DECEMBER JOGC DCEMBRE 2013 l 1083

OBSTETRICS
Key Words: Fetal membranes, premature rupture,
chorioamnionitis, premature birth
Competing Interests: None declared.
Received on June 22, 2013
Accepted on July 15, 2013
Histological Chorioamnionitis Associated with
Preterm Prelabour Rupture of Membranes at
Kingston General Hospital: A Practice Audit
Bryden Magee, MD, Graeme Smith, MD, PhD, FRCSC
Department of Obstetrics and Gynaecology, Queens University, Kingston ON
J Obstet Gynaecol Can 2013;35(12):10831089
Abstract
Objective: To determine the prevalence of histological
chorioamnionitis associated with preterm prelabour rupture of
membranes (PPROM) in women following spontaneous onset
of labour, urgent delivery or planned delivery after 34 weeks
gestation.
Methods: Charts of all women admitted to Kingston General Hospital
with PPROM prior to 34 weeks gestation over fve years were
collected. Obstetrical outcomes and histopathology reports were
reviewed.
Results: Two hundred forty-four women with PPROM were
identifed and reviewed. The majority of women (169; 69%) went
into spontaneous labour and, of those, 24 (14%) had clinical
chorioamnionitis and 79 (47%) had histological chorioamnionitis.
Of the 45 women (18%) who required urgent delivery, 27 (60%)
had clinical chorioamnionitis and 31 (69%) had histological
chorioamnionitis. Only 26 of the original 244 women with PPROM
(11%) were managed expectantly until 34 weeks gestation and
then had a planned delivery. The prevalence of histological
chorioamnionitis in this group whose placentas were sent for
histopathologic review was 24%. Overall, the clinical suspicion
of chorioamnionitis was found to be specifc (91%) but not
sensitive (37%) for identifying chorioamnionitis on the basis of
histopathology.
Conclusion: Histological chorioamnionitis complicates almost one
half of all cases of PPROM that occur prior to 34 weeks gestation.
Most women will progress to spontaneous labour or require urgent
delivery for clinical chorioamnionitis or other complications related
to ruptured membranes before reaching 34 weeks gestation.
Only a subset of women remain pregnant long enough to have
labour induced, but among those the prevalence of histological
chorioamnionitis is lower (24%).
Rsum
Objectif : Dterminer la prvalence de la chorioamnionite
histologique associe la rupture prmature des membranes
prterme (RPMP) chez les femmes la suite de lapparition
spontane du travail, dun accouchement durgence ou dun
accouchement planif aprs 34 semaines de gestation.
Mthodes : Les dossiers de toutes les femmes admises, au cours
dune priode de cinq ans, lhpital gnral de Kingston
en raison dune RPMP avant 34 semaines de gestation ont
t rassembls. Les issues obsttricales et les rapports
dhistopathologie ont fait lobjet dune analyse.
Rsultats : Deux cent quarante-quatre femmes prsentant une
RPMP ont t identifes et leurs dossiers ont fait lobjet dune
analyse. La majorit des femmes (169; 69 %) ont connu
un travail spontan et, de celles-ci, 24 (14 %) ont prsent
une chorioamnionite clinique et 79 (47 %) ont prsent une
chorioamnionite histologique. Chez les 45 femmes (18 %) qui ont
ncessit un accouchement durgence, 27 (60 %) ont prsent
une chorioamnionite clinique et 31 (69 %) ont prsent une
chorioamnionite histologique. Seulement 26 des 244 femmes
prsentant une RPMP qui ont t identifes lorigine (11 %)
ont fait lobjet dune prise en charge non interventionniste
jusqu 34 semaines de gestation, pour ensuite connatre un
accouchement planif. Au sein de ce groupe, la prvalence de
la chorioamnionite histologique (dans les cas o le placenta a fait
lobjet dune analyse histopathologique) a t de 24 %. De faon
globale, nous avons constat que les soupons cliniques lgard
de la prsence dune chorioamnionite taient spcifques (91 %),
