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CHORIOAMNIONITIS: WHAT IS THE EVIDENCE FOR CLINICAL MANAGEMENT?Juan M. Gonzalez, MD Assistant Professor Maternal-Fetal Medicine

Department of Ob/Gyn & RSUniversity of California, San Francisco

Disclosures

• No Financial Disclosures

Definition

• Chorioamnionitis

• Amnionitis• Intramamniotic infection

Pathogenesis

• Ascending of cervicovaginal flora• Facilitated by ROM

• Tranplacental• Listeria moncytogenes

• Iatrogenic • Amnio, CVS, fetal surgery

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Clin Perinatol. 2010 Jun;37(2):339-54.

EPIDEMIOLOGY

Preterm

• Intramamniotic infection with pPROM• Less than 27 weeks � 41 %• 28 to 36 weeks � 15 %

• Intraamniotic infection 1/3 of spontaneous preterm labor with intact membranes

Clin Obstet Gynecol. 1993 Dec;36(4):795-808.

Am J Obstet Gynecol. 2001 Nov;185(5):1130-6.

Term

• 2 to 4 % term deliveries

• 12 % in labor who undergo a cesarean delivery

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Risk Factors

• Low parity • Prolonged labor • Prolonged rupture of membranes • Multiple vaginal examinations in labor (consequence of longer labors)

• Internal fetal monitoring • Genital tract pathogens (STI, GBS, BV)

Microbiology

• Clinical intraamniotic infection • Bacteroides species (25 %)• G. vaginalis (24 %) • GBS (12 %)• Aerobic streptococci (13 %)• E. coli (10%)• Aerobic gram-negative rods (10 %)

J Infect Dis. 1982 Jan;145(1):1-8.

Microbiology

• 35 % of patients with clinical chorioamnionitisyield Mycoplasm hominis

J Infect Dis. 1983 Apr;147(4):650-3.

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Clinical Presentation

• Clinical chorioamnionitis

• Subclinical absence of clinical findings:• Most commonly presents as spontaneous preterm labor or pPROM

Clinical Chorioamnionitis

• Maternal fever (oral temp ≥ 38.0C or 100.4F) (all cases)

• At least two of the following: • wbc > 15k (70-90% of cases)• maternal tachycardia (> 100 bpm) (50-80% of cases)• fetal tachycardia (> 160 bpm) (50-80% of cases)• uterine tenderness or foul odor of the amniotic fluid (4-

25% of cases)

Clin Perinatol. 2010 Jun;37(2):339-54.

Test

Clinical parameters

Fever Temperature >100.4 F 95 – 100 sensitiveNewton ER. Clin Obstet Gynecol 1993;36:795

Maternal tachycardia > 100/min 50 – 80% sensitive

Fetal tachycardia >160/min 40 – 70% sensitive

Fundal tenderness Tenderness on palpation 4 – 25% sensitive

Vaginal discharge Foul-smelling discharge 5 – 22% sensitive

Amniocentesis

• Refractory to tocolytics

• pPROM to determine whether induction is indicated

• Discriminate between chorioamnionitis and other causes of fever and abdominal pain

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Amniocentesis TEST ABNORMAL FINDING COMMENT

Maternal white blood cell count (WBC)

≥15,000 cells/mm3 with preponderance of leukocytes

Labor and/or corticosteroids also may result in elevation of WBC

Amniotic fluid glucose ≤10 to 15 mg%

Excellent correlation with positive amniotic fluid culture and clinical infection

Amniotic fluid interleukin-6 ≥7.9 ng/mL

Excellent correlation with positive amniotic fluid culture and clinical infection

Amniotic fluid leukocyte esterase ≥1+ reaction

Good correlation with positive amniotic fluid culture and clinical infection

Gabbe 6th edition 2012

TEST ABNORMAL FINDING COMMENT

Amniotic fluid gram stain

Any organism in an oil immersion field

Allows id of particularly virulent organism: GBS. However, very sensitive to inoculum effect. Cannot id pathogens such as mycoplasmas.

