Determination of the timing of fetal brain damage from hypoxemia-ischemia.

OBJECTIVE: This study analyzed the cases of 55 children with cerebral palsy to evaluate methods for determination of the time before birth at which antenatal hypoxemia-ischemia damaged the brain. STUDY DESIGN: In primate fetuses persistent fetal bradycardia develops close to the time that hypoxemia-ischemia damages basal ganglia structures in the brain. The same proved true in children in this study, so this time was thereafter used as a baseline to test the values of other proposed timers of hypoxemicischemic brain damage. RESULTS: Basal ganglia lesions predominated when bradycardia lasted <30 minutes before birth. As the bradycardia duration lengthened, white matter and eventually watershed brain lesions predominated. Lymphocytosis appeared 25 minutes after the bradycardia began, and thrombocytopenia appeared at 20 to 28 hours. The lymphocytosis disappeared 14 to 18 hours after it first appeared. CONCLUSIONS: Counting back from the time that lymphocytosis ended and thrombocytopenia began can sometimes identify the time when hypoxemia-ischemia damaged the fetal brain.

Chorioamnionitis, cortisol, and acute lung disease in very low birth weight infants.

OBJECTIVE: To explore the relationship between chorioamnionitis, postnatal cortisol concentrations, and acute respiratory distress in very low birth weight infants. METHODS: Appropriate for gestational age infants weighing between 501 to 1500 g at birth were enrolled into this prospective, observational study, and data regarding respiratory distress on the first day of life were recorded. Serum cortisol concentrations were measured on (a) day 2, (b) day 3 or 4, and (c) day 5, 6, or 7 of life. On day (b) or (c), 3.5 microg/kg of cosyntropin (an adrenocorticotrophic hormone analog) was given, and a repeat specimen was drawn 30 minutes later. Chorioamnionitis was diagnosed by placental examination by one author (R.L.N.). RESULTS: Forty-two infants exposed to chorioamnionitis and 37 infants not exposed were enrolled. Chorioamnionitis correlated inversely with gestational age, and was associated with decreased measures of acute respiratory support (exogenous surfactant, fraction of inspired oxygen, and ventilator support at 12 and 24 hours). Infants with chorioamnionitis had higher cortisol concentrations, both basal and stimulated. Gestational age was not significantly related to basal cortisol, but did correlate positively with stimulated values. Cortisol values from the 16 infants exposed to prenatal glucocorticoid therapy were excluded from these analyses. CONCLUSIONS: These results provide evidence that prenatal inflammation leads to adrenal stimulation, resulting in increased cortisol secretion and accelerated lung maturation. The enhanced response to cosyntropin stimulation seen in these infants may reflect an increased adrenal capacity to respond to postnatal stressors. Because of the apparent magnitude of the effect of chorioamnionitis on cortisol measures, this factor should be included in future investigations of adrenal function in very low birth weight newborns.

Can meconium in the amniotic fluid injure the fetal brain?

OBJECTIVE: To determine if meconium in the amniotic fluid (AF) can cause cerebral palsy by stimulating umbilical and placental blood vessels to constrict. METHODS: Brain injury patterns were analyzed in 43 children whose exposure to meconium in the AF was their only identified risk for quadriplegic cerebral palsy. The times their injuries occurred were established by following lymphocyte counts in their blood after birth. RESULTS: All 43 had cerebral cortical and subcortical brain damage of the type produced by late gestational ischemia and hypoxemia. The time between the onset of injury and birth ranged from 2-38 hours. The neonates were severely acidotic at birth when birth occurred within 12-14 hours after ischemia and hypoxemia began. Thereafter, the acidosis receded as the time between its start and birth increased, presumably because vasoconstriction had ended. Severe acidosis did not recede in nine children whose cerebral palsy was due to disorders that kept them hypoxemic until birth. CONCLUSION: Meconium in the AF may sometimes initiate vasoconstriction that leads to ischemic, hypoxemic cerebral palsy.

Determining the time before birth when ischemia and hypoxemia initiated cerebral palsy.

