Prematurity

Prematurity refers to the broad category of neonates born at less than 37 weeks' gestation. Preterm birth is the leading cause of neonatal mortality and the most common reason for antenatal hospitalization.[1] Although the estimated date of confinement (EDC) is 40 weeks' gestation, the World Health Organization (WHO) broadened the range of full term to include 37-42 weeks' gestation.

Premature newborns have many physiologic challenges when adapting to the extrauterine environment. The near-term neonate (34-36 weeks' gestation) has issues of prematurity that include feeding immaturity, temperature instability, and prolonged jaundice. Serious morbidities occur in extremely low birth weight (ELBW) infants. Articles in the Neonatology section discuss in detail the most serious of these problems.

For more information, see Extremely Low Birth Weight Infant, Pediatric Acute Respiratory Distress Syndrome, Bronchopulmonary Dysplasia, Intraventricular Hemorrhage in the Preterm Infant.

Before birth, the placenta serves three major roles for the fetus: provision of all the nutrients for growth, elimination of fetal waste products, and synthesis of hormones that promote fetal growth.

With the exception of most electrolytes, the maternal circulation contains more substrate (eg, blood glucose) than the fetal circulation. In addition, the placenta is metabolically active and consumes glucose. Waste products of fetal metabolism (eg, heat, urea, bilirubin, carbon dioxide) are transferred across the placenta and eliminated by the mother's excretory organs (ie, liver, lung, kidneys, skin).

In addition, the placenta acts as a barrier to infection through mucosal macrophages and by allowing transfer of maternal immunoglobulins (immunoglobulins such as immunoglobulin G [IgG]) to the fetus beginning at 32-34 weeks' gestation. Placental dysfunction is involved in the transfer of IgG. Antibacterial activity of the amniotic fluid improves as gestational age advances.

Each of the immature organs of a premature infant has functional limitations. The tasks of caregivers in neonatal intensive care units (NICUs) are to recognize and monitor the needs of each infant and to provide appropriate support until functional maturity can be achieved.

Premature delivery can be the result of preterm labor and preterm premature rupture of the membranes (PPROM), or it can be due to maternal indications (eg, pregnancy-induced hypertension).

Chorioamnionitis

Maternal fever (>38ºC [>100.4ºF]), fetal tachycardia, maternal leukocytosis (>15,000-18,000/mm3 [15-18 × 109/L]), and uterine tenderness are universally accepted signs and symptoms of chorioamnionitis. Amniocentesis that demonstrates bacteria, white blood cells (WBCs), and a low glucose concentration confirms the diagnosis of chorioamnionitis and is an indication for delivery.

A decrease in the biophysical score or profile in association with chorioamnionitis is associated with fetal infection.

Rates of perinatal mortality, neonatal infection, and respiratory distress syndrome (RDS) increase in the presence of maternal fever and chorioamnionitis.

Intrauterine growth restriction (10th percentile for birth weight)

Intrauterine growth restriction is significantly associated with perinatal mortality and long-term morbidity.

Low socioeconomic status

Programs offering additional social support for at-risk pregnant women have not been demonstrated to reduce the numbers of extremely low birth weight (ELBW) or preterm infants.

Maternal diabetes

Pregnancies complicated by diabetes and poor glycemic control are associated with a high incidence of prematurity, macrosomia, malformation, fetal death, and neonatal death.[7]

The rate of preterm birth (< 37 weeks' gestation) is 20-22% of persons with insulin-dependent diabetes.

In women with diabetes diagnosed before pregnancy, the frequency of preeclampsia is increased as the severity of diabetes increases.[8]

Multiple gestation pregnancies

Women with multiple gestation pregnancies are at high risk of preterm labor and delivery and account for an increasing percentage of preterm births and ELBW infants. Preterm birth rate for twins increased from 40.9% in 1981 to 55% in 1997.[9]

Multiple births related to infertility treatment have dramatically increased.[10] With advances in assisted reproductive technology, multiple gestation pregnancies have increased.[11] Prepregnancy counseling of prospective parents regarding the risks related to multiple gestations is important.

Preterm birth (< 35 weeks' gestation) occurs in 26% of twins compared with 3% of singletons.

Triplet pregnancies are associated with an increased incidence of preterm labor and delivery at a decreased gestational age and birth weight, compared with singletons and twins.[12] When the data are controlled for gestational age, outcomes are similar for singletons, twins, and triplets.

Maternal age

In women aged 13-15 years, the rate of preterm birth is 5.9%.[13] This rate declines to 1.7% in women aged 18-19 years and 1.1% in women aged 20-24 years.

The rate of preterm births increases in pregnancies in which the mother is older than 40 years. The scoring system for the risk of preterm delivery uses a criterion of age older than 40 years.

