Chorioamnionitis: from pathogenesis to treatment

  • M.J. Czikk
    Correspondence
    Corresponding author: M. J. Czikk, Maternal Fetal Medicine, Department of Obstetrics and Gynaecology, Mount Sinai Hospital, c/o Dr Kellie E Murphy, 700 University Avenue, Room 3278, Toronto, ON M5G 1Z5, Canada
    Affiliations
    Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
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  • F.P. McCarthy
    Affiliations
    Anu Research Centre, Department of Obstetrics & Gynaecology, University College Cork, Cork, Ireland
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  • K.E. Murphy
    Affiliations
    Department of Obstetrics and Gynaecology, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
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      Abstract

      Chorioamnionitis refers to inflammation of the amniochorionic membrane, and is a significant cause of maternal and neonatal morbidity. Chorioamnionitis most often occurs as a result of ascending infection, and is commonly associated with premature rupture of the membranes. Chorioamnionitis is generally the result of a polymicrobial infection, with Ureaplasma urealyticum, Mycoplasma hominis and Gramnegative anaerobes being frequent causative organisms. The mainstay of treatment includes antimicrobial agents, antipyretics, expedition of delivery and supportive care. Further research is required to identify mechanistic pathways and early biomarkers that accurately predict women at higher risk of adverse maternal and neonatal outcomes, and that can thus lead to the development of additional treatment and prevention strategies.

      Keywords

      Introduction

      Chorioamnionitis (or intra-amniotic infection) refers to inflammation of the amniochorionic membrane (both chorion and amnion). It is estimated to be present in approximately 2–4% of term pregnancies [
      • Newton ER
      Chorioamnionitis and intraamniotic infection.
      ], and in approximately 40–70% of women who deliver prematurely [
      • Goldenberg RL
      • Hauth JC
      • Andrews WW
      Intrauterine infection and preterm delivery.
      ,
      • Hillier SL
      • Martius J
      • Krohn M
      • Kiviat N
      • Holmes KK
      • Eschenbach DA
      A case‐control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.
      ]. Chorioamnionitis can be defined both clinically, on the basis of maternal symptoms including fever, abdominal pain, abnormal vaginal discharge and leukocytosis [
      • Menon R
      • Taylor RN
      • Fortunato SJ
      Chorioamnionitis—a complex pathophysiologic syndrome.
      ], and histologically, with evidence of inflammation and necrosis throughout the chorionic plate and amnion [
      • Redline RW
      • Faye‐Petersen O
      • Heller D
      • Qureshi F
      • Savell V
      • Vogler C
      Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.
      ]. Chorioamnionitis is associated with significant maternal and neonatal morbidity and mortality. Neonatal morbidities include an increased risk of neonatal sepsis and pneumonia [
      • Alexander JM
      • McIntire DM
      • Leveno KJ
      Chorioamnionitis and the prognosis for term infants.
      ]. Furthermore, chorioamnionitis may result in a fetal inflammatory response syndrome, which carries with it increased risks of periventricular leukomalacia, cerebral palsy [
      • Wu YW
      • Colford Jr, JM
      Chorioamnionitis as a risk factor for cerebral palsy: a meta‐analysis.
      ] and chronic lung disease [
      • Yoon BH
      • Romero R
      • Kim KS
      • et al.
      A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia.
      ]. The earlier the degree of prematurity, the higher the likelihood of detecting histological chorioamnionitis. One study found that, of those cases delivering at 21–24 weeks, 67% demonstrate evidence of histological infection and inflammation, as compared with 22% of those delivering at 33–36 weeks [
      • Mueller‐Heubach E
      • Rubinstein DN
      • Schwarz SS
      Histologic chorioamnionitis and preterm delivery in different patient populations.
      ]. In addition to these fetal and neonatal complications, chorioamnionitis can pose significant maternal risks. These include postpartum haemorrhage, uterine atony, increased risk of caesarean section, and rarer complications such as septic shock, adult respiratory distress syndrome and coagulopathies [
      • Hauth JC
      • Gilstrap 3rd, LC
      • Hankins GD
      • Connor KD
      Term maternal and neonatal complications of acute chorioamnionitis.
      ]. Caesarean section performed in the presence of intra-amniotic infection is associated with an increased risk of maternal blood transfusion, septic pelvic thrombophlebitis, pelvic abscess formation [
      • Rouse DJ
      • Landon M
      • Leveno KJ
      • et al.
      The maternal–fetal medicine units cesarean registry: chorioamnionitis at term and its duration—relationship to outcomes.
      ] and surgical site infections [
      • Tran TS
      • Jamulitrat S
      • Chongsuvivatwong V
      • Geater A
      Risk factors for postcesarean surgical site infection.
      ]. These complications result not only in significant maternal morbidity, but also in increased healthcare costs.

