In an otherwise healthy pregnancy with isolated fetal microcephaly, which infection is most likely responsible: cytomegalovirus, Zika virus, toxoplasmosis, or herpes simplex virus?

Most Likely Cause of Fetal Microcephaly in a Healthy Pregnancy

In an otherwise healthy pregnancy with isolated fetal microcephaly, cytomegalovirus (CMV) is the most likely infectious cause, as it is the most common congenital infection worldwide, occurring in 0.2-2.2% of all live births. 1

Epidemiologic Reasoning

The answer hinges on understanding the baseline prevalence of these infections:

• CMV is by far the most common congenital infection globally, affecting 0.2-2.2% of live births in developed countries, with even higher rates in developing nations 1
• Toxoplasmosis has a much lower global prevalence at approximately 1.9 per 10,000 live births (0.019%), though this varies substantially by country 1
• Zika virus, while capable of causing severe microcephaly, has spread to over 60 countries but remains geographically limited and requires specific exposure history 1
• HSV has high maternal seroprevalence (13% of individuals aged 15-49 worldwide), but the actual rate of congenital/neonatal transmission resulting in symptomatic disease is much lower than maternal infection rates 1

Clinical Context for Each Pathogen

Cytomegalovirus (Answer A)

• Transmission occurs in 30-40% of pregnancies with primary maternal infection versus only 0.15-1.0% with recurrent infection 1
• Microcephaly is a recognized feature, though CMV more characteristically causes periventricular calcifications and ventriculomegaly 2
• Hearing loss may develop during the first year even when absent at birth 3
• The sheer prevalence makes CMV the statistical favorite in an unselected healthy pregnancy 1

Zika Virus (Answer B)

• Zika causes microcephaly in approximately 20% of fetuses infected via vertical transmission, with transplacental infection occurring in 20-40% of pregnancies 4
• First or second trimester infection is critical - teratogenicity is documented primarily when infection occurs early in pregnancy 4
• Male fetuses have 1.30 times higher risk (95% CI 1.14-1.49) compared to females 5
• Symptomatic maternal infection increases risk 1.47-fold compared to asymptomatic infection (RR 0.68 for asymptomatic) 5
• Neuroimaging shows brain atrophy and brain surface smoothness on fetal MRI 2
• However, Zika requires specific geographic exposure or travel history to endemic areas 1

Toxoplasmosis (Answer C)

• Global burden estimated at 190,100 cases annually, but this translates to very low per-pregnancy rates 1
• Neuroimaging characteristically shows randomly distributed brain calcifications (not periventricular) and ventricular dilatation 2
• Chorioretinitis is a hallmark finding 4
• Much less common than CMV in most populations 1

Herpes Simplex Virus (Answer D)

• Despite high maternal seroprevalence, neonatal herpes is rare globally 1
• Typically presents with neonatal disease rather than congenital malformations 4
• Not a typical cause of isolated fetal microcephaly 6

Distinguishing Neuroimaging Features

When microcephaly is detected, imaging patterns can provide clues:

• CMV: Periventricular calcifications, ventriculomegaly, pachygyria, white matter signal changes 2
• Zika: Brain atrophy, smooth brain surface, periventricular calcifications, ventriculomegaly 2
• Toxoplasmosis: Randomly distributed (not periventricular) calcifications, ventricular dilatation 2

Critical Diagnostic Approach

In a healthy patient with fetal microcephaly, the workup should include:

• Maternal history: Travel to Zika-endemic areas, exposure to cats/undercooked meat (toxoplasmosis), mononucleosis-like illness (CMV) 4
• Timing of infection: First/second trimester infections carry highest risk for structural abnormalities 4, 5
• Ophthalmologic examination: Chorioretinitis suggests toxoplasmosis or CMV; chorioretinal lacunae suggest other syndromes 4
• Detailed fetal MRI: Pattern of calcifications and associated brain abnormalities 2
• Serologic testing: Should be performed for all TORCH pathogens, but CMV testing should be prioritized given its prevalence 1

Common Pitfalls

• Assuming Zika without travel history: While Zika has gained attention due to recent outbreaks, it requires specific exposure and remains less common than CMV globally 1
• Missing postnatal microcephaly: Some infants with congenital infections have normal head circumference at birth but develop postnatal microcephaly within the first year 4, 3
• Overlooking asymptomatic maternal infection: Most congenital CMV occurs with asymptomatic or unrecognized maternal infection 1

The correct answer is A) CMV, based purely on epidemiologic prevalence in an unselected healthy pregnancy without additional risk factors or geographic exposures.