Zika-Associated Birth Defects Reported in Pregnancies With Laboratory Evidence of Confirmed or Possible Zika Virus Infection

U.S. Zika Pregnancy and Infant Registry, December 1, 2015-March 31, 2018

Nicole M. Roth, MPH; Megan R. Reynolds, MPH; Elizabeth L. Lewis, MPH; Kate R. Woodworth, MD; Shana Godfred-Cato, DO; Augustina Delaney, PhD; Amanda Akosa, MPH; Miguel Valencia-Prado, MD; Maura Lash, MPH; Amanda Elmore, MPH; Peter Langlois, PhD; Salma Khuwaja, MD, DrPH; Aifili Tufa, PhD; Esther M. Ellis, PhD; Eirini Nestoridi, MD; Caleb Lyu, PhD; Nicole D. Longcore, MPH; Monika Piccardi, MS; Leah Lind, MPH; Sharon Starr, MSN; Loletha Johnson, MSN; Shea E. Browne, MS; Michael Gosciminski, MPH; Paz E. Velasco, MD; Fern Johnson-Clarke, PhD; Autumn Locklear, MSPH; Mary Chan, MPH; Jane Fornoff, DPhil; Karrie-Ann E. Toews, MPS; Julius Tonzel, MPH; Natalie S. Marzec, MD; Shelby Hale, MPH; Amy E. Nance, MPH; Teri' Willabus, MPH; Dianna Contreras; Sowmya N. Adibhatla, MPH; Lisa Iguchi, MPH; Emily Potts, MPH,; Elizabeth Schiffman, MPH; Katherine Lolley, MPH; Brandi Stricklin; Elizabeth Ludwig, MD; Helentina Garstang, DCHMS; Meghan Marx; Emily Ferrell, MPH; Camille Moreno-Gorrin, MS; Kimberly Signs, DVM; Paul Romitti, PhD; Vinita Leedom, MPH; Brennan Martin, MPH; Louisa Castrodale, DVM; Amie Cook, MPH; Carolyn Fredette, MPH; Lindsay Denson, MS; Laura Cronquist; John F. Nahabedian III, MS; Neha Shinde, MPH; Kara Polen, MPH; Suzanne M. Gilboa, PhD; Stacey W. Martin, MSc; Janet D. Cragan, MD; Dana Meaney-Delman, MD; Margaret A. Honein, PhD; Van T. Tong, MPH; Cynthia A. Moore, MD, PhD


Morbidity and Mortality Weekly Report. 2022;71(3):73-79. 

In This Article

Abstract and Introduction


Zika virus infection during pregnancy can cause serious birth defects of the brain and eyes, including intracranial calcifications, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities.[1,2] The frequency of these Zika-associated brain and eye defects, based on data from the U.S. Zika Pregnancy and Infant Registry (USZPIR), has been previously reported in aggregate.[3,4] This report describes the frequency of individual Zika-associated brain and eye defects among infants from pregnancies with laboratory evidence of confirmed or possible Zika virus infection. Among 6,799 live-born infants in USZPIR born during December 1, 2015–March 31, 2018, 4.6% had any Zika-associated birth defect; in a subgroup of pregnancies with a positive nucleic acid amplification test (NAAT) for Zika virus infection, the percentage was 6.1% of live-born infants. The brain and eye defects most frequently reported included microcephaly, corpus callosum abnormalities, intracranial calcification, abnormal cortical gyral patterns, ventriculomegaly, cerebral or cortical atrophy, chorioretinal abnormalities, and optic nerve abnormalities. Among infants with any Zika-associated birth defect, one third had more than one defect reported. Certain brain and eye defects in an infant might prompt suspicion of prenatal Zika virus infection. These findings can help target surveillance efforts to the most common brain and eye defects associated with Zika virus infection during pregnancy should a Zika virus outbreak reemerge, and might provide a signal to the reemergence of Zika virus, particularly in geographic regions without ongoing comprehensive Zika virus surveillance.

To monitor the impact of the 2015–2017 Zika virus outbreak, CDC, in collaboration with state, local, and territorial health departments, established USZPIR to conduct mother-infant linked longitudinal surveillance of outcomes in pregnant women and infants with laboratory evidence of confirmed or possible Zika virus infection during pregnancy* in the 50 U.S. states, the District of Columbia (DC), U.S. territories, and freely associated states. Data from this cohort have been published previously.[3–5] Pregnancies with an outcome occurring during December 1, 2015–March 31, 2018, were included in USZPIR with data reported as of December 2020 included in this report. Jurisdictions collected prenatal, pregnancy outcome, and follow-up information for infants and children (from birth through age 5 years)§ from medical records in a standardized format.

All mother-infant data with an indication of a possible abnormality were reviewed by subject matter experts (which included CDC clinicians and researchers and external consultants); data reviewed included results from neuroimaging, ophthalmologic examinations, and clinical examinations for any criteria based on USZPIR surveillance case definition.[6] Cases that met criteria for Zika-associated abnormalities were subsequently reviewed in detail by two or more clinicians (including pediatricians, obstetrician-gynecologists, and clinical geneticists), for confirmation and classification of the individual defect or defects. All discrepancies in classification were discussed and resolved among a panel of experts. Infants who had microcephaly and were not small for gestational age at birth underwent further review; those who met criteria for a potential birth head circumference measurement inaccuracy were not included as having microcephaly in USZPIR. Infants with other abnormal radiographic findings (e.g., mineralizing vasculopathy, and isolated subependymal cysts), which were deemed as having "unknown clinical significance" by experts, were not reported.

