Physiology of The Newborn

Elizabeth A. Berdan, Bradley J. Segura and Daniel A. Saltzman

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 vs weight, and gestational age vs 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, while post-term infants have a gestation that exceeds 42 weeks. 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). The 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 1501–2500 g, very low birth weight between 1001–1500 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 Figure 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.

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, editors. Pediatric Medicine. Baltimore: William & Wilkins; 1989. p. 148.

FIGURE 1-1 Graph of conditions associated with deviations in intrauterine growth. The boxes indicate the approximate birth weight and gestational age at which the condition is likely to occur. (Adapted from Avery ME, Villee D, Baker S, et al. Neonatology. In: Avery ME, First LR, editors. Pediatric Medicine. Baltimore: Williams & Wilkins; 1989. p. 148.)

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 with 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 an 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 70–80% of maternal value 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. Following delivery, the baby depletes its hepatic glycogen stores within two to three 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.

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.¹ Infants who are at high risk for developing hypoglycemia are those who are premature, SGA, and born to mothers with gestational diabetes, severe preeclampsia, and HELLP (hemolysis, elevated liver enzymes, low platelet count). Newborns that 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 to 48 hours after a major surgical procedure, it is common to see wide variations in serum glucose levels.

Hyperglycemia

Hyperglycemia is a common problem with the use of parenteral nutrition in very immature infants who are less than 30 weeks’ gestation and less than 1.1 kg birth weight. These infants are usually fewer than 3 days of age and are frequently septic.² This hyperglycemia appears to be associated with both insulin resistance and relative insulin deficiency, reflecting the prolonged catabolism seen in very low birth weight infants.³ 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 the infant. This group of disorders was previously referred to as nesidioblastosis, which is a misnomer. Nesidioblastosis is a term used to describe hyperinsulinemic hypoglycemia attributed to dysfunctional pancreatic beta cells with a characteristically abnormal histological appearance.

Calcium

Calcium is actively transported across the placenta. Of the total amount of calcium transferred across the placenta, 75% occurs after 28 weeks’ gestation.⁴ This observation 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 due to the presence of genetic defects, pathological intrauterine conditions, or birth trauma.⁵ Hypocalcemia is defined as an ionized calcium level of less than 1.22 mmol/L (4.9 mg/dL).⁶ At greatest risk for hypocalcemia are preterm infants, newborn surgical patients, and infants of complicated pregnancies, such as those of diabetic mothers 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 IV at a dosage of 1–2 mL/kg (100–200 mg/kg) over 30 minutes while monitoring the electrocardiogram for bradycardia.¹ 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 given necrosis that 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. While 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 six hours until normal levels are obtained.

Blood volume

Total RBC volume is at its highest point at delivery. Estimation 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 they recover from their postpartum physiologic nadir. The newborn blood volume is affected by shifts of blood between the placenta and the baby prior to clamping the cord. Infants with delayed cord clamping have higher hemoglobin levels.⁷ A hematocrit greater than 50% suggests placental transfusion has occurred.

TABLE 1-2

Estimation of Blood Volume

Group	Blood Volume (mL/kg)
Premature infants	85–100
Term newborns	85
>1 month	75
3 months to adult	70

Adapted from Rowe PC, editor. The Harriet Lane Handbook. 11th eds. Chicago: Year Book Medical; 1987. p. 25.

Anemia of Prematurity

Decreased RBC production frequently contributes to anemia of prematurity. Erythropoietin is not released until a gestational age of 30 to 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.9–11 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 the very low birth weight infant (<750 g), but its regular use for other preterm infants is not likely to significantly reduce the transfusion rate.^9–11

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. The common causes of prolonged indirect hyperbilirubinemia are listed in Table 1-3.

TABLE 1-3

Causes of Prolonged Indirect Hyperbilirubinemia

Breast milk jaundice	Pyloric stenosis
Hemolytic disease	Crigler–Najjar syndrome
Hypothyroidism	Extravascular blood

Data from Maisels MJ. Neonatal jaundice. In: Avery GB, editor. Neonatology. Pathophysiology and Management of the Newborn. Philadelphia: JB Lippincott; 1987. p. 566.

