chorioamnionitis

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]

PreviousProceed to Clinical Presentation

History

The time-honored clinical signs and symptoms of chorioamnionitis include the following:

Fever (an intrapartum temperature >100.4ºF or >37.8ºC) Significant maternal tachycardia (>120 beats per minute [bpm]) Fetal tachycardia (>160-180 bpm) Purulent or foul-smelling amniotic fluid or vaginal discharge

Uterine tenderness Maternal leukocytosis (total blood leukocyte count >15,000-18,000 cells/μL)

Of these criteria, intrapartum maternal fever appears to be the most frequent.[75]

When at least 2 of the aforementioned criteria are present, the risk of neonatal sepsis is increased. Each clinical sign and symptom of chorioamnionitis, however, is by itself of low predictive value. The signs and symptoms of maternal chorioamnionitis or amniotic fluid infection are so subjective that some experts have recommended the following: If a physician is trying to decide about an evaluation and treatment of an infant, ask the obstetrician if he or she believes chorioamnionitis is present. Moreover, silent chorioamnionitis is prominent,[76] and thus signs and symptoms in the infected newborn infant take on added significance.

An increasing or decreasing total leukocyte count may be more important than a single determination. Abnormalities in either umbilical vein interleukin (IL)-6 levels or an increasing neonatal immature-to-total neutrophil ratio, along with clinical criteria associated with chorioamnionitis, improve the sensitivity and predictive accuracy of identifying the septic neonate.

Risk of neonatal infection increases as the duration of ruptured membranes lengthens.[77]

Chorioamnionitis may initiate uteroplacental bleeding or a placental abruption.[78] Intrauterine infection is increased in placenta previa and manifests with vaginal bleeding.[79] Labor and delivery may be rapid in the presence of chorioamnionitis. Alternatively, infection may cause uterine atony, requiring labor to be augmented with oxytocin. Ultimately, a poor labor pattern may require an instrumented delivery or a cesarean delivery. Each of these antepartum and intrapartum factors must be considered when evaluating the newborn for the presence of bacterial infection.

Although many cytokines and inflammatory markers have been proposed as diagnostic tests for early onset sepsis (EOS), none has been of sufficient predictive value to gain wide acceptance.[80,

81] Some cytokines are only secreted over a limited time frame during the start of infection, and inflammatory markers may be more sustained in their presence. C-reactive proteins are useful to exclude infection and stop antibiotics. Investigations suggest that procalcitonin and IL-6 used together may enhance laboratory diagnosis of EOS.[80]

Physical

The physical examination of the pregnant women with chorioamnionitis may reveal no signs or symptoms of infection.[76] Conversely, a pregnant woman with chorioamnionitis may appear ill, even toxic.

Physical symptoms may include the following:

Fever Tachycardia (>120 bpm) Hypotension Diaphoresis Cool or clammy skin Uterine tenderness Foul-smelling or abnormal vaginal discharge

The fetus may also have tachycardia (>160-180 bpm). Although heart rate characteristics used to diagnose EOS are under investigation,[82] this type of analysis has not been applied to the fetal heart rate when chorioamnionitis is evident. A biophysical profile (BPP) performed on the fetus using ultrasonography may reveal a lower than normal score, but ultrasonic biophysical profile assessment has not been predictive of clinical chorioamnionitis.[83]

Lack of fetal breathing has been associated with fetal infection.[84, 85] Intrauterine ultrasonography has identified "sludge" at the amniotic fluid interface with the cervix that is also associated with hyperechogenic, free-floating material in the amniotic fluid.[86] This finding was seen in asymptomatic women at risk for preterm delivery. Aseptic aspiration of the "sludge" showed the material had a low glucose content, many neutrophils, and gram-positive cocci. Furthermore, electronic fetal monitoring lacks precision to identify the fetal inflammatory response syndrome and subsequent neonatal sepsis.[87]

Clinical signs and symptoms of chorioamnionitis are not always associated with placental evidence of inflammation.[88] This is particularly true if maternal fever is the sole criterion for the diagnosis.

Epidural anesthesia during the intrapartum period has been associated with fever in the mother and the neonate;[89, 90] however, the pathophysiology of the fever and its adverse effects on the mother, fetus, or infant remains controversial.[91, 92, 93, 94]

Epidural anesthesia and maternal and/or neonatal fevers result in more evaluations for sepsis and antibiotic treatment in neonates, although the incidence of sepsis compared with that in a neonatal population whose mothers did not receive epidural anesthesia during labor is unknown. Epidural anesthesia during labor is associated with other types of neonatal morbidity, such as seizures, that are also risk factors for sepsis.

Although the exact mechanisms for "epidural fever" during labor remain unclear, nulliparity, dysfunctional labor, prolonged labor, maternal exhaustion, dehydration, and/or prolonged rupture of membranes may be operative in pathogenesis.[95]

In the setting of epidural anesthesia during labor, the following clinical course has been observed. The fetus usually has tachycardia when the mother is febrile during labor. At birth, the newborn may also have a fever (temperature >37.8 º C). If the neonate is not septic, the temperature elevation dissipates rapidly following birth, and the newborn subsequently exhibits normal behavior. Usually a temperature elevation in the neonate has returned to normal within 30-60 minutes after birth. Furthermore, these non-infected, febrile neonates have normal Apgar scores and appear remarkably well following birth. Such newborns can be observed for illness rather than undergoing a septic workup and antibiotic therapy. However, judgment must be based on many factors, including the intrapartum administration of broad-spectrum antibiotics to the mother.

Maternal chorioamnionitis increases the potential that the following clinical presentations may be evident in the neonate. Signs and symptoms of neonatal sepsis are often nonspecific and subtle. The neonate may demonstrate behavioral abnormalities such as lethargy, hypotonia, weak cry, and poor suck.

Tachypnea, respiratory distress (eg, expiratory grunt, retractions), cyanosis, pulmonary hemorrhage, and/or apnea (ie, pulmonary manifestations of pneumonia, sepsis, or both), must be immediately appreciated by caregivers. Nursery personnel must be aware that a neonate who is born without respiratory distress but who develops signs and symptoms of pulmonary disease in the first 6-12 hours of life has a heightened risk for congenital (infectious) pneumonia.

