Margaret Sheridan-Pereira

The Dublin randomized controlled trial of intrapartum fetal heart rate monitoring

In a randomized controlled trial involving 12,964 women, a policy of continuous electronic intrapartum fetal heart monitoring was compared with an alternative policy of intermittent auscultation, both policies including an option to measure fetal scalp blood pH. Women allocated to electronic fetal heart monitoring had shorter labors and received less analgesia. The caesarean delivery rates were 2.4% for electronic fetal heart monitoring and 2.2% for intermittent auscultation but this small difference arose from the identification of nearly twice as many fetuses with low scalp pH (less than 7.20) in the electronic fetal heart monitoring group. The forceps delivery rate was 8.2% in the electronic fetal heart monitoring group compared with 6.3% in the intermittent auscultation group, and this excess was explained by more instrumental deliveries prompted by fetal heart rate abnormalities. There were 14 stillbirths and neonatal deaths in each group, with a similar distribution of causes. There were no apparent differences in the rates of low Apgar scores, need for resuscitation, or transfer to the special care nursery. Cases of neonatal seizures and persistent abnormal neurological signs followed by survival were twice as frequent in the intermittent auscultation group, and this differential effect was related to duration of labor. Follow-up at 1 year of babies who survived neonatal seizures revealed three clearly abnormal infants in each group. The implications of these findings for both theory and practice are discussed.

Granulocyte Colony-Stimulating Factor and Granulocyte-Macrophage Colony-Stimulating Factor Have Differential Effects on Neonatal and Adult Neutrophil Survival and Function

Neutropenia is a common sequela of neonatal sepsis. Recent clinical trials have shown the beneficial effects of colony-stimulating factors (CSFs) on outcome in this group, but the exact mechanism remains unknown. Neonates and mothers who were at high-risk for infection were recruited for cord blood sampling in a university tertiary referral maternity hospital. Neonatal and adult neutrophils were evaluated for their ability to combat bacterial infection by examining their functional activity (CD11b and reactive oxygen intermediates) and their persistence at inflammatory sites (apoptosis). The mechanism for altered apoptotic responses was assessed by caspase activation assays, X chromosome–linked inhibitor of apoptosis protein expression, and cytosolic cytochrome c release. Although granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) significantly delayed neutrophil apoptosis in normal adults, only G-CSF had a similar effect in normal neonates. Neutrophils from neonates who are at high risk for infection are unresponsive to the antiapoptotic effects of G-CSF or GM-CSF, unlike maternal neutrophils, which have delayed apoptosis in response to GM-CSF. However, CD11b expression and reactive oxygen intermediate production were significantly increased in normal neonatal neutrophils that were incubated with GM-CSF versus controls but not G-CSF or lipopolysaccharide. Decreased cytosolic cytochrome c release and caspases 3 and 9 activity are associated with the CSF-mediated delay in apoptosis in adults but not in newborns. The antiapoptotic X chromosome–linked inhibitor of apoptosis protein is up-regulated in neonates compared with adults and may mediate their differential spontaneous apoptosis. These results have important implications for the use of CSFs in neonatal sepsis, as responses differ from those seen in adults. Further delineation of neonatal neutrophil responses to CSFs may improve their therapeutic potential.

Electronic fetal heart monitoring, auscultation, and neonatal outcome

In a large randomized, controlled study of fetal heart rate monitoring with either continuous electronic fetal heart monitoring or auscultation at specified intervals, only one pattern of deviation in the fetal heart rate correlated significantly with neonatal neurologic examinations at 0 to 48 hours and 72 hours to 1 week: late decelerations in stage 1 and in stage 2. Other variables from labor and delivery, specifically, duration of labor after hospital admission, failure of labor to progress, number of fetal scalp pH values, and presence of meconium were important predictors of neonatal outcome in the regression analyses. The fetal heart rate deviations did contribute significantly to the percent variance accounted for in the regression analyses with neonatal outcomes of Apgar scores at 1 and 5 minutes and serial neonatal neurologic examinations.

