[Skip to Content]
Sign In
Individual Sign In
Create an Account
Institutional Sign In
OpenAthens Shibboleth
Purchase Options:
[Skip to Content Landing]
Table 1.  
Pregnancy Outcomes for 442 Women With Completed Pregnancies With Laboratory Evidence of Possible Zika Virus Infection by Maternal Symptom Status and Timing of Symptom Onset or Exposure, US Zika Pregnancy Registry, December 2015–September 2016a
Pregnancy Outcomes for 442 Women With Completed Pregnancies With Laboratory Evidence of Possible Zika Virus Infection by Maternal Symptom Status and Timing of Symptom Onset or Exposure, US Zika Pregnancy Registry, December 2015–September 2016a
Table 2.  
Summary of Samples Providing Laboratory Evidence of Possible Zika Virus Infection for 442 Women With Completed Pregnancies in the United States Reported to the US Zika Pregnancy Registry, December 2015–September 2016a
Summary of Samples Providing Laboratory Evidence of Possible Zika Virus Infection for 442 Women With Completed Pregnancies in the United States Reported to the US Zika Pregnancy Registry, December 2015–September 2016a
Table 3.  
Summary of Laboratory Evidence of Possible Zika Virus Infection for 26 Fetuses or Infants With Birth Defects Among 442 Women With Completed Pregnancies in the United States Reported to the US Zika Pregnancy Registry, December 2015–September 2016a
Summary of Laboratory Evidence of Possible Zika Virus Infection for 26 Fetuses or Infants With Birth Defects Among 442 Women With Completed Pregnancies in the United States Reported to the US Zika Pregnancy Registry, December 2015–September 2016a
1.
Rasmussen  SA, Jamieson  DJ, Honein  MA, Petersen  LR.  Zika virus and birth defects—reviewing the evidence for causality.  N Engl J Med. 2016;374(20):1981-1987.PubMedArticle
2.
Cauchemez  S, Besnard  M, Bompard  P,  et al.  Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study.  Lancet. 2016;387(10033):2125-2132.PubMedArticle
3.
Johansson  MA, Mier-y-Teran-Romero  L, Reefhuis  J, Gilboa  SM, Hills  SL.  Zika and the risk of microcephaly.  N Engl J Med. 2016;375(1):1-4.PubMedArticle
4.
Duffy  MR, Chen  TH, Hancock  WT,  et al.  Zika virus outbreak on Yap Island, Federated States of Micronesia.  N Engl J Med. 2009;360(24):2536-2543.PubMedArticle
5.
Besnard  M, Eyrolle-Guignot  D, Guillemette-Artur  P,  et al.  Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia.  Euro Surveill. 2016;21(13):30181.PubMedArticle
6.
Microcephaly Epidemic Research Group.  Microcephaly in infants, Pernambuco State, Brazil, 2015.  Emerg Infect Dis. 2016;22(6):1090-1093.PubMedArticle
7.
Sarno  M, Sacramento  GA, Khouri  R,  et al.  Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise.  PLoS Negl Trop Dis. 2016;10(2):e0004517.PubMedArticle
8.
Schuler-Faccini  L, Ribeiro  EM, Feitosa  IM,  et al; Brazilian Medical Genetics Society–Zika Embryopathy Task Force.  Possible association between Zika virus infection and microcephaly—Brazil, 2015.  MMWR Morb Mortal Wkly Rep. 2016;65(3):59-62.PubMedArticle
9.
Pacheco  O, Beltrán  M, Nelson  CA,  et al.  Zika virus disease in Colombia—preliminary report [published online June 15, 2016].  N Engl J Med. doi:10.1056/NEJMoa1604037PubMed
10.
Brasil  P, Pereira  JP  Jr, Raja Gabaglia  C,  et al.  Zika virus infection in pregnant women in Rio de Janeiro—preliminary report [published online March 4, 2016].  N Engl J Med. doi:10.1056/NEJMoa1602412PubMed
11.
França  GV, Schuler-Faccini  L, Oliveira  WK,  et al.  Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation.  Lancet. 2016;388(10047):891-897.PubMedArticle
12.
Ventura  CV, Maia  M, Travassos  SB,  et al.  Risk factors associated with the ophthalmoscopic findings identified in infants with presumed Zika virus congenital infection.  JAMA Ophthalmol. 2016;134(8):912-918.PubMedArticle
13.
Simeone  RM, Shapiro-Mendoza  CK, Meaney-Delman  D,  et al; Zika and Pregnancy Working Group.  Possible Zika virus infection among pregnant women—United States and territories, May 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(20):514-519.PubMedArticle
14.
Meaney-Delman  D, Hills  SL, Williams  C,  et al.  Zika virus infection among US pregnant travelers—August 2015–February 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(8):211-214.PubMedArticle
15.
Adams  L, Bello-Pagan  M, Lozier  M,  et al.  Update: ongoing Zika virus transmission—Puerto Rico, November 1, 2015–July 7, 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(30):774-779.PubMedArticle
16.
Oduyebo  T, Petersen  EE, Rasmussen  SA,  et al.  Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure—United States, 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(5):122-127.PubMedArticle
17.
Meaney-Delman  D, Oduyebo  T, Polen  KN,  et al; US Zika Pregnancy Registry Prolonged Viremia Working Group.  Prolonged detection of Zika virus RNA in pregnant women.  Obstet Gynecol. 2016;128(4):724-730.PubMedArticle
18.
Oduyebo  T, Igbinosa  I, Petersen  EE,  et al.  Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.PubMedArticle
19.
Centers for Disease Control and Prevention. Zika MAC-ELISA—for use under an emergency use authorization only. Atlanta, GA: Centers for Disease Control and Prevention; 2016. http://www.fda.gov/downloads/MedicalDevices/Safety/EmergencySituations/UCM488044.pdf. Accessed November 16, 2016.
20.
Rabe  IB, Staples  JE, Villanueva  J,  et al.  Interim guidance for interpretation of Zika virus antibody test results.  MMWR Morb Mortal Wkly Rep. 2016;65(21):543-546.PubMedArticle
21.
Martines  RB, Bhatnagar  J, de Oliveira Ramos  AM,  et al.  Pathology of congenital Zika syndrome in Brazil: a case series.  Lancet. 2016;388(10047):898-904.PubMedArticle
22.
de Paula Freitas  B, de Oliveira Dias  JR, Prazeres  J,  et al.  Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil [published online February 9, 2016].  JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2016.0267PubMed
23.
Miranda  HA  II, Costa  MC, Frazão  MA, Simão  N, Franchischini  S, Moshfeghi  DM.  Expanded spectrum of congenital ocular findings in microcephaly with presumed Zika infection.  Ophthalmology. 2016;123(8):1788-1794.PubMedArticle
24.
van der Linden  V, Filho  EL, Lins  OG,  et al.  Congenital Zika syndrome with arthrogryposis: retrospective case series study.  BMJ. 2016;354:i3899.PubMedArticle
25.
Carvalho  FH, Cordeiro  KM, Peixoto  AB,  et al.  Associated ultrasonographic findings in fetuses with microcephaly because of suspected Zika virus (ZIKV) infection during pregnancy.  Prenat Diagn. 2016;36(9):882-887.PubMedArticle
26.
Leal  MC, Muniz  LF, Caldas Neto  SD, van der Linden  V, Ramos  RC.  Sensorineural hearing loss in a case of congenital Zika virus [published online June 30, 2016].  Braz J Otorhinolaryngol.PubMed
27.
Guillemette-Artur  P, Besnard  M, Eyrolle-Guignot  D, Jouannic  JM, Garel  C.  Prenatal brain MRI of fetuses with Zika virus infection.  Pediatr Radiol. 2016;46(7):1032-1039.PubMedArticle
28.
Newcombe  RG.  Two-sided confidence intervals for the single proportion: comparison of seven methods.  Stat Med. 1998;17(8):857-872.PubMedArticle
29.
Cragan  JD, Isenberg  JL, Parker  SE,  et al.  Population-based microcephaly surveillance in the United States, 2009 to 2013: an analysis of potential sources of variation.  Birth Defects Res A Clin Mol Teratol. 2016;106(11):972-982. PubMedArticle
30.
Petersen  LR, Jamieson  DJ, Honein  MA.  Zika virus.  N Engl J Med. 2016;375(3):294-295.PubMed
31.
Chye  JK, Lim  CT, Ng  KB, Lim  JM, George  R, Lam  SK.  Vertical transmission of dengue.  Clin Infect Dis. 1997;25(6):1374-1377.PubMedArticle
32.
Dejnirattisai  W, Supasa  P, Wongwiwat  W,  et al.  Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with Zika virus.  Nat Immunol. 2016;17(9):1102-1108.PubMedArticle
33.
Russell  K, Oliver  SE, Lewis  L,  et al.  Update: interim guidance for the evaluation and management of infants with possible congenital Zika virus infection—United States, August 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(33):870-878.PubMedArticle
34.
Melo  AS, Aguiar  RS, Amorim  MM,  et al.  Congenital Zika virus infection: beyond neonatal microcephaly [published online October 3, 2016].  JAMA Neurol. doi:10.1001/jamaneurol.2016.3720PubMed
35.
Moore  CA, Staples  JE, Dobyns  WB,  et al.  Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians [published online November 3, 2016].  JAMA Pediatr. doi:10.1001/jamapediatrics.2016.3982PubMed
36.
Ahlfors  K, Ivarsson  SA, Harris  S.  Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden: review of prospective studies available in the literature.  Scand J Infect Dis. 1999;31(5):443-457.PubMedArticle
37.
Alcantara  D, O’Driscoll  M.  Congenital microcephaly.  Am J Med Genet C Semin Med Genet. 2014;166C(2):124-139.PubMedArticle
38.
Webster  WS.  Teratogen update: congenital rubella.  Teratology. 1998;58(1):13-23.PubMedArticle
39.
Moura da Silva  A, Ganz  J, Sousa  P,  et al.  Early growth and neurologic outcomes of infants with probable congenital Zika virus syndrome.  Emerg Infect Dis. 2016;22(11):1953-1956. PubMedArticle
Original Investigation
January 3, 2017

