Antenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort

doi:10.1016/j.jpeds.2018.08.028

The Journal of Pediatrics

Volume 203, December 2018, Pages 163-169

https://doi.org/10.1016/j.jpeds.2018.08.028 Get rights and content

Objective

To identify risk factors for hypoxic-ischemic encephalopathy (HIE) within a recent US birth cohort.

Study design

In a retrospective cohort study of 44 572 singleton infants ≥36 weeks of gestation born at Kaiser Permanente Northern California in 2008-2015, we identified all infants with HIE based on the presence of 3 inclusion criteria: clinical signs of neonatal encephalopathy, NICU admission, and either a 10-minute Apgar of ≤5 or a base excess of ≤-15 mmol/L. Neonatal acidemia was defined as a base excess of ≤-12 mmol/L. We ascertained antenatal and intrapartum complications from electronic records. Multivariable analysis was performed using logistic regression.

Results

There were 45 infants (1.0 per 1000) with HIE and 197 (4.4 per 1000) with neonatal acidemia. Of the infants with HIE, 64% had an intrapartum complication consisting of a sentinel event (36%), clinical chorioamnionitis (40%), or both (11%). Risk factors for HIE on multivariable analysis were sentinel event (relative risk [RR], 16.1; 95% CI, 8.4-33) and clinical chorioamnionitis (RR, 5.2; 95% CI, 2.7-9.9). After removing the 16 infants with HIE who were exposed to a sentinel event from multivariate analysis, maternal age of ≥35 years (RR, 2.5; 95% CI, 1.1-5.6) and a urinary tract infection during pregnancy (RR, 2.6; 95% CI, 1.0-6.5) emerged as potential antenatal risk factors for HIE.

Conclusions

A significant proportion of HIE is preceded by a sentinel event, emphasizing the importance of developing improved methodologies to predict and prevent this perinatal complication. Strategies focused on reducing other complications such as clinical chorioamnionitis and/or maternal pyrexia may also improve our ability to prevent HIE.

Section snippets

Methods

In this retrospective cohort study, we identified all live, singleton births at 2 Kaiser Permanente Northern California (KPNC) hospitals in Oakland and Santa Clara who were ≥36 weeks of gestational age and born between January 1, 2008, and June 30, 2015. Multiple gestation births and newborns who received a physician diagnosis of congenital viral infection or congenital anomalies were excluded owing to unique predisposing factors in these populations. Study procedures were approved by the

Results

Among 44 960 singleton infants ≥36 weeks of gestational age in the birth cohort, we excluded 384 with congenital anomalies and 4 with congenital viral infection. Of the remaining 44 572 infants, 197 had neonatal acidemia (incidence 4.4 per 1000), 45 had HIE (1.0 per 1000), and 13 had HIE leading to hypoxic-ischemic brain injury or death (0.3 per 1000).

Of 197 infants with neonatal acidemia, 37 (19%) also met study criteria for HIE. Eight infants with HIE did not meet study criteria for neonatal

Discussion

HIE is a heterogeneous condition. In a recent US birth cohort of term and near-term infants, we found that an intrapartum sentinel event and a clinical diagnosis of chorioamnionitis were the strongest risk factors for both HIE and neonatal acidemia. When infants exposed to a sentinel event were excluded from analyses, additional antenatal risk factors for HIE included maternal age ≥35 years, pre-eclampsia, and maternal UTI during pregnancy.

