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Antenatal Factors That Influence Postnatal Lung Development and Injury
Spectrum of Lung Disease in Preterm Infants
The normal fetal lung at 26 weeks gestation is in a late canalicular or early saccular stage of development and surfactant deficient. Surfactant treatment and the use of more gentle modes of assisted ventilation have resulted in populations of very preterm infants with a wide range of lung diseases not easily classifiable into the traditional categories of respiratory distress syndrome (RDS), lung hypoplasia, transient tachypnea, and normal. In one large series of 1340 preterm infants born between 23 and 27 weeks gestation, the mortality rate for infants weighing 501 to 1500 g at birth was 17% (excluding deaths <12 hours of age), and bronchopulmonary dysplasia (BPD), defined as the need for supplemental oxygen at 36 weeks, occurred in 42% of surviving infants. Of the infants surviving for at least 14 days, 17% had very low supplemental oxygen needs in the first 2 weeks of postnatal life, yet these infants developed BPD. Thus, in these infants, the clinical course was not characteristic of the usual progression from RDS to BPD associated with assisted ventilation in the neonate.
A complex interplay of antenatal and postnatal factors is now recognized to affect postnatal lung development after premature birth and, ultimately, the incidence of BPD ( Fig. 71.1 ). This chapter explores some of the antenatal factors that may modulate lung development and thereby alter the postnatal clinical course of lung disease in preterm infants. Antenatal factors that influence postnatal lung development and injury are discussed below.
Chorioamnionitis—Definition
Inflammation of the chorioamnion, termed chorioamnionitis, can be confirmed only by histopathologic examination to diagnose “histologic chorioamnionitis.” In practice, clinical chorioamnionitis is diagnosed using a combination of indicators such as elevated maternal temperature, uterine tenderness, malodorous vaginal discharge, maternal leukocytosis, and fetal tachycardia. In some centers, amniocentesis is performed to diagnose chorioamnionitis. Increases in leukocytes, low glucose, elevated interleukin (IL)-6 levels, and the presence of microorganisms in the amniotic fluid constitute amniotic fluid inflammation and/or amniotic fluid infection. In a report of women with preterm labor, the presence of amniotic fluid infection or IL-6 levels greater than 11.3 ng/mL were associated with shorter time from amniocentesis to delivery when compared with cases in which amniotic fluid IL-6 levels were between 2.6 and 11.2 ng/mL. Interestingly, the majority of these women with amniotic fluid IL-6 levels greater than 11.3 ng/mL did not have microbes demonstrated in the amniotic fluid, even with the use of sophisticated sensitive molecular methods to detect microorganisms. Due to the imprecise nature of the definition and heterogeneity of clinical manifestations a National Institutes of Health (NIH) expert panel proposed to replace the term chorioamnionitis with a more general, descriptive term, Intrauterine Inflammation and/or Infection , abbreviated as Triple I. In this scheme, fever alone during labor is classified separately, while fever with one or more of the following: leukocytosis, fetal tachycardia, or purulent cervical discharge is classified as “suspected Triple I.” To be confirmed, suspected Triple I should be accompanied by objective laboratory findings of infection in amniotic fluid (AF) (e.g., positive gram stain for bacteria, low AF glucose, high white blood cell (WBC) count in the absence of a bloody tap, and/or positive AF culture results) or histopathologic evidence of infection/inflammation in the placenta, fetal membranes, or the umbilical cord vessels (funisitis). How is it possible to explain severe amniotic fluid inflammation without the detection of microorganisms? An explanation is that the organisms may be localized deep in the fetal membranes, and the resultant inflammation in the fetal membranes may induce IL-6 in the amniotic fluid. The most common microorganisms detected in the amniotic fluid with chorioamnionitis are the Ureaplasma species. The presence of low-virulence organisms such as the Ureaplasma species may not cause much inflammation in the amniotic fluid. Thus, the diagnosis of chorioamnionitis can be problematic because the clinical, histologic, microbiologic, and amniotic fluid inflammation definitions of chorioamnionitis will lead to overlapping but distinct subsets of patients. As an illustration, in a cohort of very low-birth-weight infants weighing less than 1500 g at birth, the incidence of “clinical chorioamnionitis” was 18%, but the incidence of “histologic chorioamnionitis” was 48%.
