Additional information is needed to fully describe the spectrum of findings associated with congenital Zika virus infection; however, microcephaly might not be evident at birth but can develop after birth in infants with underlying brain abnormalities. These findings underscore the importance of early neuroimaging for infants exposed to Zika virus prenatally.

Although infants with congenital Zika virus infection who have a normal head size have been described in large series, sufficient description of the features of congenital Zika syndrome in these infants has not been available. This report of a series of 13 infants with laboratory evidence of congenital Zika virus infection with normal head size at birth includes the findings from extensive imaging, neurologic, ophthalmologic, auditory, and orthopedic examinations. Follow-up of these infants has shown that for most, head growth deceleration occurs to the point of microcephaly after birth and significant neurologic sequelae are evident.

Congenital Zika virus infection can cause microcephaly and severe brain abnormalities. As more information about the associated clinical syndrome becomes available, the phenotype is expanding to include other, sometimes less severe features, such as brain abnormalities without congenital microcephaly.

Congenital Zika virus infection can cause microcephaly and severe brain abnormalities (1). Congenital Zika syndrome comprises a spectrum of clinical features (2); however, as is the case with most newly recognized teratogens, the earliest documented clinical presentation is expected to be the most severe. Initial descriptions of the effects of in utero Zika virus infection centered prominently on the finding of congenital microcephaly (3). To assess the possibility of clinical presentations that do not include congenital microcephaly, a retrospective assessment of 13 infants from the Brazilian states of Pernambuco and Ceará with normal head size at birth and laboratory evidence of congenital Zika virus infection was conducted. All infants had brain abnormalities on neuroimaging consistent with congenital Zika syndrome, including decreased brain volume, ventriculomegaly, subcortical calcifications, and cortical malformations. The earliest evaluation occurred on the second day of life. Among all infants, head growth was documented to have decelerated as early as 5 months of age, and 11 infants had microcephaly. These findings provide evidence that among infants with prenatal exposure to Zika virus, the absence of microcephaly at birth does not exclude congenital Zika virus infection or the presence of Zika-related brain and other abnormalities. These findings support the recommendation for comprehensive medical and developmental follow-up of infants exposed to Zika virus prenatally. Early neuroimaging might identify brain abnormalities related to congenital Zika infection even among infants with a normal head circumference (4).

Thirteen infants with laboratory evidence of congenital Zika virus infection and normal head size (less than or equal to 2 standard deviations [SD] below the mean for sex and gestational age) at birth (during October 2015–January 2016) are included in this report. The infants were evaluated by multidisciplinary teams at two referral centers in Brazil: the Rehabilitation Center of Association for Assistance of Disabled Children of Pernambuco, Recife, Pernambuco State, and the Infantil Albert Sabin Hospital, Fortaleza, Ceará State during the months of October 2015–October 2016.

Eleven of the infants came to clinical attention because their birth head circumference was below the level established by the Brazilian Ministry of Health as requiring further evaluation for possible congenital Zika virus infection (http://combateaedes.saude.gov.br/images/sala-de-situacao/Microcefalia-Protocolo-de-vigilancia-e-resposta-10mar2016-18h.pdfpdf iconexternal icon). This level was 33 cm before December 2, 2015, and 32 cm for gestational age ≥37 weeks after that date; however, all of these infants had head circumferences at birth that did not exceed 2 SD below the mean for gestational age, and therefore did not meet the definition for microcephaly (more than 2 SD below the mean). These 11 infants were referred for neurologic evaluation and neuroimaging. The remaining two infants who had head circumferences in the normal range at birth were referred for neurologic evaluation at ages 5 and 7 months because of developmental concerns.

A standard form was used to collect demographic and clinical information, including whether the mothers recalled having had a rash during pregnancy. All information was obtained as part of the clinical protocol or as the result of clinical indication. Informed consent was obtained for the collection, use, and publication of clinical photographs of the infants.

Laboratory evidence of congenital Zika virus infection was defined as negative laboratory test results for five infectious causes of congenital microcephaly (toxoplasmosis, cytomegalovirus, rubella, syphilis and human immunodeficiency virus) and serologic evidence of Zika virus infection (a positive Zika virus-specific immunoglobulin M (IgM) capture enzyme–linked immunosorbent assay (MAC-ELISA) result on infant cerebrospinal fluid [CSF] or serum). Conventional reverse transcription–polymerase chain reaction (RT-PCR) was performed for the detection of Zika virus and dengue virus RNA, and real-time RT-PCR was performed for chikungunya virus in the Recife location. Monoplex real-time RT-PCR for Zika virus was performed in the Fortaleza location (5,6). Maternal testing for evidence of Zika virus infection was not available during the time of the 13 pregnancies.

