Association of brain functional connectivity with neurodevelopmental outcomes in healthy full-term newborns.

OBJECTIVE: To study the association between neurodevelopmental outcomes and functional brain connectivity (FBC) in healthy term infants. METHODS: This is a retrospective study of prospectively collected High-density electroencephalography (HD-EEG) from newborns within 72 hours from birth. Developmental assessments were performed at two years of age using the Bayley Scales of Infant Development-III (BSID-III) measuring cognitive, language, motor, and socio-emotional scores. The FBC was calculated using phase synchronization analysis of source signals in delta, theta, alpha, beta, and gamma frequency bands and its association with neurodevelopmental score was assessed with stepwise regression. RESULTS: 47/163 had both HD-EEG and BSID-III scores. The FBC of frontal region was associated with cognitive score in the theta band (corrected p, regression coefficients range: p < 0.01, 1.66-1.735). Language scores were significantly associated with connectivity in all frequency bands, predominantly in the left hemisphere (p < 0.01, -2.74-2.40). The FBC of frontal and occipital brain regions of both hemispheres was related to motor score and socio-emotional development in theta, alpha, and gamma frequency bands (p < 0.01, -2.16-2.97). CONCLUSIONS: Functional connectivity of higher-order processing is already present at term age. SIGNIFICANCE: The FBC might be used to guide interventions for optimizing subsequent neurodevelopment even in low-risk newborns.

Outcomes in Pregnant Adolescent Patients Infected With SARS-CoV-2.

BACKGROUND: Pregnant patients with coronavirus disease 2019 (COVID-19) are at risk for adverse pregnancy outcomes. Although clinical outcomes for pregnant adults have been reported, the impact of COVID-19 on adolescents is lacking. We sought to evaluate obstetric outcomes of pregnant adolescents infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and compare them with uninfected adolescent controls. METHODS: Retrospective cohort study of pregnant adolescents (14-19 years) who had a positive polymerase chain reaction test for SARS-CoV-2 from April 2020 to December 2020 at Inova Health System Hospitals. Controls included pregnant adolescents who tested negative. The primary outcome was a composite of preeclampsia, preterm delivery, cesarean delivery, fetal growth restriction and stillbirth. Secondary outcomes included maternal and neonatal morbidity. RESULTS: Forty-eight pregnant adolescents who tested positive for SARS-CoV-2 were compared with 394 controls. Infected adolescents were more likely to be Hispanic (91.67% vs. 12.18%; risk ratio [RR] 41.85 [95% CI: 15.43-113.5]) and uninsured (50% vs. 7.87%; RR 7.04 [95% CI: 4.31-11.49]. Nearly 80% of infected adolescents remained asymptomatic, whereas one-third of symptomatic adolescents progressed to severe or critical COVID-19. The primary composite outcome was more prevalent in infected adolescents compared with noninfected controls (41.67% vs. 25.38%; adjusted RR 2.65 [95% CI: 1.19-5.93]). Maternal morbidity was more prevalent in infected adolescents (6.25% vs. 0.76%; adjusted RR 9.53 [95% CI: 3.83-23.71]). Primary and secondary maternal outcomes were more prevalent in younger adolescents and those with higher severity of COVID-19. Maternal SARS-CoV-2 infection was not associated with neonatal morbidity. CONCLUSIONS: Pregnant adolescents infected with SARS-CoV-2 are more likely to have adverse obstetric outcomes and maternal morbidity compared with noninfected pregnant adolescents.

Functional brain network properties of healthy full-term newborns quantified by scalp and source-reconstructed EEG.