Tobacco or marijuana use

Approximately 15-20% of pregnant women smoke tobacco. Tobacco use is a risk factor for placental abruption and accounts as a factor for 15% of preterm births and 20-30% of ELBW infants.[14, 15]

Maternal marijuana use appears to be associated with an increased risk of neonatal morbidity (eg, infection and neurologic morbidity) or death.[16]

United States data

In the general population, an estimated 10.5% of infants are born prematurely,[17] and about 50% of preterm births are preceded by preterm labor.[1, 18]

International data

Exact international numbers are not available because different countries use different definitions of birth (eg, survival after birth, survival after 1 month). Chawanpaiboon et al examined the national civil registration and vital statistics databases of 194 WHO Member States from 1990 to 2014. They estimated the global preterm birth rate for 2014 was 10.6%, of which more than 80% of preterm births were in south Asia and Sub-Saharan Africa.[19, 20]

Race- and sex-related demographics

Premature infants are born to women of every race. Extremely low birth weight (ELBW) infants are most commonly born to women of low socioeconomic status, black women, teenage females, and women older than 40 years. Women at highest risk of premature delivery can be assessed by using a scoring system that reviews their socioeconomic status, history, daily habits, and current pregnancy events.[21] About 30% of women with a high-risk score deliver prematurely compared to 2.5% of women with a low-risk score.

Primarily because of the increased incidence of preterm infants, the overall neonatal mortality rate in black populations in the United States is 2.3 times that of white populations. Improvements in socioeconomic status and perinatal care have not improved the rate of prematurity and infant mortality rate in this population.

The results from a study (N = 2549 neonates) noted that male infants born prematurely have a higher risk of grade III/IV intraventricular hemorrhage, sepsis, and major surgery than premature females. A greater risk of mortality and poorer long-term neurologic outcome were also noted; however, sex-related differences for these appeared to lose significance at 27 weeks' gestation.[22]

Female sex is associated with increased rates of survival of newborns born at 22-25 weeks' gestation.

Mortality and morbidity are inversely proportional to gestational age and birth weight. Infants with extremely low birth weight (ELBW) who are born at tertiary care centers have outcomes more favorable than those who are born at level I or II centers and then transferred.

Roberts et al found that children born at 22-27 weeks' gestation have high rates of adverse neurodevelopmental outcome at age 8 years.[23] Assessment of a regional cohort of 144 survivors of preterm birth showed that, relative to matched term controls, the preterm cohort had substantially higher rates of blindness, deafness, cerebral palsy, and intellectual impairment and disabilities caused by these impairments. Comparison of preterm children born in 1997 with those born in 1991-1992 showed that the rates of moderate or severe disability were similar in the two cohorts (19%), but the rate of mild impairment was greater in 1997 (40% vs 24%); disability rates in control groups showed virtually no change over time.[23]

Infants born at born at 23-25 weeks of gestation who receive antenatal exposure to corticosteroids appear to have a lower rate of mortality and complications compared with those who do not have such exposure.[24] Infants born at 34-36 weeks' gestation with antenatal exposure to corticosteroids between 24 and 34 weeks of gestation also appear to have a lower incidence of respiratory disorders.[25]

Morbidity/mortality

Preterm births account for approximately 70% of neonatal deaths and 36% of infant deaths, as well as 25-50% of cases of long-term neurologic impairment in children.[1]

The mortality rate is high in developing countries, especially those of Sub-Saharan Africa. The perinatal mortality rate is 70 deaths per 1000 births; the neonatal mortality rate is 45 deaths per 1000 live births. Preterm birth is the strongest independent predictor of mortality in the United States. Preterm delivery accounts for 75-80% of all neonatal morbidity and mortality.

Since the early 1960s, survival rates of premature infants substantially increased because of technological advances. From 1989-1990, infants with birth weights less than 751 g had a survival rate of 39% (range among centers, 23-48%). In 1992, the US Food and Drug Administration (FDA) approved exogenous surfactant therapy for respiratory distress syndrome (RDS), leading to a considerable improvement in survival rates. Since the FDA approved the use of surfactant and since the subsequent introduction of numerous natural surfactants, the mortality rate attributed to surfactant deficiency has been markedly reduced. See Respiratory Distress Syndrome.

Data from the Vermont Oxford Network in 1994-1996 indicated that the survival rate of infants born weighing less than 1000 g was 74.9%.[26] Survival of infants born weighing less than 1000 g and requiring cardiopulmonary resuscitation in the delivery room was substantially decreased (53.8%). The changes in obstetric and neonatal care in the first half of the decade of 1990s decreased mortality and morbidity for ELBW infants. No additional improvements in mortality and morbidity were observed at the end of the decade.

Obstetric and pediatric personnel must be familiar with their own institutional data in addition to national benchmarks related to gestational age and mortality rates. These data are essential for proper prenatal counseling of parents and/or caregivers regarding survival and resuscitation plans.

The three primary causes of mortality in infants born with a weight of less than 1000 g are respiratory failure, infection, and congenital malformation. Infection of the amniotic fluid leading to pneumonia is the major cause of mortality.[27] In infants who weigh less than 500 g at birth, immaturity is listed as the only cause of mortality. See Ethical Issues in Neonatal Care.