mais non sensibles (37 %), pour ce qui est de lidentifcation de la
chorioamnionite en fonction de lhistopathologie.
Conclusion : La prsence dune chorioamnionite histologique
complique prs de la moiti de tous les cas de RPMP qui se
manifestent avant 34 semaines de gestation. La plupart des
femmes en viendront connatre un travail spontan ou
ncessiter un accouchement durgence motiv par la prsence
dune chorioamnionite clinique ou dautres complications lies
la rupture des membranes avant 34 semaines de gestation.
Seul un sous-ensemble de femmes demeurent enceintes assez
longtemps pour pouvoir faire lobjet dun dclenchement du travail;
toutefois, chez ces femmes, la prvalence de la chorioamnionite
histologique est moindre (24 %).
1084 l DECEMBER JOGC DCEMBRE 2013
OBSTETRICS
INTRODUCTION
P
reterm prelabour rupture of membranes (PPROM)
occurs in 2% to 3% of pregnancies and can have profound
implications for the pregnancy outcomes of both mother
and fetus.
1
The most signifcant complications of PPROM
are prematurity and intrauterine infection, both of which
carry considerable risk of short- and long-term sequelae for
the newborn.
2
The use of antibiotics and corticosteroids in
the expectant management of women with PPROM has
been shown to reduce the risk of major neonatal morbidity
in preterm infants.
3,4
In keeping with these fndings, it is
our centres practice to manage women with PPROM
expectantly until 34 weeks gestation, when labour is induced.
However, the optimal time for delivery between 32 and 37
weeks is unclear. There is great variability among regional
protocols and no consensus among academic centres.
1,512
Many women who are managed expectantly deliver earlier
because of the spontaneous onset of labour or because they
develop clinical evidence of intrauterine infection, known
as clinical chorioamnionitis. Chorioamnionitis is defned as
infection of the chorioamnion and is thought to be both
a cause and a consequence of PPROM.
10
A multicentre,
prospective study in 2009 showed that when adjusted for
gestational age, chorioamnionitis in preterm infants is
strongly associated with an increased risk of early sepsis as
well as severe intraventricular hemorrhage.
13
Elevated levels
of cytokines in the blood and brain in response to maternal
infection are thought to cause neurotoxic damage to fetal
white matter. This produces the so-called fetal infammatory
response syndrome, leading to intraventricular hemorrhage,
periventricular leukomalacia, and cerebral palsy.
14
For this
reason, the treatment of chorioamnionitis includes early
administration of parenteral antibiotics and expeditious
delivery.
Antenatal signs and symptoms used to diagnose clinical
chorioamnionitis often appear late, by which point the fetus
may have already mounted an infammatory response. At
our institution, a protocol has been established to submit
all placentas from cases of PPROM for histopathologic
review. Histological chorioamnionitis is defned as the
presence of infltrating polymorphonuclear leukocytes
within the amniotic membranes, chorionic plate, and/or
umbilical cord. Although the association is not as strong
as with clinical chorioamnionitis, there remains a clinically
signifcant association between histological chorioamnionitis
and periventricular leukomalacia leading to cerebral palsy in
the preterm neonatal population.
15
If there is no evidence of preterm labour, chorioamnionitis,
or fetal distress, women who have a diagnosis of PPROM
are admitted at our centre for expectant management
with prophylactic antibiotics and a single course of
corticosteroids.
16
From this point onwards, three potential
obstetrical outcomes become manifest:
Group 1: Onset of spontaneous labour and delivery
prior to 34 weeks gestation;
Group 2: Change in maternal or fetal status requiring
urgent delivery;
Group 3: Expectant management until planned
