ChorioamnionitisTrevor Quiner MD, MSc

Disclosure Statements

I have no relevant financial relationships to disclose or conflicts of interest to resolve.

I will not discuss any unapproved or off-label, experimental or investigational use of a product, drug or device.

Objectives

1) Identify and diagnose chorioamnionitis using the traditional criteria as well as understand and apply the diagnostic criteria for intraamniotic infection or inflammation.

2) Understand the importance of and evidenced-based methods to treat chorioamnionitis to improve maternal and neonatal outcomes.

3) Identify gaps in our understanding and priorities in research concerning intraamniotic infection.

Definition(s) of Chorioamnionitis

• Variably referred to as: clinical chorioamnionitis, intraamniotic infection, intrauterine infection.

• Histological chorioamnionitis refers to the microscopic evidence of inflammation/infection of fetal membranes and placenta. Funisitis is also a histopathological diagnosis with inflammation/infection of the umbilical cord.

• Clinical chorioamnionitis has been defined differently by different studies. It has been generally accepted to be defined as maternal fever (>38.0 C) with two or more of the following:

• Maternal tachycardia• Fetal tachycardia• Fundal tenderness• WBC >15,000• Presence of purulent discharge from uterus.

Clinical Diagnosis of Chorioamnionitis

• The symptoms and signs of chorioamnionitis have varying degrees of sensitivity. A combination of maternal fever and two other signs/symptoms is more specific.

Clinical Parameter Sensitivity

Fever (>38.0 twice or >38.3 once) 95-100%

Maternal tachycardia (>100bpm) 50-80%

Fetal tachycardia (>160bpm) 40-70%

Fundal tenderness 4-25%

Vaginal discharge 5-22%

Maternal Leukocytosis 70-90%

Adapted from Tita et al Clin Perinatol. 2010 Jun

Amniotic Fluid InvestigationTest Characteristics

Culture Diagnostic gold-standard

Gram stain (>6 bacteria/HPF) 24% sensitive, 99% specific

Glucose level (<15mg/dL) 57% sensitive, 74% specific

Interleukin 6 (>7.9 ng/ml) 81% sensitive, 75% specific

Matrix Metalloproteinase (positive) 90% sensitive and 80% specific

White blood cell count (>30/cubic mm) 57% sensitive, 78% specific

Leukocyte esterase (positive) 85–91% sensitive, 95–100% specific

Adapted from Tita et al Clin Perinatol. 2010 Jun

Risk FactorRelative

RiskProlonged membrane rupture

≥ 12 hours 5.8≥ 18 hours 6.9

Prolonged laborSecond stage > 2 hours 3.7Active labor > 12 hours 4.0

Multiple digital exams (≥ 3 exams) 2-5Nulliparity 1.8GBS colonization 1.7-7.2Bacterial vaginosis 1.7Alcohol and tobacco use 7.9Meconium-stained amniotic fluid 1.4-2.3Internal monitoring 2.0Epidural anesthesia 4.1

Adapted from Tita et al Clin Perinatol. 2010 Jun

Risk factors • Risk factors are primarily

related to factors that prolong labor, interrupt the natural barriers to ascension of bacteria from the genital tract, and increase the burden of pathogenic bacteria.

Vaginal Exams

• There is an association with increased vaginal exams and women who develop intrapartum fevers. This is without correction for length of labor.

• There were several large prospective studies that identified independent risk factors for intrapartum/antepartum infection. These analyses showed increased risk with increased length of labor, increased length of ruptured membranes, increased cervical exams, and internal monitor placement but did not control for length of labor when identifying other risk factors.

• Cahill et al 2012. Controlled for length of labor.Cahill et al. Obstetrics & Gynecology. 119. June 2012.

Mechanical Cervical Ripening

Heinemann et al. American Journal of Obstetrics and Gynecology, 199(2) 2008.

Mechanical Cervical Ripening

Heinemann et al. American Journal of Obstetrics and Gynecology, 199(2) 2008.

Mechanical Cervical Ripening

Heinemann et al. American Journal of Obstetrics and Gynecology, 199(2) 2008.

