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    Figure 1.

    Congenital Zika Program at Children’s National Patient ZIKV status diagram. Cases were defined as ZIKV infection, possible ZIKV, or as unlikely ZIKV based on laboratory testing. ZIKV = Zika virus.

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Complexities of Zika Diagnosis and Evaluation in a U.S. Congenital Zika Program

Sarah B. MulkeyDivision of Fetal and Transitional Medicine, Children's National Hospital, Washington, District of Colombia;
Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;

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Emily AnsusinhaDivision of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;

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Caitlin CristanteDivision of Fetal and Transitional Medicine, Children's National Hospital, Washington, District of Colombia;

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Stephanie M. RussoDivision of Fetal and Transitional Medicine, Children's National Hospital, Washington, District of Colombia;

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Cara BiddleDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of General and Community Pediatrics, Children's National Hospital, Washington, District of Columbia;

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Youssef A. KousaDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Neurology, Children's National Hospital, Washington, District of Columbia;

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Lindsay PesacretaDivision of Fetal and Transitional Medicine, Children's National Hospital, Washington, District of Colombia;

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Barbara JantauschDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;

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Benjamin HanischDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;

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Nada HarikDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;

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Rana F. HamdyDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;

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Andrea HahnDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;

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Taeun ChangDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Neurology, Children's National Hospital, Washington, District of Columbia;

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Mohamad JaafarDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Ophthalmology, Children's National Hospital, Washington, District of Columbia;

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Tracey AmbroseDivision of Audiology, Children's National Hospital, Washington, District of Columbia;

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Gilbert VezinaDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Radiology, Children's National Hospital, Washington, District of Columbia;

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Dorothy I. BulasDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Radiology, Children's National Hospital, Washington, District of Columbia;

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David WesselDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Chief Medical Officer, Children’s National Hospital, Washington, District of Columbia;

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Adre J. du PlessisDivision of Fetal and Transitional Medicine, Children's National Hospital, Washington, District of Colombia;
Department of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Department of Neurology, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Neurology, Children's National Hospital, Washington, District of Columbia;

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Roberta L. DeBiasiDepartment of Pediatrics, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia;
Division of Pediatric Infectious Diseases, Children's National Hospital, Washington, District of Columbia;
Department of Microbiology, Immunology and Tropical Medicine, The George Washington University School of Medicine and Health Sciences, Washington, District of Columbia

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Abstract.

The objective of the study was to describe the complexity of diagnosis and evaluation of Zika-exposed pregnant women/fetuses and infants in a U.S. Congenital Zika Program. Pregnant women/fetuses and/or infants referred for clinical evaluation to the Congenital Zika Program at Children’s National (Washington, DC) from January 2016 to June 2018 were included. We recorded the timing of maternal Zika-virus (ZIKV) exposure and ZIKV laboratory testing results. Based on laboratory testing, cases were either confirmed, possible, or unlikely ZIKV infection. Prenatal and postnatal imaging by ultrasound and/or magnetic resonance imaging (MRI) were categorized as normal, nonspecific, or as findings of congenital Zika syndrome (CZS). Of 81 women–fetus/infant pairs evaluated, 72 (89%) had confirmed ZIKV exposure; 18% of women were symptomatic; only a minority presented for evaluation within the time frame for laboratory detection. Zika virus could only be confirmed in 29 (40%) cases, was possible in 26 (36%) cases, and was excluded in 17 (24%) cases. Five cases (7%) had prenatal ultrasound and MRI findings of CZS, but in only three was ZIKV confirmed by laboratory testing. Because of timing of exposure to presentation, ZIKV infection could not be excluded in many cases. Neuroimaging found CZS in 7% of cases, and in many patients, there were nonspecific imaging findings that warrant long-term follow-up. Overall, adherence to postnatal recommended follow-up evaluations was modest, representing a barrier to care. These challenges may be instructive to future pediatric multidisciplinary clinics for congenital infectious/noninfectious threats to pregnant women and their infants.

INTRODUCTION

Zika virus (ZIKV) infection emerged in South America as a threat to pregnant women with potentially devastating neurologic effects to the fetus and newborn in late 2015.1,2 Zika virus circulated intensely and spread internationally throughout 2017, affecting more than 100 countries, including the U.S. territories and limited areas of the continental United States. Congenital Zika syndrome (CZS) is defined by a phenotype of neurologic findings including microcephaly, irritability, hypo/hypertonia, arthrogryposis, seizures, deafness, and ocular abnormalities in ZIKV-exposed infants.39 Brain imaging findings in congenital ZIKV include microcephaly, subcortical calcifications, neuronal migration abnormalities, hypoplasia of the corpus callosum and cerebellum, and cerebral infarction.1013 Internationally and in the United States, recommendations for testing, evaluation, and follow-up of pregnant women and their infants evolved as data and knowledge expanded.1422

