Postnatal Cerebral Hemodynamics and Placental Vascular Malperfusion Lesions in Neonates With Congenital Heart Disease.

BACKGROUND: Neonates with congenital heart disease (CHD) have smaller brain volume at birth. High rates of placental vascular malperfusion lesions may play a role in disrupted brain development. METHODS: This is a single-center retrospective cohort study of infants born between 2010 and 2019 who were diagnosed with a major cardiac defect requiring surgery in the first year of life. Doppler ultrasound RI of the middle cerebral artery (MCA) and anterior cerebral artery were calculated within the first 72 hours of life. Placentas were evaluated using a standardized approach. RESULTS: Over the study period, there were 52 patients with hypoplastic left heart syndrome (HLHS), 22 with single-ventricle right ventricular outflow tract obstruction (SV-RVOTO), 75 with a two-ventricle cardiac defect (2V), and 25 with transposition of the great arteries (TGA). MCA Doppler RI were significantly higher for all subgroups of CHD compared with control subjects (0.68 ± 0.11 in control subjects compared with 0.78 ± 0.13 in HLHS, P = 0.03; 0.77 ± 0.10 in SV-RVOTO, P = 0.002; 0.78 ± 0.13 in 2V, P = 0.03; and 0.80 ± 0.14 in TGA; P = 0.001) with the highest average MCA RI in the TGA group. In subgroup analyses, placental fetal vascular malperfusion in the 2V group was associated with higher MCA RI, but this relationship was not present in other subgroups, nor in regards to maternal vascular malperfusion. CONCLUSIONS: Major forms of CHD are associated with significantly higher cerebral artery RI postnatally, but placental vascular malperfusion lesions may not contribute to this hemodynamic adaptation.

Association between decreased cord blood inter-alpha inhibitor levels and neonatal encephalopathy at birth.

BACKGROUND: Inter-alpha inhibitor proteins (IAIPs) are structurally related proteins found in the systemic circulation with immunomodulatory anti-inflammatory properties. Reduced levels are found in inflammatory related conditions including sepsis and necrotizing enterocolitis, and in neonatal rodents after exposure to hypoxia ischemia. In the current study, cord blood IAIP levels were measured in neonates with and without exposure to hypoxic-ischemic encephalopathy (HIE). METHODS: This is a prospective cohort study including infants born ≥36 weeks over a one-year period. Term pregnancies were divided into two groups: a "reference control" (uncomplicated term deliveries), and "moderate to severe HIE" (qualifying for therapeutic hypothermia). IAIPs were quantified using a sensitive ELISA on the cord blood samples. RESULTS: The study included 57 newborns: Reference control group (n = 13) and moderate/severe HIE group (n = 44). Measurement of IAIP cord blood concentrations in moderate to severe HIE group [278.2 (138.0, 366.0) µg/ml] revealed significantly lower IAIP concentrations compared with the control group [418.6 (384.5, 445.0) µg/ml] (p = 0.002). CONCLUSIONS: These findings suggest a potential role for IAIPs as indicators of neonates at risk for HIE. IAIP levels could have diagnostic implications in the management of HIE. Future research is required to explore the relationship between HIE and IAIPs as biomarkers for disease severity. CATEGORY OF STUDY: Translational.

Tissue Oxygenation Changes After Transfusion and Outcomes in Preterm Infants: A Secondary Near-Infrared Spectroscopy Study of the Transfusion of Prematures Randomized Clinical Trial (TOP NIRS).

