In November 2015, the Brazilian Ministry of Health reported a 20-fold increase in the number of cases of neonatal microcephaly, a severe congenital neurologic malformation with significant long-term sequelae,1,2 which has since been linked to maternal infection with the Zika virus during pregnancy.3 Semen and blood products have been shown to be infectious, raising concerns that nonvectorborne virus plays a role in the spread of Zika. In addition, Zika-specific RNA has been detected in amniotic fluid, breast milk, seminal fluid, saliva, urine, and blood, raising public health concerns for the prevention and control of Zika virus globally.4
As the Zika virus outbreak has spread across the Americas, a spectrum of neonatal neurologic and developmental abnormalities attributable to congenital infection has been described.5 Although neurologic effect in adults has also been demonstrated, including but not limited to Guillain-Barré syndrome,6,7 the preponderance of pathophysiology has occurred in fetuses and newborns, producing an understandable degree of anxiety among pregnant women in areas with local transmission as well as those pregnant women who have traveled to those regions or engaged in sexual contact with partners who have traveled to those regions.8–10 The fact that Zika virus infection is symptomatic in only 20% of patients,11 and that perinatal effect has been shown in both symptomatic and asymptomatic women, has only heightened concern among women and families in Zika virus–risk areas, including, as of July 2016, those in the Miami-Dade, Florida, and, most recently, the Brownsville, Texas, regions of the United States.12
Since the outbreak has been described, the Centers for Disease Control and Prevention (CDC) has issued evolving guidelines for health care providers in the United States regarding counseling and testing for women who are either pregnant or planning pregnancy with potential Zika virus exposure.13,14 These guidelines have sequentially expanded testing criteria to maximize the number of potentially infected pregnant women who are identified as more information regarding the implications of perinatal Zika virus infection has become available.
The importance of counseling and testing of pregnant women regarding Zika virus infection and its risks has compelled health care providers to be current regarding guidelines as they evolve to best guide women and their families through this outbreak. We describe the ongoing experience of a single U.S. metropolitan perinatal center regarding the triage and testing of pregnant women referred specifically for concerns regarding potential Zika virus infection. Although we describe the subsequent surveillance of this population that was guided by their test results, our primary focus and intent was to more completely describe the quality of care required in providing testing and counseling to this particularly concerned cohort of patients.
MATERIALS AND METHODS
We conducted a longitudinal observational study at a single perinatal referral center from January to August 2016. This center provides comprehensive consultative services to health care providers and their patients in a large population center in southern California. After the first CDC travel advisory surrounding Zika virus and pregnancy was issued in February 2016,14 a travel history was obtained on every patient seen at our center. As expanded guidelines were published throughout the study period, testing criteria based on symptoms and exposures in pregnant women were modified accordingly.13 Participants were included in the study if they had traveled to or had sexual relations with a person who traveled to a region where local Zika virus transmission had been reported. All pregnant patients who were potentially exposed to Zika virus infection between August 2015 and August 2016 were included in the data collection. Institutional review board approval was obtained from the University of California, Los Angeles (IRB #16-000285).
We sought to identify the rate of confirmed infection among pregnant women in our referral region who had established risk factors for acquiring infection, either through personal travel or travel by a sexual partner. We also sought to characterize the travel patterns of exposure risk for women in this region, because travel concerns comprise a significant proportion of questions received by our center on a daily basis. Lastly, we sought to describe rates of symptoms among these women suggesting Zika virus infection as well as any findings on their prenatal ultrasonograms that might raise concern for Zika virus infection. Patients were questioned, as recommended by clinical guidelines published by the CDC, about the presence of any of the following symptoms: rash, fever, conjunctivitis, myalgias, and headache14 during travel times or immediately after return. If exposure was through sexual contact with a partner who had traveled to a high-risk region, the patient was asked whether she had experienced any of these symptoms after that contact. The patient was also asked about condom use before and after partner exposure.
