INFEKSI INTRAUTERIN

MASITA FUJIKO
• Infeksi intrauterin atau korioamnionitis merup
akan infeksi pada cairanamnion, selaput
korioamnion dan atau uterus yang timbul
segera sebelum atau pada
saat persalinan yang disebabkan oleh bakteri
• Korioamnionitis dihubungkan dengan 20-
40% kasus sepsis neonatal dini danpneumonia
•  Infeksi iniberhubungan dengan ketuban pecah
dini dan persalinan lama.
Gambar 2. Kolonisasi bakteri koriodesidua dapat menyebabkan persalinanp
remaTUR
 Penelitian terakhir membuktikan
adanya hubungan
•  Infeksi dengan kelainan neurologis termasuk 
serebralpalsi
• Selain itu juga dapat menyebabkan sepsis,respiratory
distress, kejang,perdarahan intraventrikular 
• berat lahir rendah.
•  Pada ibu juga dapatmenyebabkan sepsis, 
endometritis pasca persalinan dan infeksi luka
•  Infeksi intrauterin disebutkan sebagai salah satu
 faktor penyebab utama dari persalinanpreterm
 ETIOLOGI
• Organisme penyebab dari korioamnionitis seringkali 
multipel 
• Gibbs, dkk(1982) mengidentifikasikan mikroorganisme
yang ditemukan dalam cairan amnionpasien dengan
korioamnionitis yaitu Bakteroides Sp (25%), Gardnerella
vaginalis(24%), grup β streptokokus (12%), streptokokus
aerob jenis lain (13%), E.coli
(10%),dan gram negatif lain (10%). 
• Hampir semua bakteri dalam penelitian tersebut
merupakan bakteri yang ditemukan pada sediaan apus
wanita dengan vaginosisbakterial. 
• Banyak penelitian menghubungkan kejadian korioamnio
nitis dengan vaginosis bakterial
 PATOFISIOLOGI
• Korioamnionitis terjadi akibat infeksi asenden
mikroorganisme dari serviksdan vagina
setelah terjadinya ketuban pecah dan persalinan
• Selain itu dapat pula
akibat infeksi transplasental yang merupakan penyebara
n hematogen dan bakteremia maternal dan induksi
bakteri pada cairan amnion akibat iatrogenik pada
pemeriksaan amniosintesis, pasca transfusi intrauterin d
an kordosintesis.
• Faktor risiko terjadinya korioamnionitis adalah waktu
antara ketuban pecah dan persalinan,penggunaan
monitor fetal internal, jumlah pemeriksaan dalam
selama persalinan,nulipara, dan adanya bakterial
vaginosis.
• Korioamnionitis terjadi paling sering saat persalinan sesuda
h pecahnyaselaput ketuban. Walaupun sangat jarang,
korioamnionitis dapat juga terjadi padakeadaan dimana
selaput ketuban masih intak
• Sebanyak 3% dari neonatus yang lahir dari ibu dengan korio
amnionitisdengan pecahnya selaput ketuban < 24 jam
sebelum persalinan, akan menderita bakteremia. Bila
pecahnya selaput ketuban terjadi >24 jam maka sebanyak
17%neonatus akan mengalami bakteremia
• Gejala pada ibu dapat asimtomatis atau
hanya berupa demam ringan dan jarang menyebabkan
sepsis pada ibu.
• Streptokokus grup A juga dapat menyebakan infeksi janin
dan rongga amnion pada selaput ketuban yang masih intak
• Organisme penyebab infeksi menyebar pertama kali ke