Birth Defects Among Fetuses and Infants of US Women With Evidence of Possible Zika Virus Infection During Pregnancy

Author Affiliations
  • 1Centers for Disease Control and Prevention, Atlanta, Georgia
  • 2New York City Department of Health and Mental Hygiene, Queens, New York
  • 3Massachusetts Department of Public Health, Boston
  • 4New York State Department of Health, Albany
  • 5Virginia Department of Health, Richmond
  • 6Texas Department of State Health Services, Austin
  • 7Florida Department of Health, Tallahassee
JAMA. 2017;317(1):59-68. doi:10.1001/jama.2016.19006
Key Points

Question  What proportion of fetuses and infants of women in the United States with laboratory evidence of possible Zika virus infection during pregnancy have birth defects?

Findings  Based on preliminary data from the US Zika Pregnancy Registry, among 442 completed pregnancies, 6% overall had a fetus or infant with evidence of a Zika virus–related birth defect, primarily microcephaly with brain abnormalities, whereas among women with possible Zika virus infection during the first trimester, 11% had a fetus or infant with a birth defect.

Meaning  These findings support the importance of screening pregnant women for Zika virus exposure.

Abstract

Importance  Understanding the risk of birth defects associated with Zika virus infection during pregnancy may help guide communication, prevention, and planning efforts. In the absence of Zika virus, microcephaly occurs in approximately 7 per 10 000 live births.

Objective  To estimate the preliminary proportion of fetuses or infants with birth defects after maternal Zika virus infection by trimester of infection and maternal symptoms.

Design, Setting, and Participants  Completed pregnancies with maternal, fetal, or infant laboratory evidence of possible recent Zika virus infection and outcomes reported in the continental United States and Hawaii from January 15 to September 22, 2016, in the US Zika Pregnancy Registry, a collaboration between the CDC and state and local health departments.

Exposures  Laboratory evidence of possible recent Zika virus infection in a maternal, placental, fetal, or infant sample.

Main Outcomes and Measures  Birth defects potentially Zika associated: brain abnormalities with or without microcephaly, neural tube defects and other early brain malformations, eye abnormalities, and other central nervous system consequences.

Results  Among 442 completed pregnancies in women (median age, 28 years; range, 15-50 years) with laboratory evidence of possible recent Zika virus infection, birth defects potentially related to Zika virus were identified in 26 (6%; 95% CI, 4%-8%) fetuses or infants. There were 21 infants with birth defects among 395 live births and 5 fetuses with birth defects among 47 pregnancy losses. Birth defects were reported for 16 of 271 (6%; 95% CI, 4%-9%) pregnant asymptomatic women and 10 of 167 (6%; 95% CI, 3%-11%) symptomatic pregnant women. Of the 26 affected fetuses or infants, 4 had microcephaly and no reported neuroimaging, 14 had microcephaly and brain abnormalities, and 4 had brain abnormalities without microcephaly; reported brain abnormalities included intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly, and cerebellar abnormalities. Infants with microcephaly (18/442) represent 4% of completed pregnancies. Birth defects were reported in 9 of 85 (11%; 95% CI, 6%-19%) completed pregnancies with maternal symptoms or exposure exclusively in the first trimester (or first trimester and periconceptional period), with no reports of birth defects among fetuses or infants with prenatal exposure to Zika virus infection only in the second or third trimesters.

Conclusions and Relevance  Among pregnant women in the United States with completed pregnancies and laboratory evidence of possible recent Zika infection, 6% of fetuses or infants had evidence of Zika-associated birth defects, primarily brain abnormalities and microcephaly, whereas among women with first-trimester Zika infection, 11% of fetuses or infants had evidence of Zika-associated birth defects. These findings support the importance of screening pregnant women for Zika virus exposure.

Introduction

Zika virus infection during pregnancy can cause microcephaly and brain abnormalities1; however, the magnitude of risk is unknown. For first-trimester maternal Zika virus infection, modeling of data from French Polynesia suggested about a 1% risk of microcephaly, and a model based on a Zika outbreak in Bahia, Brazil, suggested a risk between 1% and 13%.2,3 Additionally, available data suggest that most Zika virus infections cause mild symptoms and many are asymptomatic.4 Although microcephaly following asymptomatic Zika virus infection has been reported,59 most published reports have documented the risk of microcephaly, brain abnormalities, and other adverse outcomes among pregnant women with symptomatic Zika virus disease.8,1012 It is unclear if this is because some asymptomatic pregnant women with travel or sexual exposure to Zika virus are not tested or if women who experience symptomatic Zika virus disease are more likely to have adverse pregnancy outcomes.

This report describes the US Zika Pregnancy Registry (USZPR) and the proportion of fetuses or infants with birth defects potentially associated with maternal Zika virus infection among women in the USZPR and evaluates whether the proportion with birth defects differs based on the presence of maternal symptoms of Zika virus infection or by trimester of possible infection.

Methods

In collaboration with state, tribal, territorial, and local health departments, the Centers for Disease Control and Prevention (CDC) established the USZPR as an enhanced surveillance system to monitor pregnancy and fetal or infant outcomes among pregnant women and fetuses or infants with laboratory evidence of possible Zika virus infection to assess the proportion of birth defects occurring in infants following maternal to fetal transmission of Zika virus infection.13,14 In accordance with federal human subjects protection regulations at 45 CFR §46.101c and §46.102d and with the Guidelines for Defining Public Health Research and Public Health Non-Research, the USZPR was reviewed by a human subjects protection coordinator at the National Center for Emerging and Zoonotic Infectious Diseases of the CDC and in numerous jurisdictions and determined to be a nonresearch, public health surveillance activity exempt from institutional review board evaluation. All data reported to the CDC on pregnancies and fetal or infant outcomes potentially related to Zika virus infections are protected by an Assurance of Confidentiality (http://www.cdc.gov/od/science/integrity/confidentiality/).