Importance: Preterm infants with varying degrees of anemia have different tissue oxygen saturation responses to red blood cell (RBC) transfusion, and low cerebral saturation may be associated with adverse outcomes. Objective: To determine whether RBC transfusion in preterm infants is associated with increases in cerebral and mesenteric tissue saturation (Csat and Msat, respectively) or decreases in cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE, respectively) and whether associations vary based on degree of anemia, and to investigate the association of Csat with death or neurodevelopmental impairment (NDI) at 22 to 26 months corrected age. Design, Setting, and Participants: This was a prospective observational secondary study conducted among a subset of infants between August 2015 and April 2017 in the Transfusion of Prematures (TOP) multicenter randomized clinical trial at 16 neonatal intensive care units of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Preterm neonates with gestational age 22 to 28 weeks and birth weight 1000 g or less were randomized to higher or lower hemoglobin thresholds for transfusion. Data were analyzed between October 2020 and May 2022. Interventions: Near-infrared spectroscopy monitoring of Csat and Msat. Main Outcomes and Measures: Primary outcomes were changes in Csat, Msat, cFTOE, and mFTOE after transfusion between hemoglobin threshold groups, adjusting for age at transfusion, gestational age, birth weight stratum, and center. Secondary outcome at 22 to 26 months was death or NDI defined as cognitive delay (Bayley Scales of Infant and Toddler Development-III score <85), cerebral palsy with Gross Motor Function Classification System level II or greater, or severe vision or hearing impairment. Results: A total of 179 infants (45 [44.6%] male) with mean (SD) gestational age 25.9 (1.5) weeks were enrolled, and valid data were captured from 101 infants during 237 transfusion events. Transfusion was associated with a significant increase in mean Csat of 4.8% (95% CI, 2.7%-6.9%) in the lower-hemoglobin threshold group compared to 2.7% (95% CI, 1.2%-4.2%) in the higher-hemoglobin threshold group, while mean Msat increased 6.7% (95% CI, 2.4%-11.0%) vs 5.6% (95% CI, 2.7%-8.5%). Mean cFTOE and mFTOE decreased in both groups to a similar extent. There was no significant change in peripheral oxygen saturation (SpO2) in either group (0.2% vs -0.2%). NDI or death occurred in 36 infants (37%). Number of transfusions with mean pretransfusion Csat less than 50% was associated with NDI or death (odds ratio, 2.41; 95% CI, 1.08-5.41; P = .03). Conclusions and Relevance: In this secondary study of the TOP randomized clinical trial, Csat and Msat were increased after transfusion despite no change in SpO2. Lower pretransfusion Csat may be associated with adverse outcomes, supporting further investigation of targeted tissue saturation monitoring in preterm infants with anemia. Trial Registration: ClinicalTrials.gov Identifier: NCT01702805.

Sex Vulnerabilities to Hypoxia-Ischemia at Birth.

This cross-sectional study examines the incidence of hypoxic ischemic encephalopathy in male vs female neonates.

Evaluation of neurovascular coupling during neuroprotective therapies: A single site HEAL ancillary study.

BACKGROUND: There is a critical need for development of physiological biomarkers in infants with birth asphyxia to identify the physiologic response to therapies in real time. This is an ancillary single site study of the High-Dose Erythropoietin for Asphyxia and Encephalopathy (Wu et al., 2022 [1]) to measure neurovascular coupling (NVC) non-invasively during an ongoing blinded randomized trial. METHODS: Neonates who randomized in the HEAL enrolled at a single-center Level III Neonatal Intensive Care Unit were recruited between 2017 and 2019. Neurodevelopmental impairment was blinded and defined as any of the following: cognitive score <90 on Bayley Scales of Infant Toddler Development, third edition (BSID-III), Gross Motor Function Classification Score (GMFCS) ≥1. RESULTS: All twenty-seven neonates enrolled in HEAL were recruited and 3 died before complete recording. The rank-based analysis of covariance models demonstrated lack of difference in NVC between the two groups (Epo versus Placebo) that was consistent with the observed lack of effect on neurodevelopmental outcomes. CONCLUSION: We demonstrate no difference in neurovascular coupling after Epo administration. These findings are consistent with overall negative trial results. Physiological biomarkers can help elucidate mechanisms of neuroprotective therapies in real time in future trials.

Hypoxic-Ischemic Encephalopathy: Changing Outcomes Across the Spectrum.

