Case Based Pediatrics For Medical Students and Residents
Department of Pediatrics, University of Hawaii John A. Burns School of Medicine
Chapter III.5. Common Problems of the Premature Infant
Venkataraman Balaraman, MBBS
July 2003

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This is a 1300 gram male born via normal spontaneous vaginal delivery at 30 weeks gestation to a 25 year old G3P2 mother with a history of incompetent cervix. The mother was hospitalized at 27 weeks gestation due to cervical changes and received 2 doses of betamethasone two weeks prior to delivery. At delivery, the infant was noted to have a lusty cry. Apgar scores were 6 and 6 at one and five minutes, respectively due to poor respiratory effort, decreased tone and decreased response to stimulation. He is transported to the neonatal intensive care unit on blow-by oxygen and on admission, he is placed on nasal continuous positive airway pressure (CPAP) of 10 with an FiO2 of 0.3 (30%).

Exam: VS T36, HR 140, RR 50, BP 45/30 (mean of 38), oxygen saturation 96%. Weight 1300 gm (50th percentile), length 40 cm (50th percentile), HC 28 cm (50th percentile). His head is normocephalic with minimal molding and overlapping sutures. There are no craniofacial or oropharyngeal anomalies noted. There is fair aeration over both lung fields with clear breath sounds. He has a normal precordium and a grade 2/6 holosystolic murmur at the upper left sternal border. His pulses are equal, 2+ in strength with no radiofemoral delay. His capillary refill is 2 seconds. He has decreased tone but he responds well to stimulation and he has normal age appropriate reflexes

A chest x-ray demonstrates a normal heart size, lungs expanded to 9 ribs, and clear lung fields. On DOL (day of life) 2, the infant is taken off CPAP and placed in room air. A percutaneous central venous line is placed to provide parenteral nutrition. He is also started on small feedings of mothers' breast milk/colostrums. Thermal support is provided by an isolette. The following day he is noted to have several episodes of apnea and bradycardia. These resolve with nasal CPAP. Caffeine citrate is also started to stimulate his respiratory effort. Because of a persistent heart murmur, an echocardiogram is performed which reveals a moderate to large patent ductus arteriosus with normal cardiac anatomy and function. He is not treated for this initially since he is not exhibiting signs of congestive heart failure. Phototherapy is also started for a serum bilirubin of 12 mg/dl. A head ultrasound, done at one week of age, reveals bilateral grade I-II intraventricular hemorrhages. He continues on parenteral nutrition but his feedings had to be discontinued due to abdominal distention and the presence of excessive residual breast milk noted in a gastric aspirate obtained just prior to his next feeding. By DOL 28, the infant, now 34 weeks adjusted age, is receiving full enteral feedings of breast milk and is occasionally breast fed by his mother. A routine eye exam is performed to screen for retinopathy of prematurity. He is found to have incomplete retinal vascularization to Zone 3 in both eyes. The ophthalmologist recommends follow-up in 2-3 weeks. His hemoglobin level is 10 g/dL and he is started on supplemental iron.

Prematurity is defined as birth prior to 37 completed weeks of gestation. Although, the rate of premature birth appears to vary by geographic region, the reported incidence varies between 6 and 10%. Despite significant improvements in perinatal care, there has not been a concomitant reduction in the rate of premature births in developed countries.

Prematurity and its associated problems are major contributors to the morbidity and mortality in the first year of life (which is reflected in the infant mortality rate).

Neonatal transition is the process involved in physiologic adaptation of the fetus to extrauterine life. Premature babies are at higher risk for slower transition to neonatal life due to immaturity of organ systems and lack of body mass. Premature (also called preterm) infants generally do not tolerate labor as well as term infants. This leads to a higher incidence of low Apgar scores and need for resuscitation in the delivery room.

Preterm infants have significant problems related to thermoregulation. Significant thermal stress may occur as they transition at birth from the in-utero fluid-filled environment supported by mother to the relatively cool air-filled environment of the delivery room. This can be avoided by providing exogenous heat with a radiant warmer during transition and minimizing heat loss by drying them quickly (evaporation of amniotic fluid on the skin is a potential cause of significant heat loss).