As of November 2018, the CDC reported a total of 5,746 cases of Zika infection in residents of the United States and District of Columbia, of which 2,490 were laboratory-confirmed cases in pregnant women. Most of these cases were travel related, but other routes including sexual transmission were also confirmed. Although mosquito-borne cases (n = 231) within the continental United States occurred only in limited areas of Florida and Texas in 2016, pregnant women and their sexual partners frequently travel to areas where endemic transmission occurred. As of May 2018, outcome data for the United States and District of Columbia were available for 2,394 completed pregnancies. One hundred sixteen live-born infants and nine pregnancy losses with Zika-associated birth defects have occurred. Overall, this presents a substantial burden of disease in pregnant women in the United States.4,5,8,9,2327

At the height of epidemic transmission, nearly 10% of cases in the United States and District of Columbia occurred within the referral catchment region for our institution. Thus, there was an urgent need for a program with multidisciplinary expertise to evaluate the rising numbers of pregnant women and infants in our region with ZIKV exposure and infection. In March 2016, we established the Congenital Zika Program at Children’s National (CZPCN) in Washington, DC, the United States. One of our first cases involved the evaluation of a pregnant U.S.-resident woman with ZIKV infection and fetal magnetic resonance imaging (MRI) at 18 weeks gestation demonstrating severe fetal brain abnormalities.28,29 Since the inception of our program, we have provided multidisciplinary consultation to a large number of pregnant woman and their infants because of concern for ZIKV infection. The objective of this study was to describe a U.S. Congenital Zika Program’s experience in the diagnosis, evaluation, and early outcome findings of Zika-exposed pregnant women, fetuses, and infants. This experience may provide guidance to help reduce barriers to care, improve diagnostic tools, and therapeutics for emerging infectious threats to the woman–fetus and infant.

MATERIALS AND METHODS

Patients.

All pregnant women/fetuses and infants referred for clinical evaluation to the CZPCN from January 2016 to June 2018 were included in a clinical ZIKV cohort. We recorded the type and timing of maternal ZIKV exposure, presence and type of maternal symptoms, and the results of all maternal and infant ZIKV laboratory testing. Preconceptual exposure was defined as exposure within 2 months of conception. For asymptomatic cases, timing of exposure was ascertained by the timing of maternal travel, partner travel/sexual exposure, or time of emigration from an endemic area. We excluded cases in which ZIKV infection was unlikely based on absent epidemiologic exposure or risk factors. Based on the reason for referral, fetal gestational age or postnatal infant age, and prior prenatal or postnatal evaluations, we made individualized recommendations for ZIKV laboratory testing, fetal and/or postnatal imaging, infant audiology, and ophthalmology evaluations. The results of all clinical prenatal and postnatal assessments, and laboratory and diagnostic evaluations were recorded. Institutional review board approval was obtained for collection of clinical data for each maternal–fetus/infant dyad into a REDCap database using standardized data collection instruments.30

Congenital Zika Program at Children’s National.

Programmatically, the goals of the CZPCN were to deliver expert clinical care, contribute knowledge by performing research, and advocate for and contribute to guidance, public policy, and awareness of congenital Zika infection in our region, nationally, and internationally. The CZPCN core program consisted of specialists in pediatric infectious diseases, fetal/neonatal/pediatric neurology, fetal/newborn radiology, developmental pediatrics, complex care coordination, audiology, ophthalmology, a dedicated nurse practitioner from the fetal medicine program, and clinical/research database personnel. Referrals to the program occurred both pre- and postnatally via self-referral, obstetricians, maternal–fetal medicine specialists, or pediatricians in our region and nationally. Referrals and triage were facilitated by a Zika hotline,31 as well as referral guidelines distributed widely to community providers. In all instances, single-visit multidisciplinary prenatal consultation was provided to reduce anxiety for already-stressed families, and to optimize coordination of care and real-time interdisciplinary communication and decision-making.

During prenatal visits, counseling and up-to-date guidance regarding Zika exposure/infection was shared with families and referring physicians. Congenital Zika Program at Children’s National coordinated ZIKV testing for patients with three state/territory health departments (Virginia, Maryland, and District of Columbia), and interpreted results from commercial and public health laboratories. Samples that yielded positive results from commercial IgM testing were automatically forwarded and confirmed at state/territory public health laboratories. Plaque-reduction neutralization titers (PRNTs) were performed at the Centers for Disease Control laboratory, and cutoffs were used as per CDC guidelines with > 10 as the definition for a positive PRNT result for both Zika and Dengue viruses. Verbal and written communication of findings and recommendations were provided to referring obstetricians, maternal–fetal–medicine specialists, and pediatricians who continued to primarily manage their patients. After delivery, our team coordinated a postnatal visit to review and consolidate all laboratory testing and evaluations recommended at birth, and to help access multidisciplinary care for affected infants. Diagnostic auditory brain stem response and other advanced auditory evaluation were performed for infants born to women with laboratory-confirmed infection, who failed their newborn screen, or infants with any physical findings suggestive of CZS.

Zika virus laboratory evaluation of cases.

