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

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.

How prenatal head ultrasound reference ranges affect evaluation of possible fetal microcephaly.

OBJECTIVES: Different fetal ultrasound (US) nomograms of the head circumference (HC) have been established; however, comparisons between the detection rates of microcephaly among US nomograms are few and inconsistent. We aimed to compare the prenatal diagnostic rate of fetal microcephaly (FM) among four widely used US nomograms of the fetal HC, when applied to the same group of fetuses. METHODS: We retrospectively identified singleton pregnancies complicated by fetal HC < 5th percentile for gestational age (GA) by US, without other risk factors for FM and with normal fetal brain MRI. Raw values of HC by US were converted to z-scores using four nomograms (Chervenak = A, Hadlock = B, Gelber = C, Papageorghiou = D). Z-scores value of the HC were classified as normal, possible normal, or microcephaly if values were >-2, ≤ -2 and >-3, or ≤ -3, respectively and compared among the four nomograms. RESULTS: Fifty one fetuses at a mean (±SD) GA of 28 (±4) weeks were included. The four nomograms resulted in different z-score values of the fetal HC for the same subject (p < .001) and none of them showed 100% agreement. Reference C and D showed the highest agreement in classifying subjects as normal, possible normal, or with microcephaly (simple Kappa = 0.8915, % agreement = 94.1%), while A and B had the lowest agreement (simple Kappa = 0.0977, % agreement = 51.0%). CONCLUSIONS: Despite the use of similar prenatal cutoff z-score values of the fetal HC, the four nomograms led to different diagnostic rates of FM. More consistent diagnostic criteria are therefore needed to define FM, especially in the absence of other risk factors for FM and normal fetal brain MRI, since the prenatal diagnosis can affect pregnancy management.

Prognostic Value of Continuous Electroencephalogram Delta Power in Neonates With Hypoxic-Ischemic Encephalopathy.

The objective was to examine the discriminatory ability of electroencephalogram (EEG) delta power in neonates with hypoxic-ischemic encephalopathy (HIE) with well-defined outcomes. Prolonged continuous EEG recordings from term neonates with HIE during therapeutic hypothermia enrolled in a prospective observational study were examined. Adverse outcome was defined as death or severe brain injury by magnetic resonance imaging (MRI); favorable outcome was defined as normal or mild injury by MRI. Neonates were stratified by Sarnat grade of encephalopathy at admission. EEG was partitioned into 10-minute nonoverlapping artifact- and seizure-free epochs. Delta power was calculated and compared between the groups using receiver operating characteristic (ROC) analyses and Wilcoxon rank-sum tests. An area under the ROC curve >0.7 with P <.05 was considered a significant separation between groups. The favorable outcome group (n = 67) had higher delta power than the adverse outcome group (n = 28) across the majority of time periods from 9 to 90 hours of life. Delta power discriminated outcome groups for neonates with moderate encephalopathy (63 favorable and 14 adverse outcome) earlier in cooling (9-42 hours of life) than neonates with severe encephalopathy (21-42 hours of life). Outcome groups were differentiated after 81 hours of life in neonates with moderate and severe encephalopathy. Delta power can distinguish cooled HIE neonates with adverse outcome independently of the encephalopathy grade at presentation. Delta power may be a real-time continuous biomarker of evolving encephalopathy and brain injury/death in neonates with HIE.

Cerebral venous volume changes and pressure autoregulation in critically ill infants.

OBJECTIVE: To determine whether ventilator-related fluctuations in cerebral blood volume (CBV) are associated with cerebral pressure passivity. STUDY DESIGN: In a prospective study of newborns undergoing positive-pressure ventilation, we calculated coherence between continuous mean arterial pressure (MAP) and cerebral near-infrared spectroscopy hemoglobin difference (HbD). Significant HbD-MAP coherence indicated cerebral pressure passivity. CBV changes were measured as the spectral power of total hemoglobin (SHbT) at the ventilator frequency. A regression model tested whether SHbT predicts cerebral pressure passivity and/or death/brain injury, controlling for birth gestational age and other factors. RESULTS: We studied 68 subjects with prematurity (n = 19), congenital heart disease (n = 11), and hypoxic-ischemic encephalopathy (n = 38). SHbT, sedative use, and pCO2 were positively associated, and circulating hemoglobin negatively associated, with cerebral pressure passivity (p < 0.001), which was positively associated with brain injury (p < 0.001). CONCLUSION: In sick newborns, ventilator-related CBV fluctuations may predispose to cerebral pressure passivity, which may predispose to an adverse neonatal outcome.