      Aetiology of Chorioamnionitis

      Chorioamnionitis occurs most often as a result of ascending bacteria from the vagina and cervix, and is most commonly seen as a secondary complication of prolonged rupture of the membranes [
      • Newton ER
      Preterm labor, preterm premature rupture of membranes, and chorioamnionitis.
      ]. Less common modes of transmission include haematogenous spread or transmission following an invasive procedure (i.e. amniocentesis, chorionic villous sampling or other fetal procedure). Various bacterial, viral and, rarely, fungal agents have been linked to the underlying pathogenesis of chorioamnionitis and preterm birth (PTB). Some of these commonly identified pathogens include Ureaplasma urealyticum, Chlamydia trachomatis, Neisseria gonorrhoea, Mycoplasma hominis, group B streptococcus and Trichomonas vaginalis [
      • Romero R
      • Espinoza J
      • Goncalves LF
      • Kusanovic JP
      • Friel L
      • Hassan S
      The role of inflammation and infection in preterm birth.
      ,
      • Goldman AS
      • Schmalstieg FC
      The pathogenesis of chorioamnionitis.
      ]. Additional bacteria include Gram-negative anaerobes, including Gardnerella vaginalis and Bacteroides spp. [
      • Sperling RS
      • Newton E
      • Gibbs RS
      Intraamniotic infection in low‐birth‐weight infants.
      ].
      Cultured specimens from patients with clinical chorioamnionitis most often reveal a polymicrobial infection, with the majority of women having at least two detectable pathogens. The frequency of isolation of certain pathogens in chorioamnionitis varies with the study and the type of tissue analysed. The most frequent isolates from placentas of preterm infants were U. urealyticum (47%) and G. vaginalis (26%) [
      • Hillier SL
      • Martius J
      • Krohn M
      • Kiviat N
      • Holmes KK
      • Eschenbach DA
      A case‐control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.
      ]. Similar microbiological isolates were detected in the amniotic fluid of women with intra-amniotic infection, with the most common organisms detected being U. urealyticum (47%), any Gram-negative anaerobe (38.4%), M. hominis (30.4%), Bacteroides bivius (29.5%) and G. vaginalis (24.5%) [
      • Sperling RS
      • Newton E
      • Gibbs RS
      Intraamniotic infection in low‐birth‐weight infants.
      ].
      Viruses may also play a role in chorioamnionitis. Multiple viruses, including cytomegalovirus, adenovirus, enterovirus, respiratory syncytial virus and Epstein–Barr virus, have been isolated from amniotic fluid [
      • Baschat AA
      • Towbin J
      • Bowles NE
      • Harman CR
      • Weiner CP
      Prevalence of viral DNA in amniotic fluid of low‐risk pregnancies in the second trimester.
      ]. Recently, investigators demonstrated that placental adenovirus infection was strongly associated with histological chorioamnionitis (75% vs. 36%; p 0.026) and PTB (41% vs. 21%; OR 2.6; 95% CI 1.4–5.1; p <0.002) [
      • Tsekoura EA
      • Konstantinidou A
      • Papadopoulou S
      • et al.
      Adenovirus genome in the placenta: association with histological chorioamnionitis and preterm birth.
      ]. Although these viruses have been isolated and implicated in cases of chorioamnionitis, supportive evidence for viruses, including Epstein–Barr virus and others, actually causing chorioamnionitis is very limited.
      Fungal organisms, including several species of Candida (Candida albicans, Candida tropicalis and Candida glabrata), have also been associated with chorioamnionitis [
      • Asemota OA
      • Nyirjesy P
      • Fox R
      • Sobel JD
      Candida glabrata complicating in vitro pregnancy: successful management of subsequent pregnancy.
      ,
      • Meizoso T
      • Rivera T
      • Fernandez‐Acenero MJ
      • Mestre MJ
      • Garrido M
      • Garaulet C
      Intrauterine candidiasis: report of four cases.
      ,
      • Barth T
      • Broscheit J
      • Bussen S
      • Dietl J
      Maternal sepsis and intrauterine fetal death resulting from candida tropicalis chorioamnionitis in a woman with a retained intrauterine contraceptive device.
      ]. These infections have been reported in women with in vitro fertilization pregnancies, in those with retained intrauterine contraceptive devices, following amniocentesis, and in those with prolonged rupture of membranes [
      • Asemota OA
      • Nyirjesy P
      • Fox R
      • Sobel JD
      Candida glabrata complicating in vitro pregnancy: successful management of subsequent pregnancy.
      ,
      • Morgan MA
      • Pippitt CH
      • Thurnau GR
      Antenatal diagnosis of candida chorioamnionitis.
      ,
      • Rode ME
      • Morgan MA
      • Ruchelli E
      • Forouzan I
      Candida chorioamnionitis after serial therapeutic amniocenteses: a possible association.
      ]. Only 0.8% of candidal vaginal infections actually ascend into the uterus, and even fewer result in acute chorioamnionitis [
      • Meizoso T
      • Rivera T
      • Fernandez‐Acenero MJ
      • Mestre MJ
      • Garrido M
      • Garaulet C
      Intrauterine candidiasis: report of four cases.
      ]. However, the complications of intra-amniotic fungal infection can be severe, with a 75% risk of prematurity being associated with candidal funisitis [
      • Meizoso T
      • Rivera T
      • Fernandez‐Acenero MJ
      • Mestre MJ
      • Garrido M
      • Garaulet C
      Intrauterine candidiasis: report of four cases.
      ]. Also, there are increased risks of mortality in immature/low-birthweight (<1500 g) infants with congenital systemic candidiasis [
      • Engelhart CM
      • van de Vijver NM
      • Nienhuis SJ
      • Hasaart TH
      Fetal candida sepsis at midgestation: a case report.
      ].
      Finally, there have been case reports of methicillinresistant Staphylococcus aureus causing chorioamnionitis, but there are no reports at the time of publication of chorioamnionitis associated with vancomycin-resistant Enterococcus. Methicillin-resistant S. aureus and possibly vancomycin-resistant Enterococcus infection should be considered in women with clinical chorioamnionitis refractory to treatment, as well as in those with recurrent or prolonged admission to hospital or who themselves are healthcare workers [
      • Fowler P
      Methicillin‐resistant staphylococcus aureus chorioamnionitis: a rare cause of fetal death in our community.
      ,
      • Geisler JP
      • Horlander KM
      • Hiett AK
      Methicillin resistant staphylococcus aureus as a cause of chorioamnionitis.
      ].
      Organisms such as Mycoplasma are typically low-virulence organisms, which may explain why women with histological chorioamnionitis often have no clinical symptoms. Despite multiple reports documenting the positive culture of bacteria and/or viruses from women with chorioamnionitis, the presence of bacteria and their products alone is not sufficient to induce chorioamnionitis. In addition to the presence of these bacteria/viruses, the elicited host immune response plays an integral role in determining outcomes, including clinical chorioamnionitis, PTB and premature preterm rupture of the membranes (PPROM) [
      • Steel JH
      • Malatos S
      • Kennea N
      • et al.
      Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor.
      ,
      • Romero R
      • Espinoza J
      • Kusanovic JP
      • et al.
      The preterm parturition syndrome.
      ]. Research is ongoing, including projects such as the Human Microbiome Project. This group works to further characterize the microbial communities found in the female genital tract, both in normal pregnancy and in pathological conditions such as chorioamnionitis (31st Annual Meeting of the Society for Maternal Fetal Medicine, Abstract 73) [
      • Zhou X
      • Brotman RM
      • Gajer P
      • et al.
      Recent advances in understanding the microbiology of the female reproductive tract and the causes of premature birth.
      ].

      Risk factors for Chorioamnionitis

      Apart from colonization with bacteria and viruses, there are several risk factors for the development of chorioamnionitis. As discussed above, prematurity and PPROM are commonly associated with chorioamnionitis. At term, risk factors include long duration of labour and rupture of membranes, and nulliparity [
      • Mi Lee S
      • Romero R
      • Lee KA
      • et al.
      The frequency and risk factors of funisitis and histologic chorioamnionitis in pregnant women at term who delivered after the spontaneous onset of labor.
      ]. Furthermore, women with pre-labour rupture of membranes at term who receive multiple digital vaginal examinations, have a prolonged labour or have meconium-stained liquor are at higher risk of developing chorioamnionitis [
      • Seaward PG
      • Hannah ME
      • Myhr TL
      • et al.
      International multicentre term prelabor rupture of membranes study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term.
      ].