From our cohort of clinical cases referred to the CZPCN, we defined three ZIKV infection categories based on available laboratory testing in pregnant women and infants: confirmed ZIKV infection, possible ZIKV infection, and unlikely ZIKV infection. Confirmed ZIKV infection was defined as a pregnant woman or infant with a positive ZIKV PCR test and/or a positive Zika IgM serologic test with PRNT confirmation for Zika (> 10). Possible ZIKV infection was defined as cases in which testing was either not performed, or testing was negative, but performed outside of sensitive testing windows, specifically PCR beyond 3 weeks of exposure or birth, and/or Zika IgM testing outside of the sensitive window of 2–12 weeks, postexposure, respectively. Therefore, a negative result could not confidently rule out ZIKV infection in these cases. Unlikely ZIKV infection was defined as cases in which testing was negative and was performed within the appropriate sensitivity window.

Neuroimaging evaluation of cases.

Because fetal and postnatal MRIs were performed clinically, they were paid for by insurance, and Zika exposure by itself was not typically a covered indication for fetal MRI in the absence of suspected abnormalities by prenatal ultrasound. When clinically indicated, advanced fetal imaging with fetal ultrasound (for initial screening or confirmation of referring physicians’ findings) and fetal MRI was performed. Postnatal brain MRI was performed without sedation for patients < 6 weeks of age when recommended based on prenatal or postnatal findings. For patients older than 6 weeks and younger than 6 months, cranial ultrasound was performed, followed by brain MRI, if an abnormality was detected. Not all patients had imaging recommended, many of whom had normal outside prenatal ultrasound, and referral was only for discussion of ZIKV risk and review of laboratory results. For those cases with imaging, we evaluated and recorded the results of all prenatal ultrasounds and fetal MRIs obtained as part of clinical care, as well as the corresponding postnatal infant cranial ultrasounds and brain MRIs. Imaging findings were categorized as: 1) normal, 2) nonspecific abnormalities not classically part of CZS (e.g., germinolytic cysts, subependymal cyst, lenticulostriate vasculopathy, or nonspecific white matter changes), but that may possibly be related to ZIKV, or as 3) severe structural brain abnormalities associated with CZS.12,13 Head computed tomography (CT) was not performed in the cases because brain MRI is readily available at our institution and was the preferred imaging modality when there was either a prenatal neuroimaging concern or an abnormal postnatal cranial ultrasound.

Statistical methods.

Study data were collected and managed using REDCap electronic data capture tools hosted at Children’s National Hospital, Washington, DC.30 Demographic, epidemiologic, and laboratory data were recorded for each mother/fetus–infant pair and are presented as counts. Categorical imaging variables were compared using the Freeman-Halton extension of Fisher’s exact test.

RESULTS

Epidemiology.

Between January 2016 and June 2018, 81 U.S.-based women–fetus/infant pairs were referred for evaluation of ZIKV infection during pregnancy. Of these, nine cases were found to have no ZIKV exposure and were excluded from the analysis, yielding a ZIKV-exposed cohort of 72 women–fetus/infant pairs (Figure 1). Exposure routes to the mother included either direct arboviral exposure, sexual exposure, or both. Forty-four (61%) women were U.S. residents who had traveled to a ZIKV-endemic region (only 5% exposed within the continental United States), 13 were exposed only by partner travel (sexual exposure), and 22 were recent emigrates from areas with endemic transmission (Table 1). Symptoms occurred in 13 (18%) women; fever (n = 9) and rash (n = 6) were the most common. Exposure occurred during the preconceptual period in 24 (33%), the first trimester in 27 (38%), the second trimester in 18 (25%), and in the third trimester in three (4%) women. Referral for evaluation occurred during the prenatal period for 51 (71%) of the women–fetal/infant dyads, whereas 21 (29%) were referred only postnatally, owing to later recognized maternal exposure during pregnancy or infant physical findings potentially consistent with CZS. The reason for referral to the CZPCN was maternal ZIKV exposure in 46 (64%) cases, suspected fetal brain abnormality in 24 (33%) cases, and a postnatal brain abnormality in three (4%) cases. Of the 51 patients we evaluated prenatally, 21 (41%) had postnatal evaluations (Table 1).

Figure 1.
Figure 1.

Congenital Zika Program at Children’s National Patient ZIKV status diagram. Cases were defined as ZIKV infection, possible ZIKV, or as unlikely ZIKV based on laboratory testing. ZIKV = Zika virus.

Citation: The American Journal of Tropical Medicine and Hygiene 104, 6; 10.4269/ajtmh.20-1256

Table 1

Clinical and epidemiologic features of Congenital Zika Program at Children’s National, U.S. clinical cohort

