Pathophysiology

Before birth, the placenta serves 3 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.

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

Chorioamnionitis

Amniocentesis that demonstrates bacteria, 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)

This 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 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.
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.

Multiple gestation pregnancies

Women with multiple gestation pregnancies are at high risk of preterm labor and delivery
and account for increasing percentage of preterm births and ELBW infants

With advances in assisted reproductive technology, multiple gestation pregnancies have

increased.

Preterm birth rate for twins has increased from 40.9% in 1981 to 55% in 1997. Multiple births
related to infertility treatment have dramatically increased.[12]

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. 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%. 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 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.
Confirmation of gestational age 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. [10] 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.[3]

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

Preterm infant at 28 weeks' gestation. Note the small amount of ear

cartilage and/or flattened pinna. Preterm infant at 33 weeks'

gestation. Note the increased cartilage, recoil, and outer ridge curving inward.

A term infant has well-developed cartilage with instant recoil.

 Preterm infant at 28 weeks' gestation. Note the flat sole.
Preterm infant at 33 weeks' gestation. Note the presence of only an anterior crease.

Term gestation. Note the multiple creases.

Preterm infant at 28 weeks' gestation. No breast tissue is present, and the areolae are

barely visible. Preterm infant at 33 weeks' gestation. The

breast tissue is less than 1 cm, and the areolae are raised and/or pigmented.
This examination 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.[11]

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

Blood tests

CBC counts may reveal anemia or polycythemia that is not clinically apparent.

A high or low WBC count and numerous immature neutrophil types may also be found. An
abnormal WBC count may suggest subtle infection.

A blood type and antibody testing (Coombs test) are performed to detect blood-group
incompatibilities between the mother and infant and to identify antibodies against fetal RBCs.
Such incompatibilities increase the risk for jaundice and kernicterus.

Serum electrolytes analysis

At birth, most serum electrolyte levels reflect those of the mother.

If the mother received magnesium sulfate to inhibit labor, the baby's respiratory effort may
be compromised, and the serum magnesium value is 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 ample electrolyte and minerals from appropriate preterm formulas and fortified
human milk. These issues are more acute with decreasing gestational age.

Frequent laboratory determinations of serum sodium, potassium, and glucose in conjunction

with monitoring of daily weight and urine output in extremely low birth weight (ELBW) infants
assists the practitioner in determination of fluid requirements.

Serum glucose concentrations

These 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. All programs include testing of newborn
blood spots for a minimum of phenylketonuria, hypothyroidism, and galactosemia. The
timing of obtaining the sample varies.

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

Imaging Studies
 Imaging studies are specific to the organ system affected. Chest radiography is performed to
assess lung parenchyma in newborns with respiratory distress. Cranial ultrasonography is
performed to detect occult intracranial hemorrhage in ELBW newborns. Prematurity itself is
not an indication for an imaging study.

Medical Care
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 has established guidelines
for levels of neonatal care.[13]

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 mask (Neopuff), 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 86% and 93% by using an oxygen blender.
 Prevent barotrauma or volutrauma by using a ventilator that permits measurement of the
expired tidal volume and by keeping it 4-7 mL/kg.
 Administer surfactant early (< 2 h of age) when indicated and prophylactically in all
extremely premature neonates (< 29 wk).
Many centers are using early CPAP and a relatively permissive approach to ventilation.
Research is needed to provide evidence to support an approach that provides the best
outcome.

A retrospective analysis studied the first 48 hours in 225 infants of 23-28 weeks gestational
age. The study results noted that 140 of these infants could be stabilized with nasal CPAP in
the delivery room; 68 with a favorable outcome and 72 with a failed outcome within 48 hours;
history or initial blood gas results were poor predictors of subsequent nasal CPAP failure. A
threshold fraction of inspired oxygen (FiO2) of greater than or equal to 0.35-0.45 compared
with greater than or equal to 0.6 for intubation may shorten the time to surfactant delivery,
without a relevant increase in intubation rate.[14]

Thermoregulation

Maintenance of the neutral thermal environment is critical for minimizing stress and
optimizing growth of the premature infant. 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.

Neonates lose heat by 4 means, as follows:

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 of a small
amount of subcutaneous tissue (insulation) and decreased brown fat to produce heat.

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 extremely low birth weight (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 a decreased surfactant production and loss of functional

alveolar number, 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 plastic wrap 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 at more than 70°F (>21°C).

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 their use. Use double-backed silk tape versus tape with strong
adhesive properties (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): These are
recommended. Anchoring devices (umbilical lines) to pectin barriers results in
improved skin integrity.

Fluid and electrolyte management

Preterm infants need intense monitoring of their fluid and electrolytes because of their
increased transdermal water loss, immature renal function, and other environmental issues
(eg, radiant warming, phototherapy, mechanical ventilation).

Expected loss of extracellular water in the first week of life in the term infant is 5% of birth
weight, low birth weight (LBW) infant is 10% of birth weight, and in the ELBW infant is 15-
20%. 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 medication problems 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 warming, phototherapy, and a nonhumidified
environment, increase insensible water loss and the need for 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.
Electrolytes and calcium 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 electrolytes 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 patient's weight should be followed up every 24 hours. Results of laboratory
monitoring and change in weight dictate changes in fluid and electrolyte support.
Evidence-based guidelines

In a study of 160 very low birth weight 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.
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, while oxygen saturations remained
similar.[15, 16]

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.[15, 16]

Diet
Preterm infants born at less than 34 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.

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.

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 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. Poor early intravenous nutrition and the use of diuretics often exacerbate these
problems. Increased sodium compensates for poor renal retention.

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. [17, 18] 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. Supplementation
should include human milk fortified with minerals or formulas designed specifically for
preterm infants and should be based on infant weight rather than gestational age.