Neonatal hypoxic-ischemic encephalopathy (HIE) is a leading cause of death and neurodevelopmental impairment in neonates. Therapeutic hypothermia (TH) is the only established effective therapy and randomized trials affirm that TH reduces death and disability in moderate-to-severe HIE. Traditionally, infants with mild HIE were excluded from these trials due to the perceived low risk for impairment. Recently, multiple studies suggest that infants with untreated mild HIE may be at significant risk of abnormal neurodevelopmental outcomes. This review will focus on the changing landscape of TH, the spectrum of HIE presentations and their neurodevelopmental outcomes.

A comparison of criteria for defining metabolic acidemia in live-born neonates and its effect on predicting serious adverse neonatal outcomes.

BACKGROUND: Metabolic acidemia is a known risk factor for serious adverse neonatal outcomes in both preterm and term infants. OBJECTIVE: This study aimed to evaluate the clinical significance of delivery umbilical cord gas measurements with regard to serious adverse neonatal outcomes, and to determine if distinct thresholds for defining metabolic acidemia differ in their ability to predict such adverse neonatal complications. STUDY DESIGN: This is a retrospective cohort study of singleton live-born deliveries between January 2011 and December 2019. Stratification according to gestational age at birth (≥35 and <35 weeks of gestation) was performed, and comparisons of maternal characteristics, obstetrical complications, intrapartum events, and adverse neonatal outcomes were made between neonates with metabolic acidemia and those without. Metabolic acidemia (based on delivery umbilical cord gas analyses) was defined using both American College of Obstetricians and Gynecologists and Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria. The primary outcome of interest was hypoxic-ischemic encephalopathy requiring whole-body hypothermia. RESULTS: A total of 91,694 neonates born at ≥35 weeks of gestation met the inclusion criteria. By American College of Obstetricians and Gynecologists criteria, 2659 (2.9%) infants had metabolic acidemia. Neonates with metabolic acidemia were at markedly increased risk for neonatal intensive care unit admission, seizures, need for respiratory support, sepsis, and neonatal death. Metabolic acidemia by American College of Obstetricians and Gynecologists criteria was associated with an almost 100-fold increased risk of hypoxic-ischemic encephalopathy requiring whole-body hypothermia (relative risk, 92.69; 95% confidence interval, 64.42-133.35) in neonates born at ≥35 weeks of gestation. Diabetes mellitus, hypertensive disorders of pregnancy, postterm deliveries, prolonged second stages, chorioamnionitis, operative vaginal deliveries, placental abruption and cesarean deliveries were associated with metabolic acidemia in neonates born ≥ 35 weeks of gestation. The highest relative risk was in those diagnosed with placental abruption (relative risk, 9.07; 95% confidence interval, 7.25-11.36). The neonatal cohort born <35 weeks of gestation had similar findings. When comparing those infants born ≥ 35 weeks of gestation with metabolic acidemia by American College of Obstetricians and Gynecologists criteria vs Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria, the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria identified more neonates at risk for serious adverse neonatal outcomes. In particular, 4.9% more neonates were diagnosed with metabolic acidemia, and 16 more term neonates were identified as requiring whole-body hypothermia. Mean 1-minute and 5-minute Apgar scores were similar and reassuring among neonates born at ≥35 weeks of gestation with and without metabolic acidemia as defined by both American College of Obstetricians and Gynecologists and Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria (8 vs 8 and 9 vs 9, respectively; P<.001). Sensitivity and specificity were 86.7% and 92.2%, respectively, with the Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria, and 74.2% and 97.2% with the American College of Obstetricians and Gynecologists criteria. CONCLUSION: Infants with metabolic acidemia identified on cord gas collection at delivery are at considerably greater risk of serious adverse neonatal outcomes, including an almost 100-fold increased risk of hypoxic-ischemic encephalopathy requiring whole-body hypothermia. Use of the more sensitive Eunice Kennedy Shriver National Institute of Child Health and Human Development criteria for defining metabolic acidemia identifies more neonates born at ≥35 weeks of gestation at risk for adverse neonatal outcomes, including hypoxic-ischemic encephalopathy requiring whole-body hypothermia.

Antiseizure medication at discharge in infants with hypoxic-ischaemic encephalopathy: an observational study.

