Histological Characteristics of the Fetal Inflammatory ResponseAssociated with Neurodevelopmental Impairment and Death

in Extremely Preterm Infants

Ariel A. Salas, MD, MSPH1, Ona M. Faye-Petersen, MD2, Brian Sims, MD, PhD1, Myriam Peralta-Carcelen, MD1,

Stephanie D. Reilly, MD2, Gerald McGwin, Jr., MS, PhD3, Waldemar A. Carlo, MD1, and Namasivayam Ambalavanan, MD1,2

Objective To test the hypothesis that increasing severity of the fetal inflammatory response (FIR) wouldhave a dose-dependent relationship with severe neurodevelopmental impairment or death in extremely preterminfants.Study designWe report 347 infants of 23-28 weeks gestational age admitted to a tertiary neonatal intensive careunit between 2006 and 2008. The primary outcome was death or neurodevelopmental impairment at the 18- to 22-month follow-up. Exposure status was defined by increasing stage of funisitis (stage 1, phlebitis; stage 2, arteritiswith or without phlebitis; stage 3, subacute necrotizing funisitis) and severity of chorionic plate vasculitis (inflamma-tion with or without thrombosis).Results A FIR was detected in 110 placentas (32%). The rate of severe neurodevelopmental impairment/deathwas higher in infants with subacute necrotizing funisitis compared with infants without placental/umbilical cord in-flammation (60% vs 35%; P < .05). Among infants with stage 1 or 2 funisitis, the presence of any chorionic vasculitiswas associated with a higher rate of severe neurodevelopmental impairment/death (47% vs 23%; P < .05). Afteradjustment for confounding factors, only subacute necrotizing funisitis (risk ratio, 1.87; 95% CI, 1.04-3.35; P =.04) and chorionic plate vasculitis with thrombosis (risk ratio, 2.21; 95% CI, 1.10-4.46; P = .03) were associatedwith severe neurodevelopmental impairment/death.Conclusion Severe FIR, characterized by subacute necrotizing funisitis and severe chorionic plate vasculitiswith thrombosis, is associated with severe neurodevelopmental impairment/death in preterm infants. (J Pediatr2013;163:652-7).

Although advances in neonatal care have reduced mortality in extremely preterm infants,1 the risk of adverse neurode-velopmental outcomes remains high. Neurodevelopmental impairment at 18-22 months corrected age occurs in nearly40% of extremely low birth weight (birth weight #1.0 kg) infants.2-4 The incidence of histologically identified cho-

rioamnionitis (termed histological chorioamnionitis [HCA]) in preterm births is approximately 50% and is inversely relatedto gestational age.1,5,6 Chorioamnionitis may induce preterm delivery via a maternal inflammatory response. Exposure to in-flammation also may injure the immature brain, particularly when chorioamnionitis is associated with a fetal inflammatoryresponse (FIR).7-11 The association between HCA and neurodevelopmental impairment is inconsistent, perhaps because ofvarying definitions of intrauterine inflammation.3,9,12-18 It is possible that the maternal inflammatory response and the FIRare associated with different risks for neurodevelopmental impairment and mortality.3

Any evidence of mural inflammation in the umbilical vessels and the chorionic plate vessels indicates FIR,19-22 because thesevessels are continuous with the fetal cardiovascular system and are considered of fetal origin.6,7 Among preterm placentas withHCA, 50%-70% demonstrate funisitis,6,15 and approximately 30% have chorionic plate vasculitis.23,24 It has been estimatedthat FIR occurs in approximately 25%-40% of all preterm births5,6,9,24,25; however, the severity of the FIR has not been con-sistently reported.3,5,22,23 Evidence suggesting an association between FIR and neurodevelopmental impairment in preterm in-fants7,8,10,15,19,20 is difficult to interpret, owing to limited information regarding the severity of inflammation3 and imprecisemeasurement of effect, related mainly to sample size limitations.19

We hypothesized that an increasing duration and/or severity of placental histopathology compatible with FIR would havea dose-dependent relationship with the rate of neurodevelopmental impairment/death in preterm infants.

From the Departments of 1Pediatrics, 2Pathology, and3Epidemiology, University of Alabama at Birmingham,Birmingham, AL

The authors declare no conflicts of interest.

