Chorioamnionitis

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Chorioamnionitis (also known as “triple I”: intrauterine inflammation or infection or both) is a complication of pregnancy caused by bacterial infection or inflammation of the fetal amnion and chorion membranes.

The characteristic clinical signs and symptoms of chorioamnionitis include the following:

Maternal fever (intrapartum temperature >100.4°F or >38.0°C). [1] Other observed signs include the following [2] :

Baseline fetal tachycardia (>160 beats per min for 10 min or longer, excluding accelerations, decelerations, and periods of marked variability)

Maternal leukocytosis (total blood leukocyte count >15,000 cells/μL) in the absence of corticosteroids

Definite purulent fluid from the cervical os

Other nonspecific signs such as maternal tachycardia and uterine tenderness are deemphasized by a report from a workshop conducted by the National Institute of Child Health and Human Development (NICHD). [2]

The NICHD workshop recommended using the term “triple I” to address the heterogeneity of this disorder. The term “triple I” refers to intrauterine infection or inflammation or both, and it is defined by strict diagnostic criteria (see below); however, this terminology has not been universally accepted. [3] It is important to differentiate between clinical and histologic chorioamnionitis; the latter tend to be “silent” and present only with preterm labor or preterm premature rupture of membranes (PPROM). The risk of neonatal sepsis is increased when chorioamnionitis is diagnosed in the laboring mother; however, the risk is much lower than anticipated based on historical figures when widespread use of intrapartum antibiotics was not a common practice. [4]

See Presentation for more detail.

The diagnosis of clinical chorioamnionitis in pregnancy is commonly made based on clinical findings of fever plus fetal tachycardia, maternal leukocytosis, or purulent fluid coming from the cervical os. Additionally, the pregnant woman with chorioamnionitis may appear ill, even toxic, and she may exhibit hypotension, diaphoresis, and/or cool or clammy skin. However, especially when dealing with histologic chorioamnionitis, maternal clinical signs or symptoms of infection may be absent (silent chorioamnionitis). [5]

Furthermore, clinical signs and symptoms of chorioamnionitis are not always associated with placental evidence of inflammation. [6] This is particularly true if maternal fever is the sole criterion for the diagnosis.

Examination for suspected sepsis in the neonate of a mother with chorioamnionitis often yields nonspecific and subtle findings, which may include the following:

Behavioral abnormalities (eg, lethargy, hypotonia, weak cry, poor suck)

Pulmonary: Tachypnea, respiratory distress, cyanosis, pulmonary hemorrhage, and/or apnea

Cardiovascular: Tachycardia, hypotension, prolonged capillary refill time, cool and clammy skin, pale or mottled appearance, and/or oliguria

Gastrointestinal: Abdominal distention, vomiting, diarrhea, and/or bloody stools

Central nervous system: Thermal regulatory abnormalities, behavioral abnormalities, apnea, and/or seizures

Hematologic and/or hepatic: Pallor, petechiae or purpura, and overt bleeding

Laboratory tests

During the intrapartum period, the diagnosis of chorioamnionitis is usually based on clinical criteria, particularly for pregnancies at term.

Laboratory studies for asymptomatic pregnant mothers who present with premature labor or PROM include the following:

Examination of amniotic fluid

Maternal blood studies

Maternal urine studies

Maternal group B streptococcal (GBS) screening test

Testing in febrile pregnant women with suspected chorioamnionitis may include the following:

White blood cell (WBC) counts

C-reactive protein (CRP) levels

Alpha1-proteinase inhibitor (A1PI) complex measurement

Serum interleukin-6 (IL-6) or ferritin levels

Studies to evaluate amniotic fluid and urogenital secretions may include the following:

Bacterial cultures

Leukocyte count

Gram staining

pH

Glucose concentration

Leukocyte esterase activity [7]

Endotoxin, lactoferrin, and/or cytokine levels (especially IL-6)

Polymerase chain reaction (PCR) for specific microorganisms

Fetal fibronectin, insulinlike growth factor binding protein-1 (IGFBP-1), and sialidase levels

Proteomic profiling [8]

The criterion standard for diagnosing early-onset bacteremia, pneumonia, or meningitis in neonates is the growth of bacteria in an appropriate specimen (ie, blood, tracheal secretions, cerebrospinal fluid). Screening tests for neonatal sepsis include WBC profiles and CRP determinations.

