Physiology of The Newborn

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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 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.


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.

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:

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 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 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.

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.


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.


At birth, nearly 80% of circulating hemoglobin is fetal (a2Aγ2F). When infant erythropoiesis resumes at about 2 to 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 (P50 = 27 mmHg). Reduction of hemoglobin’s affinity for oxygen allows more oxygen to be released into the tissues at a given oxygen level as shown in Figure 1-2.

Fetal hemoglobin has a P50 value 6–8 mmHg lower than that of adult hemoglobin. This lower P50 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 to adult hemoglobin causing a decrease in P50.8 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 to 6 months of age in a term infant, the hemoglobin equilibrium curve gradually shifts to the right and the P50 value approximates that of a normal adult.


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 infants manifest hydrops. This massive edema is not strictly related to the hemoglobin level of this 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.

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.911


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.


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.1619 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


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.2325 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 image 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

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.

Neonatal Fluid Requirements

To estimate fluid requirements in the newborn requires an understanding of: (1) any preexisting fluid deficits or excesses; (2) metabolic demands; and (3) losses. Because these factors change quickly in the critically ill newborn, frequent adjustments in fluid management are necessary (Table 1-4). Hourly monitoring of intake and output allows early recognition of fluid balance that will affect treatment decisions. This dynamic approach requires two components: (1) an initial hourly fluid intake that is safe and (2) a monitoring system to detect the patient’s response to the treatment program selected. No ‘normal’ urine output exists for a given neonate, yet one may generally target 1–2 mL/kg/h.

After administering the initial hourly volume for four to eight hours, depending on the patient’s condition, the newborn is reassessed by observing urine output and concentration. With these two factors, it is possible to determine the state of hydration of most neonates and their responses to the initial volume. In more difficult cases, changes in serial serum osmolarity, sodium (Na), creatinine, and blood urea nitrogen (BUN), along with urine osmolarity, Na, and creatinine make it possible to assess the infant’s response to the initial volume and to use fluid status to guide the next 4-8 hours’ fluid intake.

Illustrative Examples

Renal Failure.

A 5 kg infant with severe sepsis secondary to Hirschsprung enterocolitis has had a urine output of 0.1 mL/kg/h for the past 8 hours. The specific gravity is 1.012; serum sodium, 150; BUN, 25 mg/dL; creatinine, 1.5 mg/dL; urine sodium, 130; and urine creatinine, 20 mg/dL.

Fractional Na excretion (FE Na):


FE Na less than 1% usually indicates a prerenal cause of oliguria, whereas greater than 3% usually implies a renal cause (e.g., acute tubular necrosis). This patient is in acute renal failure. The plan is to restrict fluids to insensible losses plus measured losses for the next 4 hours and to then reassess the plan using both urine and serum studies. Of note, while the FE urea may be a better predictor of prerenal failure in this population, both FE urea and the FE Na have limited utility in neonates, reflecting the relative immaturity of neonatal renal function.28