In this report, the number of infants with any Zika-associated birth defect and enumerated individual brain and eye defects identified in the entire cohort with laboratory evidence of confirmed or possible Zika virus infection from a maternal, placental, fetal, or infant specimen are presented. A subgroup of infants from pregnancies with confirmed Zika virus infection (i.e., positive Zika virus NAAT) are reported to examine whether findings are consistent with the entire cohort.** Zika-associated birth defects among pregnancy losses are reported separately.†† In addition, the frequency of Zika-associated birth defects by location of birth, trimester with first evidence of Zika virus exposure (based on symptom onset, travel history to a region with endemic Zika virus transmission, or positive laboratory results), maternal symptom status, and reported neuroimaging and ophthalmology examinations are presented. Analyses were conducted using SAS (version 9.4; SAS Institute). CIs were calculated using exact Poisson regression. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.§§

During December 1, 2015–March 31, 2018, among 6,799 live-born infants reported in USZPIR, 2,288 (33.7%) were born in U.S. states and DC and 4,511 (66.3%) in U.S. territories and freely associated states (Table 1). Zika virus exposure was reported for 2,121 (31.2%) pregnant women in the first trimester; 2,495 (36.7%) in the second trimester; and 2,039 (30.0%) in the third trimester. Symptoms compatible with Zika virus disease¶¶ were reported in 35% of these women.

Among live-born infants reported in USZPIR, 4.6% (315 of 6,799) had any Zika-associated birth defect. In the subgroup with positive Zika virus NAAT during pregnancy, 6.1% (138 of 2,257) infants had any Zika-associated birth defect. Among pregnancies with positive Zika virus NAAT results, and thus less likelihood of exposure misclassification, the frequency of any Zika-associated birth defect was higher among those with first*** (8.0%) and second (6.0%) trimester infections compared with third trimester infections (3.8%). Frequency of Zika-associated birth defects in infants was similar among those born to symptomatic (5.3%) and asymptomatic (4.2%) pregnant women; neuroimaging and ophthalmology examinations were reported for 4,086 (60.1%) and 2,456 (36.1%), respectively.

The most frequent structural defects reported among live-born infants and children were microcephaly; corpus callosum abnormalities; intracranial calcification; abnormal cortical gyral patterns; ventriculomegaly; cerebral or cortical atrophy; chorioretinal atrophy, scarring, or pigmentary changes; and optic nerve abnormalities (Table 2). A similar distribution of birth defects was observed in the total cohort and in the Zika virus NAAT-positive subgroup. Among infants with any Zika-associated birth defect, one third (110 of 315) had more than one birth defect identified.

Among 325 pregnancies with laboratory evidence of confirmed or possible Zika virus infection that resulted in a pregnancy loss, 13 (4.0%) fetuses had any reported Zika-associated birth defect. Defects included microcephaly, cerebral or cortical atrophy, abnormal cortical gyral patterns, corpus callosum abnormalities, cerebellar abnormalities, hydranencephaly, ventriculomegaly or hydrocephaly, and brainstem abnormalities (C Moore, CDC, unpublished data, 2022).

*Maternal laboratory evidence of confirmed or possible Zika virus infection was defined as 1) Zika virus infection detected by a Zika virus RNA nucleic acid amplification test (NAAT) (e.g., reverse transcription–polymerase chain reaction [RT-PCR]) on any maternal, placental, fetal, or infant specimen (referred to as positive Zika virus NAAT) or 2) detection of recent Zika virus infection or recent unspecified flavivirus infection by serologic tests on a maternal, fetal, or infant specimen (i.e., either positive or equivocal Zika virus immunoglobulin M [IgM] and Zika virus plaque reduction neutralization test [PRNT] titer ≥10, regardless of dengue virus PRNT value; or negative Zika virus IgM, and positive or equivocal dengue virus IgM, and Zika virus PRNT titer ≥10, regardless of dengue virus PRNT titer). Infants with positive or equivocal Zika virus IgM are included, provided a confirmatory PRNT has been performed on a maternal or infant specimen. The use of PRNT for confirmation of Zika virus infection, including during pregnancy, in women and infants, is not routinely recommended in Puerto Rico; dengue virus is endemic and cross-reactivity is likely to occur in most cases (https://www.cdc.gov/zika/laboratories/lab-guidance.html). In Puerto Rico, detection of a positive Zika virus IgM result in a pregnant woman, fetus, or infant (within 48 hours after delivery) was considered sufficient to indicate possible Zika virus infection.
U.S. territories in USZPIR are American Samoa, Puerto Rico, and the U.S. Virgin Islands; freely associated states are Federated States of Micronesia and the Marshall Islands.
§Infants and children in Puerto Rico and the U.S. Virgin Islands are followed through age 5 years; infants and children in U.S. states and DC, and U.S. territories and freely associated states are followed through age 3 years.
**Includes maternal, placental, fetal, or infant laboratory evidence of Zika virus infection based on the presence of Zika virus RNA by a positive NAAT (e.g., RT-PCR).
††Pregnancy losses include spontaneous abortions, terminations, stillbirths, and pregnancy losses not specified. Information from prenatal or postnatal imaging and autopsy were used to determine presence of Zika-associated birth defects, although pregnancy losses often had less information reported and frequently lacked postnatal imaging that could verify prenatal findings and might identify additional abnormalities.
§§45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq.
¶¶Signs and symptoms included fever, arthralgia, conjunctivitis, rash, and other clinical signs or symptoms that are consistent with Zika virus disease.
***Zika virus infections that occurred during the periconceptual period, which is defined as 4 weeks before last menstrual period, are included in the first trimester.