Other tests that may be used to diagnose early-onset neonatal sepsis include the following:

Serum IL-6 or other cytokine levels

Procalcitonin levels [9, 10]

Serum amyloid A measurements [10]

Imaging studies

Before the fetus is viable, vaginal ultrasonography can be used to identify women with a shortened cervical canal. A shortened cervical canal is associated with a higher risk of preterm delivery. [11, 12, 13]

Ultrasonography may also be used to ascertain fetal well-being, utilizing the biophysical profile (BPP).

Procedures

Procedures that may be used to evaluate suspected chorioamnionitis or neonatal early-onset sepsis (EOS) include the following:

Needle aspiration and analysis of amniotic fluid, with ultrasonographic guidance: Can confirm the diagnosis of acute chorioamnionitis

Gross/microscopic examination of placenta, fetal membranes, umbilical cord [14]

Complete blood cell (CBC) count and inflammatory biomarkers, blood culture, and chest x-ray

Controversial: Lumbar puncture of neonates

See Workup for more detail.

Therapy for the mother and/or neonate with chorioamnionitis includes early delivery, supportive care, and antibiotic administration.

Pharmacotherapy

Antibiotic agents used in the treatment of chorioamnionitis include the following:

 Ampicillin and gentamicin

Clindamycin or metronidazole when endometritis is suspected (postdelivery)

Vancomycin for penicillin-allergic patients

Alternatives: Monotherapy with ampicillin-sulbactam, ticarcillin-clavulanate, cefoxitin, cefotetan, or piperacillin-tazobactam

Penicillin G: Used exclusively for GBS intrapartum prophylaxis; if intraamniotic infection is suspected, broaden the antibiotic coverage.

Nonpharmacotherapy

Supportive care of the septic neonate may include the following:

Warmth, monitoring of vital signs

Preparedness to perform a full resuscitation, including intubation, providing positive-pressure ventilation

Treatment of hypovolemia, shock, and respiratory and/or metabolic acidosis

Surfactant replacement therapy

Glucose homeostasis

Assessment and treatment of thrombocytopenia and coagulopathy, if present

Surgical option

Cesarean section may be indicated to expedite the delivery.

Although surgical intervention in the newborn is infrequently required in early-onset bacterial infections of the neonate, conditions that may require such intervention include the following:

Epidural or brain abscess

Subcutaneous abscesses

Infections localized to the pleural space

Certain intraabdominal infections (especially if intestinal perforation is present)

Bone or joint infections

See Treatment and Medication for more detail.

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. [15] Because of a concern for early-onset sepsis (EOS) when signs and symptoms of maternal chorioamnionitis occur, 18-38 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 (positive culture from a normally sterile site like blood, tracheal aspirate, cerebrospinal fluid) at less than 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. [16, 17]

Heightened clinical evaluations for EOS began in the 1970s because group B streptococcal (GBS) infections resulted in a neonatal mortality of about 50%. [18] Over the past 50 years, awareness of GBS-related neonatal morbidity and mortality resulted in the widespread implementation of intrapartum chemoprophylaxis with antibiotics to reduce the risk of GBS disease, which led to an 85% reduction in the rate of culture-proven early-onset GBS sepsis, from approximately1.8 per 1000 live births in the early 1990s to fewer than 0.26 per 1000 live births in 2010. [19]

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 alone will identify all infected infants.

GBS infections continues to be the major cause of EOS in term neonates; however, Escherichia coli has surpassed GBS as the most significant pathogen in preterm infants for over 10 years. [20] Intrapartum ampicillin exposure (as part of GBS prophylaxis as used at some institutions) was identified as an independent risk factor for ampicillin-resistant E coli EOS, as well as for a significant increase in E coli late-onset sepsis. [21]

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. [22] 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. [23]

This article discusses intraamniotic infection during pregnancy and its effects on the fetus and newborn, as well as 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. The subject is expansive in scope, and readers are encouraged to seek more information from other sources. Other Medscape Drugs and Diseases articles of interest include Congenital PneumoniaMeningitis, Bacterial; and Neonatal Sepsis.