Growing evidence suggests that the endometrium is not normally sterile. In a clinical study using care to prevent contamination, Agostinis and colleagues demonstrated that at least one organism was isolated from endometrial cultures in 85% of nonpregnant women. Amniotic fluid sampled before 20 weeks gestation for genetic diagnostic indications can contain elevated proinflammatory mediators and be culture-positive for low-virulence pathogenic organisms. Often the infants born to mothers with such amniotic fluid markers have no overt signs of infection at delivery. Thus, a majority of fetuses may be exposed to bacterial products for a long time in utero without clinically apparent complications. Nevertheless, the most common cause of fetal death or death soon after birth for very low-birth-weight infants was sepsis or pneumonia in an autopsy series. Evidently, the effects of chorioamnionitis on the preterm fetus may range widely, from severe infection or death to normal fetal development with histologic chorioamnionitis as an incidental finding. Attempts to secure a definitive diagnosis of chorioamnionitis typically are limited by a lack of information about its duration, intensity, or extent or the organisms responsible for the clinical or histopathologic findings. In the face of exposure to commonly encountered infectious agents, down-regulation of inflammatory responses in utero may be a key coping mechanism of the fetus.
Chorioamnionitis—Pathway to Fetal Lung Inflammation
The fetal lungs are protected from the traditional mechanisms of lung injury, but infection and inflammation can reach the fetal lung. Infective organisms from the lower genital flora can ascend through the cervix, with subsequent spread of infection between the chorioamnion and the uterus; this mode of transmission is commonly associated with early preterm labor. Normal fetal swallowing will result in aspiration of any inflammatory products and organisms in the amniotic fluid. With pathogens such as group B streptococci (GBS), a pneumonia-sepsis syndrome is likely. More frequently, the fetus may mount a lung and systemic inflammatory response to signals from the inflamed fetal placenta and chorioamnion without obvious infection. The fetal inflammatory response to chorioamnionitis has been defined clinically as an elevation of IL-6 in fetal cord blood sampled by cordocentesis or in cord blood at delivery. Funisitis, or histologic inflammation of the cord, correlates with elevated cord blood IL-6 levels and signs of generalized fetal inflammation.
The rapidly progressive chorioamnionitis or bloodstream infection caused by organisms such as Escherichia coli, Listeria monocytogenes, or GBS is relatively infrequent in the preterm population. By contrast, clinically asymptomatic histologic chorioamnionitis caused by low-virulence or commensal organisms increase in frequency as gestational age at delivery decreases. In one series, approximately 70% of infants (born before 30 weeks gestation) delivered by cesarean section with intact membranes had histologic chorioamnionitis. This clinically inapparent chorioamnionitis is associated with recurrent preterm deliveries, and indicators of inflammation may be present before mid-gestation. The low frequency of blood culture–proven sepsis (approximately 2%) is remarkable because of the greater than 50% prevalence of histologic chorioamnionitis for very low-birth-weight deliveries.
Chorioamnionitis and Adverse Pulmonary Outcomes
The associations of respiratory diseases including BPD with chorioamnionitis are complex. Although a systematic review showed an association between chorioamnionitis and the development of BPD, the authors concluded that there was “strong evidence of publication bias, which suggests potential overestimation of the measure of association between chorioamnionitis and BPD.” Been and colleagues reported that the severity of RDS may be greater with chorioamnionitis and a fetal inflammatory response (funisitis) than with chorioamnionitis and no funisitis. Furthermore, clinical responses to surfactant may be less striking after exposure to chorioamnionitis with fetal inflammation. It is thus very likely that respiratory outcomes may depend on a number of factors associated with exposure to chorioamnionitis, including timing, fetal involvement, and the underlying cause of the infective process. A new meta-analysis study associates BPD with chorioamnionitis.
