Introduction

The physiology of a newborn is unique and complex in that it changes over a period of minutes, hours, days, and months. Once a human reaches adulthood, our physiology typically remains stable and predictable, with any deviation potentially leading to pathology and disease. However, a newborn's rapid and ever-changing physiology is essential in adapting to a world outside the womb. This article aims to discuss the important physiology associated with the newborn period to allow a deeper understanding of the complexities of this stage of life.

Issues of Concern

As mentioned, the physiology of a newborn is constantly evolving to adapt to extrauterine life. It is important to note these changes and ensure proper development at the appropriate times. For instance, it is essential for the infant, while taking its first breath, to shut down and remodel the intrauterine cardiovascular shunts present in the infant's body. Failure to do so can cause physiological imbalances, such as inadequate oxygenation of the brain. Additionally, it is important to understand what nutrition the infant lacks in the newborn period that requires supplementation. For instance, a newborn infant is deficient in vitamin K, putting it at risk for a hemorrhagic disease. To prevent this, all infants born should be given vitamin K prophylaxis.[1] These issues of concern, and more, will be detailed in later sections.

Organ Systems Involved

Cardiovascular System

To understand the changes occurring in the cardiovascular physiology of the newborn, one must first understand intrauterine fetal circulation and the shunts involved, which include the ductus venosus, foramen ovale, and ductus arteriosus. 

First, the blood from the mother becomes oxygenated in the placenta and enters the fetus through the umbilical vein. The oxygenated blood in the umbilical vein bypasses the hepatic circulation and is delivered to the inferior vena cava (IVC) via the ductus venosus. From the IVC, the blood flows into the right atrium. Oxygenated blood is then shunted from the right atrium to the left atrium through the foramen ovale. Blood travels to the left ventricle and into the coronary arteries and aorta from the left atrium. A small amount of blood from the right atrium does not travel through the foramen ovale and instead flows to the right ventricle and into the pulmonary artery, then the lungs. However, the majority of blood is shunted from the pulmonary artery directly to the aorta, bypassing the lungs via the ductus arteriosus. From the aorta, oxygenated blood is then delivered to the systemic circulation.[2]

• Changes in Fetal Circulation at Birth
• Decreased Pulmonary Vascular Resistance and Increased Systemic Vascular Resistance
  • With the cutting of the umbilical cord comes the removal of the low-resistance circuit, allowing for an increase in systemic circulation. Upon taking its first breath, the fluid in the newborn lungs is replaced with air, and oxygen diffuses into the blood vessels surrounding the alveoli. Relaxation of the pulmonary arteries occurs, which allows the pulmonary resistance to fall and blood to flow into the lungs.
• Closure of the Ductus Arteriosus
  • In utero, patency of the ductus arteriosus is maintained by high levels of prostaglandins, carbon monoxide, nitric oxide, and low oxygen tension. Once the newborn begins breathing, functional closure of ductus arteriosus begins and can last several days. Due to the decrease in pulmonary arterial resistance and increase in oxygen, there is a decrease in prostaglandins which aids in the closure of the ductus arteriosus. With the placenta now separated, there is also a decrease in prostaglandin synthesis, further contributing to the closure of the ductus arteriosus.[3] 
• Closure of the Foramen Ovale
  • Decreased pulmonary vasculature resistance upon the newborn's first breath causes the left atrial pressure to increase. With the left atrial pressure now higher than the right atrial pressure, the foramen ovale begins to close.
• Closure of the Ductus Venosus (DV)
• Permanent closure of the DV takes approximately one to three months, with the remnant consisting of connective tissue forming the ligamentum venosum of the liver.[4] 
• Maternal-fetal circulation is no longer needed after birth, so the umbilical vein's remnant forms the liver's round ligament.[5]

 Pulmonary System

Adapting the lungs to the external environment requires careful coordination between clearance of fetal lung fluid, surfactant secretion, and the onset of consistent breathing. During intrauterine life, the lungs are filled with fetal lung fluid secreted by the airway epithelium, which is essential for normal lung growth. The most important process in the fetal transition to extrauterine air breathing is the adequate and timely clearance of lung fluid. The bulk of the fluid clearance occurs via osmotic gradients created by active solute transport by alveolar epithelial cells. This process is regulated by hormonal changes associated with labor, as well as developmental changes in the expression of sodium channels.[6]

At birth, clamping of the umbilical cord (which removes prostaglandin secretion that suppresses breathing), diffuse tactile and cold stimuli, as well as changes in the carbon monoxide and oxygen levels in the blood, results in the rapid onset of vigorous breathing of a newborn. In the absence of severe hypoxia, most term infants will effectively initiate breathing. Specific endocrine adaptations begin before delivery and play a critical role in the clearance of fetal lung fluid at birth. Active chloride-mediated secretion of fetal lung fluid is shut down by an increase in cortisol, thyroid hormones, and catecholamines. Basal Na-K-ATPase of type II cells of the airway epithelium are activated by these hormones, allowing sodium in the fetal lung fluid to be pumped into the interstitium with water and other electrolytes, thus removing fluid from the airways. Physiologically normal newborns inflate their lungs at birth by generating large, negative pressure breaths, pulling the lung fluid from the airways into the distal airspace. The infant continues to clear lung fluid with subsequent inflation.[7] Clearance of fetal lung fluid in vaginally delivered newborns is also facilitated by the "thoracic squeeze," which compresses the fluid in the lungs and allows further clearance of fluid.