      Diagnosis

      Chorioamnionitis can be diagnosed with the use of histological or clinical criteria. The clinical diagnosis is based on signs and symptoms of local or systemic infection. A common definition includes maternal pyrexia (fever >37.5–38°C) and one of the following: abdominal pain, uterine tenderness, foul vaginal discharge, maternal tachycardia (>100 beats/min), fetal tachycardia (persistent elevation of fetal heart rate >160 - beats/min) and an elevated maternal white blood cell count (>15 000 cells/mm3) [
      • Menon R
      • Taylor RN
      • Fortunato SJ
      Chorioamnionitis—a complex pathophysiologic syndrome.
      ,
      • Fahey JO
      Clinical management of intra‐amniotic infection and chorioamnionitis: a review of the literature.
      ,
      • Tita AT
      • Andrews WW
      Diagnosis and management of clinical chorioamnionitis.
      ]. The cut-off for maternal pyrexia varies across several studies, but more recent literature generally quotes a value for definition purposes of >38.0°C, to exclude the many women with a low-grade fever during labour unrelated to an infectious process.
      Chorioamnionitis can occur histologically, and is staged on the basis of specific criteria, with increasing neutrophil infiltration and the development of necrosis, amnion basement membrane thickening and chorionic microabscesses being seen with increasing disease severity [
      • Redline RW
      • Faye‐Petersen O
      • Heller D
      • Qureshi F
      • Savell V
      • Vogler C
      Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.
      ] (Fig. 1). In addition, the fetal inflammatory response may progress from chorionic/umbilical vasculitis (neutrophil infiltration in the chorionic or umbilical vessels) to necrotizing funisitis (inflammation of the connective tissue of the umbilical cord) [
      • Redline RW
      • Faye‐Petersen O
      • Heller D
      • Qureshi F
      • Savell V
      • Vogler C
      Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.
      ]. The clinical diagnosis of chorioamnionitis, however, is not always confirmed by histological or microbiological studies. In one study of 139 pregnancies with clinical findings of chorioamnionitis, histological examination of the placenta did not support the clinical diagnosis in approximately one-third of cases [
      • Smulian JC
      • Shen‐Schwarz S
      • Vintzileos AM
      • Lake MF
      • Ananth CV
      Clinical chorioamnionitis and histologic placental inflammation.
      ].
      Figure thumbnail gr1
      FIG. 1Photomicrographs of a normal chorionic plate (a) and a chorionic plate with severe acute chorioamnionitis (b). Note the extensive neutrophil infiltration throughout the entire chorionic plate in the placenta affected by acute chorioamnionitis. Original magnification ×250. Photomicrographs courtesy of Dr Sarah Keating.
      Chorioamnionitis, as defined by positive amniotic fluid cultures, is found in 36% of women with PPROM [
      • Carroll SG
      ]. Although amniocentesis with culture of the amniotic fluid is ideal for isolating bacteria, and is the reference standard for the purposes of diagnosis, this test is associated with a delay of at least 48 h for cultures, with no evidence of predictive value for potential maternal and neonatal outcomes. There is also a lack of good-quality trials to demonstrate that this approach reduces either maternal or neonatal morbidity. One study investigated the use of amniocentesis, placental swabs and neonatal skin swabs in the subsequent management of chorioamnionitis following delivery. There was a strong association between positive amniotic cavity culture results and clinical early-onset sepsis; however, there remains insufficient evidence to justify the routine performance or recommendation of amniocentesis for the purposes of diagnosis [
      • Carroll SG
      ,
      • Berger A
      • Witt A
      • Haiden N
      • Kretzer V
      • Heinze G
      • Pollak A
      Amniotic cavity cultures, blood cultures, and surface swabs in preterm infants—useful tools for the management of early‐onset sepsis?.
      ].
      The evidence supporting the use of blood cultures for the diagnosis of chorioamnionitis is also limited. It appears that the routine use of maternal blood cultures rarely provides information that justifies a change in clinical management when patients are treated in accordance with a specific antibiotic protocol [
      • Locksmith GJ
      • Duff P
      Assessment of the value of routine blood cultures in the evaluation and treatment of patients with chorioamnionitis.
      ]. Furthermore, there is no good-quality evidence to show the benefit of the use of high vaginal swabs in the diagnosis and management of chorioamnionitis. In fact, the Royal College of Obstetricians and Gynaecologists recommends that, in the management of PPROM, women should be observed for signs of clinical chorioamnionitis, and weekly high vaginal swabs should not be performed [
      • Carroll SG
      ].
      Several laboratory assessments have been investigated for their potential usefulness in the early prediction and diagnosis of chorioamnionitis. A low vaginal ‘pool’ amniotic fluid glucose measurement (<5 mg/dL) was shown to be a predictive but not sensitive marker for infection in women with PPROM [
      • Buhimschi CS
      • Sfakianaki AK
      • Hamar BG
      • et al.
      A low vaginal ‘pool’ amniotic fluid glucose measurement is a predictive but not a sensitive marker for infection in women with preterm premature rupture of membranes.
      ]. Similarly, several potential biomarkers of early chorioamnionitis have been identified, including interleukin-6, interleukin-8, C-reactive protein, matrix metalloproteinase-8, ferritin and placental alkaline phosphatase [
      • Menon R
      • Taylor RN
      • Fortunato SJ
      Chorioamnionitis—a complex pathophysiologic syndrome.
      ]. The reliability and effectiveness of these biomarkers have not been confirmed in clinical trials. Other biomarkers, such as fetal fibronectin, relaxin, thrombin–antithrombin complex and salivary proteases, have also been investigated, but appear to be more specific in the prediction of PTB or PPROM than of chorioamnionitis [
      • Menon R
      • Taylor RN
      • Fortunato SJ
      Chorioamnionitis—a complex pathophysiologic syndrome.
      ].
      As chorioamnionitis and intrauterine infection remain strong predictive markers of impaired cognitive and neurodevelopmental outcome [
      • Yoon BH
      • Romero R
      • Park JS
      • et al.
      Fetal exposure to an intra‐amniotic inflammation and the development of cerebral palsy at the age of three years.
      ,
      • Salafia CM
      • Minior VK
      • Rosenkrantz TS
      • et al.
      Maternal, placental, and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks’ gestation.
      ], much research has revolved around the use of proteomic technology to identify biomarkers that may be used in the accurate diagnosis and prediction of neonatal outcomes in women with intrauterine inflammation [
      • Buhimschi IA
      • Christner R
      • Buhimschi CS
      Proteomic biomarker analysis of amniotic fluid for identification of intra‐amniotic inflammation.
      ,
      • Gravett MG
      • Novy MJ
      • Rosenfeld RG
      • et al.
      Diagnosis of intra‐amniotic infection by proteomic profiling and identification of novel biomarkers.
      ,
      • Romero R
      • Espinoza J
      • Rogers WT
      • et al.
      Proteomic analysis of amniotic fluid to identify women with preterm labor and intra‐amniotic inflammation/infection: the use of a novel computational method to analyze mass spectrometric profiling.
      ]. Protein markers, including neutrophil defensin-1, defensin-2, calgranulin-A and calgranulin-C, have been associated with inflammation in the amniotic fluid and placenta. These have been correlated with stages of histological chorioamnionitis, grades of choriodeciduitis and amnionitis [
      • Buhimschi IA
      • Zambrano E
      • Pettker CM
      • et al.
      Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis.
      ]. Furthermore, they have been associated with an increased risk of neonatal sepsis [
      • Buhimschi CS
      • Bhandari V
      • Hamar BD
      • et al.
      Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.
      ]. Currently, proteomics is a research technique, and is not used in clinical practice; however, future development of this technology and other diagnostic tests may prove to be important in determining patients at high risk of adverse outcomes from suspected intra-amniotic infection and chorioamnionitis.
      In summary, owing to a lack of specific and sensitive tests that are safe for both mother and fetus, the diagnosis of chorioamnionitis is based predominantly on clinical signs and symptoms. Although amniocentesis is the most sensitive tool for culturing pathogens, its routine use is not recommended. The use of blood cultures, placental swabs and high vaginal swabs has yet to be shown to alter management and improve maternal and fetal outcome.