Tachycardia, hypotension, prolonged capillary refill time, cool and clammy skin, pale or mottled appearance, oliguria (ie, cardiovascular manifestations of sepsis), or a combination of these may be observed. Many of these signs occur late in the course of EOS. Caregivers must also consider other explanations for these physical findings, such as developmental defects in the cardiovascular system (ie, cardiovascular malformations with abnormalities of aortic blood flow) or inborn errors of metabolism.

Abdominal distension, vomiting, diarrhea, bloody stools, or a combination of these may be observed. GI symptoms may be nonspecific in patients with EOS.

Thermal regulatory abnormalities (ie, hypothermia or hyperthermia), behavioral abnormalities, apnea, seizures (ie, CNS manifestations), or a combination may be seen. A bulging fontanel or nuchal rigidity is not a reliable sign of meningitis in a neonate.

Pallor, petechiae or purpura, and overt bleeding (ie, hematopoietic involvement, liver involvement, or both) may be seen and requires immediate diagnostic and therapeutic attention.

As one physiologic system may affect another, signs and symptoms may originate from more than one dysfunctional organ. However, many neonatal conditions resemble neonatal sepsis; thus, physician caregivers must have an open mind regarding other clinical conditions that may involve signs and symptoms resembling those of neonatal sepsis. Those conditions include, but are not limited to, the following:

Cardiovascular malformations, especially left-sided obstructive lesions causing poor systemic cardiac output

Endocrine disorders that may also cause shocklike states, such as different types of congenital adrenal insufficiency or hypoglycemia associated with hyperinsulinemia

Serious CNS trauma or dysfunction from any cause and subtle seizures with systemic manifestations

Anemia caused by unrecognized isoimmunization or blood loss from conditions such as fetomaternal transfusion syndrome

Causes

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.[96, 97, 98, 99, 100, 31]

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, 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.[101, 27]

Urogenital hygiene is obviously important in establishing healthy bacterial flora. Healthy bacteria (ie, lactobacilli)[102] and natural peptide antibiotics in the vagina and cervix may have a role in preventing infections during pregnancy.[103] Mucus, phagocytes, and natural antibiotic proteins (ie, lactoferrin, lysozyme, beta defensins) in the cervicovaginal secretions attempt to maintain a normal bacterial flora.[97] Bacterial interference, mainly produced via lactobacilli living in an acidic vaginal environment and producing bacteriocins, also helps to keep pathogenic bacteria from gaining a foothold in the cervicovaginal secretions.[104, 105] These mechanisms of host protection may be altered in a significant number of pregnant women who develop chorioamnionitis.

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.[106, 107]

Rectal bacterial flora is believed to be important in establishing abnormal urogenital colonization during pregnancy.[108, 109, 110] Alterations in vaginal and cervical host defense mechanisms during pregnancy cause vaginitis,[111] bacterial vaginosis, urinary infections, and other urogenital infections. Orogenital contact may also alter either colonic or urogenital microbial flora and ultimately cause ascending infection and chorioamnionitis.[112, 113] Similarly, coitus has been linked with chorioamnionitis.[114, 115]

Currently, researchers are trying to understand how host defense mechanisms prevent urogenital infection during pregnancy. The concept of bacterial communities may be important in the pathogenesis of chorioamnionitis because certain microbes provide support to others. The prevalence and diversity of bacterial species in fetal membranes during preterm labor emphasizes further research on this topic is needed.[116] Metagenomics uses nonculture, molecular methods to delineate all microbes inhabiting an environment. Thus, the intestinal microbiome is under intense scrutiny to understand necrotizing enterocolitis or inflammatory bowel disease. Initial reports using molecular methods to understand intrauterine infection, fetal inflammation, and preterm delivery have been published.[116, 117]

Clinical events associated with chorioamnionitis include the following:

History of premature birth (with increasing risk at earlier gestational age) Presence of premature labor Prematurely ruptured fetal membranes (before labor has its onset) Prolonged rupture of the fetal membranes

In a report of patients with clinical signs and symptoms of chorioamnionitis, 38% showed no histologic evidence of placental inflammation. Thus, other causes of signs and symptoms that resemble maternal chorioamnionitis must be sought.

Epidural anesthesia during labor may be associated with maternal fever and fetal tachycardia (see Special Concerns). Other conditions, such as dehydration or maternal exhaustion during labor, may result in maternal fever and must be considered as causes of the febrile state.

Proceed to Differential Diagnoses  

Differential Diagnoses

Herpes Simplex Virus Infection Urinary Tract Infection

Laboratory Studies

During the intrapartum period, diagnosis of chorioamnionitis is usually based on clinical criteria. This is particularly true for pregnancies at term. Chorioamnionitis or intra-amniotic infection (IAI), as causes for preterm labor, should always be considered. Silent chorioamnionitis is recognized as an important cause of premature labor.[76]

The asymptomatic pregnant mother who presents with premature labor or premature rupture of the membranes may require certain studies to exclude silent chorioamnionitis. To diagnose silent or obvious amniotic fluid infection or chorioamnionitis, the physician often uses laboratory examinations of the amniotic fluid, maternal blood, maternal urine, or a combination to make a diagnosis of infection.

Bacteriologic cultures of amniotic fluid and urogenital discharge may be diagnostic for causative pathogens. Investigators suggest that obtaining cervical cultures has an increased risk of initiating amniotic fluid infection in the presence or absence of ruptured membranes.

Examination of amniotic fluid and urogenital secretions

Amniotic fluid, obtained with amniocentesis, may be screened for leukocyte count, Gram stain, pH, glucose concentration, endotoxin, lactoferrin, cytokine levels (eg, interleukin [IL]-6, IL-8, or tumor necrosis factor [TNF]), or a combination of these measured factors.

Cytokines commonly quantified in either amniotic fluid or blood include IL-6, TNF-alpha, IL-1, and IL-8.[118, 50] No consensus has been reached regarding which cytokine offers the best sensitivity, specificity, and positive versus negative predictive accuracy, although IL-6 is most often cited in the literature. Elevated IL-6 levels in cord blood and amniotic fluid have been related to adverse long-term neurologic outcomes in the neonate.[119, 120] This testing has not become routine. Such diagnostic aids are certainly not used in rural communities that deliver babies.