These infants are at risk for hypoglycemia because of limited glycogen stores and relatively immature glucose homeostatic mechanisms. It is important, therefore, to provide them with either a constant infusion of glucose solution intravenously, or early adequate enteral nutrition or both, depending on the baby's gestational age and degree of illness.

Respiratory problems are among the most common and important conditions related to prematurity. The immaturity of surfactant systems leads to respiratory distress syndrome (RDS).

Another common factor leading to respiratory difficulties is the relative compliance of the total respiratory system (chest wall, lung parenchyma and airways). Since the bony thorax that assists in the process of respiration is not fully developed (abnormally increased compliance) and the lung is often surfactant deficient (abnormally decreased compliance), the premature infant has increased work of breathing to maintain adequate functional residual capacity and tidal volume. This may lead to fatigue and respiratory failure in the smallest of infants. This problem often necessitates either endotracheal intubation and mechanical ventilation, or continuous positive pressure support to the airways and chest wall in the form of nasal CPAP via nasal prongs.

An additional factor is the incomplete development of the lungs (respiratory immaturity or immature lung disease). Alveolar development is not complete until several years of life. Immature lungs are at increased risk for long term injury. Some of the risk factors contributing to this injury include positive pressure/ventilator support (barotrauma), oxygen (oxygen toxicity), infections, and aspiration.

The gastrointestinal tract, especially with respect to the digestive enzymes and absorptive surfaces, is relatively well developed in premature infants. This is in contrast to the external muscular layer and neural control which is relatively less developed. Considering these factors, the inability of the GI tract to fully support the nutritional needs of the premature infant is related to volume (the total volume capacity of the system is low) and peristalsis (incomplete development of the neuromuscular components of the GI tract). The caloric intake required for the preterm infant to approach intrauterine growth rates is in the range of 120 to 150 Kcal/kg/d. These values are typically met by the 7th to 10th DOL Typically, a combination of enteral feeding and parenteral nutrition is necessary to achieve nutritional goals. Enteral feedings are often started at volumes of 10-20 cc/kg/d and advanced daily at increments of the same value. Thus, the majority of premature infants are at total enteral feedings within the first three weeks of life. Enteral feeds may consist of either with breast milk (ideally) or commercially available premature infant formula when breast milk is not available or contraindicated. Parenteral nutrition is comprised of a mixture of dextrose (carbohydrates), amino acids (proteins) and intralipids (fat) along with electrolyte additives and multi-vitamin supplements. Electrolyte and other mineral requirements (calcium, phosphorus, iron, zinc etc.) are higher for preterm infants because the body stores for these are significantly lower (the fetus builds up body stores primarily in the third trimester of pregnancy). Specially prepared formulas for preterm infants also contain additional amounts of calcium, phosphorus, and vitamins.

Necrotizing enterocolitis is a unique GI disorder related to prematurity and characterized by inflammation and necrosis of the intestinal tract. The ileum, cecum, or colon may be involved. The etiology is multifactorial. Risk factors include systemic infection, rapid advance of enteral nutrition, decreased intestinal blood flow (relative ischemia), the presence of catheters in umbilical vessels, and poor gut motility. The pathology consists of pneumatosis intestinalis (air dissecting within the bowel wall) and areas of bowel wall necrosis, occasionally leading to frank perforation. Perforation presents clinically with pneumoperitoneum, peritonitis, abdominal wall discoloration, and/or portal venous air. Management of this condition is primarily directed towards providing gut rest (NPO status), medical supportive measures (respiratory support, parenteral nutrition, intravascular volume, antibiotics), and surgical management in the case of perforation. Infants with NEC are at increased risk for intestinal strictures later in life.

Premature infants are not able to regulate their body temperatures as well as term infants. Factors that contribute to this problem are immaturity of the hypothalamic regulatory center, lack of subcutaneous fat (insulation shield), lack of brown fat (allows for thermogenesis in adverse climatic environmental conditions) and a relatively large body surface area to body mass ratio.