OBJECTIVE: Identifying the functional brain network properties of term low-risk newborns using high-density EEG (HD-EEG) and comparing these properties with those of established functional magnetic resonance image (fMRI) - based networks. METHODS: HD-EEG was collected from 113 low-risk term newborns before delivery hospital discharge and within 72 hours of birth. Functional brain networks were reconstructed using coherence at the scalp and source levels in delta, theta, alpha, beta, and gamma frequency bands. These networks were characterized for the global and local network architecture. RESULTS: Source-level networks in all the frequency bands identified the presence of the efficient small world (small-world propensity (SWP) > 0.6) architecture with four distinct modules linked by hub regions and rich-club (coefficient > 1) topology. The modular regions included primary, association, limbic, paralimbic, and subcortical regions, which have been demonstrated in fMRI studies. In contrast, scalp-level networks did not display consistent small world architecture (SWP < 0.6), and also identified only 2-3 modules in each frequency band.The modular regions of the scalp-network primarily included frontal and occipital regions. CONCLUSIONS: Our findings show that EEG sources in low-risk newborns corroborate fMRI-based connectivity results. SIGNIFICANCE: EEG source analysis characterizes functional connectivity at the bedside of low-risk newborn infants soon after birth.

Evaluation of first trimester ultrasound fetal biometry ratios femur length/biparietal diameter, femur length/abdominal circumference and femur length/foot for the screening of skeletal dysplasia.

OBJECTIVE: Skeletal dysplasia is usually apparent in the second trimester. First trimester femur-length/biparietal diameter (FL/BPD), FL/abdominal circumference (AC) and FL/foot for the screening of skeletal dysplasia were evalauted. METHOD: Case-control study: pregnancies with molecular confirmation of skeletal dysplasia undergoing nuchal translucency (January_2007-December_2021). Controls included pregnancies without fetal abnormalities. Performance of FL/BPD, FL/AC and FL/foot was evaluated by receiver operating characteristic curves. RESULTS: Twenty-eight skeletal dysplasia cases were identified; 17 (60.71%) corresponded to lethal types. Compared to 184 controls, cases had a lower median FL/BPD (0.34 [IQR 0.30-0.38] vs. 0.44 [IQR 0.39-0.48]; p < 0.001), FL/AC (0.13 [IQR 0.09-0.15] vs. 0.15 [IQR 0.13-0.16]; p = 0.001) and FL/foot (0.84 [IQR 0.76-0.91] vs. 1.01 [IQR 0.94-1.11]; p < 0.001). FL/BPD and FL/foot ratios had a superior area under the curve (0.846 and 0.853, respectively) than FL/AC (0.64). The probability of diagnosing skeletal dysplasia increased at least 9-fold if FL/BPD <0.376 (OR 26.05, 95% CI 9.79-69.3; p < 0.001) and 14-fold if FL/foot <0.891 (OR 39.46, 95% CI 14.17-109.9; p < 0.001). Low FL/BPD and FL/foot were associated significantly with lethal types compared to viable skeletal dysplasia. CONCLUSIONS: First trimester FL/BPD and FL/foot may be of clinical utility in the detection of skeletal dysplasia especially when there is another suspicious sonographic sign or when there is a relevant family history before overt second trimester sonographic markers become apparent.

Electroencephalogram in low-risk term newborns predicts neurodevelopmental metrics at age two years.

OBJECTIVE: To determine whether neurodevelopmental biomarkers at 2 years of age are already present in the newborns' EEG at birth. METHODS: Low-risk term newborns were enrolled and studied utilizing EEG prior to discharge from the birth hospital. A 14-channel EEG montage (scalp-level) and source signals were calculated using the EEG. Their spectral power was calculated for each of the five frequency bands. Cognitive, language and motor skills were assessed using the Bayley Scales of Infant Development-III at age 2 years. The relationship between the spectral power in each frequency band and neurodevelopmental scores were quantified using the Spearman's r. The role of gender, gestational age (GA) and delivery mode, if found significant (P < 0.05), were controlled by analyzing partial correlation. RESULTS: We studied 47 newborns and found a significant association between gender, and delivery mode with EEG power. Scalp- and source-level spectral powers were positively associated with cognitive and language scores. At the source level, significant associations were identified in the parietal and occipital regions. CONCLUSIONS: Electrophysiological biomarkers of neurodevelopment at age 2 years are already present at birth in low-risk term infants. SIGNIFICANCE: Low-risk newborns' EEG utility as a screening tool to optimize neurodevelopmental outcome warrants further evaluation.

