TRANSITIONAL CIRCULATION

The newborn's lungs expand and become air filled with gradual reabsorption of fetal lung fluid. This increases the partial pressure of arterial oxygen (PaO2) of blood flowing through the newborn lung, which in turn mediates a cascade of events that completes the transition to adult circulatory patterns. Flow through the umbilical arteries ceases, and the venous flow through the cord slows and then stops. Pulmonary vascular resistance falls, and pulmonary blood flow increases (pulmonary vascular resistance continues to fall with increases in blood flow over the first 30 to 45 days of extrauterine life). The ductus venosus and ductus arteriosus close, and decreased pulmonary arterial resistance coupled with increased systemic resistance create increased blood flow through the atria. Left atrial pressure exceeds right atrial pressure, which leads to closure of the foramen ovale.

NEONATAL CARDIAC PHYSIOLOGY

Because neonates and small children have relatively noncompliant ventricular walls, they cannot increase stroke volume but rely on changes in heart rate to adjust cardiac output. Thus, sinus tachycardia is usually the first response to stress in infants and young children. The neonatal myocardium requires more oxygen than the infant's or child's heart and has a lower systolic reserve, which predisposes to congestive heart failure. Although the ductus arteriosus and foramen ovale are usually functionally closed by 15 hours of life and 3 months of age, respectively, shunting may still occur through these pathways during times of stress.2 Finally, the neonatal right ventricle is still predominant, whereas the left ventricle is predominant in older infants and children, and pulmonary vascular resistance is relatively high and oxygen responsive.

Preload is the amount of blood that the heart receives to distribute to the body. Decreasing the amount of blood flowing into the heart lowers cardiac output. Similarly, increasing the amount of blood into the heart increases cardiac output in accordance with Starling forces, to the point of maximum compliance of the ventricular wall. When the ventricular wall compliance is exceeded, cardiac output decreases dramatically and congestive heart failure occurs.

Afterload is the resistance to blood flow out of the heart and is determined in neonates by the size and compliance of the ventricles, peripheral vascular resistance (which is largely mediated by catecholamines), and, when present, anatomic obstructions such as aortic stenosis or critical coarctation of the aorta.

Contractility or inotropy, which is the ability of the cardiac muscle to pump blood out of the heart, refers to the force or power of cardiac contraction and determines the amount of work that the heart can perform. Increasing the cardiac contractility increases the stroke volume and hence the cardiac output. Cardiac contractility is normally regulated by neural or humoral mechanisms. The ability of the neonatal heart to increase contractility is limited, as previously mentioned, and stroke volume is primarily increased through increases in rate.

Cardiac rate or chronotropy is the ability of the heart muscle to pump blood out of the heart per fixed unit of contraction. In the typical circumstance, chronotropy and inotropy cannot be differentiated with regard to therapeutic maneuvers. Typically, both the cardiac rate and the relatively fixed contractility of the neonatal heart contribute to the overall cardiac output, with the former contributing more of the output. In the hearts of children older than 4 or 5 years, there is a more balanced contribution to cardiac output, with the contractility playing a much more prominent role.

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The Placenta

The placenta acting as an endocrine organ influences most aspects of fetal growth, including the supply of adequate nutrition and oxygen and regulation of hormones and growth factors. Aberrant delivery or control of any of these factors affects fetal growth; placental weight is usually directly related to birth weight.

Classic Hormones of Growth and Fetal Growth

The hormones that mediate postnatal growth do not necessarily play the same roles in fetal growth. Growth hormone (GH) is present in very high concentrations in the fetus, in contrast to the limited presence of GH receptors. Although this discrepancy suggests limited activity of GH in the fetus, GH does play a role in fetal growth as reflected in the average birth weight 1 standard deviation (SD) below the mean in GH-deficient infants. Infants with GH resistance due to abnormal, reduced or absent GH receptors (eg, Laron syndrome) have elevated GH and low serum insulin-like growth factor (IGF)-I levels; they also have decreased birth length and weight. Thyroid hormone deficiency does not directly affect human birth weight, but prolonged gestation can be a feature of congenital hypothyroidism, and this factor will itself increase weight. Placental lactogen exerts no effect on birth size in human beings. However, the concentration of placental-derived GH (from the GHV gene) is significantly decreased in the serum of a pregnant woman bearing a fetus with IUGR.

