What are the causes of hepatic calcification in a fetus?

Causes of Hepatic Calcification in the Fetus

Fetal hepatic calcifications are most commonly caused by congenital infections (particularly CMV, toxoplasmosis, and parvovirus B19), chromosomal abnormalities (especially trisomy 13,18, and 21), and vascular/thrombotic events, though isolated calcifications without associated abnormalities generally carry an excellent prognosis. 1, 2

Infectious Etiologies

Primary Infectious Causes

• Cytomegalovirus (CMV) is the most frequently identified infectious cause, accounting for 12-30% of cases when specific white matter changes are present 1
• CMV should be suspected when hepatic calcifications occur with microcephaly, sensorineural hearing loss, white matter hyperintensities, or intracranial calcifications 1
• Toxoplasmosis is another major infectious cause, with fetal ultrasonographic findings including intrahepatic calcifications, ventriculomegaly, intracranial calcifications, increased placental thickness, ascites, and echogenic bowel 1
• Parvovirus B19 is the most commonly reported infectious cause of fetal anemia and can lead to hepatic calcifications, particularly when infection occurs before 20 weeks of gestation 1, 3, 2

Additional Infectious Agents

• Syphilis, varicella zoster virus, herpes simplex virus, rubella, and Zika virus have all been associated with fetal hepatic calcifications 1, 4
• Coxsackie virus has been reported in rare cases 1
• The mechanism involves direct damage to the fetal intestinal/hepatic wall with subsequent paralytic ileus, intestinal perforation resulting in meconium peritonitis with focal calcification, or ascites secondary to hydrops 1

Chromosomal Abnormalities

Specific Aneuploidies

• Trisomy 13 is the most common chromosomal abnormality associated with hepatic calcifications when additional major abnormalities are present 2
• Trisomy 18 and trisomy 21 (Down syndrome) are also frequently associated 5, 6, 2
• Turner syndrome (45,X) and other chromosomal deletions including 22q11.2 and 1p36 have been linked 1, 2
• Approximately 18% of fetuses with hepatic calcifications have abnormal karyotypes, with 10 of 11 having other ultrasound abnormalities 2

Vascular and Thrombotic Events

Mechanisms of Calcification

• Fetal vascular injuries can lead to dystrophic calcification in the liver 1
• COL4A1 and COL4A2 pathogenic variants can genetically predispose to fetal vascular injuries, mimicking congenital infection (pseudo-TORCH syndrome) 1
• Thrombotic events during fetal development can result in focal areas of hepatic necrosis and subsequent calcification 7, 6

Hematologic Disorders

• Alpha-thalassemia, the most common hemoglobinopathy causing fetal hydrops, can be associated with hepatic calcifications 1, 5
• G6PD deficiency and pyruvate kinase deficiency are less common erythrocyte enzymopathies that may lead to fetal anemia and secondary hepatic changes 1, 5

Diagnostic Workup Algorithm

Initial Evaluation

• Perform detailed fetal ultrasound examination for associated abnormalities including intracranial calcifications, ventriculomegaly, cardiac defects, ascites, and echogenic bowel 1, 2
• Measure head circumference, as microcephaly or megalencephaly can indicate specific genetic causes 1

Maternal Serologic Testing

• STORCH panel (syphilis, toxoplasmosis, rubella, CMV, herpes) with IgG and IgM titers 1, 7, 2
• For CMV: obtain IgG avidity testing if IgM positive; retrieve Guthrie neonatal blood spot for CMV PCR if available 1
• Parvovirus B19 serology 3, 2

Genetic Testing

• Chromosomal microarray (CMA) as first-tier genomic analysis 1, 2
• Amniocentesis for fetal karyotype, particularly if additional abnormalities are present 6, 2
• Consider parental cystic fibrosis carrier screening if echogenic bowel is also present 1, 7

Specialized Testing When Indicated

• Amniocentesis with PCR for CMV DNA if primary infection suspected (most sensitive after 21 weeks and >6 weeks from maternal infection) 1
• Middle cerebral artery peak systolic velocity (MCA-PSV) Doppler if parvovirus infection confirmed, to monitor for fetal anemia 3
• Fetal MRI for detailed evaluation of brain and liver parenchyma 7

Prognosis and Management

Isolated Hepatic Calcifications

• When hepatic calcifications are isolated (no associated abnormalities, normal karyotype, negative infection workup), the prognosis is excellent 7, 6, 8, 2
• In one series of 21 isolated cases, 19 infants had good outcomes after aneuploidy and infection were excluded 2
• The incidence of isolated hepatic calcifications is approximately 1 in 1,750 to 1 in 2,000 pregnancies 6

Associated Abnormalities

• When additional major abnormalities are present, there is significant risk for chromosomal abnormalities and poor outcomes 2
• In one series, 40 of 61 cases had additional fetal abnormalities, with 18 pregnancy terminations, one intrauterine fetal death, one neonatal death, and two infants with neurologic sequelae 2

Critical Pitfalls to Avoid

• Do not assume isolated hepatic calcifications indicate poor prognosis without completing full infectious and genetic workup 8, 2
• Do not rely solely on maternal symptom history for CMV, as symptomatic maternal infection is uncommon 1
• Microcephaly has not been reported in fetal ultrasonographic findings of congenital toxoplasmosis, possibly due to associated ventriculomegaly 1
• Negative serologic results for both IgM and IgG rule out congenital CMV infection, but other titer patterns require further evaluation 1

Follow-up

• Serial ultrasound monitoring throughout pregnancy for development of additional abnormalities 7, 2
• Postnatal examination and imaging to confirm resolution or persistence of calcifications 7, 6, 8
• Long-term pediatric follow-up for neurodevelopmental outcomes, particularly if infection was confirmed 1, 2