ZIKV infection (N = 29)Possible ZIKV (N = 26)Unlikely ZIKV (N = 17)Combined (N = 72)
Visit type, n (%)
 Prenatal only9 (31)11 (42)10 (59)30 (42)
 Prenatal and postnatal7 (24)8 (31)6 (35)21 (29)
 Postnatal only13 (45)7 (27)1 (6)21 (29)
Referral reason, n (%)
 Maternal exposure only22 (76)12 (46)12 (71)46 (64)
 Prenatal brain abnormality4 (14)14 (54)5 (29)23 (32)
 Postnatal brain abnormality3 (10)0 (0)0 (0)3 (4)
Maternal exposure types
 Maternal travel14161444
 Partner travel/sexual exposure46313
 Emigrated from endemic area146222
Maternal presentation, n (%)
 Symptomatic7 (24)4 (15)2 (12)13 (18)
 Asymptomatic22 (76)21 (81)15 (88)58 (81)
 Unknown0 (0)1 (4)0 (0)1 (1)
Timing of maternal exposure, n (%)
 Preconception10 (34)13 (48)1 (6)24 (33)
 First trimester13 (45)9 (33)5 (31)27 (38)
 Second trimester4 (14)5 (19)9 (56)18 (25)
 Third trimester2 (7)0 (0)1 (6)3 (4)
Maternal Zika testing, n (%)
 PCR performed15 (52)8 (31)13 (76)36 (50)
  PCR timing
   Testing performed ≤ 3 weeks of exposure/symptom onset, n (%)(n = 15)(n = 8)(n = 13)(n = 36)
   Yes2 (13)0 (0)4 (31)6 (17)
   No11 (73)8 (100)9 (69)28 (78)
   Not documented/unknown2 (13)0 (0)0 (0)2 (6)
PCR result positive4 (27)0 (0)0 (0)4 (11)
ZIKV IgM performed29 (97)17 (65)16 (94)61 (85)
ZIKV IgM timing
 Testing within 2–12 weeks of exposure/symptom onset, n (%)(n = 29)(n = 17)(n = 16)(n = 61)
 Yes7 (24)0 (0)15 (94)23 (38)
 No16 (55)14 (82)0 (0)29 (48)
 Not documented/unknown6 (21)3 (18)1 (6)9 (15)
ZIKV IgM result positive28 (97)0 (0)0 (0)27 (44)
PRNT results, n (%)n = 26
 PRNT < 10 for Zika0 (0)
 PRNT only Zika titer > 102 (8)
 PRNT Zika and dengue titers > 1024 (92)
Infant Zika testing
 ZIKV PCR performed, n (%)n = 12n = 10n = 4n = 26
  ZIKV PCR at ≤ 3 weeks of age10 (83)6 (60)3 (75)19 (73)
  ZIKV PCR at > 3 weeks of age2 (17)4 (40)1 (25)7 (27)
PCR result positive2 (17)0 (0)0 (0)2 (8)
ZIKV IgM performed, n (%)n = 15n = 11n = 5n = 31
 ZIKV IgM at < 2 weeks of age10 (66)5 (45)3 (60)18 (58)
 ZIKV IgM at ≥ 2 weeks of age3 (20)5 (45)2 (40)10 (32)
 ZIKV IgM at unknown time2 (13)1 (10)0 (0)3 (10)
ZIKV IgM result positive5 (33)0 (0)0 (0)5 (16)
PRNT results, n (%)n = 5
 PRNT < 10 for Zika0 (0)
 PRNT only Zika titer > 100 (0)
 PRNT Zika and dengue titers > 105 (100)

PRNT = plaque reduction neutralization titer; ZIKV = zika virus. Categorical variables presented as n (%).

Laboratory testing.

Zika virus infection was confirmed in 29 (40%) cases, possible in 26 (36%) cases, and unlikely in 17 (24%) cases based on available clinical laboratory testing (Table 1). Half of the women (n = 36 [50%]) had PCR testing performed, but of those tested, the minority (n = 6 [17%]) presented for testing within the recommended windows from time of exposure. Of 15 women for whom we confirmed ZIKV infection with PCR testing, only four (27%) had a positive test result; the majority (n = 13 [87%]) had their PCR test performed at > 3 weeks from ZIKV exposure or at an unknown time period. Thus, for most of the women for whom we confirmed ZIKV infection, this was due to positive ZIKV IgM test and not by PCR. For the 26 cases in whom we could not rule out ZIKV infection, PCR testing was performed in eight of the women, but in all eight, the PCR test was > 3 weeks from exposure. Likewise, ZIKV IgM was performed at > 12 weeks or at an unknown time from exposure in 17 of 17 (100%) women, whom we categorized as possible ZIKV infection because laboratory testing could not exclude infection with certainty. For the 17 women in whom ZIKV infection was ruled out, four had a negative PCR within 3 weeks of exposure and 15 had a negative ZIKV IgM within 2–12 weeks of exposure (Table 1). Two infants had a positive PCR test, and five infants had a positive ZIKA IgM with PRNT (> 10) for both ZIKA and Dengue. The PRNT in the five infants with a positive test was performed on the day of birth in three infants, at 2 weeks of age in one infant, and at 6 weeks of age in one infant.

Neuroimaging.

Of 51 women who presented for prenatal consultation, 29 (57%) received a fetal ultrasound and 26 (51%) received fetal MRI at a mean gestational age of 26.4 weeks (range: 17–37 weeks). Fetal ultrasound and MRI were performed based on the reason for clinical referral to our center, were often performed concomitantly, and were repeated in three cases at a later gestational age because of early gestational age of initial imaging, or to follow abnormalities found on initial imaging. Fetal brain abnormalities were detected by fetal ultrasound in 12/29 (41%) and by fetal MRI in 12/26 (46%) cases that underwent fetal imaging (Table 2). Five cases had imaging findings consistent with CZS, three of whom had confirmed ZIKV infection and two of whom (a twin case) ZIKV was possible (Table 3). Seven cases had nonspecific fetal imaging findings.