Quiz Ref IDThe USZPR includes data from all US states, the District of Columbia, and all US territories except Puerto Rico; pregnancies in Puerto Rico are monitored separately by the Zika Active Pregnancy Surveillance System.13,15 Since February 5, 2016, the CDC has recommended Zika virus testing for all pregnant women who have possible exposure to Zika virus through travel, sexual contact, or local mosquito transmission regardless of symptoms.16 For this report, data from the USZPR were limited to pregnancies completed in the continental United States or Hawaii from December 2015 through September 22, 2016, and reported to the CDC from January 15, 2016, through September 22, 2016, including reports from pregnancies completed before the USZPR was established. Information for the completed pregnancies reported by September 22, 2016, was updated with additional data on these pregnancies reported to USZPR through November 10, 2016. Not included in this report are an additional 229 completed pregnancies reported to the USZPR as of November 10, 2016; complete information on key variables is not yet available for many of these recently completed pregnancies.

Completed pregnancies included those that ended in a spontaneous abortion, termination of pregnancy, stillbirth, or live-born infant; ongoing pregnancies were excluded from this report. Pregnancies can be reported to the USZPR at any point during pregnancy or postnatally; some women are tested for Zika virus infection after concerns about adverse fetal or infant effects have been noted. Most reports to the USZPR are submitted from state and local health departments. This report includes data from 9 pregnant travelers with completed pregnancies whose outcomes were reported previously and from 5 pregnant women reported to have persistent detection of Zika virus RNA.14,17

Quiz Ref IDTo meet inclusion criteria for the USZPR, either the mother, the placenta, or the fetus or infant must have had laboratory evidence of possible Zika virus infection. For this analysis, maternal samples included urine, serum, and amniotic fluid; fetal or infant samples included urine, serum, cerebrospinal fluid, umbilical cord, or any fetal tissue; and placental samples were assessed separately. Laboratory evidence of possible Zika virus infection included (1) presence of Zika virus RNA on real-time reverse transcription–polymerase chain reaction (rRT-PCR) test or other nucleic acid amplification test; (2) maternal serological evidence of a recent Zika virus infection based on a positive or equivocal result on the Zika virus IgM antibody capture enzyme-linked immunosorbent assay (http://www.fda.gov/MedicalDevices/Safety/EmergencySituations/ucm161496.htm#zika) with a Zika virus plaque reduction neutralization testing (PRNT) titer greater than or equal to 10 and either a negative dengue IgM or a dengue PRNT less than 10 or both; (3) maternal serological evidence of a recent unspecified flavivirus infection, based on positive or equivocal Zika virus IgM results and PRNT titers greater than or equal to 10 for both Zika virus and another flavivirus (eg, dengue); (4) serological evidence of a recent Zika virus infection in an infant based on positive or equivocal Zika virus IgM results; and (5) placenta or other tissue samples with immunohistochemistry staining indicative of Zika virus infection or presence of Zika virus RNA by RT-PCR.13,1821 These laboratory inclusion criteria were specified as “possible” Zika virus infection because in addition to those with laboratory confirmed Zika virus, the USZPR also includes mother-infant pairs with serological evidence of a recent unspecified flavivirus infection.

The gestational timing of Zika virus infection for symptomatic pregnant women was based on maternal report of date of symptom onset; for asymptomatic pregnant women, timing was based on the trimester of exposure (travel to an area of active Zika virus transmission or sexual exposure). The most common symptoms of Zika virus infection are fever, rash, arthralgia, and conjunctivitis.4 The estimates for the proportion with birth defects for first-trimester infection were based on pregnant women with symptoms in the first trimester of pregnancy or asymptomatic pregnant women with exposure to Zika virus infection only in the first trimester of pregnancy. Periconceptional exposures were defined as exposure in the 4 weeks before the last menstrual period and through the first 2 weeks after the last menstrual period. Pregnant women with exposure in the periconceptional period and first trimester were classified as having first-trimester exposure; those with multiple trimesters of exposure including the periconceptional period were classified by their trimester of exposure. Risk among asymptomatic pregnant women with exposure in an area of active Zika virus transmission during more than 1 trimester, including the first trimester, was assessed separately from those with known dates of infection.

Birth defects potentially associated with Zika virus infection during pregnancy (referred to as “birth defects” throughout) included brain abnormalities with or without microcephaly, neural tube defects and other early brain malformations, eye abnormalities, and other consequences of central nervous system dysfunction including arthrogryposis (joint contractures), clubfoot, congenital hip dysplasia, and congenital deafness (Box and eTable in the Supplement). The included birth defects were based primarily on case reports of outcomes occurring in association with Zika virus infection during pregnancy; there is more evidence for some of these birth defects than for others, and a causal link has not been established for all.5,10,12,2127 Because much of the focus to date has been on microcephaly and brain abnormalities, data were summarized in 2 mutually exclusive categories: (1) brain abnormalities with or without microcephaly regardless of the presence of additional birth defects and (2) neural tube defects and other early brain malformations, eye abnormalities, and other consequences of central nervous system dysfunction among those without evident brain abnormalities or microcephaly. Clinical experts reviewed reported information to ensure each infant with birth defects met the above criteria. Among fetuses with birth defects, spontaneous abortions (<20 weeks’ gestation), stillbirths (≥20 weeks’ gestation), and terminations of pregnancy were grouped together as pregnancy losses, a subset of completed pregnancies.

Box Section Ref ID
Box.

Birth Defects Potentially Related to Zika Virus Infection During Pregnancy and Monitored by the US Zika Pregnancy Registry for Enhanced Surveillance

Brain Abnormalities With and Without Microcephaly
  • Confirmed or possible congenital microcephalya

  • Intracranial calcifications

  • Cerebral atrophy

  • Abnormal cortical formation (eg, polymicrogyria, lissencephaly, pachygyria, schizencephaly, gray matter heterotopia)

  • Corpus callosum abnormalities

  • Cerebellar abnormalities

  • Porencephaly

  • Hydranencephaly

  • Ventriculomegaly/hydrocephaly (excluding “mild” ventriculomegaly without other brain abnormalities)

  • Fetal brain disruption sequence (collapsed skull, overlapping sutures, prominent occipital bone, scalp rugae)

  • Other major brain abnormalities including intraventricular hemorrhage in utero (excluding postnatal intraventricular hemorrhage)

Neural Tube Defects and Other Early Brain Malformations
  • Neural tube defects including anencephaly, acrania, encephalocele, spina bifida

  • Holoprosencephaly (arhinencephaly)

Eye Abnormalities
  • Microphthalmia/anophthalmia

  • Coloboma

  • Cataract

  • Intraocular calcifications

  • Chorioretinal anomalies involving the macula (eg, chorioretinal atrophy and scarring, macular pallor, gross pigmentary mottling and retinal hemorrhage; excluding retinopathy of prematurity)

  • Optic nerve atrophy, pallor, and other optic nerve abnormalities

Consequences of Central Nervous System Dysfunction
  • Congenital contractures (eg, arthrogryposis, clubfoot, congenital hip dysplasia) with associated brain abnormalities

  • Congenital deafness documented by postnatal audiological testing

a Live births: measured head circumference (adjusted for gestational age and sex) less than the third percentile at birth or, if not measured at birth, within first 2 weeks of life. Pregnancy loss: prenatal head circumference more than 3 SDs below the mean based on ultrasound or postnatal head circumference less than the third percentile. Birth measurements are evaluated using the Intergrowth-21st standards (http://intergrowth21.ndog.ox.ac.uk/) based on measurements within 24 hours of birth.

