Placental pathology and neonatal encephalopathy.

Neonatal encephalopathy (NE) is an important cause of neonatal morbidity and mortality worldwide; however, there remain gaps in our knowledge about its pathogenesis. The placenta has been implicated in the pathogenesis of this disease but conclusive evidence related to the placental factors that influence it is sparse. This review aims to outline the current knowledge on the role of the placenta with particular attention to its role in NE as a consequence of hypoxia-ischemia. A total of 26 original articles/review papers were used to compile this review. Three themes were identified from these publications: fetal vascular malperfusion including umbilical cord pathology, inflammatory changes in the placenta, and maternal vascular malperfusion including placental weight. These features were identified as being significant in the development of NE. Advancing our understanding of this relationship between placental pathology and NE may facilitate the development of additional antenatal screening to better identify at-risk fetuses. We highlight areas for further research through antenatal screening and placental histology.

Fetal heart rate patterns in labor and the risk of neonatal encephalopathy: A case control study.

OBJECTIVE: To describe the accuracy of intrapartum fetal heart rate abnormalities as defined by National Institute of Health and Care Excellence guidelines to predict moderate-severe neonatal encephalopathy of apparent hypoxic-ischemic etiology. STUDY DESIGN: A case-control study of HIE risk factors was conducted. Eligible babies were born in a single maternity hospital in Dublin, Ireland between September 2006, and November 2017 at ≥35 + 0 weeks' gestational age. Cases were eligible babies with moderate-severe neonatal encephalopathy of definite or apparent hypoxic-ischemic etiology. Controls were eligible babies born before and after each case with normal Apgar scores. The included subjects who had intrapartum fetal heart rate recordings were identified. Pattern features (baseline rate, variability, accelerations, decelerations [early, late, variable, prolonged], bradycardia, sinusoidal pattern) were manually identified blind to all clinical details by one of the authors. Each 15-minute segment was then algorithmically categorized (uninterpretable, normal, suspicious, pathological). RESULTS: Of 88 cases and 176 controls, 71 cases (81%) and 146 controls (83%) were admitted to the delivery suite in labor. From that group, intrapartum FHR traces longer than 15 min were available for 52 (73%) cases and 118 (83%) controls. The FHR pattern feature with the largest area under the receiver operating characteristic curve was the maximum number of consecutive segments in which the baseline was >160 bpm (0.71 [95% confidence interval: 0.62-0.80]). The category variable with the highest area under the curve was the number of suspicious segments (0.76 [95% confidence interval: 0.67-0.84]). A tri-variate logistic regression model incorporating the total number of segments, the number of "suspicious" segments classed, and the number of "pathological" segments achieved an area under the curve of 0.78 (95% confidence interval: 0.70-0.86). With 95% specificity, this model correctly identified 17 cases (33%) at a median time before delivery of 2 h and 18 min (interquartile range: 01:19-04:40). CONCLUSIONS: The power of fetal heart rate analysis to predict neonatal encephalopathy is hampered by poor specificity given the rarity of the outcome. When analyzing a suspicious trace, it is beneficial to consider the overall duration of the suspicious pattern.

Uterine activity in labour and the risk of neonatal encephalopathy: a case control study.

OBJECTIVE: To determine the relationship between intrapartum contraction frequency, rest interval duration, and cervical dilation speed and the risk of neonatal hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: This was a retrospective case-control study conducted in a maternity hospital in Dublin, Ireland. Babies born without major congenital anomalies between September 2006 and November 2017 at ≥ 35 + 0 weeks' gestational age were eligible. Cases were diagnosed with moderate-severe HIE. The controls were the first eligible baby born before and after each case with normal Apgar scores and not admitted to the neonatal unit. Intrapartum uterine activity was assessed by automated analysis of external tocography recordings. Cervical dilation was assessed by linear interpolation between vaginal examination measurements. The speed of cervical dilation was expressed as the times from 4 to 6 cm, >6 cm to the start of pushing, and from pushing to delivery. RESULTS: Intrapartum tocographs results were available in 49 of 88 cases and 121 of 176 controls. The median contraction rate in cases was 7.7 (Interquartile range [IQR]: 6.6-9.0) compared to 7.0 in controls (IQR: 6.2-7.9) (p = 0.021). The median rest interval duration was 56 s (IQR: 38-76) in cases and 62 s (IQR: 50-79) in controls (p = 0.058). Cases took longer to progress from > 6 cm to the start of pushing (cases: 02:58 [01:14-04:49], controls: 01:48 [00:51-03:34], p = 0.020) and from pushing to delivery (cases: 00:34 [00:24-01:10], controls: 00:27 [00:13-00:56], p = 0.036). CONCLUSIONS: Higher contraction frequencies and slower progress towards the end of labour are both independently associated with the risk of moderate-severe HIE. Inter-contraction rest interval duration as measured by external tocography does not provide additional accuracy.