Polymerase chain reaction (PCR) has been rapidly developed as a diagnostic aid. It is used to identify microbes such as human immunodeficiency virus, cytomegalovirus, herpes simplex, parvovirus, toxoplasmosis, and bacterial DNA in amniotic and other body fluids. PCR has been used for the diagnosis of amniotic fluid infection caused by bacterial pathogens,[121] Only university or major academic centers have this relatively expensive technology available to caregivers.

Amniocentesis to obtain amniotic fluid carries the risk of rupturing the fetal membranes. For this reason, screening tests that use cervicovaginal secretions to indicate chorioamnionitis have been reported. Potential markers of cervical or chorionic inflammation include cervical or vaginal concentrations of fetal fibronectin, insulin-like growth factor binding protein-1, and sialidase. Significant association is noted among levels of cervical IL-6, fetal fibronectin, and amnionitis. Conversely, a positive mid-gestational fetal fibronectin assay was not associated with acute histologic placental inflammation at birth.[122] Proteomic profiling of amniotic fluid detects intrauterine inflammation and/or infection and predicts subsequent neonatal sepsis.[123] Caregivers should follow this research because in the next 5 to 10 years, proteomic profiling for inflammation or nonculture-based molecular detection of microbes may become routine in obstetrical samples.

Antenatal screening uses rectovaginal specimens to detect the presence of maternal group B streptococcal (GBS) colonization at 35-37 weeks' gestation. Using these specimens, the Centers for Disease Control and Prevention (CDC) recommends selective growth of GBS in broth followed by cultivation using the plate method. This is the criterion standard assay.

Currently, the CDC does not recommend direct PCR detection of GBS in rectovaginal samples. Rather, a rectovaginal sample should undergo enhanced growth in selective broth before performing PCR. Maternal colonization with rectovaginal GBS increases the risk of chorioamnionitis, and intrapartum prophylaxis with antibiotics reduces the incidence of neonatal infection from GBS.[124, 125]

For mothers that missed GBS screening at 35-37 weeks' gestation, intrapartum testing for GBS uses rapid detection methods on vaginal secretions.[117, 126] To date, these assays have not achieved the results of the traditional culture method. Missed screening and the failure to give intrapartum antibiotics is responsible for the persistence of neonatal GBS infection.[127]

A rapid screening test for GBS that selects mothers who should receive intrapartum chemoprophylaxis reduces hospital costs by approximately $12,000 per prevented case.[128]

Studies from Europe have also shown effectiveness of GBS screening and intrapartum chemoprophylaxis, but the investigators comment on how PCR should be used.[129] Other detection methods that use molecular methods and advanced bioengineering are under investigation. Clinical caregivers should keep an eye on the literature for better methods to detect GBS during labor.

Examinations of maternal blood

WBC counts or C-reactive protein (CRP) levels in maternal blood have been used to predict acute chorioamnionitis when maternal fever is present. Different studies have supported or refuted the use of CRP to diagnose chorioamnionitis.[130, 131] The CRP level may be a better

predictor of the risk of chorioamnionitis than peripheral WBC counts, especially if the mother has received corticosteroids, which may falsely increase the total WBC count.

Other investigators have suggested that the alpha1-proteinase inhibitor complex in maternal blood is a better predictor of amniotic fluid infection than either CRP or WBC count. Analyzing amniotic fluid for leukocytes appears to be a better predictor of amniotic fluid infection than levels of either CRP or total WBC count in maternal blood. In fact, the combination of leukocytosis and a low glucose concentration in the amniotic fluid is highly indicative of chorioamnionitis and may be the best predictor of this condition.

Analysis of maternal serum for either IL-6 or ferritin content may also be helpful, because elevations in these mediators are associated with maternal or neonatal infection. Serum IL-6 levels may be more predictive of infection than CRP concentrations in maternal blood. Alpha1-proteinase inhibitor complex, cytokines, and ferritin in maternal blood have not gained widespread use as markers of acute chorioamnionitis.

The criterion standard for making a diagnosis of early onset bacteremia, pneumonia, or meningitis in neonates is the growth of bacteria in an appropriate specimen (ie, blood, tracheal secretions, cerebrospinal fluid [CSF]). Urinary tract infection is an infrequent cause of early-onset bacterial disease in the neonate; thus, suprapubic bladder taps are not usually required as part of an evaluation for EOS.[132, 133]

Controversy has arisen regarding the inclusion of the lumbar puncture as part of the evaluation for EOS. Some clinicians have argued that the neonate with meningitis has obvious manifestations, and the asymptomatic term neonate does not require a lumbar puncture as part of the evaluation for EOS. Other caregivers argue that a lumbar puncture can only be performed safely when life-threatening pulmonary dysfunction or hypertension resolves.

Other investigators have stressed that cases of meningitis are missed with this approach.[134] The medical literature contains good evidence that meningitis may occur in association with sterile blood cultures. Because meningitis is a devastating neonatal infection, no lumbar puncture may result in inadequate antibiotic therapy. Thus, many believe a lumbar puncture should be performed as part of the evaluation for EOS.

Studies that are also considered specific for infection include positive findings on Gram stains of CSF or tracheal secretions.[135]

The tracheal secretions must be obtained shortly after birth (< 4-8 h). The reason is colonization of the airways occurs from the NICU environment during this time frame. Both tracheal fluids and CSF should be sterile at birth. The presence of bacteria on microscopic analysis (ie, Gram stain) indicates that more than 10,000 colony-forming units of bacteria are present per milliliter of specimen (body fluid). However, the absence of bacteria in either CSF or tracheal secretions does not exclude infection. A final diagnosis should be based on culture results, and this testing takes hours to days.

An absence of neutrophils in CSF or tracheal secretions is expected. The presence of neutrophils in tracheal aspirates obtained after birth indicates that the fetus has mounted an inflammatory response to infection in the environment.

Studies by the primary author and separate studies by pathologists indicate that neutrophils present in tracheal secretions shortly after birth originate from the fetus or neonate and do not represent aspirated maternal neutrophils found in infected amniotic fluid. This conclusion is based on examining Y-body fluorescence in neutrophils present in the tracheal secretions of infected male neonates. In some studies, 50% of the neutrophils present in tracheal secretions of infants with suspected congenital pneumonia had Y-chromosome fluorescence, indicating a fetal origin.