dalam ruang koriodesidua, dan pada beberapa kasus dapat
melintas melalui membran korioamnion
• Setiap kehamilan dengan korioamnionitis merupakan
faktor risiko penyebab
prematuritas dan ketuban pecah dini. Banyak penelitian y
ang menghubungkanantara korioamnionitis dengan persal
inan prematur. 
• Teori yang paling banyakdipergunakan
saat ini adalah teori invasi bakteri dari
ruang koriodesidua, yangmemulai terjadinya proses persal
inan preterm. Hal ini dikarenakan pelepasan endotoksin
dan eksotoksin oleh bakteri akan mengakitivasi desidua
dan membranfetus untuk memproduksi beberapa
sitokin, yang diantaranya tumor nekrosis factor-α 
• (TNF- α), interleukin-1α, interleukin-1β, interleukin-6,
interleukin-8, dan granulositecoloni stimulating factor 
(GCsF).
 Kemudian seluruh sitokin, endotoksin daneksotoksin akan
menstimulasi sintesis prostaglandin yang akan terakumulasi
dengan
sintesis dan pelepasan metaloprotease dan komponen bioakti
f lainnya.
Prostaglandin akan menstimulasi kontraksi uterus sementara
metaloprotease akanmenyerang membran korioamnion yang
akan menyebabkan pecahnya membran.Metaloprotease akan
membentuk kolagen di serviks yang menyebabkan
terjadinyaperlunakan serviks
Persalinan prematur disebabkan akibat janin itu sendiri. Pada jan
in yangterinfeksi terjadi peningkatan kadar sekresi kortikotropi
n akibat peningkatan dari corticotropin releasing hormone
(CRH) dari hipotalamus janin dan juga produksi CRH
dari plasenta. Hal ini akan meningkatkan kadar produksi adren
al janin berupa peningkatan kortisol yang berhubungan
dengan peningkatan kadar prostaglandin
 DIAGNOSIS
• Tanda dan gejala klinis korioamnionitis meliputi
• Demam (suhu intrapartum > 100.4˚ F atau > 37,8˚ C)
• Takikardia ibu (>120x/menit)
• Takikardia janin (>160x/menit)
• Cairan ketuban berbau atau tampak purulen5.uterus teraba tegang
• Leukositosis ibu (leukosit 15.000-18.000 sel/mm3)Bila terdapat dua dari
enam gejala diatas ditemukan pada kehamilan, maka risikoterjadinya
neonatal sepsis meningkat.Gibbs, dkk mengemukakan gejala
dan tanda infeksi intrapartum yaitu suhuibu ≥ 37,8˚C dan 2 atau lebih
dari kondisi dibawah ini: takikardia ibu (>100 x/menit),takikardia janin
(>160 x/menit), nyeri uterus, cairan amnion berbau dan leukositosisibu
(>15.000 sel/mm
• Korioamnionitis seringkali bukan suatu gejala akut, namun merupakan
suatu proses kronis dan tidak menunjukkan gejala sampai persalinan
dimulai atau terjadi ketuban pecah dini. Bahkan sampai setelah
persalinan sekalipun pada wanita yang terbukti memiliki korioamnionitis
(melalui pemeriksaan histologis atau kultur) dapat tidak ditemukan
tanda klasik diatas selain tanda-tanda prematuritas
 Terdapat beberapa metode laboratorium lain yang diharapkan dapatm
embantu penegakkan diagnosis, beberapa diantaranya seperti
pemeriksaan serumCRP

