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Physiology of the Newborn
Of all pediatric patients, the neonate possesses the most distinctive and rapidly changing physiologic characteristics. These changes are necessary because the newborn must adapt from placental support to the extrauterine environment. There is also early organ adaptation and the physiologic demands of rapid growth and development. This chapter will emphasize the dynamic physiologic alterations of the neonate.
Newborns are classified based on gestational age, weight, head circumference, and length. Preterm infants are those born before 37 weeks of gestation. Term infants are those born between 37 and 42 weeks of gestation, whereas post-term infants have a gestational age that exceeds 42 weeks. With advances in neonatal intensive care, infants born as early as 21 weeks of gestation have survived, and the medical and ethical guidelines regarding the care of these extremely premature neonates continue to evolve. Babies whose weight is below the 10th percentile for age are considered small-for-gestational-age (SGA). Those at or above the 90th percentile are large-for-gestational-age (LGA). Babies whose weight falls between these extremes are appropriate-for-gestational-age (AGA). Further subclassified, premature infants are characterized as moderately low birth weight if they weigh between 1501 and 2500 g, very low birth weight between 1001 and 1500 g, and extremely low birth weight if less than 1000 g.
SGA newborns are thought to suffer intrauterine growth retardation (IUGR) as a result of placental, maternal, or fetal abnormalities. Conditions associated with IUGR are shown in Fig. 1.1 . SGA infants have a body weight below what is appropriate for their age, yet their body length and head circumference are age appropriate. To classify an infant as SGA, the gestational age must be estimated by the physical findings summarized in Table 1.1 .
Diagram of conditions associated with deviations in intrauterine growth.
Adapted from Simmons R. Abnormalities of fetal growth. In: Gleason CA, Devaskar SU, eds. Avery’s Diseases of the Newborn. Philadelphia: Saunders; 2012. p. 51.
Table 1.1
Clinical Criteria for Classification of Low Birth Weight Infants
Adapted from Avery ME, Villee D, Baker S, et al. Neonatology. In: Avery ME, First LR, eds. Pediatric Medicine. Baltimore: Williams & Wilkins; 1989. p. 148.
| Criteria | 36 Weeks (Premature) | 37–38 Weeks (Borderline Premature) | 39 Weeks (Term) |
|---|---|---|---|
| Plantar creases | Rare, shallow | Heel remains smooth | Creases throughout sole |
| Size of breast nodule | Not palpable to <3 mm | 4 mm | Visible (7 mm) |
| Head hair | Cotton wool quality | Silky; each strand can be distinguished | |
| Earlobe | Shapeless, pliable with little cartilage | Rigid with cartilage | |
| Testicular descent and scrotal changes | Small scrotum with rugal patch; testes not completely descended | Gradual descent | Enlarged scrotum creased with rugae; fully descended testes |
Although SGA infants may weigh the same as premature infants, they have different physiologic characteristics. Due to intrauterine malnutrition, body fat levels are frequently below 1% of the total body weight. This lack of body fat increases the risk of hypothermia in SGA infants. Hypoglycemia is the most common metabolic problem for neonates and develops earlier in SGA infants due to higher metabolic activity and reduced glycogen stores. The red blood cell (RBC) volume and the total blood volume are much higher in the SGA infant compared with the preterm AGA or the non-SGA full-term infant. This rise in RBC volume frequently leads to polycythemia, with an associated rise in blood viscosity. Due to an adequate length of gestation, the SGA infant has pulmonary function approaching that of the AGA or a full-term infant.
Infants born before 37 weeks of gestation, regardless of birth weight, are considered premature. The physical exam of the premature infant reveals many abnormalities. Special problems with the preterm infant include the following:
- 1.
Weak suck reflex
- 2.
Inadequate gastrointestinal absorption
- 3.
Hyaline membrane disease (HMD)
- 4.
Intraventricular hemorrhage
- 5.
Hypothermia
- 6.
Patent ductus arteriosus
- 7.
Apnea
- 8.
Hyperbilirubinemia
- 9.
Necrotizing enterocolitis (NEC)
Specific Physiologic Problems of the Newborn
Glucose Metabolism
The fetus maintains a blood glucose value of 70–80% of maternal levels by facilitated diffusion across the placenta. There is a build-up of glycogen stores in the liver, skeleton, and cardiac muscles during the later stages of fetal development, but little gluconeogenesis. The newborn must depend on glycolysis until exogenous glucose is supplied. After delivery, the baby depletes his or her hepatic glycogen stores within 2–3 hours. The newborn is severely limited in his or her ability to use fat and protein as substrates to synthesize glucose. When total parenteral nutrition (TPN) is needed, the glucose infusion rate should be initiated at 4–6 mg/kg/min and advanced 1–2 mg/kg/min to a goal of 12 mg/kg/min.
