Chorioamnionitis 

  • Author: Michael P Sherman, MD; Chief Editor: Ted Rosenkrantz, MD   more...
 
Updated: May 5, 2011
 

Background

Maternal fever during labor, and perhaps other signs and symptoms of chorioamnionitis, often results in a call to the family practitioner, pediatrician, or neonatologist related to concern for the neonate. This communication often causes an evaluation to rule out early-onset neonatal sepsis.[1] Because of a concern for early onset sepsis (EOS) when signs and symptoms of maternal chorioamnionitis occur, 10-20 newborns are evaluated and treated with antibiotics for every infant with proven bacteremia. The reason for this clinical phenomenon is that newborns who develop EOS, defined as proven infection at < 72 hours of life, have a high mortality rate. A strong association is observed between very preterm infants dying when younger than 24 hours and chorioamnionitis.[2, 3]

Heightened clinical evaluations for EOS began in the 1970s because group B streptococcal (GBS) infections resulted in a neonatal mortality of about 50%.[4] Over the past 35 years, awareness of GBS-related neonatal morbidity and mortality have resulted in intrapartum chemoprophylaxis with antibiotics to reduce the risk of GBS disease[5] In the presence of maternal chorioamnionitis, the dilemma for the physician is determining whether the neonate is truly at risk for localized (eg, bacterial pneumonia, meningitis) or systemic (eg, bacteremia) infection.

Early-onset bacterial infections in the newborn may occur when the mother has abnormal bacterial colonization of the urogenital tract, an ascending but silent amniotic fluid infection, or symptomatic chorioamnionitis. Thus, the physician cannot assume that maternal signs and symptoms will identify all infected infants.

GBS infections are no longer the major cause of EOS. Gram-negative bacteria are now most predominant,[6] particularly Escherichia coli.[7] Reports have not necessarily seen an increase in E coli -antibiotic-resistant EOS during the era of intrapartum antibiotic use.[8]

Additionally, methicillin-resistant Staphylococcus aureus (MRSA) , already a common cause of nosocomial infection in maternity and neonatal units, looms as a potential cause of EOS.[9] So far, maternal colonization during pregnancy with MRSA has not translated into an increase in MRSA-associated EOS, but close monitoring for this infection is warranted.[10]

This article summarizes the history, physical examination, and laboratory findings in both mother and infant to provide appropriate decision-making tools for cost-effective management of the neonate. An entire issue of Clinics in Perinatology was devoted to infectious diseases during pregnancy.[11] Several chapters in that monograph contain information on the pathophysiology of chorioamnionitis and its adverse consequences in the mother, fetus, and newborn. Studies have examined how inflammation and infection result in preterm birth and potential neonatal brain injury.[12, 13] [14] Reilly and Faye-Petersen have also contributed a monograph on chorioamnionitis.[15]

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Pathophysiology

Abnormal bacterial colonization of the distal colon during pregnancy may create an abnormal vaginal and cervical microbial environment.[16] More than 3 decades ago, rectovaginal colonization with GBS during pregnancy was found to be associated with GBS-related infection of the fetus or newborn.[4] Studies have demonstrated that other types of bacteria residing in the vagina, cervix, or both ascend through intact or ruptured fetal membranes and initiate amniotic fluid infection, chorioamnionitis, or both.[17]

Urinary tract infection during pregnancy can bathe the vagina with bacterial pathogens and is a recognized risk factor for neonatal sepsis. This observation is particularly true for untreated asymptomatic GBS-related bacteriuria.[18] A high maternal body mass index increases the risk of EOS caused by GBS.[19]

Bacterial vaginosis is associated with premature labor, although overt infection of the neonate with microbes causing bacterial vaginosis is uncommon. Screening for and treatment of bacterial vaginosis and other genital infections may prevent preterm birth,[20] although Cochrane reviews conflict regarding the effectiveness of therapy.[21]

Many associations related to infection and preterm birth have been made; however, the mechanisms of these relationships are not necessarily understood. For example, periodontitis is linked to prematurity, low birth weight, and fetal growth restriction.[22] Blood types A and O are also associated with an increased risk for chorioamnionitis.[23] The same researchers found relationships between alcoholism, prolonged rupture of membranes, and maternal anemia as factors related to preterm birth.[23]Obesity during pregnancy has been related to chorioamnionitis in several reports.[24, 25, 19] No association was noted between body mass index and the occurrence of maternal infectious complications when membranes ruptured before 32 weeks' gestation in one study.[26]