• C-reative protein maternal, pemeriksaan esterase leukosit cairan

amnion, dan deteksi asam organik bakterial dengan kromatografi gas-
cairan
• Peningkatan kadar CRP memiliki spesifisitas yang tinggi untuk
diagnosis korioamnionitis. Kadar CRPrata-rata pada kehamilan adalah
0,7-0,9 mg/dl. Terdapat peningkatan sedikit selamapersalinan
• Pemeriksaan langsung dari cairan amnion dapat memberikan kriteria y
anglebih pasti dari korioamnionitis. Kombinasi pewarnaan Gram dan
kultur dari hasilamniosintesis merupakan metode diagnostik terbaik
• Ditemukannya bakteri grampositif memiliki nilai prediktif positif
( positif predictive value /PPV) 93,3%, sedangkanditemukannya gram
negatif memiliki nilai prediktif negatif 85,4% ( negatif predictivevalue
• NPV). Akurasi tes tergantung dari konsentrasi bakteri saat pengambilansa
mpel
•  Pada pasien dengan suspek korioamnionitis, kadar glukosa cairanamnion
yang rendah merupakan prediktor yang baik dari hasil positif kultur
cairanamnion namun merupakan prediktor yang buruk untuk
korioamnionitis secara klinis
• Ditemukannya leukosit esterase antigen pada cairan amnion memiliki
sensitivitas91% dan nilai PPV 95%.Deteksi asam organik bakteri dengan
menggunakan kromatografi gas-cairancukup sensitif namun memerlukan
alat yang rumit dan tidak praktis
• Hasil pemeriksaan mikroskopik yang menunjang diagnosis korioamnionitis
adalah ketika terlihat set leukosit mononuclear dan polimonorfonuklear
menginfiltrasiselaput korion. Sebelum 20 minggu hampir semua sel leukos
it polimorfonuklear adalah sel yang berasal dari ibu, sedangkan
selanjutnya merupakan respon inflamasidari janin
Dari pemeriksaan-pemeriksaan diatas tidak satupun yang cukup
sensitif danspesifik digunakan secara tersendiri terlepas dari gejala
dan tanda klinis untukmendiagnosis korioamnionitis.
Telah disebutkan sebelumnya bahwa terjadinya korioamnionitis
berhubungandengan ketuban pecah dini. Untuk mendiagnosa adanya
 ketuban pecah dapatdilakukan pemeriksaan inspekulo (untuk
melihat adanya genangan atau
rembesancairan amnion), nitrazin tes, tes daun pakis, tes evaporasi, 
USG, fluoresenintraamnonitik, tes diamin oksidase, fibronektin janin
dan pemeriksaan AFP padasekret vagina
 PENATALAKSANAAN
• Korioamnionitis diterapi antimikroba dan janin dilahirkan
tanpa memandangusia gestasi. 
• Antibiotika yang diberikan adalah antibiotika intravena 
berspektrum luas. Untuk sebagian besar kasus, cukup
digunakan antibiotika tunggal. Terdapatpenelitian yang
membuktikan bahwa pemberian antibiotika
intrapartum dibandingkandengan postpartum akan
menurunkan kejadian sepsis & pneumonia neonatal
danmorbiditas postpartum ibu. 
• Standar baku jenis pemberian antibiotika untukkorioamnioniti
s akut belum ada, banyak studi melakukan evaluasi terhadapp
emberian antibiotika. Terdapat studi yang merekomendasikan
pemberian
ampisilin(2 g setiap 6 jam) ditambah dengan gentamisin (1,0-
1,5mg/kg setiap 8 jam)
• Ampisilin diberikan sebagai pilihan pertama karena dapat
melintasi plasenta dengancepat (<30 menit)
• Regimen intravena yang direkomendasikan termasuk cefoxitin (4
X2gr),cefotetan (2x2gr), piperasilin atau mezlocilin (4x3-4gr),
ampisilin sulbaktam (4x3gr),tikarsilin/klavulanat (4x3gr).
• Pada kasus yang lebih berat misalnya pada sepsis dapat
diberikan terapi kombinasi yang terdiri dari penisilin atau
ampisilin,
• Aminoglikosidadan agen anaerob seperti klindamisin (3x900gr). 
Literatur lain menganjurkanpemberian gentamisin 5mg/kgBB/ha
ri dosis tunggal
• Pada korioamnionitis lama
pemberian antibiotika belum ada standar baku. Pemberian antib
iotika intravenadapat dilanjutkan hingga 48-72 jam bebas
demam, kemudian dilanjutkan denganantibiotika oral.
Kepustakaan lain menyarankan pemberian terapi parenteral
hingga1-2 hari postpartum, tanpa tambahan antibiotika oral
sesudahnya
• Pilihan cara persalinan pada kasus korioamnionitis sebaiknya pervaginam.J