      Treatment

      Treatment of acute chorioamnionitis includes antimicrobial agents, antipyretics, expedition of delivery and management of additional symptoms. Despite the fact that chorioamnionitis is common, there is limited evidence to support one specific antibiotic regimen over another. The vast majority of studies, including several randomized controlled trials (RCTs), have used intravenous ampicillin 2 g every 6 h for coverage of Gram-positive organisms, intravenous gentamicin 1.5 mg/kg every 8 h for coverage of Gram-negative organisms, and intravenous clindamycin 900 mg every 8 h for additional coverage of anaerobes in the event of a caesarean section [
      • Locksmith GJ
      • Duff P
      Assessment of the value of routine blood cultures in the evaluation and treatment of patients with chorioamnionitis.
      ,
      • Duff P
      Antibiotic selection for infections in obstetric patients.
      ,
      • Gibbs RS
      • Dinsmoor MJ
      • Newton ER
      • Ramamurthy RS
      A randomized trial of intrapartum versus immediate postpartum treatment of women with intra‐amniotic infection.
      ,
      • Edwards RK
      • Duff P
      Single additional dose postpartum therapy for women with chorioamnionitis.
      ]. There is very little variation from this regimen in the literature with regard to intrapartum treatment. There is also little discussion of alternative drugs in the case of allergy, with one study using intravenous clindamycin 900 mg every 8 h as an alternative to ampicillin [
      • Locksmith GJ
      • Duff P
      Assessment of the value of routine blood cultures in the evaluation and treatment of patients with chorioamnionitis.
      ]. Metronidazole has also been reported as an alternative to clindamycin [
      • Duff P
      Antibiotic selection for infections in obstetric patients.
      ], and vancomycin or erythromycin as additional alternatives if the patient is allergic to penicillin [
      • Fahey JO
      Clinical management of intra‐amniotic infection and chorioamnionitis: a review of the literature.
      ]; however, there have been no RCTs to date comparing alternative regimens with the standard regimen of ampicillin and gentamicin.
      The existing trials of antibiotic treatment have focused on variations in dosing and timing of drug administration and alterations to the spectrum of coverage. One RCT found a lower risk of postpartum endometritis in women treated with clindamycin in addition to ampicillin and gentamicin who had a vaginal delivery. There were no differences in women delivering by caesarean section [
      • Maberry MC
      • Gilstrap 3rd, LC
      • Bawdon R
      • Little BB
      • Dax J
      Anaerobic coverage for intra‐amnionic infection: maternal and perinatal impact.
      ]. A subsequent study showed a reduction in the risk of postpartum endometritis with additional anaerobic coverage at caesarean section (8.8% in the ampicillin–sulbactam group vs. 35% in the ampicillin-alone group) [
      • Rijhsinghani A
      • Savopoulos SE
      • Walters JK
      • Huggins G
      • Hibbs JR
      Ampicillin/sulbactam versus ampicillin alone for cesarean section prophylaxis: a randomized double‐blind trial.
      ]. Thus, the recommendation was made to add anaerobic coverage for women with chorioamnionitis who are undergoing delivery by caesarean section [
      • Duff P
      Antibiotic selection for infections in obstetric patients.
      ].
      In previous debates about the timing of treatment for chorioamnionitis, it had been argued that antibiotic treatment intrapartum may affect neonatal cultures, mask early neonatal sepsis and thus delay treatment, leading to poorer neonatal outcomes. This issue was addressed in the late 1980s, in a prospective cohort study and an RCT comparing intrapartum and immediate postpartum treatment with ampicillin and gentamicin. Although both studies were small, with 257 women in the cohort study and only 48 enrolled in the RCT, women who received intrapartum treatment had shorter hospital stays and improved neonatal outcomes, suggesting that intrapartum treatment is superior [
      • Gibbs RS
      • Dinsmoor MJ
      • Newton ER
      • Ramamurthy RS
      A randomized trial of intrapartum versus immediate postpartum treatment of women with intra‐amniotic infection.
      ,
      • Sperling RS
      • Ramamurthy RS
      • Gibbs RS
      A comparison of intrapartum versus immediate postpartum treatment of intra‐amniotic infection.
      ]. Despite the paucity of evidence, the current standard of practice is to initiate treatment with antibiotics promptly once the diagnosis of chorioamnionitis has been made. Although delivery should be expedited, caesarean section is still reserved for the usual obstetric indications [
      ].
      Several trials have further investigated the benefits of extending treatment of intrapartum chorioamnionitis into the postpartum period beyond a single postpartum dose. One RCT randomized women delivering vaginally with a diagnosis of intrapartum chorioamnionitis to a single postpartum dose of cefotetan or continued cefotetan for a minimum of 48 h. No differences were shown between the groups in infectious morbidity, although the study was not powered to look at rare outcomes [
      • Chapman SJ
      • Owen J
      Randomized trial of single‐dose versus multiple‐dose cefotetan for the postpartum treatment of intrapartum chorioamnionitis.
      ]. A study of single vs. multiple postpartum doses of clindamycin and gentamicin in women randomized after caesarean section also revealed no differences in infectious morbidity. In particular, there was no difference in the rate of endometritis, the primary outcome. However, the predetermined sample size was not reached, and the study may thus have been underpowered to show a difference if one exists [
      • Turnquest MA
      • How HY
      • Cook CR
      • et al.
      Chorioamnionitis: is continuation of antibiotic therapy necessary after cesarean section?.
      ]. The largest randomized trial to investigate short-course vs. longer-course antibiotics postpartum after treated intrapartum chorioamnionitis was published in 2003, and enrolled 292 women. Participants were randomized to receive one additional scheduled dose of ampicillin and gentamicin postpartum or to the control group, who continued to receive ampicillin and gentamicin until they were afebrile and asymptomatic for 24 h postpartum. There were no significant differences in the primary outcome of treatment failure, and there were significantly shorter hospital stays in the study group [
      • Edwards RK
      • Duff P
      Single additional dose postpartum therapy for women with chorioamnionitis.
      ], suggesting that prolonged antibiotic therapy postpartum does not provide additional benefit beyond a single dose and leads to increased costs.
      More recently, trials of treatment of chorioamnionitis have shifted towards testing the efficiency and safety of once-daily dosing of gentamicin. Gentamicin is a commonly used aminoglycoside in pregnancy for the treatment of Gram-negative bacteria, although there is reluctance by some practitioners to use it, given the known side effects of renal toxicity and ototoxicity. It is well established that once-daily dosing has several advantages over multiple daily doses, with higher peak serum levels leading to increased efficacy of bacterial killing, and prolonged lower trough levels having a lower risk of toxicity [
      • Ward K
      • Theiler RN
      Once‐daily dosing of gentamicin in obstetrics and gynecology.
      ]. Two recent randomized trials have studied daily vs. divided dosing of gentamicin for treatment of chorioamnionitis, and have found no differences in any adverse maternal or neonatal outcomes, although both studies were underpowered to detect small differences in neonatal sepsis or permanent infant hearing loss [
      • Locksmith GJ
      • Chin A
      • Vu T
      • Shattuck KE
      • Hankins GD
      High compared with standard gentamicin dosing for chorioamnionitis: a comparison of maternal and fetal serum drug levels.
      ,
      • Lyell DJ
      • Pullen K
      • Fuh K
      • et al.
      Daily compared with 8‐hour gentamicin for the treatment of intrapartum chorioamnionitis: a randomized controlled trial.
      ]. Further studies regarding these rare but important outcomes are required before a recommendation can be made to switch to once-daily dosing in labour.
      Additional treatments in the management of acute chorioamnionitis include the antipyretic acetaminophen. A study of fetal acid–base balance showed significant improvements in intrapartum fetal heart rate monitoring as well as in bicarbonate and base excess values (based on scalp gases and cord gases) following treatment of intrapartum fever with acetaminophen [
      • Kirshon B
      • Moise Jr, KJ
      • Wasserstrum N
      Effect of acetaminophen on fetal acid–base balance in chorioamnionitis.
      ]. Finally, although there has been previous concern about the use of regional analgesia in women with intrapartum fever, there does not seem to be any evidence of increased risk of harm (i.e. epidural abscess formation or meningitis) in women with chorioamnionitis receiving regional analgesia, even in those with no prior antibioticadministration [
      • Bader AM
      • Gilbertson L
      • Kirz L
      • Datta S
      Regional anesthesia in women with chorioamnionitis.
      ,
      • Goodman EJ
      • DeHorta E
      • Taguiam JM
      Safety of spinal and epidural anesthesia in parturients with chorioamnionitis.
      ].