An entire 2016 issue of the Journal of Perinatal Medicine was devoted to clinical chorioamnionitis. [24]  Several chapters in the monograph by Romero et al contain information on the intraamniotic inflammatory response in women with clinical chorioamnionitis, molecular mechanisms to identify infecting microorganisms, and the cytokine profiles of the mother and the newborn infant. [25, 26, 27, 28, 29]

Readers are also referred to the 2017 Committee Opinion Number 712 by the American College of Obstetrics and Gynecology (ACOG) on intrapartum management of intraamniotic infection, [30] as well as an excellent 2016 review article about clinical chorioamnionitis by Kim et al in the American Journal of Obstetrics and Gynecology that discusses the definition, pathogenesis, grading, staging, and clinical significance of the most common lesions in placental disease, accompanied by illustrations of the lesions as well as diagrams. [31]

Abnormal bacterial colonization of the distal colon during pregnancy may create an abnormal vaginal and cervical microbial environment. [32] Ascending of cervical and vaginal flora through the cervical canal is the most common pathway to chorioamnionitis. Uncommonly, chorioamnionitis may occur via hematogenous spread as a result of maternal bacteremia (eg, Listeria monocytogenes), or via contamination of the amniotic cavity as a result of an invasive procedure (eg, amniocentesis, fetoscopy). Although spread of peritoneal infection to the amniotic cavity via the fallopian tubes has also been suggested, it is very unlikely. [31] Subsequent activation of the maternal and fetal inflammatory response systems generally lead to labor and/or rupture of membranes. [33] More than 3 decades ago, rectovaginal colonization with group B Streptococcus (GBS) during pregnancy was found to be associated with GBS-related infection of the fetus or newborn. [18] 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 (inflammation), or both. [34]

Urinary tract infection during pregnancy can bathe the vagina with bacterial pathogens and is a recognized risk factor for neonatal sepsis. [35]  This observation is particularly true for untreated asymptomatic GBS-related bacteriuria. [36]

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, especially if initiated before 20 weeks’ gestation. [37]

Many associations related to infection and preterm birth have been made; however, the mechanisms of these relationships are not necessarily understood. These associations include periodontitis, [38]  blood types A and O, [39] alcoholism, [39]  and obesity during pregnancy. [40]

In the mid-trimester of pregnancy (14-24 weeks), ultrasonographic evidence of a short cervix may be the only clinical finding in intraamniotic fluid infection. [11] Cervical insufficiency, regardless of bacterial culture results from amniotic fluid, is associated with intraamniotic inflammation, preterm birth, and other adverse outcomes of pregnancy. [41, 42] Related issues to cervical insufficiency are mechanical methods of cervical ripening that are also suspected of increasing maternal and neonatal infections. [43] A Cochrane review stated that vaginal prostaglandin to initiate labor after premature rupture of membranes may increase maternal and fetal infection and warrants more research. [44] 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. [45]

Maternal chorioamnionitis occurs when protective mechanisms of the urogenital tract and/or uterus fail during pregnancy or when increased numbers of microbial flora or highly pathogenic microorganisms are introduced into the urogenital environment. [45, 46, 47, 48]

Ascending infection into the vagina, then the cervix, and finally into the uterine cavity, fetal membranes, and placenta is the consequence of many factors (ie, innate host defenses, disrupted healthy bacterial flora, pathologic bacterial load, bacterial virulence factors, and toxin production). A short cervix has been recognized as either a risk factor or a surrogate for microbial invasion of the amniotic fluid. [11, 42, 49]

Urogenital hygiene is obviously important in establishing healthy bacterial flora. Healthy bacteria (ie, lactobacilli) [50]  and natural peptide antibiotics in the vagina and cervix may have roles in preventing infections during pregnancy. [51]  Mucus, phagocytes, and natural antibiotic proteins (ie, lactoferrin, lysozyme, beta defensins) in the cervicovaginal secretions attempt to maintain a normal bacterial flora. [46]  Bacterial interference, mainly produced via lactobacilli living in an acidic vaginal environment and producing bacteriocins, may help to keep pathogenic bacteria from gaining a foothold in the cervicovaginal secretions. [52] These mechanisms of host protection may be altered in a significant number of pregnant women who develop chorioamnionitis. The use of oral probiotics to alter vaginal flora and potentially reduce morbidities associated with intraamniotic infection has been studied extensively, but no clear cut benefits were realized. [53]

