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Original ArticleAntenatal Associations with Lung Maturation and Infection

Alan H. Jobe, MD, PhD

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 eitherchorioamnionitis 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, S31 S35. doi:10.1038/sj.jp.7211317

The clinician has two primary lung-related concerns when facedwith an infant born before 30 weeks gestationF minimizing theproblems resulting from lung immaturity (respiratory distress

syndromeF

RDS) and avoiding progressive lung injury(bronchopulmonary dysplasiaF BPD). This review will focus onthe complex relationships between RDS, BPD and chorioamnionitisas they are recognized clinically and as presently understood fromanimal models.

Human Fetal Lung DevelopmentF The Substrate

The fetal lung does not normally mature functionally until after 35to 36 weeks, when surfactant is present in large amounts. However,normal physiologic function does not mean a mature anatomy.

The fetal lung is in the saccular stage of development from about24 weeks gestation until secondary septation begins the process ofalveolarization at about 32 weeks gestation.1Alveolarization occursin parallel with microvascular development, primarily betweenabout 32 weeks gestation and several months after term birth.The practical consequence of the timing of this late gestationallung structural development is that the very low birth weight(VLBW) infant is born with the lung in the saccular stage oflung development. This lung must develop postnatally whilesupporting gas exchange and other metabolic functions. WhileRDS is more complex than simply surfactant deficiency, thestriking effectiveness of surfactant therapy even at very early

gestational ages mitigates many of the clinical problems ofmanaging the preterm lung soon after birth.2 Lung maturationalso is inducible with antenatal glucocorticoid therapy, which

further decreases the risk of severe lung immaturity.3 Lungstructural maturation (alveolarization and microvasculardevelopment) may not be inducible and, in fact, alveolarization isdelayed by glucocorticoids, inflammation, oxygen, mechanical

ventilation and nutritional deficiency.4 Therefore, interventionsused to maintain virtually all VLBW infants tend to disrupt normallung development.

BPD in VLBW infants is the net result of lung injury, repair and

disrupted development that should be viewed as a sequence ofadverse events or hits (Figure 1). Although infants with BPDhave chronic lung inflammation, decreased alveolar septation anddecreased microvascular development, the amount of fibrosis andreversibility or recovery potential of the lung is quite variable. BPDdescribes a wide spectrum of disease severity resulting from themultiple factors contributing to disease progression. A factor that isusually not clinically recognized or considered is antenatalexposure of the fetus to inflammation.

ChorioamnionitisF What is it?

Traditionally, chorioamnionitis was considered to be an acuteinfection of the fetal compartment with highly pathologicorganisms, generally in late gestation or after rupture ofmembranes.5 In contrast, many VLBW infants are born after theonset of spontaneous labor or preterm rupture of membranes to

women without symptoms of chorioamnionitis. However, morethan 70% of unruptured women in preterm labor who deliverbefore 30 weeks gestational age will have cultures of amniotic fluidor membranes that are positive for low pathogenic organisms.5

Similar percents of all women delivering prior to 30 weeksgestation will have histologic chorioamnionitis.6,7Amniotic fluid of

Address correspondence and reprint requests to Alan Jobe, Cincinnati Childrens Hospital,

Division of Pulmonary Biology, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, 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.

Division Pulmonary Biology, Cincinnati Childrens Hospital, Cincinnati, OH, USA.

Journal of Perinatology2005; 25:S31S35r 2005 Nature Publishing Group All rights reserved. 0743-8346/05 $30

www.nature.com/jp S31

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women in early preterm labor often contains inflammatory cellsand proinflammatory cytokines, although the women areasymptomatic.8 Many of these women may have had low-gradechorioamnionitis for weeks or months before the preterm labor.The Venn diagram illustrates the diagnostic dilemma (Figure 2).Chorioamnionitis includes overlapping populations of patients withhistologic chorioamnionitis and clinical chorioamnionitis with

subpopulations of infants that may have a systemic inflammatory

response or sepsis. Organisms may be identified without other signsof infection in some women. There have been no systemic studiesof the duration or intensity of the antenatal inflammatory exposureof VLBW infants. The important conclusion is that the majority of

VLBW infants have been exposed to some antenatal inflammation.Nevertheless, the incidence of sepsis defined as a positive bloodculture is less than 3% and a clinical diagnosis of congenital

pneumonia is seldom made in VLBW infants.9

Hits to Fetal Lung Hits During Transition Postnatal Hits

Chronic Chorioamnionitis

Fetal Lung

Initiation of

VentilationVentilation Oxygen Sepsis

Preterm

LungBPD

Corticosteroids Surfactant CorticosteroidsNutrition

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.

HistologicChorioamnionitis

ClinicalChorioamnionitis

Neonatal SIR

NeonatalInfection

No Chorio -

Molecular ID

of Organisms

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

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Clinical Associations With Chorioamnionitis in VLBWInfants

A remarkable observation is that many VLBW infants do not havesevere lung immaturity and some of these infants have no RDS.10

While antenatal corticosteroids can decrease RDS by about 50%, theeffects of corticosteroids in large animal models are modest.11

Clinical experience suggests that something else is inducing veryearly lung maturation in many VLBW infants. Watterberg et al.12

reported that ventilated infants exposed to histologicchorioamnionitis had less RDS but more BPD than control infants.In one report, ureaplasma colonization at birth was associated withless RDS.13 There has been no prospective study that evaluates boththe characteristics of the chorioamnionitis and the pulmonaryoutcomes in VLBW infants in any detail. The lung outcomes arelikely 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 chorioamnionitisdecreased the risk of BPD unless the infant was also mechanically

ventilated. The combination of ventilation and chorioamnionitisincreased the risk of BPD.

