RESPIRATORY DISTRESS SYNDROME
AMNIOCENTESIS FOR FETAL LUNG MATURITY
RETINOPATHY OF PREMATURITY
The preterm infant is susceptible to various serious medical complications during the newborn period as well as morbidities extending later into life (Table 34-1). These complications are primarily the consequence of immature organs that result from abbreviated gestation. A less commonly cited cause of morbidity and mortality is congenital malformations, which are much more prevalent in preterm births. For example, between 2010 and 2013 at Parkland Hospital, major malformations were diagnosed in 67 per 1000 singleton births < 37 weeks’ gestation. This compared with 15 per 1000 in those ≥ 38 weeks—an almost fivefold excess. The pivotal complication, however, is respiratory distress syndrome (RDS). This results from immature lungs that are unable to sustain necessary oxygenation. Resulting hypoxia is an underlying associated cause of neurological damage such as cerebral palsy. In addition, hyperoxia, a side effect of RDS treatment, causes bronchopulmonary dysplasia and retinopathy of prematurity. These complications of prematurity can be placed in perspective in terms of the human consequences. In 2009, two thirds of all infant deaths in the United States were in the 12 percent of infants who were born < 37 weeks (Mathews, 2013).
TABLE 34-1. Complications of Prematurity
Respiratory distress syndrome (RDS, HMD)
Bronchopulmonary dysplasia (BPD)
Patent ductus arteriosus (PDA)
Necrotizing enterocolitis (NEC)
Retinopathy of prematurity (ROP)
Intraventricular hemorrhage (IVH)
Periventricular leukomalacia (PVL)
Cerebral palsy (CP)
HMD = hyaline membrane disease.
RESPIRATORY DISTRESS SYNDROME
To provide blood gas exchange immediately following delivery, the lungs must rapidly fill with air while being cleared of fluid. Concurrently, pulmonary arterial blood flow 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. Sufficient surfactant, synthesized by type II pneumocytes, is essential to stabilize the air-expanded alveoli. It lowers surface tension and thereby prevents lung collapse during expiration (Chap. 7, p. 142). If surfactant is inadequate, hyaline membranes form in the distal bronchioles and alveoli, and RDS develops. Although respiratory insufficiency is generally a disease of preterm neonates, it does develop in term newborns, especially with sepsis or meconium aspiration.
In typical RDS, tachypnea develops, the chest wall retracts, and expiration is accompanied by grunting and nostril flaring. Shunting of blood through nonventilated lung contributes to hypoxemia and metabolic and respiratory acidosis. Poor peripheral circulation and systemic hypotension may be evident. The chest radiograph shows a diffuse reticulogranular infiltrate and an air-filled tracheobronchial tree—air bronchogram.
As discussed further in Chapter 33 (p. 637), respiratory insufficiency can also be caused by sepsis, pneumonia, meconium aspiration, pneumothorax, persistent fetal circulation, heart failure, and malformations involving thoracic structures, such as diaphragmatic hernia. Evidence is also accruing that common mutations in surfactant protein production may cause RDS (Garmany, 2008; Shulenin, 2004).
With inadequate surfactant, alveoli are unstable, and low pressures cause collapse at end expiration. Pneumocyte nutrition is compromised by hypoxia and systemic hypotension. Partial persistence of the fetal circulation may lead to pulmonary hypertension and a relative right-to-left shunt. Eventually, alveolar cells undergo ischemic necrosis. When oxygen therapy is initiated, the pulmonary vascular bed dilates, and the shunt reverses. Protein-filled fluid leaks into the alveolar ducts, and the cells lining the ducts slough. Hyaline membranes composed of fibrin-rich protein and cellular debris line the dilated alveoli and terminal bronchioles. The epithelium underlying the membrane becomes necrotic. With hematoxylin-eosin staining, these membranes appear amorphous and eosinophilic, like hyaline cartilage. Because of this, respiratory distress in the newborn is also termed hyaline membrane disease.
The most important factor influencing survival is neonatal intensive care. Although hypoxemia prompts supplemental oxygen, excess oxygen can damage the pulmonary epithelium and the retina. However, advances in mechanical ventilation technology have improved neonatal survival rates. For example, continuous positive airway pressure (CPAP) prevents the collapse of unstable alveoli. This allows high inspired-oxygen concentrations to be reduced, thereby minimizing its toxicity. Disadvantages include overstretch of the endothelium and epithelium, which results in barotrauma and impaired venous return (Verbrugge, 1999). High-frequency oscillatory ventilation may reduce the barotrauma risk by using a constant, low-distending pressure and small oscillations to promote alveolar patency. This technique allows optimal lung volume to be maintained and carbon dioxide to be cleared without damaging alveoli. Although mechanical ventilation has undoubtedly improved survival rates, it is also an important factor in the genesis of chronic lung disease—bronchopulmonary dysplasia.
Treatment of the ventilator-dependent neonate with glucocorticoids was used previously to prevent chronic lung disease. The American Academy of Pediatrics now recommends against their use because of limited benefits and increased adverse neuropsychological effects (Watterberg, 2010). Yeh and colleagues (2004) described significantly impaired motor and cognitive function and school performance in exposed neonates. A review by Halliday and associates (2009) supports late postnatal corticosteroid treatment only for infants who could not be weaned from mechanical ventilation. In some studies, inhaled nitric oxide was shown to be associated with improved outcomes for neonates undergoing mechanical ventilation (Ballard, 2006; Kinsella, 2006; Mestan, 2005). Other studies showed no benefits (van Meurs, 2005). Currently, such treatment is considered investigational (Chock, 2009; Stark, 2006).
