Jaundice in pregnancy

Bilirubin basics

• Haem is broken down to unconjugated bilirubin, which is water-insoluble and carried on albumin. The liver takes it up (OATP), conjugates it with UGT1A1, and exports it into bile through MRP2. Gut bacteria convert it to urobilinogen, some of which is reabsorbed and excreted in urine.

• Haemolytic causes in exam stems: autoimmune haemolysis (positive direct Coombs; methyldopa causes a warm IgG type), a delayed haemolytic transfusion reaction about a week after transfusion, *P. falciparum* malaria, G6PD deficiency after antimalarials such as primaquine, sickle cell disease and hereditary spherocytosis.
• Gilbert syndrome: low UGT1A1, mild unconjugated rise with fasting or illness; benign. Dubin–Johnson: MRP2 defect, conjugated jaundice without itch, worse with pregnancy and the pill. Rifampicin causes an early unconjugated rise by blocking uptake.
• Drug hepatitis: isoniazid, rifampicin and pyrazinamide can cause hepatocellular injury; if jaundice appears on antituberculous treatment, stop the drugs and reintroduce one at a time once tests settle.
• Cholestasis causes vitamin K malabsorption, so PT lengthens and corrects with parenteral vitamin K.

Liver tests in normal pregnancy

• ALP rises 2–4 fold (placental isoenzyme), so it is useless for cholestasis. Albumin falls (haemodilution); fibrinogen and lipids rise.
• ALT, AST, GGT and bilirubin are unchanged or slightly lower. An ALT twice the upper limit is never a normal change of pregnancy and needs explanation.

Liver disorders of pregnancy

Intrahepatic cholestasis of pregnancy

• Genetics: familial cases (mother and sister affected, recurrence in every pregnancy, cholestasis on the pill) often carry a mutation in ABCB4 (MDR3), the canalicular phospholipid floppase that moves phosphatidylcholine into bile. Without phospholipid, bile acids are not packaged into micelles and injure the bile ducts. ABCB11 (bile salt export pump) and ATP8B1 variants also contribute.
• Bile acids cross the placenta and provoke fetal arrhythmia and meconium passage. Stillbirth risk rises sharply when bile acids exceed about 100 µmol/L, guiding earlier delivery.
• Ursodeoxycholic acid displaces toxic hydrophobic bile acids and boosts canalicular export, easing itch.
• It resolves after delivery, but recurs in later pregnancies and on oestrogen-containing (combined) contraception, even when liver tests have returned to normal. Progestogen-only or non-hormonal methods are preferred.
• Persisting itch with positive anti-mitochondrial antibody suggests primary biliary cholangitis (middle-aged women, cholestasis, hypercholesterolaemia).

Acute fatty liver of pregnancy

• The fetus is homozygous for deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), part of mitochondrial fatty acid oxidation. Unmetabolised fetal long-chain fatty acids return to a heterozygous carrier mother, whose liver cannot cope. The baby later has non-ketotic hypoglycaemia, so test the baby.
• Risk factors: first pregnancy, twins, male fetus, low BMI.
• Histology: microvesicular steatosis, mainly zone 3, little necrosis.
• Failed hepatic synthesis and gluconeogenesis: long PT, low fibrinogen, very low antithrombin and hypoglycaemia. Transient diabetes insipidus occurs because the liver fails to clear placental vasopressinase.
• AFLP versus HELLP: hypoglycaemia (for example 2.6 mmol/L, 47 mg/dL), high ammonia and marked coagulopathy favour AFLP; schistocytes and very low platelets favour HELLP. Hypertension does not exclude AFLP; about half of women with AFLP have it. Both are treated by prompt delivery, and AFLP is the most dangerous pregnancy-specific liver disease.

Coincidental causes

Neonatal jaundice

• The fetus clears unconjugated bilirubin across the placenta. After birth a high red cell mass, short red cell life, low UGT1A1 and enterohepatic recycling cause physiological jaundice: after 24 hours, peaks day 3–5, gone by 2 weeks.
• Breastfeeding jaundice (first week): poor intake slows stools and increases enterohepatic recycling. Breast milk jaundice is a benign prolonged unconjugated rise in a thriving baby.
• Pathological: jaundice within 24 hours (rhesus or ABO haemolysis, G6PD deficiency), polycythaemia, sepsis.
• Cephalhaematoma (subperiosteal bleed, does not cross sutures, common after vacuum delivery): the trapped blood is broken down over days, adding bilirubin from red cells in the haematoma, so jaundice deepens with a negative antiglobulin test.
• Conjugated jaundice with pale stools and dark urine: exclude biliary atresia urgently (surgery best before 60 days).
• Kernicterus: unbound unconjugated bilirubin is lipid-soluble and crosses the blood–brain barrier, staining the basal ganglia (globus pallidus, subthalamic nucleus), auditory and oculomotor nuclei. The result is athetoid (not spastic) cerebral palsy, sensorineural deafness and upward gaze palsy with normal intelligence. Risk rises with low albumin, acidosis, prematurity and drugs that displace bilirubin (sulphonamides).
• Phototherapy: blue light (about 460 nm) converts bilirubin to water-soluble lumirubin and photoisomers excreted without conjugation; exchange transfusion for very high levels.

Remember Itch without rash in the third trimester: measure bile acids, not ALP.

Exam trap In pregnancy ALP is raised by the placenta; a raised ALT is never normal.

Exam trap Hypoglycaemia with jaundice near term means acute fatty liver until proven otherwise.

How FCPS asks about this

• Pregnant woman with jaundice after visiting a flood area, fulminant course: hepatitis E.
• Itchy palms and soles at 32 weeks: obstetric cholestasis; raised bile acids; familial cases ABCB4.
• Contraception after obstetric cholestasis: avoid the combined pill.
• AFLP versus HELLP: hypoglycaemia favours AFLP; fetal LCHAD deficiency is the cause.
• Pre-hepatic jaundice: unconjugated bilirubin, low haptoglobin, no bilirubin in urine.
• Athetosis, deafness and gaze palsy after neonatal jaundice: kernicterus in the basal ganglia and auditory nuclei.
• Jaundice deepening after vacuum delivery with a cephalhaematoma: red cell breakdown in the haematoma.