0022-3476/$ - see front matter. Copyright ª 2013 Mosby Inc.

All rights reserved. http://dx.doi.org/10.1016/j.jpeds.2013.03.081

aRR Adjusted risk ratio

BSID III Bayley Scales of Infant and Toddler Development, Third Edition

FIR Fetal inflammatory response

HCA Histological chorioamnionitis

IVH Intraventricular hemorrhage

RR Risk ratio

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Vol. 163, No. 3 � September 2013

Methods

This was a retrospective cohort study using prospectively col-lected data on inborn infants at 230/7 to 286/7 weeks gesta-tional age admitted to the tertiary neonatal intensive careunit at the University of Alabama at Birmingham between2006 and 2008. The primary composite outcome was severeneurodevelopmental impairment by 18-22 months correctedage or death at any time before follow-up. Composite scoresfor cognitive, language, and motor domains at 18-22 monthscorrected age were determined by trained and certified exam-iners using the Bayley Scales of Infant and Toddler Develop-ment, Third Edition (BSID III).26 Neurologic examinationand vision and hearing assessments were performed as well.Severe neurodevelopmental impairment was defined as thepresence of 1 or more of the following: moderate or severe ce-rebral palsy, BSID III cognitive score <70, Gross Motor Func-tion Classification System level$2, blindness, and/or hearingloss despite amplification.26,27

Demographic, clinical, and outcome data were collectedprospectively from the infants’ medical charts by trained re-search nurses. Waiver of authorization and informed consentwere obtained from the University of Alabama at Birming-ham’s Institutional Review Board. Infants with major con-genital anomalies, those without placental evaluation, andthose lost to follow-up were excluded.

At our center, placental pathology is routinely analyzed incases of preterm delivery. Each placenta and umbilical cord isassessed individually regardless of singleton or multiple ges-tation. For the present study, placentas of extremely preterminfants were evaluated by 2 pathologists (O.F.-P. and S.R.)using prospectively defined standards within the first 48hours after delivery.13,21 The presence of any vasculitis inthe umbilical cord (funisitis) or vasculitis in the placentalchorionic plate was considered to indicate FIR. For analysesof dose dependence, infants were categorized into 5 groupsby increasing stage and severity of FIR based on placentaland umbilical cord histopathology (Table I). Subacutenecrotizing funisitis is a robust indicator of duration andintensity of fetal inflammation,20,21 and chorionic platevasculitis is an important gauge of both magnitude andability of neutrophils to mount an FIR.6,20,21 The severityof maternal response was analyzed as well. Severe HCAwas defined as intense inflammation (polymorphonuclearaggregates of $10-20 cells) with or without micro-abscesses.20,21 Mild to moderate HCA was defined as HCAwithout signs of severe inflammation.21

Potential covariates includedmaternal age, gestational age,race/ethnicity, twin and other multiple gestations, clinicalchorioamnionitis identified by obstetrical assessment, pre-mature rupture of membranes more than 18 hours before de-livery, maternal preeclampsia, use of antenatal steroids, useof antepartum antibiotics, 5-minute Apgar score <3, andbirth weight. Secondary outcomes included early-onset sep-sis, defined as a positive blood culture at age #72 hours;late-onset sepsis, defined as a positive blood culture at age

$72 hours and treatment for more than 5 days; severe intra-ventricular hemorrhage (IVH), defined as grade 3 or 4 IVH28;and periventricular leukomalacia, defined as at least 1 cysticarea in the brain parenchyma identified by neuroimaging at28 days after birth.Previous data indicated that the proportion of extremely

preterm infants with severe neurodevelopmental impairmentor death was approximately 38%.2 Assuming a hypotheticalrisk ratio (RR) for severe neurodevelopmental impairment/death in exposed infants relative to unexposed infants of1.5 (least extreme RR detected), we planned a study witha minimum of 89 exposed infants and at least 177 unexposedinfants (a 1:2 of exposed to unexposed infants), for a power of80% and an a value of 0.05 using the c2 test. Unadjustedcomparisons of baseline characteristics were performed usingthe Student t-test and one-way ANOVA (Tukey method) forcontinuous variables and the c2 test and Fisher exact test forcategorical variables. Poisson regression was used to estimateRRs and 95%CIs for the association between severe neurode-velopmental impairment/death and the severity of placentalhistopathology with andwithout adjustment for birth weight,multiple gestation, and preeclampsia. A similar approach wasused for secondary outcomes including death, severeneurodevelopmental impairment, individual componentsof neurodevelopmental impairment, and short-term neuro-logic morbidity (IVH and periventricular leukomalacia).Effect-measure modification between FIR and antenatal