Maternal intentions towards infant sleeping practices in Ireland.

AIM: Mortality from Sudden Infant Death Syndrome (SIDS) has reduced by 50%-85% globally. Despite improvements from 1990 to 2009, the Irish SIDS rate has plateaued. Reasons for this are unclear, but may be related to a reduced parental SIDS awareness. Our study aimed to assess intentions regarding infant sleeping practices in mothers in Ireland. METHODS: A cross-sectional survey of post-partum mothers was performed in the Rotunda Hospital over a four month period. Mothers with a history of SIDS, miscarriage or neonatal admissions were excluded. RESULTS: Of 451 participants, unsafe sleeping positions were intended by 15.4%, reduced by Irish ethnicity [AOR = 0.52, 95% CI = 0.277-0.959, P = .036]. Safe sleep locations were intended by 66%, increased by Irish ethnicity [AOR = 2.6, 95% CI = 1.617-4.191, P < .001], and reduced by young maternal age [AOR = 0.15, 95% CI = 0.03-0.713, P = .02]. Maternal smoking was more likely in mothers with lower educational level [AOR = 3.51, 95% CI = 1.169-10.56, P = .03]. Soft bedding use was intended by 34.8%, increased in younger mothers [AOR = 2.28, 95% CI = 1.04-4.98, P = .04]. Breastfeeding was intended by 72.2%, decreased by Irish ethnicity [AOR = 0.14, 95% CI = 0.067-0.271, P < .001], and low maternal education [AOR = 0.22, 95% CI = 0.117-0.406, P < .001]. CONCLUSION: Educational campaigns on safe sleep for infants in Ireland need to address modifiable SIDS risks factors, focusing on younger, non-Irish mothers, with lower educational attainment.

A Pilot Randomized, Controlled, Double-Blind Trial of Bumetanide to Treat Neonatal Seizures.

OBJECTIVE: In the absence of controlled trials, treatment of neonatal seizures has changed minimally despite poor drug efficacy. We tested bumetanide added to phenobarbital to treat neonatal seizures in the first trial to include a standard-therapy control group. METHODS: A randomized, double-blind, dose-escalation design was employed. Neonates with postmenstrual age 33 to 44 weeks at risk of or with seizures were eligible. Subjects with electroencephalography (EEG)-confirmed seizures after ≥20 and <40mg/kg phenobarbital were randomized to receive additional phenobarbital with either placebo (control) or 0.1, 0.2, or 0.3mg/kg bumetanide (treatment). Continuous EEG monitoring data from ≥2 hours before to ≥48 hours after study drug administration (SDA) were analyzed for seizures. RESULTS: Subjects were randomized to treatment (n = 27) and control (n = 16) groups. Pharmacokinetics were highly variable among subjects and altered by hypothermia. The only statistically significant adverse event was diuresis in treated subjects (48% vs 13%, p = 0.02). One treated (4%) and 3 control subjects died (19%, p = 0.14). Among survivors, 2 of 26 treated subjects (8%) and 0 of 13 control subjects had hearing impairment, as did 1 nonrandomized subject. Total seizure burden varied widely, with much higher seizure burden in treatment versus control groups (median = 3.1 vs 1.2 min/h, p = 0.006). There was significantly greater reduction in seizure burden 0 to 4 hours and 2 to 4 hours post-SDA (both p < 0.01) compared with 2-hour baseline in treatment versus control groups with adjustment for seizure burden. INTERPRETATION: Although definitive proof of efficacy awaits an appropriately powered phase 3 trial, this randomized, controlled, multicenter trial demonstrated an additional reduction in seizure burden attributable to bumetanide over phenobarbital without increased serious adverse effects. Future trials of bumetanide and other drugs should include a control group and balance seizure severity. ANN NEUROL 2021;89:327-340.

Intrapartum uterine activity and neonatal outcomes: a systematic review.

