Williams Manual of Pregnancy Complications, 23 ed.

CHAPTER 90. Neonatal Complications of Prematurity


To provide blood–gas exchange after birth, the infant’s lungs must rapidly fill with air while being cleared of fluid, and the volume of blood that perfuses the lungs must increase remarkably. Some of the fluid is expressed as the chest is compressed during vaginal delivery, and the remainder is absorbed through the pulmonary lymphatics. The presence of sufficient surfactant synthesized by the type II pneumonocyte is essential to stabilize the air-expanded alveoli by lowering surface tension and thereby preventing lung collapse during expiration. If surfactant is inadequate, respiratory distress develops. This is characterized by the formation of hyaline membranes in the distal bronchioles and alveoli. Because of this, respiratory distress in the newborn is also termed hyaline membrane disease.

Clinical Course

In the typical case of respiratory distress syndrome, tachypnea develops and the chest wall retracts, while expiration is often accompanied by a whimper and grunt—a combination called “grunting and flaring.” Progressive shunting of blood through nonventilated lung areas contributes to hypoxemia and metabolic and respiratory acidosis. Poor peripheral circulation and systemic hypotension may be evident. The chest x-ray shows a diffuse reticulogranular infiltrate with an air-filled tracheobronchial tree (air bronchogram).

Respiratory insufficiency can also be caused by sepsis, pneumonia, meconium aspiration, pneumothorax, diaphragmatic hernia, persistent fetal circulation, and heart failure. Common causes of cardiac decompensation in the early newborn period are patent ductus arteriosus and congenital cardiac malformations.


The most important factor influencing survival is admission to a neonatal intensive care unit. Hyperoxemia is indicative of the need for oxygen. However, excess oxygen can damage the pulmonary epithelium and retina; thus, oxygen concentration administered should be at the lowest level sufficient to relieve hypoxia and acidosis.

Continuous Positive Airway Pressure

Continuous positive airway pressure (CPAP) prevents the collapse of unstable alveoli and has brought about an appreciable reduction in the mortality rate. Successful ventilation usually allows high inspired-oxygen concentrations to be reduced and thereby minimizes toxicity.

Although often necessary, mechanical ventilation results in repeated alveolar overstretching, which can disturb the integrity of the endothelium and epithelium and cause barotrauma. To obviate this, high-frequency oscillatory ventilation is used to maintain an optimal lung volume and to clear CO2 with a constant low distending pressure and small variations or oscillations that promote alveolar recruitment. It can be used in combination with inhaled nitric oxide for severe cases of pulmonary hypertension.


Administration of aerosolized surfactant has been shown to greatly decrease the incidence of hyaline membrane disease when utilized for prophylaxis as well as to improve survival when used for rescue of infants with established disease. Randomized trials have shown decreased incidence of pneumothorax and bronchopulmonary dysplasia, and a 30-percent reduction in mortality during the first 28 days of life. Preparations include biological or animal surfactants such as human, bovine (Survanta), calf lung (Infasurf), porcine (Curosurf), or synthetic (Exosurf).


Persistent hyperoxia injures the lung, especially the alveoli and capillaries. High oxygen concentrations given at high pressures can cause bronchopulmonary dysplasia, or oxygen toxicity lung disease. This is a chronic condition in which alveolar and bronchiolar epithelial damage leads to hypoxia, hypercarbia, and oxygen dependence, followed by peribronchial and interstitial fibrosis. Pulmonary hypertension is another frequent complication. If hyperoxemia is sustained, the infant is also at risk of developing retinopathy of prematurity, formerly called retrolental fibroplasia (see subsequent discussion).

Amniocentesis for Fetal Lung Maturity

Amniocentesis is often used to confirm fetal lung maturity. A number of methods are used to determine the relative concentration of surfactant-active phospholipids.

Lecithin-to-Sphingomyelin (L/S) Ratio

Lecithin (dipalmitoyl-phosphatidylcholine) plus phosphatidylinositol and especially phosphatidylglycerol are important in the formation and stabilization of the surface-active layer that prevents alveolar collapse and respiratory distress. Before 34 weeks’ gestation, lecithin and sphingomyelin are present in amnionic fluid in similar concentrations. At about 34 weeks, the concentration of lecithin relative to sphingomyelin begins to rise (Figure 90-1).