Among completed pregnancies, all fetuses or infants with one of these birth defects were included as the numerator in the preliminary estimates with outcomes for multiple gestation pregnancies counted once; the denominator was all completed pregnancies with and without birth defects. The proportion affected by birth defects was calculated as the number of fetuses or infants with birth defects among the total completed pregnancies, and the 95% confidence interval for a binomial proportion was estimated using the Wilson score interval.28 All analyses were performed using SAS software version 9.3 (SAS Institute Inc), except for the confidence intervals for proportions, which were calculated in OpenEpi version 3.01. Data were reported as proportions rather than risk estimates because of the preliminary nature of the data and potential selection bias. Separate estimates were made for asymptomatic and symptomatic pregnant women and by trimester of infection. Reports to the USZPR were summarized by laboratory evidence of Zika virus infection.

Sensitivity analyses were conducted to assess the effect of potential biases in the completed pregnancies and fetuses or infants with birth defects reported to the CDC either (1) retrospectively during early 2016 including reports of pregnancies and adverse outcomes that occurred prior to regular weekly reporting from the jurisdictions to the USZPR because these reports might have disproportionately included adverse outcomes or (2) with future or very recent estimated dates of delivery (EDD) because some pregnancy losses could potentially be associated with the occurrence of birth defects. The sensitivity analysis included only completed pregnancies with an EDD from April 2016 through August 2016; the sensitivity analysis was completed for pregnancies with any trimester of infection and specifically for pregnancies with symptoms or exposure exclusively in the first trimester (or first trimester and periconceptional period).

Results

A total of 442 pregnant women (median age, 28 years; range, 15-50 years) in the USZPR with possible Zika virus infection met inclusion criteria and had completed pregnancies. Among these women, 271 (61%) were asymptomatic, 167 (38%) were symptomatic, and 4 (1%) had missing information on symptom status. All pregnant women with completed pregnancies included in this report had travel-associated Zika virus infections, meaning the infection was acquired in US territories or outside the United States or through sexual contact with a traveler; 4 were presumed to be the result of sexual transmission in a nontraveler.

Among the 442 completed pregnancies, there were 26 fetuses or infants (6%; 95% CI, 4%-8%) with birth defects, including 21 infants with birth defects among 395 live births and 5 fetuses with birth defects among 47 pregnancy losses (spontaneous abortions, pregnancy terminations, and stillbirths). Twenty-two (85%) of these fetuses or infants had brain abnormalities, microcephaly, or both. These 22 fetuses or infants included 4 with microcephaly and no reported neuroimaging, 14 with microcephaly and brain abnormalities, and 4 with brain abnormalities without a finding of microcephaly. Reported brain abnormalities included intracranial calcifications, corpus callosum abnormalities, abnormal cortical formation, cerebral atrophy, ventriculomegaly, hydrocephaly, and cerebellar abnormalities. Eleven of the 22 fetuses or infants had intracranial calcifications with or without other brain abnormalities. Among the 4 with birth defects who did not have evident brain abnormalities or microcephaly, 2 had encephalocele, 1 had eye abnormalities, and 1 had hearing abnormalities. The 18 infants with a finding of microcephaly represent 4% (18/442) of the completed pregnancies. The 26 cases of birth defects occurred among fetuses or infants of pregnant women with Zika virus exposure in the following countries with active Zika virus transmission during their pregnancies: Barbados, Belize, Brazil, Colombia, Dominican Republic, El Salvador, Guatemala, Haiti, Honduras, Mexico, Republic of Marshall Islands, and Venezuela.

The proportion of fetuses or infants with birth defects by maternal symptom status was 6% (95% CI, 4%-9% [16/271]) for asymptomatic women and 6% (95% CI, 3%-11% [10/167]) for symptomatic women (Table 1). Among 85 pregnancies with symptom onset or exposure to Zika virus infection exclusively during the first trimester (or first trimester and periconceptional period), 9 presented with birth defects (11%; 95% CI, 6%-19%). Among 211 completed pregnancies for women with possible Zika virus exposure spanning multiple trimesters including the first trimester, 15 presented with birth defects (7%; 95% CI, 4%-11%). No birth defects were reported among the pregnancies with maternal symptoms or exposure only in the second trimester (0%; 95% CI, 0%-5% [0/76]) or third trimester (0%; 95% CI, 0%-11% [0/31]), but there are insufficient data to adequately estimate the proportion affected during these trimesters (Table 1). Gestational timing of infection was unknown for 2 of the 26 fetuses or infants with birth defects and 27 of the total completed pregnancies.

Most maternal samples had serological evidence of a recent Zika virus infection or a recent unspecified flavivirus infection (Table 2 and Table 3). The majority of mother-infant pairs included in the USZPR had laboratory evidence based only on maternal samples (360/442); 49 (11%) demonstrated presence of Zika virus in the placenta and 161 had negative results on placental testing. Approximately 41% (182/442) of all infants did not have Zika virus testing. Some mother-infant pairs had negative test results for maternal, placental, or fetal or infant samples but met the inclusion criteria based on at least 1 sample type.

In the sensitivity analysis limiting the reports to completed pregnancies with an EDD from April through August 2016, the proportion with birth defects was comparable with the overall analysis, with 22 fetuses or infants presenting with birth defects among 309 completed pregnancies (7%; 95% CI, 5%-11%). This subanalysis excluded 26 completed pregnancies (1 with birth defects) with missing information on EDD, 21 completed pregnancies (1 with birth defects) with an EDD from December 2015 through March 2016, and 86 completed pregnancies (2 with birth defects) with an EDD in September 2016 or later.

In the sensitivity analysis limiting the reports to completed pregnancies with symptom onset or exposure exclusively during the first trimester (or first trimester and periconceptional period) and an EDD from April 2016 through August 2016, the proportion with birth defects was comparable with the overall analysis, with 7 fetuses or infants presenting with birth defects among 49 completed pregnancies (14%; 95% CI, 7%-27%), comparable with the 11% observed in the primary analysis. This subanalysis excluded 4 completed pregnancies with missing information on EDD, none of which had a fetus or infant with a birth defect; 3 completed pregnancies with an EDD from December 2015 through March 2016, including 1 fetus or infant with a birth defect; and 29 completed pregnancies with an EDD in September 2016 or later, including 1 fetus or infant with a birth defect.

Discussion

Quiz Ref IDIn this report based on preliminary data for pregnant women in the USZPR with laboratory evidence of possible Zika virus infection, 6% overall had a fetus or infant with evidence of a Zika-related birth defect, and among women with timing of possible Zika infection exclusively during the first trimester, 11% had a fetus or infant with a birth defect. The birth defects primarily involved included microcephaly with brain abnormalities, such as intracranial calcifications. Preliminary estimates from the USZPR were within the range of 1% to 13% risk of microcephaly following first-trimester maternal Zika virus infection modeled on the outbreak in Bahia, Brazil, lending support to the credibility of these estimates.3

In the current report, there were no reports of birth defects among fetuses or infants with prenatal exposure to Zika virus infection only in the second trimester (0%; 95% CI, 0%-5%) or third trimester (0%; 95% CI, 0%-11%); however, the confidence intervals demonstrated the imprecision of these estimates based on current data. In addition, nearly half of the women in the USZPR had exposure during multiple trimesters of pregnancy, limiting the ability to assess timing of infection beyond the first trimester in relation to outcomes. Quiz Ref IDThe findings in this report emphasize the need for pregnant women to avoid travel to areas with active Zika virus transmission and consistently and correctly use condoms to prevent sexual transmission throughout pregnancy if their partner has recently traveled to an area of active Zika virus transmission.