Women who have an intrauterine infection do not respond to tocolytics. Preterm premature rupture of membranes (PPROM) is associated with 30-40% of premature deliveries. See Premature Rupture of Membranes. Mortality of the premature infant increases with coexisting PPROM but depends on gestational age and the expertise of the maternal-fetal monitoring team. Postnatal findings of periventricular leukomalacia (PVL) on cranial ultrasonography are highly correlated with chorioamnionitis.

In premature infants with a congenital heart defect (CHD), excluding isolated patent ductus arteriosus, the actuarial survival rate is 51% at 10 years, whereas infants with both CHD and prematurity have substantially worsened outcomes than infants who only have one of these conditions.[28] The survival rate improved as the study period (1976-1999) progressed. Congenital anomalies are an independent risk factor for mortality and morbidity in preterm birth.

In a longitudinal study of 1279 extremely premature children, (gestational age ≤28 week; birth weight < 1250 g), Robertson et al found permanent hearing loss in 3.1% and severe-to-profound loss in 1.9%.[29] Among affected children, hearing loss was delayed in onset in 10% and progressive in 28%. Prolonged supplemental oxygen use was the most important marker for predicting hearing loss.

In a retrospective analysis of data from 20,231 live births recorded between 1995 and 2003, Werner et al found that very premature infants who are delivered vaginally have fewer breathing problems than do those delivered by cesarean section.[30, 31] All of the study's infants were born after 24-34 weeks' gestation, with 69.3% of them delivered vaginally. In comparison with the vaginally delivered infants, those delivered by cesarean section were more likely to be born in respiratory distress (39.2% compared with 25.6% for vaginal delivery). Infants in the study who underwent cesarean delivery were also more likely than vaginally delivered infants to have a 5-minute Apgar score of less than 7 (10.7% vs 5.8%, respectively).[30, 31]

Complications

Premature infants are prone to have complications. These complications are gestational age dependent. Complications are inversely proportionate to gestational age.[20] These complications can range from devastating intracranial hemorrhage, sepsis, severe bronchopulmonary dysplasia (chronic lung disease), and necrotizing enterocolitis totalis to minor feeding related issues. Fortunately, not every premature infant experiences complications. Long-term consequences of prematurity can affect the cardiovascular and central nervous systems as well as the pulmonary, renal, and endocrine systems.[20]

Communicate clearly to the expectant parents regarding potential adverse outcomes. Clear up any inappropriate expectations on the part of the family. The smallest and most immature infants are at greatest risk of adverse neurodevelopmental outcomes.

When the premature infant is stabilized, parents or caregivers should participate in providing daily routine care. These kind of opportunities help foster a strong bond between the infant and the caregiver. Premature infants require social interaction on a regular basis to enhance the neurodevelopmental outcome. Book reading, storytelling, and singing with a soft voice can be part of routine social interaction with growing premature infants.

Discharge education

Discharge teaching of caretakers of the premature infant includes the following:

• Basic infant care: Bathing, skin care, taking a temperature

• Infant feeding: Feeding cues, support of breastfeeding

• Infant safety: Use of car seats, avoiding exposure to a smoky environment

• Back to sleep: Strategies to help preterm infants return to sleep

• Illness prevention (handwashing, crowd avoidance, prophylaxis against infection with respiratory syncytial virus [RSV] as indicated, compliance with immunization schedule)

• When to call healthcare provider: Poor feeding, signs of illness, change in behavior, respiratory distress

• Specifics related to chronic conditions (eg, use of a nasal canula, home oxygen therapy)

In assessing prematurity, gestational age dating by using the mother's history can be unreliable because of uncertainty of the dates. About 20% of women have an uncertain last menstrual period (LMP).

Gestational age assessment begins prenatally with obstetric ultrasonography in the first trimester. Discovery of many fetal anomalies, unsuspected multiple gestation, location of the placenta, and an accurate dating of the pregnancy are additional major benefits of early ultrasonography.

Confirmation of gestational age in the newborn is based on physical and neurologic characteristics. In 1979, the Dubowitz scoring system for determining gestational age based on neurologic and physical parameters was revised to include 12 items.[32] The Ballard Scoring System, revised again to include extremely low birth weight (ELBW) infants, remains the main tool clinicians use after delivery to confirm gestational age by means of physical examination.[2]

The major parts of the anatomy for physical characteristic markers are ear cartilage, sole creases, breast tissue, and genitalia. See the images below.

The physical examination and evaluation should be performed immediately after stabilization and before the expected weight loss occurs on the first day.

Hittner et al reported that regression of the vascularity of the lens capsule is an excellent tool to confirm a gestational age of 28-34 weeks.[33]

Neurologic criteria include muscle tone of the trunk and extremities and joint mobility. Reassessing the neurologic criteria 18-24 hours after birth is best to allow for recovery from maternal medication (eg, magnesium sulfate, analgesics), which may decrease tone and responsiveness.