steroids for the outcome of neurodevelopmental impair-ment/death was assessed by joint exposure in additive andmultiplicative scales. For this analysis, FIR and antenatal ste-roids were analyzed as risk factors. Exposure to FIR and nosteroids/incomplete course of antenatal steroids was consid-ered the high-risk category. The reference group (exposure toneither) was used to establish the baseline risk for neurodeve-lopmental impairment/death, combining all other potentialcauses of neurodevelopmental impairment/death, and to il-lustrate the effect of adding the other 3 categories (exposureto FIR and antenatal steroids (high-risk); exposure to FIR,not antenatal steroids; exposure to antenatal steroids, notFIR) to the baseline risk (departure from additivity). Underthe assumption of a possible biologic interaction, the magni-tude of risk observed in the high-risk category was expectedto be greater than the relative risks observed in the other 2nonreference categories after addition and/or multiplicationof the obtained values.All statistical analyses were performed using SAS 9.2 (SAS

Institute, Cary, North Carolina).

Results

Of a total of 399 eligible preterm infants, 347 had outcomedata at 18-22 months corrected age (87%). Of these 347 in-fants, 110 (32%) had placental/umbilical cord features indic-ative of FIR. Baseline characteristics of infants by exposure toFIR are presented in Table II. The mean birth weight was830 g, and the median gestational age was 26 weeks. The

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Table I. Groups created based on placental and umbilical cord histopathology

Group Description

No chorioamnionitis Absence of membranous, chorionic plate, and umbilical cord inflammationHCA, no funisitis Presence of HCA alone without chorionic plate vasculitis and/or funisitis. HCA was defined as an acute inflammatory

infiltrate in the free membranes, chorionic plate, or subchorionic space of the placenta, and was subclassified asmild/moderate or severe depending on the magnitude of inflammation.

HCA, stage 1 or 2 funisitis withoutchorionic plate vasculitis

Funisitis was defined as the presence of neutrophils in the walls of the umbilical vessels and/or Wharton jelly. Stage 1funisitis was defined as the presence of intramural neutrophils in the umbilical vein (umbilical phlebitis). Stage 2funisitis was defined as additional the presence of intramural neutrophils in one or both umbilical (umbilical arteritis).

HCA, stage 1 or 2 funisitis with grade 1chorionic plate vasculitis

Stage 1 and 2 funisitis defined as above, and mild chorionic plate vasculitis defined as the migration and chemotaxis ofneutrophils into and through the blood vessel walls of the chorionic plate without nonocclusive thrombosis (grade 1)

HCA, subacute necrotizing funisitis orgrade 2 chorionic plate vasculitis

Stage 3 funisitis defined as the presence of concentric umbilical perivasculitis characterized by neutrophils, cellular debris,eosinophilic precipitate, and/or mineralization arranged in a concentric band, ring, or halo around one or more umbilicalvessels, or severe chorionic plate vasculitis with intense inflammation and recent nonocclusive thrombosis (grade 2)

Definitions are adapted from Dammann et al,6 Redline,20 and Faye-Petersen et al.21

Table II. Baseline characteristics

FIR group(n = 110)

Non-FIRgroup

(n = 237) P value

MaternalAge, y, mean � SD 25 � 6 26 � 6 .06Black race, % 48 53 .39Multiple gestation, % 22 30 .13Preeclampsia, % 5 17 .003Full course of antenatal steroids, % 68 60 .14Antepartum antibiotics, % 86 72 .003Clinical chorioamnionitis, %* 36 12 .0001Rupture of membranes >18 h

before delivery, %73 38 .0001

NeonatalBirth weight, g, mean � SD 842 � 232 824 � 234 .50Gestational age, wk, median (IQR) 25 (24-27) 26 (25-28) .002Male sex, % 50 50 .97Apgar score at 5 min, median (IQR) 7 (5-8) 7 (5-8) .17Apgar score #3 at 5 min, % 9 10 .76Apgar score <7 at 5 min, % 37 35 .72Cord pH, mean � SD† 7.21 � 0.08 7.25 � 0.12 .47Respiratory distress syndrome, %z 92 88 .36Prophylactic indomethacin, % 59 63 .50Early-onset sepsis, % 3 1 .33Late-onset sepsis, % 41 35 .36IVH grade 3 or 4,x %28{ 23 14 .04Cystic periventricular

