Objective
We sought to describe placental findings in asphyxiated term newborns meeting therapeutic hypothermia criteria and to assess whether histopathologic correlation exists between these placental lesions and the severity of later brain injury.
Study Design
We conducted a prospective cohort study of the placentas of asphyxiated newborns, in whom later brain injury was defined by magnetic resonance imaging.
Results
A total of 23 newborns were enrolled. Eighty-seven percent of their placentas had an abnormality on the fetal side of the placenta, including umbilical cord lesions (39%), chorioamnionitis (35%) with fetal vasculitis (22%), chorionic plate meconium (30%), and fetal thrombotic vasculopathy (26%). A total of 48% displayed placental growth restriction. Chorioamnionitis with fetal vasculitis and chorionic plate meconium were significantly associated with brain injury ( P = .03). Placental growth restriction appears to significantly offer protection against the development of these injuries ( P = .03).
Conclusion
Therapeutic hypothermia may not be effective in asphyxiated newborns whose placentas show evidence of chorioamnionitis with fetal vasculitis and chorionic plate meconium.
The pathogenesis of neonatal hypoxic-ischemic brain injury is still not completely understood. It is unclear why newborns with similar degrees of perinatal depression can develop very different degrees of brain injury. Moreover, it is currently not known why therapeutic hypothermia, which is the most widely accepted neuroprotective strategy to minimize brain injury in asphyxiated term newborns, seems effective in decreasing brain injury in some asphyxiated newborns but does not prevent all brain injuries.
The placenta is a partial reflection of the fetal environment and may reveal underlying processes (eg, inflammation, hypoxia) that directly affect the development of brain injury. Antenatal processes in the placenta might contribute directly or indirectly to perinatal brain injury by impairing reserve, altering fetal physiologic condition, and generating potentially neurotoxic mediators. Therefore, close examination of placentas derived from pregnancies complicated by perinatal hypoxic-ischemic conditions may offer some explanation. Five major pathologic processes have been described to involve fetal placental vessels: ie, fetal thrombotic vasculopathy, pathologic umbilical cord lesions, villitis of unknown origin with or without obliterative fetal vasculopathy, chorioamnionitis with or without severe fetal vasculitis, and chorionic plate meconium. All of these pathologic processes have been linked with perinatal brain injury ; however the cause-effect relationship between these placental pathologies and the development of brain injury remains unclear.
This study was designed to: (1) describe the spectrum of placental findings in asphyxiated term newborns meeting the criteria for induced hypothermia; (2) assess how often these pathologic processes impact the fetal vascular supply in these newborns; and (3) determine whether a histopathologic correlation can be drawn between these lesions and the severity of later brain injury that developed in these patients.
Materials and Methods
We conducted a prospective cohort study of the placentas of term newborns with hypoxic-ischemic encephalopathy admitted to the neonatal intensive care unit who met the criteria for induced hypothermia : (1) gestational age ≥36 weeks and birthweight ≥2000 g; (2) evidence of fetal distress, eg, history of acute perinatal event, biophysical profile <6/10 (or 4/8) within 6 hours of birth, cord pH ≤7.0 or base deficit ≥16 mEq/L; (3) evidence of neonatal distress, such as Apgar score ≤5 at 10 minutes, postnatal blood gas pH obtained within the first hour of life ≤7.0 or base deficit ≥16 mEq/L, or continued need for ventilation initiated at birth and continued for at least 10 minutes; (4) evidence of neonatal encephalopathy by physical examination; and (5) abnormal amplitude-integrated electroencephalogram. Eligible patients received whole-body cooling to an esophageal temperature of 33.5°C, initiated by 6 hours of life and continued for 72 hours (unless contraindications developed), and then were slowly rewarmed. Clinical data were collected prospectively for each patient and included gestational age, birthweight, sex, Apgar score at 10 minutes, arterial cord pH, need of cardiopulmonary resuscitation, rate of cardiopulmonary resuscitation and intubation, and initial blood gas pH. Resuscitation score and onset of hypothermia in hours were also calculated and recorded.
Severity of brain injury was defined by magnetic resonance imaging (MRI) results. To define the exact extent of the brain injuries, ≥1 brain MRI was obtained during the first month of life. The MRI results were categorized as abnormal or normal depending on whether or not they showed MRI evidence for hypoxic-ischemic brain injury. Neuroradiologists, who were blinded to the clinical condition of the newborns, interpreted the brain MRI images.
Placentas were brought with the infants at the time of transport or collected from the pathology department of the referring hospitals. A single pathologist, who was blinded to the clinical condition of the infants, examined all the placentas. Macroscopic and microscopic pathologic findings were reported. Among macroscopic findings, the diagnosis of placental abruptio was made if there was clinical evidence of a retroplacental hematoma at birth plus evidence of retroplacental blood with or without intervillous extension found on histological examination. Placental previa was a clinical diagnosis made at birth. The 5 previously described microscopic placental findings that involve the fetal vascular supply were also categorized by the pathologist. Fetal thrombotic vasculopathy was diagnosed by the presence of chorionic plate and/or stem villus thrombi, clusters of avascular villi and/or clusters of villi with villous-stromal karyorrhexis. Villitis of unknown etiology was characterized by a maternal lymphohistiocytic infiltrate within villi. A diagnosis of chorioamnionitis was made if a maternal inflammatory response was noted near venules in the decidua capsularis and in the subchorionic fibrin above the intervillous space and subsequently spread into the adjacent chorion and amnion. Fetal vasculitis associated with chorioamnionitis was added as an entity if a fetal neutrophilic response to infection was also observed in the umbilical and chorionic vessels. Chorionic plate meconium was defined by the presence of meconium-laden macrophages, which are histiocytes that engulf meconium, in the chorionic plate.
