Necrotizing funisitis: Clinical significance and association with chronic lung disease in premature infants

Tadashi Matsuda, MD, ~ Takeo Nakajima, MD, ~ Satoshi Hattori, MD, ~ Kaoru Hanatani, MD, a

Yuichiro Fukazawa, MD, ~ Kunihiko Kobayashi, MD~ b and Seiichiro Fujimoto, MD"

Sapporo, Japan

OBJECTIVES: Our purpose was to analyze the clinical significance of necrotizing funisitis, an unusual type of chronic inflammation of the umbilical cord, and to determine whether necrotizing funisitis is associated with chronic lung disease in premature infants. STUDY DESIGN: A total of 52 perinatal factors were prospectively assessed in 18 pregnant women and their fetuses in cases of chorioamnionitis at delivery occurring at 22 to 30 gestational weeks; a statistical comparison between the necrotizing funisitis group (n = 5} and the group without necrotizing funisitis (n = 18) was carried out. RESULTS" Significant correlations were found between necrotizing funisitis and the following factors: maternal serum C-reactive protein level on admission (/3 = 0.014), fetal distress (/3 = 0.044), umbilical artery blood pH value (p = 0.037) and polynuclear neutrophilic leukocyte count at birth (/3 = 0.014), chronic lung disease (p = 0.035), need for dexamethasone therapy for chronic lung disease (/3 = 0.029), duration of oxygen supplementation (/3 = 0.026), and length of hospital stay (/3 = 0.026). CONCLUSIONS: There was a significant association between necrotizing funisitis and development of chronic lung disease, suggesting that necrotizing funisitis is an important risk factor for the development of chronic lung disease. (Am J Obstet Gynecol 1997;177:1402-7.)

Key words: Premature infant, chronic lung disease, chorioamnionitis, necrotizing funisitls

Necrotizing funisitis is a chronic, severe inflammation

of the umbilical cord in which old necrotic exudate is

concentrically deposited in a ringlike fashion around the

vessels, frequently with calcification, and it is generally

associated with chorioamnionitis, which is recognized as

one of the most significant causes of preterm delivery in the second trimester. 1 The clinical significance of necro-

tizing funisitis, however, has not been clarified, although

some studies have suggested associations with prematu- rity,2-4 stillbirth,2, 3 infection at birth, 2 susceptibility to

recurrent infection, 2 infants who are small for gestational age, 3 necrotizing enterocolitis, 3 congenital syphilis, 4 and

type 2 herpes simplex virus infection. 5

Recently, intrauterine inflammation has been re-

ported to be a more important risk factor for chronic

lung disease in premature infants than respiratory dis- tress syndrome, patent ductus arteriosus, and postnatal infections, 6-8 and chorioamnionitis complicated by ne-

crotizing funisitis has been considered not only as a cause

From the Departments of Obstetrics and Gynecology ~ and Pediatrics, ~ School of Medicine, Hokkaido University, and the Departments of Neonatology, ~ Obstetrics and Gynecology, ~ and Pathology Sapporo City General Hospital. Received for publication Januau 10, 1997; revised May 27, 1997; accepted June 23, 199z Reprint requests: Tadashi Matsuda, MD, Department of Obstetrics and Gynecology, Hokkaido University School of Medicine, North 15, West 7, Kita-hu, Sapporo, 060, Japan. Copyright © 1997 by Mosby-Year Book, Inc. 0002-9378/97 $5.00 + 0 6/1/84234

of preterm delivery but also as a possible cause of Wilson-Mikity syndrome. 9-11 Because chronic lung dis-

ease greatly affects the outcome of premature infants, 7 it

is essential to study its antenatal pathogenesis. The aim of

the current study was to analyze the clinical significance

of necrotizing funisitis and to determine whether necro-

tizing funisitis is associated with chronic lung disease in

premature infants.

Material and methods

With the approval of the Ethics Committee of Sapporo

General Hospital, all pregnant women with threatened preterm labor admitted to the hospital at 22 to 30

gestational weeks from December 1992 to February 1994 were included in this prospective observational study.

After their informed consent was obtained, patients who

fulfilled the following criteria were enrolled in the study: singleton pregnancy, no pregnancy complication except

chorioamnionitis, histopathologic diagnosis of chorio- amnionitis at delivery, no chromosomal or other congen-

ital anomalies found in the fetus or newborn infant, gestational age confirmed by both last menstrual period

and uhrasonographic evaluation in early pregnan W, and no maternal history of diseases affecting pregnancy, delivery, or neonatal outcome.

