Neonatal Research

The Branch supports basic and clinical studies concerned with the etiology, pathophysiology, therapy, and follow-up of conditions associated with the perinatal and neonatal period, including adaptation to extrauterine life, hyperbilirubinemia, and sequelae of prematurity, such as asphyxia, respiratory distress, bronchopulmonary dysplasia, hypoglycemia, anemia, and infection. In addition to the PPB, other NICHD Branches and NIH Institutes support neonatal research. Funded projects share the common aim of clarifying neonatal physiology and pathology to permit further developments in the care of these infants.

Cochrane Neonatal Review Group (CNRG)
Bilirubin, Jaundice, and Brain Injury
Hypoxia and the Fetus
Neonatal Pain and Pain Control
Fetal Erythropoeisis
Fetal Insulin Adaptation Responses
Normal and Abnormal Development of Brain Blood Vessels in the Fetus and Newborn
Blood Vessels in the Lungs of Newborn Infants
Neonatal Lung Injury

Cochrane Neonatal Review Group (CNRG) 

 The NICHD has funded the contract with CNRG since 1995, to provide systematic reviews of randomized controlled trials in neonatal medicine. The reviews are posted on the NICHD Web site (http://www.nichd.nih.gov/cochrane/cochrane.htm). The latest Cochrane Library Volume (V1, 2004) contains 169 completed reviews, the same number as in the main Cochrane Library. All reviews are performed by experts who are identified by four international editors at no cost to the NICHD. The CNRG ranks second in the total number of reviews produced for the prestigious Cochrane Collaboration. The Neonatal Cochrane Reviews have played an important role in developing policies of professional academic societies. It is a popular site for health care professionals; in fact, it is one of the most frequently visited pages on the NICHD Web site.

Bilirubin, Jaundice, and Brain Injury

Many pathological states in the fetus and newborn lead to jaundice, a condition often seen even in healthy infants because of transient developmental immaturity of liver. Branch-supported studies have helped to understand the basic biochemistry and photobiology of bilirubin, decipher the mechanism of cell injury with elevated bilirubin, and explore the value of new and evolving treatments for jaundice, such as heme oxygenase inhibitors. Among the latter, PPB-supported studies have shown that tin-mesoporphyrin is safe and effective in reducing bilirubin load in experimental animals and human infants. This avenue of therapy is currently being explored in large-scale clinical studies (J Perinatol 2003; 23:123-7; and J Mol Med 2002; 80:655-64).

Hypoxia and the Fetus

Blood vessels in the developing fetal brain respond to hypoxia (low oxygen levels) differently than do adult blood vessels. Defining the pathological mechanisms of hypoxia is crucial to understanding certain conditions in the fetus and the infant, such as intracranial hemorrhage seen in hypoxia and other brain injuries. NICHD-supported investigators have developed a unique model system of fetal hypoxia that relies on high altitude to test its effects on the development of fetal brain and cardiovascular systems.

By using the innovative "patch-clamping" technique, in which electric current changes in singleionic channels of biologic membranes can be studied under experimental conditions, researchers showed that blood vessels in different parts of the body respond differently to the same levels of hypoxia. Furthermore, the research indicated that a variety of nutritional factors, extracellular chemical signals, and molecular signals control and modulate hypoxic responses. By understanding the underlying mechanisms of certain disease conditions in newborns, researchers may be able to mediate their effects and determine how they impact the developmental origin of adult diseases.

Neonatal Pain and Pain Control

The Branch funded a large, multicenter, controlled trial of prophylactic, preemptive analgesia to reduce or control pain in high-risk newborn infants (24 to 32 weeks' gestation) who were receiving mechanical ventilation support. The findings of this study show that preemptive analgesia markedly reduced pain experience, but also increased the incidence of adverse side effects (Lancet 2004, 363:1673-1682). Researchers found a strong correlation between the need for any analgesic support and poor outcome. The study also concluded that continuous infusion of opioid analgesic was associated with more systemic side effects than intermittent use of the same, as clinically needed. These findings will have a significant impact on clinical practice.

Fetal Erythropoeisis

Many pathological conditions, including fetal anemia and hypoxia (low oxygen concentrations), may lead to low oxygen levels or anemia in the developing fetus; in response, both the fetus and placenta produce erythropoietin (EPO) to restore fetal red blood cells. To understand the mechanisms of these physiological adjustments, a group of researchers supported by the PPB examined how and to what extent the genes producing EPO were expressed in the fetal tissue of sheep. Their work showed that, during hypoxia, the fetal kidneys increased the secretion of EPO by seven-fold and the placenta by 15-fold; at the same time, both the amnion and chorion actively participated in producing EPO, but this response was not sustained if the hypoxia was prolonged. In addition to augmenting knowledge of the mechanisms of homeostatic adjustments and fetal and placental regulation of overall well-being, these studies have implications for potential treatment of anemic fetuses (J Soc Investig 2002; 9:75-79; and Am J Obstet Gynecol, In press).