Initial laboratory testing in cases of prematurity is performed to identify issues that, if corrected, improve the patient's outcome.

Blood tests

Obtain frequent blood glucose levels. This is crucial because hypoglycemia and hyperglycemia are very common in premature infants.

Complete blood cell (CBC) counts may reveal anemia or polycythemia that is not clinically apparent. A high or low white blood cell (WBC) count and numerous immature neutrophil types may also be found. An abnormal WBC count may suggest subtle infection.

Blood typing and antibody testing (Coombs test) are performed to detect blood-group incompatibilities between the mother and infant and to identify antibodies against fetal red blood cells (RBCs). Such incompatibilities increase the infant's risk for jaundice and kernicterus.

Serum electrolytes analysis

At birth, most serum electrolyte levels reflect those of the mother. For example, if the mother received magnesium sulfate to inhibit labor, the baby's respiratory effort may be compromised, and the serum magnesium value in the infant may be elevated.

The serum calcium may be low shortly after birth in small preterm babies.

Immature renal function, as well as limited bone and tissue reserves, result in the need for intravenous replacement of calcium, sodium, potassium, phosphate, and trace minerals in those infants who are taking nothing by mouth. Infants who can tolerate enteric nutrition receive adequate electrolytes and minerals from appropriate preterm formulas and fortified human milk.

Frequent laboratory determinations of serum sodium, potassium, calcium, and glucose levels in conjunction with monitoring of daily weight and urine output in extremely low birth weight (ELBW) infants assists the clinician in managing fluid and electrolytes.

Serum glucose concentrations

Serum glucose levels must be closely monitored because of the risk of hypoglycemia and hyperglycemia in preterm infants. The baby's gestational age and other medical conditions dictate the frequency of testing (see Hypoglycemia).

Metabolic screening

Every state has a metabolic screening program in the USA. All programs include testing of newborn blood spots for a minimum of phenylketonuria, hypothyroidism, and galactosemia. The timing of obtaining the sample varies and a few samples may be required at different intervals. Referring to state guidelines can be very helpful.

In general, false-positive results are most common in preterm babies. Early detection and intervention minimizes the long-term neurologic risk.

Investigational test

A systematic review and meta-analysis suggested the cervical phosphorylated insulin-like growth factor binding protein-1 (phIGFBP-1) test has the potential to predict women with symptoms of preterm labor who will not deliver within 48 hours.[34] However, its overall predictive ability was limited for identifying symptomatic and asymptomatic women at risk for preterm birth.

Imaging studies are specific to the organ system affected. Chest radiography is performed to assess the lung parenchyma and heart size in newborns with respiratory distress. Cranial ultrasonography is performed to detect occult intracranial hemorrhage in extremely low birth weight (ELBW) premature newborns.

In a systematic review and meta-analysis, Conde-Agudelo and Romero found that changes in transvaginal ultrasonographic cervical length over time was not a clinically useful test to predict preterm birth in women with singleton or twin gestations.[35] Rather, a single cervical length measurement that was obtained between 18 and 24 weeks of gestation appeared to be a better test to predict preterm birth than changes in cervical length over time.

Lumbar puncture

Perform lumbar puncture in premature infants with positive blood cultures and in those who have clinical signs of central nervous system infection. Although the decision to perform lumbar puncture in extremely low birth weight (ELBW) premature infants may be a difficult one because of their size and the surrounding clinical circumstances, when feasible, lumbar puncture should be performed if CNS infection is suspected because this will help in determining the duration of antibiotic therapy.

Consultations

In cases of prematurity, consider consulting with a developmental specialist. The risk of neurodevelopmental problems occurs as gestational age and birth weight decrease.

Hearing screening should be performed on all newborns before they are discharged.

Transfer

Transferring premature infants to a center that specializes in the care of high-risk mothers and infants improves outcomes because of the availability of resources and experience. Transfer can help in addressing neonatal issues of intravenous support and oxygenation and/or mechanical ventilation. It also provides access to pediatric subspecialists.

Consider transport and/or insurance costs of reverse transfer. Such transfer may permit the family to be near the patient and to establish a family support system. Reverse transfer may extend goodwill to the referring hospital (and forge ties to the regional neonatal intensive care unit [NICU]) and promote continuity with the referral physician for discharge. This may improve the experience of local hospital staff. This may help in decompressing the regional NICU. Reverse transfer may aid in addressing social service concerns.

Automated versus manual oxygen control

Studies have demonstrated automated oxygen control improves oxygen saturation targeting across different saturation ranges in premature infants on noninvasive and invasive respiratory support.[36, 37, 38, 39] However, whereas some studies show automated oxygen control reduces hypoxemia and hyperoxemia,[40] others show a reduction in hypoxemia,[37, 38] or in hyperoxemia but not hypoxemia.[39] Preliminary adaptive algorithms for automated oxygen control in these patient populations have also been developed and show promise.[41, 42]

Surgical Care

Premature infants generally do not require surgical care except when they develop complications (eg, hemodynamically significant patent ductus arteriosus) or require gastrostomy tube placement for oral feeding difficulties.