Typically, temperature control is maintained by providing an external heat source (radiant warmers or incubators/isolettes). These sources are set to provide heat to maintain a neutral thermal environment. In this environment, the infant has minimal energy expenditure to maintain core body temperature.

The majority of premature infants are able to regulate their body temperatures by a post conceptional age of 34 weeks. However, they remain at continued risk for poor thermal regulation at the extremes of environmental temperature. Parents should be appropriately counseled and encouraged to avoid subjecting their infant to temperature extremes.

The occurrence of physiologic jaundice in otherwise healthy term newborn infants is well recognized. Similar factors are associated with jaundice in the premature infant. These factors include a larger red cell mass at birth, shorter red cell half life, immaturity of liver enzyme systems, and poor gut motility promoting increased enterohepatic circulation. In contrast to term infants, physiologic jaundice in the premature infant tends to be visible earlier (1-2 days of age), peaks later (5-7 days of age) and may take up to two weeks to completely resolve. Whether premature infants are at greater risk for bilirubin neurotoxicity is unclear. It is well known that the potential for bilirubin neurotoxicity is increased in the presence of other associated medical conditions such as hemolysis, acidosis, respiratory failure, infections, and intraventricular hemorrhage. In the absence of such complications, there appears to be no evidence to suggest that bilirubin is more neurotoxic to the premature brain.

The most common cardiovascular problem in premature infants is the persistence of the ductus arteriosus. This vital in-utero communication pathway is programmed to close shortly after birth in term infants. This normal transition occurs less efficiently in the premature infant and the rate of spontaneous closure in inversely proportional to the degree of prematurity.

As the body systems go through other post-natal adaptations, the persistence of the ductus leads to significant problems including poor lung function related to increased pulmonary blood flow, ductal steal phenomenon leading to decreased systemic blood flow, and high output cardiac failure. Clinically, infants may present with a varied constellation of signs and symptoms that, in addition to a systolic murmur heard best at the left upper sternal border, include tachycardia, active precordium, bounding pulses, and cardiomegaly with pulmonary congestion on chest x-ray. Patent ductus arteriosus can be managed medically by using fluid restriction and indomethacin (prostaglandin inhibitor) therapy or surgically, by ductal ligation.

The germinal matrix is a unique vascular bed that is present in the region of the choroid plexus during development. Generally, this vascular system regresses completely by 32 weeks gestation. In infants born prior to 32 weeks gestation, this area is prone to vascular accidents that can lead to intraventricular hemorrhage. As is the general rule, the risk for more severe bleeding is inversely proportional to gestational age. One of the most important factors predisposing to hemorrhage in this area is hypoxic-ischemic injury. This type of intracranial hemorrhage tends to occur within the first week of life. Intraventricular hemorrhages are graded between 1 and 4 based on the extent of the hemorrhage, associated ventricular dilatation and associated parenchymal injury/infarction. Generally, Grade 1 and 2 lesions are compatible with near normal neurological outcomes while the long term neurological prognosis associated with Grade 3 and 4 lesions are more guarded.

Periventricular leukomalacia (PVL) is another manifestation of hypoxic-ischemic brain injury. It appears later than germinal matrix hemorrhages (GMH) described above. The lesions of periventricular leukomalacia are visualized as discrete cystic lesions in the periventricular white matter on cranial ultrasound. They appear primarily in the frontal and motor areas of the cerebral cortex.

All infants with the diagnosis of GMH or PVL need close neurodevelopmental follow up. They may need an early intervention program as deficits are identified. With timely developmental intervention, there is evidence that neurodevelopmental outcomes can be improved.

Apnea of prematurity is another physiologic entity that can complicate the clinical course of premature infants, especially those <34 weeks gestation. It is, in large part, related to the immaturity of the central respiratory center. By definition, apnea is the cessation of air flow/exchange. Apnea is often associated with bradycardia and hypoxemia. The majority of apnea events in premature infants are typically mixed (central and obstructive) in origin. The airway obstruction is usually the result of upper airway collapse or laryngeal closure. The response of the respiratory system to chemical stimuli (the primary process by which the respiratory center controls respirations) can be modulated by methylxanthines. The most commonly used drug to treat apnea of prematurity (AOP) is caffeine. This drug has been shown to reduce the severity and frequency of central apnea and periodic breathing in premature infants. In addition, caffeine toxicity is rare.