Pathogenic Organisms

Sperling et al. J Infect Dis. 1988

Genital Mycoplasms• Ureaplasma urealyticum is the organism

most commonly isolated from the amniotic fluid in PTL and PPROM. It has been shown to be associated with an increase in a variety of inflammatory markers in amniotic fluid and cord blood.

• Intraamniotic infection with Ureaplasma is associated with bronchopulmonary dysplasia at 28 and 36 days of life.

• Ureaplasma serum positive neonates had 2.3-fold increased risk of IVH >/=3.

• Infants with positive Ureaplasma cultures had a significantly higher risk (OR 3.1; 1.3-7.1) of poor psychomotor development index score and abnormal neurological outcome (OR 4.8; 1.7-13.8)/cerebral palsy (OR 4.8; 1.4-16.4)

Yoon et al. Am J Obstet Gynecol. 1998

Chorioamnionitis Related Outcomes

• MFMU cesarean registry analysis of 16,650 primary cesarean sections over a two year period at 13 university sites. 1,965 cases of chorioamnionitis were diagnosed and analyzed to elucidate the effects on the risk of adverse outcomes.

• The effect of duration of chorioamnionitis prior to delivery was analyzed for each maternal and neonatal adverse outcome.

Maternal Adverse Outcomes Related to Chorioamnionitis.

Rouse et al. American Journal of Obstetrics and Gynecology (2004)

Fetal-neonatal Adverse Outcomes Related to Chorioamnionitis.

Rouse et al. American Journal of Obstetrics and Gynecology (2004)

Cerebral Palsy and Chorioamnionitis• Increased risk of cerebral palsy with clinical (OR 2.41; 1.52-3.84) and

histologic (OR 1.83; 1.17-2.89) chorioamnionitis.• This increased risk remains elevated in term deliveries.

Shatrov et al. Obstetrics & Gynecology. 2010

Fetal Inflammatory Response Syndrome

• Originally defined by IL-6 concentrations in cord blood.

• The presence of FIRS increases the risk of adverse effects related to chorioamnionitis, decreases the latency to delivery, and increases the risk of long-term adverse effects.

From Kim et al. American Journal of Obstetrics and Gynecology, 213. 2015

Fetal Inflammatory Response Syndrome

From Gomez et al. American Journal of Obstetrics and Gynecology, 179. 1998

Delivery in Chorioamnionitis• While broad-spectrum antibiotics can attain adequate

bactericidal intraamniotic levels and fetal tissue levels within an hour after administration, there have only been a few reported cases of “sterilization” of the amniotic cavity and only in very early, subclinical infections. This is likely in part due to the formation of bacterial biofilms in the amniotic cavity.

• Prompt delivery is necessary to evacuate the infected space remove the fetus from the infectious source.

• Mode of delivery should be determined by obstetrical indications and not by the presence or absence of infection.

• Chorioamnionitis is an indication for delivery even in preterm pregnancies.

From Kim et al. American Journal of Obstetrics and Gynecology, 213. 2015

Rouse et al. American Journal of Obstetrics and Gynecology (2004)

Neonatal Outcomes per hour of Chorioamnionitis

5-minute Apgar ≤3 OR 1.09 (1.00-1.16)Mechanical Ventilation OR 1.07 (1.01-1.12)

Maternal Outcomes per hour of Chorioamnionitis

Uterine Atony OR 1.03 (1.00-1.06)

Uterine DysfunctionSignificant increase in multiple adverse outcomes relating to myometrial dysfunction.• Increased risk of CD = OR 1.8• Increased risk of Hemorrhage OR

1.5-1.8• In one large study 12% of primary

cesarean deliveries were complicated by chorioamnionitis with the most common indication for CD being “failure to progress”.

Mark et al. Obstetrics & Gynecology. 95(6, Part 1):909-912, June 2000.

Cesarean Delivery in Chorioamnionitis• Surgical infection (superficial, deep, organ space, endometritis) risk significantly increased.

OR 2.24 (1.25–3.83)• Addition of a single dose of clindamycin or metronidazole reduces the risk of endometritis.• The evidence for continued antibiotics after delivery is not conclusive.