delivery at 34 weeks gestation.
The primary goal of this study was to determine the risk
of histological chorioamnionitis in women with PPROM
associated with these three obstetrical outcome groups:
spontaneous onset of labour (Group 1), need for urgent
delivery (Group 2), or planned delivery at 34 weeks
(Group 3). The timing of delivery cannot be modifed in
Groups 1 and 2, as these women declare themselves early.
However, the timing of delivery for women in Group
3 may be modifed if the results suggest a high risk of
subclinical (i.e., histological) chorioamnionitis, as seen on
histopathologic review of the placentas postpartum.
METHODS
Data were collected from charts of all women admitted
to Kingston General Hospital between January 2005 and
December 2009 with PPROM before 34+0 weeks. To
retrieve these data, a broad search was undertaken in the
Better Outcomes Registry Network perinatal database to
capture all women who delivered at less than 35 weeks
gestation for any reason. All cases were then reviewed using
paper and/or electronic hospital charts to include only
those who presented with PPROM at less than 34+0 weeks.
Discharge records, interdisciplinary records, procedure
notes, and pathology reports were reviewed. Gestational age
when rupture of membranes was confrmed and gestational
age at delivery were recorded to calculate the latency period.
Labour type (spontaneous vs. induced), delivery type (vaginal
vs. Caesarean section), and presence of clinical and/or
histological chorioamnionitis were recorded.
This study was approved by the Queens University Health
Sciences and Affliated Teaching Hospitals Research Ethics
Board.
RESULTS
Between January 2005 and December 2009, 244 women
presented to Kingston General Hospital with PPROM at
or before 34 weeks gestation and subsequently delivered.
Overall, 115 (47%) women had evidence of histological
DECEMBER JOGC DCEMBRE 2013 l 1085
Histological Chorioamnionitis Associated with Preterm Prelabour Rupture of Membranes at Kingston General Hospital: A Practice Audit
chorioamnionitis. However, the prevalence of histological
chorioamnionitis was highest among the women who
presented with ruptured membranes and delivered at between
22 and 29+6 weeks gestation, as shown in Figures 1 and 2.
Each woman had one of the three obstetrical outcomes as
outlined in Figure 3.
Group 1
The majority of women (169; 69%) went into labour
spontaneously. As illustrated in Figure 4, 24 of these
women were also found to have clinical chorioamnionitis
while in labour. Histopathologic review of the placentas
postpartum showed that 21 (88%) had evidence of
histological chorioamnionitis and three (12%) did
not. The remaining 145 (86%) women who went into
spontaneous labour had no clinical signs or symptoms of
chorioamnionitis. Within this group, 119 placentas were
sent for histopathologic review, of which 58 (49%) had
evidence of histological chorioamnionitis. Twenty-six
placentas were not sent for pathological review.
The prevalence of histological chorioamnionitis among
women who laboured spontaneously after variable
latency periods (time between rupture of membranes and
spontaneous onset of labour leading to delivery) is shown
in Figure 5. Over one third of these women delivered
within one day of rupture of membranes and were found
to have the lowest prevalence of chorioamnionitis (27%).
Women who had a longer latency followed by spontaneous
onset of labour were more likely to have histological
chorioamnionitis.
Group 2
Forty-fve (18%) women required urgent delivery for a
variety of indications, outlined in Figure 6. Twenty-seven
(60%) were delivered urgently after clinical
chorioamnionitis was diagnosed based on a combination
0
20
40
60
80
100
120
1819+6 2021+6 2223+6 2425+6 2627+6 2829+6 3031+6 3233+6
N
u
m
b
e
r