      Prevention

      Strategies to prevent chorioamnionitis and subsequent adverse neonatal outcomes have focused on the identification and treatment of risk factors. One of the main risk factors for chorioamnionitis is PPROM, and there has been significant debate in the literature about whether antibiotic treatment of patients with PPROM will subsequently prevent chorioamnionitis and thus adverse neonatal outcomes. One of the largest trials to look at broad-spectrum antibiotic coverage for PPROM was the ORACLE I trial. This study did not have chorioamnionitis as a primary or secondary outcome; however, in women treated with erythromycin alone, neonatal outcome was improved, with prolonged rupture to delivery intervals, a decrease in the number of positive blood cultures and a trend to an improved neonatal composite score [
      • Kenyon SL
      • Taylor DJ
      • Tarnow‐Mordi W
      Broad‐spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE collaborative group.
      ]. A recent Cochrane meta-analysis included several trials of antibiotic use in PPROM, and included chorioamnionitis as an outcome measure [
      • Kenyon S
      • Boulvain M
      • Neilson JP
      Antibiotics for preterm rupture of membranes.
      ]. This meta-analysis revealed a significant reduction in the risk of chorioamnionitis with any antibiotic treatment (relative risk 0.66, 95% CI 0.46–0.96). There were also reductions in markers of neonatal morbidity, including neonatal infection, use of surfactant, oxygen therapy and an abnormal cerebral ultrasound finding prior to discharge [
      • Kenyon S
      • Boulvain M
      • Neilson JP
      Antibiotics for preterm rupture of membranes.
      ]. Unfortunately, the fact that trials with different antibiotic regimens were all grouped together provides no guidance for the practitioner with respect to selecting a drug for prophylactic treatment.
      One of the most common organisms isolated from both the lower genital tract and from placentas of women delivering prematurely is U. urealyticum. There is evidence that this bacterium is associated with PTB; however, the effectiveness of treatment with antibiotics is not clear. Evidence from a randomized trial suggests that treatment of U. urealyticum infection with erythromycin does not decrease vertical transmission, but it may prolong latency and decrease the risk of histological chorioamnionitis [
      • Ogasawara KK
      • Goodwin TM
      The efficacy of prophylactic erythromycin in preventing vertical transmission of ureaplasma urealyticum.
      ]. A further clinical study specifically powered to investigate the impact of treatment of U. urealyticum infection on the prevention of chorioamnionitis is warranted.
      In the setting of intact membranes, the use of antibiotics, both as a preventive measure for PTB and as a treatment for subclinical/clinical vaginal infections, has been investigated. Clinical trials have shown no benefit of antibiotic treatment for the prevention of PTB in the absence of cultured infection [
      • Kenyon SL
      • Taylor DJ
      • Tarnow‐Mordi W
      Broad‐spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE collaborative group.
      ], or even with documented microbial invasion of the amniotic cavity [
      • Ovalle A
      • Romero R
      • Gomez R
      • et al.
      Antibiotic administration to patients with preterm labor and intact membranes: is there a beneficial effect in patients with endocervical inflammation?.
      ]. Another study of 2433 African women found no differences in the risk of chorioamnionitis in women treated with antibiotics prophylactically, although rates of Trichomonas and bacterial vaginosis did decline with treatment [
      • Goldenberg RL
      • Mwatha A
      • Read JS
      • et al.
      The HPTN 024 study: the efficacy of antibiotics to prevent chorioamnionitis and preterm birth.
      ]. Although several international associations recommend treatment of bacterial vaginosis in pregnancy in women who are high risk, it is not clear that treatment itself reduces the risk of preterm labour through a reduction in intra-amniotic infection [
      • ACOG practice bulletin
      Clinical management guidelines for obstetrician–gynecologists, number 72, May 2006: vaginitis.
      ,
      • Yudin MH
      • Money DM
      Screening and management of bacterial vaginosis in pregnancy.
      ].
      The use of vaginal irrigation and intra-amniotic infusion has also been studied for the prevention of chorioamnionitis, with varying results. Vaginal irrigation with chlorhexidine did not have any adverse effects, but was unsuccessful in reducing the risk of chorioamnionitis or endometritis in treated women [
      • Rouse DJ
      • Hauth JC
      • Andrews WW
      • Mills BB
      • Maher JE
      Chlorhexidine vaginal irrigation for the prevention of peripartal infection: a placebo‐controlled randomized clinical trial.
      ]. Two small trials from the mid-1990s to late 1990s looked at amnio-infusion to reduce the risk of chorioamnionitis, and both showed a degree of benefit, although these studies were never followed with larger, appropriately powered, prospective RCTs [
      • Monahan E
      • Katz VL
      • Cox RL
      Amnioinfusion for preventing puerperal infection. A prospective study.
      ,
      • Parilla BV
      • McDermott TM
      Prophylactic amnioinfusion in pregnancies complicated by chorioamnionitis: a prospective randomized trial.
      ].
      Finally, there has also been a suggestion that antibiotic treatment of patients with meconium-stained amniotic fluid reduces intra-amniotic infection, although with no benefit in terms of lower rates of neonatal sepsis [
      • Adair CD
      • Ernest JM
      • Sanchez‐Ramos L
      • Burrus DR
      • Boles ML
      • Veille JC
      Meconium‐stained amniotic fluid‐associated infectious morbidity: a randomized, double‐blind trial of ampicillin–sulbactam prophylaxis.
      ]. Currently, there is no clear evidence for or against this treatment.