leukomalacia,x %k4 4 .91

*Clinical chorioamnionitis was considered a medical diagnosis if it was documented in themother’s medical record by obstetricians, usually based on maternal temperature, uterine ten-derness, fetal tachycardia, or other clinical variables.†n = 285; cord arterial pH.zRespiratory distress syndrome was defined as clinical features of respiratory distress and/orrequirement for oxygen or positive pressure support for more than 6 hours within the first 24hours.xn = 332; infants who survived to 28 days of age.{IVH was defined by sonogram as any blood/echodensity in the brain parenchyma (grade 4) orany ventricular enlargement with our without concurrent or previous intraventricular blood(grade 3).kCystic periventricular leukomalacia was defined by sonography as any cystic area(s) in thebrain parenchyma within 28 days.

THE JOURNAL OF PEDIATRICS � www.jpeds.com Vol. 163, No. 3

mean duration of gestation was 185 days (26 weeks and 3days), with an SD of �12 days. Slightly more than one-halfof the infants were of non-Hispanic black race/ethnicity.Clinical chorioamnionitis, prolonged premature rupture ofmembranes, and antepartum antibiotic use were morecommon in infants with FIR, whereas maternalpreeclampsia and multiple gestation were more common inthe non-FIR group. Infants with FIR were more likely to beborn at a lower gestational age and to develop severe IVH.

Placental inflammation was detected in 148 cases (43%).SevereHCAwas observed in 30%of the placentaswith inflam-mation and in 38% of the placentas with features indicative ofFIR. Severity of HCA had a strong correlation with funisitis(ranging from 8% in the absence of funisitis to 73% inthe presence of stage 3 funisitis) (Figure). Placentalinflammation (n = 148) was classified as HCA (maternalresponse) without funisitis (26%), phlebitis alone(24%), combined arteritis/phlebitis (40%), and subacutenecrotizing funisitis (10%). Increasing magnitude ofumbilical cord inflammation was associated with increasingseverity of chorionic plate vasculitis, suggesting a dose-dependent relationship (P = .02) (Figure). Two cases ofchorionic plate vasculitis were excluded from the analysisbecause they could not be categorized accurately, owing toa lack of evidence of thrombosis despite intense inflammation.

Severe neurodevelopmental impairment or death occurredin 141 infants (41%; 39% in the non-FIR group and 45% inthe FIR group; P = .31). Severe FIR was associated with higherrates of neurodevelopmental impairment/death in the crudeanalysis (P = .005) and the adjusted analysis (P = .016)(Table III). The rate of neurodevelopmental impairment/death was higher in infants with subacute necrotizing funisitisand/or severe chorionic plate compared with infants withoutHCA (P = .02). Compared with infants without HCA, infantswith both stage 1 or 2 funisitis and chorionic vasculitistended to have a higher rate of severe neurodevelopmentalimpairment/death (P = .07), but those with stage 1 or 2funisitis without chorionic vasculitis tended to have a lowerrate (P = .16). In the subgroup of infants with stage 1 or 2funisitis, the presence of chorionic vasculitis was associatedwith a greater risk of severe neurodevelopmental impairment/death (RR, 1.93; 95% CI, 1.002-3.72; P = .03). Infants with

654

subacute necrotizing funisitis were more likely to have severeneurodevelopmental impairment/death compared with thosewithout placental/umbilical cord inflammation (adjusted riskratio [aRR], 1.87; 95% CI, 1.04-3.35; P = .04). Similarly, therisk of severe neurodevelopmental impairment/death wasgreater in infants with severe chorionic plate vasculitis(aRR, 2.21; 95% CI, 1.10-4.46; P = .03).

Salas et al

Figure. Increasing severity of funisitis is associated with in-creasing severity ofA,HCA (P < .001, c2 test) andB, chorionicvasculitis (P = .02, c2 test).