o
f

p
a
t
i
e
n
t
s
No histological chorioamnionitis Histological chorioamnionitis Not reviewed by pathology
Gestational age
0
20
40
60
80
100
120
N
u
m
b
e
r

o
f

p
a
t
i
e
n
t
s
Gestational age
No histological chorioamnionitis Histological chorioamnionitis Not reviewed by pathology
1819+6 2021+6 2223+6 2425+6 2627+6 2829+6 3031+6 3234+
Figure 1. Prevalence of histological chorioamnionitis by gestational age:
gestational age at rupture of membranes
Figure 2. Prevalence of histological chorioamnionitis by gestational age:
gestational age at delivery
1086 l DECEMBER JOGC DCEMBRE 2013
OBSTETRICS
of maternal signs and symptoms, leukocyte count, and
fetal heart rate. Of these women, 21 (78%) were confrmed
as having histological chorioamnionitis. Five did not have
histological chorioamnionitis, and one placenta was not
reviewed.
Six women had urgent delivery because of abnormal fetal
heart rate tracings, specifcally recurrent decelerations and
terminal bradycardia. Five women were delivered because
of antepartum hemorrhage.
Two women had umbilical cord prolapse, requiring urgent
Caesarean section. Five women had labour induced for
other reasons: herpes simplex virus infection, a foot
presentation, refractory uterine irritability, decreasing
insulin requirements (in an insulin-dependent diabetic),
and failure to progress in labour. In total, 31 of the 45
women who required urgent delivery for any reason had
histological chorioamnionitis.
Group 3
Thirty women went on to have a planned delivery. Four
women had labour induced before 34 weeks for reasons
other than PPROM: three for IUGR, and one who
requested medical termination at 23 weeks rather than
expectant management.
Therefore, only 26 (11%) of the original 244 women remained
pregnant at 34 weeks gestation and were eligible for a planned
delivery, according to our centres protocol. Only 17 placentas
were sent for review. Of these, four (24%) had evidence of
histological chorioamnionitis and 13 (76%) did not.
As outlined in the Table, of all women presenting with
PPROM at less than 34 weeks the clinical diagnosis of
chorioamnionitis was made in 20%, while the histological
diagnosis was made in 47%. Thus, clinical chorioamnionitis
is specifc (91%) but not sensitive (37%) for identifying cases
of histological chorioamnionitis, as described in the Table.
PPROM
< 34 weeks
Group 1
Spontaneous
labour
Clinical
chorio
No
clinical
chorio
Group 2
Urgent delivery
Clinical
chorio
Other
Group 3
Planned
delivery
> 34
weeks
Other
244
169
24 145
45
27 18
30
26 4
Figure 3. Outcomes of preterm prelabour rupture of membranes
0%
20%
40%
60%
80%
100%
Clinical chorioamnionitis
n = 24
No clinical chorioamnionitis
n = 145
N
u
m
b
e
r

o
f

p
a
t
i
e
n
t
s

No histological chorioamnionitis Histological chorioamnionitis Not reviewed by pathology

Figure 4. Prevalence of clinical and histological chorioamnionitis in Group 1
DECEMBER JOGC DCEMBRE 2013 l 1087
Histological Chorioamnionitis Associated with Preterm Prelabour Rupture of Membranes at Kingston General Hospital: A Practice Audit
DISCUSSION
The results of this observational study expose several
trends in the rates of histological chorioamnionitis. The
risk of histological chorioamnionitis was found to be
inversely related to gestational age at time of rupture of
membranes and delivery, i.e., the earlier the gestational age,
the higher the risk of histological chorioamnionitis.
The rates of histological chorioamnionitis also varied
markedly when stratifed by obstetrical outcome, as seen in
the Table. The prevalence of histological chorioamnionitis
was high in Groups 1 and 2, as predicted on the basis
of the pathophysiology of PPROM being both a cause
and consequence of chorioamnionitis, which is a strong
stimulus for labour. These results support clinical practice
at our centre, where women with PPROM receive empiric
antibiotic therapy but are not treated with tocolysis
because the onset of labour may in fact be the bodys
natural response to signifcant intra-amniotic infection.
Besides preterm labour, almost 20% of women developed
other complications of PPROM, all of which resulted in
preterm delivery. Clinical chorioamnionitis was the most
common, but other known complications occurred,
including antepartum hemorrhage, abnormal fetal heart
rate tracings, and cord prolapse. Our study found that 68%
of women who were delivered urgently for any indication
had histological chorioamnionitis, which contributes to the
short- and long-term morbidity of the premature neonate.
One important objective was to determine the prevalence
of histological chorioamnionitis in women with PPROM
electively delivered at 34 weeks, according to our centres
current protocol. Interestingly, only 11% of women
remained safely pregnant long enough to consider elective
delivery at 34 weeks. In this small percentage of women
with no other indications for delivery, the prevalence of
histological chorioamnionitis was found to be 24%. To
our knowledge, this is the frst study that quantifes that
risk, and our fndings may aid physicians who struggle
to balance the risks of chorioamnionitis and prematurity
in cases of PPROM. It would be interesting to compare
our rates of histological chorioamnionitis with those of
another centre that has a different protocol (e.g., a centre
in which women with PPROM are managed expectantly
until 36 weeks). A national, multicentred study would be a
useful next step.
One of the limitations of our study is that 38 placentas
(16%) were not sent for histopathologic review. The
estimate of the risk of histological chorioamnionitis
is especially limited in Group 3, because one third of
placentas from this group were not examined. Clinicians
may be falsely reassured by women with PPROM who have
no evidence of clinical infection or labour. However, the
clinical assessment for chorioamnionitis is not sensitive;
that is, women without clinical signs or symptoms of
chorioamnionitis are still at risk of intrauterine infection.
This emphasizes the importance of sending all placentas
for histopathologic review, because those that are infected
often cannot be identifed clinically.
A further limitation of this study is that the diagnosis of
clinical chorioamnionitis at our centre is not based on a
standardized set of criteria, but is based instead on a
combination of maternal signs and symptoms, leukocyte
count, fetal heart rate changes, and clinical acumen. Women
with clinical chorioamnionitis were identifed for this study
18
0
10
20
30
40
50
60
70
1 day 2 to 7 days 1 to 2 wks 2 to 3 wks 3 to 4 wks > 4 wks
N
u
m
b
e
r