Lessons from Animal Models of Chorioamnionitis

The first experimental demonstration that fetal exposure toinflammation might modulate lung maturation was the report ofBry et al.15 that intra-amniotic injections of IL-1 induced lungmaturation in fetal rabbits. Intra-amniotic injections of endotoxin

also induce striking lung maturation in fetal sheep.16 Thematuration response (increased surfactant, improved complianceand gas exchange, thinning of the lung mesenchyme) occursafter a phase of acute lung injury (increased inflammatory cells,

proinflammatory cells and edema).17 The maturation responseis much larger than that seen with maternal corticosteroid

treatment in the sheep (Figure 3). Lung injury followed bymaturation results from the direct contact of the endotoxin withthe fetal respiratory epithelium as a result of mixing of fetal lungfluid with the endotoxin in amniotic fluid.18 Lung maturation also

can be induced with the proinflammatory cytokine IL-1 or bycolonizing the amniotic fluid with ureaplasma urealyticum, butintra-amniotic injections of TNFaor INFg donot induce inflammation or lung maturation in the sheepmodel.19,20 These maturation responses occur without anincrease in fetal cortisol, demonstrating that inflammation-mediated lung maturation occurs by pathways distinct fromcortisol.16 Chorioamnionitis is a potent inducer of lung maturationin fetal sheep.

Corticosteroids and Chorioamnionitis

In clinical practice, most women in very early preterm labor withclinically silent chorioamnionitis are treated with corticosteroids.This clinical practice is supported by clinical trial data.21

Nevertheless, it is worth considering how chorioamnionitis andantenatal corticosteroid therapy may interact. The normal fetus isimmune nave and immune immature. Chorioamnionitis exposesthe fetus to inflammation primarily via the fetal lung, whichcauses lung injury followed by the phenotype of lung maturation.18

Repeated exposures of fetal sheep to endotoxin do not causeprogressive lung inflammation or injury. Rather, the lungsuppresses the inflammatory response. Blood monocytes from the

fetal sheep have a decreased response to challenge with endotoxinin vitro 2 days after intra-amniotic exposure of the fetusF anendotoxin tolerance response22 (Figure 4). However, 7 days afterthe fetal exposure, the cells respond to endotoxin more likemonocytes from adult ewesF a maturation effect. Two fetalendotoxin 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 at125 days gestation. All values are normalized to 1.0 for control lambs. The inflammatory exposure from endotoxin caused a persistent increase in themRNA 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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the monocytes induce a persistent endotoxin tolerance response.Thus, intra-amniotic endotoxin causes a complex modulation ofthe innate immunity of the fetus.

Maternal corticosteroid treatment also suppresses fetal bloodmonocyte function below that of the already immature fetal

monocyte

23

(Figure 4). However, monocyte function evaluated 7days after the maternal treatment is increased above that of controladult monocytesF a maturation effect. Thus, eitherinflammation or corticosteroids can cause suppression or inductionof fetal monocyte function, depending on the timing. If the sheep

fetus is exposed to both maternal corticosteroids and intra-amnioticendotoxin at the same time, the corticosteroids initially suppressendotoxin-induced inflammation for several days but result inamplified inflammatory responses 5 or 15 days later.24 Bothcorticosteroids and inflammation interact to modulate the fetalinnate immune response in complicated and time-dependent ways.Inflammation is considered central to the progression of BPD. Our

results suggest that fetal exposures may modulate both fetal andpostnatal inflammatory responses to propagate the injuriesresulting in BPD. The lung maturational effects of corticosteroidsand chorioamnionitis may benefit the fetal lung by decreasingRDS, but alterations in innate immune responses may contributeto BPD.

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Preterm 2d 7d 3d 7d 14d

Controls Interval after

Maternal Betamethasone

Interval afterIntra-amniotic Endotoxin

Adult

H2O2RelativetoP

reterm

Controls

7+14d0

1

2

3

4

5

6

Figure 4. Effects of maternal betamethasone or intra-amnioticendotoxin on endotoxin-stimulated H2O2production by fetal sheepblood monocytes in vitro. All values are normalized to the pretermcontrolsF the dashed line. Preterm monocytes produce less H2O2than

monocytes from adult sheep. Pre-exposure of the fetus tobetamethasone or endotoxin suppressed H2O2 production initially butafter 7 or 14 days H2O2production increased. Fetal sheep exposed toendotoxin 7 and 14 days before delivery had monocytes with depressedfunction. Data from reference Kramer et al.22 and Kramer.23

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22. Kramer BW, Ikegami M, Moss TJM, Nitsos I, Newnham JP, Jobe AH.

Endotoxin induced chorioamnionitis modulates innate immunity

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