Toby Debra Yanowitz

Hemodynamic disturbances in premature infants born after chorioamnionitis: Association with cord blood cytokine concentrations

Chorioamnionitis and elevated cord blood inflammatory cytokine concentrations are associated with detectable disturbances of systemic and cerebral hemodynamics in premature newborns. Fifty-five infants (25–31 wk gestation) were enrolled. Chorioamnionitis was defined by placental histology. IL-6, IL-1β, and tumor necrosis factor-α were quantified by ELISA. Blood pressure, heart rate, cardiac output, stroke volume, fractional shortening, and middle cerebral artery blood flow velocities were measured at 3 ± 1 h after birth. Chorioamnionitis was evident in 22 placentas and was associated with increased IL-6 (p < 0.001), IL-1β (p = 0.035), and heart rate (p = 0.027); and with decreased mean and diastolic blood pressure (p = 0.026 and p = 0.019, respectively). IL-6 concentration correlated inversely with systolic, mean, and diastolic blood pressures. Right ventricular cardiac output was elevated (p = 0.028) in infants with fetal vessel inflammation. Maternal temperature ≥38.0°C and newborn immature-to-total white blood cell ratio ≥0.4 were associated with significant decreases in left ventricular fractional shortening (p = 0.001 and p = 0.005, respectively). Neither chorioamnionitis nor elevated cytokine concentrations were associated with changes in middle cerebral artery Doppler blood flow velocities. Chorioamnionitis and elevated cord blood IL-6 concentrations are associated with decreased blood pressure in premature newborns. Inflammation of the fetal vessels and nonspecific indicators of infection are associated with disturbances in cardiac function. Infants with chorioamnionitis and elevated cytokine concentrations do not manifest changes in cerebral Doppler indices within the first few postnatal hours. We speculate that cytokine-associated systemic hemodynamic disturbances in premature infants born after chorioamnionitis predispose such infants to perinatal brain injury.

Hemodynamic Effects of Delayed Cord Clamping in Premature Infants

BACKGROUND AND OBJECTIVE: Delayed cord clamping (DCC) has been advocated during preterm delivery to improve hemodynamic stability during the early neonatal period. The hemodynamic effects of DCC in premature infants after birth have not been previously examined. Our objective was to compare the hemodynamic differences between premature infants randomized to either DCC or immediate cord clamping (ICC). METHODS: This prospective study was conducted on a subset of infants who were enrolled in a randomized controlled trial to evaluate the effects of DCC versus ICC. Entry criteria included gestational ages of 240 to 316 weeks. Twins and infants of mothers with substance abuse were excluded. Serial Doppler studies were performed at 6 ± 2, 24 ± 4, 48 ± 6, and 108 ± 12 hours of life. Measurements included superior vena cava blood flow, right ventricle output, middle cerebral artery blood flow velocity (BFV), superior mesenteric artery BFV, left ventricle shortening fraction, and presence of a persistent ductus arteriosus. RESULTS: Twenty-five infants were enrolled in the DCC group and 26 in the ICC group. Gestational age, birth weight, and male gender were similar. Admission laboratory and clinical events were also similar. DCC resulted in significantly higher superior vena cava blood flow over the study period, as well as greater right ventricle output and right ventricular stroke volumes at 48 hours. No differences were noted in middle cerebral artery BFV, mean superior mesenteric artery BFV, shortening fraction, or the incidence of a persistent ductus arteriosus. CONCLUSIONS: DCC in premature infants is associated with potentially beneficial hemodynamic changes over the first days of life.

Variability in Cerebral Oxygen Delivery Is Reduced in Premature Neonates Exposed to Chorioamnionitis