After the patient was hospitalized, 52 perinatal factors (Table I) were recorded until the infant reached 12 months beyond the maternal expected date of confine-

1402

Volume 177, Number 6 Matsuda et N, 1403 Am J Obstet G~mcol

ment. After assessment of the factors was comple t ed in all

of the patients enro l led in the study, the patients were

dNided into two groups, a necrot iz ing funisitis group and

a group wi thout necrot iz ing fnnisitis, on the basis of the

results of a his topathologic examinat ion, and each factor

was statistically compared between the two groups.

The details of maternal, fetal, and neonatal management

during the study period and the criteria for the perinatal

factors are described here. Threa tened preteiTn labor was

diagnosed when regular uterine contractions occurred at a

frequency of at least one every 10 minutes for at least 60

minutes. On admission one or more tocolytics (ritodrine

hydrochloride, magnesium sulfate, indomethacin, nifedi-

pine) plus appropriate antibiotics were administered to the

patients with either increased polynuclear neutrophilic

leukocyte counts or positive test results for C-reactive pro-

tein, or both, on the basis of the results of microbiologic

examinations of urine, cervical mucus or discharge, and

amniotic fluid obtained by transabdominal puncture. Clin-

ical chorioamnionitis u~s defined according to the criteria

proposed by Gibbs et al. 12 All patients judged to have a

weak or lower rating in a stable microbubble test of

amniotic fluid ~3 were treated with intramuscular dexameth-

asone (total dose of 24 mg, divided into three dosages,

given every 8 hours) to p romote fetal lung maturation.

Even when premature rupture of the membranes was

present, if there was no evidence of fetal distress, reffactoP/

inflammatory- reaction, or progressive celwical dilatation,

tocolytic therapy was cont inued until fetal lung maturity was

demonstrated by" stable microbubble test. Premature rup-

ture of membranes was diagnosed on the basis of physical

findings (i.e., clear leakage of amniotic fluid before the

onset of labor) and the results of the phenaphthazine test.

Fetal distress was diagnosed on the basis of either fetal heart

rate moni tor ing patterns or the presence of scores -<6

points on the biophysical profile scoring system, ~4 or both.

Tocolysis failure was defined as either progression of cervi-

cal dilatation beyond 5 cm or delivery, or both. Oligohy-

dramnios was diagnosed when a depth of amniotic pockets

-<5 cm was found on fou>quadrant assessment with ultra-

sonographic examination. ~5 Maternal fever was defined as a

body temperature of >37.5 ° C. Cesarean section was per-

formed when fetal distress or maternal or obstetric indica-

tions were present. Maternal serologic testing was per-

formed to screen for congenital syphilis.

All infants were resuscitated, and their Apgar scores

were de t e rmined by a neonatologis t in the delivery room.

They were then prompt ly t ranspor ted to neonata l inten-

sive care units. Small-for-gestational-age infants were

def ined as those weighing -1.5 SD or less than the m e a n

birth weight of Japanese infants at the same n u m b e r of

gestational weeks. Infect ion at birth was diagnosed on

the basis of unstable vital signs, positive C-reactive pro-

tein test result, and microbiologic examinat ions of arte-

rial b lood and gastric and endot rachea l aspirates. Infants

Table I. Perinatal factors for analysis

Antenatal factors Gestational weeks on admission Gestational weeks at delivery Time from admission to delivery Premature rupture of membranes Duration of premature rupture of membranes Administration of dexamethasone to promote fetal lung

maturation History of cmwical cerclage Fetal distress Oligohydramnios Tocolysis failure Maternal fever Outcome of microbiologic examination for cervical mucus

or discharge Fetal presentation (vertex or not) Delivm y mode (vaginal or cesarean section)

Postnatal factors of neonate Sex Birth weight Stillbirth Apgar score ~<3 at 1 minute after birth Apgar score <--7 at 5 minutes after birth pH of umbilical artery blood at birth Small-for-gestationaI-age infant Congenital syphilis Respiratory distress syndrome Drug therapy for patent ductus arteriosus Surgical ligation of patent ductus arteriosus Susceptibility to recurrent infection Necrotizing enterocolitis Wilson-Mikity syndrome Chronic lung disease Mechanical ventilation Duration of mechanical ventilation Duration of oxygen supplementation Dexametbasone therapy for chronic lung disease Duration of hospital stay Time from expected date of maternal confinement to