OBJECTIVE: To test the hypothesis that lymphocyte and normoblast counts in neonatal blood can be used to identify the time that ischemia and hypoxemia produced cerebral palsy. METHODS: Blood lymphocyte and normoblast counts were analyzed at intervals after birth in 16 neonates for whom we knew the time when antenatal ischemic and hypoxemic brain damage began. These counts were compared with counts from normal newborns, infants with low Apgar scores and no cerebral palsy, and infants with cerebral palsy caused by developmental and other early gestational disorders. RESULTS: Lymphocyte counts increased to more than 10,000/mm3 and normoblast counts to 2000/mm3 or more within 2 hours after the brain-damaging ischemia and hypoxemia began. Lymphocyte counts returned to normal levels 24 hours after the damaging event took place, and normoblast counts in 24-36 hours. Normal neonates had a mean +/- one standard deviation lymphocyte count of 4430 +/- 1418/mm3 and a normoblast count of 560 +/- 771/mm3. CONCLUSION: Following the changing counts of lymphocytes and normoblasts in neonates' blood may accurately identify the time before birth when brain-damaging ischemia and hypoxemia began.

Redefinition of the sudden infant death syndrome: the disadvantages.

For many years the definition of SIDS has been the sudden death of an infant that was unexpected by history and in which a thorough postmortem examination failed to demonstrate an adequate cause of death. In 1991 a report was published in this journal from a panel convened by the NICHD which recommended that the diagnosis of SIDS not be made unless a death scene investigation has been conducted. The panel recommended further exclusions from the diagnosis of SIDS of certain "unresolved" cases. We believe the changes recommended by the NICHD panel are impractical and may have a serious negative impact on SIDS research and on the surviving family members of the SIDS victims.

The clinical significance of absent subchorionic fibrin in the placenta.

Patchy fibrin is normally present beneath the chorionic plate of the placenta. The present study attempted to determine whether it has any clinical significance. In 31,622 placentas the amount of this fibrin was related to markers of fetal activity. Fibrin was often absent when the markers indicated hypoactivity. The markers of fetal hypoactivity were neonatal hypotonia, neonatal lethargy, the presence of Down's syndrome, and a short umbilical cord. Umbilical cord length is strongly influenced by tension applied to it by fetal movements--the fewer the movements, the shorter the cord. Children with no subchorionic fibrin subsequently had increased frequencies of cerebral palsy and low intelligence quotient values. Children who were hyperactive at one year of age had increased levels of subchorionic fibrin, which suggests that they were hyperactive before birth. All of these findings raise the possibility that normal fetal movements sometimes traumatize the placenta, which leads to fibrin deposits beneath its surface.

Maternal body weight and pregnancy outcome.

Pregnancies that produced 56,857 children were analyzed to evaluate the relationship of the mothers' relative pregravid body weight to pregnancy outcome. Perinatal mortality rates progressively increased from 37 of 1000 in offspring of thin subjects to 121 of 1000 in the offspring of obese subjects (p less than 0.001). Nearly half of this mortality increase was due to preterm deliveries, particularly before 31 wk of gestation. More than half of the increase in preterm births was caused by acute chorioamnionitis. Other factors that made major contributions to the overall mortality increase were rises in the frequencies of older gravidas (ages 35-50 y), gravidas who had diabetes mellitus, children who had major congenital malformations, and dizygous twins.

Preventing the sudden infant death syndrome.

Current efforts in the US to prevent the sudden infant death syndrome (SIDS) are largely based on pneumocardiogram screening and home apnoea monitoring. This technology does not prevent most SIDS deaths because the screening procedures lack the sensitivity and specificity needed to identify most high risk infants. In the UK the largest efforts to prevent SIDS have been based on infant health surveillance. These efforts appear to have been ineffective and along with the US failures highlight the need for new strategies to prevent SIDS. One strategy might be to develop methods to avoid known risk factors for SIDS. Prominent among these risk factors are cigarette smoking and the use of psychotropic drugs during pregnancy, overheating and infections in infants. Possible approaches to avoid these and other risks are described in the present paper.

Origins of cerebral palsy.