Exogenous surfactant products can prevent RDS. They contain biological or animal surfactants such as bovine—Survanta, calf—Infasurf, porcine—Curosurf, or synthetic—Exosurf. Lucinactant—Surfaxin R—is a synthetic form that contains sinulpeptide KL4 to diminish lung inflammation (Zhu, 2008). In a Cochrane review, Pfister and coworkers (2007) found that animal-derived and synthetic surfactants were comparable.
Surfactant therapy has been credited with the largest drop in infant mortality rates observed in 25 years (Jobe, 1993). It has been used for prophylaxis of preterm, at-risk newborns and for rescue of those with established disease. Given together, antenatal corticosteroids and surfactant result in an even greater reduction in the overall death rate. In their review, Seger and Soll (2009) found that infants who received prophylactic surfactant had decreased risks of pneumothorax, pulmonary interstitial emphysema, bronchopulmonary dysplasia, and mortality.
Persistent hyperoxia injures the lung, especially the alveoli and capillaries. High oxygen concentrations given at high pressures can cause bronchopulmonary dysplasia. With this, alveolar and bronchiolar epithelial damage leads to hypoxia, hypercarbia, and chronic oxygen dependence from peribronchial and interstitial fibrosis. According to Baraldi and Filippone (2007), most cases are now seen in infants born before 30 weeks’ gestation and represent a developmental disorder secondary to alveolarization injury. Severe disease and death rates are decreasing, however, long-term pulmonary dysfunction is encountered later. Pulmonary hypertension is another frequent complication. If hyperoxemia is sustained, the infant also is at risk of developing retinopathy of prematurity, formerly called retrolental fibroplasia (p. 656). When any of these develop, the likelihood of subsequent neurosensory impairment is substantively increased (Schmidt, 2003).
The National Institutes of Health (1994, 2000) concluded that a single course of antenatal corticosteroid therapy reduced respiratory distress and intraventricular hemorrhage in preterm infants born between 24 and 34 weeks (p. 657). The American College of Obstetricians and Gynecologists and American Academy of Pediatrics (2012) considers all women at risk for preterm birth in this gestational-age range to be potential candidates for therapy. This is discussed further is Chapter 42 (p. 850). After 34 weeks, approximately 4 percent of infants develop respiratory distress syndrome (Consortium on Safe Labor, 2010).
Amniocentesis for Fetal Lung Maturity
Delivery for fetal indications is necessary when the risks to the fetus from a hostile intrauterine environment are greater than the risk of severe neonatal problems, even if the fetus is preterm. If this degree of risk is absent and the criteria for elective delivery at term are not met, then amniocentesis and amnionic fluid analysis can be used to confirm fetal lung maturity. To accomplish this, there are several methods to determine the relative concentration of surfactant-active phospholipids in amnionic fluid. Fluid acquisition is similar to that described for second-trimester amniocentesis (Chap. 16, p. 297). With this sampling, complications requiring urgent delivery arise in up to 1 percent of procedures (American College of Obstetricians and Gynecologists, 2008). Following analysis, the probability of respiratory distress developing in a given infant depends on the test used and fetal gestational age. Importantly, administration of corticosteroids to induce pulmonary maturation has variable effects on some of these tests.
Lecithin–Sphingomyelin (L/S) Ratio. Although not used nearly as much as in the past, the labor-intensive L/S ratio for many years was the gold-standard test. Dipalmitoylphosphatidylcholine (DPPC), that is, lecithin—along with phosphatidylinositol and especially phosphatidylglycerol (PG)—is an important component of the surface-active layer that prevents alveolar collapse (Chap. 32, p. 624). Before 34 weeks, lecithin and sphingomyelin are present in amnionic fluid in similar concentrations. At 32 to 34 weeks, the concentration of lecithin relative to sphingomyelin begins to rise (Fig. 34-1).
FIGURE 34-1 Changes in mean concentrations of lecithin and sphingomyelin in amnionic fluid during gestation in normal pregnancy. (Redrawn from Gluck, 1973, with permission.)
Gluck (1971) reported that the risk of neonatal respiratory distress is slight whenever the concentration of lecithin is at least twice that of sphingomyelin—the L/S ratio. Conversely, there is increased risk of respiratory distress when this ratio is < 2. Because lecithin and sphingomyelin are found in blood and meconium, contamination with these substances may falsely lower a mature L/S ratio.
Phosphatidylglycerol. Previously, respiratory distress was thought to develop despite an L/S ratio > 2 in infants of women with diabetes. Some recommend that phosphatidylglycerol be documented in amnionic fluid of these women. Based on current evidence, it is unclear if either diabetes, per se, or its level of control causes false-positive phospholipid test results for fetal lung maturity (American College of Obstetricians and Gynecologists, 2008).
Fluorescence Polarization. This automated assay measures the surfactant-to-albumin ratio in uncentrifuged amnionic fluid and gives results in approximately 30 minutes. A ratio of ≥ 50 with the commercially available TDx-FLMtest predicted fetal lung maturity in 100 percent of cases (Steinfeld, 1992). Subsequent investigators found the TDx-FLM to be equal or superior to the L/S ratio, foam stability index, or phosphatidylglycerol assessment, including testing in diabetic pregnancies (Eriksen, 1996; Karcher, 2005). The recently modified TDx-FLM II is used by many hospitals as their primary test of pulmonary maturity, with a threshold ratio of 55 mg/g.