Conversely, 10% of neutrophils in gastric aspirates from the same infants had Y-chromosomal fluorescence. Thus, neutrophils in gastric aspirates are primarily maternal neutrophils, and they represent WBCs present in infected amniotic fluid that is swallowed by the fetus.

Alternatively, the flux of fetal airway fluid is outward from the lung. Maternal neutrophils can gain access to the fetal lung only when gasping occurs during fetal asphyxia.

The male neutrophils observed in the gastric aspirates of these infants with congenital pneumonia indicated that neutrophils were swallowed after they left the fetal lung via the outward flux of airway fluid.

Bacterial antigen detection in CSF is also a useful test to indicate bacterial infection. Bacterial antigen detection in the urine should not be used in a neonate's evaluation for sepsis. Many factors can cause false-positive or false-negative test results during bacterial antigen detection in the urine. Surface cultures have no role in decision-making regarding the diagnosis and treatment of the neonate with early-onset bacterial infection.

All other tests used to diagnose early-onset bacterial infection in the neonate should be considered screening tests. The most common laboratory studies used to screen for neonatal sepsis are WBC profiles and CRP determinations. These tests, at best, are presumptive indicators of infection.

WBC profiles (leukopenia [< 5000/µL], leukocytosis [>30,000/µL], a markedly diminished absolute neutrophil count [< 500-1500/µL], an immature-total neutrophil ratio [>0.3-0.4]) are a commonly used screening test for the septic neonate. Note that the immature-to-total neutrophil ratio of 0.3-0.4 is higher than the previous value of 0.2 reported in the classic studies of Manroe (1977 and 1979).[136, 137] Clinical pathologists have been less accepting of the immature-to-total neutrophil ratio as a diagnostic aid in neonatal sepsis.[138]

Studies have re-examined the WBC counts and the leukocyte profiles present in extremely preterm infants[139] and at high altitude.[54] Other diagnostic tests (eg, inflammatory factors, adhesion molecules, cytokines, neutrophil surface antigens, or even bacterial DNA) may be superior alternatives to this test. To date, these markers of neonatal inflammation/infection have not replaced leukocyte counts as diagnostic methods.

WBC profiles and kinetics are influenced by the genetic make-up of the patient, the gestational age, maternal noninfectious disorders such as pregnancy-induced hypertension (PIH), medications administered to the mother, fetal disease, and other factors. Reference range WBC counts in the neonate do not exclude infection, and serial studies of WBC indices at approximately 6-hour intervals may be more useful in detecting sepsis.[140] A continued assessment of WBC kinetics offers more information regarding decision making. For example, a physician should be particularly concerned with a falling total WBC count, a declining absolute mature neutrophil count, and a rising immature-to-total neutrophil ratio. These findings, taken together, indicate depletion in the bone marrow–related storage pool of neutrophils.[141]

Transfusion of neutrophils is no longer used because during preparation the granulocytes secrete their antimicrobial peptides, and thus these microbicides are not available for killing in phagosomes.

The predictive accuracy of WBC indices for the diagnosis of the EOS is poor. Likewise, the accuracy of CRP determinations to predict neonatal infections shortly after birth is low. However, a negative CRP is a reason to stop antibiotic therapy after 48 hours.[142]

Akin to maternal diagnostic studies for infection, alpha1-proteinase inhibitor complex, cytokines (eg, IL-1 and IL-6 in particular, IL-1 receptor antagonist), and detection of bacterial products in neonatal blood have not gained widespread use as markers of neonatal sepsis. However, these effectors of inflammation may prove to have better predictive accuracy than WBC tests or the

CRP. Procalcitonin may have better sensitivity, specificity, and positive and negative predictive value than CRP in the diagnosis of early onset neonatal sepsis.[143] None of these tests for EOS are routinely used, especially in suburban or rural hospitals with maternity services.

The study of surface markers of inflammation on leukocytes has provided variable diagnostic use in EOS.[144, 145] More research is needed in this field.

Molecular methods to identify pathogenic bacteria in neonatal blood have engendered enormous interest because a rapid diagnosis is possible.[146, 147, 148, 149] Most hospital laboratories do not have the equipment because it is expense and the training of laboratory personal takes considerable time. A wide range of molecular probes are also required to accomplish this diagnostic task. Caregivers should pay close attention to field.

Imaging Studies

Ultrasonography may be used to ascertain fetal well-being. A biophysical profile (BPP) provides information about the status of the fetus. A low BPP score, and especially the loss of fetal breathing movements, has been associated with fetal bacterial infection after premature rupture of membranes.[85, 84] Other investigations have not confirmed the importance of a low BPP score. Specifically, the absence of fetal breathing, may not be a reliable test for amnionitis prior to 32 weeks' gestation.[150, 151]

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.[152, 27, 86] Researchers suggest a shortened cervical canal or cervical insufficiency are linked to ascending urogenital infection that initiates premature labor, premature rupture of the membranes, or both.

Other Tests

The common tests used to diagnose maternal chorioamnionitis are discussed above. Tests still in investigational stages and that have not yet come to the bedside are also discussed above.

Procedures

Needle aspiration and analysis of amniotic fluid is the only invasive procedure used to confirm the diagnosis of acute chorioamnionitis. This procedure can be risky with intact fetal membranes, because the fetal membranes can rupture during or after the procedure.

Bleeding or placental abruption can also be a consequence of amniotic fluid aspiration. The procedure should be performed using ultrasonographic guidance to avoid fetal injury. For these reasons, aspiration of amniotic fluid to diagnose maternal chorioamnionitis has enjoyed limited application in obstetric practice.

Histologic Findings

Gross and microscopic examinations of the placenta, fetal membranes, and umbilical cord for evidence of inflammation and infection are crucial to make a definitive diagnosis of chorioamnionitis.[15] Histologic chorioamnionitis is a reliable indicator of infection whether or not it is clinically apparent.[153] Nevertheless, anatomic studies should be correlated with a culture aseptically obtained from the fetal surface of the placenta.

The microbiologic cultures should include an attempt to isolate aerobic and anaerobic bacteria. Special microbiologic techniques may be required for certain microorganisms such as Listeria monocytogenes. Only in these ways can the pathologist help the bedside clinician delineate the

cause of maternal chorioamnionitis and neonatal sepsis. Clinicians are encouraged to ask pathologists for help in their search for infections causing disease in the pregnant woman, fetus, and newborn. Obstetricians must also obtain the placenta, fetal membranes, and umbilical cord samples for analytical studies when suspicious clinical circumstances are noted.