Analyses were undertaken to determine the causes of cerebral palsy in a prospective study of 43,437 full-term children. Presumed causes were found for about 71% of the 34 quadriplegic and 40% of the 116 nonquadriplegic patients with cerebral palsy. Risk estimates based on predictive models, adjusted for multiple factors, suggest that 53% of the quadriplegic patients with cerebral palsy could be attributed to congenital disorders, 14% to birth asphyxia, and 8% to other identified disorders. Thirty-five percent of the nonquadriplegic patients with cerebral palsy could be attributed to congenital disorders and 6% to other disorders. In the victims of cerebral palsy, characteristic consequences of birth asphyxia were more often the result of nonasphyxial disorders. These included meconium in the amniotic fluid, low 10-minute Apgar scores, neonatal apnea spells, seizures, persisting neurologic abnormalities, and slow head growth after birth.

New brain stem and bone marrow abnormalities in victims of sudden infant death syndrome.

The study looked for new abnormalities in 31 victims of sudden infant death syndrome (SIDS). The focus was on respiratory control centers in the brain stem, because some SIDS victims have had abnormalities in respiratory control during sleep. A major respiratory control area (lateral reticular nucleus) of the medulla was hypomyelinated in 9 of the 31 SIDS victims. In a second study, the size of the 12th cranial nerve nucleus and its neuronal composition were analyzed because this nucleus regulates tongue movements, and the tongue has been postulated to help obstruct the airway in some SIDS victims. The 12th nucleus was found to have a neuronal deficit in more than two thirds of the SIDS victims. Finally, the SIDS victims were found to have a normoblastic hyperplasia in their bone marrows, a presumed response to chronic hypoxemia during sleep.

Pregnancy hypertension, placental evidences of low uteroplacental blood flow, and spontaneous premature delivery.

This study was undertaken to determine if preeclampsia and low uteroplacental blood flow cause spontaneous preterm births. No non-invasive methods are currently available to accurately measure uteroplacental blood flow, so surrogates that are known to be associated with low uteroplacental flow were used. These are preeclampsia, placental infarcts, abnormally small placental villi, and excessive syncytial knots. Preeclampsia was associated with a frequency of spontaneous preterm births that was 41% greater than expected (P less than .001). Normotensive gestations with placental findings of low uteroplacental blood flow ended preterm 147% more frequently than expected, and when a woman had two such pregnancies in succession, the second had a particularly high frequency of spontaneous preterm delivery (64%). Overall, preeclampsia and placental findings of low uteroplacental blood flow were associated with 26% of the spontaneous preterm deliveries in this study. Preeclampsia and low uteroplacental blood flow may be major causes of preterm birth.

Acute myometritis and chorioamnionitis during cesarean section of asymptomatic women.

Postoperative endomyometritis develops in as many as 85% of women undergoing cesarean section, which is 10- to 30-fold higher than after vaginal delivery. The timing and mechanism by which the infecting organisms gain access to the uterine cavity are unclear. One possibility is that the infection may occur postpartum by ascending colonization of the wound. Alternatively, myometritis may be already present at the time the cesarean section is performed in asymptomatic patients. With tissue necrosis, the stage is then set for puerperal endomyometritis. To study this second alternative mechanism, myometrial and placental biopsy specimens were obtained in 91 asymptomatic patients at the time of cesarean section. Histologic evidence of chorioamnionitis was identified in 10% (9/91) of patients. Acute myometritis was present in 11% (10/91) of the myometrial biopsy specimens. Seven of the nine women (77%) with subclinical acute chorioamnionitis demonstrated extension of the inflammation into the myometrium. Thirty-two percent (8/25) of women in labor and 31% (5/16) of those with rupture of membranes for greater than 6 hours had acute chorioamnionitis or myometritis, which is significantly higher (p less than 0.01) than in women without these risk factors. These findings suggest that approximately one third of asymptomatic women with rupture of the membranes for more than 6 hours or who are in labor at the time of cesarean section demonstrate histologic evidence of subclinical chorioamnionitis. In most of these patients the myometrium is also involved. The uterine incision is then performed through infected myometrium, possibly setting the stage for puerperal endomyometritis.