Other Tests. The foam stability or shake test depends on the ability of surfactant in amnionic fluid, when mixed appropriately with ethanol, to generate stable foam at the air–liquid interface (Clements, 1972). Problems include errors caused by slight contamination and frequent false-negative test results. Alternatively, the Lumadex-FSI test, fluorescent polarization (microviscometry), and amnionic fluid absorbance at 650-nm wavelength have all been used with variable success. The lamellar body count is a rapid, simple, and accurate method of assessing fetal lung maturity and is comparable to TDx-FLM and L/S ratio (Karcher, 2005).
This newborn bowel disorder has clinical findings of abdominal distention, ileus, and bloody stools. There is usually radiological evidence of pneumatosis intestinalis—bowel wall gas derived from invading bacteria. Bowel perforation may prompt resection. Necrotizing enterocolitis is seen primarily in low-birthweight newborns but occasionally is encountered in mature neonates. Various hypothesized causes include perinatal hypotension, hypoxia, sepsis, umbilical catheterization, exchange transfusions, and the feeding of cow milk and hypertonic solutions (Kliegman, 1984). All of these can ultimately lead to intestinal ischemia, and reperfusion injury likely also has a role (Czyrko, 1991). The unifying hypothesis for these pathological processes is the uncontrolled inflammatory response to bacterial colonization of the preterm intestine (Grave, 2007).
Treatment for necrotizing enterocolitis is controversial (van Vliet, 2013). A randomized trial of laparotomy versus peritoneal drainage found no difference in survival rates in preterm infants (Moss, 2006). In an observational study, however, Blakely (2006) found that death rates and neurodevelopmental outcomes assessed at 18 to 22 months were more favorable with laparotomy compared with drainage.
RETINOPATHY OF PREMATURITY
Formerly known as retrolental fibroplasia, by 1950, retinopathy of prematurity had become the largest single cause of blindness in this country. After the discovery that the disease resulted from hyperoxemia, its frequency decreased remarkably. The fetal retina vascularizes centrifugally from the optic nerve starting at approximately the fourth month and continues until shortly after birth. During vascularization, excessive oxygen induces severe retinal vasoconstriction with endothelial damage and vessel obliteration, especially in the temporal portion. Neovascularization results, and the new vessels penetrate the retina and extend into the vitreous. Here, they are prone to leak proteins 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. Preterm birth results in a “relative” hyperoxia compared with in utero oxygen content even in infants not exposed to higher Fio2. To better understand the oxygen saturation threshold necessary to minimize retinopathy without increasing other adverse outcomes, the National Institute of Child Health and Human Development (NICHD) Neonatal Network performed a randomized trial of oxygenation in 1316 infants born between 24 and 27 weeks (SUPPORT Study Group, 2010). The target range of oxygen saturation was 85 to 89 percent in one arm of this trial and 91 to 95 percent in the other arm. Death before discharge occurred significantly more frequently in the lower-oxygen saturation group—20 versus 16 percent. However, severe retinopathy among survivors developed significantly less often in the lower-oxygen saturation group—8.6 versus 17.9 percent. This study generated considerable controversy as to whether the consent process was adequate for a trial with such end points (Drazen, 2013).
Central nervous system injury in preterm infants usually creates different neuroanatomical sequelae compared with that in term infants (Chap. 33, p. 639). In preterm infants, cerebral lesions detected by neuroimaging include intraventricular hemorrhage, periventricular hemorrhagic infarction, cystic periventricular leukomalacia, and diffuse white matter injury. All of these are strongly associated with adverse neurodevelopmental outcome. Locatelli and colleagues (2010) found a significantly increased incidence of neurological damage in preterm infants who had periventricular hemorrhage, periventricular leukomalacia, or both.
Cranial sonography remains the preferred approach for detecting frequently occurring brain abnormalities and acute events. It is readily available and reliable for detecting common abnormalities and monitoring brain growth. Because cystic injuries may take 2 to 5 weeks to evolve, serial scans are obtained during this time. In infants whose findings are transient and resolve in the neonatal period, prognosis is improved compared with those whose lesions remain and evolve. At the same time, however, between 4 and 10 percent of prematurely born children may develop cerebral palsy in the absence of lesions. Put another way, 90 to 96 percent of preterm infants with cerebral palsy have cerebral lesions that are detectable using cranial sonography.
There are four major categories of intracranial hemorrhage in the neonate (Volpe, 1995). Subdural hemorrhage is usually the result of trauma. Subarachnoid hemorrhage and intracerebellar hemorrhageusually result from trauma in term infants and hypoxia in preterm infants. Periventricular-intraventricular hemorrhage results from either trauma or asphyxia in half of term infants and has no discernible cause in a fourth. In preterm neonates, the pathogenesis of periventricular hemorrhage is multifactorial and includes hypoxic-ischemic events, anatomical factors, coagulopathy, and many others. The prognosis after hemorrhage depends on its location and extent. For example, subdural and subarachnoid hemorrhage often result in minimal, if any, neurological abnormalities. Bleeding into the parenchyma, however, can cause serious permanent damage.
When the fragile capillaries in the germinal matrix rupture, there is bleeding into surrounding tissues that may extend into the ventricular system and brain parenchyma. This type of hemorrhage is common in preterm neonates, especially those born before 32 weeks. However, it can also develop at later gestational ages and even in term neonates. Most hemorrhages develop within 72 hours of birth, but they have been observed as late as 24 days (Perlman, 1986). Because intraventricular hemorrhage usually is recognized within 3 days of delivery, its genesis is often erroneously attributed to birth events. It is important to realize that prelabor intraventricular hemorrhage also can occur (Achiron, 1993; Nores, 1996).