• Jika persalinan tidak timbul spontan, maka dilakukan induksi persalinan,
baik denganmedikamentosa atau mekanik
• Persalinan perabdominam meningkatkan risikodemam postpartum akibat
infeksi (endometritis) pada ibu. Endometritis dapat
terjadipada 30% pasien dengan persalinan perabdominam, dibandingkan ri
siko padapersalinan pervaginam hanya 10%. Morbiditas ibu meningkat 5x li
pat padapersalinan perabdominam jika dibandingkan
dengan persalinan pervaginam
• Namunpersalinan perabdominam dapat dipertimbangkan bila persalinan
diperkirakan belumselesai dalam interval 12 jam setelah diagnosis
ditegakkan. Hal ini didasarkan
darisuatu penelitian yang mengemukakan tidak terdapatnya perbedaan pe
ningkataninfeksi neonatus jika jarak antara diagnosis korioamnionitis dan
persalinan < 12 jam,namun peningkatan kejadian infeksi neonatus setelah
interval 12 jam belum dapat dipastikan.
• Pada suatu penelitian persalinan perabdominam berhubungan dengan
meningkatnya kejadian atonia uteri, perawatan ibu di ICU dan skor apgar
 yang rendah
 MORBIDITAS DAN MORTALITAS AKIBAT
KORIOAMNIONITIS
• Korioamnionitis mengakibatkan mortalitas perinatal yang signifikan,
terutamapada neonatus dengan berat badan lahir rendah, dimana terjadi
peningkatan 3-4xlipat kematian perinatal diantara neonatus
dengan berat lahir yang rendah yangdilahirkan dari ibu yang menderita
korioamnionitis. Selain itu terjadi juga kejadian
respiratory distress syndrome
(RDS), perdarahan intraventrikular, dan sepsisneonatal atau meningitis
• Janin memiliki risiko tinggi terhadap kejadian
pneumonianeonatal ataupun kongenital akibat aspirasi cairan amion yang 
terinfeksi.Korioamnionitis dihubungkan dengan 20-40% kasus sepsis
neonatal dan pneumonia.Korioamnionitis merupakan penyebab nyata
terjadinya morbiditas maternal,namun jarang mengakibatkan mortalitas
maternal. Bakteremia dapat terjadi pada 2- 5% kasus.
•  Infeksi intrapartum meningkatkan risiko infeksi puerpuralis padapersalina
n pervaginam menjadi 13%, dibandingkan dengan persalinan yang
tidakdisertai dengan infeksi intrapartum hanya 6%
• Pada ibu korioamnionitis dapatmengakibatkan metritis, peritonitis, sepsis
hingga kematian ibu.
•TERIMA KASIH
• Preterm delivery is the chief problem in obstetrics today,
accounting for 70 percent of perinatal mortality and nearly half of
long-term neurologic morbidity.1,2 Approximately 10 percent of
all births are preterm, but most of the serious illness and death is
concentrated in the 1 to 2 percent of infants who are born at less
than 32 weeks of gestation and who weigh less than 1500 g.
Approximately 20 percent of preterm births are the result of a
physician's decision to bring about delivery for maternal or fetal
indications, and the remainder follow the spontaneous onset of
labor or rupture of the membranes.3 The rate of preterm delivery
has not decreased in the past several decades,4 but the survival
rate of infants delivered prematurely has increased, so that 80
percent of infants weighing 500 to 1000 g now survive. The
percentage of survivors with handicaps, however, has changed
little, so that the absolute number of surviving preterm infants
with handicaps has increased.2,5
• Bacterial infections within the uterus can occur
between the maternal tissues and the fetal membranes
(i.e., within the choriodecidual space), within the fetal
membranes (the amnion and chorion), within the
placenta, within the amniotic fluid, or within the
umbilical cord or the fetus (Potential Sites of Bacterial
Infection within the Uterus.). Infection of the fetal
membranes, as documented by histologic findings or
culture, is called chorioamnionitis; infection of the
umbilical cord is called funisitis; and infection of the
amniotic fluid is called amnionitis. Although the
placental villi may be preferentially involved in blood-
borne intrauterine infections such as malaria, bacterial
infection within the placenta (villitis) is rare.
• ORGANISMS