Based on data from population-based birth defects surveillance programs for 2009-2013, the median prevalence of microcephaly in the United States was approximately 7 per 10 000 live births.29 There are no published estimates of the prevalence of the birth defects potentially related to Zika virus infection during pregnancy combined. Among completed pregnancies in the USZPR, 6% overall were affected by 1 or more of these defects and 4% had a finding of microcephaly; this prevalence is substantially higher than the background prevalence of microcephaly.

In this study, the proportion of completed pregnancies affected by birth defects was similar following either symptomatic Zika virus disease or asymptomatic infection during pregnancy. Most reported birth defects were among fetuses or infants of women with symptoms or exposure (for those with asymptomatic infection) in the first trimester of pregnancy or in multiple trimesters including the first trimester, but timing of infection was unknown for several pregnancies. The sensitivity analysis resulted in similar estimates when the completed pregnancies were limited to those with EDDs from April through August 2016 for both all completed pregnancies and those with symptom onset or exposure exclusively in the periconceptional period or first trimester, suggesting that the estimates based on total reports are not unduly biased.

The CDC’s guidance recommends Zika virus testing for all women with possible exposure during pregnancy, regardless of symptoms.16 The findings that there were similar proportions with birth defects among those with symptomatic and asymptomatic maternal infections supports the importance of screening all pregnant women for Zika virus exposure and testing in accordance with CDC guidance. If 80% of all Zika virus infections are presumed to be asymptomatic,4 then the 61% of completed pregnancies reported to the USZPR with asymptomatic infection might represent underascertainment of asymptomatic infections. In addition, serological testing results can be difficult to interpret in persons with other prior or recent flavivirus infections (eg, dengue), further complicating the diagnosis of Zika virus infection. Some of the pregnant women in the USZPR with recent unspecified flavivirus infection might actually have been infected with dengue virus.30 Although mother to fetal transmission of dengue virus is presumed to be uncommon, the potential association between congenital dengue virus infection and adverse birth outcomes is unclear.31 In addition, prior dengue virus infection might be a cofactor that could affect the risk of adverse birth outcomes following Zika virus infection during pregnancy.32

The CDC’s guidance for the evaluation of infants with possible congenital Zika virus infection was initially released in January 2016 and has been updated twice, most recently in August 2016.33 Guidance currently recommends testing of the infant when there is laboratory evidence of possible maternal Zika virus infection. Guidance further recommends to consider testing in situations in which there is maternal exposure during pregnancy to Zika virus infection and no maternal testing was done or when maternal testing results were negative but testing was conducted outside the period when molecular and serological testing results would be expected to be positive. It is concerning that 3 (12%) of 26 infants with birth defects and 182 (41%) of all 442 fetuses or infants from completed pregnancies had no reported testing of fetal or infant samples. This lack of reported testing could have been due to short-term delays in obtaining testing and test results; a critical issue is ensuring that pediatric clinicians are aware of maternal Zika virus exposure or testing results and thus can readily identify infants who should be tested. More research is needed to define optimal testing strategies for identifying congenitally infected infants; some infants with evidence of congenital Zika virus infection prenatally and evidence of Zika virus in fetal tissue have negative results on cord blood samples by both PCR and IgM.34

Quiz Ref IDEighty-five percent of the fetuses or infants with potentially Zika-associated birth defects in this report had brain abnormalities or microcephaly, with most having both microcephaly and specific brain abnormalities. Although much of the attention has focused on microcephaly, the underlying brain abnormalities, particularly those not easily detectable on clinical assessment of the newborn, are of paramount concern. For example, case reports have highlighted the potential for underlying brain abnormalities such as ventriculomegaly among normocephalic infants with prenatal Zika virus exposure. More complete clinical evaluation of infants including neuroimaging and audiological, ophthalmological, neurological, and developmental assessments will be needed to fully describe the extent of brain abnormalities and other adverse outcomes in affected fetuses or infants.34,35

There are important limitations to consider. First, selection bias in who is included in the USZPR is possible, and the exact gestational timing of Zika virus infection is not known for many of the included women. Pregnant women with symptoms of Zika virus infection were presumably more likely to be tested than asymptomatic women; thus, infection ascertainment was likely more complete among those with symptoms.

Second, pregnant women with a history of possible exposure to Zika virus through travel or sex might have been more likely to be tested for Zika virus infection if fetal abnormalities were detected prenatally or if they delivered an infant with a birth defect. Therefore, identification of infections among pregnancies with abnormalities was likely higher than among pregnancies with unremarkable prenatal or postnatal findings; the USZPR does not have adequate data with which to quantify this potential bias. Conversely, birth defects might not have been completely ascertained among pregnancy losses including stillbirths; thus, birth defects might be underestimated.

Third, we cannot enumerate the number of completed pregnancies or fetuses or infants with or without birth defects that have not yet been reported to the USZPR; therefore, these preliminary estimates might overestimate the proportion affected by birth defects if completed pregnancies with adverse outcomes were reported to the USZPR more promptly than those with apparently normal outcomes.

Fourth, laboratory diagnostics currently do not identify pregnant women who were infected early in pregnancy but were tested later in pregnancy, at a time when viral RNA was no longer present and Zika virus IgM had waned. Because of the timing of infection and testing or limitations of current laboratory tests for Zika virus in mothers and infants, an infant with Zika-associated birth defects born to a mother who tested negative might have also tested negative or not have been tested, and Zika virus may never be identified as the potential cause of those defects.

Fifth, some mother-infant pairs demonstrated laboratory evidence of an unspecified flavivirus infection; therefore, some of these might not have had Zika virus infections. Sixth, the preliminary data reported to the USZPR include very little demographic information and incomplete information on other potential risk factors for birth defects. Finally, there are other causes of microcephaly, brain abnormalities, and other birth defects, including genetic and infectious causes, about which the USZPR has limited information.3638

Longitudinal monitoring of the infants with possible congenital Zika virus infection is essential to fully characterize the outcomes. There are some reports of normocephalic infants with congenital Zika virus infection who have abnormal postnatal brain development or adverse effects that are not immediately apparent at birth.11,39 In addition, future observations can elucidate the possible role of Zika virus infection in other outcomes, including spontaneous abortions and stillbirths as well as other structural birth defects that are not currently part of the inclusion criteria for Zika-associated birth defects surveillance.

Conclusion

Among pregnant women in the United States with completed pregnancies and laboratory evidence of possible recent Zika infection, 6% of fetuses or infants had evidence of Zika-associated birth defects, primarily brain abnormalities and microcephaly, whereas among women with first-trimester Zika infection, 11% of fetuses or infants had evidence of Zika-associated birth defects. These findings support the importance of screening pregnant women for Zika virus exposure.

Back to top
Article Information

Corresponding Author: Margaret A. Honein, PhD, Centers for Disease Control and Prevention, 1600 Clifton Rd NE, Atlanta, GA 30333 (mrh7@cdc.gov).

Published Online: December 13, 2016. doi:10.1001/jama.2016.19006

Author Contributions: Dr Honein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Honein, Ahmad, Shapiro-Mendoza, Fine, L. R. Petersen, Boyle, Meaney-Delman, Jamieson.

Acquisition, analysis, or interpretation of data: Honein, Dawson, E. E. Petersen, Jones, Lee, Yazdy, Ahmad, Macdonald, Evert, Bingham, Ellington, Shapiro-Mendoza, Oduyebo, Fine, Brown, Sommer, Gupta, Cavicchia, Slavinski, White, Owen, Boyle, Meaney-Delman, Jamieson.

Drafting of the manuscript: Honein, Ahmad, L. R. Petersen, Meaney-Delman.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Honein, Dawson, Jones, Ahmad, Ellington, Sommer, Meaney-Delman.