Staging

Redline and colleagues proposed a scoring system for placental examination that promotes consistency when pathologists judge the severity of chorioamnionitis.[154]

Several physiologic scores have been proposed for neonates who have life-threatening illness, but a recent report could not conclude that these scores accurately predicted neonatal morbidity and mortality during infection.[155]

Medical Care

This section addresses 2 topics. The first topic includes maternal interventions to treat suspected chorioamnionitis and protect the fetus from infection. The second topic includes the diagnostic approach and the appropriate treatment of neonates born to mothers with suspected chorioamnionitis.

The observation that epidural anesthesia during labor may create findings suggestive of maternal chorioamnionitis is discussed. A maternal fever that occurs when epidural anesthesia is administered during the intrapartum period has often been interpreted as chorioamnionitis. This may not be the case, and the neonate is needlessly treated after birth.

Using ampicillin as the chemoprophylactic agent to prevent group B streptococcal (GBS) disease in the neonate is associated with other issues. Ampicillin-resistant E coli infections in the mother and her infant are reported as an increasing problem. The use of penicillin rather than ampicillin as the chemotherapeutic agent to prevent GBS infections of the newborn is encouraged.[156] The effectiveness of erythromycin, clindamycin, and vancomycin for prevention of neonatal GBS disease requires additional study. These antibiotics are often applied when a mother gives a history of penicillin allergy. Frequently, the maternal history of penicillin allergy is poorly documented.

Obstetric management influencing neonatal outcome

When acute chorioamnionitis is evident, delivery must be expedited. Upon signs of serious fetal distress, delivery must be emergent. Withholding maternal antibiotics to obtain postnatal cultures from the neonate is no longer appropriate. This strategy was once an accepted practice based on the assumption that waiting to obtain cultures from the newborn helps to determine the cause of infection. The morbidity and mortality in the mother and newborn may actually increase because of a delay in administering antibiotics. Studies suggest that obtaining cultures from the mother and beginning antibiotics before delivery probably improves the outcome for the neonate.[75]

The postnatal physician must decide whether the fetus was infected and whether antibiotics given before birth should be continued in the neonate. Those antibiotics may differ from those administered to the mother. The history, physical findings, and findings of certain laboratory studies can assist the physician in deciding whether to continue antibiotics started during the intrapartum period. Because antibiotic chemoprophylaxis reduces the risk of GBS infection in neonates, the physician must always consider beginning penicillin during the intrapartum period when a mother has defined risk factors for GBS disease.[157, 156] The physician for the infant must judge whether the chemoprophylaxis was sufficient to prevent infection (especially in a healthy, full-term neonate) or whether the infant must continue antibiotic therapy after birth.

The US Centers for Disease Control and Prevention (CDC) guidelines outline the strategies for screening and treatment to prevent neonatal disease caused byGBS.[158, 124] New CDC guidelines for the prevention and treatment of neonatal GBS disease will be published by 2011.

Determining the appropriate procedures to prevent fetal infection in the setting of premature, prelabor, rupture of membranes is more complex. The mother who has preterm labor or premature rupture of membranes at less than 34 weeks' gestation and no clinical signs or symptoms of chorioamnionitis should receive corticosteroid therapy.[43]

Attitudes towards antibiotic use have changed. If GBS colonization of the mother is not present, and signs and symptoms of chorioamnionitis are absent, pregnant women with preterm labor or premature rupture of membranes at more than 36 weeks' gestation should be observed for infection. Thus, prophylactic antibiotics are not given in these circumstances. Mothers at term gestation with accepted risk factors for GBS infection in their fetus should also receive chemoprophylaxis. Infants at risk of preterm birth, and in whom GBS status is unknown, receive antibiotics during latency until GBS screening is completed. A period of observation for maternal and/or fetal infection is also required after admission, although signs and symptoms may not be evident (ie, silent disease).

Planned early birth versus expectant management for women with premature, prelabor rupture of membranes prior to 37 weeks' gestation and planned home versus hospital care for women with premature, prelabor rupture of membranes prior to 37 weeks' gestation have been reviewed.[159,

160] The preexisting studies were judged inadequate for clinical decision-making on these two topics.

Some obstetricians have observed little effect of corticosteroids on lung maturity after 32 weeks' gestation, whereas others have extended the use of corticosteroids to 34 weeks' gestation. Studies have not clearly demonstrated that the use of corticosteroids increases the risk of bacterial infection in the fetus.[43]

The use of intrapartum penicillin or ampicillin is now a recognized therapy to prevent fetal infection or early onset neonatal infections associated with urogenital colonization by GBS.[161,

156] Amstey and Gibbs recommended that penicillin G rather than ampicillin be administered to the mother for the prevention of early-onset neonatal GBS disease.[162] Their rationale was that penicillin G chemoprophylaxis does not increase colonization of the urogenital tract with ampicillin-resistant gram-negative bacteria. This assumption now seems correct, based on a report showing intrapartum ampicillin did not increase neonatal infections caused by ampicillin-resistant E coli.[8]

Conversely, reports showed an increased occurrence of infections caused by ampicillin-resistant E coli in premature neonates.[163, 164] These mothers had received ampicillin for chemoprophylaxis rather than penicillin, and these authors again recommended use of intrapartum penicillin to prevent fetal or early onset neonatal infections caused by GBS.

Neonatal immunology and the risks created by maternal chorioamnionitis

Newborns are vulnerable to infection because of an immature immune system.[165] Factors that render neonates susceptible to bacterial infections include reduced numbers and/or function of macrophages and dendritic cells in peripheral tissues (eg, lung); lower numbers of neutrophils in the bone marrow storage pool;[141] decreased immunoglobulin G (IgG) and complement levels, especially in prematurely born infants; an inability to respond to bacterial carbohydrate antigens; an increased percentage of T cells bearing naïve cell surfaces and correspondingly underdeveloped functional behaviors related to foreign antigens; and anatomic and biochemical immaturity of skin and mucosal barriers (eg, lung and gut epithelia) as they relate to local host defenses.