• Bacteria may invade the uterus by migration from the abdominal cavity through the fallopian tubes,

inadvertent needle contamination at the time of amniocentesis or chorionic-villus sampling,

hematogenous spread through the placenta, or passage through the cervix from the vagina.

• In women in spontaneous preterm labor with intact membranes, the most commonly identified

bacteria are Ureaplasma urealyticum, Mycoplasma hominis, Gardnerella vaginalis,peptostreptococci,

and bacteroides species — all vaginal organisms of relatively low virulence.20-25The organisms often

associated with genital tract infection in nonpregnant women, Neisseria gonorrhoeae and Chlamydia

trachomatis, are rarely found in the uterus before membrane rupture, whereas those most often

associated with chorioamnionitis and fetal infection after membrane rupture, group B streptococci

and Escherichia coli, are found only occasionally. Rarely, non–genital tract organisms, such as mouth

organisms of the genus capnocytophaga, are found in the uterus in association with preterm labor

and chorioamnionitis26; these organisms may reach the uterus through the placenta from the

circulation or perhaps by oral–genital contact. Nevertheless, most bacteria found in the uterus in

association with preterm labor are of vaginal origin. Although it has not been studied extensively,

intrauterine viral infection is probably not a common cause of spontaneous preterm delivery.27
• Vaginal organisms appear to ascend first into the choriodecidual space (Figure 1); in some women they

then cross the intact chorioamniotic membranes into the amniotic fluid, and some of the fetuses

ultimately become infected.28 Evidence of infection by this route comes from a study of 609 women

whose fetuses were delivered by cesarean section before membrane rupture (Figure 2FIGURE

2Frequency of Positive Cultures of Chorioamnionic Tissue as a Function of the Length of Gestation

among Women Presenting in Spontaneous Labor with Intact Fetal Membranes and Who Deliver Their

Infants by Cesarean Section.19-21,29–,).19-21,29 Half of the 121 women with positive membrane

cultures also had organisms in the amniotic fluid. When cultures from both sites were positive, the

organisms usually were the same. A much smaller portion of the fetuses had positive blood or

cerebrospinal fluid cultures at delivery. Women with positive membrane cultures had an active

inflammatory response, as indicated by histologic findings of leukocytosis in the membranes and the

presence of high concentrations of interleukin-6 in the amniotic fluid.29These findings may explain why

women with negative amniotic fluid cultures but with high cytokine concentrations in the amniotic fluid

are so resistant to tocolytic drugs. Apparently, these women often have an infection in the

chorioamnion, a location not amenable to culture before delivery.