OBJECTIVES: To assess variability in continuation of antiseizure medication (ASM) at discharge and to evaluate if continuation of ASM at discharge is associated with death or disability among infants with hypoxic-ischaemic encephalopathy (HIE) and seizures. DESIGN: Retrospective study of infants enrolled in three National Institute of Child Health and Human Development Neonatal Research Network Trials of therapeutic hypothermia. SETTING: 22 US centres. PATIENTS: Infants with HIE who survived to discharge and had clinical or electrographic seizures treated with ASM. EXPOSURES: ASM continued or discontinued at discharge. OUTCOMES: Death or moderate-to-severe disability at 18-22 months, using trial definitions. Multivariable logistic regression evaluated the association between continuation of ASM at discharge and the primary outcome, adjusting for severity of HIE, hypothermia trial treatment arm, use of electroencephalogram, discharge on gavage feeds, Apgar Score at 5 min, birth year and centre. RESULTS: Of 302 infants included, 61% were continued on ASMs at discharge (range 13%-100% among 22 centres). Electroencephalogram use occurred in 92% of the cohort. Infants with severe HIE comprised 24% and 22% of those discharged with and without ASM, respectively. The risk of death or moderate-to-severe disability was greater for infants continued on ASM at discharge, compared with those infants discharged without ASM (44% vs 28%, adjusted OR 2.14; 95% CI 1.13 to 4.05). CONCLUSIONS: In infants with HIE and seizures, continuation of ASM at discharge varies substantially among centres and may be associated with a higher risk of death or disability at 18-22 months of age.

Placental clearance not synthesis tempers exaggerated pro-inflammatory cytokine response in neonates exposed to chorioamnionitis.

BACKGROUND: The source and clearance of cytokines in the fetal circulation in term pregnancies complicated by chorioamnionitis remains unclear as are the contributions of placental transport, synthesis, and clearance. The objectives of the study were to determine (1) fetal and/or placental contributions to synthesis and/or clearance of inflammatory and anti-inflammatory cytokines in term pregnancies complicated by chorioamnionitis and (2) whether this differs in pregnancies further complicated by fetal hypoxia. METHODS: Prospective cohort study of pregnancies >37 weeks gestational age that included: Group 1, uncomplicated cesarean delivery without labor (n = 20); Group 2, uncomplicated vaginal delivery (n = 30); Group 3, pregnancies complicated by chorioamnionitis (n = 10); Group 4, complicated by chorioamnionitis + fetal hypoxia (n = 10). Umbilical arterial (UmA) and venous (UmV) blood were assayed for IL-1ß, IL-2, IL-6, IL-8, TNFα, and IL-10. RESULTS: IL-6 and IL-8 were below assay detection in UmA and UmV blood in Group 1 and increased in Group 2 (P < 0.01), UmA¼UmV (P < 0.01). Their concentrations increased further in Groups 3 and 4 (P = 0.003), UmA¼UmV. Placental clearance was concentration dependent that approaches saturation in the presence of chorioamnionitis. CONCLUSIONS: Marked increases in fetal synthesis of IL-6 and IL-8 occur in chorioamnionitis. Synthesis increase further when complicated by fetal hypoxia. Cytokine removal occurs via placental concentration-dependent mechanisms, potentially contributing to adverse fetal effects. IMPACT: The source and role of the placenta in synthesis and/or clearance of inflammatory mediators in term pregnancies complicated by clinical chorioamnionitis are unclear; however, conventional wisdom suggests the placenta is their source. This is the first study demonstrating that circulating concentrations of fetal IL-6 and IL-8 in clinical chorioamnionitis ± birth asphyxia in term pregnancies are of fetal origin. Circulating fetal inflammatory cytokines are cleared by concentration-dependent placental mechanisms that are nearly saturated in chorioamnionitis ± fetal hypoxia. These observations provide additional insight into understanding the fetal immune response in term pregnancies complicated by clinical chorioamnionitis.

Placental pathologic lesions associated with stroke in term neonates.

