Update: Interim Guidance for the Diagnosis, Evaluation, and Management of Infants With Possible Congenital Zika Virus Infection — United States, October 2017

Tolulope Adebanjo, MD; Shana Godfred-Cato, DO; Laura Viens, MD; Marc Fischer, MD; J. Erin Staples, MD, PhD; Wendi Kuhnert-Tallman, PhD; Henry Walke, MD; Titilope Oduyebo, MD; Kara Polen, MPH; Georgina Peacock, MD; Dana Meaney-Delman, MD; Margaret A. Honein, PhD; Sonja A. Rasmussen, MD; Cynthia A. Moore, MD, PhD

Disclosures

Morbidity and Mortality Weekly Report. 2017;66(41):1089-1099.

Abstract and Introduction

Introduction

CDC has updated its interim guidance for U.S. health care providers caring for infants with possible congenital Zika virus infection^[1] in response to recently published updated guidance for health care providers caring for pregnant women with possible Zika virus exposure,^[2] unknown sensitivity and specificity of currently available diagnostic tests for congenital Zika virus infection, and recognition of additional clinical findings associated with congenital Zika virus infection. All infants born to mothers with possible Zika virus exposure* during pregnancy should receive a standard evaluation at birth and at each subsequent well-child visit including a comprehensive physical examination, age-appropriate vision screening and developmental monitoring and screening using validated tools,^[3–5] and newborn hearing screen at birth, preferably using auditory brainstem response (ABR) methodology.^[6] Specific guidance for laboratory testing and clinical evaluation are provided for three clinical scenarios in the setting of possible maternal Zika virus exposure: 1) infants with clinical findings consistent with congenital Zika syndrome regardless of maternal testing results, 2) infants without clinical findings consistent with congenital Zika syndrome who were born to mothers with laboratory evidence of possible Zika virus infection, and 3) infants without clinical findings consistent with congenital Zika syndrome who were born to mothers without laboratory evidence of possible Zika virus infection. Infants in the first two scenarios should receive further testing and evaluation for Zika virus, whereas for the third group, further testing and clinical evaluation for Zika virus are not recommended. Health care providers should remain alert for abnormal findings (e.g., postnatal-onset microcephaly and eye abnormalities without microcephaly) in infants with possible congenital Zika virus exposure without apparent abnormalities at birth.

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* Possible Zika virus exposure includes travel to, or residence in an area with mosquitoborne Zika virus transmission or sex without the use of condoms with a partner who has traveled to or resides in an area with mosquitoborne Zika virus transmission.
† Laboratory evidence of possible Zika virus infection during pregnancy is defined as 1) Zika virus infection detected by a Zika virus RNA nucleic acid test (NAT) on any maternal, placental, or fetal specimen (referred to as NAT-confirmed), or 2) diagnosis of Zika virus infection, timing of infection cannot be determined or unspecified flavivirus infection, timing of infection cannot be determined by serologic tests on a maternal specimen (i.e., positive/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). The use of PRNT for confirmation of Zika virus infection, including in pregnant women, is not routinely recommended in Puerto Rico (https://www.cdc.gov/zika/laboratories/lab-guidance.html).
§ Assessment of visual acuity (if able, responses to teller or grating tests), pupillary response, external examination, anterior segment examination, intraocular pressure measurement if indicated, and dilated fundus examination. After 3–4 months of age, also assess ocular motility, cycloplegia refraction and accommodation by dynamic retinoscopy. If physical abnormalities are present, recommend photo documentation if resources are available. (https://www.aao.org/preferred-practice-pattern/pediatric-eye-evaluations-ppp--september-2012#sectionII.comprehensiveophthamalicexamination).

Table. Interpretation of results of laboratory testing of infant's blood, urine, and/or cerebrospinal fluid for evidence of congenital Zika virus infection
Infant test result*		Interpretation
NAT	IgM	Interpretation
Positive	Any result	Confirmed congenital Zika virus infection^†
Negative	Nonnegative	Probable congenital Zika virus infection^§,¶
Negative	Negative	Congenital Zika virus infection unlikely^§,**

Abbreviations: IgM = immunoglobulin M; NAT = nucleic acid test.
* Infant serum, urine, or cerebrospinal fluid.
^† Distinguishing between congenital and postnatal infection is difficult in infants who live in areas where there is ongoing transmission of Zika virus and who are not tested soon after birth. If the timing of infection cannot be determined, infants should be evaluated as if they had congenital Zika virus infection.
^§ Laboratory results should be interpreted in the context of timing of infection during pregnancy, maternal serology results, clinical findings consistent with congenital Zika syndrome, and any confirmatory testing with plaque reduction neutralization testing.
^¶ If Zika virus plaque reduction neutralization test is negative, this suggests that the infant's Zika virus IgM test is a false positive.
** Congenital Zika virus infection is unlikely if specimens are collected within the first few days after birth and the clinical evaluation is normal; however, health care providers should remain alert for any new findings of congenital Zika virus infection.