Sequential Neuroimaging of the Fetus and Newborn With In Utero Zika Virus Exposure.

Importance: The evolution of fetal brain injury by Zika virus (ZIKV) infection is not well described. Objectives: To perform longitudinal neuroimaging of fetuses and infants exposed to in utero maternal ZIKV infection using concomitant magnetic resonance imaging (MRI) and ultrasonography (US), as well as to determine the duration of viremia in pregnant women with ZIKV infection and whether the duration of viremia correlated with fetal and/or infant brain abnormalities. Design, Setting, and Participants: A cohort of 82 pregnant women with clinical criteria for probable ZIKV infection in Barranquilla, Colombia, and Washington, DC, were enrolled from June 15, 2016, through June 27, 2017, with Colombian women identified by community recruitment and physician referral and travel-related cases of American women recruited from a Congenital Zika Program. Interventions and Exposures: Women received 1 or more MRI and US examinations during the second and/or third trimesters. Postnatally, infants underwent brain MRI and cranial US. Blood samples were tested for ZIKV. Main Outcomes and Measures: The neuroimaging studies were evaluated for brain injury and cerebral biometry. Results: Of the 82 women, 80 were from Colombia and 2 were from the United States. In 3 of 82 cases (4%), fetal MRI demonstrated abnormalities consistent with congenital ZIKV infection. Two cases had heterotopias and malformations in cortical development and 1 case had a parietal encephalocele, Chiari II malformation, and microcephaly. In 1 case, US results remained normal despite fetal abnormalities detected on MRI. Prolonged maternal polymerase chain reaction positivity was present in 1 case. Of the remaining 79 cases with normal results of prenatal imaging, postnatal brain MRI was acquired in 53 infants and demonstrated mild abnormalities in 7 (13%). Fifty-seven infants underwent postnatal cranial US, which detected changes of lenticulostriate vasculopathy, choroid plexus cysts, germinolytic/subependymal cysts, and/or calcification in 21 infants (37%). Conclusions and Relevance: In a cohort of pregnant women with ZIKV infection, prenatal US examination appeared to detect all but 1 abnormal fetal case. Postnatal neuroimaging in infants who had normal prenatal imaging revealed new mild abnormalities. For most patients, prenatal and postnatal US may identify ZIKV-related brain injury.

Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis.

BACKGROUND: Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV). MATERIALS AND METHODS: HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis. RESULTS: HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] < 0.7). The pattern of HRV change was significantly associated with the clinical severity of NEC (stage II vs. stage III). CONCLUSION: Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach.

Neuroimaging Findings in Normocephalic Newborns With Intrauterine Zika Virus Exposure.

BACKGROUND: Congenital Zika infection can result in a spectrum of neurological abnormalities in the newborn. Newborns exposed to Zika virus in utero often have neuroimaging as part of their clinical evaluation. METHODS: Through the Congenital Zika Program at Children's National Health System in Washington DC, we performed fetal or neonatal neuroimaging, including magnetic resonance imaging and ultrasound, on over 70 fetuses or neonates with intrauterine Zika exposure. Novel findings on neonatal brain magnetic resonance imaging were observed in two instances. RESULTS: Gadolinium-contrast magnetic resonance imaging showed enhancement of multiple cranial nerves at three days of age on one infant. Another infant underwent magnetic resonance imaging at 16 days of age and was shown to have a chronic ischemic cerebral infarction. This infant had previously normal fetal magnetic resonance imaging. CONCLUSION: Cranial nerve enhancement and cerebral infarction may be among the expanding list of neurological findings in congenital Zika infection. Postnatal brain magnetic resonance imaging should be considered for newborns exposed to Zika virus in utero.