Hypoglycemia
Clinical signs of hypoglycemia are nonspecific and subtle. Seizure and coma are the most common manifestations of severe hypoglycemia. Neonatal hypoglycemia is generally defined as a glucose level lower than 50 mg/dL. Infants who are at high risk for developing hypoglycemia are those who are premature; SGA; or born to mothers with gestational diabetes, severe preeclampsia, or HELLP (hemolysis, elevated liver enzymes, low platelet count). Newborns who require surgical procedures are at particular risk of developing hypoglycemia; therefore, a 10% glucose infusion is typically started on admission to the hospital. Hypoglycemia is treated with an infusion of 1–2 mL/kg (4–8 mg/kg/min) of 10% glucose. If an emergency operation is required, concentrations of up to 25% glucose may be used. Traditionally, central venous access has been a prerequisite for glucose infusions exceeding 12.5%. During the first 36–48 hours after a major operation, it is common to see wide variations in serum glucose levels.
Hyperglycemia
Hyperglycemia is a common problem associated with the use of parenteral nutrition in very immature infants born at less than 30 weeks’ gestation and birth weight of less than 1.1 kg. These infants are usually less than 3 days of age and are frequently septic. The hyperglycemia appears to be associated with both insulin resistance and relative insulin deficiency, reflecting the prolonged catabolism seen in very low birth weight infants. Historically, neonatal hyperglycemia has been linked to intraventricular hemorrhage, dehydration, and electrolyte losses; however, a causal relationship has not been established. Congenital hyperinsulinism refers to an inherited disorder that is the most common cause of recurrent hypoglycemia in infants. This group of disorders was previously referred to as nesidioblastosis, which is a misnomer, as nesidioblastosis is a term used to describe hyperinsulinemic hypoglycemia attributed to dysfunctional pancreatic beta cells with a characteristically abnormal histologic appearance.
Calcium
Calcium is actively transported across the placenta. Of the total amount of calcium transferred across the placenta, 75% is observed after 28 weeks’ gestation, which partially accounts for the high incidence of hypocalcemia in preterm infants. Neonates are predisposed to hypocalcemia due to limited calcium stores, renal immaturity, and relative hypoparathyroidism secondary to suppression by high fetal calcium levels. Some infants are at further risk for neonatal calcium disturbances owing to the presence of genetic defects, pathologic intrauterine conditions, or birth trauma. Hypocalcemia is defined as an ionized calcium level of less than 1.22 mmol/L (4.9 mg/dL). At greatest risk for hypocalcemia are preterm infants, newborn surgical patients, and infants born to mothers with complicated pregnancies, such as those with diabetes or those receiving bicarbonate infusions. Calcitonin, which inhibits calcium mobilization from the bone, is increased in premature and asphyxiated infants.
Signs of hypocalcemia are similar to those of hypoglycemia and may include jitteriness, seizures, cyanosis, vomiting, and myocardial arrhythmias. Hypocalcemic infants have increased muscle tone, which helps differentiate infants with hypocalcemia from those with hypoglycemia. Symptomatic hypocalcemia is treated with 10% calcium gluconate administered intravenous at a dosage of 1–2 mL/kg (100–200 mg/kg) over 30 minutes while monitoring the electrocardiogram for bradycardia. Asymptomatic hypocalcemia is best treated with calcium gluconate in a dose of 50 mg of elemental calcium/kg/day added to the maintenance fluid: 1 mL of 10% calcium gluconate contains 9 mg of elemental calcium. If possible, parenteral calcium should be given through a central venous line, as skin and soft tissue necrosis may occur should the peripheral IV infiltrate.
Magnesium
Magnesium is actively transported across the placenta. Half of total body magnesium is in the plasma and soft tissues. Hypomagnesemia is observed with growth retardation, maternal diabetes, after exchange transfusions, and with hypoparathyroidism. Although the mechanisms by which magnesium and calcium interact are not clearly defined, they appear to be interrelated. The same infants at risk for hypocalcemia are also at risk for hypomagnesemia. Magnesium deficiency should be suspected and confirmed in an infant who has seizures that do not respond to calcium therapy. Emergent treatment consists of magnesium sulfate 25–50 mg/kg IV every 6 hours until normal levels are obtained.
