Elizabeth Cristofalo

Randomized Trial of Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants

OBJECTIVE To compare the duration of parenteral nutrition, growth, and morbidity in extremely premature infants fed exclusive diets of either bovine milk-based preterm formula (BOV) or donor human milk and human milk-based human milk fortifier (HUM), in a randomized trial of formula vs human milk. STUDY DESIGN Multicenter randomized controlled trial. The authors studied extremely preterm infants whose mothers did not provide their milk. Infants were fed either BOV or an exclusive human milk diet of pasteurized donor human milk and HUM. The major outcome was duration of parenteral nutrition. Secondary outcomes were growth, respiratory support, and necrotizing enterocolitis (NEC). RESULTS Birth weight (983 vs 996 g) and gestational age (27.5 vs 27.7 wk), in BOV and HUM, respectively, were similar. There was a significant difference in median parenteral nutrition days: 36 vs 27, in BOV vs HUM, respectively (P = .04). The incidence of NEC in BOV was 21% (5 cases) vs 3% in HUM (1 case), P = .08; surgical NEC was significantly higher in BOV (4 cases) than HUM (0 cases), P = .04. CONCLUSIONS In extremely preterm infants given exclusive diets of preterm formula vs human milk, there was a significantly greater duration of parenteral nutrition and higher rate of surgical NEC in infants receiving preterm formula. This trial supports the use of an exclusive human milk diet to nourish extremely preterm infants in the neonatal intensive care unit.

Caffeine Modulates TNF-α Production by Cord Blood Monocytes: The Role of Adenosine Receptors

Caffeine, a nonspecific adenosine receptor (AR) antagonist is widely used to treat apnea of prematurity. Because adenosine modulates multiple biologic processes including inflammation, we hypothesized that AR blockade by caffeine would increase cytokine release from neonatal monocytes. Using cord blood monocytes (CBM), we investigated 1) the changes in AR mRNA profile by real time quantitative reverse-transcription polymerase-chain-reaction (qRT-PCR) and protein expression (western blot) after in vitro culture, caffeine or lipopolysaccharide (LPS) exposure, and 2) the modulation of cytokine release and cyclic adenosine monophosphate (cAMP) production by enzyme-linked immunosorbent assay (ELISA) induced by caffeine and specific AR antagonists: DPCPX(A1R), ZM241385(A2aR), MRS1754(A2bR), and MRS1220(A3R). After 48 h in culture, A2aR and A2bR gene expression increased 1.9 (p = 0.04) and 2.5-fold (p = 0.003), respectively. A1R protein expression directly correlated with increasing LPS concentrations (p = 0.01), with minimal expression preexposure. Only caffeine (50 μM) and DPCPX (10 nM) decreased tumor necrosis factor-alpha (TNF-α) release from LPS activated-CBM by 20 and 25% (p = 0.01) and TNF-α gene expression by 30 and 50%, respectively, in conjunction with a ≥2-fold increase in cAMP (p < 0.05). AR blockade did not modulate other measured cytokines. The induction of A1R after LPS exposure suggests an important role of this receptor in the control of inflammation in neonates. Our findings also suggest that caffeine, via A1R blockade, increases cAMP production and inhibits pretranscriptional TNF-α production by CBM.

