title: Testing for Zika virus infection in pregnancy: key concepts to deal with an emerging epidemic.
abstract: Zika virus is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Following epidemics in Micronesia and French Polynesia during the past decade, more recent Zika virus infection outbreaks were first reported in South America as early as May 2013 and spread to now 50 countries throughout the Americas. Although no other flavivirus has previously been known to cause major fetal malformations following perinatal infection, reports of a causal link between Zika virus and microcephaly, brain and ocular malformations, and fetal loss emerged from hard-hit regions of Brazil by October 2015. Among the minority of infected women with symptoms, clinical manifestations of Zika virus infection may include fever, headache, arthralgia, myalgia, and maculopapular rash; however, only 1 of every 4-5 people who are infected have any symptoms. Thus, clinical symptom reporting is an ineffective screening tool for the relative risk assessment of Zika virus infection in the majority of patients. As previously occurred with other largely asymptomatic viral infections posing perinatal transmission risk (such as HIV or cytomegalovirus), we must develop and implement rapid, sensitive, and specific screening and diagnostic testing for both viral detection and estimation of timing of exposure. Unfortunately, despite an unprecedented surge in attempts to rapidly advance perinatal clinical testing for a previously obscure arbovirus, there are several ongoing hindrances to molecular- and sonographic-based screening and diagnosis of congenital Zika virus infection. These include the following: (1) difficulty in estimating the timing of exposure for women living in endemic areas and thus limited interpretability of immunoglobulin M serologies; (2) cross-reaction of immunoglobulin serologies with other endemic flaviruses, such as dengue; (3) persistent viremia and viruria in pregnancy weeks to months after primary exposure; and (4) fetal brain malformations and anomalies preceding the sonographic detection of microcephaly. In this commentary, we discuss screening and diagnostic considerations that are grounded not only in the realities of current obstetrical practice in a largely global population but also in basic immunology and virology. We review recent epidemiological data pertaining to the risk of congenital Zika virus malformations based on trimester of exposure and consider side by side with emerging data demonstrating replication of Zika virus in placental and fetal tissue throughout gestation. We discuss limitations to ultrasound based strategies that rely largely or solely on the detection of microcephaly and provide alternative neurosonographic approaches for the detection of malformations that may precede or occur independent of a small head circumference. This expert review provides information that is of value for the following: (1) obstetrician, maternal-fetal medicine specialist, midwife, patient, and family in cases of suspected Zika virus infection; (2) review of the methodology for laboratory testing to explore the presence of the virus and the immune response; (3) ultrasound-based assessment of the fetus suspected to be exposed to Zika virus with particular emphasis on the central nervous system; and (4) identification of areas ready for development.
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Catherine
authors.initials: C
authors.lastname: Eppes
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Martha
authors.initials: M
authors.lastname: Rac
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX; Department of Pathology and Immunology, Texas Children's Hospital, Houston, TX.
authors.forename: James
authors.initials: J
authors.lastname: Dunn
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX; National School for Tropical Medicine, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Department of Pathology and Immunology, Texas Children's Hospital, Houston, TX; Department of Pediatrics, Texas Children's Hospital, Houston, TX.
authors.forename: James
authors.initials: J
authors.lastname: Versalovic
authors.affiliation: National School for Tropical Medicine, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Texas Children's Hospital, Houston, TX.
authors.forename: Kristy O
authors.initials: KO
authors.lastname: Murray
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Suter
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Magda
authors.initials: M
authors.lastname: Sanz Cortes
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Espinoza
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Maxim D
authors.initials: MD
authors.lastname: Seferovic
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Wesley
authors.initials: W
authors.lastname: Lee
authors.affiliation: National School for Tropical Medicine, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Texas Children's Hospital, Houston, TX.
authors.forename: Peter
authors.initials: P
authors.lastname: Hotez
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Joan
authors.initials: J
authors.lastname: Mastrobattista
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Clark
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; National School for Tropical Medicine, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Belfort
authors.affiliation: Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Baylor College of Medicine, Houston, TX; National School for Tropical Medicine, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Departments of Obstetrics and Gynecology, Division of Maternal-Fetal Medicine, Texas Children's Hospital, Houston, TX. Electronic address: aagaardt@bcm.edu.
authors.forename: Kjersti M
authors.initials: KM
authors.lastname: Aagaard
mesh_terms: D021821:Communicable Diseases, Emerging / Q000151:congenital / Q000175:diagnosis* / Q000453:epidemiology*; D058872:Epidemics; D005260:Female; D006801:Humans; D008831:Microcephaly / Q000175:diagnosis / Q000821:virology; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious / Q000175:diagnosis* / Q000453:epidemiology*; D011296:Prenatal Diagnosis / Q000379:methods*; D000071243:Zika Virus Infection / Q000151:congenital / Q000175:diagnosis* / Q000453:epidemiology*
keywords: Centers for Disease Control and Prevention recommendations; Dengue virus; Food and Drug Administration regulations; Zika virus; Zika virus in pregnancy; amniotic fluid analysis; counseling of the patient at risk; epidemiology; fetal magnetic resonance imaging; flaviviridae family; head circumference; immunoglobulin M serology; microcephaly; neurosonography; perinatal viral infection; plaque reduction neutralization test; reverse transcriptase–polymerase chain reaction; transplacental transmission of viruses; viral culture; viral detection with polymerase chain reaction; viral detection with real-time reverse transcriptase–polymerase chain reaction