Retinal vascularization is incomplete until the completion of 32 weeks gestation. Thus, for infants born prior to this gestation, there is a risk of abnormal vascularization of the retina leading to retinopathy of prematurity (ROP). This is a disorder of angiogenesis that could potentially lead to blindness secondary to retinal detachment. The classification of ROP is based both, on the severity of the vascular disease, and the zone of the retina that is affected. The American Academy of Pediatrics and the American Academy of Ophthalmologists have jointly recommended a schedule for screening high risk premature infants for this disorder. Later on in life, prematurely born infants are at higher risk for refractive errors and, therefore, need to be closely monitored. It is recommended that they have a comprehensive ophthalmologic examination at 6 months to one year of age.

Premature infants are at the same risk for developing anemia of infancy as are term infants. This physiologic process occurs generally between the ages of 6 to 12 weeks. In addition, premature infants are at higher risk for protracted anemia, because they are born with lower body iron stores. This situation is further compounded by significant phlebotomy losses in the neonatal period related to hospitalization after birth. Anemia of prematurity may at least partially be overcome by the use of erythropoietin, which is used to stimulate erythropoiesis. Nevertheless, it is important to replenish the body's iron stores and the provision of supplemental iron is critical until the hemoglobin levels reach normal values for age. In this respect, the iron supplementation during therapy should be at the levels used in the treatment of anemia at any other age (up to 6 mg/kg/d of elemental iron).

Premature infants are at higher risk for infections. This risk is multifactorial. The primary source of immunity for the neonate is passively derived antibodies from the mother and this tends to occur primarily in the third trimester. Thus, the relative amount of antibody transferred is affected by the duration of gestation. Additionally, a significant proportion of premature infants who are hospitalized in intensive care units, require interventions such as IV therapy, and placement of central vascular catheters for providing nutrition, and invasive monitoring. All of these factors contribute to the increased risk of infections in this population. Premature infants present with nonspecific signs and symptoms of infection. This mandates close monitoring for infectious complications, both during hospitalization, in the immediate neonatal period, and in subsequent months during the first year of life.

Given their propensity for infections, the American Academy of Pediatrics recommends that all childhood immunizations be administered to premature infants at the appropriate chronological age. The only exception to this rule is the hepatitis B immunization, which should be initiated only after the infant's weight exceeds 2 kg. Despite lower titers of antibody response in these infants, there is no recommendation for additional doses of specific immunizations.

Passive prophylaxis for respiratory syncytial virus (RSV) infection is currently recommended during the cooler winter months for certain premature infants at highest risk for serious complications from RSV. These guidelines are evolving. The most current recommendation is published in the Red Book 2003 of the American Academy of Pediatrics. These infants will also benefit from receiving influenza immunization at 6 months chronological age during the cooler winter months (3).

The premature infant is ready for discharge when he/she is able to fulfill the following criteria: 1) ability to appropriately regulate their temperature without the need for technological support, 2) ability to ingest adequate calories to achieve consistent growth, and 3) to have demonstrated other parameters of global physiologic stability (the absence of clinically significant apnea, bradycardia, or hypoxemia). In addition, and most importantly, it is critical that the parents/caregivers feel comfortable with the care of the infant in the home environment. One of the issues that may alleviate some of the parental anxiety is training in infant CPR. Thus, the process of discharge of the infant is a continuum that begins several days to weeks prior to the actual discharge of the infant. Many of these infants will have additional needs and it is important that all of these needs and appropriate community resources are identified prior to discharge. At the time of discharge, the routine mandated screening for hearing and metabolic diseases should be completed with the results forwarded to the primary care physician.