Growth Factors and Oncogenes in Fetal Growth

Oncogenes may be responsible for neoplastic growth in postnatal life, but expression of these genes is important in the normal development of many fetal organs. Remarkably, the same oncogenes that cause postnatal neoplasia are prevented from causing tumors in the normally differentiating fetus. For example, a mutation in the von Hippel-Lindau gene predisposes to retinal, cerebellar, and spinal hemangioblastomas, renal cell carcinomas, and pheochromocytomas, but the normal VHL gene is expressed in all three germ cell layers of the embryo and in the central nervous system, kidneys, testis, and lung of the fetus, suggesting a role in normal fetal development for this gene.

Insulin-Like Growth Factors, Receptors, and Binding Proteins

IGF-I in the fetus is regulated by metabolic factors other than GH, in contrast to the dependence of IGF-I generation upon GH in postnatal life. One explanation is that there are fewer GH receptors in the fetus than after birth. In the human fetus, serum GH falls during later gestation owing to maturation of central nervous system's negative control, whereas serum IGF-I and IGF-binding protein (IGFBP)-3 rise during gestation, demonstrating their independence from GH stimulation.

Studies of knockout mice, which lack various growth factors or binding proteins, indicate a role for IGF-II in growth during early gestation and one for IGF-I during later gestation. Knockout of type 1 IGF receptors leads to a more profound growth failure than is found in IGF-I knockout mice alone, suggesting that factors other than IGF-I (eg, IGF-II) exert effects on fetal growth through the type 1 receptor.

Study of transgenic mice overexpressing IGFBPs supports the concepts that excess IGFBP-1 stunts fetal growth while excess IGFBP-3 leads to selective organomegaly. For example, overexpression of IGFBP-3 in mice led to organomegaly of the spleen, liver, and heart, although birth weight was not different from that of wild-type mice.

Although controversy remains over some of the data regarding IGFs and fetal growth, a summary of the complex IGF system in the fetus, based on the evidence from various species, appears to apply to the human being as follows.

  1. IGFs are detectable in many fetal tissues from the first trimester onward.

  2. Concentrations of IGFs in the fetal circulation increase during pregnancy, and at term the concentrations of IGF-I are directly related to birth weight.

  3. In mice, disruption of the IGF genes leads to severe growth retardation.

  4. There is a striking increase in IGFBP-1 and IGFBP-2 concentrations in amniotic fluid at the end of the first trimester.

  5. The major binding proteins in the human fetus are IGFBP-1 and IGFBP-2.

  6. From as early as 16 weeks, there is an inverse correlation between fetal concentrations of IGFBP-1 and birth weight.

  7. In the mother, circulating concentrations of IGF-I and IGFBP-1 increase during pregnancy.

  8. Maternal IGFBP-1 concentrations are elevated in severe pre-eclampsia and IUGR.

  9. Fetal concentrations of IGFBP-1 are elevated in cases of IUGR, especially those associated with specific evidence of reduced uteroplacental blood flow. Production of IGFBP-1 appears to be a sensitive indicator of the short- or long-term response to reduced fetal nutrition.

Insulin

Although insulin is a major regulatory factor for carbohydrate metabolism, many lines of evidence demonstrate that it is a growth factor as well and has importance in fetal growth. Macrosomia is a well-known effect of fetal hyperinsulinism as is found in the infant of the diabetic mother. Errors in the normal pattern of IGF-II gene expression from the paternal chromosome and type 2 IGF receptor (for IGF-II) from the maternally derived gene underlie the pathogenesis of Beckwith-Wiedemann syndrome. Affected infants are large and have elevated insulin concentrations. Increased weight gain in pregnant women over 40 lb leads to significantly increased risk of fetal macrosomia in gestational diabetes mellitus as well as in those with normal glucose tolerance test results.

