Mark Hiatt

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 ×g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; feto-placental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n= 537), or after a longer interval (n= 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born ≥1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8;p= 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9;p= 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

The Apgar Score and Its Components in the Preterm Infant

Objective. The Apgar score is well-characterized in full-term infants but not in premature infants. The objective of this study was to assess the Apgar score in preterm infants with respect to the relationships between the 1- and 5-minute scores, the correlation of the Apgar score with pH and with other variables, and the relationship among the individual Apgar components. Methodology. We recorded Apgar scores at 1 and 5 minutes in a population-based cohort of preterm infants (n = 1105) with birth weight <2000 g, from three intensive care nurseries in central New Jersey. Linear correlation analysis was used to examine the relationship between 1- and 5-minute Apgar scores and between the individual components of the Apgar score. Multiple regression analysis was used to explore the relationship between various perinatal characteristics and the Apgar score, and between pH and Apgar score. Stepwise logistic regression analysis was used to assess the determinants of mortality. Results. The 1-minute Apgar score median (25%, 75%) was 6(4,8) and correlated with the 5-minute score of 8(7,9) atr = .78. Slight but significant differences were seen between male (n = 557) and female (n = 508) infants in the 1-minute (6[4,8] and 7[4,8]) Apgar scores. One- and 5-minute scores of white infants (7[4,8] and 8[7,9]; n = 713) were significantly higher than those of black infants (5[3,7] and 8[6,9]; n = 280). Birth weight and gestational age were both linearly related to both Apgar scores. Low Apgar score (<3 at 1 minute and <6 at 5 minutes) was significantly associated with birth weight, gestational age and mode of delivery. Low arterial blood pH (<7.01) at birth was significantly related to low Apgar score. One hundred fifty-nine infants died; these infants were significantly smaller (983 ± 382 vs 1462 ± 369 g), less mature (27 vs 31 weeks), had lower arterial blood pH (7.20 ± 0.18 vs 7.31 ± 0.11), had lower 1- (3[2,6] vs 7[4,8]) and 5-minute Apgar scores (6[4,8] vs 8[7,9]), and a greater incidence of low Apgar score (32% vs 6%) than did survivors. Conclusions. Among the components of the Apgar score, respiratory effort, muscle tone, and reflex activity correlated well with one another; heart rate correlated less well; and color the least. Our data confirms the limited use of the Apgar score in preterm infants and demonstrates the different responses of the Apgar scores components.

Umbilical vein interleukin 6 and tumor necrosis factor alpha plasma concentrations in the very preterm infant

Objective. To examine the relationship between umbilical vein plasma concentrations of interleukin 6 (IL‐6) and tumor necrosis factor (TNF)‐alpha and early neonatal sepsis in the very preterm infant, and the histopathologic findings of chorioamnionitis in the placentas from these pregnancies. Methods. A prospective study was conducted in 43 very preterm, singleton infants delivered at or before 32 weeks of gestation. IL‐6 and TNF‐alpha were measured by enzyme‐linked immunoassay. Placentas from these pregnancies were histologically examined for the presence of chorioamnionitis. Infants were prospectively classified as confirmed sepsis group, clinical sepsis group or control group. IL‐6 and TNF‐alpha plasma concentrations were not normally distributed, so they were transformed to their natural log values for statistical analysis. Results. The enrolled infants had a mean gestational age of 27.2 ± 2.7 weeks and a mean birth weight of 956 ± 325 g. Three (7%) infants had confirmed sepsis, 18 (42%) were in the clinical sepsis group and 22 (51%) were in the control group. IL‐6 concentrations but not TNF‐alpha were significantly higher (P < 0.05) in the confirmed (8.9 ± 1.7) and clinical sepsis (5.5 ± 2.4) groups in comparison with the control group (2.1 ± 1.6). We examined 42 placentas. Twenty‐three (55%) had no evidence of chorioamnionitis, 1 (2%) had mild grade, 8 (19%) had a moderate grade and 10 (24%) had a severe grade of chorioamnionitis. IL‐6 was significantly elevated in the moderate (5.9 ± 1.6 vs. 1.9 ± 1.6) and severe grade (7.2 ± 2.3 vs. 1.9 ± 1.6) of chorioamnionitis, in the presence of acute deciduitis (6.0 ± 2.7 vs. 2.1 ± 1.8), chorionic vasculitis (6.8 ± 2.1 vs. 2.2 ± 1.9) and funisitis (7.3 ± 1.9 vs. 2.7 ± 2.3) (P < 0.05) TNF‐alpha plasma concentrations were not significantly different. Conclusion. An elevated umbilical vein IL‐6 concentration is a good indicator of sepsis syndrome in the very preterm infant and also correlates with histologic chorioamnionitis in these pregnancies.