Objective: To determine the birth prevalence of perinatal stroke in term born infants at our high-volume delivery center and assess the frequency of both gross and histologic placental pathologies associated with perinatal stroke using the Amsterdam Placental Workshop Group Consensus Statement guidelines and definitions. Study Design: A single-center retrospective cohort study spanning 2010-2020. Results: There were 129,759 live births at Parkland Hospital during the study period and a total of 18 term born infants leading to a birth prevalence of 1 in 6,829 infants. Perinatal risk factors were found in all but one patient, and 74% presented with seizures. Pathologic placental examination was available in 56% of the cohort and only one patient had normal placental examination. Acute histologic chorioamnionitis was described in five placentas (50%) and an additional two had isolated umbilical and/or chorionic plate vasculitis with or without funisitis compared to a rate of 28% with acute inflammation in a Control group. Chronic inflammation in the form of villitis of unknown etiology was described in three of the acutely inflamed placentas and was high-grade in each of those while none of the placentas from our Control group showed evidence of any chronic lesion. Conclusion: Both acute and chronic placental inflammation are common in perinatal stroke; placental examination should be considered an essential component to the diagnostic workup.

Feasibility of EEG Phase-Amplitude Coupling to Stratify Encephalopathy Severity in Neonatal HIE Using Short Time Window.

Goal: It is challenging to clinically discern the severity of neonatal hypoxic ischemic encephalopathy (HIE) within hours after birth in time for therapeutic decision-making for hypothermia. The goal of this study was to determine the shortest duration of the EEG based PAC index to provide real-time guidance for clinical decision-making for neonates with HIE. Methods: Neonates were recruited from a single-center Level III NICU between 2017 and 2019. A time-dependent, PAC-frequency-averaged index, tPACm, was calculated to characterize intrinsic coupling between the amplitudes of 12−30 Hz and the phases of 1−2 Hz oscillation from 6-h EEG data at electrode P3 during the first day of life, using different sizes of moving windows including 10 s, 20 s, 1 min, 2 min, 5 min, 10 min, 20 min, 30 min, 60 min, and 120 min. Time-dependent receiver operating characteristic (ROC) curves were generated to examine the performance of the accurate window tPACm as a neurophysiologic biomarker. Results: A total of 33 neonates (mild-HIE, n = 15 and moderate/severe HIE, n = 18) were enrolled. Mixed effects models demonstrated that tPACm between the two groups was significantly different with window time segments of 3−120 min. By observing the estimates of group differences in tPACm across different window sizes, we found 20 min was the shortest window size to optimally distinguish the two groups (p < 0.001). Time-varying ROC showed significant average area-under-the-curve of 0.82. Conclusions: We demonstrated the feasibility of using tPACm with a 20 min EEG time window to differentiate the severity of HIE and facilitate earlier diagnosis and treatment initiation.

Neuroprotection for hypoxic-ischemic encephalopathy: Contributions from the neonatal research network.

Therapeutic hypothermia (TH) is now well established as the standard of care treatment for moderate to severe neonatal encephalopathy secondary to perinatal hypoxic ischemic encephalopathy (HIE) in infants ≥36 weeks gestation in high income countries. The Neonatal Research Network (NRN) contributed greatly to the study of TH as a neuroprotectant with three trials now completed in infants ≥36 weeks gestation and the only large randomized-controlled trial of TH in preterm infants now in the follow-up phase. Data from the first NRN TH trial combined with data from other large trials of TH affirm the safety and neuroprotective qualities of TH and highlight the importance of providing TH to all infants who qualify. In this review we will highlight the findings of the three NRN trials of TH in the term infant population and the secondary analyses that continue to inform the care of patients with HIE.

Placental vascular malperfusion lesions in fetal congenital heart disease.

