived of these survival signals, maternal endothelium produces less nitric oxide and prostacyclin and more endothelin, while platelets make more thromboxane. The result is widespread vasoconstriction, capillary leak and platelet activation. Anti-VEGF drugs such as bevacizumab cause hypertension and proteinuria, a pharmacologic mimic of the disease.

Pathology. The signature renal lesion is glomerular endotheliosis: swollen endothelial cells lose their fenestrations and occlude capillary lumens, producing bloodless glomeruli, proteinuria and a fall in GFR that reverses after delivery. Decidual vessels show acute atherosis (fibrinoid necrosis with lipid-laden macrophages), and the placenta shows infarcts.

Risk factors and prevention. Nulliparity, prior preeclampsia, chronic hypertension, pregestational diabetes, chronic kidney disease, antiphospholipid syndrome or SLE, multiple gestation, obesity, age ≥35, IVF and molar pregnancy all raise risk. High-risk women take low-dose aspirin (81 mg) daily from 12–28 weeks, ideally before 16 weeks, until delivery. Low-dose aspirin preferentially suppresses platelet thromboxane A2, shifting the balance toward prostacyclin.

Severe features, eclampsia and HELLP

Severe features. Systolic BP ≥160 or diastolic ≥110, platelets below 100,000/μL, transaminases at least twice normal or severe persistent RUQ or epigastric pain (from swelling that stretches the liver capsule), creatinine above 1.1 mg/dL or doubled, pulmonary edema, and new headache or visual disturbance such as scotomata. Delivery of the placenta is the only cure; antihypertensives (labetalol, hydralazine, nifedipine) and magnesium sulfate stabilize the mother until delivery.

Eclampsia. New generalized tonic-clonic seizures in a woman with preeclampsia. Seizures can occur without prior severe hypertension and up to several weeks postpartum. Cerebral vasogenic edema resembling posterior reversible encephalopathy syndrome (PRES) underlies them. Magnesium sulfate prevents and treats eclamptic seizures more effectively than phenytoin or benzodiazepines.

Magnesium toxicity progresses from loss of deep tendon reflexes to respiratory depression and cardiac arrest, so reflexes are monitored; magnesium is renally cleared, so oliguria raises the risk. The antidote is calcium gluconate.

HELLP syndrome. Microangiopathic hemolysis (schistocytes, raised LDH, low haptoglobin) as red cells shear on fibrin in injured microvessels; elevated transaminases from periportal hemorrhagic necrosis; and platelets below 100,000/μL. RUQ or epigastric pain dominates, and hypertension may be mild or absent. A subcapsular hepatic hematoma can rupture into the peritoneum. Delivery is required.

Liver disorders unique to pregnancy

Acute fatty liver of pregnancy. A maternal emergency: nausea, vomiting, abdominal pain and jaundice progress to liver failure with hypoglycemia, coagulopathy, hyperammonemia, acute kidney injury and DIC. Biopsy shows microvesicular fat in hepatocytes. The classic association is a fetus with long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency, a mitochondrial fatty acid oxidation defect: long-chain metabolites from the fetus and placenta overwhelm the heterozygous mother's liver. Treatment is prompt delivery, and the newborn is tested for LCHAD deficiency, which causes hypoketotic hypoglycemia and cardiomyopathy. Hypoglycemia and a high ammonia with normal BP favor AFLP over HELLP.

Intrahepatic cholestasis of pregnancy. Intense itching of the palms and soles without a rash, with serum bile acids of at least 10 μmol/L as the key test; transaminases rise mildly and jaundice is uncommon. The mother is otherwise well, but bile acids threaten the fetus with sudden stillbirth, preterm birth and meconium-stained fluid, so ursodeoxycholic acid is given and delivery is planned early (earlier with higher bile acids). It resolves after birth and tends to recur in later pregnancies.

Gestational diabetes

A diabetogenic placenta. Human placental lactogen (hPL, human chorionic somatomammotropin), together with progesterone, cortisol, prolactin and placental growth hormone, produces insulin resistance that rises with placental mass through the second and third trimesters. The effect spares glucose for the fetus and mobilizes fatty acids for the mother. Gestational diabetes develops when maternal β cells cannot raise insulin output enough, and it resolves once the placenta is delivered.

Screening and treatment. Because insulin resistance peaks late, screening is done at 24–28 weeks: a 1-hour 50-g glucose challenge followed, if abnormal, by a 3-hour 100-g oral glucose tolerance test, or a one-step 2-hour 75-g test. Women with risk factors are tested at the first visit. Treatment starts with diet and exercise; insulin is preferred when drugs are needed because it does not cross the placenta. A 75-g OGTT is repeated 4–12 weeks postpartum, and prior gestational diabetes markedly raises lifetime risk of type 2 diabetes.

Fetal consequences. Glucose crosses the placenta by facilitated diffusion, but maternal insulin does not. Fetal hyperglycemia causes β-cell hyperplasia and hyperinsulinemia, and insulin acts as a fetal growth hormone, producing macrosomia with fat concentrated in the shoulders and trunk. This predisposes to shoulder dystocia, brachial plexus (Erb) palsy and clavicle fracture. After the cord is clamped the glucose supply stops while insulin stays high, causing neonatal hypoglycemia in the first hours. Insulin also antagonizes cortisol's induction of surfactant, so RDS can occur even near term. Polycythemia, hyperbilirubinemia and hypocalcemia are additional neonatal problems.

Structural malformations (caudal regression, transposition of the great arteries and VSD, neural tube defects) come from hyperglycemia during organogenesis, so they complicate pregestational diabetes, not gestational diabetes that begins in the second half of pregnancy.

Amniotic fluid disorders

Mechanisms. Amniotic fluid in the second half of pregnancy is mostly fetal urine, and it is removed mainly by fetal swallowing. Polyhydramnios therefore follows failure to swallow or absorb fluid, or excess urine output. Oligohydramnios follows absent urine, loss through ruptured membranes, or placental insufficiency (preeclampsia, growth restriction), in which fetal blood is redistributed away from the kidneys.

Potter sequence. Prolonged severe oligohydramnios compresses the fetus and deprives the developing lungs of the fluid they need to grow. The result is flattened nose, low-set ears, recessed chin and wrinkled skin (Potter facies), limb deformities such as clubfoot, and pulmonary hypoplasia, the usual cause of death. Bilateral renal agenesis is the classic cause.