Just as increased insulin stimulates fetal growth, syndromes of fetal insulin deficiency such as congenital diabetes mellitus, pancreatic dysgenesis, or fetal insulin resistance (eg, leprechaunism) are characterized by IUGR. Infants born to diabetic mothers with vascular disease, hypertension, and or eclampsia or preeclampsia also have IUGR and are born SGA. In that situation, it is clear that limited nutrient delivery compromises the growth of the infant.

Epidermal Growth Factor

Epidermal growth factor (EGF) is involved with fetal growth, and expression varies with disordered fetal growth. Microvilli purified from the placentas of infants with IUGR have decreased or absent placental epidermal growth factor receptor (EGF-R) phosphorylation and tyrosine kinase activity. Maternal smoking decreases birth weight by an average of 200 g, with the major effect occurring late in pregnancy; the placenta responds to smoking by significant changes in its vascularity, which leads to fetal hypoxia. There are decreased numbers of EGF-Rs and a reduced affinity of these receptors for EGF in the placentas of women who are smokers. Hypertensive patients also have decreased numbers of placental EGF-Rs, which may result in IUGR.

EGF levels in amniotic fluid are normally increased near term but decreased in pregnancies complicated by IUGR—although not, conversely, increased in infants who are large for gestational age. EGF levels in the first urines to be voided by IUGR and macrosomic infants are lower than in control infants.

EGF administered to fetal monkeys results in histologic and biochemical maturation of their lungs, leading to improved air exchange and a diminished requirement for respiratory support. Surfactant apoprotein A concentration and the lecithin-sphingomyelin ratio are both significantly higher in the amniotic fluid of EGF-treated fetuses. Whereas birth weight is not affected by EGF, adrenal and gut weights, standardized for body weight, are increased significantly. Furthermore, EGF stimulates gut muscle, gut enzyme maturation, and gut size and content, improving the ability of the infant to absorb nutrients. Lastly, EGF advances the maturation of the fetal adrenal cortex, increasing the expression of 3-beta-hydroxysteroid dehydrogenase. Because EGF can be absorbed orally, this raises a question as to whether EGF could be a useful treatment for premature infants or, postnatally, for causing more rapid maturation of the neonate and improving survival in premature infants.

Fibroblast Growth Factor

Genetically engineered fibroblast growth factor receptor 2 (FGF-R)-deficient mice are severely growth-retarded and die before gastrulation. Aberrant FGF signaling during limb and skeletal development in the human being can lead to syndromes of dysmorphia. For example, achondroplasia is due to mutations in the transmembrane domain of the type 3 FGF-R.

Genetic, Maternal, and Uterine Factors

Maternal factors, often expressed through the uterine environment, exert more influence on birth size than paternal factors. The height of the mother correlates better with fetal size than the height of the father. However, there is a genetic component to length at birth that is not sex specific. Firstborn infants are on the average 100 g heavier than subsequent infants; maternal age over 38 years leads to decreased birth weight; and male infants are heavier than female infants by an average of 150 to 200 g. Poor maternal nutrition is the most important condition leading to low birth weight and length on a worldwide basis. Chronic maternal disease and eclampsia can also lead to poor fetal growth. Maternal alcohol ingestion has severe adverse effects on fetal length and mental development and predisposes to other physical abnormalities seen in the fetal alcohol syndrome such as microcephaly, mental retardation, midfacial hypoplasia, short palpebral fissures, wide-bridged nose, long philtrum, and narrow vermilion border of the lips. Affected infants never recover from this loss of length but attain normal growth rates in the postnatal period. Abuse of other substances and chronic use of some medications (eg,phenytoin) can cause IUGR. Cigarette smoking causes not only retarded intrauterine growth but also decreased postnatal growth for as long as 5 years after parturition. Maternal infection—most commonly toxoplasmosis, rubella, cytomegalovirus infection, herpes simplex infection, and HIV infection—leads to many developmental abnormalities as well as short birth length. In multiple births, the weight of each fetus is usually less than that of the average singleton. Uterine tumors or malformations may decrease fetal growth.