BACKGROUND: Fetuses with congenital heart disease are at increased risk of perinatal morbidity and mortality, which is highly influenced by their prenatal health. Placental function is vital for the health of the fetus, but increased rates of pathologic lesions of the placenta have been observed in pregnancies complicated by fetal congenital heart disease. OBJECTIVE: This study aimed to determine the prevalence of both gross and histologic placental pathologies in a cohort of pregnancies complicated by fetal congenital heart disease vs healthy controls using the Amsterdam Placental Workshop Group Consensus Statement sampling and definitions of placental lesions. STUDY DESIGN: This single-center retrospective cohort study included placental examinations from pregnancies diagnosed prenatally with fetal congenital heart disease between 2010 and 2019; moreover, control placentas were collected from pregnancies without maternal or fetal complications. Placentas were sampled and evaluated according to the Amsterdam Placental Workshop Group Consensus Statement and gross and histopathologic diagnoses determined. RESULTS: Approximately 80% of fetuses diagnosed with congenital heart disease (n=305) had a placental examination for comparison with controls (n=40). Of note, 239 placentas (78%) in the group with fetal congenital heart disease had at least 1 gross or histopathologic lesion compared with 11 placentas (28%) in the control group (P<.01). One-third of placentas complicated by fetal congenital heart disease met the criteria for small for gestational age, and 48% of placentas had one or more chronic lesions, including maternal vascular malperfusion (23% vs 0%; P<.01), villitis of unknown etiology (22% vs 0%; P<.01), fetal vascular malperfusion (20% vs 0%; P<.01), and other chronic lesions (16% vs 0%; P<.01). Acute inflammation was equally present in both the group with fetal congenital heart disease and the control group (28% vs 28%; P=1.00). Although gestational age and birthweight z score were similar between the 2 groups, birth head circumference was 1.5 cm less in pregnancies complicated by fetal congenital heart disease with a significantly lower z score compared with the control group (-0.52±1.22 vs 0.06±0.69; P<.01). CONCLUSION: Vascular malperfusion lesions and chronic forms of inflammation occur at markedly higher rates in placentas complicated by fetal congenital heart disease, which may contribute to the decreased head circumference at birth. Further work in neuroplacentology is needed to explore connections among cardiac defects, placental vascular malperfusion lesions, and fetal brain development.

Early brain and abdominal oxygenation in extremely low birth weight infants.

BACKGROUND: Extremely low birth weight (ELBW) infants are at risk for end-organ hypoxia and ischemia. Regional tissue oxygenation of the brain and gut as monitored with near-infrared spectroscopy (NIRS) may change with postnatal age, but normal ranges are not well defined. METHODS: A prospective study of ELBW preterm infants utilized NIRS monitoring to assess changes in cerebral and mesenteric saturation (Csat and Msat) over the first week after birth. This secondary study of a multicenter trial comparing hemoglobin transfusion thresholds assessed cerebral and mesenteric fractional tissue oxygen extraction (cFTOE and mFTOE) and relationships with perinatal variables. RESULTS: In 124 infants, both Csat and Msat declined over the first week, with a corresponding increase in oxygen extraction. With lower gestational age, lower birth weight, and 5-min Apgar score ≤5, there was a greater increase in oxygen extraction in the brain compared to the gut. Infants managed with a lower hemoglobin transfusion threshold receiving ≥2 transfusions in the first week had the lowest Csat and highest cFTOE (p < 0.001). CONCLUSION: Brain oxygen extraction preferentially increased in more immature and anemic preterm infants. NIRS monitoring may enhance understanding of cerebral and mesenteric oxygenation patterns and inform future protective strategies in the preterm ELBW population. IMPACT: Simultaneous monitoring of cerebral and mesenteric tissue saturation demonstrates the balance of oxygenation between preterm brain and gut and may inform protective strategies. Over the first week, oxygen saturation of the brain and gut declines as oxygen extraction increases. A low hemoglobin transfusion threshold is associated with lower cerebral saturation and higher cerebral oxygen extraction compared to a high hemoglobin transfusion threshold, although this did not translate into clinically relevant differences in the TOP trial primary outcome. Greater oxygen extraction by the brain compared to the gut occurs with lower gestational age, lower birth weight, and 5-min Apgar score ≤5.

Neuroplacentology in congenital heart disease: placental connections to neurodevelopmental outcomes.