Sentinel events such as uterine rupture or placental

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Cited by (59)

Genetic and Congenital Anomalies in Infants With Hypoxic-Ischemic Encephalopathy
2024, Pediatric Neurology
Infants with hypoxic ischemic encephalopathy (HIE) may have underlying conditions predisposing them to hypoxic-ischemic injury during labor and delivery. It is unclear how genetic and congenital anomalies impact outcomes of HIE.
Infants with HIE enrolled in a phase III trial underwent genetic testing when clinically indicated. Infants with known genetic or congenital anomalies were excluded. The primary outcome, i.e., death or neurodevelopmental impairment (NDI), was determined at age two years by a standardized neurological examination, Bayley Scales of Infant Development, Third Edition (BSID-III), and the Gross Motor Function Classification Scales. Secondary outcomes included cerebral palsy and BSID-III motor, cognitive, and language scores at age two years.
Of 500 infants with HIE, 24 (5%, 95% confidence interval 3% to 7%) were diagnosed with a genetic (n = 15) or congenital (n = 14) anomaly. Infants with and without genetic or congenital anomalies had similar rates of severe encephalopathy and findings on brain magnetic resonance imaging. However, infants with genetic or congenital anomalies were more likely to have death or NDI (75% vs 50%, P = 0.02). Among survivors, those with a genetic or congenital anomaly were more likely to be diagnosed with cerebral palsy (32% vs 13%, P = 0.02), and had lower BSID-III scores in all three domains than HIE survivors without such anomalies.
Among infants with HIE, 5% were diagnosed with a genetic or congenital anomaly. Despite similar clinical markers of HIE severity, infants with HIE and a genetic or congenital anomaly had worse neurodevelopmental outcomes than infants with HIE alone.
A predictive model for perinatal hypoxic ischemic encephalopathy using linked maternal and neonatal hospital data
2024, Annals of Epidemiology
To build an evidence-based model to estimate case-specific risk of perinatal hypoxic ischemic encephalopathy.
A retrospective, cross-sectional study of all births in Hawaii, Michigan, and New Jersey between 2010 and 2015, using linked maternal labor/delivery and neonatal birth records. Stepwise logistic regression and competitive Akaike information criterion were used to identify the most parsimonious model. Predictive ability of the model was measured with bootstrapped optimism-adjusted area under the ROC curve.
Among 836,216 births there were 376 (0.45 per 1000) cases of hypoxic ischemic encephalopathy. The final model included 28 variables, 24 associated with increased risk, and 4 that were protective. The optimism-adjusted area under the ROC curve was 0.84. Estimated risk in the study population ranged from 1 in ∼323,000 to 1 in 2.5. The final model confirmed known risk factors (e.g., sentinel events and shoulder dystocia) and identified novel risk factors, such as maternal race and insurance status.
Our study shows that risk of perinatal hypoxic ischemic encephalopathy injury can be estimated with high confidence. Our model fills a notable gap in the study of hypoxic ischemic encephalopathy prevention: the estimation of risk, particularly in the United States population which is unique with respect to racial and socioeconomic disparities.
Acquired Brain Injuries Across the Perinatal Spectrum: Pathophysiology and Emerging Therapies
2023, Pediatric Neurology
The development of the central nervous system can be directly disrupted by a variety of acquired factors, including infectious, inflammatory, hypoxic-ischemic, and toxic insults. Influences external to the fetus also impact neurodevelopment, including placental health, maternal comorbidities, adverse experiences, environmental exposures, and social determinants of health. Acquired perinatal brain insults tend to affect the developing brain in a stage-specific manner that reflects the susceptible cell types, developmental processes, and risk factors present at the time of the insult. In this review, we discuss the pathophysiology, neurodevelopmental outcomes, and management of common acquired perinatal brain conditions. In the fetal brain, we divide insults based on trimester, and in the postnatal brain, we focus on common pathologies that have a presentation dependent on gestational age at birth: white matter injury and germinal matrix hemorrhage/intraventricular hemorrhage in preterm infants and hypoxic-ischemic encephalopathy in term infants. Although specific treatments for fetal and newborn brain disorders are currently limited, we emphasize therapies in preclinical or early clinical phases of the development pipeline. The growing number of novel cell type- and stage-specific emerging therapies suggests that in the near future we may have a dramatically improved ability to treat acquired perinatal brain disorders and to mitigate the associated neurodevelopmental consequences.
Placental pathology as a marker of brain injury in infants with hypoxic ischemic encephalopathy
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Citation Excerpt :