discharge Intracranial hemorrhage Periventricular leukomalacia Photocoagulation or cryotherapy for retinopathy of

prematurity Survival prognosis

Laboratox T results of maternal and cord blood analysis Polynuclear neutrophilic leukocyte count Plasma neutrophil elastase-%-protease inhibitor complex

level Serum C-reactive protein level Serum IgM level

Pathologic outcome of intrauterine inflammation Chorioamnionitis Acute funisitis Necrotizing funisitis

who requi red mechanica l venti lat ion were initially sup-

por ted by an in termi t tent mandatory, venti lat ion m o d e at

the m i n i m u m convent ional setting, and if it was insuffi-

cient, they were switched to high-frequency oscillatory or

pat ient- tr iggered ventilation. Respiratory distress syn-

d rome was managed with surfactant r ep lacemen t thera-

py,16 consisting of Surfacten TA (Tokyo Tanabe, Tokyo),

and diagnosed on the basis of the ult imate outcome.

Hemodynamical ly significant pa ten t ductus arteriosus

was diagnosed on the basis of the echocardiographic

1404 Matsuda et al. December 1997 Am J Obstet GynecoI

b 10 mm =l

, !/! i ¸

Fig. 1. Pathologic findings of necrotizing {gmisitis in low-power view of short-axis cross-section of umbilical cord. There is striking necrotizing inflammation in "vVharton's jelly characterized by presence of numerous degenerating neutrophils, abundant basophilic debris (N), and calcification (C) accumu- lated in form of ringlike or crescentic bands around umbilical vessels. (a, Hematoxylin and eosin, b, yon Kossa's stain. Original magnification ×5.)

findings. Mefenamic acid was selected as the initial drug

therapy, and if hemodynamically significant patent duc-

ms arteriosus was present >72 hours after birth or if the

ductus arteriosus later reopened, surgical ligation was

performed secondarily. Chronic lung disease was diag-

nosed when the infant's oxygen requirement was greater

than could be obtained from room air at 28 days of age,

signs of persistent respiratory distress were present, and

the chest x-ray film appeared hazy or had an emphyse- matous and fibrous appearance. 7 Wilson-Mikity syn-

drome was diagnosed by using the criteria in the original report. 9 Oxygen supplementation for chronic lung dis-

ease was continued until the Pao 2 could be maintained at

>50 torr and the infants were free of cyanosis at rest in

room air. Progressive chronic lung disease was managed

with dexamethasone therapy, according to the protocol

of Avery et al l 7 Intracranial hemorrhage and periven-

tricular leukomalacia were diagnosed by radiologists on

t h e basis of repeated uhrasonographic examinations after birth and the computed tomography or magnetic

resonance imaging findings. Either photocoagulation or

cryotherapy, or both, was performed for retinopathy of prematurity when retinal lesions reached stage III in the

international classification.

Maternal blood polynuclear neutrophilic leukocytes, the C-reactive protein level, and a complex of neutrophil

elastase and c%-protease inhibitor were examined twice,

on admission and immediately before delivery, to com- pare the time course of the inflammatory reaction in the

two groups. Polynuclear neutrophilic leukocytes, C-reac- tive protein, neutrophil elastase-ch-protease inhibitor complex, and immunoglobulin M (IgM) were examined in cord blood. Blood gas analysis of umbilical artery blood was performed with a model 278 Blood Gas System (Ciba Coming Diagnostic Corp., Medfield, Mass.). Se- rum C-reactive protein and IgM levels were measured by

laser nephelometry. Blood samples supplemented with

ethylenediaminetetraacetic acid-disodium salt for com-

plex assay were centrifuged at 30,000g for 5 minutes at

3°C immediately after collection, and the separated

plasma was stored frozen at -80 ° C until assayed. The

enzyme-linked inmmnoassay for neutrophil elastase-cz l-

protease inhibitor complex was performed with commer-

cially available kits (Merck, Darmstadt, Germany).

Microbiologic examinations, including Gram stain,

culture for aerobic and anaerobic bacteria, and antibi-

otic sensitivity testing, were carried out frequently on

cervical mucus, cervical discharge including leaked am-

niotic fluid after premature rupture of membranes,

amniotic fluid obtained by transabdominal puncture,

neonatal arterial blood, urine, stools, and endotracheai

and gastric aspirates. Positive Gram stain results and

cultures of cervical mucus or discharge on admission in

the two groups were compared.

