Introduction
Neonatal encephalopathy (NE) is a syndrome of disturbed neurologic function in the earliest days of life, manifested by a subnormal level of consciousness or seizures and depression of tone and reflexes, and is often accompanied by difficulty with initiating and maintaining respiration in neonates with evidence of perinatal hypoxia-asphyxia. Epidemiological studies have shown that placental pathology is associated with NE, and when present, it doubles the risk of NE. Placental lesions such as chorioamnionitis are also associated with childhood disabilities, including cerebral palsy. In the past, studies of the role of placental pathologies in the newborn with asphyxia have been limited by methodological design, including small sample sizes and, most importantly, a lack of uniform reporting of the placental histopathology. To address this, new guidelines for placental pathology have been suggested, emphasizing a new classification of findings into categories consistent with: (1) amniotic fluid infection (chorioamnionitis, with or without fetal responses), (2) maternal under perfusion (infarction, fibrin, placental hypoplasia), and (3) fetal vascular thromboocclusive disorders (placental vascular thrombosis). While some studies have used this objective classification to correlate placental pathologies in NE, they only examined early magnetic resonance imaging (MRI) outcomes. Thus, it is unclear if placental pathologic findings using a uniform classification are associated with the severity of NE identified during the immediate neonatal period but also later in terms of neurodevelopmental outcome (NDO). The objectives of this large retrospective cohort study were to determine the association of placental pathology with: (1) severity of NE in the first 6 hours after birth, and (2) abnormal NDO in neonates requiring systemic hypothermia therapy.
Materials and Methods
Study design
This cohort included all neonates born with a gestational age of ≥36 weeks and birthweight of >1800 g admitted to the neonatal intensive care unit (ICU) at Parkland Hospital, Dallas, TX, from January 2006 through November 2011 with evidence of perinatal acidosis and varying degrees of NE determined using a standardized neurological examination; in addition, all neonates had gross and histologic evaluation of their placenta. All the neonates were inborn at Parkland Hospital. The study met the Health Insurance Portability and Accountability Act requirements, and the institutional review board of the University of Texas Southwestern Medical Center approved the acquisition and review of the clinical data. The medical charts were reviewed, and the following data were recorded: need for and extent of delivery room resuscitation, ie, the need for chest compressions ± medications; Apgar scores at 1, 5, and 10 minutes; umbilical arterial blood gas parameters; first arterial blood gas after ICU admission; presence of NE by standard neurologic exam; death; whether or not qualified for and received systemic hypothermia therapy; presence and type of placental pathology; and NDO at follow-up.
Placental pathology
Placentas from all the infants included in the study were sent to the pathology department and examined. Placentas associated with specific maternal-fetal complications seen in pregnancy, including thick meconium in amniotic fluid, nonreassuring fetal heart rate pattern, infant depression at birth, and need for presence of the neonatal resuscitation team, are routinely collected in the delivery suite at Parkland Hospital for gross and histologic examination by a pediatric pathologist according to a specific protocol. Initial gross examination of the umbilical cord, membranes, and placental disc is performed. Placental weight is obtained after removal of the umbilical cord, fetal membranes, and nonadherent blood clots. The placental disc is then serially sectioned at 1- to 2-cm intervals and examined for intraparenchymal lesions. Representative sections of the umbilical cord, fetal membranes, normal placental parenchyma, and any abnormalities seen on gross exam are submitted for standard histological examination. The group of pathologists at our institution use the Redline classification for major placental findings and use the diagnostic terminology for placental lesions tested in the 2005 Redline paper. A representative set of placentas (n = 30) were randomly chosen by a pediatric pathologist (F.J-W.), who reassessed the histology while blinded to the placental reports, clinical history, and the outcomes. This was matched with the pathology report and resulted in 100% concordance. The random review of 30 placentas was done to validate the initial pathologist’s reading. Placental pathologies were classified into (1) chorioamnionitis with or without fetal response, (2) chronic villitis of unknown origin (VUE) with or without obliterative fetal vasculopathy, (3) fetal vascular thromboocclusive