Almost half of hemorrhages are clinically silent, and most small germinal matrix hemorrhages and those confined to the cerebral ventricles resolve without impairment (Weindling, 1995). Large lesions can result in hydrocephalus or in degenerated cystic areas termed periventricular leukomalacia (p. 657). Importantly, the extent of periventricular leukomalacia correlates with cerebral palsy risk.
Pathology. Damage to the germinal matrix capillary network predisposes to subsequent extravasation of blood into the surrounding tissue. In preterm infants, this capillary network is especially fragile for several reasons. First, the subependymal germinal matrix provides poor support for the vessels coursing through it. Second, venous anatomy in this region causes stasis and congestion, which makes vessels susceptible to bursting with increased intravascular pressure. Third, vascular autoregulation is impaired before 32 weeks (Matsuda, 2006; Volpe, 1987). Even if extensive hemorrhage or other complications of preterm birth do not cause death, survivors can have major neurodevelopmental handicaps. DeVries and associates (1985) attribute most long-term sequelae of intraventricular-periventricular hemorrhage to periventricular leukomalacia. These degenerated cystic areas develop mostcommonly as a result of ischemia and least commonly in direct response to hemorrhage.
Incidence and Severity. The incidence of ventricular hemorrhage depends on gestational age at birth. Approximately half of all neonates born before 34 weeks, but only 4 percent of those born at term, will have some evidence of hemorrhage (Hayden, 1985). Very-low-birthweight infants have the earliest onset of hemorrhage, the greatest likelihood of parenchymal tissue involvement, and thus the highest mortality rate (Perlman, 1986). Preterm black infants are at disparate risk for intraventricular hemorrhage (Reddick, 2008).
The severity of intraventricular hemorrhage can be assessed by neuroimaging studies. Papile and coworkers (1978) devised the most widely used grading scheme to quantify the extent of a lesion and estimate prognosis.
Grade I—hemorrhage limited to the germinal matrix
Grade II—intraventricular hemorrhage
Grade III—hemorrhage with ventricular dilatation
Grade IV—parenchymal extension of hemorrhage
Data from the Neonatal Research Network indicate that 30 percent of infants born weighing 501 to 1500 g develop intracranial hemorrhage, and 12 percent are grade III or IV (Fanaroff, 2007). Jakobi and associates (1992) showed that infants with grade I or II intraventricular hemorrhage had a greater than 90-percent survival rate and a 3-percent rate of handicap—similar to control infants without hemorrhage of the same age. The survival rate for infants with grade III or IV hemorrhage, however, was only 50 percent. Extremely-low-birthweight infants with grade I or II hemorrhage have poorer neurodevelopmental outcomes at 20 months than controls (Patra, 2006).
Contributing Factors. Events that predispose to germinal matrix hemorrhage and subsequent periventricular leukomalacia are multifactorial and complex. As noted, the preterm fetus has fragile intracranial blood vessels that make it particularly susceptible. Moreover, preterm birth is frequently associated with infection, which further predisposes to endothelial activation, platelet adherence, and thrombi (Redline, 2008). RDS and mechanical ventilation are commonly associated factors (Sarkar, 2009).
Prevention with Antenatal Corticosteroids. These agents, given at least 24 hours before delivery, appear to prevent or reduce intraventricular hemorrhage incidence and severity. A Consensus Development Conference of the National Institutes of Health (1994) concluded that such therapy reduced rates of mortality, respiratory distress, and intraventricular hemorrhage in preterm infants born between 24 and 32 weeks and that the benefits were additive with those from surfactant therapy. The consensus panel also concluded that benefits of antenatal corticosteroid therapy probably extend to women with preterm premature membrane rupture. A second consensus statement by the National Institutes of Health (2000) recommended that repeated courses of corticosteroids should not be given. They noted that there were insufficient data to prove benefit or to document the safety of multiple courses (Chap. 42, p. 850).
Subsequently, the Maternal-Fetal Medicine Units Network reported that repeated corticosteroid courses were associated with some improved preterm neonatal outcomes, but also with reduced birthweight and increased risk for fetal-growth restriction (Wapner, 2006). Surveillance of this cohort through age 2 to 3 years found that children exposed to repeated—versus single-dose—steroid courses did not differ significantly in physical or neurocognitive measures (Wapner, 2007). It was worrisome, however, that there was a nonsignificant 5.7-fold relative risk of cerebral palsy in infants exposed to multiple steroid courses. At the same time, the 2-year follow-up of the Australasian Collaborative Trial was reported by Crowther (2007). In more than 1100 infants, the incidence of cerebral palsy was almost identical—4.2 versus 4.8 percent—in those given repeated versus single-course steroids, respectively.
Other Preventative Methods. The efficacy of phenobarbital, vitamin K, vitamin E, or indomethacin in diminishing the frequency and severity of intracranial hemorrhage, when administered either to the neonate or to the mother during labor, remains controversial (Chiswick, 1991; Hanigan, 1988; Thorp, 1995). Data from various sources suggest that magnesium sulfate may prevent the sequelae of periventricular hemorrhage, as discussed on page 659.