Premature infants exposed to chorioamnionitis are at increased risk for periventricular leukomalacia (PVL) and intraventricular hemorrhage (IVH), lesions that may result from inflammation and/or fluctuations in cerebral blood flow. The effect of chorioamnionitis on near-infrared spectroscopy (NIRS) measures of cerebral oxygen delivery has not been evaluated previously. Forty-nine infants born at 25–31 6/7 wk gestation underwent NIRS examination on d 1, 2, 3, and 7 of life. Variability in NIRS tracings was analyzed by partitioning each tracing into three components: long-term, intermediate, and short-term variability; the latter two components were analyzed. Chorioamnionitis-exposed infants manifest reduced intermediate variability in cerebral oxygenated and deoxygenated Hb but not total Hb. Infants with severe IVH/PVL had the lowest intermediate variability on d 1. Short-term variability was similar between chorioamnionitis-exposed and unexposed infants, and between infants with versus without severe IVH or PVL. We conclude that intermediate-term variability in NIRS cerebral oxygen delivery is reduced in chorioamnionitis-exposed infants. We speculate that intermediate variability represents the important time frame for evaluating the pathogenesis of perinatal brain injury. Further studies are needed to determine how these findings relate to cerebral blood flow autoregulation and oxygen utilization in premature infants.

Low blood pressure among very-low-birth-weight infants with fetal vessel inflammation

OBJECTIVE: To test the hypothesis that fetal vessel inflammation (FVI: funisitis and/or fetal vasculitis) is associated with lower blood pressure (BP) over the first week of life and an increased risk of periventricular leukomalacia (PVL) among premature infants.STUDY DESIGN: A total of 255 infants born at <1350 g to normotensive mothers were stratified by gestational age (GA) and grouped by presence/absence of FVI on placental pathology. Daily highest (Hi) and lowest (Lo) systolic BP (BPsys), mean BP (BPmn) and diastolic BP (BPdia) over first 7 days of life were analyzed by repeated measures ANOVA and regression analysis. Cranial ultrasounds were obtained at 2 weeks of life.RESULTS: Infants ≥30 weeks gestation with FVI had lower HiBPsys, HiBPmn, HiBPdia, LoBPsys, LoBPmn and LoBPdia (p<0.001) than did infants without FVI. Infants with PVL (all ≤27 weeks gestation) had lower LoBPmn and LoBPdia (p<0.01) than controls. FVI did not increase the risk of PVL in these infants.CONCLUSION: FVI and PVL are associated with reduced BP over the first week of life.

Prophylactic Indomethacin Reduces Grades III and IV Intraventricular Hemorrhages when Compared to Early Indomethacin Treatment of a Patent Ductus Arteriosus

OBJECTIVE: To determine the relative risk of severe intraventricular hemorrhage (IVH) between two very early indomethacin treatment strategies.STUDY DESIGN: Retrospective chart review of infants <29 weeks gestation and <1350 g who received either indomethacin prophylaxis or very early echocardiography with indomethacin treatment only if the ductus arteriosus was patent.RESULTS: A total of one hundred and two infants received prophylactic indomethacin (pINDO). Echochardiography was performed on 158 infants, of whom 117 received indomethacin. Infants receiving pINDO had lower gestational age, but similar birth weight, gender, race, antenatal steroid exposure, delivery mode, Apgar scores, and need for resuscitation as infants evaluated by echocardiography. Grades III to IV IVH was observed less frequently in infants who received pINDO (OR 0.27, 95% CI 0.10 to 0.77, p=0.014). Frequency of side effects and recurrent patent ductus arteriosus did not differ between treatment groups.CONCLUSION: pINDO reduces severe IVH when compared to an early echocardiography strategy.

Placental Inflammation and Fetal Hemodynamics in a Rat Model of Chorioamnionitis

The relative contributions of inflammation and ischemia to the pathogenesis of periventricular leukomalacia (PVL) have not been elucidated. We hypothesized that fetal cardiovascular function and cerebral blood flow velocity (BFV) would be decreased in a rat model of chorioamnionitis. We also tested whether placental inflammation was related to proximity to the cervix in our model of chorioamnionitis [intracervical lipopolysaccharide (LPS) or vehicle (PBS) injection]. On embryonic d 15, Sprague-Dawley rats underwent baseline maternal and fetal echocardiography, followed by LPS or PBS injection, then serial echocardiographic evaluations until embryonic day (ED) 21. One hour after birth, pups had middle cerebral artery (MCA) BFV measured. Placentas of LPS-exposed pups exhibited uniform, higher inflammation grades (p < 0.001). All fetal BFVs increased with advancing GA (p < 0.001) whereas resistance index (RI) decreased (p < 0.001). There was no difference in fetal BFV between the groups other than a reduced gestation-related increase in descending aorta BFV in LPS-exposed rats (p < 0.05). Newborn pups exposed to LPS had lower heart rate (p = 0.006) and MCA BFV (p = 0.024) and higher RI (p = 0.003) and pulsatility index (PI; p = 0.004). In conclusion, intracervical LPS injection produces an inflammation independent of placental position, a blunted increase in gestation-related aortic BFV, and a decrease in MCA BFV in newborn pups.