• TIMING OF INFECTION
• Why very early, but not later, preterm deliveries are associated with intrauterine infection
has never been satisfactorily explained. It is also not clear when the bacteria ascend from
the vagina. However, recent evidence suggests that intrauterine infection may occur quite
early in pregnancy and remain undetected for months. For example, U. urealyticum has been
detected in some samples of amniotic fluid obtained for routine chromosomal analysis at 15
to 18 weeks of gestation. Most of these women had delivery at around 24 weeks.30-32
 Furthermore, high concentrations of interleukin-6 in the amniotic fluid at 15 to 20 weeks
were associated with spontaneous preterm delivery as late as 32 to 34 weeks.33,34
• In another example suggesting chronic infection, high fibronectin concentrations in the
cervix or vagina at 24 weeks (considered a marker of upper genital tract infection) were
associated with the development of chorioamnionitis an average of 7 weeks later.35 Finally,
some nonpregnant women with bacterial vaginosis have intrauterine colonization associated
with chronic plasma-cell endometritis.14,36 It is therefore possible that the intrauterine
colonization associated with spontaneous preterm labor is present at conception. It is
important to emphasize that most of these chronic upper genital tract infections remain
asymptomatic and are not associated with fever, a tender uterus, or peripheral-blood
leukocytosis.
• If intrauterine organisms are not cleared within four to eight weeks after
the expanding membranes seal the endometrial cavity near mid-
pregnancy, the infection often becomes symptomatic and results in
spontaneous preterm labor or rupture of the membranes. According to this
scenario, once the organisms already in the uterus are destroyed by the
mother's immune system, few new intrauterine infections occur as long as
the membranes remain intact, since organisms no longer ascend from the
vagina to the uterus. Although unproved, this hypothesis may explain the
frequent association between infection and early preterm delivery and the
relative rarity of intrauterine infection as women approach term. An
alternative hypothesis to explain this association is related to the timing of
the initiation of the fetal immune response. It may be that only with a
maturing immune system is the fetus able to generate the cytokine or
hormonal response necessary to initiate labor.
• BACTERIAL VAGINOSIS
• Women who have bacterial vaginosis, defined as a decrease in the
normally occurring lactobacillus species and a massive increase in other
organisms, including G. vaginalis, bacteroides species, mobiluncus
species, U. urealyticum, and M. hominis, have a doubled risk of
spontaneous preterm delivery.37-41 It is unknown whether bacterial
vaginosis can actually cause preterm labor and delivery if the organisms
do not ascend into the uterus. Bacterial vaginosis is associated with
increased concentrations of elastase, mucinase, and sialidase in the
vagina and cervix.42,43However, since the vast majority of women who
have early spontaneous preterm delivery have organisms in the uterus,
it may not be necessary to invoke the local action of vaginal infection as
the cause of the preterm delivery. It is more likely that bacterial
vaginosis is a marker of intrauterine colonization with similar
organisms.25,44,45 If vaginal infection alone (in the absence of
ascending infection) or infections such as periodontitis46 and urinary
tract infection47 actually cause spontaneous preterm delivery, the
mechanisms are unknown. One possible explanation is activation of a
local inflammatory response by cytokines or endotoxins carried in the
blood from the vagina to the uterus.
• MECHANISMS OF PRETERM DELIVERY DUE TO INFECTION
• Data from animal, in vitro, and human studies all provide a consistent picture of how
bacterial infection results in spontaneous preterm delivery (Figure 3FIGURE 3Potential
Pathways from Choriodecidual Bacterial Colonization to Preterm Delivery.).28,29,48-58
Bacterial invasion of the choriodecidual space, acting in part through release of endotoxins
and exotoxins, activates the decidua and the fetal membranes to produce a number of
cytokines, including tumor necrosis factor α, interleukin-1α, interleukin-1β, interleukin-6,
interleukin-8, and granulocyte colony-stimulating factor.28,29,48-58 Furthermore,
cytokines, endotoxins, and exotoxins stimulate prostaglandin synthesis and release and also
initiate neutrophil chemotaxis, infiltration, and activation, culminating in the synthesis and
release of metalloproteases and other bioactive substances. The prostaglandins stimulate
uterine contractions while the metalloproteases attack the chorioamniotic membranes,
leading to rupture. The metalloproteases also remodel the collagen in the cervix and soften
it.57-59
• Other pathways may have a role as well. For example, prostaglandin dehydrogenases in
chorionic tissue inactivate prostaglandins produced in the amnion, preventing them from
reaching the myometrium and causing contractions.60-62 Chorionic infection decreases the
activity of these dehydrogenases, allowing increasing quantities of prostaglandins to reach