disease, and 4) maternal placental under perfusion. A priori definition of a “major placental pathology” was determined by an independent pathologist blinded to clinical outcomes. This definition was standardized at our institution and excludes the minor placental pathology in each major category of placental pathologies that show little or no clinical consequence and are present in most of the placental histological examinations of normal term neonates. The definition of major pathology includes the following placental lesions: (1) increased intervillous fibrin deposition/retroplacental hemorrhage/infarction involving ≥20% of placental volume, (2) fetal vascular thromboocclusive disease with >1 focus of avascular villi/thrombotic vasculopathy, (3) patchy/diffuse chronic villitis with or without obliterative fetal vasculopathy, (4) chorioamnionitis with/without fetal response, and (5) small for gestational age/large for gestational age placentas. Chronic villitis consists of chronic inflammation of chorionic villi. The etiology of chronic villitis appears to be immune-mediated and consists of chronic inflammation of the chorionic villi characterized as lymphohistiocytic infiltration of the villous tree. This inflammation is traditionally classified into low-grade villitis (focal/multifocal villitis) and high-grade villitis (patchy/diffuse villitis). Low-grade lesions include focal villitis, a small cluster of ≤10 affected villi, and multifocal villitis, ≥2 small clusters of ≤10 affected villi. High-grade lesions included patchy villitis defined as a large cluster of >10 affected villi but ≤25% of the terminal villi plus diffuse villitis and the presence of extensive inflammation with multiple large clusters present on all slides.
Assessment of severity of the encephalopathy
Umbilical artery blood samples are routinely collected from a double-clamped section of the umbilical cord for all deliveries at Parkland Hospital; furthermore, a recent review from our department demonstrated that >90% of deliveries had a sample analyzed. The presence of perinatal acidemia and the type was determined from the arterial pH, partial pressure of carbon dioxide, and base deficit; validation of an arterial sample was the presence of an arterial partial pressure of oxygen <29 mm Hg. Newborns with fetal acidemia were identified using the same criteria used to nbsp; screen for NE as described by Shankaran et al in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. These criteria included a pH of ≤7.0 or a base deficit of ≥16 mEq/L in umbilical artery blood or any postnatal blood sample within 1 hour of age. An infant with a history of an acute perinatal event and no blood gas available or a pH from 7.01-7.15 or a base deficit from 10-15.9 mEq/L, with a 10-minute Apgar score of ≤5, or assisted ventilation initiated at birth and continued for at least 10 minutes was also included.
The neurological examination consisted of modified Sarnat staging done by neonatal faculty certified by a gold standard examiner in a standardized manner. Specifically, the physical examination assessed: (1) level of consciousness, (2) spontaneous activity, (3) posture, (4) tone, (5) primitive reflexes, and (6) autonomic nervous system. The hypothermia group was comprised of newborns with a composite exam (at least 3 of 6 categories) consistent with a diagnosis of moderate or severe encephalopathy. Hypothermia was maintained for 72 hours using a cooling blanket (Blanketrol II; Cincinnati Sub-Zero, Cincinnati, OH) and maintaining the esophageal temperature at 33.5°C by the blanket servomechanism. The mild encephalopathy group included newborns with 1-2 abnormal categories in the neurological assessment, who did not meet criteria for hypothermia and received routine supportive care.
Neurodevelopmental follow-up
The primary outcome was predefined as a composite of death or moderate to severe delays in neurodevelopment ≤24 months of age. A moderate delay was defined by Bayley-III 1-2 SD below the normal, that is, lowest composite score of 70-84 in any of the 3 domains: cognitive, language, and motor. Severe delay was defined as any Bayley-III composite score >2 SD below normal, that is, <70 on any of the 3 tested domains or a complete inability to assign a score owing to severe mental deficiency or cerebral palsy. MRI was performed in all cooled infants between 5-14 days of life including sagittal, axial T1, and axial T2 imaging as per clinical protocol.
Neurodevelopmental testing was performed at the Children’s Medical Center of Dallas in the Neonatal Follow-up Clinic using the Bayley-III. The assessments were administered by a trained pediatric developmental specialist with 11 years of experience, in conjunction with a neurodevelopmental pediatrician with 25 years of experience. Both were blinded to the patients’ neonatal course and were assisted by a certified translator-interpreter for non-English-speaking subjects.