Oral hygiene may influence rectal and urogenital bacterial flora during pregnancy. Although the theory is controversial, intense interest has focused on a connection among periodontitis, abnormal rectal colonization, and preterm delivery, [54, 55] as well as whether treatment for periodontal disease during pregnancy decrease the incidence of preterm birth. [56] Orogenital contact may also alter either colonic or urogenital microbial flora and ultimately cause ascending infection and chorioamnionitis, as seen in some case reports. [57, 58]  

Currently, researchers are trying to understand how host defense mechanisms prevent urogenital infection during pregnancy. An intense area of research is the concept of bacterial communities living in the cervicovaginal area (microbiome) that are metabolically active to produce biochemicals (metalobome) that support their existence as well as prevent pathogenic bacteria from gaining access to the amniotic cavity and subsequently cause chorioamnionitis. [59, 60, 61] The prevalence and diversity of bacterial species in fetal membranes during preterm labor emphasizes that further research on this topic is needed. [62, 63] Metagenomics uses nonculture, molecular methods to delineate all microbes inhabiting an environment. Thus, the cervicovaginal and intestinal microbiome are under intense scrutiny to understand preterm labor, preterm premature rupture of membranes (PPROM), and chorioamnionitis relative to the mother, and necrotizing enterocolitis, sepsis, and neurologic injury relative to the newborn. Several published reports exist regarding using molecular methods to understand intrauterine infection, fetal inflammation, and preterm delivery. [61, 62, 64]

Clinical events associated with chorioamnionitis include the following:

A retrospective study (2012-2015) suggests that prolonged spontaneous active labor beyond the median not only significantly raises the risk of chorioamnionitis but also increases the odds of cesarean delivery. [65]

In a report of patients with clinical signs and symptoms of chorioamnionitis at term, and using both cultivation and molecular techniques of amniotic fluid, investigators noted almost 40% of women clinically diagnosed with chorioamnionitis did not have any evidence of bacteria in the amniotic cavity. [66] Additionally, nearly 50% did not have evidence of acute inflammatory lesions of the placenta (ie, histologic chorioamnionitis). Thus, other causes of signs and symptoms that resemble maternal chorioamnionitis must be sought.

Epidural anesthesia during labor is associated with maternal fever [67] and fetal tachycardia (see Special Concerns in the Diagnostic Considerations section). A sterile inflammatory response in the placenta and the fetus has been shown to be associated with epidural-related maternal fever. [68] Other conditions, such as dehydration or maternal exhaustion during labor, may result in maternal fever and must also be considered as causes of the febrile state.

The prevalence of maternal chorioamnionitis in the United States varies with different publications, but it appears to be inversely correlated with gestational age at birth. In a 2014 study that assessed the entire US population and linked infant birth and death certificate files for the year 2008, the prevalence of chorioamnionitis was 9.7 per 1000 live births. [69] Studies that looked at placentas found histologic chorioamnionitis present in 3%-5% of term placentas and in 94% of placentas delivered at 21-24 weeks of gestation. [31]

The risk of chorioamnionitis increases based on health conditions and behaviors, as outlined in the Pathophysiology section. 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 cases of preterm birth as compared with delivery of the healthy term infant. Signs of placental inflammation are present in 42% of extremely low birth weight infants. [70] Most investigators agree that infection is directly or indirectly associated with 40%-60% of all preterm births. [71]

Infants exposed to maternal acute chorioamnionitis are at increased risk for early-onset sepsis (EOS). The risk is modified by gestational age and maternal treatment with intrapartum antibiotics. Data from the 1980s and 1990s showed that 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%. [72]

More recent reports continue to indicate that the risk of EOS in infants born to women with chorioamnionitis remains strongly dependent on gestational age, but this risk is much lower compared to old data. In three reports including 1892 infants born at 35 weeks or more of gestation to mothers with clinical chorioamnionitis, [73, 74, 75] the rates of EOS (positive blood culture at < 72 hours of age) were only 0.47%, 1.24%, and 0.72% (number needed to treat [NNT] to prevent one infection: 80-210). In contrast, 4.8%-16.9% of preterm infants exposed to chorioamnionitis develop EOS (NNT: 6-21). [4, 76]  None of these studies stratified risk according to presence or absence of clinical signs of illness; however, more recent data from the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network suggest the risk to be very low in asymptomatic late preterm and term neonates. [77]