The long term outcome of premature infants is inversely related to gestational age (better outcomes in older infants), and directly related to the clinical course in the neonatal period, and the associated morbidities and diagnoses during their hospitalization. In general, these infants need close neurodevelopmental monitoring and early interventions for identified problems. They are at increased risk for repeated hospitalization for various residual problems of prematurity such as bronchopulmonary dysplasia, failure to thrive, and feeding problems. Developmental outcome is also related to the home environment and the ability of the family to properly nurture the infant. Unfortunately, the stress associated with parenting a high-risk infant often leads to dysfunctional family dynamics. In addition, these infants are frequently born into families who are already high-risk. On a positive note, if an optimal nurturing environment is provided, there is evidence to suggest that it can result in a significant improvement in overall long term outcome.


1. True/False: Morbidity associated with prematurity is a significant contributor to the infant mortality rate.

2. Strategies to reduce thermal stress at birth should include (mark all correct answers):
. . . . a. Keeping the delivery room warm and performing the stabilization under a preheated radiant warmer.
. . . . b. Drying the infant and then wrapping them up with the same blanket.
. . . . c. In a stable premature infant allowing skin to skin bonding with the mother.

3. Premature infants are at higher risk for hypoglycemia because (choose one):
. . . . a. They are born with adequate glycogen stores but have immature homeostatic mechanisms to mobilize glucose.
. . . . b. They are born with inadequate glycogen stores but have mature homeostatic mechanisms to mobilize glucose.
. . . . c. They are born with inadequate glycogen stores and have immature homeostatic mechanisms to mobilize glucose.

4. Respiratory Problems in premature infants may be secondary to (choose one):
. . . . a. Surfactant deficiency
. . . . b. Increased chest wall compliance
. . . . c. Incomplete alveolar development
. . . . d. All of the above

5. Feeding difficulties in premature infants are usually secondary to (choose one):
. . . . a. Immature development of the intestinal enzyme systems.
. . . . b. Immature neuromuscular development of the intestinal tract.

6. In contrast to term infants, the following statements are true regarding physiologic jaundice in the premature infant in the neonatal period (choose one):
. . . . a. Has its onset later, reaches its peak later and has slower resolution.
. . . . b. Has its onset earlier, peaks earlier and has earlier resolution.
. . . . c. Has its onset earlier, peaks later and has slower resolution.

7. The following statements regarding the persistence of ductus arteriosus are true in the premature infant (choose one):
. . . . a. Is one of the most common cardiovascular dysfunction.
. . . . b. May be asymptomatic and spontaneously resolve in many.
. . . . c. Can be treated with medications.
. . . . d. All of the above.

8. Hypoxic-Ischemic brain injury can lead to (choose one):
. . . . a. Germinal matrix hemorrhage/intraventricular hemorrhage
. . . . b. Periventricular leukomalacia
. . . . c. Both
. . . . d. None

9. Apnea events in premature infants are usually (choose one):
. . . . a. Central because of immaturity of the brain respiratory center.
. . . . b. Obstructive secondary to collapse of the upper airway structures and closure of the glottis.
. . . . c. Neither a or b.
. . . . d. Both a and b.

10. In premature infants, routine immunizations should be (choose one):
. . . . a. Administered at a post-conceptual age of two months.
. . . . b. Administered at a post-natal age of two months.

11. True/False: The weight of the premature infant is an absolute criterion for discharge from the hospital

Related x-rays

Newborn radiographs: Available online at:


1. Avery GB, Fletcher MA, MacDonald MG (eds). Neonatology: Pathophysiology and Management of the Newborn, 5th Edition. 1999, Philadelphia: Lippincott Williams & Wilkins Publishers.

2. Behrman RE, Kliegman RM, Jenson HB (eds). Nelson Textbook of Pediatrics, 16th edition. 2000, Philadelphia: WB Saunders Company.

3. Pickering LK, et al (eds). 2003 Red Book: Report of the Committee on Infectious Diseases, 25th edition. 2000, Elk Grove Village, IL: American Academy of Pediatrics.

Answers to questions

1.true, 2.a,c, 3c, 4.d, 5.b, 6.c, 7.d, 8.c, 9.d, 10.b, 11.false

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