Peripheral arterial chemoreceptors and sudden infant death syndrome

Sudden infant death syndrome (SIDS) is the major cause of death in infants between 1 month and 1 year of age. Two particular concerns are that (1) premature or low birth weight (<2500-g) infants have a 2- to 40-fold greater risk of dying of SIDS (depending on the sleep position) than infants born at term and of normal birth weight, and that (2) the proportion of premature infants dying of SIDS has increased from 12 to 34% between 1988 and 2003. Hypo- and hypersensitivity of peripheral arterial chemoreceptors (PACs) may be one biological mechanism that could help to explain the epidemiological association between the increased incidence of SIDS in formerly premature infants. Because premature infants are often exposed to the extremes of oxygen stress during early postnatal development, they are more likely to have a maladaptive response of PACs later in their lives. As the first line of defense that mediates an increase in ventilation to a hypoxic challenge during wakefulness and sleep, PACs also mediate arousal responses during sleep in response to an asphyxial event that is often associated with upper airway obstruction. In most mammalian species, PACs are not fully developed at birth and thus are vulnerable to plasticity-induced changes mediated by environmental exposures such as the extremes of oxygen tension. Hypoxic or hyperoxic exposure during early postnatal development can lead to hyposensitive or hypersensitive PAC responses later in life. Although baseline chemoreceptor activity may not be the cause of an initial hypoxic or asphyxial event, the level of peripheral chemoreceptor drive does modulate the (1) time to arousal, (2) resumption of airflow during airway obstruction, (3) escape behaviors during rebreathing, and (4) cardiorespiratory responses that result from activation of the laryngeal chemoreflex. The laryngeal chemoreflex can be stimulated by reflux of gastric contents above the upper esophageal sphincter, or an increase in nasopharyngeal secretions from upper respiratory tract infections--events that contribute to some cases of SIDS. In this review, evidence is presented that both hypo- and hypersensitivity of PACs may be disadvantageous to the premature infant who is placed in an at risk environment for the occurrence of hypoxemia/asphyxia event thereby predisposing the infant to SIDS.

Women's response to fetal choroid plexus cysts detected by prenatal ultrasound

Objectives:To determine maternal responses to detection of a minor structural variant, the choroid plexus cyst (CPC), in their fetus on prenatal ultrasound.Study design:We interviewed 34 pregnant women with an isolated CPC detected on mid-pregnancy ultrasound about their objective experience at diagnosis, emotional response and subsequent reactions. Audiotaped, transcribed responses were evaluated by two independent raters and analyzed qualitatively and quantitatively.Results:All women reported negative emotional responses including shock, distress, fear and decreased attachment, despite counseling by 82% of providers that the CPC was probably benign. Three women underwent amniocentesis purely for reassurance after CPC detection. Most (79%) sought information beyond what their physician provided, frequently on the internet. One half of women reported that intense negative responses were temporary. However, weeks after diagnosis, 62% continued to believe that the CPC presented some danger to their baby.Conclusions:Detection of CPC prenatally can evoke profound, negative maternal emotional responses despite accurate provider counseling. Practitioners should consider these responses when counseling parents about these and other structural variants of unclear functional significance.Sponsor:The Thomas Wilson Sanitarium for the Children of Baltimore City.

Preterm birth: Transition to adulthood

Preterm birth is associated with greater difficulty with transitions from childhood to adolescence to adulthood. Adolescents and young adults born preterm have higher rates of cerebral palsy, intellectual disability, cognitive impairment, learning disability, executive dysfunction, attention deficit disorder, and social-emotional difficulties than their peers born fullterm. Compared to individuals born fullterm, more preterm survivors have major neurodevelopmental or psychiatric disability and need financial supports and societal resources. Neuroimaging studies of adolescents and adults born preterm report higher rates of brain injury, differences in regional brain structure, and different brain circuits than in those born fullterm. Making the transition to adulthood is more difficult for young adults who were born preterm than their peers born fullterm, in that fewer complete high school and higher education, find and keep meaningful employment, and live independently from their parents. As a group, they do not tend to be risk-takers, and they have lower rates of alcohol abuse, use of illicit drugs, and criminal offenses than do their peers. Despite their many challenges, the majority of adults born preterm function well, form personal relationships, integrate well into their community, and are as satisfied with their quality of life as are their peers. Concerns regarding current preterm infants, with more extremely preterm survivors, overwhelming our medical, educational, and societal resources should serve as an impetus for research on prevention of preterm births and brain injury, as well as how to support and promote their ongoing neuromaturation and recovery from injury.

Isolated prenatal choroid plexus cysts do not affect child development.

To examine the effect of isolated prenatal choroid plexus cysts (CPCs) on child cognitive, behavioral, motor, and autonomic development at 18 months of age.