Chorioamnionitis in preterm infants may also be associated with adverse longer-term respiratory outcomes. Jones and colleagues classified 95 preterm infants according to histologic examination of the placenta. They observed lower maximal expiratory flows at 40 weeks postconceptional age but interestingly noted that this outcome was mainly due to females being affected. In the Boston prospective study of 1096 preterm subjects, those born at less than 33 weeks gestation with chorioamnionitis had the greatest risk for wheezing and physician-diagnosed asthma, up to the follow-up age of 2.2 years. We reported that compared to non-exposed infants, late preterm infants exposed to chorioamnionitis had increased diagnosis of childhood asthma or wheezing disorders without an increase in neonatal morbidity. , Although the mechanisms are not well understood, chorioamnionitis decreased the activity of anti-inflammatory Tregs and increased cord blood IL-6 levels correlating with childhood wheezing. , Although chorioamnionitis certainly affects lung development, further work is required to identify the specific cell populations and associated inflammatory pathways that drive long-term high-risk respiratory compromise.
Clinical Lung Maturation
Although chorioamnionitis is generally considered to have adverse effects on the fetus, some reports indicate a clinical benefit. Watterberg and colleagues reported that histologic chorioamnionitis and high IL-1β levels in airway samples determined on the first postnatal day predicted a decreased incidence of RDS but an increased incidence of BPD. Infants in whom blood cultures were positive for Ureaplasma urealyticum also had a lower incidence of RDS but a higher incidence of BPD than infants with negative blood cultures. Higher cord plasma levels of IL-6 predicted a lower incidence of RDS in another report. Although these small clinical series may reflect a reporting bias, chorioamnionitis was associated with improved survival for 881 infants born at less than 26 weeks gestation in the United Kingdom and Ireland in 1995. Histologic chorioamnionitis also was associated with less RDS in 446 consecutive singleton births before 32 weeks gestation ( Table 71.1 ).
Table 71.1
Associations Between Histologic Chorioamnionitis and Outcomes for 446 Consecutive Singleton Deliveries Before 32 Weeks Gestation.
From Andrews WW, Goldenberg RL, Faye-Petersen O, et al. The Alabama Preterm Birth study: polymorphonuclear and mononuclear cell placental infiltrations, other markers of inflammation, and outcomes in 23- to 32-week preterm newborn infants. Am J Obstet Gynecol . 2006;195:803–808.
| Clinical Outcome | Neutrophils in Membranes | Neutrophils in Cord | Statistically Significant | ||
|---|---|---|---|---|---|
| Yes (%) | No (%) | Yes (%) | No (%) | ||
| Ureaplasma + Mycoplasma | 81 | 32 | 49 | 21 | • |
| RDS | 61 | 73 | 57 | 72 | • |
| BPD (need for O 2 at 36 weeks) | 7 | 9 | 7 | 8 | |
| IVH (grade 3 or 4) | 10 | 8 | 11 | 9 | |
| NEC | 18 | 14 | 22 | 14 | • |
| SIRS | 44 | 18 | 55 | 20 | |
| Death | 10 | 9 | 11 | 10 | • |
BPD , Bronchopulmonary dysplasia; IVH , intravascular hemorrhage; NEC , necrotizing enterocolitis; RDS , respiratory distress syndrome; SIRS , systemic inflammatory response syndrome.
The associations of chorioamnionitis with outcomes such as RDS and BPD are quite complex. In a large epidemiologic report, histologic chorioamnionitis predicted a decreased incidence of BPD unless the infant received mechanical ventilation or developed postnatal sepsis, which in combination with histologic chorioamnionitis increased the risk for BPD. This study suggests that fetal exposure to inflammation can induce clinically apparent maturation of the lung, but that subsequent injury (as from ventilation or sepsis) may increase the injury response, thereby resulting in BPD.
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