Chromosomal Abnormalities and Malformation Syndromes

Infant's with abnormal karyotypes may have malformation syndromes and may also demonstrate poor fetal or postnatal growth. In most cases, endocrine abnormalities have not been noted. For further discussion of this extensive subject, the reader is referred to other sources listed in the references at the end of this chapter.

Fetal Origins of Adult Disease

The metabolic syndrome, “syndrome X,” or the insulin resistance syndrome consists of (1) hypertension, (2) impaired glucose tolerance, and (3) elevated triglycerides among other features (see Chapter 17). Insulin resistance is a cardinal feature and might be the basis for most or all of these complications or may be just one feature of the syndrome, according to some. The metabolic syndrome is one of the long-lasting effects of abnormalities in fetal growth. Evidence from many international studies indicates a relationship between low birth weight or low weight at 1 year of age and chronic disease in adulthood. An opposing view is that catch-up growth, rather than low birth weight, is responsible for these defects long into the child's future.

Inanition during the last two trimesters of pregnancy, which occurred during the famine in Holland during World War II, led to an 8% to 9% decrease in birth weight; however, female infants born under these conditions later gave birth to normal-sized infants. On the other hand, in the Dutch and Leningrad famines, infants born after early gestational starvation of their mothers, but with improved maternal nutrition in late gestation were of normal size at birth. However, the female infants, born of normal size after this early gestational maternal starvation themselves gave birth to small infants (SGA of 300-500 g decrease). In other populations, women with a history of SGA tend to have SGA infants themselves, and some studies show that generations of malnutrition must be followed by generations of normal nutrition before there is correction of the birth weight of subsequent infants. The sparse environment of the fetus early in gestation in a mother with various degrees of starvation programs the fetal metabolism for survival of the fetus but later in life these survival techniques become maladaptive in an environment of plenty. Insulin resistance in fetal life may spare nutrients from utilization in muscle, thus leaving them available for the brain; this mechanism would serve to minimize central nervous system damage in the fetus during periods of malnutrition. The complexity of the situation is not completely understood but is the target of extensive research in vivo, in vitro, and in long-term clinical studies.

Birth weight and rate of postnatal growth (ie, catch-up growth)—not prematurity alone—are inversely related to cardiovascular mortality and the prevalence of the metabolic syndrome. It is not yet clear what the optimal nutrition is for a premature or small-for-gestational-age infant to avoid this metabolic programming.

Studies of otherwise normal but thin children, who had a history of SGA, demonstrated insulin resistance before the teenage years, supporting the concept of early metabolic programming. Present-day adults, who were born in the Netherlands during the Dutch famine who had the lowest birth weights and the lowest maternal weights (those subjects whose mothers experienced malnutrition during the last two trimesters noted above), show a degree of insulin resistance that is directly related to their degree of SGA, further documenting the relationship between fetal undernutrition and adult insulin resistance as the etiology of poor growth.

On the other hand, large infants born to mothers with diabetes mellitus often develop childhood obesity and insulin resistance even if they have a period of normal weight between 1 and 5 years of age. Remarkably, studies of the offspring of Dutch mothers exposed to famine during World War II in the first two trimesters (the time in which birth weight is least affected by maternal starvation) demonstrated a two-fold increase in the incidence of obesity at 18 years of age, compared with a 40% decrease in the incidence of obesity if the individual was exposed to famine in the last trimester (the time in which birth weight is most negatively impacted by maternal starvation).

Individuals born SGA also have variations in pubertal development and reproductive hormones. SGA girls tend to have earlier puberty, or if puberty occurs at an average age, more rapid progression of puberty or polycystic ovarian syndrome (PCOS). Adult males born SGA have increased aromatase and increased 5-alpha reductase demonstrating effects on reproduction in the male as well as the female. In sum, prenatal and early postnatal growth affects the older child and adult in many ways.

 

 

 

 

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