Amniotic fluid culture

Growth of aerobic or anaerobic microorganism

Results are not immediately available

Blood cultures

Growth of aerobic or anaerobic microorganism

+ in 5% to 10% of patients; done in seriously ill pts or at risk for bacterial endocarditis, immunocompromised, or has a poor response to initial tx

Gabbe 6th edition 2012

Test

Amniotic fluid parameters

Culture Microbial growth Diagnostic gold-standard

Gram stainBacteria or white blood cells (>6/HPF)

24% sensitive, 99% specificRomero R, et al. Am J Obstet Gynecol 1993;169(4):839–51

Glucose level <15mg/dlAffected by maternal hyperglycemia 57% sensitive, 74% specificRomero R, et al. Am J Obstet Gynecol 1993;169(4):839–51

Interleukin 6 >7.9 ng/ml 81% sensitive, 75% specificRomero R, et al. Am J Obstet Gynecol 1993;169(4):839–51

White blood cell count >30/cubic mm 57% sensitive, 78% specificRomero R, et al. Am J Obstet Gynecol 1993;169(4):839–51

Leukocyte esterase Positive (dipsticks)85–91% sensitive, 95–100% specificRiggs JW, et al. Semin Perinatol 1998;22(4):251–9Hoskins IA, et al. Am J Perinatol 1990;7(2):130–2

Clinical Management

• Maternal bacteremia:3 – 12 % of infected patients

• Cesarean delivery is required: 8 % develop a wound infection 1 % develop a pelvic abscessIncrease risk of endomyometritis and venous thrombosis

Gabbe 6th edition 2012

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Clinical Management

• Three separate investigations show intrapartumtreatment is superior to treatment after delivery. • Decrease in bacteremia • Decrease pneumonia • Decrease in maternal fever and hospitalization

Sperling RS et al. Obstet Gynecol 70:861, 1987.

Gilstrap LC et al. Am J Obstet Gynecol 159:579, 1988.

Gibbs RS et al. Obstet Gynecol 72:823, 1988.

Clinical Management

• 2002 meta-analysis (N = 181) compared intrapartum versus postpartum antibiotic therapy

• Intrapartum: • Reduction in neonatal sepsis (RR 0.08; CI 0.00 - 1.44)

• Pneumonia (RR 0.15; CI 0.01 – 2.92)

Hopkins L, Cocharane Database Syst Rev 2002

Regimen

• Antibiotic should be initiated as soon as Dx is made

• Administer broad spectrum antibiotics to cover: • Beta-lactamase producing aerobes • Anaerobes

• Main goal is to target GBS and E.coli

Regimen

• Ampicillin (2 g every 6 hours) or penicillin (5 million units every 6 hours)

plus • Gentamicin (1.5 mg/kg every 8 hours or 7 mg/kg/ideal body weight every 24 hours)

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Other Regimens

• Ampicillin-sulbactam• 3 grams intravenously every six hours

• Ticarcillin-clavulanate• 3.1 grams intravenously every four hours

• Cefoxitin• 2 grams intravenously every six hours

Regimen • Penicillin-allergic patients

• Substitute ampicillin for:

• Vancomycin 1 gram every 12 hours • If GBS+ and Clinda resistant/resistance unknown: Vancomycin /Gentamicin

OR

• Clindamycin 900 mg every 8 hours • If GBS-negative or Clinda-sensitive GBS: Clindamycin /Gentamicin

Regimen

Chorioamnionitis and Cesarean delivery:

• If Amp/Gent or Vanco/Gent used • add Clindamycin

or • Metronidazole

(ideally prior to skin incision) for anaerobic coverage

Duration Postpartum

• Post-partum management if vaginal delivery: • antibiotics are continued for one dose after delivery unless the

woman is diagnosed with endometritis

No difference in treatment failure or infection-related complications in RCT evaluating:

• single postpartum dose of antibiotics (Amp/Gent in study)

versus

• continuing until 24 hours afebrile postpartum

Edwards et al. Obstet Gynecol 102:957, 2003.

