Periviable birth: executive summary of a Joint Workshop by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Society for Maternal-Fetal Medicine, American Academy of Pediatrics, and American College of Obstetricians and Gynecologists.

This is an executive summary of a workshop on the management and counseling issues of women anticipated to deliver at a periviable gestation (broadly defined as 20 0/7 through 25 6/7 weeks of gestation), and the treatment options for the newborn. Upon review of the available literature, the workshop panel noted that the rates of neonatal survival and neurodevelopmental disabilities among the survivors vary greatly across the periviable gestations and are significantly influenced by the obstetric and neonatal management practices (for example, antenatal steroid, tocolytic agents and antibiotic administration; cesarean birth; and local protocols for perinatal care, neonatal resuscitation and intensive care support). These are, in turn, influenced by the variations in local and regional definitions of limits of viability. Because of the complexities in making difficult management decisions, obstetric and neonatal teams should confer prior to meeting with the family, when feasible. Family counseling should be coordinated with the goal of creating mutual trust, respect and understanding, and should incorporate evidence-based counseling methods. Since clinical circumstances can change rapidly with increasing gestational age, counseling should include discussion of the benefits and risks of various maternal and neonatal interventions at the time of counseling. There should be a plan for follow-up counseling as clinical circumstances evolve. The panel proposed a research agenda and recommended developing educational curricula on the care and counseling of families facing the birth of a periviable infant.

Prophylactic indomethacin infusion increases fractional cerebral oxygen extraction in ELBW neonates.

OBJECTIVE: Intraventricular hemorrhage (IVH) occurs in up to 25% of very low birth weight (VLBW) preterm neonates. Previous studies found that indomethacin administered in the first 6 h of life reduces the incidence of severe IVH in VLBW neonates and decreases cerebral blood flow, suggesting a decrease in cerebral oxygen delivery. Using near-infrared spectroscopy (NIRS), we monitored cerebral oxygenation before, during and after slow indomethacin infusion in extremely low birth weight (ELBW) neonates to determine whether indomethacin decreases cerebral oxygen saturation and increases cerebral oxygen extraction. STUDY DESIGN: Twenty-seven ELBW neonates less than 30 weeks gestational age treated with indomethacin for IVH prophylaxis were monitored for arterial oxygen saturation (SaO(2)) and NIRS-determined regional cerebral oxygen saturation (rSO(2)). At 30 to 60 s intervals, SaO(2), rSO(2) and mean arterial pressure (MAP) were recorded using a VitalSync. Average fractional cerebral oxygen extraction was calculated for the hour before indomethacin infusion, during the infusion and 2 h after infusion. RESULT: Fractional cerebral oxygen extraction increased from baseline after indomethacin administration from 0.23±0.11 to 0.25±0.10 (P=0.034). CONCLUSION: Fractional cerebral oxygen extraction increased 9% with indomethacin 0.1 mg kg(-1) given over 1 to 2 h. However, the clinical implications of this small increase in extraction, likely representative of decreased cerebral perfusion, are unknown but may be harmful to the developing brain.

The evaluation and management of postnatal thromboses.

In the pediatric population, neonates have the highest risk for thromboembolism (TE), most likely due to the frequent use of intravascular catheters. This increased risk is attributed to multiple risk factors. Randomized clinical trials dealing with management of postnatal thromboses do not exist, thus, opinions differ regarding optimal diagnostic and therapeutic interventions. This review begins with an actual case study illustrating the complexity and severity of these types of cases, and then evaluates the neonatal hemostatic system with discussion of the common sites of postnatal thrombosis, perinatal and prothrombotic risk factors, and potential treatment options. A proposed step-wise evaluation of neonates with symptomatic postnatal thromboses will be suggested, as well as future research and registry directions. Owing to the complexity of ischemic perinatal stroke, this topic will not be reviewed.

Absence of physiological tolerance to cocaine in pregnant sheep.

