What are the causes of fetal hydrocephalus?

Causes of Fetal Hydrocephalus

Fetal hydrocephalus results from diverse etiologies including structural CNS malformations (most commonly spina bifida/myelomeningocele, aqueductal stenosis, and Dandy-Walker malformation), chromosomal abnormalities, infections, genetic mutations, and hemorrhage. 1, 2

Structural/Congenital Malformations

The most common structural causes include:

• Spina bifida (myelomeningocele) is one of the most frequent causes of congenital hydrocephalus, often associated with Arnold-Chiari malformation 1, 2
• Aqueductal stenosis represents a major obstructive cause, blocking CSF flow through the cerebral aqueduct 1, 3
• Dandy-Walker malformation involves cystic dilation of the fourth ventricle with cerebellar hypoplasia 1
• Other CNS malformations that disrupt normal CSF circulation and absorption pathways 4, 2

Genetic Causes

• X-linked hydrocephalus comprises approximately 5% of all congenital hydrocephalus cases, caused by mutations in the L1CAM gene at Xq28 encoding neural cell adhesion molecule L1 4
• Gene mutations that disrupt brain morphogenesis and alter biomechanics of the CSF-brain interface can cause congenital hydrocephalus present at or near birth 2
• Gender determination is appropriate when isolated hydrocephalus is identified to consider X-linked aqueductal stenosis 3

Chromosomal Abnormalities

• Aneuploidy accounts for 7-16% of cases, particularly in early-onset fetal hydrocephalus 5
• Turner syndrome (45,X) and Down syndrome (trisomy 21) are common chromosomal causes, with Turner syndrome associated with 50-80% of cystic hygromas that can lead to hydrops and hydrocephalus 6
• Trisomies 13,18, and triploidy have also been associated with fetal hydrocephalus 6

Infectious Causes

• Parvovirus B19 is the most commonly reported infectious cause, leading to fetal anemia and potential hydrops through inhibition of erythropoiesis 6
• Cytomegalovirus (CMV) accounts for 5-10% of cases in most series 6
• Toxoplasmosis and syphilis are additional infectious etiologies 6
• Other viral infections including Coxsackie virus, varicella, herpes viruses, and respiratory syncytial virus have been reported 6

Hemorrhagic Causes

• Intracranial hemorrhage from trauma or vascular malformations can obstruct CSF pathways 4, 2
• Fetomaternal hemorrhage leading to severe fetal anemia can result in hydrops and associated hydrocephalus 6

Hematologic Disorders

• Alpha thalassemia is the most common hemoglobinopathy causing fetal hydrops (which may be associated with hydrocephalus), accounting for 28-55% of cases in Southeast Asian populations and about 10% in other series 6
• G6PD deficiency and pyruvate kinase deficiency are less common erythrocyte enzymopathies that can lead to fetal anemia and hydrops 6

Thoracic Abnormalities

• Congenital pulmonary airway malformation (CPAM) is the most frequent pulmonary lesion associated with hydrops, which may accompany hydrocephalus 6
• Congenital hydrothorax/chylothorax from lymphatic obstruction can cause mediastinal shift impairing venous return 6

Cardiovascular Abnormalities

• Structural cardiac defects account for 17-35% of nonimmune hydrops cases 5
• Fetal arrhythmias, particularly congenital heart block from maternal autoimmune antibodies (anti-Ro/SSA, anti-La/SSB) or structural abnormalities 6

Important Clinical Considerations

Communicating hydrocephalus must be distinguished from obstructive ventriculomegaly by demonstrating dilation of the subarachnoid cistern on ultrasound 3. This distinction is critical as the pathophysiology and potential interventions differ.

Mild ventriculomegaly without head enlargement may represent a normal variant rather than true hydrocephalus, requiring careful serial monitoring to determine if progression occurs 3.

The presence of multiple associated anomalies, especially other CNS malformations, carries a dismal prognosis for viable outcome 3. Isolated hydrocephalus has better potential outcomes and represents a small subset that might benefit from prenatal intervention 3.

Recurrence risk for non-X-linked congenital hydrocephalus is generally low, with empiric risk figures ranging from <1% to 4% in various studies 4. However, prenatal diagnosis can be challenging as ventriculomegaly typically develops after 20 weeks gestation 4.