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Duration Postpartum • Post-partum management of chorioamnionitis if Cesarean

delivery: • If Amp/Gent or Vanco/Gent used

• add Clindamycin or

• Metronidazole

Edwards’ study included vaginal delivery and cesarean.

Underpowered to compare single-dose vs. continued dose just including Cesarean.

Given the high risk of endometritis in the setting of chorioamnionitis and Cesarean, continue antibiotics until 24 hours afebrile postpartum

Edwards et al. Obstet Gynecol 102:957, 2003.

Regimen

• There is NO evidence for oral antibiotics after discontinuation of parental therapy.

Dinsmoor MJ et al. Obstet Gynecol 1991; 77:60.

Antipyretics

• Maternal fever + fetal acidosis confers a 12.5% risk of neonatal encephalopathy (OR 94, 95 % CI 29 - 307)

• Independent effect:• Fever OR 8.1, 95 % CI 3.5 - 18.6• Neonatal acidosis OR 11.5, 95 % CI 5.0 – 26.5

Impey LW et al Am J Obstet Gynecol 2008; 198:49.

Route of Delivery

• Bactericidal concentrations in fetus one-half to one hour after infusion

• Average time between diagnosis and delivery is 3 to 5 hours

• No evidence that duration of infection correlates with outcomes

Gibbs RS et al Am J Obstet Gynecol 1991; 164:1317

Gilstrap LC 3rd et al Obstet Gynecol Clin North Am 1989; 16:373

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Rouse DJ et al Am J Obstet Gynecol 2004; 191:211

Rouse DJ et al Am J Obstet Gynecol 2004; 191:211

• Prolonged first or second stage of labor has been associated with an increased risk of chorioamnionitis

• Whether this relationship is causal is unclear �evolving chorioamnionitis may predispose to longer labor

• Neither chorioamnionitis nor its duration should be an indication for cesarean delivery

ACOG Number 1, March 2014

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Short-Term Outcomes

• Case-control study (N = 67) microbiologically confirmed clinical chorioamnionitis at term.

• Pneumonia 4 %• Neonatal bacteremia 4 %• No difference in low Apgar scores

Yoder RP et al Am J Obstet Gynecol.145:695 1983.

Short-Term Outcomes

• Among preterm neonates those with chorioamnionitis had higher:

• Perinatal death (13 % vs 3 %, P < .05)• RDS (34 % vs 16 %, P < .01)• Infection (17 % vs 7 %, P < .05)

Garite TJ Obstet Gynecol. 59:539-545 1982.

Short-Term Outcomes

• More likely to require cesarean

• Uterine dysfunction • Inadequate uterine response to oxytocin• Abnormal labor progress

Creasy and Resink 7th Edition 2014

Long-Term Outcomes

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Long-Term Outcomes Diagnosis N RR (95% CI)

PRETERM INFANTS

Cerebral Palsy

Clinical chorioamnionitis 11 1.9 (1.4-2.5)

Histologic chorioamnionitis 5 1.6 (0.9-2.7)

Cystic Periventricular Leukomalacia

Clinical chorioamnionitis 6 3.0 (2.2-4.0)

Histologic chorioamnionitis 7 2.1 (1.5-2.9)

CI, confidence interval; RR, relative risk.

Grether JK, Nelson KB JAMA278:207, 1997; Wu YW, Colford JM Jr JAMA284:1417, 2000.

Creasy and Resink 7th edition 2014.

Long-Term Outcomes

Diagnosis N RR (95% CI)

TERM INFANTS

Cerebral Palsy

Clinical chorioamnionitis 2 4.7 (1.3-16.2)

Histologic chorioamnionitis 1 8.9 (1.9-40)

CI, confidence interval; RR, relative risk.