FIGURE 90-1 Changes in mean concentrations of lecithin and sphingomyelin in amnionic fluid during gestation in normal pregnancy. (This figure was published in American Journal of Obstetrics and Gynecology, vol. 115, No. 4, L Gluck and MV Kulvich, Lecithin-sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy, pp. 539, Copyright Elsevier 1973.)

The risk of neonatal respiratory distress is very slight whenever the concentration of lecithin is at least twice that of sphingomyelin. Conversely, there is increased risk of respiratory distress when the L/S ratio is less than 2. Because lecithin and sphingomyelin are found in blood and meconium, contamination with these substances may confound the results. Blood has an L/S ratio of 1.3 to 1.5 and could thus either raise or lower the true value, whereas meconium usually lowers the L/S ratio. An immature L/S ratio is more predictive of the need for ventilatory support than gestational age or birth weight. With some pregnancy complications, respiratory distress may develop despite a mature L/S ratio. This has been reported most frequently with diabetes, but the concept is controversial.


Because of uncertainty about the predictive value of the L/S ratio alone, some clinicians consider the presence of phosphatidylglycerol (PG) to be mandatory prior to elective delivery, particularly in the diabetic mother. Phosphatidylglycerol is believed to enhance the surface-active properties of lecithin and sphingomyelin. Its identification in amnionic fluid provides more assurance, but not necessarily an absolute guarantee, that respiratory distress will not develop. Because PG is not detected in blood, meconium, or vaginal secretions, these contaminants do not confuse the interpretation. Although the presence of PG is reassuring, its absence is not necessarily an indicator that respiratory distress is likely to develop after delivery.


This automated assay measures the surfactant-to-albumin ratio in uncentrifuged amnionic fluid and gives results in approximately 30 minutes. A TDx value of 50 or greater has been reported to predict fetal lung maturity in 100 percent of cases. Many hospitals use the TDx-FLM as their first-line test of pulmonary maturity, followed by the L/S ratio in indeterminate samples.

Other Tests

The foam stability or shake test was introduced in 1972 to reduce the time and effort inherent in precise measurement of the L/S ratio. The test depends upon the ability of surfactant in amnionic fluid, when mixed appropriately with ethanol, to generate stable foam at the air–liquid interface. There are two problems with the test: (1) slight contamination of amnionic fluid, reagents, or glassware, as well as errors in measurement may alter the test results; and (2) a false-negative test is rather common. Some laboratories use this as a screening test, and if negative, use another test to better quantify the L/S ratio.


Retinopathy of prematurity (ROP) by 1950 had become the largest single cause of blindness in the United States. After the discovery that the etiology of the disease was hyperoxemia, its frequency decreased remarkably.


The retina vascularizes centrifugally from the optic nerve, starting at about the fourth fetal month and continuing until shortly after birth. During the time of vascularization, retinal vessels are easily damaged by excessive oxygen. The temporal portion of the retina is most vulnerable. Oxygen induces severe vasoconstriction, endothelial damage, and vessel obliteration. When the oxygen level is reduced, there is neovascularization at the site of previous vascular damage. The new vessels penetrate the retina and extend intravitreally, where they are prone to leak proteinaceous material or burst with subsequent hemorrhage. Adhesions then form, which detach the retina.


Precise levels of hyperoxemia that can be sustained without causing retinopathy are not known. Retinopathy is unlikely if inhaled air is enriched with oxygen to no more than 40 percent. Unfortunately, very immature infants who develop respiratory distress will most likely require ventilation with high oxygen concentrations to maintain life until respiratory distress clears.