      Summary

      Chorioamnionitis is a common obstetric problem, and if untreated can lead to significant maternal and neonatal morbidity and mortality. Chorioamnionitis is diagnosed on the basis of either clinical and/or histological findings. Once it has been identified, prompt treatment is recommended with broad-spectrum antibiotics, antipyretics, supportive care and expedition of delivery. Further research is needed to characterize the microbial communities found in the female genital tract, both in normal pregnancy and in pathological conditions such as chorioamnionitis. Similarly, further research is needed to identify screening and predictive investigations, with appropriate prospective validation of any potential test prior to its widespread use. Ongoing research on novel biomarkers may help to provide further information on the aetiology, causative pathways and potential interventions to help in the treatment and prevention of chorioamnionitis.

      Acknowledgements

      The authors would like to sincerely thank S. Keating, Department of Pathology & Laboratory Medicine, Mount Sinai Hospital, Toronto, Canada for her permission to reproduce the images that have been used in this article.

      Funding

      F. P. McCarthy is funded by Molecular Medicine Ireland.

      Author's Contributions

      M. J. Czikk, F. P. McCarthy and K. E. Murphy—drafting and editing of the manuscript, and critical discussion.

      Transparency Declaration

      Conflicts of interest: nothing to declare.

      References

        • Newton ER
        Chorioamnionitis and intraamniotic infection.
        Clin Obstet Gynecol. 1993; 36: 795-808
        • Goldenberg RL
        • Hauth JC
        • Andrews WW
        Intrauterine infection and preterm delivery.
        N Engl J Med. 2000; 342: 1500-1507
        • Hillier SL
        • Martius J
        • Krohn M
        • Kiviat N
        • Holmes KK
        • Eschenbach DA
        A case‐control study of chorioamnionic infection and histologic chorioamnionitis in prematurity.
        N Engl J Med. 1988; 319: 972-978
        • Menon R
        • Taylor RN
        • Fortunato SJ
        Chorioamnionitis—a complex pathophysiologic syndrome.
        Placenta. 2010; 31: 113-120
        • Redline RW
        • Faye‐Petersen O
        • Heller D
        • Qureshi F
        • Savell V
        • Vogler C
        Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns.
        Pediatr Dev Pathol. 2003; 6: 435-448
        • Alexander JM
        • McIntire DM
        • Leveno KJ
        Chorioamnionitis and the prognosis for term infants.
        Obstet Gynecol. 1999; 94: 274-278
        • Wu YW
        • Colford Jr, JM
        Chorioamnionitis as a risk factor for cerebral palsy: a meta‐analysis.
        JAMA. 2000; 284: 1417-1424
        • Yoon BH
        • Romero R
        • Kim KS
        • et al.
        A systemic fetal inflammatory response and the development of bronchopulmonary dysplasia.
        Am J Obstet Gynecol. 1999; 181: 773-779
        • Mueller‐Heubach E
        • Rubinstein DN
        • Schwarz SS
        Histologic chorioamnionitis and preterm delivery in different patient populations.
        Obstet Gynecol. 1990; 75: 622-626
        • Hauth JC
        • Gilstrap 3rd, LC
        • Hankins GD
        • Connor KD
        Term maternal and neonatal complications of acute chorioamnionitis.
        Obstet Gynecol. 1985; 66: 59-62
        • Rouse DJ
        • Landon M
        • Leveno KJ
        • et al.
        The maternal–fetal medicine units cesarean registry: chorioamnionitis at term and its duration—relationship to outcomes.
        Am J Obstet Gynecol. 2004; 191: 211-216
        • Tran TS
        • Jamulitrat S
        • Chongsuvivatwong V
        • Geater A
        Risk factors for postcesarean surgical site infection.
        Obstet Gynecol. 2000; 95: 367-371
        • Newton ER
        Preterm labor, preterm premature rupture of membranes, and chorioamnionitis.
        Clin Perinatol. 2005; 32: 571-600
        • Romero R
        • Espinoza J
        • Goncalves LF
        • Kusanovic JP
        • Friel L
        • Hassan S
        The role of inflammation and infection in preterm birth.
        Semin Reprod Med. 2007; 25: 21-39
        • Goldman AS
        • Schmalstieg FC
        The pathogenesis of chorioamnionitis.
        J Pediatr. 2008; 153: 3-4
        • Sperling RS
        • Newton E
        • Gibbs RS
        Intraamniotic infection in low‐birth‐weight infants.
        J Infect Dis. 1988; 157: 113-117
        • Baschat AA
        • Towbin J
        • Bowles NE
        • Harman CR
        • Weiner CP
        Prevalence of viral DNA in amniotic fluid of low‐risk pregnancies in the second trimester.
        J Matern Fetal Neonatal Med. 2003; 13: 381-384
        • Tsekoura EA
        • Konstantinidou A
        • Papadopoulou S
        • et al.
        Adenovirus genome in the placenta: association with histological chorioamnionitis and preterm birth.
        J Med Virol. 2010; 82: 1379-1383
        • Asemota OA
        • Nyirjesy P
        • Fox R
        • Sobel JD
        Candida glabrata complicating in vitro pregnancy: successful management of subsequent pregnancy.
        Fertil Steril. 2011; 95: 803.e1-803.e2
        • Meizoso T
        • Rivera T
        • Fernandez‐Acenero MJ
        • Mestre MJ
        • Garrido M
        • Garaulet C
        Intrauterine candidiasis: report of four cases.
        Arch Gynecol Obstet. 2008; 278: 173-176
        • Barth T
        • Broscheit J
        • Bussen S
        • Dietl J
        Maternal sepsis and intrauterine fetal death resulting from candida tropicalis chorioamnionitis in a woman with a retained intrauterine contraceptive device.