Box 1. Areas of expertise and organizations represented at the Forum on the Diagnosis, Evaluation, and Management of Zika Virus Infection among Infants — Atlanta, Georgia, August 30–31, 2017
Specialties represented Audiology Clinical genetics Developmental and behavioral pediatrics Infectious disease Maternal-fetal medicine Neonatology Neurology Obstetrics and gynecology Ophthalmology Pediatrics Pediatric rehabilitation and medicine Radiology Professional organizations American Academy of Pediatrics (including representation from the Puerto Rico chapter) American College of Obstetricians and Gynecologists Association of Maternal and Child Health Programs Association of Public Health Laboratories Association of State and Territorial Health Officials Council of State and Territorial Epidemiologists Family Voices March of Dimes National Association of County and City Health Officials National Association of Pediatric Nurse Practitioners Public health organizations California Department of Public Health County of San Diego Health and Human Services Agency Department of Health of Puerto Rico Florida Department of Health New York City Department of Health and Mental Hygiene Texas Department of State Health Services Federal agencies Administration for Children and Families Centers for Disease Control and Prevention Centers for Medicare & Medicaid Services Maternal and Child Health Bureau, Health Resources and Services Administration National Institute of Child Health and Human Development, National Institutes of Health Office of the Assistant Secretary for Preparedness and Response

Box 2. Standard evaluation recommended at birth and during each well visit for all infants with possible congenital Zika virus exposure during pregnancy — United States, October 2017
Comprehensive physical exam, including growth parameters Developmental monitoring and screening using validated screening tools recommended by the American Academy of Pediatrics (https://www.aap.org/en-us/advocacy-and-policy/aap-health-initiatives/Screening/Pages/Screening-Tools.aspx) Vision screening as recommended by the American Academy of Pediatrics Policy Statement "Visual System Assessment in Infants, Children, and Young Adults by Pediatricians" (https://pediatrics.aappublications.org/content/137/1/e20153596) Newborn hearing screen at birth, preferably with automated auditory brainstem response

Box 3. Consultations for infants with clinical findings consistent with congenital Zika syndrome — United States, October 2017
Consider consultation with the following specialists: Infectious disease specialist for evaluation for other congenital infections (e.g., toxoplasmosis, syphilis, rubella, cytomegalovirus, or herpes simplex virus) and assistance with Zika virus diagnosis, testing, and counseling Neurologist by age 1 month for comprehensive neurologic examination and consideration for other evaluations such as advanced neuroimaging and EEG Ophthalmologist for comprehensive eye exam by age 1 month Clinical geneticist for confirmation of the clinical phenotype and evaluation for other causes of microcephaly or congenital anomalies Early intervention and developmental specialists Family and supportive services Additional possible consultations, based on clinical findings of the infant: Endocrinologist for evaluation of hypothalamic or pituitary dysfunction and consideration for thyroid testing Lactation specialist, nutritionist, gastroenterologist, or speech or occupational therapist for evaluation for dysphagia and management of feeding issues Orthopedist, physiatrist, or physical therapist for the management of hypertonia, clubfoot or arthrogrypotic-like conditions Pulmonologist or otolaryngologist for concerns about aspiration

Authors and Disclosures

Tolulope Adebanjo, MD^1,2, Shana Godfred-Cato, DO³, Laura Viens, MD⁴, Marc Fischer, MD⁵, J. Erin Staples, MD, PhD⁵, Wendi Kuhnert-Tallman, PhD⁶, Henry Walke, MD⁷, Titilope Oduyebo, MD⁸, Kara Polen, MPH⁹, Georgina Peacock, MD¹⁰, Dana Meaney-Delman, MD⁶, Margaret A. Honein, PhD⁹, Sonja A. Rasmussen, MD¹¹, Cynthia A. Moore, MD, PhD⁹

¹Epidemic Intelligence Service, CDC; ²Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, CDC; ³Eagle Medical Services, LLC; ⁴Chickasaw Nation Industries, Inc; ⁵Division of Vector-Borne Diseases, National Center for Emerging and Zoonotic Infectious Diseases, CDC; ⁶Office of the Director, National Center for Emerging and Zoonotic Infectious Diseases, CDC; ⁷Division of High-Consequence Pathogens and Pathology, National Center for Emerging and Zoonotic Infectious Diseases, CDC; ⁸Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion; ⁹Division of Congenital and Developmental Disorders, National Center on Birth Defects and Developmental Disabilities, CDC; ¹⁰Division of Human Development and Disability, National Center on Birth Defects and Developmental Disabilities, CDC; ¹¹Division of Public Health Information Dissemination, Center for Surveillance, Epidemiology and Laboratory Services, CDC.

Corresponding author: Tolulope Adebanjo, zikamch@cdc.gov, 800–232-4636.