OBJECTIVE: To determine whether repetitive administration of cocaine to sheep during pregnancy altered basal hemodynamic states in the mother and fetus, and to determine whether this cocaine exposure would alter subsequent hemodynamic responses to cocaine. METHODS: Cocaine or saline was administered to 16 pregnant sheep daily from day 75 to day 128 of gestation (term = 145 days). At 128 days' gestation, maternal and fetal basal physiological measurements, including organ-specific blood flow in the fetus, were determined. Each experimental and control ewe then received cocaine 2 mg/kg and these physiological parameters were again measured over the next 30 min to determine whether the experimental animals had developed tolerance to the effects of cocaine. RESULTS: No differences were seen in basal physiological parameters between treatment groups. Likewise, following an acute administration of cocaine, physiological parameters in both groups responded in a similar fashion. Fetal hypoxemia occurred in both groups after the ewe received cocaine. In response to hypoxemia, whether it was the animals' first or 53rd exposure to cocaine, fetal cerebral, myocardial and adrenal blood flow increased so that oxygen delivery was unimpaired. CONCLUSIONS: For the cardiovascular parameters measured in this study, we found no tolerance to cocaine in the ewe or fetus. The acute hemodynamic effects of maternal cocaine administration were as severe for animals having received it more than 50 times as for those that received it for the first time.

Elimination of cocaine by pregnant sheep following single or multiple exposures.

To test the hypothesis that chronic exposure to cocaine would alter drug elimination in pregnant and fetal sheep compared to a single exposure, we administered intravenous cocaine HCl to 8 pregnant sheep daily as a bolus, followed by a 2-h infusion beginning at gestational age 75 days. Eight additional animals received an equivalent volume of saline. Three days after maternal and fetal catheter placement on day 125, ewes in both groups received cocaine HCl, 2 mg/kg, as a bolus. Maternal and fetal plasma samples were serially obtained and analyzed for cocaine and benzoylecognine. Cocaine half-life in the ewes and fetuses exposed to cocaine was no different from that in animals exposed to saline. We conclude that cocaine is rapidly metabolized in pregnant sheep and that chronic administration does not alter drug clearance.

Congenital autoimmune neutropenia in two premature neonates.

Autoimmune neutropenia (AIN) has been reported in infants and children, but not in neonates. AIN is caused by antibodies produced by the patient against their own neutrophils; therefore, it differs from the more common alloimmune neonatal neutropenia and the neonatal neutropenia because of a maternal autoimmune disease in which antineutrophil antibodies of maternal origin cross the placenta. We observed 2 cases of congenital AIN in premature neonates. These are the youngest reported cases, and indicate that AIN can have a prenatal onset. Examination of the bone marrow biopsies revealed an increase in B lymphocytes and myeloperoxidase-positive cells with a maturation arrest at the myelocyte stage. Recombinant human granulocyte colony-stimulating factor effectively treated the neutropenia, as it does in infantile AIN. Ten months after the diagnosis, 1 of the patients still requires recombinant human granulocyte colony-stimulating administration.

Nitric oxide inhalation increases alveolar gas exchange by decreasing deadspace volume.

OBJECTIVE: To test the hypothesis that nitric oxide inhalation facilitates CO2 elimination by decreasing alveolar deadspace in an ovine model of acute lung injury. DESIGN: Prospective, placebo-controlled, randomized, crossover model. SETTING: University research laboratory. SUBJECTS: Eleven mixed-breed adult sheep. INTERVENTIONS: To induce acute lung injury, hydrochloric acid was instilled into the tracheas of paralyzed sheep receiving controlled mechanical ventilation. Each sheep breathed 0 ppm, 5 ppm, and 20 ppm nitric oxide in random order. MEASUREMENTS AND MAIN RESULTS: Estimates of alveolar deadspace volumes and arterial-to-end tidal CO2 partial pressure differences were used as indicators of CO2 elimination efficiency. At a constant minute ventilation, nitric oxide inhalation caused dose-independent decreases in Paco2 (p <.05), alveolar deadspace (p <.01), and arterial-to-end tidal CO2 partial pressure differences (p <.01). We found that estimates of arterial-to-end tidal CO2 partial pressure differences may be used to predict alveolar deadspace volume (r2 =.86, p <.05). CONCLUSIONS: Estimates of arterial-to-end tidal CO2 partial pressure differences are reliable indicators of alveolar deadspace. Both values decreased during nitric oxide inhalation in our model of acutely injured lungs. This finding supports the idea that nitric oxide inhalation facilitates CO2 elimination in acutely injured lungs. Future studies are needed to determine whether nitric oxide therapy can be used to reduce the work of breathing in selected patients with cardiopulmonary disorders.