The effect of delayed cord clamping on blood sugar levels on 34-36 week neonates exposed to late preterm antenatal steroids.

OBJECTIVE: Neonatal hypoglycemia is a known side effect of antenatal betamethasone (BMZ) given for fetal maturation. We sought to investigate if delayed cord clamping (DCC) has an impact on neonatal hypoglycemia induced by antenatal late preterm BMZ administration. MATERIAL AND METHODS: Retrospective cohort study (January 2019-May 2019) of pregnancies undergoing delivery at 34-0/7 to 36-6/7 weeks at a single center included in two groups: DCC + BMZ and BMZ-only (no DCC). The primary outcome was the occurrence of neonatal hypoglycemia at the first hour after delivery. RESULTS: A total of 62/188, 32.98% (DCC + BMZ group) and 45/100, 45% (DCC-only group) infants presented with hypoglycemia at 1-h after birth (adjusted p = .06; OR 0.73, 95% CI 0.54-1.01). When stratified according to gestational age at delivery, DCC was associated with a 46% reduction in the occurrence of neonatal hypoglycemia among those born at 35-0/7 to 35-6/7 weeks (adjusted p = .033; OR 0.54, 95% CI 0.33-0.88) and 35% reduction among those born at 36-0/7 to 36-67 weeks (adjusted p = .046; OR 0.65, 95% CI 0.43-0.97). CONCLUSION: In our cohort, delayed cord clamping in infants receiving late preterm BMZ born between 35-0/7 and 36-6/7 weeks' gestation protects from early neonatal hypoglycemia.

Autonomic development in preterm infants is associated with morbidity of prematurity.

BACKGROUND: Previous studies have described an association between preterm birth and maturation of the autonomic nervous system (ANS); however, this may be impacted by multiple factors, including prematurity-related complications. Our aim was to evaluate for the effect of prematurity-related morbidity on ANS development in preterm infants in the NICU. METHODS: We compared time and frequency domains of heart rate variability (HRV) as a measure of ANS tone in 56 preterm infants from 2 NICUs (28 from each). One cohort was from a high-morbidity regional referral NICU, the other from a community-based inborn NICU with low prematurity-related morbidity. Propensity score matching was used to balance the groups by a 1:1 nearest neighbor design. ANS tone was analyzed. RESULTS: The two cohorts showed parallel maturational trajectory of the alpha 1 time-domain metric, with the cohort from the high-morbidity NICU having lower autonomic tone. The maturational trajectories between the two cohorts differed in all other time-domain metrics (alpha 2, RMS1, RMS2). There was no difference between groups by frequency-domain metrics. CONCLUSIONS: Prematurity-associated morbidities correlate with autonomic development in premature infants and may have a greater impact on the extrauterine maturation of this system than birth gestational age. IMPACT: Autonomic nervous system development measured by time-domain metrics of heart rate variability correlate with morbidities associated with premature birth. This study builds upon our previously published work that showed that development of autonomic tone was not impacted by gestational age at birth. This study adds to our understanding of autonomic nervous system development in a preterm extrauterine environment. Our study suggests that gestational age at birth may have less impact on autonomic nervous system development than previously thought.

Pharmacological treatment in pregnant women with moderate symptoms of coronavirus disease 2019 (COVID-19) pneumonia.