Labor Promotes Neonatal Neutrophil Survival and Lipopolysaccharide Responsiveness

Labor is a mild proinflammatory state that is associated with fetal leukocytosis. Elective cesarean section has been linked with increased neonatal morbidity, which may be partially immune mediated. We hypothesized that labor may alter neutrophil phenotype and thereby decrease neonatal complications. We characterized neutrophil function and survival in normal neonates after either uncomplicated vaginal delivery (VD) or elective cesarean section (CS) without labor. Spontaneous neutrophil apoptosis is delayed in cord blood neutrophils of neonates after normal labor (VD) compared with CS, as assessed by propidium iodide DNA incorporation using flow cytometry. This demonstrates their ability to maintain an inflammatory response. CD11b expression on neonatal neutrophils after CS is decreased, providing further evidence of altered activation or priming. Lipopolysaccharide responsiveness, characterized by CD11b and apoptosis, is similar in VD and adults, but CS-derived neutrophils are unresponsive. Baseline TLR-4 levels are elevated in CS in contrast to the other groups, although expression is not up-regulated by lipopolysaccharide co-incubation. Neonatal neutrophil survival and function are altered by labor and may increase antibacterial function and neutrophilia. This suggests that labor of any duration may be immunologically beneficial to the normal term neonate.

Effects of heat shock and hypoxia on neonatal neutrophil lipopolysaccharide responses: altered apoptosis, Toll-like receptor-4 and CD11b expression compared with adults.

Background: Dysfunctional inflammatory responses have been implicated in several neonatal inflammatory disorders following infection and hypoxia. Objectives: We aimed to study the effects of in vitro hypoxia and heat shock (HS) on normal adult and newborn neutrophil migration (CD11b) and persistence (apoptosis) following lipopolysaccharide (LPS) stimulation. Methods: The mechanism for altered LPS responses was assessed at the level of the LPS signalling receptors, Toll-like receptor-4 (TLR-4), TLR-2 and CD14 expression in normal neonates and adults. Results: In adults, although hypoxia delayed neutrophil apoptosis, LPS enhanced this response. In contrast, HS (42°C) increased adult apoptotic rates and abrogated the LPS responses. Both hypoxia and HS prevented the LPS-induced increase in adult CD11b although it was unaltered in neonates. Adult TLR-4 neutrophil expression was increased by LPS and hypoxia, and decreased in HS, possibly explaining their variable LPS responsiveness. In contrast, neonatal neutrophils were LPS hyporesponsive which may be mediated by failure of TLR-4 upregulation with LPS. Conclusions: Neonates do not have increased LPS responsiveness in hypoxia or heat shock in vitro, which may prevent hyperinflammation and thereby minimise tissue damage in inflammation or infection.

The construction of a scored neonatal neurological examination for assessment of neurological integrity in full-term neonates.

We describe the construction of a scored form for the neurological examination of the full-term neonate. Extensive data analyses were obtained from a large sample of neonatal neurological examinations performed by one examiner (MSP). Examinations were used from neonates with ages ≥ 48 hours (n = 727) and 72 hours to 1 week (n = 510) with gestational ages greater than or equal to 37 weeks. Forty-four items from several neonatal assessments were used in these neurological examinations. Further subdivision yielded a total of 65 items. Correlations were obtained for the 65 items. We factored the matrix of these correlations, using several solutions of factor analysis. Thirty-two items were thus grouped and pruned into seven dimensions (factors) to provide a scorable neonatal neurological examination (Neoneuro) with an internal consistency or reliability of 0.80. From the total scores, cut points are recommended for categories of normality/abnormality: normal, mildly abnormal, moderately abnormal, and severely abnormal. This scoring system is well-based both theoretically and psychometrically. The quantified computer-compatible scoring system permits evaluation of individual neonates, as well as comparison of samples of neonates on item scores, subscores (factor scores), and total scores. Such quantification will permit documentation of the natural history of specific abnormalities and the evaluation of various therapies.

254 Maternal and Neonatal Lipopolysaccharide Responses are Altered in Neonatal Encephalopathy

Systemic hypoxia-ischaemia at birth may alter the neonatal neutrophil phenotype. Neutrophils from adults (n=15), normal newborns (n=20), newborns requiring resuscitation at birth and their respective paired maternal samples (n=17) were incubated alone or with Lipopolysaccharide (LPS). Surface receptor CD11b and the percentage apoptosis (persistence of inflammatory response) were assessed using flow cytometry. Maternal neutrophil apoptosis is delayed compared with adults and neonates. Neutrophil apoptosis was delayed in neonates requiring resuscitation at birth and was exaggerated further in infants who developed mild neurological signs. Newborns with severe neurological signs had increased apoptosis and decreased CD11b. None of the infants who required resuscitation at birth were LPS responsive irrespective of neurological outcome. Similarly, maternal neutrophils had a delay in apoptosis in all groups but were LPS hyporesponsive in the groups whose infants had moderate/severe neurological signs. Maternal neutrophil function may be a useful adjunct to neonatal diagnosis. Neonates are LPS hyporesponsive after resuscitation. However, downregulation of neonatal responses in hypoxia may also prevent excessive immune activation and tissue damage in this vulnerable group.