Emerging treatments, such as the use of intravenous immunoglobulins and hematopoietic growth factors, may correct deficiencies of the neonatal immune system.[166] The use of immunotherapy still requires more investigation before these treatments become a standard of care.[167]

Specifically, the routine use of intravenous immunoglobins to treat neonatal sepsis is not established, but may be evident in the near future.[168] The mainstays of current neonatal intensive care for bacterial sepsis in neonates are prompt recognition of bacterial infection, antimicrobial therapy, and supportive care. In this review, supportive care is only briefly discussed below. Readers are referred to the eMedicine article Neonatal Sepsisfor a more in-depth care of these critically-ill neonates.

Treatment of the neonate

Communication between obstetric and pediatric caregivers is essential to recognize neonatal infection.

Recognition or suspicion of maternal chorioamnionitis is essential to reducing neonatal morbidity and mortality caused by early-onset bacterial infections in the neonate. Nurses and physicians who care for the mother must communicate their concerns about maternal infection to the nurses and physicians who care for the newborn after birth. Caregivers in the nursery must be critically aware of a neonate's signs and symptoms in relationship to the antepartum and intrapartum history.

Signs and symptoms in the mother that suggest chorioamnionitis and increase the risk of fetal or neonatal infection are described in Physical. Although numerous ways to approach the diagnosis and treatment of neonatal sepsis are recognized, a hands-on assessment is the main key to recognition. The experienced physician or nurse in the nursery may indicate to fellow caregivers that the newborn has a septic appearance.

Surgical Care

Surgical interventions are infrequently required in early onset bacterial infections of the neonate. The conditions that may require intervention include epidural or brain abscess, subcutaneous abscesses, infections localized to the pleural space, certain intra-abdominal infections (especially if intestinal perforation is present), and bone or joint infections.

Consultations

Depending on the hospital setting and the status of the neonate, a family physician may seek pediatric consultation. Depending on the severity or nature of infection in a hospital setting, the pediatrician may seek consultation with a neonatologist, a pediatric infectious disease subspecialist, or both. If organ system failure is present or impending organ system failure (eg, respiratory, cardiovascular, renal) secondary to infection is a concern, the infant should be transferred to an appropriate level 3 or level 4 neonatal intensive care unit (NICU). Transportation to a level 3 or 4 NICU is clearly indicated for extremely premature infants requiring high-frequency oscillatory ventilation or near-term or term neonates (≥ 35 weeks' gestation) who are close to meeting criteria for extracorporeal membrane oxygenation (ECMO).

Diet

Seriously or critically-ill newborns with early-onset bacterial infections often require parenteral nutrition until the condition improves. The use of intravenous lipids during proven bacteremia is the subject of controversy. The fear is that lipid inclusions may interfere with phagocytosis of microbes by hepatic, splenic, or pulmonary macrophages. Infections involving the GI tract may need a special approach to enteral nutrition when the feedings are reinstituted.

Activity

Activity and illness is generally related to adults because neonates are typically at rest and are not stressed when seriously or critically ill.

Medication Summary

Early delivery, supportive care, and antibiotic administration for the mother with chorioamnionitis are discussed in Medical Care. The antibiotics used most often to treat mothers with acute chorioamnionitis are also discussed.[75]

The treatment of bacterial vaginosis has also been discussed above; however, antibiotic therapy for this condition is often not successful.[169, 170]

The treatment of the potentially septic neonate is complex. An overview of the treatment for early-onset neonatal infection is summarized in Medical Care.

Maternal antibiotics for chorioamnionitis

The standard drug treatment in the mother with chorioamnionitis includes ampicillin and an aminoglycoside (ie, usually gentamicin), although clindamycin may be added for anaerobic pathogens.[75] Clindamycin may also be used if the mother is allergic to penicillin, although some experts propose use of a cephalosporin. In cases involving premature labor or premature, pre-labor rupture of membranes, penicillin or ampicillin is frequently administered as a chemotherapeutic agent to prevent group B streptococcal (GBS) colonization of the fetus. The use of penicillin alone is suggested for GBS chemoprophylaxis during the intrapartum period. Using penicillin rather than ampicillin may avoid colonization of the fetus with ampicillin-resistant E coli. The rationale for ampicillin use when maternal chorioamnionitis is suspected is that ampicillin would treat GBS, Haemophilus species, many enterococci strains, and Lmonocytogenes.

For more information on intrapartum antibiotic use to prevent GBS, see the eMedicine topic Bacterial Infections and Pregnancy.

Clindamycin may treat S aureus and anaerobes. Gentamicin provides broad-spectrum coverage against gram-negative bacteria. These antibiotics should be given intravenously. The drugs mentioned above are generally safe for mother and fetus. An absolute contraindication to use of these antibiotics is a known allergic reaction to them. Renal function must always be considered when using antibiotics, especially aminoglycosides.

If a urinary tract infection is present, the appropriate antibiotic or combination of antibiotics should be used to treat the specific bacterium isolated from the urine.

Erythromycin is infrequently used in women allergic to penicillin. Its ability to enter urogenital secretions has been questioned, especially in the treatment of Ureaplasma urealyticum -related or Mycoplasma hominis -related colonization in pregnant women. An effective treatment of Ureaplasma or Mycoplasma infections in mothers or their infants is needed because these potential pathogens cause substantial morbidity and even mortality in the preterm neonate.[171, 55]

Of the invasive GBS strains that were isolated in one study, resistance to either clindamycin or erythromycin was in excess of 20%, whereas colonizing isolates of GBS had resistance in more than 40% of cases.[172] A report from the CDC noted that, of 4882 isolates of GBS, 15% and 32% were resistant to clindamycin and erythromycin, respectively.[173] This suggests that erythromycin or clindamycin used as chemoprophylaxis to prevent GBS infection in neonates is problematic in women with penicillin allergy.

Dosages of antibiotics to treat maternal chorioamnionitis are not provided because this is a pediatric review addressing maternal chorioamnionitis as it affects the newborn infant.

Supportive, immune, and antibiotic therapy of early onset bacterial infection

An extensive discussion of the management of septic neonates is not possible in this article but is available in other eMedicine chapters (see Neonatal Sepsis). Critical points to ensure intact survival of the neonate are mentioned for completeness. For example, ventilator management and surfactant replacement therapy can be used to treat the neonate with congenital bacterial pneumonia, but a complete discussion of the techniques involved in this therapy are covered in other articles. Physicians and nurses attending the delivery of a newborn whose mother is suspected of having chorioamnionitis should be ready to perform a full resuscitation, including intubation, providing positive-pressure ventilation, and treatment of hypovolemia, shock, and respiratory and/or metabolic acidosis. Low Apgar scores may be another indicator of sepsis.