Blood pressure ranges in premature infants. I. The first hours of life

We studied blood pressure in the first hours of life in a cohort of 1105 preterm infants weighing 501 to 2000 gm; these infants represented 83% of all births at these weights that resulted in admission to three intensive care nurseries during a 34-month period between 1984 and 1987. To assess the effects of specific risk factors, we identified 244 healthy infants, 164 infants who received mechanical ventilation but had no other conditions, 47 infants whose only risk factor was the presence of hypertension or preeclampsia in the mother, and 86 infants with depressed Apgar scores regardless of the presence of the other conditions. We documented each infants minimum and maximum systolic (Smin, Smax) and diastolic (Dmin, Dmax) pressures during the first 3 to 6 hours of life. In the healthy group, Smin was 47 mmHg; Smax, 59 mmHg; Dmin, 24 mmHg; and Dmax, 35 mmHg. In the ventilation group, Smin was 41 mmHg; Smax, 57 mmHg; Dmin, 22 mmHg; and Dmax, 35 mmHg. The Smin and Dmin values were both significantly lower in infants who received mechanical ventilation than in healthy infants (p < 0.01). In the maternal hypertension group, Smin was 49 mmHg; Smax, 59 mmHg; Dmin, 25 mmHg; and Dmax, 34 mmHg. Only the Smin value was significantly higher than in healthy infants. In the group with low Apgar scores, Smin was 33 mmHg; Smax, 51 mmHg; Dmin, 19 Hg; and Dmax, 34 mmHg. Thus all these values were significantly lower than in all the other groups (p < 0.05). Of infants with low Apgar scores, 20% to 50% had values below the 5th percentile for healthy infants. Birth weight and gestational age correlated with blood pressure limits only in the infants with low Apgar scores. We conclude that in healthy premature infants the limits of systolic and diastolic blood pressure are independent of birth weight and gestational age. Infants with low Apgar scores tend to have lower pressures, and infants whose mothers have hypertension have higher pressures than infants in the healthy cohort.

Maternal behavior toward premature twins: implications for development.

Assisted reproductive techniques and fertility enhancing therapies have increased multiple births and, therefore, the risk of prematurity and its developmental consequences. Parent intervention is an effective source of compensation for the cognitive effects of prematurity. We hypothesized that relative to parents of preterm singletons, parents of preterm twins are less able to provide such enhancing care, resulting in a developmental disadvantage for preterm twins. Maternal-infant interactions of premature singletons (n = 22; birth weight = 1668 +/- 350 g, gestational age = 32.3 +/- 2.1 weeks) and premature twins (n = 8; birth weight = 1618 +/- 249 g; gestational age = 32.0 +/- 2.6 weeks) with comparable demographic and medical status were observed at home at 1 and 8 months corrected age using a 30 min checklist of developmentally facilitative behavior. Mental (MDI) and psychomotor (PDI) indices of the Bayley Scales of Infant Development and Caldwell Home Observations for Measurement of the Environment (HOME) inventories were administered (18 months corrected age). Compared with mothers of premature singletons, mothers of premature twins exhibited fewer initiatives (P < 0.001) and responses (P < 0.01) and were less responsive to positive signals (P < 0.01) and crying (P < 0.01). Unprompted by the infant, twin mothers lifted or held (P < 0.05), touched (P < 0.01), patted (P < 0.05) or talked (P < 0.01) less. Singleton MDIs surpassed twins (119.4 +/- 7.7 vs 103.6 +/- 7.7; P < 0.01). Maternal verbal behavior and the acceptance of child factor (HOME), both favoring singletons, correlated with MDI (R-square = 0.46, P < 0.0002). Mothers of premature twins exhibited fewer initiatives and responses toward offspring than did mothers of premature singletons. Maternal behavior was predictive of cognitive development.