o
f

p
a
t
i
e
n
t
s
Latency period
No histological chorioamnionitis Histological chorioamnionitis Not reviewed by pathology
Figure 5. Latency period and prevalence of histological chorioamnionitis in Group 1
1088 l DECEMBER JOGC DCEMBRE 2013
OBSTETRICS
by having written evidence of the diagnosis in their chart
(progress notes or procedure suite records). The diagnosis
was not assumed on the basis of biochemical values or
vital signs. Some cases of clinical infection may therefore
have been overlooked if the diagnosis was not written
explicitly in the medical record.
A fnal limitation is that we did not perform amniocentesis
routinely for gram stain, culture, or other rapid biomarkers
of infection. Although amniotic culture provides a
defnitive diagnosis of intra-amniotic infection, it requires
an invasive procedure and can take up to 48 hours for
results. The combination of rapid amniotic tests such as
IL-6, gram stain, and leucocyte count lacks specifcity, and
therefore our centre has not found it to be superior to
clinical diagnosis.
17
CONCLUSION
Most pregnant women who presented with PPROM
progressed to spontaneous labour or required urgent
delivery for chorioamnionitis or other complications of
ruptured membranes before reaching 34 weeks. Within
these two groups, the risk of histological chorioamnionitis
was high (51%). In the subset of women with PPROM
who remained pregnant long enough to be considered
for elective delivery, the prevalence of histological
chorioamnionitis was lower (24%) at 34 weeks. However,
this rate should be interpreted cautiously, because one
third of the placentas in this group were not submitted for
pathologic review. Histopathologic review of all placentas
in cases of PPROM should be encouraged, regardless
of the indication for delivery, because histological
chorioamnionitis is prevalent and a known independent risk
factor of neonatal morbidity. This information will better
our understanding of the risks of expectant management
versus urgent delivery and may contribute to a consensus
on the optimal timing of delivery in women with PPROM.
REFERENCES
1. Smith GN, Rafuse C, Anand N, Brennan B, Connors G, Crane J, et al.
Prevalence, management, and outcomes of preterm prelabour rupture
of the membranes of women in Canada. J Obstet Gynaecol Can
2005;27(6):54753.
2. Patrick LA, Smith GN. Proinfammatory cytokines: a link between
chorioamnionitis and fetal brain injury. J Obstet Gynaecol Can
2002;24(9):7059.
3. Kenyon S, Boulvain M, Neilson JP. Antibiotics for preterm rupture of
membranes. Cochrane Database Syst Rev 2010(8):001058.
60%
13%
11%
5%
11%
Clinical chorioamnionitis
Abnormal fetal heart rate
Antepartum hemorrhage
Cord prolapse
Other*
Figure 6. Indications for urgent delivery
Prevalence of histological chorioamnionitis by group
Clinical
chorioamnionitis
Histological
chorioamnionitis
No histological
chorioamnionitis
Placenta
not sent
Group 1: Spontaneous labour Yes 21 3 0
No 58 61 26
Group 2: Urgent delivery Yes 21 5 1
No 10 6 2
Group 3: Planned delivery Yes
No 5 16 9
