Objective
Obstetric antecedents were analyzed in births in which the infant received whole-body cooling for neonatal encephalopathy.
Study Design
This retrospective cohort study included all live-born singleton infants delivered at or beyond 36 weeks’ gestation from October 2005 through December 2011. Infants who had received whole-body cooling identified by review of a prospective neonatal registry were compared with a control group comprising the remaining obstetric population delivered at greater than 36 weeks but not cooled. Univariable analysis was followed up by a staged, stepwise selection of variables with the intent to rank significant risk factors for cooling.
Results
A total of 86,371 women delivered during the study period and 98 infants received whole-body cooling (1.1 per 1000 live births). Of these 98 infants, 80 newborns (88%) had moderate encephalopathy and 10 (12%) had severe encephalopathy prior to cooling. Maternal age of 15 years or younger, low parity, maternal body habitus (body mass index of ≥40 kg/m 2 ), diabetes, preeclampsia, induction, epidural analgesia, chorioamnionitis, length of labor, and mode of delivery were associated with significantly increased risk of infant cooling during a univariable analysis. Catastrophic events to include umbilical cord prolapse (odds ratio [OR], 14; 95% confidence interval [CI], 3–72), placental abruption (OR, 17; 95% CI, 7–44), uterine rupture (OR, 130; 95% CI, 11–1477) were the strongest factors associated with infant cooling after staged-stepwise logistic analysis.
Conclusion
A variety of intrapartum characteristics were associated with infant cooling for neonatal encephalopathy, with the most powerful antecedents being umbilical cord prolapse, placental abruption, and uterine rupture.
Ten years ago, the American College of Obstetricians and Gynecologists and the American Academy of Pediatrics welcomed the findings of the Task Force on Neonatal Encephalopathy and Cerebral Palsy. The members of this task force defined neonatal encephalopathy and its subset of hypoxic-ischemic encephalopathy (HIE) as a combination of abnormal consciousness, tone and reflexes, feeding, respiration, or seizures in term and near-term infants. The prevalence of fetal asphyxia in the term infant was reported as 25 per 1000 live births, and of these, 15% were either moderate or severe (3.75 per 1000 live births). Until recently, the prognosis for moderately-affected infants was poor with a 10% risk of death and 30% risk of neurological disability among survivors. These adverse outcomes were further increased for those severely affected with a 60% risk of death and near universal risk of neurological disability.
The profound impact of neonatal encephalopathy on infant morbidity and mortality stimulated research aimed at mitigating these infant consequences. Experiments in animals beginning in the late 1990s suggested that reducing brain temperature 2-5°C after an inciting event could reduce the incidence of cerebral damage resulting from neonatal encephalopathy. These findings led to several studies worldwide to determine whether brain cooling administered to infants suffering neonatal encephalopathy could ameliorate the development of subsequent cerebral palsy. Gluckman et al reported in early 2005 a randomized trial of head cooling vs conventional care without cooling in 234 term infants. In another trial by Shankaran et al reported in late 2005, 239 term infants with neonatal encephalopathy were randomized to whole-body cooling or usual care. The rate of death or moderate to severe cerebral palsy was 44% in the cooled group compared with 62% in the control group ( P = .01). These studies and others that subsequently followed in more than 1000 newborns have served to emphasize that rigorously defined neonatal encephalopathy at birth is a marker for fetal hypoxemia-ischemia severe enough to lead to cerebral palsy later in life.
We reasoned that infants qualifying for body cooling might serve as a surrogate for identifying obstetric antecedents associated with neonatal encephalopathy at birth. Obstetric antecedents were analyzed according to 4 subgroups to include maternal demographics, antepartum obstetric characteristics, intrapartum characteristics, and infant characteristics in the delivery room.
Materials and Methods
This retrospective study included infants born at Parkland Hospital (Dallas, TX) from October 2005 through December 2011. Parkland Hospital is a public supported institution serving Dallas County, TX, and has a level IV neonatal intensive care unit adjacent to the labor and delivery units. The obstetrics service is staffed by house officers and faculty of the Department of Obstetrics and Gynecology at the University of Texas Southwestern Medical School. The neonatology service is staffed by house officers and faculty members in the Department of Pediatrics. This analysis included all live-born singleton infants delivered at or beyond 36 0/7 weeks’ gestation.