OBJECTIVE: Pregnant women with moderate symptoms of COVID-19 are at risk for progressing to severe or critical illness. While there are limited data on the management of severe COVID-19 during pregnancy, information on pharmacological treatments of moderate COVID-19 is lacking. We report clinical outcomes of pregnant women hospitalized due to moderate COVID-19 illness treated with a 5-day course of remdesivir, antibiotics, and/or glucocorticoids. MATERIALS AND METHODS: Case series of pregnant women hospitalized with moderate symptoms of COVID -19 pneumonia at two INOVA Health System hospitals from April 1 to December 31, 2020. Primary outcome was clinical recovery (breathing on ambient air and/or hospital discharge) on hospital day 7 (HD7). Cox regression analysis was performed to evaluate which variables were associated with the primary outcome. RESULTS: Out of 748 pregnant women with confirmed infection by reverse transcriptase polymerase chain reaction, 35 were hospitalized due to moderate symptoms of COVID-19 pneumonia (median gestational age 29 weeks). There was no maternal death. Seventeen patients received remdesivir within 48 hours of hospitalization: 15 remained with moderate symptoms and 2 (who also received glucocorticoids) had progressed to critical COVID-19 at remdesivir initiation; all 17 women in this group achieved clinical recovery on HD7. Seven women received remdesivir >48 hours following admission after they began treatment with glucocorticoids ± antibiotics and worsened to severe or critical disease; they all required supplemental oxygen on HD7. Eleven women were treated with antibiotics ± glucocorticoids but no remdesivir; on HD7, 3/11 achieved clinical recovery. Clinical recovery was significantly different among treatment groups; p < 0.001. When analyzing only women who remained with moderate symptoms at pharmacological treatments initiation, all 15 on remdesivir and only 3 of 11 on antibiotics achieved clinical recovery on HD7; p < 0.001. Delaying remdesivir for >48 hours after admission (HR 2.32, 95% CI 1.45-4.16) and >4-day duration of symptoms prior to hospitalization (HR 1.65, 95% CI 1.27-3.50) had an inverse association with clinical recovery. Incidental oligohydramnios was seen in 3/24 (12.5%) of women within 5 days of completing remdesivir treatment. Elevated transaminases was prevalent in women treated with remdesivir (8/24, 33.3%). CONCLUSION: In our cohort, prompt initiation of remdesivir in pregnant women hospitalized with moderate symptoms of COVID-19 pneumonia within 48 hours of admission prevented worsening and allowed a fast clinical recovery by HD7. Deferring remdesivir for >48 hours after hospitalization and duration of symptoms >4 days before admission were independently associated with delayed clinical recovery and longer hospital admission. Ultrasound evaluation of the amniotic fluid in patients recovering from COVID-19 hospitalization should be considered.

Cerebral cortical autonomic connectivity in low-risk term newborns.

PURPOSE: The mature central autonomic network includes connectivity between autonomic nervous system brainstem centers and the cerebral cortex. The study objective was to evaluate the regional connectivity between the cerebral cortex and brainstem autonomic centers in term newborns by measuring coherence between high-density electroencephalography and heart rate variability as measured by electrocardiography. METHODS: Low-risk term newborns with birth gestational age of 39-40 weeks were prospectively enrolled and studied using time-synced electroencephalography and electrocardiography for up to 60 min before discharge from the birth hospital. The ccortical autonomicc nervous system association was analyzed using coherence between electroencephalography-delta power and heart rate variability. Heart rate variability measured the parasympathetic tone (root mean square of successive differences of heart rate) and sympathetic tone (standard deviation of heart rate). RESULTS: One hundred and twenty-nine low-risk term infants were included. High coherence delta-root mean square of successive differences was found in central, bitemporal, and occipital brain regions, with less robust coherence delta-standard deviation in the central region and bitemporal areas. CONCLUSIONS: Our findings describe a topography of ccortical autonomicc connectivity present at term in low-risk newborns, which was more robust to parasympathetic than sympathetic brainstem centers and was independent of newborn state.

Autonomic nervous system maturation in the premature extrauterine milieu.