Statistical analysis
Continuous data were summarized with either a mean ± SD or median with interquartile ranks (25th-75th percentile), and categorical data were summarized according to the percent of the population. Data for cooled infants are presented as moderate and severe encephalopathy combined due to the expected small number of cases with severe encephalopathy. Primary analysis of the data used a χ 2 analysis or Fisher exact test for categorical data, and Mann-Whitney rank sum test when for continuous data. The significance level was P < .05. Univariate logistic regression model was used to evaluate the odds of having an abnormal outcome by Bayley score in the secondary analysis. The variables were selected with a cutoff of .05 and evaluating the correlation between the variables. If a Spearman correlation was high then only 1 variable was included in the logistic regression.
Materials and Methods
Study design
This cohort included all neonates born with a gestational age of ≥36 weeks and birthweight of >1800 g admitted to the neonatal intensive care unit (ICU) at Parkland Hospital, Dallas, TX, from January 2006 through November 2011 with evidence of perinatal acidosis and varying degrees of NE determined using a standardized neurological examination; in addition, all neonates had gross and histologic evaluation of their placenta. All the neonates were inborn at Parkland Hospital. The study met the Health Insurance Portability and Accountability Act requirements, and the institutional review board of the University of Texas Southwestern Medical Center approved the acquisition and review of the clinical data. The medical charts were reviewed, and the following data were recorded: need for and extent of delivery room resuscitation, ie, the need for chest compressions ± medications; Apgar scores at 1, 5, and 10 minutes; umbilical arterial blood gas parameters; first arterial blood gas after ICU admission; presence of NE by standard neurologic exam; death; whether or not qualified for and received systemic hypothermia therapy; presence and type of placental pathology; and NDO at follow-up.
Placental pathology
Placentas from all the infants included in the study were sent to the pathology department and examined. Placentas associated with specific maternal-fetal complications seen in pregnancy, including thick meconium in amniotic fluid, nonreassuring fetal heart rate pattern, infant depression at birth, and need for presence of the neonatal resuscitation team, are routinely collected in the delivery suite at Parkland Hospital for gross and histologic examination by a pediatric pathologist according to a specific protocol. Initial gross examination of the umbilical cord, membranes, and placental disc is performed. Placental weight is obtained after removal of the umbilical cord, fetal membranes, and nonadherent blood clots. The placental disc is then serially sectioned at 1- to 2-cm intervals and examined for intraparenchymal lesions. Representative sections of the umbilical cord, fetal membranes, normal placental parenchyma, and any abnormalities seen on gross exam are submitted for standard histological examination. The group of pathologists at our institution use the Redline classification for major placental findings and use the diagnostic terminology for placental lesions tested in the 2005 Redline paper. A representative set of placentas (n = 30) were randomly chosen by a pediatric pathologist (F.J-W.), who reassessed the histology while blinded to the placental reports, clinical history, and the outcomes. This was matched with the pathology report and resulted in 100% concordance. The random review of 30 placentas was done to validate the initial pathologist’s reading. Placental pathologies were classified into (1) chorioamnionitis with or without fetal response, (2) chronic villitis of unknown origin (VUE) with or without obliterative fetal vasculopathy, (3) fetal vascular thromboocclusive disease, and 4) maternal placental under perfusion. A priori definition of a “major placental pathology” was determined by an independent pathologist blinded to clinical outcomes. This definition was standardized at our institution and excludes the minor placental pathology in each major category of placental pathologies that show little or no clinical consequence and are present in most of the placental histological examinations of normal term neonates. The definition of major pathology includes the following placental lesions: (1) increased intervillous fibrin deposition/retroplacental hemorrhage/infarction involving ≥20% of placental volume, (2) fetal vascular thromboocclusive disease with >1 focus of avascular villi/thrombotic vasculopathy, (3) patchy/diffuse chronic villitis with or without obliterative fetal vasculopathy, (4) chorioamnionitis with/without fetal response, and (5) small for gestational age/large for gestational age placentas. Chronic villitis consists of chronic inflammation of chorionic villi. The etiology of chronic villitis appears to be immune-mediated and consists of chronic inflammation of the chorionic villi characterized as lymphohistiocytic infiltration of the villous tree. This inflammation is traditionally classified into low-grade villitis (focal/multifocal villitis) and high-grade villitis (patchy/diffuse villitis). Low-grade lesions include focal villitis, a small cluster of ≤10 affected villi, and multifocal villitis, ≥2 small clusters of ≤10 affected villi. High-grade lesions included patchy villitis defined as a large cluster of >10 affected villi but ≤25% of the terminal villi plus diffuse villitis and the presence of extensive inflammation with multiple large clusters present on all slides.