It is generally agreed that avoiding significant hypoxia both before and after preterm delivery is paramount (Low, 1995). There is presently no convincing evidence, however, that routine cesarean delivery for the preterm fetus presenting cephalic will decrease the incidence of periventricular hemorrhage. Anderson and colleagues (1992) found no significant difference in the overall frequency of hemorrhage in infants whose birthweights were below 1750 g and who were delivered without labor compared with those delivered during latent or active labor. Infants delivered of mothers in active labor, however, tended to have more grade III or IV hemorrhages.
This pathological description refers to cystic areas deep in brain white matter that develop after hemorrhagic or ischemic infarction. Tissue ischemia leads to regional necrosis. Because brain tissue does not regenerate and the preterm neonate has minimal gliosis, these irreversibly damaged areas appear as echolucent cysts on neuroimaging studies. Generally, they require at least 2 weeks to form but may develop as long as 4 months after the initial insult. Thus, their presence at birth may help to determine the timing of a hemorrhagic event.
This term refers to a group of conditions that are characterized by chronic movement or posture abnormalities that are cerebral in origin, arise early in life, and are nonprogressive (Nelson, 2003). Epilepsy and mental retardation frequently accompany cerebral palsy. The cause(s) of cerebral palsy are different in preterm and term infants (Chap. 33, p. 640).
Cerebral palsy is commonly classified by the type of neurological dysfunction—spastic, dyskinetic, or ataxic—as well as the number and distribution of limbs involved—quadriplegia, diplegia, hemiplegia, or monoplegia. The major types and their frequencies are:
1. Spastic quadriplegia, which has a strong association with mental retardation and seizure disorders—20 percent
2. Diplegia, which is common in preterm or low-birthweight infants—30 percent
3. Hemiplegia—30 percent
4. Choreoathetoid types—15 percent
5. Mixed varieties (Freeman, 1988; Rosen, 1992).
Incidence and Epidemiological Correlates
According to the Centers for Disease Control and Prevention, the prevalence of cerebral palsy in the United States was 3.1 per 1000 children in 2000 (Bhasin, 2006). Importantly, this rate either has remained essentially unchanged or has increased since the 1950s (Torfs, 1990; Winter, 2002). In some countries, the incidence has risen because advances in the care of very preterm infants have improved their survival, but not their neurological prognosis. For example, Moster and associates (2008) presented long-term follow-up of more than 900,000 births in Norway. Of nonanomalous term infants, the cerebral palsy rate was 0.1 percent compared with 9.1 percent in those born at 23 to 27 weeks. Similarly, O’Callaghan and coworkers (2011) studied the epidemiological associations of cerebral palsy and found preterm birth to be the greatest risk factor.
Various clinical and pathological data link severe intraventricular hemorrhage—grade III or IV—and resulting periventricular leukomalacia to cerebral palsy. As described earlier, grade I or II hemorrhages usually resolve without extensive tissue injury. Luthy (1987) reported a 16-fold increased risk of cerebral palsy for low-birthweight infants who had grade III or IV hemorrhage compared with the risk in infants who had either no or grade I or II hemorrhage.
Preterm infants are most susceptible to brain ischemia and periventricular leukomalacia. Before 32 weeks, the vascular anatomy of the brain is composed of two systems. One penetrates into the cortex—the ventriculopedal system. The other reaches down to the ventricles, but then curves to flow outward—the ventriculofugal system (Weindling, 1995). There are no vascular anastomoses connecting these two systems. As a result, the area between these systems, through which the pyramidal tracts pass near the lateral cerebral ventricles, is a watershed area vulnerable to ischemia. Vascular insufficiency before 32 weeks leading to ischemia would affect this watershed area first. Resulting damage of the pyramidal tracts may cause spastic diplegia. After 32 weeks, vascular flow shifts toward the cortex. Thus, hypoxic injury after this time primarily damages the cortical region.
Periventricular leukomalacia is more strongly linked to infection and inflammation than to intraventricular hemorrhage. Zupan and colleagues (1996) studied 753 infants born between 24 and 32 weeks, 9 percent of whom developed periventricular leukomalacia. Those born before 28 weeks, those who had inflammatory events during the last days to weeks before delivery, or those who had both were at highest risk. Perlman and associates (1996) found that periventricular leukomalacia was strongly associated with prolonged membrane rupture, chorioamnionitis, and neonatal hypotension. Bailis and coworkers (2008) reported that chronic—and not acute—placental inflammation was associated with leukomalacia.
Fetal infection may be the key element in the pathway between preterm birth and cerebral palsy (Burd, 2012; Leviton, 2010). In the pathway proposed in Figure 34-2, antenatal reproductive tract infection evokes the production of cytokines such as tumor necrosis factor and interleukins-1, -6, and -8. These in turn stimulate prostaglandin production and preterm labor (Chap. 42, p. 838). Preterm intracranial blood vessels are susceptible to rupture and damage, and the cytokines that stimulate preterm labor also have direct toxic effects on oligodendrocytes and myelin. Vessel rupture, tissue hypoxia, and cytokine-mediated damage result in massive neuronal cell death. Glutamate is released, stimulating membrane receptors to allow excess calcium to enter the neurons. High intracellular calcium levels are toxic to white matter, and glutamate may be directly toxic to oligodendrocytes (Oka, 1993).
FIGURE 34-2 Schematic representation of the hypothesized pathway between maternal or intrauterine infection and preterm birth or periventricular leukomalacia. Both potentially lead to cerebral palsy. LPS = lipopolysaccharide; PG = prostaglandin.