M1 histopathologic examinations were performed by the

same pathologist who was unaware of the clinical course and data on each patient. On the basis of the criteria of

Salafia et al., '8 histologic chorioamnionitis was defined as

the presence of acute inflammatory change in any tissue sample of amnion, chorion-decidua, and chorionic plate,

and acute funisitis was defined similarly in umbilical cord. Necrotizing funisitis was diagnosed on the basis of the

presence of necrotizing inflammation in Wharton's jelly characterized by degenerating neutrophils, basophilic de-

bris, and calcification accumulated in the form of ringlike or crescentic bands around the umbilical vessels, according

to the criteria of Navarro and Blanc. 2 Statistical analysis was performed by Wilcoxon's signed

rank test for both paired and unpaired continuous variables and Fisher's exact test for categoric variables with two-tailed p value. A p value < 0.05 was considered

significant.

Volume 177, Number 6 Matsuda et al. I405 _~ j Obstet Gynecol

Table II. Compar ison of perinatal factors between cases with and without necrot iz ing funisitis

Necrotizing funisitis

Negative (n = 13)

Positive (n = 5) Significance

Basic clinical characters Gestational age on admission (wk) Gestational age at delivery (wk) Male sex Birth weight (gin)

Antenatal factors Fetal distress

Postnatal factors of neonate pH of umbilical artery blood at birth Chronic lung disease Duration of oxygen supplementation (wk) Dexamethasone therapy for chronic lung disease Duration of hospitalization (wk) Duration from expected date of maternal

confinement to discharge (wk)

25.8 -+ 2.7 26.0 ±-+ 2.3 NS 27.1 ± 2.4 26.6 ± 1.8 NS

5 (36) 3 (6O) NS 1012 -+ 382 920 ± 304 NS

1 (8) 3 (60) p = 0.044

7.34 ± 0.05 7.28 + 0.06 p = 0.037 5 (36) 5 (100) p = 0.035

10.4 + 10.1 25.3 ± 9.7 p = 0.026 4 (31) 5 (100) p = 0.029

16.6 + 8.7 27.0 ± 7.9 p = 0.026 3.6 _+ 7.0 13.6 ± 6.9 p = 0.019

Continuous variables are shown as mean _+ SD. Categoric variables are shown as number of positive cases, with percentage in parentheses. NS, Not significant.

Results

A total of 35 p regnan t women were admit ted at 22 to

30 gestational weeks with th rea tened p re te rm labor

dur ing the per iod of this study. A histopathologic diag-

nosis of chor ioamnioni t i s was made at the t ime of

deliver}, in 26 of them, and among the o ther 9 women

there were 5 with gestosis and fetal distress, 3 with

cervical atony, and 1 with n o n i m m u n e hydrops fetalis.

The re were no in t rauter ine fetal deaths, but there was

one stillbirth because abrupt io placentae, without cho-

r ioamnionit is , occur red at 26 gestational weeks. A total of

18 of the 26 patients were enrol led in the study. The 8

patients who were exc luded consisted of 6 with twin

pregnancy, 1 with acute hepatitis caused by herpes

s implex virus infection, and 1 whose fetus had trisomy 21.

A diagnosis of necrot iz ing funisitis was made in 5 of the

18 cases enro l led (necrot izing funisitis group) ; necrotiz-

ing funisitis was not present in the o ther 13 cases

(non-nec ro t i z ing funisitis group) , but acute funisitis

occur red in 7 of them.

Fig. 1 displays the typical pathologic findings in the

umbilical cord stained with hematoxyl in and eosin (a) and by Von Kossa's stain (b) in the necrot iz ing funisitis

group.

Table I1 shows the results of the statistical analysis of

antenatal and postnatal factors in the two groups, l imited

only to the basic clinical characteristics and the signifi-

cant correlations.

A m o n g the antenatal factors, fetal distress was found to

be significantly more f r equen t in the necrot iz ing funisitis

group than in the n o n - n e c r o t i z i n g funisitis group, but

no significant differences between the two groups were

found for any of the o the r factors. None of the patients

had symptoms or signs of e i ther oral or genital herpes. In

microbiologic examinat ion, the following bacter ia were

isolated and identif ied in cervical mucus or discharge

only on admission: Streptococcus agalactiae, Enterococcus sp., and coagulase-negative streptococci f rom 5 patients in

the non-nec ro t i z ing funisitis group and Bacteroidesfragi- lis, Bacteroides hivius, Escherichia coli, KlebsieUa pneumoniae, Enterococcus sp., and coagulase-negative streptococci f rom

4 patients in the necrot iz ing funisitis group.