Impact of Race and Ethnicity on the Outcome of Preterm Infants Below 32 Weeks Gestation

OBJECTIVES: To determine the impact of race/ethnicity on mortality and morbidity such as intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), bronchopulmonary dysplasia (BPD) and bacteriologically confirmed sepsis, assisted ventilation, surfactant administration, intrauterine growth retardation (IUGR), and patent ductus arteriosus (PDA) among very prematurely delivered infants.STUDY DESIGN: Retrospective study of a cohort of 1006 preterm neonates with gestational age ranging from 22 to 32 weeks discharged from the Neonatal Intensive Care Unit (NICU) between 1998 and 2001. Subgroup analysis according to gestational age (GA) (22 to 24, 25 to 28, and 29 to 32 weeks) and plurality (singleton and multiple) was performed using the χ 2 test and an analysis of variance.RESULTS: Of the 1006 infants, 54.3% were white, 21.7% black, 13.7% Hispanic, and 10.3% were classified as Other. Multiple births among white infants were approximately twice that in (42.4%) black infants (22.1%), and was also significantly higher than in the Hispanic (28.3%) and other race/ethnic groups (25.2%). Overall, a higher proportion of black infants were born with a GA ≤28 weeks (n=115, 55.3%) than white (n=201, 37.1%) and Hispanic (n=53, 38.4%), p<0.05. Therefore, black neonates had a lower GA (27.9±2.9 weeks) and birth weight (1170±463 g) as compared to white (p<0.0002) and Hispanic infants (p<0.0001). There was no significant impact of race/ethnicity on the mean gestational age in any of the gestational age categories. Infant mortality and morbidity in each gestational age category by race/ethnicity were comparable. The multiple birth black infants were seen to have a lower gestational age and birth weight as compared to singleton black as well as to white, Hispanic and other race/ethnic groups. However, this did not influence morbidity and mortality in multiple birth black neonates. The result of this study showed that the level of prematurity and not plurality predominantly influences the rate of infant mortality and morbidity in each race/ethnic category.CONCLUSIONS:The reduction in gestational age and birth weight in black neonates is not associated with an increased risk of infant mortality and morbidity. In general, the outcomes of black singleton and multiple pregnancies were comparable with those of white, Hispanic and other race/ethnic groups.

Association of Lipid Peroxidation with Antenatal Betamethasone and Oxygen Radical Disorders in Preterm Infants

Introduction: Premature infants are highly susceptible to ‘oxygen radical diseases’ (ORD), including bronchopulmonary dysplasia, intraventricular hemorrhage/white matter injury, retinopathy of prematurity, and necrotizing enterocolitis. The incidence of ORD is reduced following antenatal treatment with betamethasone. Oxidant-mediated injury is characterized at the cellular level by peroxidation of lipid membranes. This results in the generation of malondialdehyde (MDA), which can be quantified indirectly by measurement of thiobarbituric acid-reacting substances (TBARS). There is currently no effective way to quantify the risk for ORD. In this study, we analyzed the correlation of early urinary MDA and TBARS with prenatal betamethasone administration and with the development of ORD. Methods: Preterm infants (<30 weeks gestation, n = 25) born at St. Peter’s University Hospital were enrolled. Urine samples were collected during the first 10 days of life and stored at –70°C for 0–21 days. TBARS were quantified by spectrophotometric assay, and malondialdehyde levels measured by HPLC. Subjects were screened for the subsequent development of ORD. Betamethasone administration was defined as one or more doses ≧24 h prior to delivery. Results: Urinary MDA levels increased on days 2–3 and 5–10 relative to day 1 from birth. Maximal urinary MDA concentrations were significantly higher in the ORD group compared to controls, and there was a trend toward increased urinary TBARS in the presence of ORD. Infants receiving prenatal betamethasone demonstrated higher maximal urinary TBARS values during the first 10 days of life than control infants. The length of sample storage from 0 to 3 weeks at –70°C did not significantly affect TBARS measurements. Conclusions: Elevated urinary MDA measurements in the first 10 days are correlated with the risk for ORD. Urinary TBARS concentrations, which are correlated with MDA measurements, can be quantified rapidly and are stable for short-term storage. Our findings suggest that urinary TBARS may be adaptable as a practical tool for assessing the risk for ORD in neonatal intensive care unit patients, allowing clinicians to optimize the use of preventive strategies. Antenatal betamethasone is associated with increased urinary TBARS in the first 10 days of life, indicating that the protective effects of corticosteroids are not mediated through reductions in oxidant-mediated lipid peroxidation.