BACKGROUND: Increased uterine activity (UA) may not allow adequate recovery time for foetal oxygenation. METHODS: The aim of the study was to determine if increased UA during labour is associated with an increased risk of either short- or long-term neurological injury in term neonates, or with neonatal proxy measures of intrapartum hypoxia-ischemia. MEDLINE, CINAHL, and ClinicalTrials.gov were searched using the following terms: uterine activity, excessive uterine activity, XSUA, uterine hyperstimulation, and tachysystole. Any study that analysed the relationship between UA during term labour and neurological outcomes/selected proxy neurological outcomes was eligible for inclusion. Outcomes from individual studies were reported in tables and presented descriptively with odds ratios (OR) and 95% confidence intervals (CI) for dichotomous outcomes and means with standard deviations for continuous outcomes. Where group numbers were provided, ORs and their CIs were calculated according to Altman. MAIN RESULTS: Twelve studies met the inclusion criteria. Seven studies featured umbilical artery pH as an individual outcome. Umbilical artery base excess and Apgar scores were both reported as individual outcomes in four studies. No study examined long term neurodevelopmental outcomes and only one study reported on encephalopathy as an outcome. The evidence for a relationship between UA and adverse infant outcomes was inconsistent. The reported estimated effect size varied from non-existent to clinically significant. CONCLUSIONS: There is some evidence that increased UA may be a non-specific predictor of depressed neurological function in the newborn, but it is inconsistent and insufficient to support the conclusion that an association generally exists.

A wavelet-based algorithm for automated analysis of external tocography: How does it compare to human interpretation?

BACKGROUND: Studies which use external tocography to explore the relationship between increased intrapartum uterine activity and foetal outcomes are feasible because the technology is safe and ubiquitous. However, periods of poor signal quality are common. We developed an algorithm which aims to calculate tocograph summary variables based on well-recorded contractions only, ignoring artefact and excluding sections deemed uninterpretable. The aim of this study was to test that algorithm's reliability. METHODS: Whole recordings from labours at ≥35 weeks of gestation were randomly selected without regard to quality. Contractions and rest intervals were measured by two humans independently, and by the algorithm using two sets of models; one based on a series of pre-defined thresholds, and another trained to imitate one of the human interpreters. The absolute agreement intraclass correlation coefficient (ICC) was calculated using a two-way random effects model. RESULTS: The training dataset included data from 106 tocographs. Of the tested algorithms, AdaBoost showed the highest initial cross-validated accuracy and proceeded to optimization. Forty tocographs were included in the validation set. The ICCs for the per tocograph mean contraction rates were; human B to human A: 0.940 (0.890-0.968), human A to initial models: 0.944 (0.898-0.970), human A to trained models 0.962 (0.927-0.980), human B to initial models: 0.930 (0.872-0.962), human B to trained models: 0.948 (0.903-0.972). CONCLUSIONS: The algorithm described approximates interpretation of external tocography performed by trained humans. The performance of the AdaBoost trained models was marginally superior compared to the initial models.

Subcutaneous fat necrosis of the newborn.

A term infant developed subcutaneous fat necrosis of the newborn (SFNN) 17 days following completion of therapeutic hypothermia for hypoxic ischaemic encephalopathy. Initial calcium was normal, however hypercalcaemia requiring hyperhydration and furosemide developed at 4 weeks. Parathyroid hormone and vitamin D were suppressed. At 13 months, she remains on low calcium formula, and has gross motor delay, central hypotonia and early hand preference. Review of 102 articles yielded 119 SFNN cases. Asphyxia was reported in 78%. Twenty-one per cent had hypoglycaemia. Twenty per cent underwent therapeutic hypothermia. Median onset of skin lesions was day 6 (range: 1-70), with a median duration of 62 days (range: 14-390). Hypercalcaemia developed in 53% (median onset day 28, range: 1-210). Fifty-two per cent of hypercalcaemia was asymptomatic. Outcome information was provided in 106/119 cases; 87% reported a full resolution. Persistent calcinosis was present in 6%. Babies treated with therapeutic hypothermia should be closely monitored for SFNN, and development of hypercalcaemia.

Timing of administration of antenatal magnesium sulfate and umbilical cord blood magnesium levels in preterm babies.

BACKGROUND: The optimum timing of administration of magnesium sulfate (MgSO4) in relation to delivery is not known. The general consensus is to achieve administration to the mother at least 4 hours prior to preterm delivery. OBJECTIVE: To investigate potential predictors of umbilical cord blood magnesium (Mg) concentrations, in particular, timing of antenatal MgSO4 administration in relation to delivery. STUDY DESIGN: A prospective observational study of infants delivered at less than 32 weeks' gestational age. Cord bloods samples were collected at delivery and Mg levels analyzed. RESULTS: Of the 81 included cases, five received no antenatal MgSO4, 65 received a 4 g bolus only, and 11 received a 4 g bolus and 1 g/hour infusion. The median time of bolus administration before delivery was 104 minutes (IQR: 57-215). The mean magnesium level was 0.934 mmol/L in the no antenatal MgSO4 group, 1.018 mmol/L in the bolus only group, and 1.225 mmol/L in the bolus and infusion group (p < .05). In the bolus only group, the highest mean magnesium concentration (1.091 mmol/L) was achieved with administration 1-2 hours before delivery, but the difference was small and not statistically significant. On multiple regression analysis, lower birthweight Z scores and gestational age were independently associated with higher cord blood Mg levels. CONCLUSIONS: In the bolus only group, the highest mean Mg levels were observed with administration 1-2 hours before delivery, but the findings were not statistically significant. Compared to the rest of the cohort, higher Mg levels were found when a bolus was followed by an infusion. Following a MgSO4 bolus, some growth restricted extremely preterm babies may have higher Mg levels than would be otherwise expected.