The ontogeny of glutamate receptors and D-aspartate binding sites in the ovine CNS.

The ontogeny of ligand binding to N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate (KA) receptors and to the high affinity, sodium-dependent D-aspartate binding site in prenatal and postnatal ovine brains was studied using quantitative in vitro autoradiography. In general, the binding density for each of the excitatory amino acid receptors peaked during late prenatal and early postnatal development. In contrast, binding density for D-aspartate remained low during late prenatal and early postnatal development and peaked in the adult. These data suggest that an excess number of excitatory amino acid receptors and/or a relative deficiency of transporters may make the immature brain more vulnerable to the pathologic effects of glutamate and other related excitatory amino acids.

Medication use in neonatal resuscitation.

The American Heart Association has published guidelines for medication use in neonatal resuscitation. These recommendations should not, however, be regarded as standards or as the final word on resuscitation in neonates. Little work has been performed to justify these recommendations directly; therefore, it was necessary to make recommendations by extrapolating from studies not specifically designed to answer questions concerning the neonate. For example, the optimum dose of epinephrine administered either intravenously or endotracheally in a neonate with hemodynamically significant bradycardia is simply not known. The American Heart Association guidelines were made with reasoning based on the information available, even though the information is tangential. Similarly, since no data exist to document the benefit of NaHCO3 and some data would suggest harmful effects, its routine use is discouraged. Fertile areas for research exist to define better the optimum doses of epinephrine required in newborn resuscitation and to further delineate the importance and safety of rapid reversal of acidosis in newborn resuscitation.

Accuracy of different methods for heart rate determination during simulated neonatal resuscitations.

OBJECTIVE: We hypothesized that during a simulated neonatal resuscitation, heart rate determination with the Neonatal Resuscitation Program's (NRP) 6-second method is difficult and results in inaccuracies. We tried to determine whether a simple electronic timing device improves accuracy of heart rate determination. METHODS: One-hundred fourteen clinicians determined four heart rates under conditions simulating a resuscitation by three different methods: their own method, NRP's 6-second method, and an electronic timing device method. Responses were scored as correct if they would have resulted in the same intervention as called for by NRP criteria for each specific heart rate tested. RESULTS: Of 1368 total responses, 267 (19.5%) were incorrect, which could have led to either an inappropriate intervention or lack of an appropriate intervention. The electronic timing device resulted in fewer errors (4%) compared with when clinicians used their own methods (32%) and the NRP's 6-second method (22%). CONCLUSION: The use of a simple electronic timing device improves accuracy of heart rate determination compared with the NRP's 6-second method or when clinicians use their own methods.

Rates of local cerebral protein synthesis in fetal and neonatal sheep.

During gestation there is likely to be a constantly changing rate of protein synthesis in the brain that may exhibit regional specificity. With the use of the quantitative autoradiographic L-[1-(14)C]leucine method for the determination of local rates of leucine incorporation into cerebral protein (lCPS(Leu)), we have sought to characterize this important process. lCPS(Leu) was measured in nine fetal sheep (118-139 days gestational age) and five newborn lambs (1-5 days of age). In other experiments, the fraction of leucine in the precursor pool for protein synthesis in the brain derived from the arterial plasma was determined to be 0.57 +/- 0.04 (mean +/- SE) in one fetus and two lambs. This value was used in the calculation of lCPS(Leu) in 35 regions of the central nervous system, pineal body, and whole brain. Regardless of age, lCPS(Leu) was highest in the pineal body, brain stem, and hypothalamic nuclei and lowest in white matter. In sensorimotor cortex, corona radiata, pyramidal tracts, and whole brain, lCPS(Leu) was positively correlated with prenatal age (P < or = 0.05). These increases in lCPS(Leu) probably reflect myelination in the cerebrum, which is known to occur in late gestation.

