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Original Article

Antenatal Associations with Lung Maturation and Infection

Alan H. Jobe, MD, PhD
The fetal lung is in the saccular stage of development from about 24 weeks gestation until secondary septation begins the process of alveolarization at about 32 weeks gestation.1 Alveolarization occurs in parallel with microvascular development, primarily between about 32 weeks gestation and several months after term birth. The practical consequence of the timing of this late gestational lung structural development is that the very low birth weight (VLBW) infant is born with the lung in the saccular stage of lung development. This lung must develop postnatally while supporting gas exchange and other metabolic functions. While RDS is more complex than simply surfactant deciency, the striking effectiveness of surfactant therapy even at very early gestational ages mitigates many of the clinical problems of managing the preterm lung soon after birth.2 Lung maturation also is inducible with antenatal glucocorticoid therapy, which further decreases the risk of severe lung immaturity.3 Lung structural maturation (alveolarization and microvascular development) may not be inducible and, in fact, alveolarization is delayed by glucocorticoids, inammation, oxygen, mechanical ventilation and nutritional deciency.4 Therefore, interventions used to maintain virtually all VLBW infants tend to disrupt normal lung development. BPD in VLBW infants is the net result of lung injury, repair and disrupted development that should be viewed as a sequence of adverse events or hits (Figure 1). Although infants with BPD have chronic lung inammation, decreased alveolar septation and decreased microvascular development, the amount of brosis and reversibility or recovery potential of the lung is quite variable. BPD describes a wide spectrum of disease severity resulting from the multiple factors contributing to disease progression. A factor that is usually not clinically recognized or considered is antenatal exposure of the fetus to inammation. Chorioamnionitis F What is it? Traditionally, chorioamnionitis was considered to be an acute infection of the fetal compartment with highly pathologic organisms, generally in late gestation or after rupture of membranes.5 In contrast, many VLBW infants are born after the onset of spontaneous labor or preterm rupture of membranes to women without symptoms of chorioamnionitis. However, more than 70% of unruptured women in preterm labor who deliver before 30 weeks gestational age will have cultures of amniotic uid or membranes that are positive for low pathogenic organisms.5 Similar percents of all women delivering prior to 30 weeks gestation will have histologic chorioamnionitis.6,7 Amniotic uid of

Chronic clinically unapparent chorioamnionitis is a common antenatal exposure for very preterm infants, and these infants have variable degrees of lung maturation and a high risk of developing bronchopulmonary dysplasia. Exposure of fetal sheep to intra-amniotic endotoxin or IL-1a induces chorioamnionitis and lung injury (decreased alveolarization and microvascular injury), which resolves to a phenotype of striking lung maturation (increased surfactant, improved gas exchange and lung mechanics). The immune responses of the fetus also are suppressed or induced (matured) in time and dose-dependent ways by either chorioamnionitis or antenatal corticosteroids. These experimental observations contribute to explanations of why preterm infants have variable degrees of lung maturation at birth and unpredictably develop bronchopulmonary dysplasia BPD. Journal of Perinatology (2005) 25, S31S35. doi:10.1038/sj.jp.7211317

The clinician has two primary lung-related concerns when faced with an infant born before 30 weeks gestation F minimizing the problems resulting from lung immaturity (respiratory distress syndrome F RDS) and avoiding progressive lung injury (bronchopulmonary dysplasia F BPD). This review will focus on the complex relationships between RDS, BPD and chorioamnionitis as they are recognized clinically and as presently understood from animal models. Human Fetal Lung Development F The Substrate The fetal lung does not normally mature functionally until after 35 to 36 weeks, when surfactant is present in large amounts. However, normal physiologic function does not mean a mature anatomy.

Division Pulmonary Biology, Cincinnati Childrens Hospital, Cincinnati, OH, USA. This is a review article of talk for symposium: Evidence vs Experience in Neonatal Practices (8 and 9 October 2004) for J Perinatol. This work was supported by Grants HD-12714 and HL65397 from the National Institutes of Health. Disclosure: None. Research Support: Fisher & Paykel,NHLBI, NICHD. Employee: Cincinnati Childrens Hospital. Share Holder: Mutual Funds- Independently managed. Address correspondence and reprint requests to Alan Jobe, Cincinnati Childrens Hospital, Division of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA.