September 2013 ORIGINAL ARTICLES

The overall mortality rate was 28% (Table III). Subacutenecrotizing funisitis and/or severe chorionic plate vasculitiswere associated with a greater risk of mortality comparedwith infants without placental inflammation (P = .04).Differences in baseline characteristics by groups createdbased on placental and umbilical cord histopathology areshown in Table IV (available at www.jpeds.com).

Of the 250 infants assessed at follow-up, 44 (18%) were di-agnosed with severe neurodevelopmental impairment(Table III). The presence of subacute necrotizing funisitisand/or severe chorionic plate vasculitis was associated witha greater risk of severe neurodevelopmental impairment.Infants with subacute necrotizing funisitis and/or severechorionic plate vasculitis were at greater risk for a BSID IIIlanguage score <70 compared with those without placental

Table III. Dose-dependent relationship between FIR and neu

Neurodeveimpairmen

n (%) aR

No HCA 70 (35)HCA, no funisitis 22 (58) 1.5HCA, stage 1 or 2 funisitis without chorionic vasculitis 6 (23) 0.8HCA, stage 1 or 2 funisitis with grade 1 chorionic vasculitis 28 (47) 1.2HCA, subacute necrotizing funisitis or grade 2 chorionic vasculitis 15 (60) 1.9

*Adjusted for 100-g increment in birth weight, singleton birth, and preeclampsia.

Histological Characteristics of the Fetal Inflammatory ResponseDeath in Extremely Preterm Infants

inflammation (aRR, 2.57; 95% CI, 1.02-6.46; P = .04)(Table V; available at www.jpeds.com).Severe IVH was observed in 57 of the 332 infants surviving

to 28 days (17%). After adjustment, severe FIR (subacutenecrotizing funisitis and/or grade 2 chorionic vasculitis)was not associated with an increased risk of severe IVH(aRR, 1.52; 95%CI, 0.64-3.64; P = .57) or periventricular leu-komalacia. Early-onset sepsis was documented in 1% of theinfants without evidence of placental inflammation, in 3%of those with HCA alone, and in 3% of those with FIR (P =.22); however, our study was not powered to determine a dif-ference in early-onset sepsis (<2%) among these groups. Theprevalence of a 5-minute Apgar score of#3 was greater in in-fants with subacute necrotizing funisitis than in those with-out evidence of placental inflammation (31% vs 9%; P =.007). Approximately 11% of placentas with intact mem-branes and absence of clinical chorioamnionitis exhibitedfeatures consistent with FIR. A comparative analysis of FIRand no antenatal steroids/incomplete course of antenatal ste-roids demonstrated no biological interaction for severe neu-rodevelopmental impairment/death (Table VI; available atwww.jpeds.com).

Discussion

Our data show that prolonged/severe FIR, characterized bysubacute necrotizing funisitis and severe chorionic plate vas-culitis with thrombosis, is associated with higher mortalityand neurodevelopmental impairment at age 18-22 monthsin extremely preterm infants, even after adjustment for po-tential confounders. We found that mild funisitis with anychorionic plate vasculitis was associated with a greater riskof neurodevelopmental impairment/death compared withmild funisitis without chorionic plate vasculitis, demonstrat-ing the importance of chorionic plate vasculitis as an indica-tor of greater intensity of fetal inflammation and asa predictor of neurodevelopmental impairment/death. Ourfindings also confirm the strong dose-dependent relationshipbetween chorionic plate vasculitis and increasing duration ofumbilical cord inflammation.19

The exposure rates found in this single-center study mightdiffer from those reported in population-based studies, giventhat our center is a regional perinatal center with a high-riskobstetric service (referral bias). This type of bias could

rodevelopmental impairment/death

lopmentalt or death Death

Neurodevelopmentalimpairment

R (95% CI)* n (%) aRR (95% CI)* n (%) aRR (95% CI)*

Referent 45 (23) Referent 25 (16) Referent0 (1.04-2.14) 16 (42) 1.62 (1.00-2.21) 6 (27) 1.88 (0.89-3.96)1 (0.44-1.50) 5 (19) 1.12 (0.52-2.39) 1 (5) 0.59 (0.14-2.51)2 (0.88-1.70) 21 (36) 1.39 (0.89-2.15) 7 (18) 1.19 (0.59-2.40)4 (1.27-2.96) 10 (40) 2.01 (1.12-3.59) 5 (33) 2.52 (1.11-5.72)