the myometrium. Another pathway by which infection may cause preterm delivery involves
the fetus itself. In fetuses with infections, increases in both fetal hypothalamic and
placental production of corticotropin-releasing hormone cause an increase in fetal
corticotropin secretion, which in turn increases fetal adrenal production of cortisol. The
increase in cortisol secretion results in increased production of prostaglandins.63 Also,
when the fetus itself is infected, the fetal production of cytokines is increased and the time
to delivery is markedly decreased.64 However, the relative contributions of the maternal
and the fetal compartments to the overall inflammatory response are unknown
• MARKERS OF INFECTION
• Intrauterine infection is often chronic, and it is usually asymptomatic until labor begins or the membranes
rupture. Even during labor, most women who are later demonstrated (by histologic findings or culture) to have
chorioamnionitis have no symptoms other than preterm labor — no fever, abdominal pain, or peripheral-blood
leukocytosis, and there is usually no fetal tachycardia.65Therefore, identifying women with intrauterine
infections is a major challenge. Substances found in abnormal quantities in amniotic fluid and at other sites in
women with intrauterine infection are listed in Table 1TABLE 1Markers of Intrauterine Infection in Pregnant
Women..66
• The best-studied site of infection is the amniotic fluid. As well as containing bacteria, amniotic fluid from
women with intrauterine infections has lower glucose concentrations, higher white-cell counts, and higher
concentrations of complement C3 and various cytokines than fluid from uninfected women.29,67,68 However,
detecting bacteria or measuring cytokines and other analytes in amniotic fluid requires amniocentesis, and it is
not clear that amniocentesis improves the outcome of pregnancy, even in women with symptoms of preterm
labor. At present, it is not appropriate to obtain amniotic fluid routinely to test for intrauterine infection in
women who are not in labor.
• Positive results on tests of vaginal secretions for bacterial vaginosis, whether done by Gram's staining69 or by
the use of Amsel's criteria (homogeneous vaginal discharge, white cells ringed by bacteria, an amine odor
when vaginal fluid is combined with potassium hydroxide, and pH above 4.5),70 are associated with
intrauterine infection and predict preterm delivery.37-41 In women with preterm labor and asymptomatic
women, a positive result on the test of vaginal or cervical secretions for fibronectin, a protein of the placental
membranes, not only is the best predictor of spontaneous preterm delivery, but also is strongly associated with
subsequent chorioamnionitis and neonatal sepsis.35,71-73 It is believed that intrauterine infection disrupts the
extracellular choriodecidual basement membrane, causing leakage of this protein into the cervix and vagina.
72,73
• In women with symptoms of preterm labor, high concentrations of many cytokines
in the vaginal or cervical secretions, including tumor necrosis factor α, interleukin-
1, interleukin-6, and interleukin-8, are associated with early preterm delivery.74,75
 In women receiving routine prenatal care, high cervical concentrations of
interleukin-6 also predict subsequent preterm delivery and add to the predictive
value of measurements of fibronectin.76 However, other than testing for bacterial
vaginosis, no vaginal or cervical test is commonly used to predict intrauterine
infection.
• A short cervix, as determined by ultrasonography, correlates with several markers
of infection and chorioamnionitis.77,78 Although a short cervix might facilitate the
ascension of bacteria into the uterus, it is also likely that in some women, the cervix
shortens in response to an upper genital tract infection that has already occurred.
However, since an early preterm delivery due to infection may be indistinguishable
from one due to a structurally inadequate cervix, it remains uncertain whether the
length of the cervix shortens before or after a silent uterine infection.
• Women with symptoms of preterm labor who later have a preterm delivery have high serum
concentrations of interleukin-6, interleukin-8, and tumor necrosis factor α.79 Among women without
symptoms of preterm labor who are screened routinely, granulocyte colony-stimulating factor is the only
cytokine whose circulating concentrations in serum have been found to be high before the onset of
preterm labor.80 Noncytokine markers of infection include high serum C-reactive protein and ferritin
concentrations.81-83 In women receiving routine prenatal care, low serum ferritin concentrations are
indicative of low iron stores, but high serum ferritin concentrations appear to represent an acute-phase
reaction and predict preterm delivery. Serum ferritin concentrations also double within a week after
membrane rupture, probably indicating progressive intrauterine infection.84 High cervical
concentrations of ferritin also predict subsequent spontaneous preterm delivery.85
• Among the markers of intrauterine infection, bacterial vaginosis and a history of early preterm delivery
can be determined before pregnancy. Before 20 weeks of gestation, bacterial vaginosis, high