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Lung Maturation and Infection

Hits to Fetal Lung

Hits During Transition

Postnatal Hits

Chronic Chorioamnionitis

Initiation of Ventilation




Fetal Lung

Preterm Lung






Figure 1. The progression from the fetal lung to preterm delivery and ultimately to BPD occurs because of a series of events and interventions, hits, that cause lung injury and alter lung development.

No Chorio Molecular ID of Organisms

Neonatal SIR Histologic Chorioamnionitis Neonatal Infection

Clinical Chorioamnionitis

Figure 2. A schematic diagram of all infants born at less than 30 weeks gestation. Clinical and/or histologic chorioamnionitis complicate many of these pregnancies. Neonatal infection and systemic inammatory responses (SIR) represent subpopulations of infants. Some infants may have been exposed to organisms that did not cause inammation.

women in early preterm labor often contains inammatory cells and proinammatory cytokines, although the women are asymptomatic.8 Many of these women may have had low-grade chorioamnionitis for weeks or months before the preterm labor. The Venn diagram illustrates the diagnostic dilemma (Figure 2). Chorioamnionitis includes overlapping populations of patients with histologic chorioamnionitis and clinical chorioamnionitis with subpopulations of infants that may have a systemic inammatory

response or sepsis. Organisms may be identied without other signs of infection in some women. There have been no systemic studies of the duration or intensity of the antenatal inammatory exposure of VLBW infants. The important conclusion is that the majority of VLBW infants have been exposed to some antenatal inammation. Nevertheless, the incidence of sepsis dened as a positive blood culture is less than 3% and a clinical diagnosis of congenital pneumonia is seldom made in VLBW infants.9
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Clinical Associations With Chorioamnionitis in VLBW Infants A remarkable observation is that many VLBW infants do not have severe lung immaturity and some of these infants have no RDS.10 While antenatal corticosteroids can decrease RDS by about 50%, the effects of corticosteroids in large animal models are modest.11 Clinical experience suggests that something else is inducing very early lung maturation in many VLBW infants. Watterberg et al.12 reported that ventilated infants exposed to histologic chorioamnionitis had less RDS but more BPD than control infants. In one report, ureaplasma colonization at birth was associated with less RDS.13 There has been no prospective study that evaluates both the characteristics of the chorioamnionitis and the pulmonary outcomes in VLBW infants in any detail. The lung outcomes are likely to depend on the type, duration and intensity of the chorioamnionitis as well as other therapies such as corticosteroids. For example, Van Marter et al.14 found that chorioamnionitis decreased the risk of BPD unless the infant was also mechanically ventilated. The combination of ventilation and chorioamnionitis increased the risk of BPD. Lessons from Animal Models of Chorioamnionitis The rst experimental demonstration that fetal exposure to inammation might modulate lung maturation was the report of Bry et al.15 that intra-amniotic injections of IL-1 induced lung maturation in fetal rabbits. Intra-amniotic injections of endotoxin also induce striking lung maturation in fetal sheep.16 The maturation response (increased surfactant, improved compliance and gas exchange, thinning of the lung mesenchyme) occurs after a phase of acute lung injury (increased inammatory cells, proinammatory cells and edema).17 The maturation response is much larger than that seen with maternal corticosteroid

treatment in the sheep (Figure 3). Lung injury followed by maturation results from the direct contact of the endotoxin with the fetal respiratory epithelium as a result of mixing of fetal lung uid with the endotoxin in amniotic uid.18 Lung maturation also can be induced with the proinammatory cytokine IL-1 or by colonizing the amniotic uid with ureaplasma urealyticum, but intra-amniotic injections of TNFa or INFg do not induce inammation or lung maturation in the sheep model.19,20 These maturation responses occur without an increase in fetal cortisol, demonstrating that inammationmediated lung maturation occurs by pathways distinct from cortisol.16 Chorioamnionitis is a potent inducer of lung maturation in fetal sheep.