Table 2

Fetal and postnatal clinical neuroimaging in U.S. cohort

Fetal and postnatal neuroimagingZIKV infection (n = 29)Possible ZIKV (n = 26)Unlikely ZIKV (n = 17)Combined (n = 72)P-value
Fetal US performed, n (%)8 (28)12 (46)9 (53)29 (40)0.17
 Normal4 (50)5 (42)8 (89)17 (59)0.11
 Nonspecific abnormalities1 (13)5 (42)1 (11)7 (24)
 CZS3 (38)2 (17)0 (0)5 (17)
Fetal MRI performed, n (%)7 (24)11 (42)8 (47)26 (36)0.23
 Normal4 (57)4 (36)6 (75)14 (54)0.09
 Nonspecific abnormalities0 (0)5 (45)2 (25)7 (27)
 CZS3 (43)2 (18)0 (0)5 (19)
Postnatal cranial US performed, n (%)9 (31)7 (26)1 (6)17 (24)0.17
 Normal5 (56)3 (44)1 (100)9 (53)1.0
 Nonspecific abnormalities4 (44)4 (57)0 (0)8 (47)
 CZS0 (0)0 (0)0 (0)0 (0)
Postnatal brain MRI performed, n (%)6 (21)7 (26)1 (6)14 (19)0.31
 Normal3 (50)1 (14)0 (0)4 (29)0.52
 Nonspecific abnormalities3 (50)4 (57)1 (100)8 (57)
 CZS0 (0)2 (29)0 (0)2 (14)

CZS = congenital Zika syndrome; MRI = magnetic resonance imaging; US = ultrasound. Categorical variables presented as n (%) and compared using the Freeman-Halton extension of Fisher's exact test.

Table 3

Fetal and infant brain MRI findings in cases with confirmed or possible ZIKV infection

CasePatient: woman + fetus or infantFetal GA (weeks) or postnatal age (days)MRI result (fetal or infant)Maternal ZIKV testingImaging categoryOutcomeInfant ZIKV testing
PCRIgMPRNTPCRIgMPRNT
ZIKV infection confirmed (N = 5)
1Woman/fetus18 6/7Subependymal heterotopias, abnormal cortical indentationND+ZIKV 80CZSElective terminationND
DEN1 < 10
DEN2 < 10
2Woman/fetus20 1/7Cerebral volume loss, small corpus callosum++ZIKV 2560CZSElective terminationHigh ZIKV RNA loads in fetal brain, placenta, membranes, and umbilical cord; virus isolated from the brain
DEN1 10240
DEN2 10240
3Woman/fetus25Abnormal skull shape, severe microcephaly with thin cortical mantle, pontine hypoplasia, multilevel contractures of extremities++CZSDied at birth (27 weeks gestation)ND
ZIKV 1280
DEN1 1280
DEN2 80
4.1Woman/fetus18 5/7Normal++NDNormalTerm birthSee infant 4.2 below
22 5/7
28 3/7
4.2Infant16Right parietal area of chronic encephalomalaciaSee mother 4.1 aboveNSANormal development at 1 year- by WIDEA, AIMSHigh backgroundZIKV 1280
DEN1 > 80
DEN2 > 20
5Infant2Enhancement of multiple cranial nerves (III, IV, V, VII, VIII) post-contrast+ZIKV 1280NSALost to follow-upHigh backgroundZIKV 1280
DEN1 10240DEN1 1280
DEN2 5120DEN2 1280
Possible ZIKV infection (N = 6)
6.1Woman/fetus (twin A and twin B)27 6/7Twin A and B- bilateral malformations of cortical development, microcephaly, ventriculomegalyNDNDCZS (twin A and twin B)Live twin birth at 36 6/7 GASee infants 6.2 and 6.3 below
6.2Infant (twin A)32Microcephaly, diffuse white matter atrophy, cortical dysplasia, ex vacuo ventriculomegaly, polymicrogyria, atrophic brain stemSee mother 6.1 aboveCZSTerm birth—died at 1 year of ageNDND
Appendicular hypertonia, global developmental delay, cortical visual impairment, dysphagia, infantile spasms
6.3Infant (twin B)32Microcephaly, severe cerebral white matter atrophy, extensive calcifications, bilateral cortical dysplasia/polymicrogyria, atrophic brain stemSee mother 6.1 aboveCZSTerm birth—mixed axial hypotonia and appendicular hypertonia, global developmental delay, cortical visual impairment, dysphagia, infantile spasmsNDND
7.1Woman/fetus23 1/7Hypoplasia of the corpus callosum, ventriculomegaly, small cerebral measurementsNDNDNSASee infant 7.2 below
7.2Infant25Thin corpus callosum, perisylvian polymicrogyriaSee mother 7.1 aboveNSABirth HC at 3rd percentileSent, no resultSent, no resultND
8Woman/fetus21 4/7Prominent choroid plexus cystsNDNDNSALive birth at term, ASQ at 26 months with borderline low gross motor and personal–socialND
9.1Woman/fetus33 6/7Bilateral moderate ventriculomegalyNDNDNSALive birth at termSee infant 9.2 below
9.2Infant30Bilateral mild ventriculomegaly, thin corpus callosum, low white matter volumeSee aboveNSAASQ and WIDEA normal at 18mo.ND
10Woman/fetus28 1/7Bilateral germinolytic cysts, microcephaly (HC and BPD < 3rd percentile by ultrasound)NDNDNSAUnknownND
11.1Woman/fetus35 1/7Germinolytic cysts, mild ventriculomegaly, multifocal white matter, subcortical abnormalitiesNDNDNSALive birth at termSee infant 11.2 below
11.2Infant14Bilateral germinolytic cysts, multifocal areas of white matter necrosis, unrotated hippocampus, thin corpus callosumSee mother 11.1 aboveNSAASQ borderline for fine motor at 16 months.NDND