Associated with Neurodevelopmental Impairment and 655

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explain the wide discrepancy in the association between HCAand neurodevelopmental impairment reported in previousstudies, particularly for the direction of effect (protective vsrisk factor), which seems to be highly dependent on theoften-underreported severity of FIR.3,5 One limitation ofour study is that the cause of preterm delivery (ie, spontane-ous vs indicated) was not recorded in our database. Higherrates of spontaneous preterm delivery may be associatedwith increased placental inflammation. Another limitationis that the rate of exposure may differ between those who sur-vive and are followed up from those who are not evaluatedowing to death or loss to follow-up.29 To reduce the likeli-hood of survival bias, and to include the worst outcomes,death was included in the primary outcome. Defining neuro-developmental impairment based on a list of heterogeneouslong-term outcomes is another limitation; however, mostclinical studies measuring long-term outcomes in preterminfants use similar operational definitions despite this limita-tion. Finally, our classification is limited to characteristics ofinflammation in the placenta. Other noninflammatory pla-cental features, such as those inherent in multiple gestation(eg, monochorionic vs dichorionic placentas) and other vas-cular changes in the placenta also may be associated withpoor neurologic outcomes.30

The association between prolonged/severity of fetal in-flammation and neurodevelopmental impairment/deathidentified in the present study is unlikely to be explained bychance and is independent of birth weight. Strengths of thestudy include minimization of information bias for exposurestatus using standardized histopathological methods for di-agnosis of severity of FIR compatible with previous defini-tions6,20,21,31 that have a high level of intraobserver andinterobserver agreement, strong external validity, use ofaRRs instead of ORs to avoid overestimation of risk, anda sufficient sample size. The use of BSID III, a conservativeestimator of neurodevelopmental impairment for assessingneurodevelopment,26 is a further strength of this study.

There is biological plausibility for the association betweenfetal inflammation and neurodevelopmental impairment,possibly related to alterations in fetal cytokine concentra-tions that can cause brain injury.7-11,14,18,32 Cytokineconcentration has a linear relationship with increasing sever-ity of fetal inflammation.31 Cytokine concentrations in cordblood are elevated in the presence of chorionic vasculitis.19

Several observational studies have reported an elevated riskof motor impairment in infants with higher cytokine con-centrations.14,18,32

The majority of previous studies evaluating the associationbetween FIR and neurodevelopmental impairment found as-sociations with lower cognitive scores7,15 and cerebralpalsy,9,14 but others did not.3,13 The lack of consistency in re-porting the severity of FIR hinders comparisons of studies. Ingeneral, only severe FIR is associated with white matter in-jury, lower cognitive scores, and cerebral palsy, especially inthe presence of chorionic plate vasculitis.7,14,20

HCA is a risk factor for early mortality, particularly in in-fants born to mothers with clinical signs of chorioamnioni-

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tis.16 Studies comparing any HCA with the absence ofplacental inflammation have reported higher survival ratesassociated with HCA.3,5 Studies comparing mortality in in-fants with HCA alone (maternal response only) and thosewith HCA and FIR (maternal and fetal response) have re-ported higher mortality in preterm infants with FIR.3,25

These findings underscore the importance of reportingwell-defined features of increasing duration and severity ofplacental inflammation. A time-dependent dual effect of in-flammation on neurodevelopmental outcomes is plausi-ble.11,14 Brief exposure to mild inflammation may induceneuroprotection via immune processes11,18 and amplifica-tion of repair mechanisms in the developing brain.3,5,11

The absence of significant differences in cord pH valuesbased on increasing prolongation/severity of FIR observedin our study suggests that neonatal injury in the presenceof fetal inflammation is independent of metabolic acidosisat birth. Finally, the lack of associations among antenatalsteroid use, placental/fetal inflammation, and neurodeve-lopmental impairment/death suggests that antenatal ste-roids improve neurodevelopmental outcomes and reducemortality regardless of the stage or degree of placentalinflammation.2,12,27

Our study indicates that early prediction of outcomes inpreterm infants may be improved by including the presenceof subacute necrotizing funisitis and severe chorionic platevasculitis as a categorical variable in regression models. Sim-ilarly, the use of detailed placental pathology for early detec-tion of infants with FIR may help guide individualizedpostnatal care and stratification in clinical trials evaluatingneurodevelopmental impairment and death in this vulnera-ble population. n

Submitted for publication Nov 30, 2012; last revision received Feb 18, 2013;

accepted Mar 29, 2013.