Corticosteroids and Chorioamnionitis In clinical practice, most women in very early preterm labor with clinically silent chorioamnionitis are treated with corticosteroids. This clinical practice is supported by clinical trial data.21 Nevertheless, it is worth considering how chorioamnionitis and antenatal corticosteroid therapy may interact. The normal fetus is ve and immune immature. Chorioamnionitis exposes immune na the fetus to inammation primarily via the fetal lung, which causes lung injury followed by the phenotype of lung maturation.18 Repeated exposures of fetal sheep to endotoxin do not cause progressive lung inammation or injury. Rather, the lung suppresses the inammatory response. Blood monocytes from the fetal sheep have a decreased response to challenge with endotoxin in vitro 2 days after intra-amniotic exposure of the fetus F an endotoxin tolerance response22 (Figure 4). However, 7 days after the fetal exposure, the cells respond to endotoxin more like monocytes from adult ewes F a maturation effect. Two fetal endotoxin exposures 14 and 7 days before the third challenge of

Figure 3. Antenatal intra-amniotic endotoxin or maternal betamethasone exposure of fetal sheep for different intervals before preterm delivery at 125 days gestation. All values are normalized to 1.0 for control lambs. The inammatory exposure from endotoxin caused a persistent increase in the mRNA for surfactant protein A (SP-A). In contrast, the corticosteroid effect was much less. The amount of SP-A in the alveolar wash also increased much more after endotoxin than betamethasone. Data from references. Jobe et al.,16 Ballard et al.,25 Bachurski et al.,26 Tan et al.27
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H2O2 Relative to Preterm Controls

6 5 4 3 2 1 0

Preterm Adult Controls







Interval after Maternal Betamethasone

Interval after Intra-amniotic Endotoxin

Figure 4. Effects of maternal betamethasone or intra-amniotic endotoxin on endotoxin-stimulated H2O2 production by fetal sheep blood monocytes in vitro. All values are normalized to the preterm controls F the dashed line. Preterm monocytes produce less H2O2 than monocytes from adult sheep. Pre-exposure of the fetus to betamethasone or endotoxin suppressed H2O2 production initially but after 7 or 14 days H2O2 production increased. Fetal sheep exposed to endotoxin 7 and 14 days before delivery had monocytes with depressed function. Data from reference Kramer et al.22 and Kramer.23

the monocytes induce a persistent endotoxin tolerance response. Thus, intra-amniotic endotoxin causes a complex modulation of the innate immunity of the fetus. Maternal corticosteroid treatment also suppresses fetal blood monocyte function below that of the already immature fetal monocyte23 (Figure 4). However, monocyte function evaluated 7 days after the maternal treatment is increased above that of control adult monocytes F a maturation effect. Thus, either inammation or corticosteroids can cause suppression or induction of fetal monocyte function, depending on the timing. If the sheep fetus is exposed to both maternal corticosteroids and intra-amniotic endotoxin at the same time, the corticosteroids initially suppress endotoxin-induced inammation for several days but result in amplied inammatory responses 5 or 15 days later.24 Both corticosteroids and inammation interact to modulate the fetal innate immune response in complicated and time-dependent ways. Inammation is considered central to the progression of BPD. Our results suggest that fetal exposures may modulate both fetal and postnatal inammatory responses to propagate the injuries resulting in BPD. The lung maturational effects of corticosteroids and chorioamnionitis may benet the fetal lung by decreasing RDS, but alterations in innate immune responses may contribute to BPD.

1. Burri PH. Structural aspects of prenatal and postnatal development and growth of the lung In: McDonald JA, editor. Lung Growth and Development. New York: Marcel Dekker Inc.; 1997 p. 135. S34