After initial stabilization of a neonate with potential infection in the delivery room, attention is directed toward the following variables that influence survival:

Warmth, monitoring of vital signs, and maintenance of fluid, electrolyte balance, and correction of significant metabolic acidosis

Management of the circulation, including correction of hypovolemia and enhancement of cardiac performance with inotropic drugs if sepsis-related myocardial dysfunction is noted

Glucose homeostasis Treatment of respiratory distress that may entail surfactant replacement (for pneumonia,

respiratory distress syndrome) and different modes of assisted ventilation (Inhaled nitric oxide may be considered as a therapy in the presence of pulmonary hypertension.)

Assessment and treatment of thrombocytopenia and coagulopathy, if present

The aforementioned elements of supportive care are essential to reducing morbidity and mortality. When myocardial dysfunction, cardiovascular collapse, and severe pulmonary hypertension are not reversible, extracorporeal membrane oxygenation (ECMO) may be a life-saving intervention. In critically-ill septic neonates that are near-term or term, the importance of early referral for ECMO cannot be overstated.

Pulmonary hypertension can complicate the management of neonatal sepsis, and inhaled nitric oxide may reverse this complication. The use of inhaled nitric oxide in a non-ECMO facility may be problematic. This is particularly true if the septic neonate deteriorates and must be transferred to an ECMO facility while on inhaled nitric oxide therapy. The referring facility may not have the capability to provide inhaled nitric oxide during transport to the ECMO facility. In this circumstance, the seriously-ill infant may become critically ill with the cessation of inhaled nitric oxide therapy during transport. Therefore, guidelines for referral to an ECMO center should be established for each neonatal ICU (NICU) based on the center's own resources and ability to safely transport such infants.

Guidelines for immunotherapy in early onset sepsis (EOS) are not well established. Treatments used include administration of granulocyte or granulocyte-macrophage colony-stimulating factors (eg, filgrastim, sargramostim); intravenous administration of immunoglobulin G (IgG),[168] particularly if a high-titer IgG antibody is specifically directed against the bacterial pathogen; and leukocyte transfusions for depletion of neutrophils in the bone marrow storage pool. Despite research on each of these immunotherapies, no agreement regarding their use has been reached. A neonatologist, pediatric infectious disease subspecialist, or both should be consulted if immunotherapy is contemplated.

Antibiotic therapy for early onset bacterial infection of the neonate usually includes the administration of a penicillin (ie, ampicillin is most often used for additional coverage against Haemophilus species, enterococci, and listeriosis) and an aminoglycoside (ie, usually

gentamicin). Generally, gentamicin provides ample coverage against gram-negative bacteria that cause EOS. The third-generation cephalosporins should be used as part of the antibiotic regimen if resistant E coli is suspected based on maternal history, amniotic fluid cultures, and the clinical picture. Cefotaxime has been advocated by experts when meningitis is suspected or when an asphyxiated infant or an extremely preterm infant is being treated and severe renal dysfunction may occur.

Antibiotic administration in newborns is based on birth weight criteria and gestational age at birth. Doses of antibiotics change as postnatal age increase and renal function improves. Administration of aminoglycosides should include changes in dosing based on pharmacokinetics.

Final decisions about antibiotics should be based on positive culture results from appropriate anatomic sites. If renal dysfunction is present, antibiotic dosages should be adjusted during the course of their administration. This is particularly true for aminoglycoside administration in extremely premature newborns and in newborns with urogenital anomalies.

Recommendations on the appropriate antibiotic dose can be found in soft-cover neonatology textbooks (ie, Neonatology: Management, Procedures, On-Call Problems, Diseases, and Drugsor Manual of Neonatal Care) and classic textbooks of neonatal-perinatal medicine. Specific textbooks about antibiotic use in pediatric patients, including neonates (ie, Nelson's Pocketbook of Pediatric Antimicrobial Therapy), have also been written. For this article, the NEOFAX 2009 was used for selecting the dose per kilogram and the dosing interval for specific antibiotics. The review on antibiotics to treat EOS is not exhaustive.

Lastly, the physician must consider the duration of antibiotic therapy. This is particularly true when deciding the duration of antibiotic treatment for well-appearing term neonates. In the era of managed care, in which cost reductions are typical, discontinuing antibiotics in healthy term neonates within 24-48 hours of initiating therapy is probably safe. With current bacteriologic techniques, more than 90-95% of neonatal blood cultures become positive within 48 hours of the time they are cultivated. A negative C-reactive protein (CRP) result when reviewed at 48 hours after birth suggests antibiotic treatment can be stopped.

In neonates with proven infection, the well-being of the infected newborn should guide the duration of antibiotic therapy. The bacterium causing the infection and the site of the infection also influence the duration of antibiotic therapy. For example, bacterial pneumonia is often treated for 7-10 days with antibiotics. Bacteremia is often treated with antibiotics for 10-14 days. This duration is based on the potential for recurrence with shorter courses of treatment (ie, 10 days of antibiotics is often considered a minimum for GBS-associated bacteremia).

Cerebrospinal fluid (CSF) infections may require antibiotic therapy for 2-4 weeks based on the bacterium responsible for the infection, findings on an analysis of CSF indicating the resolution of infection, and the presence of complications associated with meningitis. For uncomplicated GBS-related infections of the CSF, 2 weeks may be sufficient; other gram-positive and all gram-negative bacteria often require 3-4 weeks of antibiotic therapy. Surgical interventions for localized CNS infections (eg, an infectious epidural collection, brain abscess) or the presence of post-infectious hydrocephalus may indicate antibiotic therapy needs to be provided for as long as 4-6 weeks.

The following information reviews the antibiotics that are commonly used to treat early-onset bacterial infections in the neonate. The antibiotics covered are not exhaustive. For example, the use of azithromycin to treat congenital pneumonia caused by Urealyticum or Mycoplasma is not reviewed. A report that used azithromycin to treat pregnant women revealed this antibiotic was less effective compared with other antimicrobials.[174] Issues related to infections caused by these microbes and other special bacteria in neonates may require consultation with a neonatologist or a pediatric infectious diseases subspecialist.