Spectral Analysis of Heart Rate Variability in Premature Infants with Feeding Bradycardia

An elevated level of baseline parasympathetic activity was noted in a group of premature infants suffering from bradycardia during feeding. At approximately 34 wk post-conceptional age, the heart rates of 12 infants with feeding bradycardia (birth weight = 1539 ± 279 g; gestational age = 31.0 ± 1.6 wk) and 10 controls (birth weight = 1710 ± 304 g; gestational age = 32.0 ± 1.4 wk) were recorded 1 h before and 1 h after feeding. EKG data were digitized and 3.2-min segments of data were analyzed to determine the spectral power at very low (VLF = 0.003–0.03 Hz), low (LF = 0.03–0.39 Hz), and high (HF = 0.40–1.00 Hz) frequencies. In preterm infants with feeding bradycardia, an elevation in baseline parasympathetic activity was evident before feeding, as indicated by significantly higher HF power and a lower LF/HF ratio. This elevation in baseline parasympathetic activity may contribute to the observed bradycardia during feeding.

Spectral Analysis of Heart Variability in the Newborn Infant

We investigated the relationship between spectral power and both mean heart rate (HR) and heart rate variability (HRV). Spectral power was calculated using digital heart rate recordings from term infants. Regression analysis revealed a positive correlation between low-frequency (LF) sympathetic power and HR, and a negative correlation between high-frequency (HF) parasympathetic power and HR. HRV correlated positively in all regions of the power spectrum. In awake infants, the contribution of HF power to total power (HF/TP) was significantly decreased. LF power tended to be greater, however, this trend was not statistically significant. By following expected autonomic patterns, the findings of this study confirm that spectral analysis provides a noninvasive method for the assessment of autonomic activity influencing the newborn heart. The correlation between spectral power and HRV can serve as an additional tool in the study of autonomic dysfunction.

Maternal grief after sudden infant death syndrome

ABSTRACT. Six months after the death of their infants of Sudden Infant Death Syndrome (SIDS), the subjective impression of mothers anonymously rating their initial and present grief was that there had been a reduction in all symptoms (p < .001). However, an increase in the relative ranking of some cognitive symptoms over somatic ones, the association of certain lifestyles and situational variables with higher levels of grief, and the implication for future symptoms of family decisions made during bereavement underscore the importance of continuing active support for these families. In relative ranking, guilt rose from 10th to 5th most prominent symptom, particularly among the 34% of mothers whose infants manifested clinical symptoms (p < .05). Single mothers had higher grief scores both initially (p < .05) and at 6 months (p < .002), were almost three times more likely to become pregnant within 6 months of the death but only one-third as likely to attend a support group, and were also more likely to move after the death (44% vs 25%). Mothers whose infants had been discovered by another caregiver reached out more to a crisis intervention service of a support program available to SIDS families (p < .05). Mothers without surviving children had grief levels comparable with those with children but were less likely to rate their pediatricians support as satisfactory, increasing the probability that they would change physicians with subsequent children, thereby losing continuity of care and support. J Dev Behav Pediatr 14:156–162, 1993. Index terms: SIDS, parental bereavement.