Hayes et al. have reported a higher incidence of sentinel events in mild HIE compared to moderate-severe HIE, similar to our cohort [35]. Parker et al. reported sentinel events to be more common in infants with moderate-severe HIE undergoing hypothermia compared to infants with only acidemia [41]. Two studies have reported a lower incidence of placental inflammation and funisitis in the presence of sentinel events in infants with HIE, similar to our result [20,21].
Hypoxic Ischemic Encephalopathy (HIE) can lead to devastating consequences for the affected infant. Although therapeutic cooling benefits infants with moderate and severe HIE, differentiating mild from moderate-severe HIE may be challenging. The placenta reflects the fetal intrauterine environment and may reveal underlying processes that affect brain injury.
To describe placental histopathology using the Amsterdam Placental Workshop Group Criteria in different grades of HIE.
Retrospective cohort.
Infants admitted to a tertiary care neonatal intensive care unit with a diagnosis of HIE between 2011 and 2016.
Maternal and neonatal clinical variables and placental histopathology using the Amsterdam Placental Workshop Group Criteria were compared between mild and moderate-severe HIE. Mann-Whitney or t-test or ꭓ² were performed for bivariate associations as appropriate. To explain the relationship between placental pathology and severity of HIE odds ratios (ORs) and 95 % confidence intervals (CIs) were calculated using logistic regression models.
Of the 73 infants in the study, 23 had mild and 50 moderate-sever HIE. There was no difference in maternal and neonatal characteristics except for sentinel events which were higher in the moderate- severe group. On placental histopathology, acute inflammation, including fetal inflammatory reaction (FIR) were significantly higher in the moderate-severe group. After adjusting for confounders, FIR remained significantly associated with moderate-severe HIE, ORs 6.29, 95 % CI 1.5–25.
Our study demonstrates FIR in the placenta is associated with severity of HIE.
Trends of neonatal hypoxic-ischemic encephalopathy prevalence and associated risk factors in the United States, 2010 to 2018
2022, American Journal of Obstetrics and Gynecology
Citation Excerpt :
Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most common causes of neonatal morbidity and mortality.1,2 The incidence of HIE is 1 to 3 in 1000 live births in developed countries3–6; the incidence of HIE is approximately 10 times higher in resource-limited countries.7,8 The overall mortality rate of HIE is 15% to 25% with 40% to 50% of survivors developing long-term neurologic disabilities.4–6,8
Despite recent advances in perinatal care, neonatal hypoxic-ischemic encephalopathy remains one of the most common causes of neonatal morbidity and mortality. The trends for prevalence and mortality of neonatal hypoxic-ischemic encephalopathy have not been examined in the era of therapeutic hypothermia in the United States.
This study aimed to determine (1) the overall and gestational age–specific (35–36, ≥37, and >42 weeks) trends of hypoxic-ischemic encephalopathy prevalence and use of therapeutic hypothermia, (2) the trends of mortality in association with hypoxic-ischemic encephalopathy, (3) the confounding variables associated with hypoxic-ischemic encephalopathy, and (4) the clinical outcomes of neonates with hypoxic-ischemic encephalopathy.
This study used National Inpatient Sample datasets from 2010 to 2018. Moreover, the study included infants with a gestational age of ≥35 weeks with a documented hypoxic-ischemic encephalopathy diagnosis (mild, moderate, severe, or unspecified). We calculated trends in hypoxic-ischemic encephalopathy prevalence and the use of therapeutic hypothermia using chi-squared testing. Furthermore, this study used logistic regression models to control for confounders.
A total of 32,180,617 infants were included, of which 31,249,100 were term (gestational age of ≥37 weeks) and 931,517 were late preterm (gestational age of 35–36 weeks). Hypoxic-ischemic encephalopathy prevalence slightly increased from 0.093% in 2010–2012 to 0.097% in 2016–2018 (P=.01) in term infants and did not significantly change in late preterm infants (P=.20). There were 6235 term infants (20.8%) and 449 late preterm infants (21.1%) with hypoxic-ischemic encephalopathy who were managed with therapeutic hypothermia. The use of therapeutic hypothermia in both term and late preterm infants has increased over the years (P<.01). The mortality rate with hypoxic-ischemic encephalopathy decreased over time from 11.5% to 12.3% between 2010 to 2012, and from 8.3% to 10.6% betweenn 2016 to 2018 (P<.01). The factors with the strongest association with hypoxic-ischemic encephalopathy were placental infarction or insufficiency (odds ratio, 144; 95% confidence interval, 134–157), placental abruption (odds ratio, 101; 95% confidence interval, 91–112), cord prolapse (odds ratio, 74; 95% confidence interval, 65–84), and maternal anemia (odds ratio, 26; 95% confidence interval, 20–37).
Hypoxic-ischemic encephalopathy prevalence in neonates essentially remained the same at 1 per 1000 live births. The use of therapeutic hypothermia increased, and the mortality rate decreased in infants with hypoxic-ischemic encephalopathy. The identification of hypoxic-ischemic encephalopathy–associated factors should promote increased vigilance to optimize newborn outcomes.
Acute kidney injury in infants with hypoxic-ischemic encephalopathy
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View all citing articles on Scopus