AIMS = Alberta Infant Motor Scale; ASQ = Ages and Stages Questionnaire; BPD = biparietal diameter; CZS = congenital Zika syndrome; DEN = dengue virus; GA = gestational age; HC = head circumference; IVH = intraventricular hemorrhage; ND = not done; MRI = magnetic resonance imaging; NSA = nonspecific abnormality potentially ZIKV-related; − = negative test; + = positive test; PRNT = plaque reduction neutralization titer; WIDEA = Warner Initial Developmental Evaluation of Adaptive and Functional Skills.

Postnatal imaging was performed in 18 infants because of prenatal laboratory evidence of maternal infection, abnormal prenatal imaging, or another postnatal clinical indication. Cranial ultrasound was abnormal in 8/17 (47%) infants. Detected abnormalities were all nonspecific and included lenticulostriate vasculopathy (n = 2), germinolytic cysts (n = 3), choroid plexus cysts (n = 2), and mild-to-moderate lateral ventriculomegaly (n = 2). Postnatal brain MRI was abnormal in 10 of 14 (71%) infants (Tables 2 and 3). In two infants, twins with possible ZIKV infection, the imaging findings were consistent with CZS, whereas in the other eight infants, brain MRI findings were nonspecific. One of the cases with ZIKV infection and postnatal MRI had an isolated subacute cerebral infarction and another case had enhancement of multiple cranial nerves on post-contrast brain MRI.11 The odds of having abnormal or nonspecific pre- and/or postnatal neuroimaging findings was increased, but below the level of significance, in the cases with ZIKV infection or possible ZIKV infection compared with those in whom ZIKV was unlikely (odds ratio = 3.38; 95% CI: 0.72–15.89, p = 0.122).

Outcome of evaluated cases.

Of 51 cases with prenatal evaluation, the pregnancy outcome was live birth in 43, elective termination in two, fetal demise in one, and unknown in five. Three cases with confirmed ZIKV infection had the phenotype of CZS. One of these cases was live-born but because of prenatal imaging findings of CZS was made comfort care at delivery and died shortly after birth. One affected twin infant with laboratory testing in the category of possible ZIKV infection died within the first year of life because of the severe neurologic abnormalities, whereas the surviving twin had persistent neurologic abnormalities including infantile spasms. One infant with possible ZIKV had repair of congenital heart disease shortly after birth.

Adherence was modest to recommended postnatal follow-up evaluations (Table 4). Formal audiological testing (beyond routine neonatal hearing screen) was indicated and recommended based on current CDC Zika guidelines in 24 infants. Of these 24 infants, 16 (67%) completed the recommended audiological testing by otoacoustic emission or brain stem auditory evoked response, and all were normal. In our cohort, only two of 18 (11%) infants who completed ophthalmologic evaluation had an abnormal finding. The abnormal cases were the twins, both of whom had brain findings consistent with CZS. Their ophthalmologic findings were strabismus, poor fixation with no visual tracking, and optic nerve atrophy. Six of 26 (23%) infants had an abnormal finding on an early evaluation by a pediatric neurologist with findings of microcephaly (n = 2), seizures (n = 1), decreased head and truncal control (n = 2), hypertonia (n = 2), abnormal fixation/tracking (n = 2), and delayed developmental milestones (n = 4).

Table 4

Completion of recommended audiologic, ophthalmologic, and neurologic postnatal evaluations in the clinical cohort

AudiologyOphthalmologyNeurology
Indicated or recommended by the CZPCNN = 24N = 23N = 20
 Completed16 (67)15 (65)17 (85)
 Not completed8 (33)8 (35)3 (15)
Completed examinations*N = 18N = 18N = 26
 Normal18 (100)16 (89)20 (77)
 Abnormal02 (11)6 (23)

CZPCN = Congenital Zika Program at Children’s National. N (%) reported.

Additional patients received examinations that were outside of specific recommendations by the CZPCN.