In the mid trimester of pregnancy, ultrasonographic evidence of a short cervix may be the only clinical finding in intraamniotic fluid infection.[27] Cervical insufficiency, regardless of bacterial culture results in amniotic fluid, is associated with intraamniotic inflammation, preterm birth and other adverse outcomes of pregnancy.[28] Related issues to cervical insufficiency are mechanical methods of cervical ripening that are also suspected of increasing maternal and neonatal infections.[29] A Cochrane review states that vaginal prostaglandin to initiate labor after premature rupture of membranes may increase maternal and fetal infection and warrants more research.[30] Each of these factors may be associated with altered host defenses that allow ascending infection from the urogenital tract to placental tissues and amniotic fluid.[31]

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Epidemiology

Frequency

United States

Incidence of maternal chorioamnionitis in the US population cannot be stated with accuracy, but the occurrence declines as pregnancy advances toward term gestation.[15] The risk of chorioamnionitis increases based on health conditions and behaviors, as outlined in Pathophysiology. Furthermore, factors such as gestational age, economic conditions, and ethnic differences influence the incidence. Histopathology of the placenta suggests inflammation may occur in the normal course of parturition at term gestation, thus complicating the definition of chorioamnionitis. An increase in histopathologic chorioamnionitis is noted in preterm birth compared with delivery of the healthy term infant. Signs of placental inflammation are present in 42% of extremely low birth weight infants.[32] Most agree that infection is directly or indirectly associated with 40-60% of all preterm births.[33]

Asymptomatic infants born at term gestation to mothers who received intrapartum treatment for clinical chorioamnionitis have a 1.5% incidence rate of positive blood cultures, whereas symptomatic term infants with chorioamnionitis born to mothers who received intrapartum treatment have a 13% incidence rate of positive cultures 13%.[34] The incidence of a positive blood culture in any full-term infant is 1 in 1250 births.[35] Thus, intrapartum antibiotic therapy of mothers who have chorioamnionitis decreases EOS in their full-term infants.[36]

International

Developed countries (eg, Canada, western European countries, Australia) probably have an incidence equal to, or perhaps even less than, the rate of chorioamnionitis observed in the United States. In underdeveloped countries, premature rupture of membranes has a strong association with chorioamnionitis, and chorioamnionitis in this setting results in preterm birth with a high mortality rate.[37] Classic studies by Naeye demonstrated that malnourished pregnant women in Africa had a higher risk of ascending urogenital infection with subsequent amniotic fluid infection.[38]

The pathophysiology increased the risk of fetal infection and perinatal death. Infection in these malnourished women in Africa was attributed to a decrease in host defense factors in amniotic fluid that regularly prevents disease in this liquor.[39] In developed countries where women receive suboptimal care and have poor nutrition during pregnancy, a higher incidence of infection can be expected because of altered immunedefenses.[40]

The bacterial pathogens that cause EOS in developing countries differ from the microbes that cause disease in the United States, Canada, Europe, Australia, and other more developed countries.[41, 42] For ill-defined reasons, the prevalence of GBS disease is lower in developing countries. As developing countries sustain economic development, the prevalence of different bacterial pathogens assumes a profile closer to developed countries. Information on EOS in China is beginning to appear, but the findings are akin to India, which has a lower incidence of GBS compared with Western countries. The maternal risk factors for EOS in developing countries are similar to those in developed countries.[41]

Mortality/Morbidity

Compared with neonatal deaths associated with maternal chorioamnionitis, mortality in mothers of these infants is rare. In a study of infants born at 23-32 weeks' gestation with evidence of intrauterine infection and inflammation, the neonatal death rate was 9.9-11.1%.[43] This study is well known because the analysis concluded that administration of corticosteroids did not worsen neonatal outcome when intrauterine inflammation and infection were present.

In a debatable publication from the same study, Andrews et al concluded that in utero inflammation was not associated with an increased risk of severe adverse neurodevelopmental outcomes at age 6 years.[10] Rather, these preterm infants born at 23-32 weeks' gestation had unfavorable outcomes because of their gestational age at birth, neonatal complications, and the IQ of the caregiver in the home after discharge. As is discussed below, other evidence refutes conclusions about chorioamnionitis and neurodevelopmental outcomes made by Andrews et al.[10] [14, 44, 45]