Two groups of infants were identified. One group included infants who had received whole-body cooling and who were identified by review of a previously described prospective neonatal registry that included infants admitted to the neonatal intensive care unit and who received whole-body cooling. Infants with major malformations, imminent death, or transfer to an outside facility were excluded. Imminent death was defined as occurring or likely to occur within 24 hours of birth rendering hypothermia futile. A control group included the obstetric population of births delivered at or beyond 36 0/7 weeks but who were not treated with cooling. These infants were identified using a preexisting obstetric database for all births at Parkland Hospital.
Nurses attending each delivery complete an obstetric data sheet, and research nurses assessed the data for consistency and completeness before electronic storage. Infant outcomes were abstracted from discharge records. Gestational age was based on the best obstetric estimate using the date of the last menstrual period and ultrasonography. Body mass index (kilograms per square meter) was calculated using the last prenatal clinic weight prior to delivery. Uterine rupture was defined as any through and through disruption of the uterine muscle and serosa as such part of the fetus (ie, part of the fetus, cord, or placenta outside the uterine cavity) at the time of delivery. Placental abruption was defined as abruption noted at the time of delivery by the attendants by presence of the placenta with adherent clot, clot compression of the implantation surface, and with associated obstetrical hemorrhage.
The study protocol was approved by the institutional review board of the University of Texas Southwestern Medical Center at Dallas.
Biochemical screening for acidemia
Umbilical-artery blood samples were routinely obtained in all births from a doubly clamped segment of the umbilical cord into a heparinized 3 mL syringe and placed in ice for transport to the hospital laboratory for the measurement of blood gases. Newborns with fetal acidemia were identified using the same criteria used to screen for neonatal encephalopathy 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 less or a base deficit of 16 mEq/L or greater 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 either no blood gas available or a pH from 7.01 to 7.15 or a base deficit from 10 to 15.9 mEq/L, with a 10 minute Apgar score of 5 or less, or assisted ventilation initiated at birth and continued for at least 10 minutes was also included.
Neurological assessment to identify infants for cooling
If the biochemical evidence of acidemia was met, the newborn received a neurological examination performed by a neonatologist certified to assess eligibility for whole-body cooling. Neonatologists were certified by one study investigator to use the modified Sarnat staging for all infants meeting criteria for fetal acidosis. Certification was obtained through participation in the National Institute of Child Health and Human Development Neonatal Research Network.
Examiners were not blinded prior to performing the examination. Moderate or severe neonatal encephalopathy was classified based on the following: (1) level of consciousness (lethargy; stupor/coma); (2) spontaneous activity (decreased; no activity); (3) posture (distal flexion; complete extension; decerebrate); (4) tone (hypotonic; flaccid); (5) primitive reflexes (weak to absent suck or Moro); and (6) autonomic nervous system signs (pupils [constricted; deviation/dilated/nonreactive to light], heart rate [bradycardia; variable heart rate], and breathing patterns [periodic breathing; apnea]). Each category was scored as 1 (normal or mild), 2 (moderate), or 3 (severe). If the examiner was not definitive in scoring the infant in any particular category (eg, a score of 1-2), the worst score of the 2 was assigned.
Infants were grouped based on how many abnormal categories (0 abnormal, 1 abnormal, or 2 abnormal) they had on the initial neurological examination. If 3 or more categories had a score of 2 or greater, the infant received whole-body cooling. Newborns were cooled for 72 hours using a cooling blanket (Blanketrol II; Cincinnati Sub-Zero, Cincinnati, OH) with an esophageal temperature maintained at 33.5°C by the blanket servomechanism according to the published protocol.
Statistical analysis
Statistical analysis using SAS version 9.2 (SAS Institute Inc, Cary, NC) included χ 2 , Student t test, and multiple logistic regression. A univariable analysis was followed by a staged, stepwise selection of variables with the intent to rank significant predictors of infant cooling by the value of their adjusted odds ratios (ORs). Stepwise selection of variables was sequentially performed for maternal demographics, antepartum, intrapartum, and infant characteristics as multivariable logistic regression. Significance levels for entry and exit of these variables into the model were less than .10 in each case. Levels less than .05 were considered significant for the adjusted analysis.
Results
A total of 86,371 women delivered a singleton, live-born infant at or beyond 36 weeks’ gestation. Ninety-eight infants received whole-body cooling (1.1 per 1000 live births) at a mean age of 4.5 ± 1 hours. Of these 98 infants, 80 (88%) had moderate encephalopathy and 10 (12%) had severe encephalopathy prior to cooling. Ten infants (11%) died in the first week of life from severe multiorgan failure. Cerebral imaging showed watershed or basal ganglia injury in 47% of the survivors. Only 1 infant qualified to receive cooling but did not because this neonate was judged to be terminal with imminent death and died at 8 hours of life from multiple organ failure and cardiovascular arrest.