Assessment of severity of the encephalopathy
Umbilical artery blood samples are routinely collected from a double-clamped section of the umbilical cord for all deliveries at Parkland Hospital; furthermore, a recent review from our department demonstrated that >90% of deliveries had a sample analyzed. The presence of perinatal acidemia and the type was determined from the arterial pH, partial pressure of carbon dioxide, and base deficit; validation of an arterial sample was the presence of an arterial partial pressure of oxygen <29 mm Hg. Newborns with fetal acidemia were identified using the same criteria used to nbsp; screen for NE as described by Shankaran et al in the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. These criteria included a pH of ≤7.0 or a base deficit of ≥16 mEq/L in umbilical artery blood or any postnatal blood sample within 1 hour of age. An infant with a history of an acute perinatal event and no blood gas available or a pH from 7.01-7.15 or a base deficit from 10-15.9 mEq/L, with a 10-minute Apgar score of ≤5, or assisted ventilation initiated at birth and continued for at least 10 minutes was also included.
The neurological examination consisted of modified Sarnat staging done by neonatal faculty certified by a gold standard examiner in a standardized manner. Specifically, the physical examination assessed: (1) level of consciousness, (2) spontaneous activity, (3) posture, (4) tone, (5) primitive reflexes, and (6) autonomic nervous system. The hypothermia group was comprised of newborns with a composite exam (at least 3 of 6 categories) consistent with a diagnosis of moderate or severe encephalopathy. Hypothermia was maintained for 72 hours using a cooling blanket (Blanketrol II; Cincinnati Sub-Zero, Cincinnati, OH) and maintaining the esophageal temperature at 33.5°C by the blanket servomechanism. The mild encephalopathy group included newborns with 1-2 abnormal categories in the neurological assessment, who did not meet criteria for hypothermia and received routine supportive care.
Neurodevelopmental follow-up
The primary outcome was predefined as a composite of death or moderate to severe delays in neurodevelopment ≤24 months of age. A moderate delay was defined by Bayley-III 1-2 SD below the normal, that is, lowest composite score of 70-84 in any of the 3 domains: cognitive, language, and motor. Severe delay was defined as any Bayley-III composite score >2 SD below normal, that is, <70 on any of the 3 tested domains or a complete inability to assign a score owing to severe mental deficiency or cerebral palsy. MRI was performed in all cooled infants between 5-14 days of life including sagittal, axial T1, and axial T2 imaging as per clinical protocol.
Neurodevelopmental testing was performed at the Children’s Medical Center of Dallas in the Neonatal Follow-up Clinic using the Bayley-III. The assessments were administered by a trained pediatric developmental specialist with 11 years of experience, in conjunction with a neurodevelopmental pediatrician with 25 years of experience. Both were blinded to the patients’ neonatal course and were assisted by a certified translator-interpreter for non-English-speaking subjects.
Statistical analysis
Continuous data were summarized with either a mean ± SD or median with interquartile ranks (25th-75th percentile), and categorical data were summarized according to the percent of the population. Data for cooled infants are presented as moderate and severe encephalopathy combined due to the expected small number of cases with severe encephalopathy. Primary analysis of the data used a χ 2 analysis or Fisher exact test for categorical data, and Mann-Whitney rank sum test when for continuous data. The significance level was P < .05. Univariate logistic regression model was used to evaluate the odds of having an abnormal outcome by Bayley score in the secondary analysis. The variables were selected with a cutoff of .05 and evaluating the correlation between the variables. If a Spearman correlation was high then only 1 variable was included in the logistic regression.
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