There are four major categories of neonatal intracranial hemorrhage (IVH): subdural, subarachnoid, intracerebral, and periventricular–intraventricular. Subdural hemorrhage is usually due to trauma. Subarachnoid and intracerebellar hemorrhages usually result from trauma in term infants, but are commonly due to hypoxia in preterm infants. Periventricular–intraventricular hemorrhages result from either trauma or asphyxia in term infants but have no discernible cause in 25 percent of cases. In preterm neonates, the pathogenesis of periventricular hemorrhage is multifactorial and includes hypoxic–ischemic events, anatomical considerations, coagulopathy, and many other factors. The prognosis after hemorrhage depends upon the location and extent of the bleeding. Subdural and subarachnoid bleeding, for example, often results in minimal, if any, neurological abnormalities. Bleeding into the parenchyma of the brain, however, can cause serious permanent damage.

Periventricular–Intraventricular Hemorrhage

When the fragile capillaries of the germinal matrix rupture, bleeding into surrounding tissues occurs, which may extend into the ventricular system and brain parenchyma. Unfortunately, it is a common problem in preterm infants. Although a variety of external perinatal and postnatal influences undoubtedly alter the incidence and severity of this type of hemorrhage, preterm birth before 32 weeks has the greatest impact. These lesions can develop at later gestational ages, however, and are occasionally seen in term neonates.

Most hemorrhages develop within 72 hours of birth, but they have been observed as late as 24 days. Almost half are clinically silent, and most small germinal matrix hemorrhages and those confined to the cerebral ventricles resolve without impairment. Large lesions can result in hydrocephalus or periventricular leukomalacia, a correlate of cerebral palsy, discussed subsequently. Because intraventricular hemorrhages are usually recognized within 3 days of delivery, their genesis is often erroneously attributed to birth events. It is important to realize that prelabor intraventricular hemorrhage is well recognized.


The primary pathological process is damage to the germinal matrix capillary network, which predisposes to subsequent extravasation of blood into the surrounding tissue. This capillary network is especially fragile in preterm infants for the following reasons: (1) the subependymal germinal matrix provides poor support for the vessels coursing through it; (2) venous anatomy in this region causes venous stasis and congestion susceptible to vessel bursting with increased intravascular pressure; and (3) vascular autoregulation is impaired before 32 weeks. If extensive hemorrhage or other complications of preterm birth do not cause death, survivors can have major neurodevelop-mental handicaps.

Most long-term sequelae of periventricular–intraventricular hemorrhages are due to cystic areas called periventricular leukomalacia. These areas develop more commonly as a result of ischemia and less commonly in direct response to hemorrhage, and are discussed later.

Incidence and Severity

The incidence of intraventricular hemorrhage depends upon gestational age at birth and birth weight. About half of all neonates born before 34 weeks will have evidence of some hemorrhage, and this incidence decreases to 4 percent at term. Very low-birth-weight infants have the earliest onset of hemorrhage, the greatest likelihood for progression into parenchymal tissue, and the most severe long-term prognosis.

The severity of intraventricular hemorrhage can be assessed by ultrasound and computed tomography, and various grading schemes are used to quantify the extent of the lesion. The scheme proposed by Papile LA, Burstein J, Burstein R, Koffler H. (Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm. J Pediatr 92:529, 1978) is commonly used:

• Grade I: Hemorrhage limited to the germinal matrix

• Grade II: Intraventricular hemorrhage

• Grade III: Hemorrhage with ventricular dilatation

• Grade IV: Parenchymal extension of hemorrhage

The severity of the hemorrhage strongly influences prognosis. Infants with grade I or II hemorrhage have over 90-percent survival with 3-percent handicap. The survival rate for infants with grade III or IV hemorrhage, however, is only 50 percent.

Contributing Factors

Events that predispose to germinal matrix hemorrhage and subsequent periventricular leukomalacia are multifactorial and complex. Associated complications of preterm birth—which, for example, is frequently associated with infection—predispose to tissue ischemia. Respiratory distress syndrome and mechanical ventilation are commonly associated factors.

Prevention and Treatment

Administration of corticosteroids to the mother before delivery has been reported to decrease the incidence of intraventricular hemorrhage. In a consensus statement developed by the National Institutes of Health (NIH) in 1994, it was concluded that antenatal corticosteroid therapy reduced mortality, respiratory distress, and intraventricular hemorrhage in preterm infants between 24 and 32 weeks. A second consensus conference held by the NIH in 2000 and concluded that repeated courses of antenatal steroids should not be given. It is generally agreed that avoiding significant hypoxia both before and after preterm delivery is of paramount importance. There is presently no convincing evidence, however, that routine cesarean delivery for the preterm fetus presenting cephalic will decrease the incidence of periventricular hemorrhage. There is no association with the presence of labor or its duration.