Blood Volume
Total RBC volume is at its highest point at delivery. Estimations of blood volume for premature infants, term neonates, and infants are summarized in Table 1.2 . By about 3 months of age, total blood volume per kilogram is nearly equal to adult levels as infants recover from their postpartum physiologic nadir. The newborn blood volume is affected by shifts of blood between the placenta and the baby before clamping the cord. Infants with delayed cord clamping (typically defined as greater than 1 minute after birth) have higher hemoglobin levels. A hematocrit greater than 50% suggests placental transfusion has occurred. Although this effect on hemoglobin levels does not persist, iron stores are positively impacted up to 6 months of age by delayed cord clamping.
Table 1.2
Estimation of Blood Volume
Adapted from Rowe PC, ed. The Harriet Lane Handbook.11th ed. Chicago: Year Book Medical; 1987. p. 25.
| Group | Blood Volume (mL/kg) |
|---|---|
| Premature infants | 85–100 |
| Term newborns | 85 |
| >1 month | 75 |
| 3 months to adult | 70 |
Hemoglobin
At birth, nearly 80% of circulating hemoglobin is fetal (a2Aγ2F). When infant erythropoiesis resumes at about 2–3 months of age, most new hemoglobin is adult. When the oxygen level is 27 mmHg, 50% of the bound oxygen is released from adult hemoglobin ( P 50 = 27 mmHg). Reduction of the affinity of hemoglobin for oxygen allows more oxygen to be released into the tissues at a given oxygen level as shown in Fig. 1.2 .
Fetal hemoglobin has a P 50 value 6–8 mmHg lower than that of adult hemoglobin. This lower P 50 value allows more efficient oxygen delivery from the placenta to the fetal tissues. The fetal hemoglobin equilibrium curve is shifted to the left of the normal adult hemoglobin equilibrium curve. Fetal hemoglobin binds less avidly to 2,3-diphosphoglycerate (2,3-DPG) compared with adult hemoglobin, causing a decrease in P 50 . This is somewhat of a disadvantage to the newborn because lower peripheral oxygen levels are needed before oxygen is released from fetal hemoglobin. By 4–6 months of age in a term infant, the hemoglobin equilibrium curve gradually shifts to the right and the P 50 value approximates that of a normal adult.
Polycythemia
A central venous hemoglobin level greater than 22 g/dL or a hematocrit value greater than 65% during the first week of life is defined as polycythemia. After the central venous hematocrit value reaches 65%, further increases result in rapid exponential increases in blood viscosity. Neonatal polycythemia occurs in infants of diabetic mothers, infants of mothers with toxemia of pregnancy, or SGA infants. Polycythemia is treated using a partial exchange of the infant’s blood with fresh whole blood or 5% albumin. This is frequently done for hematocrit values greater than 65%.
Anemia
Anemia present at birth is due to hemolysis, blood loss, or decreased erythrocyte production.
Hemolytic Anemia
Hemolytic anemia is most often a result of placental transfer of maternal antibodies that are destroying the infant’s erythrocytes. This can be determined by the direct Coombs test. The most common severe anemia is Rh incompatibility. Hemolytic disease in the newborn produces jaundice, pallor, and hepatosplenomegaly. The most severely affected fetuses manifest hydrops. This massive edema is not strictly related to the hemoglobin level of the infant. ABO incompatibility frequently results in hyperbilirubinemia, but rarely causes anemia.
Congenital infections, hemoglobinopathies (sickle cell disease), and thalassemias produce hemolytic anemia. In a severely affected infant with a positive-reacting direct Coombs test result, a cord hemoglobin level less than 10.5 g/dL, or a cord bilirubin level greater than 4.5 mg/dL, immediate exchange transfusion is indicated. For less severely affected infants, exchange transfusion is indicated when the total indirect bilirubin level is greater than 20 mg/dL.
Hemorrhagic Anemia
Significant anemia can develop from hemorrhage that occurs during placental abruption. Internal bleeding (intraventricular, subgaleal, mediastinal, intra-abdominal) in infants can also often lead to severe anemia. Usually, hemorrhage occurs acutely during delivery, with the baby occasionally requiring a transfusion. Twin–twin transfusion reactions can produce polycythemia in one baby and profound anemia in the other. Severe cases can lead to death in the donor and hydrops in the recipient.