*Herpes simplex virus, foot presentation, decreasing insulin req., refractory uterine
irritabilty, failure to progress in labour
DECEMBER JOGC DCEMBRE 2013 l 1089
Histological Chorioamnionitis Associated with Preterm Prelabour Rupture of Membranes at Kingston General Hospital: A Practice Audit
4. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung
maturation for women at risk of preterm birth. Cochrane Database Syst
Rev 2006;3:004454.
5. Buchanan SL, Crowther CA, Levett KM, Middleton P, Morris J.
Planned early birth versus expectant management for women with
preterm prelabour rupture of membranes prior to 37 weeks gestation
for improving pregnancy outcome. Cochrane Database Syst Rev
2010(3):004735.
6. Mercer BM, Crocker LG, Boe NM, Sibai BM. Induction versus expectant
management in premature rupture of the membranes with mature
amniotic-fuid at 32 to 36 weeksa randomized trial. Am J Obstet
Gynecol 1993;169(4):77582.
7. Hartling L, Chari R, Friesen C, Vandermeer B, Lacaze-Masmonteil T.
A systematic review of intentional delivery in women with preterm
prelabor rupture of membranes. J Matern Fetal Neonatal Med
2006;19(3):17787.
8. Naef RW3rd, Allbert JR, Ross EL, Weber BM, Martin RW, Morrison JC.
Premature rupture of membranes at 34 to 37 weeks gestation: aggressive
versus conservative management. Am J Obstet Gynecol
1998;178(1 Pt 1):12630.
9. Cox SM, Leveno KJ. Intentional delivery versus expectant management
with preterm ruptured membranes at 3034 weeks gestation. Obstet
Gynecol 1995;86(6):8759.
10. Garite TJ, Freeman RK. Chorioamnionitis in the preterm gestation.
Obstet Gynecol 1982;59(5):53945.
11. van der Ham DP, Nijhuis JG, Mol BW, van Beek JJ, Bijlenga D,
Groenewout M, et al. Induction of labour versus expectant management
in women with preterm prelabour rupture of membranes between 34 and
37 weeks (the PPROMEXIL-trial). BMC Pregnancy Childbirth 2007;7:11.
doi:10.1186/14712393711.
12. Al-Mandeel H, Alhindi M, Sauve R. Effects of intentional delivery on
maternal and neonatal outcome in pregnancies with preterm prelabour
rupture of membranes between 28 and 34 weeks of gestation: a systemic
review and meta-analysis. J Matern Fetal Neonatal Med 2013;26(1):839.
13. Soraisham AS, Singhal N, McMillan DD, Sauve RS, Lee SK, Canadian
Neonatal Network. A multicenter study on the clinical outcome
of chorioamnionitis in preterm infants. Am J Obstet Gynecol
2009;200(4):372.e1,372.e6.
14. Wu YW, Escobar GJ, Grether JK, Croen LA, Greene JD, Newman TB.
Chorioamnionitis and cerebral palsy in term and near-term infants.
JAMA 2003; 290(20):267784.
15. Shatrov JG, Birch SC, Lam LT, Quinlivan JA, McIntyre S, Mendz GL.
Chorioamnionitis and cerebral palsy: a meta-analysis. Obstet Gynecol
2010;116(2 Pt 1):38792.
16. Society of Obstetricians and Gynaecologists of Canada. Antibiotic
Therapy in Preterm Premature Rupture of the Membranes. SOGC
Clinical Practice Guideline No. 233. J Obstet Gynaecol Can
2009;31(9):8637.
17. Canavan TP, Simhan HN, Caritis S. An evidence-based approach to the
evaluation and treatment of premature rupture of membranes: part I.
Obstet Gynecol Surv 2004;59(9):66977.