DISCUSSION

Zika virus evaluation for the pregnant woman and her infant is a clinical challenge, even in a dedicated multidisciplinary Congenital Zika Program. Laboratory testing is often not accomplished within the recommended time window from ZIKV exposure, which results in a significant number of patients in whom ZIKV infection cannot be ruled out. Likewise, recommended follow-up evaluations for the ZIKV-exposed infant are often not completed, despite physician recommendations. Furthermore, guidelines for recommended follow-up changed over time, which further impacted adherence to recommendations. These challenges are not unique to a U.S. congenital Zika program, but are common to the U.S. Zika Pregnancy and Infant Registry and Central and South American ZIKV cohorts.9,26,32 Adherence to recommended follow-up evaluations may have been improved by having a checklist for clinical evaluations at the beginning of program initiation that was followed by all clinicians providing different aspects of multidisciplinary care to pre- and postnatal patients and by having a dedicated clinical support staff to contact patients and simplify scheduling of postnatal recommendations. The experience of our program during the ZIKV epidemic may be instructive to other Children’s Hospitals in evaluating their cohorts exposed to new emerging threats like COVID-19.

Currently available laboratory testing for ZIKV in both the exposed pregnant woman and the infant is suboptimal, and is not sufficiently sensitive or specific to exclude or confirm infection in the majority of exposed pregnancies.33,34 This problem is related to both the limitations of test performance and cross-reactivity with other related flaviviruses. More importantly, the practical reality of the issue with testing is that most women do not present in the 0–3 week window for optimal PCR performance, nor during the 2–12 week window for optimal serologic evaluation, and many women are asymptomatic, making defining the time of exposure challenging. Thus, in our “real-world” clinical cohort, only 7% of women were definitively diagnosed by PCR (and/or PRNT positive solely for Zika), and we could only exclude Zika infection with confidence in 24% of cases. This left many women and infants for whom Zika infection could not be excluded. For the infants of these pregnant women, the concern for potential neurologic, neurodevelopmental, and neurocognitive sequelae that may ensue over the early childhood years is a real concern.6,35,36 Furthermore, the need for coordinated postnatal evaluation of infants born to exposed women with absent, inconclusive, or poorly timed testing (the majority) cannot be overstated, particularly for normal appearing infants.11

Neuroimaging was an essential part of fetal neurology counseling in our program. Advanced fetal imaging with MRI with concomitant fetal ultrasound can detect significant abnormalities when present1012 and, for patients with normal fetal imaging, provided additional assurance following exposure, particularly if imaging remained normal several months after the exposure. In a cohort of Colombian pregnant women with symptomatic Zika infection, we found that serial radiographic evaluation by fetal ultrasound detected most of the Zika-associated brain abnormalities.12 In our U.S. cohort, we had one circumstance of a significant neurologic abnormality detected postnatally that was not appreciated prenatally.37 However, for the vast majority of patients, prenatal and postnatal imaging correlated well and MRI did not identify major structural abnormalities that ultrasound did not. The large number of choroid plexus and germinolytic cysts identified by postnatal cranial ultrasound requires further evaluation in larger populations as well as correlation with long-term neurodevelopmental outcome studies, which are in progress at our center and others.35,36,3840 Head CT is an additional neuroimaging modality that can be used to evaluate for ZIKV-associated brain abnormalities and has higher sensitivity for identifying cerebral calcifications, is faster, and less subject to movement artifacts than brain MRI but has the disadvantage of some radiation exposure. For sites without availability of un-sedated brain MRI or for an infant that is beyond 6 weeks of age and would require sedation, head CT may be the preferable modality for neuroimaging.

Even focused programs face challenges in achieving full compliance with recommended evaluations of Zika-exposed infants. Similar to Centers for Disease Control aggregate data,8 in our cohort, only about two-thirds of the recommended follow-up audiology and ophthalmology evaluations were completed, and only 24% of infants completed recommended cranial ultrasound. Some recommendations were not completed because of loss of follow-up when patients moved back to their home countries. In addition, the recommendations for testing of infants with prenatal ZIKV exposure have been revised over the past 4 years, with removal of recommendations for laboratory testing, and radiographic, audiological, and ophthalmologic evaluation of normal appearing infants born to exposed women without laboratory confirmation.41 Achieving high compliance rates with recommendations requires aggressive attention by the team, and engaged families in ongoing treatment plans, and this is hard to achieve even with a well-established, connected team. In some areas of the United States and its’ territories, lack of pediatric subspecialty expertise can limit compliance with recommended infant evaluations. To address this barrier, a Zika Health Brigade in 2018 brought multispecialty pediatric providers to the U.S. Virgin Islands and completed almost 100 infant evaluations in a week.32

Important programmatic lessons were learned, which are applicable to other institutions/centers considering the establishment of similar programs for Zika and other emerging infectious and noninfectious threats to the pregnant woman and fetus: First, a multidisciplinary and coordinated program optimizes delivery of care, particularly during pregnancy and for the infant. A single coordinated multidisciplinary visit may reduce the burden of coordination of multispecialty care and minimize anxiety for already stressed families. Clinical care delivery can drive and inform research to increase knowledge, which feeds back to optimize clinical care and guidance to patients. At the time of the initial emergence of the virus, when the potential scope of transmission within the United States was unclear, we interfaced with regional Disaster Preparedness and Response authorities to provide Zika-specific guidance and planning, benefitting from our prior experience and expertise with the pediatric Ebola response.42 Subsequently, CZPCN was designated as a participant in the Zika Care Connect program,43 and we maintained a dedicated hotline for both individuals and providers with questions and/or referrals.31