Univariable analysis of obstetric antecedents for infant cooling
Maternal demographics of women with infants receiving whole-body cooling compared with those in whom infants did not require cooling are shown in Table 1 . Maternal age of 15 years or younger, nulliparity, and maternal body habitus (body mass index of ≥40 kg/m 2 ) were associated with a significantly increased risk of infant cooling. Several antepartum obstetric characteristics, to include pregestational diabetes and preeclampsia, were significantly increased in women with infants requiring cooling ( Table 2 ). Intrapartum obstetric characteristics such as labor induction, epidural analgesia, chorioamnionitis, admission to delivery interval, and mode of delivery were also significantly related to cooling ( Table 3 ).
| Demographic | Infants cooled (n = 98) | Infants not cooled (n = 86,273) | P value |
|---|---|---|---|
| Age, y | 26.9 ± 6.2 | 26.5 ± 6.0 | .552 |
| ≤15 | 4 (4) | 825 (1) | .002 |
| ≥35 | 11 (11) | 9568 (11) | .966 |
| Race/ethnicity | .195 | ||
| Black | 13 (13) | 8474 (10) | |
| White | 3 (3) | 3779 (4) | |
| Hispanic | 77 (79) | 71,921 (83) | |
| Other | 5 (5) | 2099 (2) | |
| Parity | < .001 | ||
| 0 | 56 (57) | 25,590 (30) | |
| 1 | 20 (20) | 26,387 (31) | |
| ≥2 | 22 (22) | 34,296 (40) | |
| BMI, kg/m 2 | |||
| ≥35 | 51 (52) | 45,862 (53) | .788 |
| ≥40 | 14 (14) | 6295 (7) | .012 |
| Characteristic | Infants cooled (n = 98) | Infants not cooled (n = 86,273) | P value |
|---|---|---|---|
| Chronic hypertension | 0 (0) | 297 (0.3) | .561 |
| Diabetes | |||
| Gestational | 8 (8) | 5351 (6) | .421 |
| Pregestational | 7 (7) | 741 (1) | < .001 |
| Prior cesarean | 16 (16) | 15,415 (18) | .691 |
| ≥42 wks | 1 (1) | 3047 (4) | .178 |
| Breech | 4 (4) | 2563 (3) | .518 |
| Preeclampsia a | 14 (14) | 2852 (3) | < .001 |
a Preeclampsia was defined as a blood pressure of 140/90 mm Hg plus 2 plus proteinuria or more.
| Characteristic | Infants cooled (n = 98) | Infants not cooled (n = 86,273) | P value |
|---|---|---|---|
| Induction | 32 (33) | 14,060 (16) | < .001 |
| Augmentation | 27 (28) | 19,633 (23) | .258 |
| Artificial rupture of membranes | 62 (63) | 56,496 (65) | .644 |
| Epidural analgesia | 58 (59) | 42,401 (49) | .047 |
| Chorioamnionitis | 26 (27) | 5684 (7) | < .001 |
| Admission to delivery, h | |||
| Median | 12.8 [3, 24] | 6.0 [2, 11] | < .001 |
| >95th percentile for entire cohort a | 26 (27) | 4291 (5) | < .001 |
| Mode of delivery | |||
| Spontaneous delivery | 25 (26) | 60,140 (70) | < .001 |
| Operative vaginal delivery | 9 (9) | 2153 (2) | < .001 |
| Scheduled cesarean | 2 (2) | 6537 (8) | .060 |
| Cesarean for NRFHR b | 23 (23) | 3553 (4) | < .001 |
| Cesarean for dystocia | 16 (16) | 3834 (4) | < .001 |
| Repeat cesarean in labor | 14 (14) | 5084 (6) | < .001 |
| Cesarean, other indications | 9 (9) | 4972 (6) | .147 |
| Placental abruption | 8 (8) | 163 (0.2) | < .001 |
| Uterine rupture | 2 (2) | 3 (0) | < .001 |
| Cord prolapse | 2 (2) | 80 (0.1) | < .001 |
| Shoulder dystocia | 1 (1) | 356 (0.4) | .349 |
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