Shanks et al. Treatment Utility of Postpartum Antibiotics in Chorioamnionitis Study. Am J Perinatol 2016

Antibiotics

• A Cochrane Database from 2014 found 11 studies investigating timing, regimen, duration of antibiotics in chorioamnionitis. Overall the evidence was rated “low to very low” quality and few conclusions were made. But what evidence available supports the recommendation for prompt initiation of broad spectrum antibiotics prior to delivery for improved maternal and fetal outcomes.

• The traditional choice of antibiotics has been a combination of ampicillin and gentamicin with the thought to have coverage over GBS and gram negative rods which were the most commonly identified pathogens. Clindamycin has been added for women undergoing cesarean delivery to cover anaerobes. Other studied broad spectrum antibiotic regimens seem to be effective.

Gentamicin Dosing

• Single-dose gentamicin (5.1mg/kg/24hr) compared with traditional gentamicin dosing (1.5mg/kg/8h) showed higher peak levels, less time above potential toxic levels, and less peak time lost to the post-antibiotic effect.

• No nephrotoxic or ototoxic effects were seen in infants exposed to single-dose gentamicin in utero.

• Single-dose gentamicin is more cost effective.

Maternal Serum Levels Fetal Serum Levels

Locksmith. Obstet Gynecol 2005.Ward et al. Clinical Obstetrics and Gynecology 2008.Ward, K., & Theiler, R. N. Clinical Obstetrics and Gynecology(2008).

Timing of Antibiotics

• In one study of 257 women with culture proven chorioamnionitis, initiation of antibiotics (penicillin and gentamicin) postpartum as opposed to intrapartum was associated with increased risk of neonatal sepsis (19.6% vs. 2.8%; p<0.001).

• In a small RCT of women with chorioamnionitis 26 women received intrapartum antibiotics and 19 women received antibiotics after cord clamping. The intrapartum group was noted to have significantly decreased neonatal sepsis (0 vs 21%, p=0.03), decreased postpartum stay, fewer febrile days, and lower peak temperatures (p=0.05).

Maternal Fever Reduction

• One cohort study showed an increased risk (OR 7.4; 2.4-21.9) of neonatal encephalopathy with maternal fever.

• Use of antipyretics and other fever reducing methods may be of benefit.

• A meeting of experts in obstetrics and neonatology met to form a proposal for greater uniformity in nomenclature, diagnosis and treatment of the maternal-fetal/neonate dyad with an effort to minimize over-diagnosis and over-treatment in order to improve outcomes and decrease over-utilization of medical resources.

Terminology Features and Comments

Isolated maternal fever“Documented fever”

Maternal oral temperature 39.0°C or greater (102.2°F) on any one occasion is documented fever. If the oral temperature is between 38.0°C (100.4°F) and 39.0°C (102.2°F), repeat the measurement in 30 minutes; if the repeat value remains at least 38.0°C (100.4°F), it is documented fever.

Suspected Triple I Fever without a clear source plus any of the following:1) baseline fetal tachycardia (greater than 160 beats per min for 10 min or longer, excluding accelerations, decelerations, and periods of marked variability)2) maternal white blood cell count greater than 15,000 per mm3 in the absence of corticosteroids3) definite purulent fluid from the cervical os

Confirmed Triple I All of the above plus:1) amniocentesis-proven infection through a positive Gram stain2) low glucose or positive amniotic fluid culture3) placental pathology revealing diagnostic features of infection

Adapted from Higgins et al. Obstetrics & Gynecology, 127(3) 2016

Intrauterine Infection or Inflammation

Neonatal Antibiotics

• The CDC, AAP, and NIHCE all recommend empiric antibiotic treatment of “well-appearing” neonates exposed to chorioamnionitis.

• There are potential risks to unneeded antibiotic administration including nosocomial infection with resistant organisms from NICU admission, alteration of gut microbiota, and adverse effects on attachment and breastfeeding establishment.

• This workshop suggests modification of current guidelines for well-appearing neonates born to women with suspected or confirmed triple I.

• Sepsis calculator www.dor.Kaiser.org/external/DORExternal/research/InfectionProbabilityCalculator.aspx

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