Myocardial and cerebral oxygen delivery are not adversely affected by cocaine administration to early-gestation fetal sheep.

OBJECTIVES: Cocaine administration to near-term pregnant sheep causes fetal hypoxemia, but oxygen delivery to the heart and brain are preserved because of increased blood flow. We hypothesized that cocaine administration during earlier fetal gestation impairs oxygen delivery to the heart and brain. STUDY DESIGN: Ten pregnant ewes and fetuses at 0.7 term gestation underwent surgical instrumentation. After 48 hours of recovery fetal blood pressure, heart rate, cerebral and myocardial blood flow, and arterial oxygen content were determined before and during cocaine administration to the ewe. RESULTS: Fetal hypoxemia was not noted in these animals. Fetal myocardial blood flow increased from 220 +/- 100 ml per 100 gm per minute to 349 +/- 183 ml per 100 gm per minute (p=0.03), and oxygen delivery increased from 16 +/- 5 ml of oxygen per 100 gm per minute to 22 +/- ml of oxygen per 100 gm per minute (p=0.02). Fetal cerebral blood flow and oxygen delivery remained unchanged. CONCLUSION: Cerebral and myocardial oxygen delivery are unimpeded by maternal cocaine administration in 0.7 term gestation ovine fetuses.

Cocaine does not compromise cerebral or myocardial oxygen delivery in fetal sheep.

Eight time-dated pregnant ewes at 125 days' gestation (145 days = term) underwent surgery for placement of fetal vascular catheters, electrodes for recording fetal behavioural state, and maternal venous catheters. Three days later, fetal cerebral and myocardial blood flow were determined by the coloured microsphere technique under four conditions: (1) during rapid-eye movement (REM) sleep, before fetal cocaine infusion, (2) 30 min after initiation of a cocaine infusion to the fetus at 0.2 mg/kg per min, (3) during REM sleep, before maternal cocaine infusion, and (4) 30 min after initiation of a cocaine infusion to the ewe at 0.3 mg/kg per min. Cocaine infusion directly to the fetal lamb did not cause hypoxaemia or significantly change cerebral or myocardial blood flow or oxygen delivery. Cocaine administered to the ewe led to a drop in fetal oxygen tension from 3.0 +/- 0.5 to 2.5 +/- 0.3 kPa (P < 0.0001) and in fetal oxygen content from 3.8 +/- 0.7 to 2.8 +/- 0.4 mmol O2/L (P < 0.0001). Prior to maternal cocaine administration, fetal cerebral blood flow was 146 +/- 103 mL/100 g per min and during maternal cocaine infusion it went to 184 +/- 147 mL/100 g per min (P = NS) while myocardial blood flow increased from 156 +/- 92 to 333 +/- 178 mL/100 g per min (P < 0.002). This increase in blood flow negated the effects of hypoxaemia so that cerebral oxygen delivery was unaffected while myocardial oxygen delivery increased an average of 67%. It is concluded that cocaine administration to pregnant sheep does not impede fetal cerebral or myocardial oxygen delivery.

Fetal behavioral state patterns during and after prolonged exposure to cocaine in sheep.