Asymmetry of Cerebral Blood Flow Velocity in Low Birth Weight Infants

Background: In premature infants, intraventricular hemorrhage occurs more commonly in the left than the right hemisphere. We have demonstrated previously that cerebral blood flow velocity is lower in the left than the right middle cerebral artery in the first few hours after birth. This may be due to the open ductus arteriosus. Objective: To test the hypothesis that blood flow velocity is lower in the left than the right middle cerebral artery only when the ductus arteriosus is open. Study Design: Infants born at 25–33 weeks’ gestation were enrolled. Middle cerebral artery blood flow velocities and coefficients of variation were measured on the left, followed by the right, on days 1 and 7 of life. Echocardiography identified 67 infants (25–33 weeks, 517–2,371 g) whose ductus arteriosus was open on day 1 and closed on day 7. Results: Systolic (26.4 ± 7.4 vs. 29.6 ± 7.2 cm/s), mean (12.4 ± 4.0 vs. 15.6 ± 4.6 cm/s) and end-diastolic (5.3 ± 2.2 vs. 6.8 ± 2.9 cm/s) blood flow velocities were lower (p < 0.01) and the corresponding coefficients of variation were higher (p < 0.01) on the left on day 1. Neither the absolute Doppler blood flow velocities nor the coefficients of variation differed between the left and right sides on day 7. Conclusions: Blood flow velocity is lower and more variable in the left compared to the right middle cerebral artery on day 1 of life in premature infants. These differences are not found on day 7. We speculate that this difference is due to the associated ductus arteriosus patency.

Effect of Preeclampsia on Blood Pressure in Newborn Very Low Birth Weight Infants

Objective. To test the hypothesis that very low birth infants born to mothers with preeclampsia have higher blood pressure over the first week of life than infants whose mothers did not have preeclampsia. Method. Infants born at < 1,350 g who survived at least one week were stratified by gestational age ( ≤ 28 weeks and ≥ 29 completed weeks) and grouped by the presence or absence of preeclampsia. Highest and lowest systolic and mean and diastolic blood pressures were recorded for each of the first seven days of life. Serial blood pressures were analyzed by repeated measures ANOVA. The presence of hypertension (defined as ≥ 3 days with the highest systolic blood pressure > 90th percentile for gestational age stratum and day-specific range) was analyzed by binary logistic regression. Results. Infants ≥ 29 weeks gestational age born to mothers with preeclampsia had higher blood pressures than did controls. Infants ≤ 28 weeks gestational age born to preeclamptic and nonpreeclamptic mothers had similar blood pressures. In the combined cohort, hypertension was not more prevalent among infants born to women with preeclampsia. Conclusions. Preeclampsia is associated with higher blood pressure in very low birth weight neonates who are ≥ 29 weeks gestation. The long-term significance of this finding is not known.

Pulmonary Hemorrhage in Very Low Birth Weight Infants: A Case-Control Analysis

In this case-control analysis, pulmonary hemorrhage cases (n = 22) were more likely than gestational age-matched controls (n = 44) to be small for gestational age, have moderate-to-large patent ductus arteriosus, extubate rapidly, and develop grade III-IV intraventricular hemorrhage (P < .05). Cases were more likely to die (P = .000), especially if not exposed to indomethacin (P = .007).

Superior mesenteric artery blood flow velocities following medical treatment of a patent ductus arteriosus

We examined superior mesenteric artery blood flow velocity in response to feeding in infants randomized to trophic feeds (n = 16) or nil per os (n = 18) during previous treatment for patent ductus arteriosus. Blood flow velocity increased earlier in the fed infants, but was similar in the 2 groups at 30 minutes after feeding.