: Funded by the University of California San Francisco (UCSF) National Center of Excellence in Women's Health, through the UCSF Resource Allocation Program. Y.W. provided expert witness testimony in medicolegal cases involving hypoxic-ischemic encephalopathy. E.H. is an obstetrician and senior scientist at Perigen, a company that creates perinatal software. The other authors declare no conflicts of interest.

: Portions of this study were presented at the Pediatric Academic Societies annual meeting, April 30-May 3, 2016, Baltimore, Maryland.

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Original ArticlesAntenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort

Objective

Study design

Results

Conclusions

Section snippets

Methods

Results

Discussion

Early Hum Dev

Am J Obstet Gynecol

Lancet

Am J Obstet Gynecol

Pediatr Neurol

Eur J Paediatr Neurol

J Pediatr

J Pediatr

Lancet

Pediatr Neurol

Exp Neurol

Am J Obstet Gynecol

Hum Pathol

Am J Obstet Gynecol

Pediatr Neurol

Childhood outcomes after hypothermia for neonatal encephalopathy

N Engl J Med

Intrapartum risk factors for newborn encephalopathy: the Western Australian case-control study [see comments]

BMJ

Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study

BMJ

Antenatal antecedents of moderate or severe neonatal encephalopathy in term infants—a regional review

Aust N Z J Obstet Gynaecol

Antecedents of neonatal encephalopathy in the Vermont Oxford Network Encephalopathy Registry

Pediatrics

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

Am J Obstet Gynecol

Antepartum and intrapartum factors preceding neonatal hypoxic-ischemic encephalopathy

Pediatrics

Obstetric antecedents to body-cooling treatment of the newborn infant

Am J Obstet Gynecol

Antepartum and intrapartum risk factors for neonatal encephalopathy at term

Am J Perinatol

JCAHO issues warning on kernicterus danger

Hosp Peer Rev

Patterns of brain injury in neonates exposed to perinatal sentinel events

Pediatrics

Does aetiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy influence the outcome of treatment?

Dev Med Child Neurol

Short-term outcomes after perinatal hypoxic ischemic encephalopathy: a report from the Children's Hospitals Neonatal Consortium HIE focus group

J Perinatol

Association and prediction of neonatal acidemia

Am J Obstet Gynecol

The limits of electronic fetal heart rate monitoring in the prevention of neonatal metabolic acidemia

Am J Obstet Gynecol

Fetal acidemia and electronic fetal heart rate patterns: is there evidence of an association?

J Matern Fetal Neonatal Med

Strength of association between umbilical cord pH and perinatal and long term outcomes: systematic review and meta-analysis

BMJ

Original Articles
Antenatal and Intrapartum Risk Factors for Hypoxic-Ischemic Encephalopathy in a US Birth Cohort