Many studies have shown that infection and cytokines can directly damage the immature brain. Inoculation of rabbit embryos with Escherichia coli causes histological damage in white matter (Yoon, 1997a). Moreover, tumor necrosis factor and interleukin-6 were more frequently found in the brains of infants who died with periventricular leukomalacia (Yoon, 1997b). Cytokines are strongly linked to white matter lesions even when organisms cannot be demonstrated (Yoon, 2000).
Andrews and colleagues (2008) provided data that raise questions regarding an increased incidence of adverse neurodevelopmental outcomes related to chorioamnionitis. In a cohort of infants born between 23 and 32 weeks, they studied several surrogate indicators and direct markers of in utero inflammation. These included clinical findings, cytokine levels, histological findings, and microbial culture results. Infants undergoing comprehensive psychoneurological testing had similar incidences of intelligence quotient (IQ) scores < 70, cerebral palsy, or both, regardless of these markers. The researchers interpreted their findings to support current practices that employ efforts to delay delivery with preterm pregnancies in the absence of overt intrauterine infection. This does not apply to preterm pregnancy in which clinical chorioamnionitis is diagnosed (Soraisham, 2009). Of 3094 singletons born < 33 weeks, 15 percent had evidence of clinical chorioamnionitis, which included foul-smelling amnionic fluid, maternal fever, uterine tenderness, fetal tachycardia, and maternal leukocytosis. Compared with noninfected infants, cases complicated by chorioamnionitis had significantly increased rates of early-onset sepsis—4.8 versus 0.9 percent—and intraventricular hemorrhage—22 versus 12 percent.
Because epidemiological evidence suggested that maternal magnesium sulfate therapy had a fetal neuroprotective effect, three large randomized trials have been performed to investigate this hypothesis. These studies are discussed in detail in Chapter 42 (p. 854), as well as other evidence that magnesium sulfate is effective in reducing cerebral palsy in preterm infants.
Achiron R, Pinchas OH, Reichman B, et al: Fetal intracranial haemorrhage: clinical significance of in-utero ultrasonic diagnosis. Br J Obstet Gynaecol 100:995, 1993
American College of Obstetricians and Gynecologists: Fetal lung maturity. Practice Bulletin No. 97, September 2008
American College of Obstetricians and Gynecologists and American Academy of Pediatrics: Guidelines for perinatal care. 7th ed. Washington, 2012
Anderson GD, Bada HS, Shaver DC, et al: The effect of cesarean section on intraventricular hemorrhage in the preterm infant. Am J Obstet Gynecol 166:1091, 1992
Andrews WW, Cliver SP, Biasini F, et al: Early preterm birth: association between in utero exposure to acute inflammation and severe neurodevelopmental disability at 6 years of age. Am J Obstet Gynecol 198:466, 2008
Bailis A, Maleki Z, Askin F, et al: Histopathological placental features associated with development of periventricular leukomalacia in preterm infants. Am J Obstet Gynecol 199(6):S43, 2008
Ballard RA, Truog WE, Cnaan A, et al: Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med 355:343, 2006
Baraldi E, Filippone M: Chronic lung disease after premature birth. N Engl J Med 357:1946, 2007
Bhasin TK, Brocksen S, Avchen RN, et al: Prevalence of four developmental disabilities among children aged 8 years—metropolitan Atlanta developmental disabilities surveillance program, 1996 and 2000. MMWR 55:22, 2006
Blakely ML, Tyson JE, Lally KP, et al: Laparotomy versus peritoneal drainage for necrotizing enterocolitis or isolated intestinal perforation in extremely low birth weight infants: outcomes through 18 months adjusted age. Pediatrics 117:e680, 2006
Burd I, Balakrishnan B, Kannan S: Models of fetal brain injury, intrauterine inflammation, and preterm birth. Am J Reprod Immunol 67(4):287, 2012
Chiswick M, Gladman G, Sinha S, et al: Vitamin E supplementation and periventricular hemorrhage in the newborn. Am J Clin Nutr 53:370S, 1991
Chock VY, Van Meurs KP, Hintz SR, et al: Inhaled nitric oxide for preterm premature rupture of membranes, oligohydramnios, and pulmonary hypoplasia. Am J Perinatol 26(4):317, 2009
Clements JA, Platzker ACG, Tierney DF, et al: Assessment of the risk of respiratory distress syndrome by a rapid test for surfactant in amniotic fluid. N Engl J Med 286:1077, 1972
Consortium on Safe Labor: Respiratory morbidity in late preterm births. JAMA 304(4):419, 2010
Crowther CA, Doyle LW, Haslam RR, et al: Outcomes at 2 years of age after repeat doses of antenatal corticosteroids. N Engl J Med 357:1179, 2007
Czyrko C, Steigman C, Turley DL, et al: The role of reperfusion injury in occlusive intestinal ischemia of the neonate: malonaldehyde-derived fluorescent products and correlation of histology. J Surg Res 51:1, 1991