Grether JK, Nelson KB JAMA278:207, 1997; Wu YW, Colford JM Jr JAMA284:1417, 2000.

Creasy and Resink 7th edition 2014.

Prevention

• Ineffective:• Chlorhexidine vaginal washes during labor1

• Antepartum treatment of bacterial vaginosis 2

• Broad-spectrum antibiotics in patients with preterm labor but intact membranes3

Rouse DJ et al Am J Obstet Gynecol. 176:617 1997. 1

Carey JC et al N Engl J Med. 342:534 2000. 2

Egarter C et al Obstet Gynecol. 88:303 1996. 3

Prevention

• Intrapartum prophylaxis to prevent neonatal GBS sepsis decrease chorioamnionitis

• Screening based strategy versus risk-based

Locksmith GJ et al Am J Obstet Gynecol. 180:416 1999.

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Prevention

• Active management of laborLopez-Zeno JA et al N Engl J Med. 326:450 1992.

• Induction of labor after PROM at term Mozurkewich EL et al Am J Obstet Gynecol. 89:1035 1997.

• Prophylactic antibiotics in selected patients with pPROM

Mercer BM Lancet. 346:1271 1995.

Prevention

• Largest randomized study found induction with oxytocin induction in PROM • Reduced:

• the time interval between premature rupture of membranes and delivery

• chorioamnionitis• postpartum febrile morbidity• neonatal antibiotic treatments

• Without increasing cesarean deliveries or neonatal infections

ACOG PB Number 107, August 2009.Hannah ME et al N Engl J Med 1996; 334:1005–10.

Prevention • Intravaginal PGE2 for IOL with PROM appears to be safe

and effective

• Randomized study IOL with PROM at term, only 1 dose of intravaginal misoprostol was necessary for successful labor induction in 86%

• No evidence that use of either prostaglandin increases the risk of infection in women with ROM

• Insufficient evidence to guide on use of mechanical dilators in ruptured membranes.

ACOG PB Number 107, August 2009.

Ray DA, Garite TJ. Am J Obstet Gynecol 1992;166:836–43.Sanchez-Ramos L et al Obstet Gynecol 1997;89:909–12.

Prevention • Meta-analysis (N = 6,814) PROM at term compared:

• IOL with prostaglandins or oxytocin • expectant management

• In patients which underwent IOL significant reduction in the risk of:• chorioamnionitis• endometritis• number of neonates requiring admission to NICU

Dare MR et al Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005302.

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Summary • Chorioamnionitis is polymicrobial

• results from migration of cervicovaginal flora through the cervical canal

• Other causes include transplacental infection • bacteremia • invasive procedures

• Maternal fever ≥100.4 F. • Clinical diagnosis is strengthened by risk factors for the disease

and excluding sources of fever • Nonspecific clinical signs: leukocytosis, maternal and fetal

tachycardia, uterine tenderness, malodorous amniotic fluid

Tita, A et al Clin Perinatol. 2010;37(2):339-354.

Summary

• Amniocentesis may be helpful in cases of diagnostic uncertainty

• Chorioamnionitis may impair myometrialcontractility �can result:• labor abnormalities• need for cesarean delivery (with higher rate of complications)

• postpartum hemorrhage

Tita, A et al Clin Perinatol. 2010;37(2):339-354.

Summary

• Broad spectrum antibiotics should be started at diagnosis to minimize maternal and fetal morbidity.• Vaginal delivery: a single dose of antibiotics after delivery

• Cesarean section: afebrile for at least 24 hours

Tita, A et al Clin Perinatol. 2010;37(2):339-354.

Summary

• In the setting of chorioamnionitis, prompt induction or augmentation of labor• cesarean delivery reserved for standard obstetrical indications

• Immediate cesarean in the setting reassuring intrapartum fetal testing, adequate progress of labor, and administration of antibiotics does not improve neonatal or maternal outcome.

• Adverse neonatal outcomes associated with chorioamnionitis

Tita, A et al Clin Perinatol. 2010;37(2):339-354.