Hearing impairment and hypoxia ischaemic encephalopathy: Incidence and associated factors.

OBJECTIVE: To establish the local incidence of hearing loss in newborns with Hypoxic Ischaemic Encephalopathy (HIE) and to identify associated risk factors. STUDY DESIGN: Retrospective Cohort Study. Neonatal Intensive Care Unit (NICU) dual stage hearing screening protocol, including automated otoacoustic emissions (AOAE) and automated auditory brainstem response (AABR) testing. RESULTS: 57 newborns received therapeutic hypothermia for HIE. Twelve babies (21%) died. Audiology data was incomplete in 3 babies. Complete data was available for 42 babies (male n = 24), 4 (9.5%) of whom had hearing impairment. The development of hearing loss was associated with abnormal blood glucose levels (p = 0.006), low Apgar score at 1 min (p = 0.0219) and evidence of multi organ dysfunction [high creatinine (p = 0.0172 and 0.0198) and raised liver transaminases (aspartate aminotransferase (AST) p = 0.0012, alanine aminotransferase (ALT) p = 0.0037)]. An association with gentamicin was not found. CONCLUSION: This study confirms that hearing impairment is common in term infants who have undergone therapeutic hypothermia for moderate/severe HIE. Blood glucose should be monitored carefully in these infants and developmental surveillance should include formal audiology. Further larger studies are needed to clarify the role, if any, of hypothermia per se in causation of hearing loss and to fully identify risk factors for hearing impairment in this population. WHAT IS NEW: The current study confirms that hearing impairment is common in term infants who have undergone therapeutic hypothermia for moderate/severe HIE. No association between gentamicin use and the development of hearing impairment was found however initial blood glucose outside the normal range was of significance. Other factors associated with hearing impairment were low Apgar scores, greater need for resuscitation and evidence of multi organ dysfunction (renal and liver failure).

Neurodevelopmental outcome in survivors of hypoxic ischemic encephalopathy without cerebral palsy.

To access outcome following hypoxic ischemic encephalopathy (HIE), survivors without cerebral palsy were invited for formal developmental assessment. Children aged ≥ 42 months were assessed using the NEPSY-2, Movement Assessment Battery for Children 2 (Movement ABC-2), Behavior Rating Inventory of Executive Function, and the Child Behavior Checklist. Children aged < 42 months were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (BSITD-3). One hundred forty-six children attended for assessments [Grade 1 (112), Grade 2 (33), and Grade 3 (1)]. BSITD-3 did not identify significant rates of impairment on cognitive, motor, or language subtests. A significant proportion of children scored < 3rd percentile on the adaptive behavior scale. In older age groups, difficulties were seen in 16/24 NEPSY-2 subtests and on timed assessments using Movement ABC-2. Difficulties arose especially in the "control" aspects of cognition and behavior. Behavioral difficulties were common with internalizing problems predominating. There was a graded effect with grade 2 cases differing significantly from grade 1 cases. CONCLUSION: Following HIE, children may experience attention, memory, and behavior difficulties which are not always evident at a young age. The adaptive behavior questionnaire may be a useful tool to select children requiring developmental surveillance beyond 2 years of age. What is known: • Diversity of outcome across grades of HIE is reported and few studies have looked at the milder consequences of HIE at school age. What is new: • Following HIE children may experience attention, memory, and behavior difficulties which are not always evident at a young age. • The adaptive behavior questionnaire may be a useful tool to select children requiring developmental surveillance beyond 2 years of age.

Brain magnetic resonance imaging and outcome after hypoxic ischaemic encephalopathy.