Developed countries (eg, Canada, Western Europe, 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. [78] Classic studies by Naeye et al demonstrated that malnourished pregnant women in Africa had a higher risk of ascending urogenital infection with subsequent amniotic fluid infection. [79]  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. [80] 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 immune defenses. [81]

The bacterial pathogens that cause EOS in developing countries differ from the microbes that cause disease in the United States and other more developed countries, with Klebsiella pneumonia and Pseudomonas aeruginosa being the most common organisms in two reports from India and Pakistan. [82, 83]  For ill-defined reasons, the prevalence of group B streptococcal (GBS) disease is lower in developing countries. It is speculated that as developing countries sustain economic development, the prevalence of different bacterial pathogens assumes a profile closer to that of developed countries.

In select populations, race may increase the risk of maternal chorioamnionitis and preterm delivery. [84] Studying histologic chorioamnionitis and preterm birth, Holzman et al observed evidence of inflammatory pathology in 12% of placentas from white women and women of other races compared to 55% in black women. [85]  However, it is difficult to separate race form other hostile environmental circumstances (eg, violence, inadequate prenatal care, malnutrition) that could lead to chorioamnionitis and adverse maternal and neonatal outcomes.

Existing data on the role of sex in EOS are conflicting. Although some researchers identified male sex as a risk factor for EOS, [17] others failed to demonstrate this association. [86, 21] Advanced maternal age alone, defined as being older than 35 years, has not been identified as a risk factor for chorioamnionitis. However, teenage pregnancy raises the risk of chorioamnionitis. [87, 88, 89]

Acute chorioamnionitis may result in labor abnormalities (dysfunctional labor) that increase the risk for cesarean delivery, uterine atony, and postpartum bleeding, as well as the need for blood transfusion. [2, 90] These complications are likely to occur more often when the amniotic fluid is infected with invasive organisms (eg, E coli and group B Streptococcus [GBS]) as compared with low-virulence organisms (eg, Ureaplasma urealyticum). [91] Chorioamnionitis may also lead to the development of other infectious complications, including endometritis, localized pelvic infections requiring drainage, septic pelvic thrombophlebitis, and intraabdominal infections. [92] More serious sequelae such as sepsis, coagulopathy, and adult respiratory distress syndrome are rare, especially when treatment with broad-spectrum antibiotics is initiated. Additionally, chorioamnionitis may initiate uteroplacental bleeding or a placental abruption. [93]  The risk of intrauterine infection is increased in placenta previa and may manifest with vaginal bleeding. [94]

The most serious risks of neonatal exposure to chorioamnionitis are preterm delivery [95] and early-onset neonatal infections (especially sepsis and pneumonia). Other adverse outcomes include perinatal death, asphyxia, intraventricular hemorrhage (IVH), cerebral white matter damage, and long-term disability (including cerebral palsy), as well as other morbidities related to preterm birth. [96, 97] The outcome of neonatal infections depends on the causative organism, the nature of the infection, the time of infection onset to time of administration of appropriate therapy, the symptoms at time of birth, and the gestational age of the infant. Prematurity and birth defects are confounding factors that must be considered when a prognosis is offered to parents or caregivers of an infected newborn. Outcomes may not be evident during the neonatal period, and long-term follow-up care is indicated in these infected neonates.

Neonatal mortality and morbidity

In a study that evaluated the whole US population and linked infant birth and death certificate files for the year 2008, the neonatal mortality rate for infants exposed to chorioamnionitis was 1.40 per1000 live births (LB) versus 0.81 per 1000 LB for infants without chorioamnionitis, with an odds ratio (OR) of 1.72 and a 95% confidence interval (CI) 1.20-2.45. [69] The OR for neonatal death for infants with chorioamnionitis exposure who received antibiotics versus those who did not was 0.69 (95% CI = 0.21-2.26). [69]  In another 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%. [98]

Preterm infants born to mothers with chorioamnionitis have unfavorable short-term (meningitis and intraventricular hemorrhage and periventricular leukomalacia) and long-term (cerebral palsy and neurodevelopmental impairment) neurologic outcomes. [99, 100]  Cerebral palsy (CP) [101]  and cognitive impairment without CP [102]  have been linked to exposure to maternal chorioamnionitis. In particular, funisitis and the fetal inflammatory response syndrome have been associated with white matter brain injury or periventricular leukomalacia that is linked to activation of cytokine networks. [103, 104]  Interleukin (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 syndrome (FIRS) that results in brain injury. [105, 106, 107] However, more recent systematic reviews suggest that the evidence for a causal or associative role of chorioamnionitis in CP is weak [108] and that improvements in neonatal intensive care may have attenuated the impact of chorioamnionitis on brain health outcomes. [109]