DeVries LS, Dubowitz V, Lary S, et al: Predictive value of cranial ultrasound in the newborn baby: a reappraisal. Lancet 2:137, 1985
Drazen JM, Solomon CG, Greene MF: Informed consent and SUPPORT. N Engl J Med 368(20):1929, 2013
Eriksen N, Tey A, Prieto J, et al: Fetal lung maturity in diabetic patients using the TDx FLM assay. Am J Obstet Gynecol 174:348, 1996
Fanaroff AA, Stoll BJ, Wright LL, et al: Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 196:147.e1, 2007
Freeman JM, Nelson KB: Intrapartum asphyxia and cerebral palsy. Pediatrics 82:240, 1988
Garmany TH, Wambach JA, Heins HB, et al: Population and disease-based prevalence of the common mutations associated with surfactant deficiency. Pediatr Res 63(6):645, 2008
Gluck L, Kulovich MV: Lecithin-sphingomyelin ratios in amniotic fluid in normal and abnormal pregnancy. Am J Obstet Gynecol 115:539, 1973
Gluck L, Kulovich MV, Borer RC Jr, et al: Diagnosis of the respiratory distress syndrome by amniocentesis. Am J Obstet Gynecol 109:440, 1971
Grave G, Nelson SA, Walker A, et al: New therapies and preventive approaches for necrotizing enterocolitis: report of a research planning workshop. Pediatr Res 62:1, 2007
Halliday HL, Ehrenkranz RA, Doyle LW: Late (> 7 days) postnatal corticosteroids for chronic lung disease in preterm infants. Cochrane Database Syst Rev 1:CD001145, 2009
Hanigan WC, Kennedy G, Roemisch F, et al: Administration of indomethacin for the prevention of periventricular–intraventricular hemorrhage in high-risk neonates. J Pediatr 112:941, 1988
Hayden CK, Shattuck KE, Richardson CJ, et al: Subependymal germinal matrix hemorrhage in full-term neonates. Pediatrics 75:714, 1985
Jakobi P, Weissman A, Zimmer EZ, et al: Survival and long-term morbidity in preterm infants with and without a clinical diagnosis of periventricular, intraventricular hemorrhage. Eur J Obstet Gynecol Reprod Biol 46:73, 1992
Jobe AH: Pulmonary surfactant therapy. N Engl J Med 328:861, 1993
Karcher R, Sykes E, Batton D, et al: Gestational age-specific predicted risk of neonatal respiratory distress syndrome using lamellar body count and surfactant-to-albumin ratio in amniotic fluid. Am J Obstet Gynecol 193:1680, 2005
Kinsella JP, Cutter GR, Walsh WF, et al: Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med 355:354, 2006
Kliegman RM, Fanaroff AA: Necrotizing enterocolitis. N Engl J Med 310:1093, 1984
Leviton A, Allred EN, Kuban KCK, et al: Microbiologic and histologic characteristics of the extremely preterm infant’s placenta predict white matter damage and later cerebral palsy. The ELGAN study. Pediatr Res 67:95, 2010
Locatelli A, Andreani M, Pizzardi A, et al: Antenatal variables associated with severe adverse neurodevelopmental outcome among neonates born at less than 32 weeks. Eur J Obstet Gynecol Reprod Biol 152(2):143, 2010
Low JA, Panagiotopoulos C, Derrick EJ: Newborn complications after intrapartum asphyxia with metabolic acidosis in the preterm fetus. Am J Obstet Gynecol 172:805, 1995
Luthy DA, Shy KK, Strickland D, et al: Status of infants at birth and risk for adverse neonatal events and long-term sequelae: a study in low birthweight infants. Am J Obstet Gynecol 157:676, 1987
Mathews TJ, MacDorman MF: Infant mortality statistics from the 2009 period linked birth/infant death data set. Natl Vital Stat Rep 61(8):1, 2013
Matsuda T, Okuyama K, Cho K, et al: Cerebral hemodynamics during the induction of antenatal periventricular leukomalacia by hemorrhagic hypotension in chronically instrumented fetal sheep. Am J Obstet Gynecol 194:1057, 2006
Mestan KK, Marks JD, Hecox K, et al: Neurodevelopmental outcomes of premature infants treated with inhaled nitric oxide. N Engl J Med 353:23, 2005
Moss RL, Dimmitt RA, Barnhart DC, et al: Laparotomy versus peritoneal drainage for necrotizing enterocolitis and perforation. N Engl J Med 354:2225, 2006
Moster D, Lie RT, Markestad T: Long-term medical and social consequences of preterm birth. N Engl J Med 359:262, 2008
National Institutes of Health: Antenatal corticosteroids revisited: repeat courses. NIH Consens Statement 17(2):1, 2000
National Institutes of Health: The effects of corticosteroids for fetal maturation on perinatal outcomes. NIH Consens Statement 12(2):1, 1994
Nelson KB: Can we prevent cerebral palsy? N Engl J Med 349:1765, 2003
Nores J, Roberts A, Carr S: Prenatal diagnosis and management of fetuses with intracranial hemorrhage. Am J Obstet Gynecol 174:424, 1996
O’Callaghan ME, MacLennan AH, Gibson, CS, et al: Epidemiologic associations with cerebral palsy. Obstet Gynecol 118:576, 2011
Oka A, Belliveau MJ, Rosenberg PA, et al: Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention. J Neurosci 13:1441, 1993
Papile LA, Burstein J, Burstein R, et al: Incidence and evolution of subependymal and intraventricular hemorrhage: a study of infants with birth weights less than 1500 gm. J Pediatr 92:529, 1978
Patra K, Wilson-Costello D, Taylor HG, et al: Grades I-II intraventricular hemorrhage in extremely low birth weight infants: effects on neurodevelopment. J Pediatr 149:169, 2006