In the newborn, the work of breathing is usually labored (i.e., accessory muscle use, intercostal retractions, grunting) to overcome the high surface tension, which is one reason why newborns have an increased respiratory rate (30 to 60 breaths per minute). Other reasons include compensation for high metabolic rate and perfusion-ventilation differences. More importantly, the presence of circulatory shunts forces the infant to increase the work of breathing. As the fluid leaves the alveoli in the lungs, the effort of breathing is reduced. Due to immature central drive responses, newborns may have periods of apnea lasting less than 5 seconds. While this is considered abnormal in adults, it is normal for newborns to have apneic episodes.[8]

Hematological System

Blood is comprised of two major components; plasma and cells (red blood cells, white blood cells, and platelets). In utero, blood is produced by the liver and picked up by the bone marrow after birth. Red blood cells carry hemoglobin (Hb) which transports oxygen and iron from the lungs to tissues and organs of the body. There are multiple types of hemoglobin, with those pertinent to this discussion being HbF and HbA. HbF is the primary hemoglobin the fetus produces, and its role is to adequately transport oxygen in low-oxygen environments. HbF has a high affinity for oxygen, making it suitable for oxygen extraction from maternal hemoglobin across the placenta. Not only is HbF important for intrauterine development, but it is also important in the newborn period due to impaired oxygen delivery to the tissues. Around six months of age, HbF is replaced with HbA, also known as adult hemoglobin. 

Infants lack vitamin K due to immature hepatocyte function, and lack of enteric bacteria that produce vitamin K. Vitamin K is used in the synthesis of clotting factors II, VII, IX, X, and proteins C and S. Therefore, those who lack vitamin K have an increased risk of any form of hemorrhage, from any cause. As a result, due to the deficiency of vitamin K, a prophylactic shot of vitamin K is given to every newborn to protect against hemorrhagic disease.[9]

Metabolism and Thermoregulation

Soon after birth, the newborn's temperature rapidly drops in response to the cold extrauterine environment. To counteract this temperature change, the neonate accelerates heat production via nonshivering thermogenesis (NST), which involves lipolysis of brown adipose tissue, which is present around the kidneys and muscles of the back. Heat is produced by uncoupling ATP synthesis via the oxidation of fatty acids in the mitochondria, utilizing uncoupled protein. Adequate oxygenation is required for thermogenesis; thus, a hypoxic neonate cannot adequately produce enough heat to increase its temperature.[10] Infants typically do not utilize shivering thermogenesis (increase in skeletal muscle activity and limb movements) to increase their body heat until approximately six months of age, as they lack sufficiently developed skeletal muscle mass.[11] Newborn infants are typically tachycardic (120 to 160 beats/minute), which can be attributed to the high metabolic rate of activity needed to maintain breathing, feeding, and thermogenesis.

Related Testing

Newborn Screening

Within the United States, there exists a list of disorders that the Department of Health and Human Services (HHS) recommends that states screen each newborn for, titled the Recommended Uniform Screening Panel (RUSP). Most of these tests are diagnosed using filter paper and a few drops of blood from the newborn's heel. The optimal time to screen for these disorders is between 36 and 72 hours of life.[12]

• Metabolic disorders
  • Organic acid metabolism disorders
  • Fatty acid oxidation disorders
  • Amino acid disorders (e.g., homocystinuria, phenylketonuria, maple syrup urine disease)
• Endocrine disorders
  • Congenital adrenal hyperplasia (CAH)
  • Primary congenital hypothyroidism
• Hemoglobin disorders
  • Sickle cell anemia
  • Beta thalassemia
• Other
  • Glycogen storage disease type II (Pompe)
  • Critical congenital heart disease
  • Cystic fibrosis (CF)
  • Classic galactosemia
  • Hearing loss
  • Severe combined immunodeficiencies (SCID)
  • X-linked adrenoleukodystrophy (XLA)
  • Spinal muscular atrophy (SMA)
  • Biotinidase deficiency
  • Mucopolysaccharidosis type I and II

Pathophysiology

Cardiovascular System

Congenital heart disease (CHD) is one of the most common congenital defects, with most (approximately 80%) occurring due to multifactorial causes arising through various combinations of genetic and environmental issues and about 20% attributed to chromosomal abnormalities or teratogens. Down syndrome and velocardiofacial syndrome are the two most commonly seen syndromes in patients with congenital heart disease.[13]

There are two main categories of CHDs; cyanotic and acyanotic.