Fetal Insulin Adaptation Responses

Accumulating evidence supports the hypothesis that adult-onset coronary artery disease, diabetes, and hypertension may have developmental origins. For instance, it is known that when the fetal supply of glucose and other nutrients is deficient, the fetus does not grow adequately. Thus, abnormal fetal metabolism of glucose may be related not just to poor fetal growth, but also to adult onset of diabetes. A number of Branch-supported investigators are studying fetal endocrine functions and their relationships to glucose homeostasis, specifically those related to fetal insulin production, the size of the pancreatic islet cells, and factors affecting fetal growth. One group of researchers studying how pancreatic cells respond to changing blood glucose levels in fetal sheep found that exposure to hypoglycemia for 14 days, with subsequent recovery to normal blood glucose levels, led to a weaker insulin response in subsequent challenges or hypoglycemia as compared to adult controls. The sheep fetuses subjected to chronic starvation were not able to respond to glucose infusion by producing insulin. This lack of insulin response may underlie the origin of diabetes in later life. These findings strongly indicate that programming of pancreatic insulin-secretion responsiveness can occur in fetal life, predisposing to type 2 diabetes in adult life. (Placenta 2004; 25:70-7; and J Physiol 2003; 15:95-105).

Normal and Abnormal Development of Brain Blood Vessels in the Fetus and Newborn

It is known that the cerebral arteries receive a large fraction of cardiac output because of high brain metabolism; however, the mechanisms that control metabolic rate and blood flow are not well understood. Many chemical messengers are involved in mediating such responses. Using a variety of developmental animal models, PPB-supported researchers have shown that endotheliumdependent relaxation is depressed in immature cerebral arteries. Such depression, they found, involved attenuation of endothelial sensitivity to shear-stress (the force of blood circulating in arteries) in the neonate, resulting from a decrease in the specific activity of endothelial NO synthase (eNOS) in fetal arteries, a situation not present in adult arteries (Arch Physiol Biochem 2003; 111:36-44; J Physiol 2003; 549:625-33; High Alt Med Biol 2003; 4:203-13; and J App Physiol 2003; 94:724-32).

These results suggest that maturation has a dramatic influence on the relative balance of different components of the endothelium-dependent vasodilator pathway. Understanding the molecular mechanisms through which postnatal maturation of blood vessels occurs is crucial to deciphering the complexities of growth and maturation. Further, elucidation of the key roles played by hormones and growth factors are critical to understanding the fundamental biology of growth and development. This line of work provides a glimpse into how such regulations evolve and offers an avenue to test new strategies for clinical management of neonatal vascular pathologies. Such knowledge will also enhance understanding of fetal origins of adult cardiovascular disorders (High Alt Med Biol 2003; 4:203-213).

Blood Vessels in the Lungs of Newborn Infants

Normal functioning of the blood vessels in the lungs of newborn infants is critical for healthy transition from the fetal to neonatal period and beyond. Infants who have persistent pulmonary hypertension (PPHN) experience poor outcomes and are at risk for problems later in life. Research by NICHD-supported scientists is helping explain the mechanisms of PPHN in newborns as a way to improve the infants' outcomes. The research showed that the increase in pulmonary blood flow normally occurring at birth is related to an increase in synthesis and release of adenosine triphosphate (ATP), which is made in response to increasing levels of oxygen in the blood of normal infants. ATP released into the plasma not only acts as a signal to increase the pulmonary blood flow, but also interacts with NO synthase (NOS) to stimulate NO release into the pulmonary circulation; researchers found that, in models of PPHN, this mechanism was altered. Instead of replying on NOS, in PPHN, other enzymes were involved in the release of superoxide, a vasoconstrictor. These findings may uncover possible therapeutic agents that can help correct the imbalance in NOS function that occurs in PPHN (Am J Physiol Heart Circ Physiol 2003; 285:H204-11).

Neonatal Lung Injury

PPB-funded investigators are working to understand factors that enhance fetal and neonatal lung injury from inflammatory mediators in premature animals and to develop treatment strategies that will reduce the development of bronchopulmonary dysplasia, a chronic lung disease seen in a large proportion of surviving, extremely premature infants. Researchers induced amniotic fluid inflammation in pregnant sheep using endotoxin and delivered the lambs on the 130th day of gestation (equivalent to 34 weeks of human pregnancy); the fetal lambs were delivered and were supported by various ventilatory strategies. The results showed that endotoxin-exposed lungs required higher ventilation pressures, although ventilation, per se, did not increase lung injury. However, the trachea and lungs of the ventilated and antenatal endotoxin-exposed animals contained six-to-12 times more inflammatory cells, indicating that fetal lung inflammation had a very serious effect on the developing immature lungs (Am J Physiol Lung Cell Mol Physiol 2004; 286; 3:L573-9).

The same group of investigators is trying to determine whether continuous positive airway pressure (CPAP) can reduce the need for mechanical ventilation in preterm infants as a strategy to minimize lung injury. They studied premature lambs randomized to: no ventilation, conventional mechanical ventilation, or CPAP. The CPAP lambs breathed without distress and maintained normal blood carbon dioxide levels; their lungs also held more air compared to the ventilated lambs. Lung washing revealed about seven times more neutrophils (inflammatory cells) in ventilated lambs when compared to unventilated and CPAP lambs. These findings suggest that early CPAP may be a safe strategy to support infants with lung disease, rather than implementing early positive pressure ventilation (Pediatr Res 2002; 52; 3:387-92).

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