Stabilization in the delivery room with prompt respiratory and thermal management is crucial to the immediate and long-term outcome of premature infants, particularly extremely premature infants. The American Academy of Pediatrics (AAP) has established guidelines for levels of neonatal care.[43]

Principles of respiratory management are as follows:

• Recruit and maintain adequate lung volume or optimal lung volume. In infants with respiratory distress, this step may be accomplished with early continuous positive airway pressure (CPAP) given nasally, by nasal mask, or by using an endotracheal tube when ventilation and/or surfactant is administered.

• Avoid hyperoxia and hypoxia by immediately attaching a pulse oximeter and keeping the oxygen saturation (SaO2) between 90% and 95% by using blended oxygen. The lower limits of the pulse oximeter alarm should be set closer to the lower saturation limit, and the upper alarm limit should be no more than 95%.[4]

• Prevent/minimize barotrauma or volutrauma by using a ventilator. Permissive hypercapnia on an individualized protocol can lead to better respiratory outcomes. Normal tidal volume is 4-7 mL/kg.

• Administer surfactant early (age < 2 hours) when indicated. Routine use of prophylactic surfactant solely for prematurity is not advisable.

Many centers use early CPAP and have a relatively permissive approach to ventilation. Avoidance of mechanical ventilation or endotracheal tube placement is a welcome step. Efforts should be made to use CPAP as a first line of respiratory support if infant has spontaneous respiration.

A retrospective analysis that studied the first 48 hours in 225 infants of 23-28 weeks' gestational age found that clinical history or initial blood gas results were poor predictors of subsequent nasal CPAP failure.[44] Of the 225 infants, 140 could be stabilized with nasal CPAP in the delivery room; 68 with a favorable outcome and 72 with a failed outcome within 48 hours. The investigators noted that a threshold fraction of inspired oxygen (FiO2) of 0.35-0.45 or greater compared with 0.6 or above for intubation may shorten the time to surfactant delivery, without a relevant increase in intubation rate.[44]

In select extubated preterm infants, nasal cannulae appears to be comparable to CPAP. In a multicenter, randomized, noninferiority study, Manley and colleagues reported that in extubated preterm infants with a gestational age of at least 26 weeks but less than 32 weeks, breathing support using high-flow nasal cannulae (HFNC) was comparable to that using nasal CPAP.[45] Results were derived from 303 extubated preterm infants who were treated with HFNC (151 infants) or CPAP (152 infants).

During the 7 days following extubation, the failure rate was 34.2% in the HFNC group and 25.8% in the CPAP group.[45] However, the reintubation rate in the infants treated with HFNC (17.8%) was lower than in the CPAP group (25.2%), because half of the infants in whom HFNC failed were successfully treated with CPAP. The nasal trauma rate was 39.5% in the HFNC group and 54.3% in the CPAP group.[45]

In January 2014 the AAP released a policy statement on respiratory support for newborn preterm infants.[46, 47] Management of these preterm infants must be individualized, and the healthcare setting and team must be considered. The AAP recommendations also include the following[46, 47] :

• Early use of CPAP with subsequent selective use of surfactants: Compared with routine intubation with prophylactic or early surfactant therapy, early postnatal CPAP in extremely preterm infants reduces the rates of bronchopulmonary dysplasia and death

• If mechanical ventilation is necessary: Early administration of surfactant and then rapid extubation is preferable to prolonged ventilation

The AAP notes that early CPAP alone does not increase the risk for adverse outcomes if surfactant therapy is either delayed or not administered.[46, 47] Moreover, early administration of CPAP may reduce the duration of mechanical ventilation and postnatal corticosteroid therapy.

Thermoregulation

Maintenance of the neutral thermal environment is critical for minimizing stress and optimizing growth of all newborns, but especially for premature infants. The neutral thermal environment is defined as the environmental temperature in which the neonate maintains a normal temperature and is consuming minimal oxygen for metabolism.

Use radiant warmers with skin probes to regulate the desired temperature (in general, a normal body temperature of 36.5º-37.5ºC [97.7º-99.5ºF][5] ). A heated and humidified isolette is ideal for extremely low birth weight (ELBW) infants. Food-grade plastic wrap/sheets can also be very helpful immediately after birth to control humidity and prevent heat loss in ELBW infants. The environmental temperature should be maintained to at least 25ºC (77º F).[5]

Neonates lose heat by four means, as follows[5] :

1. Evaporation: Evaporation is energy consumed by a fluid as it converts from a liquid to gas. This is primarily in the delivery room. Completely drying the infant is of primary importance in prevention of hypothermia. This step can be omitted if other resuscitative measures are taking place.

2. Conduction: This is direct transfer of heat from a warm body to a cool object by contact (eg, placing an infant on a cold scale).