The trimmed weight of each placenta was measured according to standard guidelines and reported on percentile curves according to gestational age.
Maximum nucleated red blood cell (nRBC) count in each newborn was also recorded, as an indicator of significant intrauterine stress. We used 2 different cutoffs for recording the nRBC elevations. A value >1000 nRBC/mm 3 was considered elevated as per standard guidelines. The higher cutoff >2500 nRBC/mm 3 was also considered separately, as previously associated with placental lesions in term newborns who develop cerebral palsy.
Statistical analysis was performed to assess differences between newborns with and without MRI evidence of hypoxic-ischemic brain injury. The analysis focused on examining the data for correlations between placental pathologies and presence or not of brain injury on MRI. Fisher’s exact test was used for categorical data and t test for continuous data. A P value < .05 was considered significant.
Results
A total of 23 term neonates with perinatally acquired hypoxic-ischemic encephalopathy met the criteria for hypothermia treatment and were enrolled in the study ( Table 1 ). Among these 23 newborns, 7 developed significant MRI evidence of hypoxic-ischemic injury involving basal ganglia in 86% (6/7) of these newborns and cortical gray matter and white matter in 57% (6/7) of these newborns ( Table 2 ); and 16 did not ( Table 2 ). In addition, 1 newborn had a component of intracranial hemorrhage, 2 had petechial hemorrhages in the periventricular white matter, and 1 had a nonocclusive dural venous sinus thrombosis. There were no significant differences in the clinical characteristics between the 7 newborns with and the 16 without MRI evidence of hypoxic-ischemic brain injury ( Table 1 ).
| Characteristic | All asphyxiated newborns meeting criteria for induced hypothermia (n = 23) | Asphyxiated newborns with MRI evidence of hypoxic-ischemic brain injury (n = 7) | Asphyxiated newborns without MRI evidence of hypoxic-ischemic brain injury (n = 16) | P value |
|---|---|---|---|---|
| Gestational age, wk | 39.4 ± 1.2 | 39.8 ± 0.8 | 39.3 ± 1.4 | .27 |
| Birthweight, g | 3385 ± 408 | 3578 ± 291 | 3301 ± 431 | .09 |
| Sex, n (%) | 1.00 | |||
| Male | 13 (57) | 4 (57) | 9 (56) | |
| Female | 10 (43) | 3 (43) | 7 (44) | |
| Apgar score ≤5 at 10 min | 18 (78) | 7 (100) | 11 (69) | .27 |
| Arterial cord pH | 6.9 ± 0.2 | 6.8 ± 0.3 | 6.9 ± 0.2 | .96 |
| Resuscitation score | 5.1 ± 1.2 | 5.8 ± 0.5 | 5.0 ± 1.3 | .52 |
| Need of CPR, n (%) | 14 (61) | 5 (71) | 9 (56) | .65 |
| CPR and intubation | 14 (61) | 5 (71) | 9 (56) | .65 |
| Initial postnatal blood gas pH | 7.1 ± 0.2 | 7.1 ± 0.3 | 7.1 ± 0.2 | .66 |
| Onset of hypothermia, h | 4.5 ± 1.2 | 4.8 ± 1.5 | 4.4 ± 1.1 | .44 |
| Patient no. | Outcome on brain MRI |
|---|---|
| 1 |
|
| 2 | − No MRI evidence for hypoxic-ischemic injury |
| 3 | − No MRI evidence for hypoxic-ischemic injury |
| 4 | − No MRI evidence for hypoxic-ischemic injury |
| 5 | − No MRI evidence for hypoxic-ischemic injury |
| 6 | − No MRI evidence for hypoxic-ischemic injury |
| 7 | − No MRI evidence for hypoxic-ischemic injury |
| 8 | − No MRI evidence for hypoxic-ischemic injury |
| 9 |
|
| 10 | − No MRI evidence for hypoxic-ischemic injury |
| 11 | − No MRI evidence for hypoxic-ischemic injury |
| 12 | − No MRI evidence for hypoxic-ischemic injury |
| 13 |
|
| 14 | − No MRI evidence for hypoxic-ischemic injury |
| 15 | − No MRI evidence for hypoxic-ischemic injury |
| 16 |
|
| 17 | − MRI evidence for hypoxic-ischemic injury in BG |
| 18 | − MRI evidence for hypoxic-ischemic injury in BG |
| 19 | − MRI evidence for hypoxic-ischemic injury in BG |
| 20 | − MRI evidence for hypoxic-ischemic injury in CGM + WM + BG |
| 21 | − MRI evidence for hypoxic-ischemic injury in CGM + WM + BG |
| 22 | − MRI evidence for hypoxic-ischemic injury in CGM + WM |
| 23 | − MRI evidence for hypoxic-ischemic injury in CGM + WM + BG |
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