Administrative, technical, or material support: E. E. Petersen, Jones, Lee, Yazdy, Ahmad, Ellington, Shapiro-Mendoza, Oduyebo, Fine, Brown, Gupta, Cavicchia, Slavinski, Owen, L. R. Petersen, Boyle, Meaney-Delman, Jamieson.

Study supervision: Honein, Ahmad, L. R. Petersen, Boyle, Jamieson.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Group Information: Members of the US Zika Pregnancy Registry Collaboration were Miranda Daniels, MPH (Alabama Department of Public Health); Alabama Department of Public Health Bureaus of Communicable Diseases and Family Health Services; Hayley D. Belisle-Yaglom, MS, MPH (Arizona Department of Health Services); Irene Ruberto, PhD, MPH (Arizona Department of Health Services); Jennifer Adair, BSN, RN (Maricopa County Department of Public Health); Melissa Kretschmer, CVT, MA (Maricopa County Department of Public Health); Lucy Im, MPH (Arkansas Department of Health); Charsey Porse, PhD, MPH (California Department of Public Health); Sharon Messenger, PhD (California Department of Public Health); Jacklyn Wong, PhD (California Department of Public Health); Barbara Warmerdam (California Department of Public Health); Olga Barer, BS (California Department of Public Health); Brenda Hansen, MA, MS (California Department of Public Health); Richard Olney, MD, MPH (California Department of Public Health); Karen Ramstrom, DO, MSPH (California Department of Public Health); Devra Barter, MS (Colorado Department of Public Health and Environment); Jennifer House, DVM, MPH, DACVPM (Colorado Department of Public Health and Environment); Epidemiology and Emerging Infections Program, Connecticut Department of Public Health; Delaware Division of Public Health; District of Columbia Department of Health, Division of Epidemiology, Disease Surveillance & Investigation; Leah Eisenstein, MPH (Florida Department of Health); Nicole Kikuchi, MPH (Florida Department of Health); Janet J. Hamilton, MPH (Florida Department of Health); Amanda Feldpausch, MPH (Georgia Department of Public Health); Sarah Y. Park, MD, FAAP (Hawaii Department of Health); Sylvia Mann, MS, CGC (Hawaii Department of Health); Illinois Zika Response Team; Taryn Stevens, MPH (Indiana State Department of Health); Iowa Department of Public Health; Kansas Department of Health and Environment; Kentucky Department for Public Health Zika Pregnancy Registry Workgroup; Louisiana Department of Health’s Office of Public Health; Sara Robinson, MPH (Maine); Richard Brooks, MD, MPH (Maryland Department of Health and Mental Hygiene); Erin Jenkins, MPH (Maryland Department of Health and Mental Hygiene); Julie E. Dunn, PhD (Massachusetts Department of Public Health); Susan Soliva, MPH (Massachusetts Department of Public Health); Sarah Scotland, MPH (Massachusetts Department of Public Health); Cathleen A. Higgins (Massachusetts Department of Public Health); Gerlinde S. Munshi, MA (Massachusetts Department of Public Health); Angela E. Lin, MD (Massachusetts General Hospital for Children); Michigan Zika Pregnancy Registry Workgroup; Elizabeth Schiffman, MPH, MA (Minnesota Department of Health); Sheryl Hand, RN, BSN (Mississippi State Department of Health); Missouri Department of Health and Senior Services; Christine L. Mulgrew, PhD, MPH (Montana Department of Public Health & Human Services); Jeff Hamik, MS (Nebraska Department of Health and Human Services); Samir Koirala, MBBS, MSc (Nebraska Department of Health and Human Services); Office of Public Health Informatics and Epidemiology at the Nevada Division of Public and Behavioral Health; Carolyn Fredette, MPH (New Hampshire Department of Health and Human Services); Abigail Mathewson, DVM, MPH (New Hampshire Department of Health and Human Services); Joseph A. Sweatlock, PhD, DABTJ (New Jersey Department of Health); Karen Worthington (New Jersey Department of Health); Kara McGinnis Pilote, MA, MPH (New Jersey Department of Health); Kristin Garafalo, MPH, CHES (New Jersey Department of Health); Edward Lifshitz, MD, FACP (New Jersey Department of Health); Joy Rende, MSA, RNC-MN, NE-BC (New Jersey Department of Health); Mary Knapp, MSN, RN (New Jersey Department of Health); Regina Grazel, MSN, RN, BC, APN-C (New Jersey Department of Health); Nancy Nolet Mimm, DNP-C, MSN, APHN-BC (New Jersey Department of Health); Abubakar Ropri, MPH (New Mexico Department of Health); Lou C. Smith, MD, MPH (New York State Department of Health); Amy Robbins, MPH (New York State Department of Health); Lou Ann Lance, MSN, RN (New York State Department of Health); Helen M. Blanchette, RN, BSN (New York State Department of Health); Elizabeth Dufort, MD, FAAP (New York State Department of Health); Bryon Backenson, MS (New York State Department of Health); Daniel Kuhles, MD, MPH (New York State Department of Health); Lauren Culver Barlow, MS, RD, RN (Suffolk County Department of Health Services); Maria I. Souto, MPH (Rockland County Department of Health); Debra Blog, MD, MPH (New York State Department of Health); Jemma Rowlands, MPH (New York State Department of Health); Stephanie E. Ostrowski, PhD (New York State Department of Health); Susan Wong, PhD (Wadsworth Center, New York State Department of Health); Kirsten St. George, PhD (Wadsworth Center, New York State Department of Health); Laura Kramer, PhD (Wadsworth Center, New York State Department of Health); Ronald Limberger, PhD (Wadsworth Center, New York State Department of Health); Al Dupuis, BS (Wadsworth Center, New York State Department of Health); Amy Dean, PhD (Wadsworth Center, New York State Department of Health); Kimberly Alvarez, MPH (New York State Department of Health); Julius N. Ade, MD, PhD, MPH (New York State Department of Health); Rachel Wester, MPH, RN (New York State Department of Health); Kadri Ajileye, MD, MPH (New York State Department of Health); Amy Burns, MS (New York State Department of Health); Brenda Naizby, BSN (New York State Department of Health); Patricia Many, MS, RN (New York State Department of Health); Christina Hidalgo, MPH (New York State Department of Health); Ann Sullivan-Frohm, BSE (New York State Department of Health); Hwa-Gan Chang, PhD (New York State Department of Health); Jacquelin Griffin, PMP, CSM (New York State Department of Health); MaryJo Polfleit (New York State Department of Health); Kimberley Seward, MPH (New York State Department of Health); Inderbir Sohi, MSPH (New York State Department of Health); Rene Hull, BS (Wadsworth Center, New York State Department of Health); Li Zheng, MS, BS (Wadsworth Center, New York State Department of Health); Meghan Fuschino, MS, BS (Wadsworth Center, New York State Department of Health); Chantelle Seaver, MS, BS (Wadsworth Center, New York