BACKGROUND: In premature infants, we investigated whether the duration of extrauterine development influenced autonomic nervous system (ANS) maturation. METHODS: We performed a longitudinal cohort study of ANS maturation in preterm infants. Eligibility included birth gestational age (GA) < 37 weeks, NICU admission, and expected survival. The cohort was divided into three birth GA groups: Group 1 (≤29 weeks), Group 2 (30-33 weeks), and Group 3 (≥34 weeks). ECG data were recorded weekly and analyzed for sympathetic and parasympathetic tone using heart rate variability (HRV). Quantile regression modeled the slope of ANS maturation among the groups by postnatal age to term-equivalent age (TEA) (≥37 weeks). RESULTS: One hundred infants, median (Q1-Q3) birth GA of 31.9 (28.7-33.9) weeks, were enrolled: Group 1 (n = 35); Group 2 (n = 40); and Group 3 (n = 25). Earlier birth GA was associated with lower sympathetic and parasympathetic tone. However, the rate of autonomic maturation was similar, and at TEA there was no difference in HRV metrics across the three groups. The majority of infants (91%) did not experience significant neonatal morbidities. CONCLUSION: Premature infants with low prematurity-related systemic morbidity have maturational trajectories of ANS development that are comparable across a wide range of ex-utero durations regardless of birth GA. IMPACT: Heart rate variability can evaluate the maturation of the autonomic nervous system. Metrics of both the sympathetic and parasympathetic nervous system show maturation in the premature extrauterine milieu. The autonomic nervous system in preterm infants shows comparable maturation across a wide range of birth gestational ages. Preterm newborns with low medical morbidity have maturation of their autonomic nervous system while in the NICU. Modern NICU advances appear to support autonomic development in the preterm infant.

Fetal acute cerebral vasoreactivity to maternal hyperoxia in low-risk pregnancies: a cross-sectional study.

OBJECTIVE: To establish whether fetal cerebral vasoreactivity (CVRO2 ), following maternal hyperoxia, is predicted by fetal cerebral and uteroplacental Doppler pulsatility indices (PI) at baseline, fetal pulmonary vasoreactivity to oxygen (PVRO2 ), gestational age (GA), or sex. METHODS: Pulsatility index of middle (MCA), anterior (ACA), posterior cerebral (PCA), umbilical (UA), uterine (UtA), and branch of the pulmonary arteries (PA) were obtained, by ultrasound, before (baseline), during (hyperoxia) and after 15 minutes of maternal administration of 8 L/min of 100% oxygen, through a non-rebreathing face mask, in normal singleton pregnancies within 20 to 38 weeks' gestation. CVRO2 was defined as changes greater than zero in z score of PI of the cerebral arteries from baseline to hyperoxia. Logistic modeling was applied to identify CVRO2 predictors. RESULTS: A total of 97 pregnancies were eligible. In the overall population, median z scores of PI of MCA, ACA, and PCA did not differ between study phases. Based on the logistic model, baseline z scores for cerebral PI and GA were the best predictors of CVRO2 . CONCLUSIONS: In low-risk pregnancies, fetal CVRO2 to hyperoxia does not occur uniformly but depends on cerebral PI and GA at baseline. These findings may provide useful reference points when oxygen is administered in high-risk pregnancies.

Heart rate variability is depressed in the early transitional period for newborns with complex congenital heart disease.