Contributors
E. Oscar Alleyne, DrPH, National Association of County and City Health Officials; Martina Badell, MD, Emory University; James F. Bale, Jr, MD, University of Utah School of Medicine; Wanda D. Barfield, MD, CDC; Richard Beigi, MD, Magee-Women's Hospital of the University of Pittsburgh Medical Center; Audina M. Berrocal, MD, Bascom Palmer Eye Institute, University of Miami Miller School of Medicine; Carina Blackmore, DVM, PhD, Florida Department of Health; Eric C. Blank, DrPH, Association of Public Health Laboratories; Jennifer Bolden Pitre, JD, Family Voices, Inc; Coleen Boyle, PhD, CDC; Erin Conners, PhD, New York City Department of Health and Mental Hygiene; Christine Curry, MD, PhD, University of Miami Miller School of Medicine; Richard N. Danila, PhD, Minnesota Department of Health, Council of State and Territorial Epidemiologists; Alberto De La Vega, MD, University of Puerto Rico School of Medicine; Roberta L. DeBiasi, MD, The George Washington University School of Medicine and Health Sciences; Gail J. Demmler-Harrison, MD, Baylor College of Medicine; Siobhan M. Dolan, MD, Albert Einstein College of Medicine; Rita W. Driggers, MD, Johns Hopkins University School of Medicine; Eric Dziuban, MD, CDC; John Eichwald, MA, CDC; Catherine Eppes, MD, Baylor College of Medicine; Nicole Fehrenbach, MPP, CDC; Meg Fisher, MD, Unterberg Children's Hospital at Monmouth Medical Center; Kimberly B. Fortner, MD, University of Tennessee Medical Center; Elizabeth Garbarczyk, Centers for Medicare & Medicaid Services; Francisco García, MD, Pima County Department of Health; Stephanie Gaw, MD, PhD, University of California, San Francisco School of Medicine; Valerie Godoshian, MPH, CDC; Ivan A. Gonzalez, MD, University of Miami Miller School of Medicine; Caitlin Green, MPH, CDC; Dixie D. Griffin, MD, Affinity Pediatrics, Tift Regional Health System; Manda Hall, MD, Texas Department of State Health Services, Association of Maternal and Child Health Programs; Amy Houtrow, MD, PhD, University of Pittsburgh School of Medicine; Mark Hudak, MD, University of Florida College of Medicine-Jacksonville; Lisa L. Hunter, PhD, Cincinnati Children's Hospital; David Kimberlin, MD, University of Alabama at Birmingham; Linda M. Lawrence, MD, American Association for Pediatric Ophthalmology and Strabismus; Ellen H. Lee, MD, New York City Department of Health and Mental Hygiene; Rebecca Leeb, PhD, CDC; Deborah Levine, MD, Harvard Medical School; Claritsa Malave, MD, Health Resources and Services Administration, Puerto Rico Office; Yvonne (Bonnie) Maldonado, MD, Stanford University School of Medicine; Lynne Mofenson, MD, Elizabeth Glaser Pediatric AIDS Foundation; Sarah B. Mulkey, MD, PhD, The George Washington University School of Medicine and Health Sciences; Flor M. Munoz, MD, Baylor College of Medicine; Scott Needle, MD, Healthcare Network of Southwest Florida; Chloe Oram, CDC; Cassandra G. Pasley, JD, Florida Department of Health; Maria Paz Carlos, DVM, PhD, Maternal and Child Health Bureau, Health Resources and Services Administration; Alyssa Pensirikul, MD, University of Miami Miller School of Medicine; Emily E. Petersen, MD, CDC; Lawrence Platt, MD, David Geffen School of Medicine at University of California, Los Angeles; S. Grace Prakalapakorn, MD, CDC Duke University School of Medicine; Sarah Reagan-Steiner, MD, CDC; Jeannie Rodriguez, PhD, National Association of Pediatric Nurse Practitioners, Emory University; Elizabeth Rosenblum, MD, American Academy of Family Physicians University of California San Diego; Pablo J. Sánchez, MD, Nationwide Children's Hospital; Magdalena Sanz Cortes, MD, PhD, Baylor College of Medicine; David J. Schonfeld, MD, University of Southern California; Carrie K. Shapiro-Mendoza, PhD, CDC; Dean E. Sidelinger, MD, County of San Diego Health and Human Services Agency; V. Fan Tait, MD, American Academy of Pediatrics; Miguel Valencia-Prado, MD, Department of Health of Puerto Rico; Lisa F. Waddell, MD, March of Dimes; Michael D. Warren, MD, Association of Maternal and Child Health Programs Tennessee Department of Health; Susan Wiley, MD, Cincinnati Children's Hospital Medical Center; Eileen Yamada, MD, California Department of Public Health; Marshalyn Yeargin-Allsopp, MD, CDC; Fernando Ysern, MD, Puerto Rico Chapter, American Academy of Pediatrics; Christopher M. Zahn, MD, American College of Obstetricians and Gynecologists.

Conflict of Interest
No conflicts of interest were reported.