Ultrasound evaluation of patients at risk either because of positive test results or inability to test because of timing of the patient visit was guided by reports of Zika-associated findings as described by Brasil et al, the largest published prospective cohort to date that followed pregnant women with confirmed Zika virus infection. We also referred to the consensus statement published by the World Health Organization, which describes ultrasound findings associated with congenital Zika syndrome.15 In addition, although echogenic intracardiac foci have not specifically been linked to known Zika virus infection, they were included as a finding of concern in our study given the prior description of prenatally visualized hyperechogenic cardiac valves in cases of known neonatal Zika virus infection.16,17 Microcephaly was defined as head circumference measurements that were 3 standard deviations below the mean, as reinforced by a recent policy statement by the Society for Maternal-Fetal Medicine (SMFM).18,19
Before the revised CDC guidelines of July 25, 2016,13 Zika virus polymerase chain reaction (PCR) testing on blood and urine was offered only to those women who described Zika virus–suggestive symptoms after potential exposure. After the revised guidelines, PCR testing was offered to all women regardless of symptoms who presented within 2 weeks of potential exposure in them or a sexual partner. For those who presented 2–12 weeks postexposure, testing was offered with the approved MAC-ELISA immunoglobulin M (IgM) assay. Patients with positive or equivocal IgM results had confirmatory testing of the original sample through plaque reduction neutralization testing in an approved reference laboratory. Testing was offered initially through public health laboratories and then, later in the study period, through commercial laboratories that had been approved to conduct these tests under emergency use authorizations from the U.S. Food and Drug Administration.
Descriptive statistics as well as Kruskal-Wallis tests for nonparametric data were used to evaluate the results. Stata 14 was used for descriptive statistics and Kruskal-Wallis tests, and EpiTools was used for the analysis of confidence intervals.
During the defined study period, we identified 185 pregnant women who had potential Zika virus exposure either through travel (94%) or sexual contact (6%) (Table 1). Time of exposure during travel is further categorized as short term (less than 30 days in a high-risk region) or long term (more than 30 days in a high-risk region). None of the patients with exposure secondary to sexual contact with a partner described using condoms before evaluation in our center. Our cohort ranged in age from 25 to 51 years (median age 34 years). The majority of our patients were Caucasian (63%) followed by Asian (16%), Hispanic (14%), African American (2%), and Middle Eastern (3%). The majority of patients (51%) had traveled to a Zika risk area before the CDC's initial Zika travel advisory published in February 2016, which first described expanded testing during pregnancy, independent of the woman's symptoms. The majority of all exposures occurred either just before conception or during the first trimester (64%).
Geographic exposure data showed Mexico (44%), North America (17%), and the Caribbean (16%) to be the most common areas in which patients' personal or partner exposures potentially occurred. As outbreaks of local infection began to be described and tracked in the Miami-Dade area, however, travel exposures from this region provided a large proportion of exposure cases in the later part of the study period (17% of all exposures).
Within our cohort, 67% of patients reported mosquito bites, but only 10% of patients overall reported any symptoms suggestive of Zika virus infection. The patients reporting symptoms had mostly traveled to Mexico and the Caribbean (53%).
Five patients (3%, 95% confidence interval [CI] 1.1–6.2%) had prenatal ultrasound findings suggestive of possible Zika virus infection; all these findings ultimately had negative Zika virus testing results. Findings reported as potential markers for Zika virus included microcephaly, echogenic intracardiac foci, and intracranial ventricular calcifications. All findings resolved before delivery or resulted in a neonate without evidence of Zika virus sequelae (Table 2).
After assessment of testing appropriateness per guidelines in place at the time of the patient encounter, Zika virus–specific testing was ordered on 153 patients. The other 32 women fell outside guideline-based testing timeframes postexposure and were alternatively offered serial fetal ultrasound surveillance through the third trimester. The most common tests ordered were IgM assays, in 141 patients, with the majority of these (71%, CI 63.7–78.0%) performed in public compared with commercial laboratories. Maternal serum PCR testing was ordered in 12 patients, almost all after the change in testing criteria in July 2016. After the U.S. Food and Drug Administration permitted some commercial laboratories to run IgM and PCR testing under an Emergency Use Authorization,20 issues of cost and turnaround time were discussed with all patients, who were then given the option of using either a commercial or public laboratory for testing. Patient laboratory preference appears to have been at least partly affected by the significant differences seen in turnaround times for test results. The range and mean time for results was markedly shorter for commercial compared with public laboratories: 2–25 compared with 13–158 days (median 6 compared with 34 days, P<.001).