Regarding postnatal factors, there were no small-for-

gestational-age infants, infections at birth, cases of con-

genital syphilis, susceptibility to recur ren t infection, or

cases of necrot iz ing enterocolitis, and thus these factors

were excluded f rom the statistical analysis. Umbil ical

artery b lood pH was significantly lower in the necrot iz ing

funisitis group than in the non-nec ro t i z ing funisitis

group, chronic lung disease and dexamethasone therapy

were significantly more frequent , and the dura t ion of

oxygen supplementa t ion and hospitalization and the

t ime from expected date of maternal con f inemen t to

discharge were longer. Intracranial hemor rhage oc-

curred in 3 cases, 1 in the necrot iz ing funisitis group and

2 in the non -nec ro t i z ing funisitis group. These hemor-

rhages were small subependymal hematomas without

intraventr icular hemorrhage , and cerebral palsy devel-

oped in 2 of the 3 patients with per iventr icular leukoma-

lacia. Al though not statistically significant between the

two groups (p = 0.065), 2 infant deaths and 2 cases of

Wilson-Mikity syndrome were exclusively present in the

necrot iz ing funisitis group. The main cause of death in

the 2 infants was progressive cot pu lmona le caused by

severe chronic lung disease. They died 203 and 218 days

after birth, respectively.

Compar ison of the two groups in regard to polynu-

clear neut rophi l ic leukocytes, neu t rophi l e las tase-%-

1406 Matsuda et al. December 1997 Am J Obstet Gynecol

Table IlL Comparison of laboratory values in maternal and cord blood between cases with and without necrotizing

funisitis

Necrotizing funisitis

Negative (n = 13)

Positive (n = 5) Significance

Maternal blood On admission

Polynuclear neutrophilic leukocytes (cells/b~1) 9,088 _+ 4,199 Neutrophil elastase-%-protease inhibitor complex (b~g/L) 117 ± 30 C-reactive protein (mg/dl) 1.3 -+ 1.9

At delivery Polynuclear neutrophilic leukocytes (cells/l*l) 9,893 -+ 3,132 Neutrophil elastase-%-protease inhibitor complex (p~g/L) 214 ± 173" C-reactive protein (mg/dl) 2.3 ± 2.1

Cord blood At delivery

Polynuclear neutrophilic leukocytes (cells/hal) 7,426 -+ 3,435 Neutrophil elastase-%-protease inhibitor complex (b~g/L) 170 -+ 122 C-reactive protein (mg/dl) 0.1 +- 0.2 IgM (mg/dl) 13.7 -+ 16.3

11,482 +- 1,912 p = 0.094 167 ± 64 p = 0.059 2.4 -+ 1.0 p = 0.014

12,774 -+ 3,228 p = 0.075 166 + 53 p = 0.703 2.9 -+ 2.3 p = 0.633

19,499 -+ 11,527 p = 0.014 200 -+ 159 p - 0.443 0.1 ± 0.1 p = 0.703

63.0 -+ 79.7 p = 0.117

all data are mean -- SD. *p = 0.001 (results of paired Wilcoxon signed rank test for comparison of nentrophil elastase-%-protease inhibitor

on admission and at the time of delive U in cases without necrotizing funisitis). complex value

protease inhibitor complex, and C-reactive protein level

in maternal blood on admission and at the time of

delivery (Table Ill) revealed that C-reactive protein levels

on admission were statistically higher in the necrotizing

funisitis group. Paired Wilcoxon's signed rank test

showed a significant elevation of maternal neutrophil

elastase-%-protease inhibitor complex levels between

admission and delivery in the non-necrotizing funisitis

group but not in the necrotizing funisitis group. No

marked tendency for such elevations was found for any

other marker in these two groups. There was a significant

elevation of polynuclear neutrophilic leukocytes in cord

blood (Table III) in the necrotizing funisitis group.

Mthough the mean IgM value in the necrotizing funisitis

group was higher than in the non-necrotizing funisitis

group, the difference was not statistically significant.