3. Convection: This is the loss of heat from the warm air next to the skin to moving air currents (eg, windchill effect). Double-walled isolettes help to reduce convective heat loss.

4. Radiation: This is the loss of heat that radiates from a warm body to a cool surface (eg, window, outside wall).

Preterm infants are relatively unable to compensate for cold stress because they have only a small amount of subcutaneous tissue (insulation) and decreased brown fat to produce heat. Note that preterm infants do not shiver. The increased surface area to body mass allows for rapid heat loss, especially from the head. Decreased posturing ability further diminishes their ability to compensate.

In ELBW infants, immature skin further complicates thermoregulation due to increased evaporative water loss. (See Extremely Low Birth Weight Infant.)

Consequences of cold stress are increased metabolism with loss of weight or failure to gain weight and increased use of glucose with depletion of glycogen stores and hypoglycemia.

Metabolic acidosis results in decreased surfactant production and loss of functional alveolar numbers, which results in hypoxia. The hypoxia causes pulmonary vasoconstriction and further hypoxia. Increased oxygen consumption results in hypoxia, anaerobic metabolism, and lactic acid production.

In the intensive care nursery, radiant warmers may be used to compensate for heat loss. Incubators are more efficient than radiant warmers because the heated environment decreases heat loss due to conduction, convection, and radiation. With radiant warmers, consider using food-grade plastic wrap/sheets and a humidified environment for ELBW infants. New devices function as both an incubator and an overhead warmer to enable access for procedures. In all nurseries, maintain the environmental temperature above 23º-25ºC (>74º-77ºF).

Temperature maintenance is especially critical during neonatal resuscitation, when the same principles apply. (See Neonatal Resuscitation).

Skin care

Premature infants have immature skin, a decreased or absent stratum corneum, decreased cohesiveness between skin layers, increased water fixation, and tissue edema. The immature skin integrity leads to easy injury, transdermal absorption of drugs and other materials in contact with the skin, and increased risk for infection.

The National Association of Neonatal Nurses (NANN) and the Association of Women's Health, Obstetric and Neonatal Nurses (AWHONN) recommended the following areas of newborn skin care, which are based on clinical and laboratory research:

1. Bathing: Use only water and no soap for infants who weigh less than 1000 g. Decrease the frequency of using cleansers. Only use neutral-pH cleansers.

2. Disinfectants (eg, povidone-iodine, chlorhexidine): Completely remove these agents after the procedure to decrease transdermal absorption. Isopropyl alcohol use is discouraged because it is relatively ineffective as a disinfectant and is drying to the skin. Alcohol burns, and cracked skin can result.

3. Adhesives: Minimize the use of adhesives. Use double-backed silk tape versus tape with strong adhesive properties (eg, Elastoplast). Use hydrogel electrodes. Avoid solvents or bonding agents.

4. Transepidermal water loss: Place infants born at 30 weeks' gestation in a high-humidity (>70%) environment.

5. Topical solutions: Review ingredients of any topical solution placed on the skin of a preterm infant. Transdermal absorption can occur. Discourage use of solvents for adhesive removal.

6. Pectin barriers (eg, DuoDERM extra thin, Restore extra thin): Pectin barriers are recommended. Anchoring devices (umbilical lines) to pectin barriers results in improved skin integrity.

Fluid and electrolyte management

Preterm infants require intense monitoring of their fluid and electrolyte levels because of their increased transdermal water loss, immature renal function,[6] and other environmental issues (eg, radiant warming, phototherapy, mechanical ventilation). The degree of prematurity dictates the initial fluid management. The following are general principles of fluid and electrolyte management when caring for premature infants:

• The initial fluid should be a solution of glucose and water.

• Calcium may be added in the initial fluid.

• Total parenteral nutrition should be started as early as possible, especially for extremely low birth weight (ELBW) infants.

Expected loss of extracellular water in the first week of life in term infants is 5% of birth weight; 10% of birth weight in low birth weight (LBW) infants; and 15-20% of birth weight in ELBW infants. Data curves, which Dancis developed in the 1940s, may be useful in monitoring weight loss in each group of infants.

The degree of prematurity and the infant's specific medical issues dictate initial fluid therapy. However, the following general principles apply to all preterm infants:

• Initial fluids should be a solution of glucose and water. More mature infants can be started at 60-80 mL/kg/d. The most immature infants may need up to 100-150 mL/kg/d. (See Extremely Low Birth Weight Infant.)

• Environmental aspects of care (eg, radiant warmer, phototherapy, and a nonhumidified environment) increase insensible water loss and the need for more fluids. Mechanical ventilation, use of double-walled isolettes, and provision of humidity decrease insensible water loss.

• The glucose infusion rate (GIR) is usually started at 4-6 mg/kg/min. In general, to obtain this rate, a solution of dextrose 10% in water (D10W) should be used initially. The exception is the ELBW infant who should initially be given dextrose 5% in water (D5W) to provide the same GIR and to prevent hyperglycemia.