Periventricular Leukomalacia

The preterm infant is also at risk for periventricular leukomalacia (PVL). This is related to the blood supply of the developing brain before 32 weeks. The blood supply to the preterm brain is composed of two systems: the ventriculopedal system, which penetrates into the cortex, and the ventriculofugal system. The area between these two blood supplies corresponds to an area near the lateral cerebral ventricles through which the pyramidal tracts pass. It is called the watershed area because this region is very vulnerable to ischemia. Any intracranial vascular injury occurring before 32 weeks and leading to ischemia affects the watershed area first, damaging the pyramidal tracts and resulting in spastic diplegia. After 32 weeks, the blood supply shifts away from the brainstem and basal ganglia toward the cortex. Hypoxic injury after this time primarily damages the cortical region. Although some of the same factors that appear to cause intraventricular hemorrhage are associated with periventricular leukomalacia, the latter seems to be more strongly linked to infection and inflammation. Investigators have shown strong association among periventricular leukomalacia, prolonged ruptured membranes, chorioamnionitis, and neonatal hypotension.

Perinatal Infection

Fetal infection may be a key element in the pathway between preterm birth, intraventricular hemorrhage, periventricular leukomalacia, and cerebral palsy. Antenatal reproductive tract infection is characterized by the production of cytokines, including interleukins 1, 6, and 8, and others. These stimulate prostaglandin production, which may in time lead to preterm birth. These cytokines also have direct toxic effects on oligodendrocytes and myelin in the brain.


Aggressive treatment of or prophylaxis with antibiotics in the woman delivering preterm, particularly with ruptured membranes, may prevent intraventricular hemorrhage in the newborn infant (see Chapter 34).

Possible neuroprotective benefits (prevention of cerebral palsy) of magnesium sulfate given to the mother are undergoing investigation. In addition, magnesium has been reported to stabilize intracranial vascular tone, minimize fluctuations in cerebral blood flow, reduce reperfusion injury, and block calcium-mediated intracellular damage. It also appears to reduce synthesis of cytokines and bacterial endotoxins, and thus may minimize the inflammatory effects of infection.


This bowel disorder commonly presents with clinical findings of abdominal distention, ileus, and bloody stools. There is usually radiological evidence of pneumatosis intestinalis caused by intestinal wall gas as the consequence of invasion by gas-forming bacteria and bowel perforation. Abdominal distention or blood in the stools may signal developing enterocolitis. At times it is so severe that bowel resection is necessary.

The disease is primarily seen in low-birth-weight infants, but occasionally is encountered in mature neonates. Various causes have been suggested, including perinatal hypotension, hypoxia, or sepsis, as well as umbilical catheters, exchange transfusions, and the feeding of cow milk and hypertonic solutions. The disease tends to occur in clusters, and coronaviruses have been suspected of having an etiological role. It is reported that 6 percent of preterm infants develop necrotizing enterocolitis (NEC).


All of the concerns described previously are amplified as the limits of viability are reached in the 23- to 25-week age group (Table 90-1; see also Chapter 32). The mortality rate in this age group is high, and survivors frequently have devastating neurological, ophthalmological, or pulmonary injury as a result of immaturity. Table 90-1 shows outcome data for infants born at 22 to 25 weeks’ gestation. In this study, only 1 infant born prior to 23 weeks survived. Although survival increased at or beyond 23 weeks, moderate-to-severe disability was seen in 90 percent of the infants at 6 years of age following birth at 22 to 24 weeks.

TABLE 90-1. 6-Year Outcomes of Surviving Infants Born from 22 to 25 Weeks in the United Kingdom in 1995


For further reading in Williams Obstetrics, 23rd ed.,

see Chapter 29, “Diseases and Injuries of the Fetus and Newborn.”