For the IgM results, eight returned positive or equivocal (5% of all tests, CI 2.5–10.0%) with only one confirmed as positive by plaque reduction neutralization testing. Overall, 1 of 185 (0.5%, CI 0.06–2.5%) of all those consulted and 1 of 153 (0.7%, CI 0.07–3.0%) of those pregnant women tested had a confirmed Zika virus infection with no confirmed fetal or neonatal infections (Fig. 1). There were no results positive for Dengue and Chikungunya viruses. The one woman with serologically confirmed Zika virus infection had a 12-day risk of exposure while in Honduras in her early first trimester. She did report mosquito bites, but denied any symptoms suggestive of Zika virus infection. Intracranial calcifications were suspected on ultrasound evaluation in the second trimester; however, it ultimately resolved on serial evaluation in the third trimester. This patient opted to undergo diagnostic amniocentesis in the second trimester with negative amniotic fluid Zika virus PCR results. She subsequently delivered a normally grown neonate with no stigmata of Zika virus infection. Polymerase chain reaction testing for Zika virus was ordered on the neonate's cord blood; however, results are unavailable for review secondary to a laboratory error. At 3 months of age, the infant has shown no signs of Zika sequelae on serial pediatric examinations.
Pregnant patients in the southern California region referred to our center have had potential Zika virus exposure primarily related to travel to areas at high risk for local transmission with a smaller proportion describing possible exposure through travel by a sexual partner. In our study cohort, despite extensive potential travel exposure to 23 international countries documenting local transmission of the Zika virus, including within the United States, we have confirmed only one maternal Zika virus infection and identified no fetal or neonatal infections to date. In our increasingly mobile society, a patient's primary location of residence appeared to be an uncommon source of potential Zika virus and we believe that our center's experience is likely generalizable to patients across the United States, because patients are still likely to travel for work or pleasure as they would outside of pregnancy. We believe our experience is generalizable to other centers in the United States at low risk for mosquito-borne rather than sexually transmitted Zika virus infection. We found that 94% of potential exposure occurred through travel to endemic areas. Unless the Zika virus is found in Aedes mosquitos in the United States beyond the Miami-Dade region of Florida and the Gulf Coast region of Texas, travel-related risks will likely predominate in other obstetric centers. In these cases, a heightened suspicion may have an effect on prenatal ultrasonograms, resulting in an increased suspicion and increased reporting for certain ultrasound markers as Zika virus–specific findings, as may have been the case in our series. However, all the patients in our series in whom initial ultrasonograms were thought to carry potential findings ultimately had negative Zika virus test results and had resolution of those ultrasound findings before delivery. Given the overall benign nature of an isolated echogenic intracardiac focus, as supported by the recent practice statement by the SMFM,21 and the lack of any evidence of a strong association between this as an isolated finding and congenital Zika virus infection, we plan to no longer consider an isolated echogenic intracardiac focus as a potential Zika virus–associated fetal ultrasound finding in our practice.
Strengths of this study include the prospective nature of data collection and the strict adherence to CDC and SMFM guidelines as they evolved over time. We searched PubMed between January 1, 2015, and March 14, 2017, with the terms Zika, screening, management, and the United States; to the best of the authors' knowledge, this publication is one of the largest descriptions of screening and management of potentially Zika virus–infected pregnant patients from one center in the United States. The wide range of travel exposures and the fact that the pattern of exposures is similar to those reported by the U.S. Zika Pregnancy Registry supports the generalizability of this study.22 We do recognize, however, that this study is descriptive in nature and that conclusions regarding risk for fetal infection and neonatal outcomes cannot be made as a result of the study design and the low numbers of overall confirmed Zika virus infection.
Despite low rates of maternal infection and no cases of neonatal infection in our current cohort, as the outbreak continues to unfold, especially in potentially larger nonimmune populations in the United States, clinicians need to be able to interpret and triage patient and physician concerns and to manage evaluation and testing in accordance with guidelines that are current at the time of patient presentation or referral. In addition, the costs of screening sizeable populations of concerned, exposed patients who may ultimately have low rates of positive results raise issues regarding best use of limited resources. Until the latter part of this study period, however, testing was only available and performed in public laboratories with no cost incurred by patients. As commercial testing became available, patients were offered both public and commercial options for Zika testing. However, essentially no patients opted for the lower cost public option when the lower turnaround time factor for commercial laboratories was discussed despite potential costs that could arise. These issues also need to be taken into account when counseling patients regarding testing. Because the implications of perinatal Zika virus exposure and infection are consistently evolving, we found it to be particularly critical to be as current as possible through frequent referral to and strict adherence to the evolving recommendations made by the CDC (https://www.cdc.gov/zika/hc-providers/index.html; last accessed March 14, 2017) to provide the most appropriate counseling and surveillance of Zika virus-exposed patients.
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19. Society for Maternal-Fetal Medicine Publications Committee. Ultrasound screening for fetal microcephaly following Zika virus exposure. Am J Obstet Gynecol 2016;214:B2–4.
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