2. Soll RF. Prophylactic natural surfactant extract for preventing morbidity and mortality in preterm infants. Cochrane Database of Systematic Reviews 2003;1. 3. Crowley P. Prophylactic corticosteroids for preterm birth. The Cochrane Library, Issue 2, Oxford: Update Software 2001. 4. Jobe AH. The new BPD: an arrest of lung development. Pediatr Res 1999;46:6413. 5. Goldenberg RL, Hauth JC, Andrews WW. Intrauterine infection and preterm delivery. N Engl J Med 2000;342:15007. 6. Viscardi RM, Muhumuza CK, Rodriguez A, et al. Inammatory markers in intrauterine and fetal blood and cerebrospinal uid compartments are associated with adverse pulmonary and neurologic outcomes in preterm infants. Pediatr Res 2004;55:100917. 7. Lahra MM, Jeffery HE. A fetal response to chorioamnionitis is associated with early survival after preterm birth. Am J Obstet Gynecol 2004;190:14751. 8. Yoon BH, Romero R, Jun JK, Park KH, Gomez R, Choi JH. Amniotic uid cytokines (interleukin-6, tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia. Am J Obstet Gynecol 1997;177:82530. 9. Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA. Changes in pathogens causing early-onset sepsis in very-low-birth- weight infants. N Engl J Med 2002;347:2407. 10. Charafeddine L, DAngio CT, Phelps DL. Atypical chronic lung disease patterns in neonates. Pediatrics 1999;103:75965. 11. Jobe AH, Ikegami M. Fetal responses to glucocorticoids In: Mendelson CR, editor. Endocrinology of the Lung. Totowa: Humana Press; 2000 p. 4557. 12. Watterberg KL, Demers LM, Scott SM, Murphy S. Chorioamnionitis and early lung inammation in infants in whom bronchopulmonary dysplasia develops. Pediatrics 1996;97:2105. 13. Hannaford K, Todd DA, Jeffery H, John E, Blyth K, Gilbert GL. Role of Ureaplasma urealyticum in lung disease of prematurity. Arch Dis Child Fetal Neonatal Ed 1999;81:F1627. 14. Van Marter LJ, Dammann O, Allred EN, et al. Chorioamnionitis, mechanical ventilation, and postnatal sepsis as modulators of chronic lung disease in preterm infants. J Pediatr 2002;140:1716. 15. Bry K, Lappalainen U, Hallman M. Intra-amniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth. J Clin Invest 1997;99:29929. 16. Jobe AH, Newnham JP, Willet KE, et al. Endotoxin induced lung maturation in preterm lambs is not mediated by cortisol. Am J Respir Crit Care Med 2000;162:165661. 17. Kramer BW, Kramer S, Ikegami M, Jobe A. Injury, inammation and remodeling in fetal sheep lung after intra-amniotic endotoxin. Am J Physiol Lung Cell Mol Physiol 2002;283:L4529. 18. Moss TJ, Nitsos I, Kramer BW, Ikegami M, Newnham J, Jobe A. Intraamniotic endotoxin induces lung maturation by direct effects on the developing respiratory tract in preterm sheep. Am J Obstet Gynecol 2002;187:105965. 19. Ikegami M, Moss TJM, Kallapur SG, et al. Minimal lung and systemic responses to TNFa in preterm sheep. Am J Physiol 2003;285:L1219. 20. Willet K, Kramer BW, Kallapur SG, et al. Intra-amniotic injection of IL-1 induces inammation and maturation in fetal sheep lung. Am J Physiol 2001;282:L41120. 21. Harding JE, Pang J, Knight DB, Liggins GC. Do antenatal corticosteroids help in the setting of preterm rupture of membranes? Am J Obstet Gynecol 2001;184:1319.
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22. Kramer BW, Ikegami M, Moss TJM, Nitsos I, Newnham JP, Jobe AH. Endotoxin induced chorioamnionitis modulates innate immunity of monocytes in preterm sheep. Am J Respir Crit Care Med 2005;171: 737. 23. Kramer BW. Antenatal betamethasone changes cord blood monocyte responses to endotoxin in preterm lambs. Pediatr Res 2004;55:7648. 24. Kallapur SG, Kramer BW, Moss TJ, et al. Maternal glucocorticoids increase endotoxin-induced lung inammation in preterm lambs. Am J Physiol Lung Cell Mol Physiol 2003;284:L63342.

25. Ballard PL, Ning Y, Polk D, Ikegami M, Jobe A. Glucocorticoid regulation of surfactant components in immature lambs. Am J Physiol 1997;273:L104857. 26. Bachurski CJ, Ross GF, Ikegami M, Kramer BW, Jobe AH. Intra-amniotic endotoxin increases pulmonary surfactant components and induces SP-B processing in fetal sheep. Am J Physiol Lung Cell Mol Physiol 2001;280:L27985. 27. Tan RC, Ikegami M, Jobe AH, Possmayer F, Ballard PL. Developmental and glucocorticoid regulation of surfactant protein mRNAs in preterm lambs. Am J Physiol 1999;277:L11428.

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