The relationship of chorioamnionitis and neonatal cardiopulmonary morbidity is conflicting. Different studies have evaluated the risk of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), and childhood asthma after fetal exposure to chorioamnionitis. Although some studies showed chorioamnionitis to be associated with lower risk of RDS, [110, 111] other studies found an increased risk of RDS [111, 112] or no association after adjusting to other variables. [99]  Similar conflicting data exist for the link of chorioamnionitis and BPD; however, a 2017 French national prospective, population-based, cohort study that included 2513 live-born singletons delivered at 24-31 weeks of gestation and 1731 placentas concluded that histologic chorioamnionitis is not associated with BPD. [113]

Chorioamnionitis caused by Ureaplasma has been studied extensively [114] (including in animal models) and has been linked to congenital pneumonia, prolonged mechanical ventilation, and cytokine release in the neonatal lungs with subsequent development of BPD. [115] However, studies that looked at antibiotic therapy with erythromycin to reduce the incidence BPD when the neonatal lungs are colonized or infected with Ureaplasma have been disappointing. More recent studies with azithromycin are encouraging. [116, 117]

The link between fetal exposure to chorioamnionitis and the future development of childhood asthma was implied by a systematic review but there was much variation in the included studies with regard to the type of maternal infection, age of the children, and methods of exposure ascertainment that made the conclusion less certain. [118] Lastly, with regard to the association between chorioamnionitis and patent ductus arteriosus, two meta-analyses reached opposing conclusions about the association. [119, 120]

Parents or other caregivers of infected neonates need specific instructions about the subsequent care of these infants. This is particularly true for secondary complications associated with such infections. For example, parents/caregivers of an infant with meningitis that has postinfectious hydrocephalus requiring ventriculoperitoneal shunt placement need to have specific instructions about shunt-related malfunction or shunt-related infection. Education of the parents/caregivers related to the recognition and management of seizures should be mandatory before discharge.

Similarly, parents/caregivers of patients with long-term pulmonary complications of congenital pneumonia may require specific education (eg, administration of oxygen or use of bronchodilators at home). Parental education in neonatal resuscitation is indicated for many graduates of the neonatal intensive care unit (NICU).

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(“Documented” fever)

Suspected Triple I

Fever without a clear source plus any of the following:

Confirmed Triple I

All of the above plus:

Fayez M Bany-Mohammed, MD HS Clinical Professor of Pediatrics, Program Director, Neonatal-Perinatal Medicine Fellowship Program, Department of Pediatrics, Division of Neonatology, University of California, Irvine, School of Medicine; Attending Neonatologist, Neonatal ICU, UCI Medical Center and St Francis Medical Center

Fayez M Bany-Mohammed, MD is a member of the following medical societies: American Academy of Pediatrics, California Association of Neonatologists

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, 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, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

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 Pediatric Society, Eastern Society for Pediatric Research, American Medical Association, Connecticut State Medical Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Michael P Sherman, MD, FAAP Professor, Department of Child Health, University of Missouri-Columbia School of Medicine; Neonatologist, Women’s and Children’s Hospital; Professor Emeritus, Department of Pediatrics, University of California, Davis, School of Medicine

Michael P Sherman, MD, FAAP is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American Association of Immunologists, American Pediatric Society, American Society for Microbiology, American Thoracic Society, European Society for Paediatric Research, Pediatric Infectious Diseases Society, Perinatal Research Society, Society for Pediatric Research, Western Society for Pediatric Research

Disclosure: Nothing to disclose.

Katsufumi Otsuki, MD, PhD Associate Professor, Chief, Department of Obstetrics and Gynecology, Showa University Koto-Toyosu Hospital, Japan

Disclosure: Nothing to disclose.

Naomi F Lauriello, MD Associate Professor of Neonatology, University of Missouri Women’s and Children’s Hospital

Naomi F Lauriello, MD is a member of the following medical societies: American Academy of Pediatrics

Disclosure: Nothing to disclose.

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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