Our study is limited by retrospective collection of clinical data. Many women presented to the CZPCN who did not have symptoms of ZIKV infection but had a travel or emigration history compatible with potential exposure during a discrete time window. Therefore, their exposure timing was ascertained based on their travel and/or their partners travel dates or timing of emigration to the United States as opposed to the timing of clinical symptoms. Multiple providers administered clinical care to pregnant women and their infants over the past 4 years during which guidelines for the evaluation of pregnant women and infants with ZIKV exposure changed. The changing recommendations as more data became available may have affected messaging of the long-term risk and importance of adherence to all recommended follow-up evaluations. Our findings are likely generalizable to other clinical settings in the United States and internationally, in which pregnant women and infants present at varying times from exposure, patients are lost-to-follow-up after initial consultation, and there is modest adherence to follow-up recommendations, representing a barrier to care. For some cases lost to follow-up after initial consultation, the phone number was no longer working or the address was no longer current, so despite multiple attempts, follow-up visits could not be scheduled. For some parents that we were able to reach and who declined follow-up, they stated that their child was “doing fine.” We believe that adherence to follow-up could have been improved by having a clinical follow-up checklist used by all providers in the program caring for these infants to ensure the same recommendations are given, availability of a dedicated social worker, and by better communication with referring primary care pediatricians. Coordination of infant follow-up audiology, ophthalmology, infectious disease, and neurology assessments in a single clinic also may have improved adherence to recommendations.

CONCLUSION

In summary, there were multiple complexities to the evaluation and diagnosis of ZIKV exposed pregnant women and their infants in a U.S. Congenital Zika Program. For many of the patients we evaluated, ZIKV could not be confidently excluded, resulting in a large number of cases at risk for potential neurologic sequelae and in whom we recommended postnatal follow-up assessments. Despite access to a multidisciplinary clinical program, adherence to guidelines for the comprehensive evaluation of ZIKV exposed infants was modest. Nevertheless, the resulting clinical care, research, and advocacy efforts of the program benefitted patients and contributed to advancing knowledge related to CZS.12,35 This model and lessons learned may be generalizable to other institutions considering similar programs in response to new emerging threats to the pregnant woman and infant to help reduce barriers to care and optimize multidisciplinary evaluation and treatment of pregnant women and infants with congenital infectious exposures.

Acknowledgments:

We thank Children’s National Hospital for supporting our Congenital Zika Program. We appreciate the work of Diedtra Henderson, senior public relations specialist/science writer at Children’s National Hospital for helping to share the work of CZPCN regionally, nationally, and internationally. In some cases, this news led to patients traveling from afar to seek our consultation. We thank the women, their families, and the infants whom we have cared for who have been affected by ZIKV.

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Author Notes

Address correspondence to Sarah B. Mulkey, Children’s National Hospital, Prenatal Pediatrics Institute, 111 Michigan Ave., NW Washington, DC 20010. E-mail: sbmulkey@childrensnational.org

Disclosures: DeBiasi, Mulkey, and Biddle had a contract by U.S. Centers for Disease Control/Vysnova to provide Zika-related technical expertise; Mulkey (Awardee), DeBiasi, Biddle, and du Plessis (mentors) receive research support for neurodevelopmental follow-up of Zika-exposed infants from the Thrasher Research Fund.

Financial support: The Congenital Zika Program was established with support of internal Special Purpose Funds from Children’s National Hospital and the Ikaria Fund.

Authors’ addresses: Sarah B. Mulkey, Emily Ansusinha, Stephanie M. Russo¸Cara Biddle, Youssef A. Kousa, Lindsay Pesacreta, Barbara Jantausch, Benjamin Hanisch, Nada Harik, Rana F. Hamdy, Andrea Hahn, Taeun Chang, Mohamad Jaafar, Tracey Ambrose, Gilbert Vezina, Dorothy I. Bulas, David Wessel, Adre J. du Plessis, and Roberta L. DeBiasi, Children’s National Hospital, Washington, DC, E-mails: sbmulkey@childrensnational.org, eansusinha@childrensnational.org, smarierusso@gmail.com, cbiddle@childrensnational.org, ykousa@childrensnational.org, lpesacre@childrensnational.org, bjantaus@childrensnational.org, bhanisch@childrensnational.org, nharik@childrensnational.org, rhamdy2@childrensnational.org, alhahn@childrensnational.org, tchang@childrensnational.org, mjaafar@childrensnational.org, tambrose@childrensnational.org, gvezina@childrensnational.org, dbulas@childrensnational.org, dwessel@childrensnational.org, adupless@childrensnational.org, and rdebiasi@childrensnational.org. Caitlin Cristante, University of Chicago School of Medicine, Chicago, IL, E-mail: caitante@gmail.com.

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