Children with congenital heart disease (CHD) are living longer due to effective medical and surgical management. However, the majority have neurodevelopmental delays or disorders. The role of the placenta in fetal brain development is unclear and is the focus of an emerging field known as neuroplacentology. In this review, we summarize neurodevelopmental outcomes in CHD and their brain imaging correlates both in utero and postnatally. We review differences in the structure and function of the placenta in pregnancies complicated by fetal CHD and introduce the concept of a placental inefficiency phenotype that occurs in severe forms of fetal CHD, characterized by a myriad of pathologies. We propose that in CHD placental dysfunction contributes to decreased fetal cerebral oxygen delivery resulting in poor brain growth, brain abnormalities, and impaired neurodevelopment. We conclude the review with key areas for future research in neuroplacentology in the fetal CHD population, including (1) differences in structure and function of the CHD placenta, (2) modifiable and nonmodifiable factors that impact the hemodynamic balance between placental and cerebral circulations, (3) interventions to improve placental function and protect brain development in utero, and (4) the role of genetic and epigenetic influences on the placenta-heart-brain connection. IMPACT: Neuroplacentology seeks to understand placental connections to fetal brain development. In fetuses with CHD, brain growth abnormalities begin in utero. Placental microstructure as well as perfusion and function are abnormal in fetal CHD.

Association Between Increased Seizures During Rewarming After Hypothermia for Neonatal Hypoxic Ischemic Encephalopathy and Abnormal Neurodevelopmental Outcomes at 2-Year Follow-up: A Nested Multisite Cohort Study.

Importance: Compared with normothermia, hypothermia has been shown to reduce death or disability in neonatal hypoxic ischemic encephalopathy but data on seizures during rewarming and associated outcomes are scarce. Objective: To determine whether electrographic seizures are more likely to occur during rewarming compared with the preceding period and whether they are associated with abnormal outcomes in asphyxiated neonates receiving hypothermia therapy. Design, Setting, and Participants: This prespecified nested cohort study of infants enrolled in the Optimizing Cooling (OC) multicenter Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Neonatal Research Network trial from December 2011 to December 2013 with 2 years' follow-up randomized infants to either 72 hours of cooling (group A) or 120 hours (group B). The main trial included 364 infants. Of these, 194 were screened, 10 declined consent, and 120 met all predefined inclusion criteria. A total of 112 (90%) had complete data for death or disability. Data were analyzed from January 2018 to January 2020. Interventions: Serial amplitude electroencephalography recordings were compared in the 12 hours prior and 12 hours during rewarming for evidence of electrographic seizure activity by 2 central amplitude-integrated electroencephalography readers blinded to treatment arm and rewarming epoch. Odds ratios and 95% CIs were evaluated following adjustment for center, prior seizures, depth of cooling, and encephalopathy severity. Main Outcomes and Measures: The primary outcome was the occurrence of electrographic seizures during rewarming initiated at 72 or 120 hours compared with the preceding 12-hour epoch. Secondary outcomes included death or moderate or severe disability at age 18 to 22 months. The hypothesis was that seizures during rewarming were associated with higher odds of abnormal neurodevelopmental outcomes. Results: A total of 120 newborns (70 male [58%]) were enrolled (66 in group A and 54 in group B). The mean (SD) gestational age was 39 (1) weeks. There was excellent interrater agreement (κ, 0.99) in detection of seizures. More infants had electrographic seizures during the rewarming epoch compared with the preceding epoch (group A, 27% vs 14%; P = .001; group B, 21% vs 10%; P = .03). Adjusted odd ratios (95% CIs) for seizure frequency during rewarming were 2.7 (1.0-7.5) for group A and 3.2 (0.9-11.6) for group B. The composite death or moderate to severe disability outcome at 2 years was significantly higher in infants with electrographic seizures during rewarming (relative risk [95% CI], 1.7 [1.25-2.37]) after adjusting for baseline clinical encephalopathy and seizures as well as center. Conclusions and Relevance: Findings that higher odds of electrographic seizures during rewarming are associated with death or disability at 2 years highlight the necessity of electroencephalography monitoring during rewarming in infants at risk. Trial Registration: ClinicalTrials.gov Identifier: NCT01192776.