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. While specific cutoffs defining the need for therapy have not been universally accepted, the following recommendations are consistent with most practice patterns.¹² 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.¹³ 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%) and extreme prematurity are two risk factors that have been demonstrated.¹⁴ The risk and extent of ROP is probably related to the degree of vascular immaturity and abnormal retinal angiogenesis in response to hypoxia. ROP is found in 1.9% of premature infants in large neonatal units.¹⁵ 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 to cryotherapy in long-term follow-up studies.^16–19 The American Academy of Pediatrics’ guidelines recommends a screening examination for all infants who received oxygen therapy who weigh less than 1500 g and are fewer 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.²⁰

Thermoregulation

Newborns have difficulty maintaining body temperature due to their relatively large surface area, poor thermal regulation, and small mass to act as a heat sink. Heat loss may occur owing to: (1) evaporation (wet newborn); (2) conduction (skin contact with cool surface); (3) convection (air currents blowing over newborn); and (4) radiation (non-contact loss of heat to cooler surface, which is the most difficult factor to control). Thermoneutrality is the range of ambient temperatures that the newborn can maintain a normal body temperature with a minimal metabolic rate by vasomotor control. The critical temperature is the temperature that requires adaptive metabolic responses to the cold in an effort to replace lost heat. Infants produce heat by increasing metabolic activity by shivering like an adult, nonshivering thermogenesis, and futile cycling of ions in skeletal muscle.²¹ Brown adipose tissue (BAT) may be involved in thermoregulatory feeding and sleep cycles in the infant with an increase in body temperature signaling an increase in metabolic demand.²² The uncoupling of mitochondrial respiration that occurs in BAT where energy is not conserved in ATP but rather is released as heat may be rendered inactive by vasopressors, anesthetic agents, and nutritional depletion.^23–25 Failure to maintain thermoneutrality leads to serious metabolic and physiologic consequences. Double-walled incubators offer the best thermoneutral environment, whereas radiant warmers cannot prevent convection heat loss and lead to higher insensible water loss. In the operating room, special care must be exercised to maintain the neonate’s body temperature in the normal range.

Fluids and Electrolytes

At 12 weeks of gestation, the fetus has a total body water content that is 94% of body weight. This amount decreases to 80% by 32 weeks’ gestation and 78% by term (Fig. 1-3). A further 3–5% reduction in total body water content occurs in the first 3 to 5 days of life. Body water continues to decline and reaches adult levels (approximately 60% of body weight) by years of age. Extracellular water also declines by 1 to 3 years of age. Premature delivery requires the newborn to complete both fetal and term water unloading tasks. Surprisingly, the premature infant can complete fetal water unloading by one week following birth. Postnatal reduction in extracellular fluid volume has such a high physiologic priority that it occurs even in the presence of relatively large variations of fluid intake.²⁶

FIGURE 1-3 Friss–Hansen’s classic chart relating total body weight (TBW) and extracellular (ECF) and intracellular (ICF) fluid to percentage of body weight, from early gestation to adolescence. (Adapted from Welch KJ, Randolph JG, Ravitch MM, et al, editors. Pediatric Surgery. 4th ed. Chicago: Year Book Medical; 1986. p. 24.)

Glomerular Filtration Rate and Early Renal Function

The glomerular filtration rate (GFR) of newborns is slower than that of adults.²⁷ From 21 mL/min/1.73 m² at birth in the term infant, GFR quickly increases to 60 mL/min/1.73 m² by 2 weeks of age. GFR reaches adult levels by 18 months to 2 years of age. A preterm infant has a GFR that is only slightly slower than that of a full-term infant. In addition to this difference in GFR, the concentrating capacity of the preterm and the full-term infant is well below that of the adult. An infant responding to water deprivation increases urine osmolarity to a maximum of 600 mOsm/kg. This is in contrast to the adult, whose urine concentration can reach 1200 mOsm/kg. It appears that the difference in concentrating capacity is due to the insensitivity of the collecting tubules of the newborn to antidiuretic hormone. Although the newborn cannot concentrate urine as efficiently as the adult, the newborn can excrete very dilute urine at 30–50 mOsm/kg. Newborns are unable to excrete excess sodium, an inability thought to be due to a tubular defect. Term babies are able to conserve sodium, but premature infants are considered ‘salt wasters’ because they have an inappropriate urinary sodium excretion, even with restricted sodium intake.