PURPOSE: To compare early changes in autonomic nervous system (ANS) tone between newborns with complex congenital heart disease (CHD) and newborns without CHD. METHODS: We performed a case-control study of heart rate variability (HRV) in newborns with complex CHD [transposition of the great arteries (TGA) or hypoplastic left heart syndrome (HLHS)] and low-risk control newborns without CHD. Cases with CHD were admitted following birth to a pediatric cardiac intensive care unit and had archived continuous ECG data. Control infants were prospectively enrolled at birth. ECG data in cases and controls were analyzed for HRV in the time and frequency domains at 24 h of age. We analyzed the following HRV metrics: alpha short (αs), alpha long (αL), root mean square short and long (RMSs and RMSL), low-frequency (LF) power, normalized LF (nLF), high-frequency (HF) power, and normalized HF (nHF). We used ANOVA to compare HRV metrics between groups and to control for medication exposures. RESULTS: HRV data from 57 infants with CHD (TGA, n = 33 and HLHS, n = 24) and from 29 controls were analyzed. The HRV metrics αS, RMSL, LF, and nLF were significantly lower in infants with CHD than in the controls. Due to the effect of normalization, nHF was higher in CHD infants (P < 0.0001), although absolute HF was lower (P = 0.0461). After adjusting for medications, αS and nLF remained lower and nHF higher in newborns with CHD (P < 0.0005). CONCLUSIONS: Infants with complex CHD have depressed autonomic balance in the early postnatal period, which may complicate the fetal-neonatal transition.

The effect of labor and delivery mode on electrocortical and brainstem autonomic function during neonatal transition.

Delivery of the newborn occurs either vaginally or via caesarean section. It is not known whether the mode of delivery and exposure to labor affects early autonomic nervous system (ANS) function, as measured by heart rate variability (HRV), or cortical electroencephalogram (EEG) activity. The objective of the study was to determine if autonomic function in newborns differs by mode of delivery. Simultaneous recording of EEG and electrocardiogram were collected in low-risk term newborns at <72 hours of age to measure HRV, the asymmetry index, and EEG power. Newborns were compared by delivery type: vaginal delivery (VD), cesarean section (CS) after labor (L-CS), or elective CS (E-CS). Quantile Regression controlled for gestational age, postnatal age, and percent active states. One hundred and eighteen newborns were studied at 25.2 (11.4) hours of age. Sixty-two (52.5%) were born by VD, 22 by L-CS (18.6%), and 34 by E-CS (28.8%). HRV metrics didn't differ by delivery mode. Asymmetry index was higher in L-CS compared to VD and E-CS (P = 0.03). On EEG, L-CS newborns showed lower relative gamma power compared to VD and E-CS (P = 0.005). The study found that overall ANS tone is not altered by mode of delivery in low-risk term newborns.

Autonomic nervous system depression at term in neurologically normal premature infants.

BACKGROUND: Premature infants are vulnerable to destructive brain injury and disturbed neurological development. Prematurity may alter maturation of the central autonomic nervous system (ANS). AIMS: To compare ANS function (using heart rate variability; HRV) between preterm infants with normal neuroimaging at term equivalent age and low-risk term controls. Study design, subjects. We performed a case-control study of preterm infants born ≤28 weeks gestational age that had normal brain imaging and archived continuous EKG data at term equivalent age. We documented other factors thought to influence ANS maturation (e.g. infection, ventilation days, and postnatal steroids). Controls were low-risk term gestational age newborns from uncomplicated pregnancies/deliveries. We characterized HRV metrics using frequency-(Welch periodogram) and time-domain (detrended fluctuation) analyses. Sympathetic tone was characterized by α1, root mean square analysis (RMS1 and RMS2), low-frequency (LF) power, and normalized LF (nLF) and parasympathetic tone was characterized by high-frequency (HF) power and normalized HF (nHF). α2 characterized ultraslow changes in heart rate. We used ANCOVA to compare HRV metrics between groups. Outcome measures, results. HRV from 26 preterm infants were compared to 55 controls. Analyzed HRV data for preterm infants were recorded at median (range) gestational age of 39 (36-39) weeks and for controls at 39 (37-41) weeks gestational age. α1, RMS2, LF and HF were significantly higher in control infants and remained significant after controlling for infection, ventilator days, and postnatal steroids (P < .005). CONCLUSIONS: Autonomic maturation is impaired in a premature extrauterine environment. In the absence of destructive brain injury, our data suggest an important role for disturbed programming in this impaired autonomic development.