OBJECTIVE: To correlate pattern of injury on neonatal brain magnetic resonance imaging (MRI) with outcome in infants ≥36 + 0 weeks gestation with hypoxic ischaemic encephalopathy. METHODS: Prospective cohort study. Images were blindly reviewed. Children were assessed using a variety of standardised assessments. RESULTS: MRI brain was performed on 88 infants. Follow up was available in 73(83%) infants. Eight of 25(32%) children with normal imaging had below normal assessment scores. Eight infants (12%) had isolated punctate white matter lesions and five of these had abnormal assessment scores. Death and cerebral palsy were seen only in children with imaging scores ≥3 on basal ganglia/thalami (BGT) score or ≥4 on watershed score. No developmental concerns were raised in 3/7(43%) infants with isolated watershed injury. Ten of 13(77%) infants with isolated BGT injury died or developed cerebral palsy. All 23 children with posterior limb of the internal capsule (PLIC) injury displayed developmental difficulties. CONCLUSIONS: Almost one-third of infants with a normal MRI brain may be at risk of developmental problems. Punctate foci of white matter injury are common and not always benign. PLIC involvement is usually associated with neurological sequelae including isolated cognitive deficits. Worst outcomes are associated with basal ganglia injury.

A case-control study of hypoxic-ischemic encephalopathy in newborn infants at >36 weeks gestation.

OBJECTIVE: The purpose of this study was to determine risk factors that are associated with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: This was a case-control study that included newborn infants with HIE who were admitted to the hospital between January 2001 and December 2008. Two control newborn infants were chosen for each case. Logistic regression and classification and regression tree (CART) analysis that compared control infants and cases with grade 1 HIE and control infants and cases with grades 2 and 3 HIE was performed. RESULTS: Two hundred thirty-seven cases (newborn infants with grade 1 encephalopathy, 155; newborn infants with grade 2 encephalopathy, 61; newborn infants with grade 3 encephalopathy, 21) and 489 control infants were included. Variables that were associated independently with HIE included higher grade meconium, growth restriction, large head circumference, oligohydramnios, male sex, fetal bradycardia, maternal pyrexia and increased uterine contractility. CART analysis ranked high-grade meconium, oligohydramnios, and the presence of obstetric complications as the most discriminating variables and defined distinct risk groups with HIE rates that ranged from 0-86%. CONCLUSION: CART analysis provides information to help identify the time at which intervention in labor may be of benefit.

The placenta in infants >36 weeks gestation with neonatal encephalopathy: a case control study.

OBJECTIVE: To determine placental characteristics associated with neonatal encephalopathy (NE) and correlate these with short- and long-term neurodevelopmental outcome. DESIGN: Case/control study. SETTING: Neonatal Intensive Care Unit, Rotunda Hospital, Dublin, Ireland. PATIENTS: Newborns ≥36 weeks gestation, with NE (cases). Healthy term newborns (controls). INTERVENTIONS: Placental pathology was obtained from the official placental report. Brain MRI was blindly reviewed. Children were assessed using a variety of standardised assessments. Data were analysed using multinomial logistic regression analysis. MAIN OUTCOME MEASURES: RRR for grade of encephalopathy. OR for neurodevelopmental outcome. RESULTS: Placental reports were available on 141 cases (76 grade 1; 46 grade 2; 19 grade 3) and 309 control infants. Meconium phagocytosis, haemorrhage, raised placental to birth weight ratio and/or markers of infection/inflammation were independently associated with NE and showed a synergistic effect, when combined, for short- and long-term impairments. CONCLUSIONS: Evaluation of the mechanisms leading to the placental characteristics identified may help to characterise the causal pathway of NE.

Behavioural and emotional outcome of very low birth weight infants--literature review.

OBJECTIVE: To examine whether low birth weight (LBW) children are at greater risk for behavioural and emotional problems than normal birth weight children. METHODS: Electronic databases (PubMed, Google) were searched. Key search terms (LBW, emotional behavioural outcome) were used to identify possible studies. Selection of studies was limited to those including detailed assessment of behavioural and/or emotional outcome of very low birth weight or very preterm infants with normal term infants as controls, published from the year 2000 to date. A total of 20 studies were identified for inclusion in our review. RESULTS: Overall studies showed a significant increase in behavioural problems in particular poor attention span, withdrawn behaviour and poorer adaptive functioning. Rates of a clinically significant neurobehavioural impairment in cases ranged from 25% to 55% with controls displaying a relatively constant rate of around 7%. Attention problems without hyperactivity (ADD) were more common than 'classical attention deficit/hyperactivity disorder' in LBW children. Only 4% of the LBW children had previously been referred to a consultant psychiatric suggesting that at present these problems are being under-recognised. CONCLUSION: VLBW or very preterm infants are at significant risk of behavioural and emotional problems. The risk is further increased when cognitive or motor difficulties are present or when social circumstances are poor.