• Electrolytes should not be added until 24 hours of age, when urine output is adequate. Electrolyte and calcium levels should be monitored at 12-24 hours of age depending on the degree on prematurity and other medical issues.

• Basal needs are sodium is 2-3 mEq/kg/d, potassium 1-2 mEq/kg/d, and calcium 600 mg/kg/d (as calcium gluconate). Urinary losses, which may increase in the most immature of infants and in those exposed to diuretics, dictate the need for supplemental sodium.

• Infants who develop acute tubular necrosis (ATN) should be treated with fluid restriction that equals insensible water loss plus urine output. Additional fluid is administered by closely and frequently monitoring the output and electrolyte levels during the post-ATN diuretic phase.

• Hyponatremia and weight gain should be treated with decreasing fluid administration. Monitoring of urinary electrolyte losses is sometimes helpful in replacement therapy.

• The infant's weight should be followed up every 24 hours. Results of laboratory monitoring, urine output and change in weight dictate changes in fluid and electrolyte support.

Evidence-based guidelines

In a study of 160 very LBW infants (≤1250 g), the introduction of evidence-based guidelines focusing on preventing heat loss, reducing exposure to supplemental oxygen, and increasing the use of noninvasive respiratory support led to significantly improved outcomes.[48, 49] Average admission temperatures increased (36.4°C vs 36.7° C), and the percentage of infants admitted with moderate or severe hypothermia decreased (14% vs 1%). Exposure to oxygen decreased during the first 10 minutes of life, whereas oxygen saturations remained similar.[48, 49]

Decreases were also observed in the median duration of invasive ventilation procedures (5 days vs 1 day) and the duration of hospital stay (80 vs 60 days) after the guidelines were introduced.[48, 49]

Kangaroo mother care

A multistakeholder group of newborn health advocates proposed accelerating global kangaroo mother care (KMC) as the standard of care for preterm infants.[50, 51] KMC consists of various preterm infant care practices that include skin-to-skin contact, breastfeeding, and close postdischarge follow-up. According to the advocacy group, achieving universal KMC coverage could potentially save an estimated 450,000 preterm newborns annually, but current global coverage of KMC is lower than 1%.[50] With a goal of achieving 50% coverage of KMC by the year 2020, the group planned a series of actions, including revising the World Health Organization KMC guidelines, incorporating high-quality KMC into national policies, conducting more research, and engaging health professional associations.[50]

Studies in multiple resource-poor areas indicate that KMC coverage has improved, but has fallen short of the 50% goal. Government leadership, healthcare implementation, standardized tracking and reporting systems, and social and cultural support are needed to fully achieve the benefits of KMC.[52, 53, 54]

Dexamethasone may affect hearing and intelligence in preterm infants

A meta-analysis indicated that dexamethasone use in preterm infants may have significant deleterious effects on hearing and intelligence.[55] The study looked at 10 randomized, controlled trials involving a total of 1038 preterm infants, including 512 who received intravenous dexamethasone and 526 who received a placebo. The investigators found a significantly lower intelligence quotient in patients who received dexamethasone treatment within 7 days following birth, relative to the placebo group.[55]

In infants who began treatment with dexamethasone more than 7 days after birth, the incidence of hearing loss was significantly greater than in the control group, although the change in intelligence quotient was comparable to that in the placebo group. The investigators also found that the incidence of cerebral palsy and visual impairment were similar in the dexamethasone and placebo groups whether dexamethasone was received within 7 days following birth or later.[55]

Discharge criteria

Perform developmental assessment and intervention, as appropriate.

Discharge criteria in cases of prematurity are as follows:

• The parents and/or caregivers are capable. That is, they demonstrate an ability to meet the needs of the infant.

• The patient's caloric intake is adequate for growth.

• The patient has been weaned from the supplemental heat.

• Medical problems are defined and manageable at home.

• No apnea or bradycardia is present for some time.

Preterm infants born at less than 35 weeks' gestation have poor coordination of the suck and swallow reflexes and decreased intestinal motility. Nutrition in the first several days after birth often is provided intravenously. Even the relatively healthy preterm infant may not reach full enteral nutrition until a week or longer after birth.

In a study of nearly 700 premature infants receiving parenteral therapy, researchers found that chromium supplements (0.2 mcg/kg/day) in the first week of life improved glucose tolerance and calorie absorption.[56] These benefits were also observed in very low birth weight infants. In the study, rates of hyperglycemia were similar in infants who received chromium supplements and those who did not. At similar hyperglycemia levels, infants treated with chromium tolerated significantly higher mean glucose infusion rates (8.4 vs 8 mg/kg/min) and significantly greater daily mean parenteral calorie intake (74.8 vs 71.5 kcal/kg/day).[56]

In a review of 15 studies comprising 979 infants, investigators found similar safety and efficacy between newer lipid emulsions (LE) from alternative lipid sources with reduced polyunsaturated fatty acid (PUFA) content and that of conventional pure soybean oil-based LEs that have high PUFA content for the parenteral nutrition of preterm infants.[57] There were no statistically significant differences in clinically important outcomes including death, growth, bronchopulmonary dysplasia, sepsis, retinopathy of prematurity of stage 3 or higher, and parenteral nutrition-associated liver disease with the use of newer alternative LEs versus the conventional pure soy oil-based LEs.