concentrations of fibronectin in the vaginal fluid,86 and a short cervix have all been associated with
chronic infection. Soon after mid-pregnancy, in women not in labor, high cervical or vaginal fibronectin
concentrations, a short cervix, high concentrations of several cytokines in the vaginal or cervical fluid,
and high serum granulocyte colony-stimulating factor and ferritin concentrations have all been
associated with an increased risk of spontaneous preterm delivery. Finally, preterm labor between 20
and 28 weeks of gestation is itself highly correlated with intrauterine infection, and this relation is even
stronger among women with a short cervix, high cervical or vaginal fibronectin concentrations, or high
concentrations of various cytokines in the amniotic, cervical, or vaginal fluids or in the serum.
• Despite these correlations, none of these markers have been found useful in the development of
strategies to reduce prematurity or delay delivery among women with or without symptoms of labor,
except that women at high risk who have bacterial vaginosis may benefit from antibiotic treatment. For
this reason, measurements of the other markers in an effort to reduce the frequency of preterm delivery
are not indicated.
• TREATMENT OF INFECTION TO PREVENT PRETERM DELIVERY
• In the early 1970s, a prolonged course of tetracycline, beginning in the middle trimester, was found to reduce the frequency
of preterm delivery both in women who had asymptomatic bacteriuria and in those who did not.7 This treatment fell into
disuse, probably because of tetracycline-related tooth and bone dysplasias in the infants. The results of treatment with
erythromycin, targeting ureaplasma or mycoplasma in the vagina or cervix, have been mixed.87 It should be noted that
ureaplasma is part of the vaginal microflora in many women, and its presence in the lower genital tract, unlike its presence
in the upper genital tract, has not been associated with an increased risk of spontaneous preterm delivery.88
• In recent years, trials of prenatal treatment for the prevention of preterm delivery have focused on bacterial vaginosis, with
intriguing but mixed results.89-94 The overall results suggest that in women with a previous preterm delivery and with
bacterial vaginosis diagnosed in the second trimester, treatment for one week or more with oral metronidazole, and
perhaps with erythromycin, results in a significant reduction in the incidence of preterm delivery.89-91 There was no
significant reduction in preterm delivery when antibiotics were administered vaginally, when shorter courses of antibiotics
or antibiotic regimens not including metronidazole were used, or when the women treated were at low risk (usually defined
as not having had a prior preterm delivery).91-94
• For women with intact membranes and with symptoms of preterm labor, antibiotic treatment does not usually delay
delivery, reduce the risk of preterm delivery, or improve the neonatal outcome.95In these trials, the women were usually
treated with penicillin and cephalosporin derivatives or erythromycin. However, in two small, randomized trials, a prolonged
course of metronidazole plus ampicillin resulted in a substantial delay until delivery, an increase of 200 to 300 g in the mean
birth weight, a reduction in the incidence of preterm delivery, and in lower neonatal morbidity, as compared with placebo.
96,97 Because of our concern about the excessive use of antibiotics in pregnancy and the small samples in both studies, we
are reluctant to recommend changes in practice at this time.
• For women who present with preterm rupture of the membranes, preventing preterm delivery is not a reasonable goal.
However, there is substantial evidence that antibiotic treatment of these women for a week or more significantly increases
the time to delivery and reduces the incidence of chorioamnionitis and improves various measures of neonatal morbidity. 98
 Similarly, in women who test positive for group B streptococcus in the vagina, there is now evidence that penicillin
treatment during labor reduces the rate of neonatal group B streptococcal sepsis, but not that of spontaneous preterm
delivery.99
• CONCLUSIONS
• The recent increase in knowledge about infection and preterm
delivery has raised many questions and suggested new strategies for
prevention. It is not known how and when bacteria invade the uterus
and whether additional, as yet undocumented, infections with viruses,
protozoa, or bacteria other than those already described are involved
in preterm delivery.100 Having more information about the chronicity
of uterine infections both before and during pregnancy and the
mechanisms by which the mother and fetus respond to bacterial
infection is crucial to developing a better understanding of these
infections. Because chronic upper genital tract infections are largely
asymptomatic, more discriminating markers to identify women with
these infections for study and intervention are needed. Finally, a
deeper understanding of the relation between intrauterine infection
and spontaneous preterm delivery will permit the clinical investigation
of treatments to reduce spontaneous preterm delivery and its
associated long-term morbidity and mortality.