Comment

A number of perinatal factors were prospectively

examined in the second trimester in 18 pregnant

women with chorioamnionit is and were statistically

compared between the necrotizing funisitis group and

the non-necro t iz ing funisitis group to analyze the

clinical significance of necrotizing funisitis, especially

its association with chronic lung disease in premature

infants. It was demonstrated that chronic lung disease

developed in the premature infants with necrotizing

funisitis, and these infants required dexamethasone

therapy more frequently and had longer durations of

oxygen supplementat ion and hospitalization than

those without necrotizing funisitis. Their prognosis for

survival was poor because of advanced cor pulmonale

in association with severe chronic lung disease. Thus

necrotizing f'unisitis is concluded to be an important

factor for the development of chronic lung disease in

premature infants.

Although the pathogenesis of chronic lung disease in

premature infants is complex and multifactorial, there

are two possible processes in the mechanism of chronic

lung disease induced by necrotizing funisitis. In the first

process, in chorioamnionitis some inflammation induc-

ers such as cytokines, which are released into and accu-

mulate in amniotic fluid, diffuse into the fetal lung fluid

and directly injure the extracellular matrix of the lung

tissue. Evidence supporting this process is that inflamma-

tory cytokine levels in amniotic fluid are higher in

chorioamnionitis than in its absence 19-2t and that post,

natal acute lung inflammation is greater in premature

infants with chorioamnionitis than in those without

chorioamnionitis.S, n In the second process, in the pres-

ence of necrotizing funisitis, because neutrophils have

been chronically activated in the umbilical vessels and

some inflammatory factors have been continuously re-

leased into the fetal circulation, the defensive potential

against inflammation in immature fetuses is depleted,

leading to increased susceptibility to lung damage. In the

current study fetuses with necrotizing funisitis were

proved to have significant levels of acidemia and neutro-

philia at birth when compared with fetuses without

necrotizing funisitis, suggesting that the former had

been exposed to more inflammatory stresses than those

without necrotizing funisitis. Involvement of certain spe-

cific bacteria in the occurrence of necrotizing funisitis

could be ruled out, because a variety of microbes was

Volume 177, Number 6 Matsuda et al. 1407 Am J Obstet Gynecol

isolated f rom cervical mucus or discharge of both necro-

tizing funisitis and non -nec ro t i z ing funisitis groups.

We expec ted that the inf lammatory reactants in ma-

ternal b lood would rapidly increase before delivery in the

necrot iz ing funisitis group. However, the neu t rophi l

e!astase-%-protease inhibi tor complex levels were mark-

edly h igher at the t ime of delivery than on admission in

the non -nec ro t i z ing funisitis group instead. No such

changes were observed in any of the inf lammatory pa-

rameters tested in the necrot iz ing funisitis group. Never-

theless, most of the inf lammatory parameters on admis-

sion were h igher in the necrot iz ing funisitis group than

in the non -nec ro t i z ing funisitis group. In this context it

is conceivable that in chor ioamnioni t i s wi thout necrotiz-

ing funisitis the in f lammat ion progressed in u te ro after

the beg inn ing of the th rea tened p re te rm labor and led

to acute funisitis; in addit ion, in chor ioamnioni t i s with

necrot iz ing funisitis, the inf lammat ion had silently devel-

oped in u te ro and already reached its m a x i m u m at e i ther

p re te rm labor or p rema tu re rup ture of membranes , or

both. Presumably, necrot iz ing funisitis is not a conse-

quence of acute funisitis but has its own pathogenesis .

It has previously been repor t ed that necrot iz ing funisi-

tis is associated with prematuri ty, stillbirth, small-for-

gestational-age infants, presence of infect ion at birth,

susceptibility to r ecur ren t infect ion, necrot iz ing entero-

colitis, congeni ta l syphilis, and herpes s implex virus type

2 infection. 2-5 However, none of these factors, except

premamri ty , were observed in e i ther the necrot iz ing

funisitis group or the non -nec ro t i z i ng funisitis group in

the cur ren t study. Thus it is unlikely that these factors are

diagnostic characteristics for necrot iz ing funisitis, and

the inc idence of these factors may d e p e n d greatly on

antenatal fetal m a n a g e m e n t and neonata l intensive care.

We have described the clinical significance of necrotizing

funisifls in the second trimester on the basis of our prospective

obsezvational study. Necrotizing funisifis seemed to be an

important antenatal factor associated with the postnatal devel-

opment of chronic lung disease in premature infants. Further

research is necessary to ascertain the pathogenesis of necrotiz-

ing funisitis and the mechanism of chronic lung disease

induced by necrotizing funisitis.

We thank Otsuka Assay Laboratory for technical assis- tance with m e a s u r e m e n t of the plasma neut rophi l elas- tase-ch-protease inhibi tor complex levels.

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