Colostrum

If available, colostrum is the preferred initial nourishment. Colostrum contains digestible proteins, antibody (secretory immunoglobulin A [IgA]), growth factors, and other components that in the aggregate promote intestinal villous growth and influence the intestinal colonization.

Mature breast milk

Mature breast milk replaces transitional milk by 10-12 days after birth. The caloric density varies among mothers based in part on the mother's nutritional status. Note that for ELBW infants, breast milk is often inadequate to sustain growth.

Most calories are contained in lactose (35%) and fat (50%). In the more preterm infants, lactase activity is low which may contribute to less-than-optimal digestion of lactose and absorption of carbohydrate. This improves with gestational age.

Calcium, sodium, potassium, and trace mineral levels in breast milk are insufficient to meet the needs of the preterm infant. Therefore, minerals, protein, carbohydrates, and lipids are often added to breast milk to support optimal growth in the form of commercially available breast milk fortifiers.

Approximately 120-150 cal/kg/d are required for growth. Small preterm infants with increased metabolic needs due to complications such as bronchopulmonary dysplasia may require as much as 180 cal/kg/d to grow.

Formula

Preterm formulas have been developed to address the specific needs and digestive abilities of the preterm infant. The typical formula contains more easily digested glucose polymers (50% of carbohydrates) and medium chain triglycerides that minimize the need for active lipase activity.

Although preterm formula contains more calcium and phosphorus than breast milk, osteopenia of prematurity and poorly mineralized primary teeth remain clinically significant problems.[51] Poor early intravenous nutrition and the use of diuretics often exacerbate these problems. Increased sodium compensates for poor renal retention. Exercise has an important potential role for preventing and treating osteopenia of prematurity.[51]

The formulas contain additional trace minerals and vitamins.

Dietary guidelines

Guidelines issued in 2013 by the American Academy of Pediatrics offer the first dietary recommendations for vitamin D and calcium intake specifically for preterm infants.[58, 59] Bone mineral requirements of preterm infants differ significantly from those of full-term babies. The guidelines recommend 200-400 IU of vitamin D daily for preterm infants with very low birth weight (VLBW) (ie, < 1500 g). When the infant's weight rises above approximately 1500 g and the baby can tolerate full enteral nutrition, an increase to 400 IU/day is advised.

To prevent rickets in preterm infants, the guidelines also recommend that high amounts of mineral supplements be used in infants who weigh less than 1800-2000 g.[58, 59] Supplementation should include human milk fortified with minerals or infant formulas designed specifically for preterm infants and should be based on infant weight rather than gestational age.

Extremely low birth weight (ELBW) and very low birth weight (VLBW) infants require close monitoring of their neurodevelopmental progress. Early identification of developmental concerns and appropriate intervention leads to better outcomes. Anticipatory guidance must be given to parents or caregivers to achieve the best possible outcome.

Premature infants require close monitoring of nutrition, growth, and development on a regular basis by the pediatrician. ELBW infants and infants with complications need to see a developmental specialist to identify concerns early on to provide appropriate therapies. Pediatric dietitian consult is indicated if nutrition issues arise.

Prematurity is not a specific illness. Medications administered to an infant are prescribed for a specific purpose and are discussed in each of the articles mentioned previously about specific disease processes.

A 2013 study found that injections of the erythropoiesis-stimulating agent darbepoetin alfa (Darbe) may eliminate or reduce the need for red blood cell transfusions in preterm infants.[60, 61] In the study, which included 102 preterm infants at four high-altitude medical centers, infants were randomized to treatment with erythropoietin (Epo) 400 U/kg, given subcutaneously thrice weekly; darbepoetin alfa 10 μg/kg, given subcutaneously once a week with sham dosing two other times a week; or placebo in three sham doses a week through 35 weeks' gestation, discharge, transfer to another hospital, or death. Doses were adjusted for body weight weekly.[60, 61]

Infants in the darbepoetin alfa and erythropoietin groups received significantly fewer transfusions and had significantly fewer donor exposures than those in the placebo group, and 59% of the darbepoetin alfa-treated infants and 52% of the erythropoietin-treated infants received no transfusions at all, compared with 38% of infants in the placebo group. Compared with infants in the placebo group, darbepoetin alfa- and erythropoietin-treated infants had significantly higher changes in absolute reticulocyte counts and hematocrits.[60, 61] Use of an erythropoiesis-stimulating agent can be helpful; however, the potential for neovascularization and tumor progression cannot be ignored.[62]