Infants born to mothers with chorioamnionitis have unfavorable neurologic outcomes. Cerebral palsy (CP)[46] and cognitive impairment without CP[47] have a relationship to the presence of maternal chorioamnionitis. Functional polymorphism in the cytokine interleukin (IL)-6 gene is a risk factor for CP.[48] In particular, funisitis and the fetal inflammatory response syndrome are related to white matter brain injury or periventricular leukomalacia that is linked to activation of cytokine networks.[49] IL-1beta, IL-6, IL-8, IL-17, IL-18, and tumor necrosis factor (TNF)-alpha are among the cytokines identified as agents related to the fetal inflammatory response (FIR) syndrome.[50, 12, 51] When extremely preterm infants have histopathologic evidence of inflammatory or infectious lesions and a severe vascular response in the placenta, the risk of CP is increased.[52]

In addition to activation of inflammation and adverse neurologic outcomes, the risk of long-term pulmonary disease may be heightened.[53] Controversy is declining about the significance of colonization or in utero infection because many studies show Ureaplasma and Mycoplasma are strongly related to FIR and chronic lung disease of prematurity.[54, 55, 56]Congenital pneumonia caused by Ureaplasma and Mycoplasma often requires longer mechanical ventilation and oxygen therapy of preterm infants and initiates a prolonged cytokine release in the neonatal lung.

Antibiotic treatment to reduce the incidence of chronic lung disease of prematurity when the neonatal lung is colonized or infected with Ureaplasma or Mycoplasma has been disappointing. Chorioamnionitis has been linked to EOS, necrotizing enterocolitis, severe intraventricular hemorrhage in preterm infants[57] , and spontaneous intestinalperforation.[58]

Term infants born to mothers with chorioamnionitis have far less chance of dying; however, the long-term morbidity in term infants is still problematic. In a reasonably homogeneous population of near-term and term infants born in the Kaiser Permanente Care Program, Wu and colleagues concluded chorioamnionitis is an independent risk factor for CP.[59]

In preterm infants with EOS, elevated numbers of nucleated RBCs were related to increased concentrations of IL-6 in cord blood.[60] Term infants with evidence of placental inflammation also have elevated circulating fetal nucleated RBCs, and this finding can be associated with CP.[61]

Using amniotic fluid (AF), investigators are using proteomics and nonculture microbial identification methods, called metagenomics, to delineate all microbiota in AF and their relationship to increased intrauterine protein expression.[62, 63, 64] Many proteins identified in AF are inflammatory, but unanticipated molecules are also found. These findings are associated with poor neurodevelopmental outcomes in the infants.

Race

In select populations, race may increase the risk of maternal chorioamnionitis and preterm delivery. Studying histologic chorioamnionitis and preterm birth, Holzman and others observed evidence of inflammatory pathology in 12% of placentas from white women and women of other races compared with 55% in black women.[65] If one considers race in the context of adverse circumstances (ie, violence, human immunodeficiency virus [HIV]-infection) associated with inadequate care[66, 67] or malnutrition during pregnancy,[68, 69] then the incidence of placental inflammation is increased.

Sex

Gender plays an important role in neonatal infection.[70, 3] Among infants with preterm birth at less than 34 weeks' gestation, prolonged rupture of the fetal membranes and male gender was a risk factor for EOS. More recent studies of EOS caused by ampicillin-resistant E coli did not find that male gender was a risk factor.[7]

Age

Advanced maternal age alone, defined as older than 35 years, has not been identified as a risk factor for chorioamnionitis. However, teenage pregnancy increases the risk of chorioamnionitis. Risks factors associated with teenage pregnancy and chorioamnionitis include smoking, alcohol use, anemia, unemployment, urinary tract infection, and bacterial vaginosis.[71, 72, 73, 74]

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Contributor Information and Disclosures
Author

Michael P Sherman, MD  Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Director, Fellowship Training Program in Neonatal-Perinatal Medicine, NICU, Columbia Regional Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine

Michael P Sherman, MD is a member of the following medical societies: American Academy of Pediatrics, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, European Society for Paediatric Research, Perinatal Research Society, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Katsufumi Otsuki, MD, PhD  Associate Professor, Department of Obstetrics and Gynecology, Showa University School of Medicine, Tokyo, Japan

Disclosure: Nothing to disclose.

Specialty Editor Board

Ted Rosenkrantz, MD  Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Arun K Pramanik, MD, MBBS  Professor of Pediatrics, Director of Neonatal Fellowship, Louisiana State University Health Sciences Center

Arun K Pramanik, MD, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, National Perinatal Association, and Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Carol L Wagner, MD  Professor of Pediatrics, Medical University of South Carolina

Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD  Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine

Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research

Disclosure: Nothing to disclose.

Acknowledgments

Research by the author, Michael Sherman, is supported by NIH grant R44 HD 057744 and a grant from the Gerber Foundation. The author appreciates the review of the manuscript undertaken by Jan Sherman, RN, NNP, PhD, and her helpful recommendations for improvement.

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