• Cyanotic - right-to-left shunts
  • Tetralogy of Fallot
  • Transposition of the great vessels
  • Tricuspid atresia
  • Total anomalous pulmonary venous return (TAPVR)
  • Truncus arteriosus
• Acyanotic - further classified into:
  • Left-to-right shunts
    • Atrial septal defect (ASD)
    • Ventricular septal defect (VSD)
    • Patent ductus arteriosus (PDA)
  • Outflow obstruction
    • Pulmonary stenosis
    • Aortic stenosis
    • Coarctation of the aorta

In the cases of shunts, the severity of the symptoms is determined by the size of the shunt and the amount of blood being shunted. Small left-to-right (acyanotic) shunts are typically benign and do not require surgical intervention. However, larger left-to-right shunts will eventually need surgical intervention to avoid chronic volume overload of the heart and, eventually, pulmonary arterial hypertension. Also, if these shunts are not fixed, a left-to-right shunt can evolve and cause a reversal of blood flow from right to left, leading to Eisenmenger syndrome.[14] Right-to-left (cyanotic) shunts allow the deoxygenated blood from the systemic circulation to bypass the lungs and return to the body without becoming oxygenated. These shunts are more severe, and cyanosis is typically present at birth. 

Pulmonary

It is well known that the adequate development of the fetal lung and surfactant secretion is an essential adaptation in preparation for birth and extrauterine life. From approximately weeks 22-28 of gestation, surfactant begins to be synthesized. Pulmonary surfactant is a composition of proteins and lipids found within the fluid lining the alveolar surface of the lungs. The primary role of surfactant is to prevent alveolar collapse at low lung volumes.[15] As delivery approaches, fetal lung fluid secretion ceases, causing a decrease in the volume of fetal lung fluid. The pulmonary pathophysiology of a newborn can be categorized based on timing and/or method of birth. Preterm infants, for example, have immature lungs that prove challenging to ventilate due to inadequate surfactant to decrease surface tension.

• Preterm (birth prior to 37 weeks gestation)
  • Neonatal respiratory distress syndrome (NRDS)[16]
    • Cause: Deficiency of pulmonary surfactant
    • Clinical features: tachypnea, hypoxia, cyanosis, decreased breath sounds
    • Complications: bronchopulmonary dysplasia, pneumothorax
  • Apnea of prematurity (AOP)[17]
    • Causes: immature medullary respiratory center and/or weak airway or breathing muscles
    • Clinical features: cessation of breathing for > 20 seconds and typically accompanied by bradycardia
• Cesarean section
  • Transient tachypnea of the newborn (TTN)[6]
    • Cause: delayed resorption of fetal lung fluid
    • Clinical features: tachypnea, diffuse crackles on auscultation

Endocrine

The endocrine system is typically adequately developed at birth, and no immediate endocrine abnormalities occur. However, there exist particular circumstances in which abnormalities may be seen at the time of birth.

• If a pregnant mother bearing a female child is treated with an androgenic hormone or develops an androgenic tumor during pregnancy, this can lead to masculinization of the female sexual organs and hermaphroditism. 
• Poorly managed maternal type 2 diabetes mellitus is the most common cause of large for gestational age (LGA) newborns, as high insulin levels stimulate fetal growth and contribute to increased birth weight. However, infants born to mothers with uncontrolled type 1 diabetes mellitus are typically small for gestational age due to a lack of insulin secretion and have a high mortality rate if they do not make it to full term. If they do not survive, 75% of these deaths are due to respiratory distress syndrome.
• Women with hyperthyroidism, or those treated with excess thyroid hormone, are more likely to give birth to an infant with temporary hypothyroidism. If a fetus lacks thyroid hormone secretion, it may develop cretin dwarfism, which involves poor bone growth and mental retardation. However, if the woman had a thyroidectomy before pregnancy, her pituitary gland may secrete excess quantities of thyrotropin during gestation, and the infant may be born with temporary hyperthyroidism.[18]

Neonatal Jaundice

Bilirubin formed in the fetus can cross the placenta into the mother and be excreted through the liver of the mother. Immediately after birth, the only means for the neonate to rid itself of excess bilirubin is through its own liver, which functions poorly for the first week or so of life and is incapable of conjugating significant quantities of bilirubin with glucuronic acid for excretion into the bile. Approximately 60% of term and 80% of preterm infants develop what is known as "physiologic jaundice" in the first 1-2 weeks after birth, which includes yellowing the skin, sclera, and mucous membranes. Physiologic jaundice appears after the first 24 hours of life, is characterized by a peak bilirubin concentration < 15 mg/dL, and is typically a mild, self-limiting condition that resolves without treatment. On the other hand, pathologic jaundice is characterized by jaundice appearing within the first 24 hours of life, a peak bilirubin concentration > 15 mg/dL, and persistence of jaundice beyond one week in term infants and two weeks in preterm infants. Causes of pathologic jaundice include sepsis, hemolytic disease, polycythemia, bruising (e.g., cephalohematoma), metabolic disorders, and inborn errors of metabolism (e.g., Crigler-Najjar syndrome).[19]

Clinical Significance

Throughout the formation and birth of a human being, numerous problems may potentially arise. Below is a summary of some of the most common and clinically relevant issues that may exist at birth.