OBJECTIVE: Studies on the effects of cocaine in fetal animals have been limited to acute exposures to the drug. We hypothesized that a prolonged infusion of cocaine to the fetal sheep would initially interrupt normal behavioral state cycling but the effects would be short lived as the fetus gained tolerance to the drug. STUDY DESIGN: The study was performed in a university laboratory on six time-dated pregnant ewes at 125 days' gestation. Fetal sheep, surgically instrumented 3 days before study, were given cocaine hydrochloride 0.6 mg/min for 6 hours. Fetal behavioral state before, during, and after the infusion was compared by repeated-measures analysis of variance. RESULTS: Infusion of cocaine caused a drop in the percentage time that the fetuses spent in both rapid-eye-movement (p < 0.03) and non-rapid-eye movement (p < 0.001) sleep, which was sustained throughout the 6-hour infusion. This was related to a decrease in the number of rapid-eye-movement and non-rapid-eye-movement episodes as opposed to a decrease in the lengths of these behavioral states. With cessation of cocaine infusion, the fetal sheep showed an increase in rapid-eye-movement sleep, with a higher percentage than during control periods (p < 0.02). CONCLUSIONS: Cocaine disrupts fetal rapid-eye-movement sleep without evidence for tolerance to the drug over a 6-hour period. "Catch-up" rapid-eye-movement sleep occurs with cessation of cocaine infusion. Neurobehavioral abnormalities associated with in utero cocaine exposure may be caused by chronic disruption of rapid-eye-movement sleep.

Accidental catheterization of internal iliac artery branches: a serious complication of umbilical artery catheterization.

Umbilical artery catheters can accidentally enter branches of the internal iliac artery during attempted placement in the aorta. The three branches likely to be catheterized are the superior gluteal, inferior gluteal, and internal pudendal arteries. If these misplacements are not recognized and promptly corrected, arterial obstruction may lead to ischemia and infarction of the iliac bone, gluteal muscles, sciatic nerve, perineum, and overlying skin. We present three patients who suffered long-term consequences of umbilical artery catheter misplacements and discuss the radiographic verification of catheter placement that is essential before infusing medications.

Term neonates with hemolytic disease of the newborn and necrotizing enterocolitis: a report of two cases.

Necrotizing enterocolitis in term infants is uncommon, and when it occurs it is usually associated with risk factors such as asphyxia, congenital heart disease, or polycythemia. It has been reported in term neonates after exchange transfusion for hemolytic disease of the newborn; therefore exchange transfusion is recognized as a risk factor. We report two term neonates with hemolytic disease of the newborn resulting from anti-c rhesus incompatibility in whom necrotizing enterocolitis developed before exchange transfusions. These cases implicate hemolytic disease of the newborn without exchange transfusion as a risk factor for necrotizing enterocolitis in term infants.

Early-onset respiratory failure caused by severe congenital neuromuscular disease.

Two unrelated infants with low Apgar scores, pneumothoraces, and severe pulmonary hypertension were treated with extracorporeal membrane oxygenation while receiving chemical sedation and neuromuscular paralysis. After decannulation from extracorporeal membrane oxygenation, hypotonia and hypoventilation persisted. Neurologic evaluation confirmed that both infants had a congenital myopathy.

Multiple coronary thromboemboli and myocardial infarction in a newborn infant.

We report the case of a newborn infant with myocardial infarction caused by thromboembolic occlusion of the left main coronary artery. The clinical presentation was similar to that of hypoplastic left heart. This infant had no condition previously associated with perinatal myocardial infarction. Recognition and management of this rare condition, including the use of thrombolytic therapy, and the implication of deficient natural anticoagulant factors as a cause are discussed.

Epinephrine absorption following endotracheal administration: effects of hypoxia-induced low pulmonary blood flow.

To investigate the effects of hypoxia-induced decreased pulmonary blood flow on the trans-pulmonary absorption of epinephrine, we measured pulmonary blood flow and arterial plasma tritium counts per minute following endotracheal [3H]epinephrine administration in six chronically instrumented newborn lambs. The lambs were ventilated alternately with room air and with an hypoxic gas mixture sufficient to decrease pulmonary blood flow to approximately 50% of baseline values. Using this model, we found that hypoxia-induced low pulmonary blood flow did not lead to lower concentrations of epinephrine following endotracheal administration, but rather higher concentrations (P < 0.03). In all six lambs, counts per minute of tritium were higher following administration during low pulmonary blood flow. There was a negative correlation between pulmonary blood flow and arterial plasma tritium counts per minute (r = -0.64, P < 0.03). We conclude that trans-pulmonary absorption of epinephrine is not decreased during times of hypoxia-induced low pulmonary blood flow. These data lend support to the clinical practice of intratracheal epinephrine administration during neonatal resuscitation.