        Acta Obstet Gynecol Scand. 2002; 81: 981-982
        • Morgan MA
        • Pippitt CH
        • Thurnau GR
        Antenatal diagnosis of candida chorioamnionitis.
        South Med J. 1989; 82: 276
        • Rode ME
        • Morgan MA
        • Ruchelli E
        • Forouzan I
        Candida chorioamnionitis after serial therapeutic amniocenteses: a possible association.
        J Perinatol. 2000; 20: 335-337
        • Engelhart CM
        • van de Vijver NM
        • Nienhuis SJ
        • Hasaart TH
        Fetal candida sepsis at midgestation: a case report.
        Eur J Obstet Gynecol Reprod Biol. 1998; 77: 107-109
        • Fowler P
        Methicillin‐resistant staphylococcus aureus chorioamnionitis: a rare cause of fetal death in our community.
        Aust NZ J Obstet Gynaecol. 2002; 42: 97-98
        • Geisler JP
        • Horlander KM
        • Hiett AK
        Methicillin resistant staphylococcus aureus as a cause of chorioamnionitis.
        Clin Exp Obstet Gynecol. 1998; 25: 119-120
        • Steel JH
        • Malatos S
        • Kennea N
        • et al.
        Bacteria and inflammatory cells in fetal membranes do not always cause preterm labor.
        Pediatr Res. 2005; 57: 404-411
        • Romero R
        • Espinoza J
        • Kusanovic JP
        • et al.
        The preterm parturition syndrome.
        Br J Obstet Gynaecol. 2006; 113: 17-42
        • Zhou X
        • Brotman RM
        • Gajer P
        • et al.
        Recent advances in understanding the microbiology of the female reproductive tract and the causes of premature birth.
        Infect Dis Obstet Gynecol. 2010; 2010: 737425
        • Mi Lee S
        • Romero R
        • Lee KA
        • et al.
        The frequency and risk factors of funisitis and histologic chorioamnionitis in pregnant women at term who delivered after the spontaneous onset of labor.
        J Matern Fetal Neonatal Med. 2011; 24: 37-42
        • Seaward PG
        • Hannah ME
        • Myhr TL
        • et al.
        International multicentre term prelabor rupture of membranes study: evaluation of predictors of clinical chorioamnionitis and postpartum fever in patients with prelabor rupture of membranes at term.
        Am J Obstet Gynecol. 1997; 177: 1024-1029
        • Fahey JO
        Clinical management of intra‐amniotic infection and chorioamnionitis: a review of the literature.
        J Midwifery Womens Health. 2008; 53: 227-235
        • Tita AT
        • Andrews WW
        Diagnosis and management of clinical chorioamnionitis.
        Clin Perinatol. 2010; 37: 339-354
        • Smulian JC
        • Shen‐Schwarz S
        • Vintzileos AM
        • Lake MF
        • Ananth CV
        Clinical chorioamnionitis and histologic placental inflammation.
        Obstet Gynecol. 1999; 94: 1000-1005
        • Carroll SG
        Preterm prelabour rupture of membranes. Green Top Guideline No. 44. Royal College of Obstetricians and Gynaecologists, 2006 (Minor amendment October 2010).
        • Berger A
        • Witt A
        • Haiden N
        • Kretzer V
        • Heinze G
        • Pollak A
        Amniotic cavity cultures, blood cultures, and surface swabs in preterm infants—useful tools for the management of early‐onset sepsis?.
        J Perinat Med. 2004; 32: 446-452
        • Locksmith GJ
        • Duff P
        Assessment of the value of routine blood cultures in the evaluation and treatment of patients with chorioamnionitis.
        Infect Dis Obstet Gynecol. 1994; 2: 111-114
        • Buhimschi CS
        • Sfakianaki AK
        • Hamar BG
        • et al.
        A low vaginal ‘pool’ amniotic fluid glucose measurement is a predictive but not a sensitive marker for infection in women with preterm premature rupture of membranes.
        Am J Obstet Gynecol. 2006; 194: 309-316
        • Yoon BH
        • Romero R
        • Park JS
        • et al.
        Fetal exposure to an intra‐amniotic inflammation and the development of cerebral palsy at the age of three years.
        Am J Obstet Gynecol. 2000; 182: 675-681
        • Salafia CM
        • Minior VK
        • Rosenkrantz TS
        • et al.
        Maternal, placental, and neonatal associations with early germinal matrix/intraventricular hemorrhage in infants born before 32 weeks’ gestation.
        Am J Perinatol. 1995; 12: 429-436
        • Buhimschi IA
        • Christner R
        • Buhimschi CS
        Proteomic biomarker analysis of amniotic fluid for identification of intra‐amniotic inflammation.
        Br J Obstet Gynaecol. 2005; 112: 173-181
        • Gravett MG
        • Novy MJ
        • Rosenfeld RG
        • et al.
        Diagnosis of intra‐amniotic infection by proteomic profiling and identification of novel biomarkers.
        JAMA. 2004; 292: 462-469
        • Romero R
        • Espinoza J
        • Rogers WT
        • et al.
        Proteomic analysis of amniotic fluid to identify women with preterm labor and intra‐amniotic inflammation/infection: the use of a novel computational method to analyze mass spectrometric profiling.
        J Matern Fetal Neonatal Med. 2008; 21: 367-388
        • Buhimschi IA
        • Zambrano E
        • Pettker CM
        • et al.
        Using proteomic analysis of the human amniotic fluid to identify histologic chorioamnionitis.
        Obstet Gynecol. 2008; 111: 403-412
        • Buhimschi CS
        • Bhandari V
        • Hamar BD
        • et al.
        Proteomic profiling of the amniotic fluid to detect inflammation, infection, and neonatal sepsis.
        PLoS Med. 2007; 4: e18
        • Duff P
        Antibiotic selection for infections in obstetric patients.