Anemia of Prematurity
Decreased RBC production frequently contributes to anemia of prematurity. Erythropoietin is not released until a gestational age of 30–34 weeks has been reached. These preterm infants have large numbers of erythropoietin-sensitive RBC progenitors. Research has focused on the role of recombinant erythropoietin (epoetin alpha) in treating anemia in preterm infants. Successful increases in hematocrit levels using epoetin may obviate the need for blood transfusions and reduce the risk of blood borne infections and reactions. Studies suggest that routine use of epoetin is probably helpful for very low birth weight infants (<750 g), but its regular use for other preterm infants is not likely to significantly reduce the transfusion rate.
Jaundice
In the hepatocyte, bilirubin created by hemolysis is conjugated to glucuronic acid and rendered water soluble. Conjugated (also known as direct) bilirubin is excreted in bile. Unconjugated bilirubin interferes with cellular respiration and is toxic to neural cells. Subsequent neural damage is termed kernicterus and produces athetoid cerebral palsy, seizures, sensorineural hearing loss, and, rarely, death.
The newborn’s liver has a metabolic excretory capacity for bilirubin that is not equal to its task. Even healthy full-term infants usually have an elevated unconjugated bilirubin level. This peaks about the third day of life at approximately 6.5–7.0 mg/dL and does not return to normal until the tenth day of life. A total bilirubin level greater than 7 mg/dL in the first 24 hours or greater than 13 mg/dL at any time in full-term newborns often prompts an investigation for the cause. Breast-fed infants usually have serum bilirubin levels 1–2 mg/dL greater than formula-fed babies. Various factors have been associated with breast milk jaundice including substances in breast milk (e.g., steroids, fats, cytokines, β-glucuronidase, and epidermal growth factor), difficulties with breast-feeding, and infant weight loss. However, new studies also implicate differences in extrahepatic UDP-glucuronosyltransferase 1A1. The common causes of prolonged indirect hyperbilirubinemia are listed in Table 1.3 .
Table 1.3
Causes of Prolonged Indirect Hyperbilirubinemia
Data from Maisels MJ. Neonatal jaundice. In: Avery GB, ed. Neonatology. Pathophysiology and Management of the Newborn. Philadelphia: JB Lippincott; 1987. p. 566.
| Breast milk jaundice | Pyloric stenosis |
| Hemolytic disease | Crigler–Najjar syndrome |
| Hypothyroidism | Extravascular blood |
Pathologic jaundice within the first 36 hours of life is usually due to excessive production of bilirubin. Hyperbilirubinemia is managed based on the infant’s weight. Although specific cutoffs defining the need for therapy have not been universally accepted, the following recommendations are consistent with most practice patterns. Phototherapy is initiated for newborns: (1) less than 1500 g, when the serum bilirubin level reaches 5 mg/dL; (2) 1500–2000 g, when the serum bilirubin level reaches 8 mg/dL; or (3) 2000–2500 g, when the serum bilirubin level reaches 10 mg/dL. Formula-fed term infants without hemolytic disease are treated by phototherapy when levels reach 13 mg/dL. For hemolytic-related hyperbilirubinemia, phototherapy is recommended when the serum bilirubin level exceeds 10 mg/dL by 12 hours of life, 12 mg/dL by 18 hours, 14 mg/dL by 24 hours, or 15 mg/dL by 36 hours. An absolute bilirubin level that triggers exchange transfusion is still not established, but most exchange transfusion decisions are based on the serum bilirubin level and its rate of rise.
Retinopathy of Prematurity
Retinopathy of prematurity (ROP) develops during the active phases of retinal vascular development from the 16th week of gestation. In full-term infants the retina is fully developed and ROP cannot occur. The exact causes are unknown, but oxygen exposure (greater than 93–95%), low birth weight, and extreme prematurity are risk factors that have been demonstrated. The risk and extent of ROP are probably related to the degree of vascular immaturity and abnormal retinal angiogenesis mediated to a large extent through vascular endothelial growth factor in response to hypoxia. In the United States, ROP is found in 0.17% of all live births and 1.9% of premature infants in large neonatal units. Retrolental fibroplasia (RLF) is the pathologic change observed in the retina and overlying vitreous after the acute phases of ROP subsides. Treatment of ROP with laser photocoagulation has been shown to have the added benefit of superior visual acuity and less myopia when compared with cryotherapy in long-term follow-up studies. The American Academy of Pediatrics’ guidelines recommend a screening examination for all infants who received oxygen therapy who weigh less than 1500 g and were born at less than 32 weeks’ gestation, and selected infants with a birth weight between 1500 and 2000 g or gestational age of more than 32 weeks with an unstable clinical course, including those requiring cardiorespiratory support.
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