Transfontanellar duplex brain ultrasonography resistive indices as a prognostic tool in neonatal hypoxic-ischemic encephalopathy before and after treatment with therapeutic hypothermia

Objective:Prior to therapeutic hypothermia (that is, cooling), transfontanellar duplex brain sonography resistive indices (RI) were studied as a bedside non-invasive measures of cerebral hemodynamics in neonates who suffered from hypoxic-ischemic encephalopathy (HIE). We compared pre- and post-cooling RI values and examined the relationships between RI values and specific long-term neurodevelopmental outcomes.Study Design:Transfontanellar duplex brain sonography, including RI, were obtained for 28 neonates prior to cooling and for 20 neonates following cooling. All RI values were sampled in the anterior cerebral artery at the beginning of each ultrasound study. Neurodevelopmental assessment was conducted between ages 20–32 months with the Mullen Scale of Early Learning. The relationships between pre- and post-cooling RI and cognitive and motor outcomes were studied.Result:Neonates with RI values <0.60 prior to and following cooling were more likely to die or have severe neurodevelopmental disability by ages 20–32 months than those with RI>0.60. Lower RI values were associated with specific neurodevelopmental deficits in motor skill attainment.Conclusion:Pre- and post-cooling transfontanellar duplex brain sonography RI values may be a useful prognostic tool, in conjunction with other clinical information, for neonates diagnosed with HIE. The results of this study suggest that further study of the prognostic value of RI values for short- and long-term outcomes is warranted.

Posthemorrhagic Hydrocephalus in Preterm Neonates: Socioeconomic Characteristics in a Single-Institution Experience

Patients with posthemorrhagic hydrocephalus (PHH) from germinal matrix hemorrhage of prematurity often require numerous early interventions, as well as long-term follow-up care from pediatric neurosurgeons, which continues to place high demands on the existing workforce and pediatric health care system. There are established correlations between premature birth and low socioeconomic status. The aim of this study is to characterize the demographic profile and follow-up patterns in this subpopulation of surgically treated infants with PHH from prematurity. Methods: A retrospective analysis of the electronic patient records for a single institution, from 2007 to 2010, was performed. All patients who underwent neurosurgical intervention for the treatment of PHH were selected for further analysis. Data elements available within the records included patient demographic features, inpatient treatments and procedures, inpatient mortality rates, length of stay, and postoperative follow-up at the institution. Socioeconomic status was assessed using the median household income for the patient’s zip code, as reported in the United States Census for the year 2000. Results: A total of 40 patients who underwent neurosurgical intervention for PHH at a single institution were identified. More patients were female (52.5%); the majority of patients were Black (57.5%). No patients were uninsured; most patients had public insurance (62.5%), and 65% were below the Maryland State median household income (USD 52,868). There were trends toward more frequent emergency room visits among those covered by public insurance and those below the state and national median house income, although differences were not statistically significant. Conclusions: Our data indicate that the majority of patients fall within lower household income brackets, are born into households earning less than the statewide median household income, and are covered by public insurance. In light of the socioeconomic profile of the patient population reported here, these data may prove to be useful in preventative strategies aimed toward prematurity, PHH, and the ongoing treatment of hydrocephalus by pediatric neurosurgeons and other pediatric subspecialists.

Extrauterine Neuromaturation of Low Risk Preterm Infants

The objective of the study was to follow neuromaturation in preterm infants. From serial exams in 90 low risk very low birthweight infants, each infants Maturity Scores (the sum of tone, reflex, and response items) were plotted against postmenstrual age (PMA) when examined. Each infants estimated line of best fit provides two descriptors of that infants neuromaturation: slope (Individual Maturity Slope) and y-value (Predicted Maturity Score at 32-wk PMA). We found that Maturity Scores increased with PMA; 96% had correlation coefficients >0.8. Mean Actual and Predicted Maturity Scores at 32-wk PMA were 60 and 58, respectively, in 65 infants. When stratified by gestational age, Mean Actual Maturity Score at 30-wk PMA were 50 whether infants were 1 or several weeks old when examined. Therefore, low risk preterm infants demonstrated individual variability in rate of neuromaturation. Tone, reflexes, and responses nonetheless emerged in a predictable pattern, whether neuromaturation was intrauterine or extrauterine. This unique tool that measures preterm neuromaturation requires expertise but no technology. It has an exciting potential for providing insight into how emerging central nervous system function and structure influence each other, as well as how the central nervous system recovers from injury.