State Department of Health); Tabassum Rahman, MS, BS (Wadsworth Center, New York State Department of Health); Greg Farrell, BS (Wadsworth Center, New York State Department of Health); Scott Brunt, BS (Wadsworth Center, New York State Department of Health); Michael Popowich, BS (Wadsworth Center, New York State Department of Health); Patrick Bryant, PhD (Wadsworth Center, New York State Department of Health); Daryl Lamson, BS (Wadsworth Center, New York State Department of Health); Karen Kulas, BS (Wadsworth Center, New York State Department of Health); William Lee, PhD (Wadsworth Center, New York State Department of Health); Valerie Demarest, BS (Wadsworth Center, New York State Department of Health); Timothy Rem (Wadsworth Center, New York State Department of Health); Randy Stone (Wadsworth Center, New York State Department of Health); Sharon Casterlin (Wadsworth Center, New York State Department of Health); Mary Marchewka (Wadsworth Center, New York State Department of Health); Andrea Furuya, PhD (Wadsworth Center, New York State Department of Health); Kyle Carson, BS (Wadsworth Center, New York State Department of Health); Steven Bush, MS, BS (Wadsworth Center, New York State Department of Health); Joel Ackelsberg, MD, MPH (New York City Department of Health and Mental Hygiene); Byron Alex, MD, MPH (New York City Department of Health and Mental Hygiene); Vennus Ballen, MD, MPH (New York City Department of Health and Mental Hygiene); Jennifer Baumgartner, MPH (New York City Department of Health and Mental Hygiene); Danielle Bloch, MPH (New York City Department of Health and Mental Hygiene); Sandhya Clark, MPH (New York City Department of Health and Mental Hygiene); Erin Conners, PhD (New York City Department of Health and Mental Hygiene); Alexander Davidson, MPH (New York City Department of Health and Mental Hygiene); Catherine Dentinger, FNP (New York City Department of Health and Mental Hygiene); Bisram Deocharan, PhD (New York City Department of Health and Mental Hygiene); Andrea DeVito, MPH (New York City Department of Health and Mental Hygiene); Kristen Forney, MPH (New York City Department of Health and Mental Hygiene); Jie Fu, PhD (New York City Department of Health and Mental Hygiene); Gili Hrusa, MPH (New York City Department of Health and Mental Hygiene); Maryam Iqbal, MPH (New York City Department of Health and Mental Hygiene); Lucretia Jones, DrPH, MPH (New York City Department of Health and Mental Hygiene); Hannah Kubinson, MPH (New York City Department of Health and Mental Hygiene); Maura Lash, RN, MPH (New York City Department of Health and Mental Hygiene); Marcelle Layton, MD (New York City Department of Health and Mental Hygiene); Christopher Lee, MD, MSc, MPH (New York City Department of Health and Mental Hygiene); Dakai Liu, MD, PhD (New York City Department of Health and Mental Hygiene); Natasha McIntosh, MPH (New York City Department of Health and Mental Hygiene); Emily McGibbon, MPH (New York City Department of Health and Mental Hygiene); Morgan Moy, MPH (New York City Department of Health and Mental Hygiene); Stephanie Ngai, MPH (New York City Department of Health and Mental Hygiene); Panagiotis Papadopoulos, MPH (New York City Department of Health and Mental Hygiene); Hilary Parton, MPH (New York City Department of Health and Mental Hygiene); Eric Peterson, MPH (New York City Department of Health and Mental Hygiene); Jose Poy, MPH (New York City Department of Health and Mental Hygiene); Amado Punsalang, PhD (New York City Department of Health and Mental Hygiene); Jennifer Rakeman, PhD (New York City Department of Health and Mental Hygiene); Altaf Shaikh, MSc (New York City Department of Health and Mental Hygiene); Alaina Stoute, MPH (New York City Department of Health and Mental Hygiene); Corinne Thompson, PhD (New York City Department of Health and Mental Hygiene); Anthony Tran, DrPH, MPH, D(ABMM) (New York City Department of Health and Mental Hygiene); Don Weiss, MD, MPH (New York City Department of Health and Mental Hygiene); Emily Westheimer, MPH (New York City Department of Health and Mental Hygiene); Eliza Wilson, BSMT (New York City Department of Health and Mental Hygiene); Ann Winters, MD (New York City Department of Health and Mental Hygiene); David Yang, BS (New York City Department of Health and Mental Hygiene); Mohammad Younis, MS, MPA (New York City Department of Health and Mental Hygiene); Jennifer MacFarquhar, MPH, RN, CIC (North Carolina Department of Health and Human Services); Laura Cronquist, BS (North Dakota Department of Health); Michele Feist, BS (North Dakota Department of Health); Martín F. Celaya (CDC, epidemiology field assignee); Ohio Department of Health; Lisa Caton, MS, RN (Oklahoma State Department of Health); Kristy Bradley, DVM, MPH (Oklahoma State Department of Health); Oregon Public Health Division Acute and Communicable Disease Program; Leah Lind, MPH (Pennsylvania Department of Health); Kumar Nalluswami, MD, MPH (Pennsylvania Department of Health); Center for Acute Infectious Disease Epidemiology, Rhode Island Department of Health; Daniel Drociuk (South Carolina Department of Health and Environmental Control); Vinita Leedom, MPH, CIC (South Carolina Department of Health and Environmental Control); Jan Bollock, RN (South Dakota Department of Health); Tennessee Department of Health; Kelly Broussard, MPH (Texas Department of State Health Services); Dallin Peterson (Utah Department of Health); Amy Nance, MPH (Utah Department of Health); Patsy Kelso, PhD (Vermont Department of Health); Katie Kurkjian (CDC, Career Epidemiology Field Officer Program); Virginia Department of Health, Office of Epidemiology, Division of Disease Surveillance and Investigation; Virginia Department of Health, Office of Community Health Services; Hanna Oltean, MPH (Washington State Department of Health); West Virginia Bureau for Public Health, Office of Maternal, Child and Family Health; Angela Rohan, PhD (CDC, Wisconsin Department of Health Services); Katie Bryan, MPH (Wyoming Department of Health); Alys Adamski, PhD, MPH (CDC); Jeanne Bertolli, PhD, MPH (CDC); Melissa L. Danielson, MSPH (CDC); Valerie Godoshian, MPH (CDC); Caitlin Green, MPH (CDC); Christina Hillard, MA (CDC); Amy Lambert, PhD (CDC); Andrea Neiman, PhD, MPH (CDC); Kimberly Newsome, BSN, MPH (CDC); Kara Polen, MPH (CDC); Ann Powers, PhD (CDC); Marion Rice, MPH (CDC); Regina M. Simeone, MS, MPH (CDC); Robyn A. Stoddard, DVM, PhD (CDC); Tonya Williams, PhD, MS (CDC); Kathryn E. Arnold, MD (CDC); Shannon Fleck-Derderian, MPH (CDC); Sumaiya Khan, MPH (CDC); Fleetwood Loustalot, FNP, PhD (CDC); Megan Reynolds, MPH, MDiv (CDC); Infectious Diseases Pathology Branch (CDC).