Perlman JM, Risser R, Broyles RS: Bilateral cystic periventricular leukomalacia in the premature infant: associated risk factors. Pediatrics 97:822, 1996
Perlman JM, Volpe JJ: Intraventricular hemorrhage in extremely small premature infants. Am J Dis Child 140:1122, 1986
Pfister RH, Soll RF, Wiswell T: Protein containing synthetic surfactant versus animal derived surfactant extract for the prevention and treatment of respiratory distress syndrome. Cochrane Database Syst Rev 4:CD006069, 2007
Reddick K, Canzoneri B, Roeder H, et al: Racial disparities and neonatal outcomes in preterm infants with intraventricular hemorrhage. Am J Obstet Gynecol 199(6):S71, 2008
Redline RW: Placental pathology: a systematic approach with clinical correlations. Placenta 22:S86, 2008
Rosen MG, Dickinson JC: The incidence of cerebral palsy. Am J Obstet Gynecol 167:417, 1992
Sarkar S, Bhagat I, Dechert R, et al: Severe intraventricular hemorrhage in preterm infants: comparison of risk factors and short-term neonatal morbidities between grade 3 and grade 4 intraventricular hemorrhage. Am J Perinatol 26:419, 2009
Schmidt B, Asztalos EV, Roberts RS, et al: Impact of bronchopulmonary dysplasia, brain injury, and severe retinopathy on the outcome of extremely low-birth-weight infants at 18 months. JAMA 289:1124, 2003
Seger N, Soll R: Animal derived surfactant extract for treatment of respiratory distress syndrome. Cochrane Database Syst Rev 2:CD007836, 2009
Shulenin S, Nogee LM, Annilo T, et al: ABCA3 gene mutations in newborns with fatal surfactant deficiency. N Engl J Med 350:1296, 2004
Soraisham AS, Singhal Nalini, McMillan DD, et al: A multicenter study on the clinical outcome of chorioamnionitis in preterm infants. Am J Obstet Gynecol 200:372.e1, 2009
Stark AR: Inhaled NO for preterm infants—getting to yes? N Engl J Med 355:404, 2006
Steinfeld JD, Samuels P, Bulley MA, et al: The utility of the TDx test in the assessment of fetal lung maturity. Obstet Gynecol 79:460, 1992
SUPPORT Study Group of the Eunice Kennedy Shriver NICHD Neonatal Research Network: Target ranges of oxygen saturation in extremely preterm infants. N Engl J Med 362(21):1959, 2010
Thorp JA, Ferette-Smith D, Gaston L, et al: Antenatal vitamin K and phenobarbital for preventing intracranial hemorrhage in the premature newborn: a randomized double-blind placebo-controlled trial. Am J Obstet Gynecol 172:253, 1995
Torfs CP, van den Berg B, Oechsli FW, et al: Prenatal and perinatal factors in the etiology of cerebral palsy. J Pediatr 116:615, 1990
van Meurs KP, Wright LL, Ehrenkranz RA, et al: Inhaled nitric oxide for premature infants with severe respiratory failure. N Engl J Med 353:13, 2005
van Vliet EO, de Klieviet JF, Oosterlaan J, et al: Perinatal infections and neurodevelopmental outcome in very preterm and very low-birth-weight infants: a meta-analysis. JAMA Pediatr 167(7):662, 2013
Verbrugge SJ, Lachmann B: Mechanisms of ventilation-induced lung injury: physiological rationale to prevent it. Monaldi Arch Chest Dis 54:22, 1999
Volpe JJ: Neurology of the Newborn, 3rd ed. Philadelphia, Saunders, 1995, p 373
Volpe JJ, Hill A: Neurologic disorders. In Avery GB (ed): Neonatology, 3rd ed. Philadelphia, JB Lippincott, 1987, p 1073
Wapner RJ, Sorokin Y, Mele L, et al: Long-term outcomes after repeated doses of antenatal corticosteroids. N Engl J Med 357:1190, 2007
Wapner RJ, Sorokin Y, Thom EA, et al: Single versus weekly courses of antenatal corticosteroids: evaluation of safety and efficacy. Am J Obstet Gynecol 195:633, 2006
Watterberg KL; American Academy of Pediatrics Committee on Fetus and Newborn: Policy statement–postnatal corticosteroids to prevent or treat bronchopulmonary dysplasia. Pediatrics 126(4):800, 2010
Weindling M: Periventricular haemorrhage and periventricular leukomalacia. Br J Obstet Gynaecol 102:278, 1995
Winter S, Autry A, Boyle C, et al: Trends in the prevalence of cerebral palsy in a population-based study. Pediatrics 110:1220, 2002
Yeh TF, Lin YJ, Lin HC, et al: Outcomes at school age after postnatal dexamethasone therapy for lung disease of prematurity. N Engl J Med 350:1304, 2004
Yoon BH, Kim CJ, Romero R, et al: Experimentally induced intrauterine infection causes fetal brain white matter lesions in rabbits. Am J Obstet Gynecol 177:797, 1997a
Yoon BH, Romero R, Kim CJ, et al: High expression of tumor necrosis factor-alpha and interleukin-6 in periventricular leukomalacia. Am J Obstet Gynecol 177:406, 1997b
Yoon BH, Romero R, Park JS, et al: Fetal exposure to an intra-amniotic inflammation and the development of cerebral palsy at the age of three years. Am J Obstet Gynecol 182:675, 2000
Zhu Y, Miller TL, Chidekel A, et al: KL4-surfactant (lucinactant) protects human airway epithelium from hyperoxia. Pediatr Res 64(2):154, 2008
Zupan V, Gonzalez P, Lacaze-Masmonteil T, et al: Periventricular leukomalacia: risk factors revisited. Dev Med Child Neurol 38:1061, 1996