        Semin Perinatol. 1993; 17: 367-378
        • Gibbs RS
        • Dinsmoor MJ
        • Newton ER
        • Ramamurthy RS
        A randomized trial of intrapartum versus immediate postpartum treatment of women with intra‐amniotic infection.
        Obstet Gynecol. 1988; 72: 823-828
        • Edwards RK
        • Duff P
        Single additional dose postpartum therapy for women with chorioamnionitis.
        Obstet Gynecol. 2003; 102: 957-961
        • Maberry MC
        • Gilstrap 3rd, LC
        • Bawdon R
        • Little BB
        • Dax J
        Anaerobic coverage for intra‐amnionic infection: maternal and perinatal impact.
        Am J Perinatol. 1991; 8: 338-341
        • Rijhsinghani A
        • Savopoulos SE
        • Walters JK
        • Huggins G
        • Hibbs JR
        Ampicillin/sulbactam versus ampicillin alone for cesarean section prophylaxis: a randomized double‐blind trial.
        Am J Perinatol. 1995; 12: 322-324
        • Sperling RS
        • Ramamurthy RS
        • Gibbs RS
        A comparison of intrapartum versus immediate postpartum treatment of intra‐amniotic infection.
        Obstet Gynecol. 1987; 70: 861-865
      1. Lockwood C Lemons J Guidelines for perinatal care. 6th edn. American Academy of Pediatrics, American College of Obstetricians and Gynecologists, Washington D.C.2007
        • Chapman SJ
        • Owen J
        Randomized trial of single‐dose versus multiple‐dose cefotetan for the postpartum treatment of intrapartum chorioamnionitis.
        Am J Obstet Gynecol. 1997; 177: 831-834
        • Turnquest MA
        • How HY
        • Cook CR
        • et al.
        Chorioamnionitis: is continuation of antibiotic therapy necessary after cesarean section?.
        Am J Obstet Gynecol. 1998; 179: 1261-1266
        • Ward K
        • Theiler RN
        Once‐daily dosing of gentamicin in obstetrics and gynecology.
        Clin Obstet Gynecol. 2008; 51: 498-506
        • Locksmith GJ
        • Chin A
        • Vu T
        • Shattuck KE
        • Hankins GD
        High compared with standard gentamicin dosing for chorioamnionitis: a comparison of maternal and fetal serum drug levels.
        Obstet Gynecol. 2005; 105: 473-479
        • Lyell DJ
        • Pullen K
        • Fuh K
        • et al.
        Daily compared with 8‐hour gentamicin for the treatment of intrapartum chorioamnionitis: a randomized controlled trial.
        Obstet Gynecol. 2010; 115: 344-349
        • Kirshon B
        • Moise Jr, KJ
        • Wasserstrum N
        Effect of acetaminophen on fetal acid–base balance in chorioamnionitis.
        J Reprod Med. 1989; 34: 955-959
        • Bader AM
        • Gilbertson L
        • Kirz L
        • Datta S
        Regional anesthesia in women with chorioamnionitis.
        Reg Anesth. 1992; 17: 84-86
        • Goodman EJ
        • DeHorta E
        • Taguiam JM
        Safety of spinal and epidural anesthesia in parturients with chorioamnionitis.
        Reg Anesth. 1996; 21: 436-441
        • Kenyon SL
        • Taylor DJ
        • Tarnow‐Mordi W
        Broad‐spectrum antibiotics for preterm, prelabour rupture of fetal membranes: the ORACLE I randomised trial. ORACLE collaborative group.
        Lancet. 2001; 357: 979-988
        • Kenyon S
        • Boulvain M
        • Neilson JP
        Antibiotics for preterm rupture of membranes.
        Cochrane Database Syst Rev. 2010; (CD001058)
        • Ogasawara KK
        • Goodwin TM
        The efficacy of prophylactic erythromycin in preventing vertical transmission of ureaplasma urealyticum.
        Am J Perinatol. 1997; 14: 233-237
        • Kenyon SL
        • Taylor DJ
        • Tarnow‐Mordi W
        Broad‐spectrum antibiotics for spontaneous preterm labour: the ORACLE II randomised trial. ORACLE collaborative group.
        Lancet. 2001; 357: 989-994
        • Ovalle A
        • Romero R
        • Gomez R
        • et al.
        Antibiotic administration to patients with preterm labor and intact membranes: is there a beneficial effect in patients with endocervical inflammation?.
        J Matern Fetal Neonatal Med. 2006; 19: 453-464
        • Goldenberg RL
        • Mwatha A
        • Read JS
        • et al.
        The HPTN 024 study: the efficacy of antibiotics to prevent chorioamnionitis and preterm birth.
        Am J Obstet Gynecol. 2006; 194: 650-661
        • ACOG practice bulletin
        Clinical management guidelines for obstetrician–gynecologists, number 72, May 2006: vaginitis.
        Obstet Gynecol. 2006; 107: 1195-1206
        • Yudin MH
        • Money DM
        Screening and management of bacterial vaginosis in pregnancy.
        J Obstet Gynaecol Can. 2008; 30: 702-716
        • Rouse DJ
        • Hauth JC
        • Andrews WW
        • Mills BB
        • Maher JE
        Chlorhexidine vaginal irrigation for the prevention of peripartal infection: a placebo‐controlled randomized clinical trial.
        Am J Obstet Gynecol. 1997; 176: 617-622
        • Monahan E
        • Katz VL
        • Cox RL
        Amnioinfusion for preventing puerperal infection. A prospective study.
        J Reprod Med. 1995; 40: 721-723
        • Parilla BV
        • McDermott TM
        Prophylactic amnioinfusion in pregnancies complicated by chorioamnionitis: a prospective randomized trial.
        Am J Perinatol. 1998; 15: 649-652
        • Adair CD
        • Ernest JM
        • Sanchez‐Ramos L
        • Burrus DR
        • Boles ML
        • Veille JC
        Meconium‐stained amniotic fluid‐associated infectious morbidity: a randomized, double‐blind trial of ampicillin–sulbactam prophylaxis.
        Obstet Gynecol. 1996; 88: 216-220