Disclaimer: The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the CDC.

References
1.
Rasmussen  SA, Jamieson  DJ, Honein  MA, Petersen  LR.  Zika virus and birth defects—reviewing the evidence for causality.  N Engl J Med. 2016;374(20):1981-1987.PubMedArticle
2.
Cauchemez  S, Besnard  M, Bompard  P,  et al.  Association between Zika virus and microcephaly in French Polynesia, 2013-15: a retrospective study.  Lancet. 2016;387(10033):2125-2132.PubMedArticle
3.
Johansson  MA, Mier-y-Teran-Romero  L, Reefhuis  J, Gilboa  SM, Hills  SL.  Zika and the risk of microcephaly.  N Engl J Med. 2016;375(1):1-4.PubMedArticle
4.
Duffy  MR, Chen  TH, Hancock  WT,  et al.  Zika virus outbreak on Yap Island, Federated States of Micronesia.  N Engl J Med. 2009;360(24):2536-2543.PubMedArticle
5.
Besnard  M, Eyrolle-Guignot  D, Guillemette-Artur  P,  et al.  Congenital cerebral malformations and dysfunction in fetuses and newborns following the 2013 to 2014 Zika virus epidemic in French Polynesia.  Euro Surveill. 2016;21(13):30181.PubMedArticle
6.
Microcephaly Epidemic Research Group.  Microcephaly in infants, Pernambuco State, Brazil, 2015.  Emerg Infect Dis. 2016;22(6):1090-1093.PubMedArticle
7.
Sarno  M, Sacramento  GA, Khouri  R,  et al.  Zika virus infection and stillbirths: a case of hydrops fetalis, hydranencephaly and fetal demise.  PLoS Negl Trop Dis. 2016;10(2):e0004517.PubMedArticle
8.
Schuler-Faccini  L, Ribeiro  EM, Feitosa  IM,  et al; Brazilian Medical Genetics Society–Zika Embryopathy Task Force.  Possible association between Zika virus infection and microcephaly—Brazil, 2015.  MMWR Morb Mortal Wkly Rep. 2016;65(3):59-62.PubMedArticle
9.
Pacheco  O, Beltrán  M, Nelson  CA,  et al.  Zika virus disease in Colombia—preliminary report [published online June 15, 2016].  N Engl J Med. doi:10.1056/NEJMoa1604037PubMed
10.
Brasil  P, Pereira  JP  Jr, Raja Gabaglia  C,  et al.  Zika virus infection in pregnant women in Rio de Janeiro—preliminary report [published online March 4, 2016].  N Engl J Med. doi:10.1056/NEJMoa1602412PubMed
11.
França  GV, Schuler-Faccini  L, Oliveira  WK,  et al.  Congenital Zika virus syndrome in Brazil: a case series of the first 1501 livebirths with complete investigation.  Lancet. 2016;388(10047):891-897.PubMedArticle
12.
Ventura  CV, Maia  M, Travassos  SB,  et al.  Risk factors associated with the ophthalmoscopic findings identified in infants with presumed Zika virus congenital infection.  JAMA Ophthalmol. 2016;134(8):912-918.PubMedArticle
13.
Simeone  RM, Shapiro-Mendoza  CK, Meaney-Delman  D,  et al; Zika and Pregnancy Working Group.  Possible Zika virus infection among pregnant women—United States and territories, May 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(20):514-519.PubMedArticle
14.
Meaney-Delman  D, Hills  SL, Williams  C,  et al.  Zika virus infection among US pregnant travelers—August 2015–February 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(8):211-214.PubMedArticle
15.
Adams  L, Bello-Pagan  M, Lozier  M,  et al.  Update: ongoing Zika virus transmission—Puerto Rico, November 1, 2015–July 7, 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(30):774-779.PubMedArticle
16.
Oduyebo  T, Petersen  EE, Rasmussen  SA,  et al.  Update: interim guidelines for health care providers caring for pregnant women and women of reproductive age with possible Zika virus exposure—United States, 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(5):122-127.PubMedArticle
17.
Meaney-Delman  D, Oduyebo  T, Polen  KN,  et al; US Zika Pregnancy Registry Prolonged Viremia Working Group.  Prolonged detection of Zika virus RNA in pregnant women.  Obstet Gynecol. 2016;128(4):724-730.PubMedArticle
18.
Oduyebo  T, Igbinosa  I, Petersen  EE,  et al.  Update: interim guidance for health care providers caring for pregnant women with possible Zika virus exposure—United States, July 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(29):739-744.PubMedArticle
19.
Centers for Disease Control and Prevention. Zika MAC-ELISA—for use under an emergency use authorization only. Atlanta, GA: Centers for Disease Control and Prevention; 2016. http://www.fda.gov/downloads/MedicalDevices/Safety/EmergencySituations/UCM488044.pdf. Accessed November 16, 2016.
20.
Rabe  IB, Staples  JE, Villanueva  J,  et al.  Interim guidance for interpretation of Zika virus antibody test results.  MMWR Morb Mortal Wkly Rep. 2016;65(21):543-546.PubMedArticle
21.
Martines  RB, Bhatnagar  J, de Oliveira Ramos  AM,  et al.  Pathology of congenital Zika syndrome in Brazil: a case series.  Lancet. 2016;388(10047):898-904.PubMedArticle
22.
de Paula Freitas  B, de Oliveira Dias  JR, Prazeres  J,  et al.  Ocular findings in infants with microcephaly associated with presumed Zika virus congenital infection in Salvador, Brazil [published online February 9, 2016].  JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2016.0267PubMed
23.
Miranda  HA  II, Costa  MC, Frazão  MA, Simão  N, Franchischini  S, Moshfeghi  DM.  Expanded spectrum of congenital ocular findings in microcephaly with presumed Zika infection.  Ophthalmology. 2016;123(8):1788-1794.PubMedArticle
24.
van der Linden  V, Filho  EL, Lins  OG,  et al.  Congenital Zika syndrome with arthrogryposis: retrospective case series study.  BMJ. 2016;354:i3899.PubMedArticle
25.
Carvalho  FH, Cordeiro  KM, Peixoto  AB,  et al.  Associated ultrasonographic findings in fetuses with microcephaly because of suspected Zika virus (ZIKV) infection during pregnancy.  Prenat Diagn. 2016;36(9):882-887.PubMedArticle
26.
Leal  MC, Muniz  LF, Caldas Neto  SD, van der Linden  V, Ramos  RC.  Sensorineural hearing loss in a case of congenital Zika virus [published online June 30, 2016].  Braz J Otorhinolaryngol.PubMed
27.
Guillemette-Artur  P, Besnard  M, Eyrolle-Guignot  D, Jouannic  JM, Garel  C.  Prenatal brain MRI of fetuses with Zika virus infection.  Pediatr Radiol. 2016;46(7):1032-1039.PubMedArticle
28.
Newcombe  RG.  Two-sided confidence intervals for the single proportion: comparison of seven methods.  Stat Med. 1998;17(8):857-872.PubMedArticle
29.
Cragan  JD, Isenberg  JL, Parker  SE,  et al.  Population-based microcephaly surveillance in the United States, 2009 to 2013: an analysis of potential sources of variation.  Birth Defects Res A Clin Mol Teratol. 2016;106(11):972-982. PubMedArticle
30.
Petersen  LR, Jamieson  DJ, Honein  MA.  Zika virus.  N Engl J Med. 2016;375(3):294-295.PubMed
31.
Chye  JK, Lim  CT, Ng  KB, Lim  JM, George  R, Lam  SK.  Vertical transmission of dengue.  Clin Infect Dis. 1997;25(6):1374-1377.PubMedArticle
32.
Dejnirattisai  W, Supasa  P, Wongwiwat  W,  et al.  Dengue virus sero-cross-reactivity drives antibody-dependent enhancement of infection with Zika virus.  Nat Immunol. 2016;17(9):1102-1108.PubMedArticle
33.
Russell  K, Oliver  SE, Lewis  L,  et al.  Update: interim guidance for the evaluation and management of infants with possible congenital Zika virus infection—United States, August 2016.  MMWR Morb Mortal Wkly Rep. 2016;65(33):870-878.PubMedArticle
34.
Melo  AS, Aguiar  RS, Amorim  MM,  et al.  Congenital Zika virus infection: beyond neonatal microcephaly [published online October 3, 2016].  JAMA Neurol. doi:10.1001/jamaneurol.2016.3720PubMed
35.
Moore  CA, Staples  JE, Dobyns  WB,  et al.  Characterizing the pattern of anomalies in congenital Zika syndrome for pediatric clinicians [published online November 3, 2016].  JAMA Pediatr. doi:10.1001/jamapediatrics.2016.3982PubMed
36.
Ahlfors  K, Ivarsson  SA, Harris  S.  Report on a long-term study of maternal and congenital cytomegalovirus infection in Sweden: review of prospective studies available in the literature.  Scand J Infect Dis. 1999;31(5):443-457.PubMedArticle
37.
Alcantara  D, O’Driscoll  M.  Congenital microcephaly.  Am J Med Genet C Semin Med Genet. 2014;166C(2):124-139.PubMedArticle
38.
Webster  WS.  Teratogen update: congenital rubella.  Teratology. 1998;58(1):13-23.PubMedArticle
39.
Moura da Silva  A, Ganz  J, Sousa  P,  et al.  Early growth and neurologic outcomes of infants with probable congenital Zika virus syndrome.  Emerg Infect Dis. 2016;22(11):1953-1956. PubMedArticle
×