Reprint requests: Namasivayam Ambalavanan, MD, University of Alabama at

Birmingham, Women and Infants Center, 176F, Suite 9380, 619 South 20th St,

Birmingham, AL 35249. E-mail: nambalavanan@peds.uab.edu

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Associated with Neurodevelopmental Impairment and 657

Table IV. Baseline characteristics based on placental and umbilical cord histopathology

No HCA(n = 199)

HCA, no funisitis(n = 38)

HCA, stage 1 or 2 funisitiswithout chorionicvasculitis (n = 26)

HCA, stage 1 or 2 funisitiswith grade 1 chorionicvasculitis (n = 59)

HCA, subacutenecrotizing funisitisor grade 2 chorionicvasculitis (n = 25)

Maternal age, y, mean � SD 26 � 6 24 � 5 25 � 7 27 � 6 26 � 4Black race, % 49 37 54 51 52Multiple gestation, % 30 26 12* 32 8*Preeclampsia, % 19 5* 0z 8* 4*Full course of antenatal steroids, % 59 63 65 71 64Antepartum antibiotics, % 72 71 96* 80 92*Clinical chorioamnionitis, % 7 40* 27* 42* 32*Rupture of membranes >18 h beforedelivery, %

36 53* 77* 68* 80*

Birth weight, g, mean � SD 828 � 235 802 � 237 892 � 206 801 � 221 885 � 274Gestational age, wk, median (IQR) 27 (25-28) 25 (24-26)* 26 (24-28) 25 (24-27)* 25 (24-27)Male sex, % 50 50 58 48 48Apgar score at 5 min, median (IQR) 7 (6-8) 7 (4-7) 7 (7-8) 7 (5-7) 7 (4-8)Cord pH, mean � SD 7.25 � 0.02 7.27 � 0.12 7.32 � 0.09 7.28 � 0.08 7.28 � 0.11Respiratory distress syndrome, % 89 82 83 94 92Prophylactic indomethacin, % 64 61 50 64 58IVH grade 3 or 4, % †28 12 24 12 31* 17Periventricular leukomalacia, %† 5 0z 8 4 0z

*P < .05 compared with the no-HCA group.†n = 332.zStatistical test not performed.

Table V. Long-term neurologic morbidity in extremely preterm infants in relation to severity of placental inflammation

Cerebral palsy,n (%)

Language score<70, n (%)

Cognitive score<70, n (%)

Hearingimpairment, n (%)

Blindness,n (%)

No HCA (n = 154) 7 (4) 23 (15) 11 (7) 6 (4) 6 (4)HCA, no funisitis (n = 22) 4 (18) 3 (14) 3 (14) 0 (0) 0 (0)HCA, stage 1 or 2 funisitis without chorionic vasculitis (n = 21) 0 (0) 2 (10) 2 (10) 0 (0) 0 (0)HCA, stage 1 or 2 funisitis with grade 1 chorionic vasculitis (n = 38) 3 (8) 3 (8) 5 (13) 0 (0) 0 (0)HCA, subacute necrotizing funisitis or grade 2 chorionic vasculitis (n = 15) 1 (7) 5 (33) 2 (13) 2 (13) 0 (0)

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Table VI. Assessment of biological interaction: FIR, antenatal steroids, and neurodevelopmental impairment/death

Histological evidence of FIR

No (overall risk, 39%); incomplete course ofantenatal steroids

Yes (overall risk, 45%); incomplete course ofantenatal steroids

No Yes No Yes

Neurodevelopmentalimpairment/death, n (%)

47 (37) 45 (41) 29 (43) 20 (48)

Controls, n (%) 81 (63) 64 (59) 39 (57) 22 (52)RR (95% CI) Reference 1.12 (0.82-1.55) 1.16 (0.81-1.66) 1.30 (0.88-1.92)

September 2013 ORIGINAL ARTICLES

Histological Characteristics of the Fetal Inflammatory Response Associated with Neurodevelopmental Impairment andDeath in Extremely Preterm Infants

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