For this report, microcephaly was defined as head circumference (HC) (also known as occipitofrontal circumference) more than 2 SD below the mean for gestational age and sex, according to the Fetal International and Newborn Growth Consortium for the 21st Century (INTERGROWTH-21st) for fetal and newborn growth (https://intergrowth21.tghn.org/external icon) and the World Health Organization Child Growth Standards for infants (www.who.int/childgrowth/en/external icon). Birth weight was evaluated and classified as appropriate, small, or large for gestational age and sex, also using INTERGROWTH-21st standards.

All infants had clinical neurologic and orthopedic evaluations, and brain imaging with computerized tomography (CT) scan without contrast, magnetic resonance imaging (MRI) without contrast, or both, and radiographs of the hips to identify congenital dislocation. In addition, all infants had clinical noninstrumental evaluation of dysphagia by a speech therapist, ophthalmologic examination with ophthalmoscopy assessment, and 11 of 13 infants had auditory evaluation by screening (auditory short latency brainstem evoked response [ABR] to click stimuli) and diagnostic tests (confirmatory frequency-specific ABR with tone burst stimuli) using the routine recommended by Brazilian Heath Ministry and the American Academy of Pediatrics Joint Committee on Infant Hearing (7). Infants clinically suspected of having seizure activity had an electroencephalogram to confirm.

The case series included nine male infants and four female infants (Table 1). Eleven patients were born at term (37–41 weeks’ gestation) and two were preterm (35 and 36 weeks’ gestation). Six of 13 mothers described a cutaneous rash between the second and fifth months of pregnancy. All infants had birth weights that were appropriate for gestational age (i.e., within 2 SD of the mean for sex and gestational age). Craniofacial disproportion was noted in six infants; three had redundant skin on the scalp at birth. Three infants had hip dysplasia, including one infant with arthrogryposis who had bilateral dislocated hips.

All infants had positive tests for Zika virus–specific IgM in either CSF only (nine infants), serum only (two infants) or CSF and serum (two infants). Seven CSF specimens were tested for Zika virus RNA by RT-PCR and all were negative; two of these infants also had negative RT-PCR testing in serum collected at the same time as CSF. RT-PCR testing results on the two serum-only specimens are pending. No Zika virus testing was performed on urine. Most infants (eight of 13) were tested within the first month of life; however, the date of testing of CSF for two infants is not known. Three infants were tested for Zika virus outside the neonatal period. Although identified at birth because of head size, one infant was not tested until age 4 months; two infants were tested at ages 5 months and 7 months when they were first evaluated because of developmental delay. One infant with both CSF and serum IgM testing positive at birth tested negative on serum re-testing at 6 months of age; another remained positive on re-testing at age 5 months.

HCs at birth ranged from 0.30 to -2.00 SD from the mean for gestational age and sex (Table 1). All infants showed a decrease in the rate of HC growth between birth and the time of the last examination. In 11 of 13 infants, postnatal microcephaly was diagnosed because of an HC measurement more than 2 SD below the mean for age and sex. Neuroimaging (CT scan in 13 infants and MRI in 10 infants) showed malformations of cortical development, which were most predominant anteriorly, and calcifications, predominantly in the subcortical region (especially in the transition area between the cortex and white matter). All neuroimaging showed evidence of decreased brain volume, with ventriculomegaly in all infants, and increased extra-axial CSF space in two of 13 infants (Table 2) (Figure).

Dysphagia was found on clinical evaluation in 10 of 13 infants. Seven infants had a diagnosis of epilepsy. Five infants had some degree of irritability, which improved by age 4 months. Most infants (12 of 13) had good visual interaction; one infant exhibited no eye contact. Three of 13 infants had chorioretinal abnormalities. All 11 infants tested had normal hearing evaluations. All infants had some degree of hypertonia; 12 of 13 had pyramidal and extrapyramidal signs with dystonic movement. One infant had spastic hemiparesis and another had bilateral hemiparesis, more severe on the left side. One infant with arthrogryposis was difficult to assess because of increased tone in some muscles and decreased in others. Nine of 13 infants had no voluntary movement of the hands and had a grasp reflex. Good head control was present in eight of 13 infants (supplemental material at https://stacks.cdc.gov/view/cdc/42517).