Risk of Vertical Transmission

Vertical transmission to the fetus can occur irrespective of symptomatic or asymptomatic infection in the pregnant woman and the risk can persist throughout pregnancy. The exact frequency of maternal-to-fetal transmission of Zika virus is difficult to determine accurately.

The greatest risk of serious fetal sequelae is seen if the infection occurs within the first and second trimester. However, they can also be seen with infections in the third trimester.

In a cohort study of 130 infants whose mothers developed symptomatic ZIKV in pregnancy which was confirmed with PCR testing, the vertical transmission rate was 65 percent [8]. Other reports have suggested lower rates. The rate was 26 percent (76/291) in a prospective cohort study from French Guiana [9].

Consequences of Vertical Transmission

The overall risk of any abnormality or birth defect varies widely (6 to 8 percent in studies in the United States versus over 40 percent in a Brazilian study) among fetuses and infants of women with ZIKV infection during pregnancy [10,11,12].

Beyond birth defects, there also have been reports of fetal loss (miscarriage, stillbirth), hydrops fetalis, fetal growth restriction, neurologic and positional abnormalities, and impaired neurodevelopment.

Spectrum of AbnormalitiesCNS Manifestations

The virus shows neurotropism in-vivo and in-vitro. There are stages of affection where the infection from the mother leads to consequent infection of the placenta and the fetus. etal brain gets preferentially affected involving the neuronal progenitor cells which leads to disruption of neuronal growth, proliferation, migration, and differentiation. This leads to impaired brain development. This reflects as congenital microcephaly, Guillain Barré syndrome, myelitis, and meningoencephalitis.

The ultrasound manifestations in the fetus can appear as early as two weeks. However, these are more prominent in the second and third trimester. The three most common findings detected on a prenatal ultrasound include microcephaly, ventriculomegaly and intracranial calcifications, especially along the grey matter-white matter junction rather than punctate calcifications as seen with other congenital infections.

Microcephaly When the fetal head is significantly smaller than expected for gestational age it is labeled as microcephaly. It is a sign of underlying pathology. The overall frequency of microcephaly following in utero Zika virus exposure is 5–7% and it can be primary (noted at birth) or secondary (developing in the first months of life) [13].

It generally reflects that the infection occurred early in pregnancy. Both disproportionate and proportionate microcephaly can be observed suggesting that it can affect fetal growth in addition to its destructive effect on the fetal brain. It can be detected as early as 18 weeks of gestation. Irrespective of which criteria is used to define microcephaly, it is important to note that the head circumference should be disproportionately smaller in comparison to abdominal circumference and femur length and not explained by other etiologies or congenital malformations (Table 2). Zika virus related microcephaly should be suspected if microcephaly is associated with a molecular or epidemiological link to Zika virus in the absence of other conditions known to cause microcephaly.

Table 2 Various standard definitions of microcephaly

A molecular or epidemiological link with Zika virus is defined as:

The pregnant woman is a confirmed case of Zika virus disease; or

The pregnant woman had unprotected sexual contact with a confirmed case, or a history of symptoms or signs consistent with Zika virus infection and residing/traveling in an area with ongoing Zika virus transmission during her pregnancy; or

Presence of Zika virus in amniotic fluid (identified through amniocentesis and RT-PCR assay); or

Presence of Zika virus in fetal brain tissue (identified post-mortem through RT-PCR assay)

Regardless of the criteria used, for in utero diagnosis of Zika virus-induced microcephaly, the occipitofrontal circumference should be disproportionately small in comparison with the abdominal circumference and femur length and not explained by other etiologies or congenital disorders. If the occipitofrontal circumference is ≥ 3rd percentile but is notably disproportionately small compared with the abdominal circumference and fetal length or if central nervous system abnormalities are noted, additional evaluation for ZIKV infection may be appropriate.

The various other features that can be found are [17]:

Irregular head shape including a sloping/slanted forehead, cystic lesions, intraventricular adhesions, callosal dysgenesis or agenesis, cerebellar hypoplasia or vermian dysgenesis, enlarged cisterna magna, abnormal cortical development with reduced amount of brain parenchyma, arthrogryposis, club foot and microphthalmia.

The reported sensitivity of ultrasound is 22% and specificity 98% for detection of infection [18].

In Zika virus specific associated neuroanatomic anomalies such as diffuse calcification of subcortical parenchyma and thalamus, ventriculomegaly, lissencephaly, and pachygyria have been distinctively highlighted [19], along with a constellation of particular neuro- pathological findings such as: gliosis, abnormal neuronal migration, dysmaturation of nerve cells, hypomyelination, loss of descending axons, and spinal motor neurons.

The principal clinical features of congenital Zika syndrome (CZS) in the newborn include microcephaly, facial disproportion, hypertonia/spasticity, hyperreflexia, seizures, irritability, arthrogryposis, ocular abnormalities and sensorineural hearing loss. The unique features of CZS that are rarely seen with other congenital infections are:

Severe microcephaly with partially collapsed skull

Thin cerebral cortices with subcortical calcifications

Macular scarring and focal pigmentary retinal mottling

Congenital contractures

Marked early hypotonia

Fetal Growth Abnormalities

Infection with Zika virus can result in symmetric or asymmetric fetal growth restriction [20].

In a United States cohort of women with antenatal ZIKV infection, 11.2 percent were small for gestational age, compared with 5.8 percent of controls.

Cardiac Anomalies

Zika outbreak in the Brazilian study reported that 11% (13/120) of fetuses had non-severe cardiac defects (ASD, VSD, PDA) [21]. The frequency was increased in babies whose mothers developed a rash in the second half of pregnancy or those who were noted to have abnormal postnatal central nervous system imaging and in those who were preterm.

Trimester Specific Risks of Affection

Infection with Zika virus can result in fetal loss (miscarriage, stillbirth) and hydrops fetalis. Placental insufficiency from injury or infarction is the possible mechanism for fetal loss in the latter half of pregnancy (Table 3).

Table 3 Effect on the fetus by Zika virus infection in various trimesters [22]