• Cephalohematoma
• Caput succedaneum
• Transient head molding
• Bulging fontanelles (increased intracranial pressure)
• Brachial plexus injuries/facial nerve palsy
• Subgaleal hemorrhage
• Clavicle fracture
• Conjunctivitis
• Torticollis
• Club foot
• Hip dysplasia
• Neural tube defects
• Cleft lip/palate
• Choanal atresia
• Hirschsprung disease

Vitamin K Deficiency Bleeding

All newborns are vitamin K deficient, as vitamin K does not cross the placenta, is not in breast milk, and is not produced by the newborn's gut. Due to this lack of vitamin K, newborns are deficient in vitamin-K-dependent clotting factors, placing them at risk of bleeding and fatal hemorrhage. A vitamin K injection should be given at birth to prevent this from occurring. Those newborns that do not receive this injection are at risk of intracranial, subgaleal, or gastrointestinal bleeding.[20]

Metabolism and Thermoregulation

As their brown adipose tissue has not developed enough to provide an adequate heat response, preterm infants are at a specific disadvantage regarding thermoregulation. To aid in the thermoregulation of infants, specifically those preterm, important steps should be taken. First, immediately after delivery, the newborn should be dried several times using warm cloths. The newborn should be placed in a bed warmer that utilizes convection to warm the bed and the air surrounding the infant. In addition, some preterm infants would specifically benefit from an incubator, a crib-like unit enclosed by a plastic dome, to aid in increasing the humidity and reducing cold external airflow.

Newborn Nutrition

Before birth, the fetus derives most of its energy from the glucose obtained from the mother's blood. Following birth, the amount of glucose stored in the newborn's body as liver and muscle glycogen is sufficient to supply the newborn needs for only a few hours. The liver at birth is still not functionally adequate to undergo gluconeogenesis, so the glucose concentration falls as low as 30 to 40 mg/dl of plasma, which is less than half the normal value. The infant uses its stored fats and proteins for metabolism until the mother's milk can be provided 2 or 3 days later. The infant's weight decreases 5 to 10%, as much as 20%, within the first 2 or 3 days of life. Most of this weight loss is from fluid rather than body solids. There are specific vitamins and minerals that an infant needs to ensure proper growth and development.

• Calcium and vitamin D
  • Rapid ossification of bones at birth means a supply of calcium in infancy is necessary. However, calcium absorption in the GI tract is poor in the absence of vitamin D. Therefore, within only a few weeks, severe rickets can develop in infants with vitamin D deficiency. This is of particular concern in premature babies, as their GI tracts absorb calcium even less effectively than term infants.
• Iron
  • If the mother obtains adequate iron in her diet, the infant's liver has typically stored enough iron to keep forming blood cells for 4-6 months after birth. Insufficient iron in the mother's diet can lead to severe anemia in the infant after about three months of life. 
• Vitamin C (ascorbic acid)
  • Required for the proper formation of bone and cartilage but is not stored in significant quantities in the fetal tissues. Unless she has severe vitamin C deficiency, adequate amounts are typically present in the mother's breast milk. It is important to note that cow's milk has 1/4 the amount of vitamin C as human milk and is not recommended in the newborn period.

Immunity

Before birth, the antibodies from the mother diffuse through the placenta into the fetus. After birth, a newborn is not able to form antibodies of its own to any significant extent, and by the end of the first month of life, the newborn's antibodies have decreased to less than half of their level at birth, which correlates to a decrease in the immunity of the newborn. However, the antibodies obtained from the mother before birth can protect the infant from most infectious diseases for around six months. This includes protection from measles, polio, and diphtheria. This is why newborns do not need vaccination against these diseases immediately after birth. However, at birth, newborns should receive a vaccination against hepatitis B. It is essential to understand that maternally inherited antibodies do not protect the infant against pertussis (whooping cough), so immunization against this disease is recommended at two months of life. At around 12 to 20 months of life, the infant's immune system forms its own antibodies. It is recommended that children should receive a combination vaccination against diphtheria, tetanus, and acellular pertussis (DTaP) at ages 2, 4, 6, and 15 months; and then again at 4 to 6 years of age.[21]