Antibiotic Agents

Class Summary

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the clinical setting. Antibiotic combinations are usually recommended for serious Gram-negative bacillary infections. This approach ensures coverage for a broad range of organisms and polymicrobial infections. In addition, it prevents resistance in bacterial subpopulations and provides additive or synergistic effects. Once organisms and sensitivities are known, the use of antibiotic monotherapy is then recommended. The exception would be bacteria that could attain a highly-resistant plasmid against antimicrobials.[175] Information about antimicrobials used to treat neonates and the source for this review is NEOFAX2009.[176]

Aqueous crystalline penicillin G is considered the first-line agent for GBS. Ampicillin may be used, however, recent concern surrounds ampicillin-resistant E coli infections. Other modified penicillins such as oxacillin or nafcillin (antistaphylococcal), netilmicin (antipseudomonal or other Gram-negative enteric bacteria), and piperacillin (antipseudomonal) are not typically used as first-line antibiotics for treatment of early-onset neonatal infections. The aforementioned modified penicillins are designed to treat infections caused by penicillin-resistant bacteria that can express beta-lactamase. These modified penicillins are usually reserved for the treatment of postnatally acquired infections in hospitalized neonates. Methicillin-resistant staphylococcal infections have emerged in pregnant women, and neonates with EOS who have these staphylococci are reported; such infections require treatment with vancomycin.

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Penicillin G, aqueous crystalline (Pfizerpen)

Aqueous crystalline penicillin G (pen G) administered IV is the DOC for GBS bacteremia or meningitis. Pen G is also known as benzylpenicillin. Do not confuse pen G with benzathine or procaine penicillin used only for IM injections; pen G is the original antibiotic in the penicillin class and inhibits synthesis of the bacterial cell wall. Pen G may provide adequate coverage for S pneumoniae when it is a cause of early onset bacterial infection in neonates (infrequent) but this bacterium can also have resistance to pen G.

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Ampicillin

A more broad-spectrum aminopenicillin used for many years as either a definitive or a prophylactic therapy for early-onset bacterial infection of neonates (ie, GBS and susceptible E coli). May provide additional coverage against Haemophilus species, many enterococci, other streptococci, Listeria monocytogenes, and a limited number of susceptible gram-negative enteric bacteria. Indicated for neonatal bacteremia or meningitis due to GBS.

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Cefotaxime (Claforan)

A third-generation cephalosporin with enhanced potency against many gram-negative bacteria. Generally considered inactive against enterococci, Listeria, and most strains of pseudomonads and bacteroides. Some experts consider this antibiotic the preferred therapy for neonatal meningitis caused by gram-negative bacteria if the bacterium is sensitive to it (and in conjunction with an aminoglycoside). This preference is based on more effective CNS penetration of cefotaxime. Indicated when aminoglycosides may be contraindicated (eg, significant renal failure) or when aminoglycosides may have enhanced toxicity.

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Gentamicin

Gentamicin is one of the aminoglycoside antibiotics (ie, amikacin, netilmicin, and tobramycin). Generally, gentamicin has activity against Pseudomonas aeruginosa, whereas kanamycin does not. First choice for prophylactic or definitive therapy of early-onset bacterial infections in neonates because it has broad activity against many gram-negative bacilli. Amikacin and tobramycin are usually reserved to treat nosocomial infections caused by gram-negative bacteria that are resistant to gentamicin.

Aminoglycosides should not be used alone to treat infections potentially caused by gram-positive bacteria. Thus, a penicillin is always included in the treatment of early-onset bacterial infections in neonates. Furthermore, to prevent the emergence of highly antibiotic-resistant gram-negative bacteria, nosocomial infections in hospitalized neonates should never be treated with an aminoglycoside alone. A second antibiotic should be administered in addition to the aminoglycoside, and its mechanism of action that causes microbial death should be different from that of the aminoglycoside.

This antibiotic has a black box warning. Elevated blood concentrations of aminoglycosides may cause significant injury to the kidney and the vestibular/auditory nerve. Concurrent use of furosemide or other loop diuretics and use of vancomycin can increase nephrotoxicity. Thus, peak and trough levels of aminoglycosides in neonatal sera must be measured if their use is going to exceed an initial period of prophylaxis (ie, 48 h after birth) to exclude sepsis.

Aminoglycosides demonstrate concentration-dependent killing of bacteria, suggesting a potential benefit related to higher serum concentrations that are achieved with less-frequent dosing (eg, once daily administration).

Further Inpatient Care

Both the mother with suspected chorioamnionitis and her newborn with suspected sepsis require frequent assessments over the first 48 hours following birth. Mothers with chorioamnionitis who appear well after a brief intravenous course of antibiotics may be discharged on oral antibiotic therapy, but comprehensive outpatient follow-up care is required. General and gynecologic health is usually normal after maternal chorioamnionitis.

Term neonates undergoing an evaluation to exclude sepsis who consistently appear well can probably go home with their mothers within 48 hours after birth. Septic-appearing neonates usually receive any antibiotic therapy via the parenteral route until treatment is deemed complete and the infant is well.

Further Outpatient Care

Depending on the nature of the infection and other risk factors associated with the hospitalization (eg, extreme prematurity, need for home oxygen), an outpatient follow-up visit may be scheduled

from 1 day to 2 weeks after discharge. Home health care follow-up visits by a reliable and well-trained nursing service may also be indicated.

Inpatient & Outpatient Medications

Outpatient antibiotics used to treat a term neonate with rule-out sepsis have not been evaluated. Some managed care plans have discharged neonates with proven infection who appear well after antibiotic therapy. These newborns complete a course of intravenous antibiotics at home. The intravenous antibiotics are often administered via a percutaneous venous line placed before hospital discharge. A visiting nurse comes to the home to administer the antibiotics twice daily.

Depending on the type of infection found in the neonate, the duration of intravenous therapy with antibiotics ranges from 7 days (eg, perhaps pneumonia with rapid improvement) to 4-6 weeks (eg, osteomyelitis). The actual duration of treatment for different types of neonatal infections has not been studied. The duration of treatment for neonatal infections is often based on experience rather than evidence-based.

Transfer

Infected neonates born at hospitals with level 1 (normal) or level 2 (special care) nurseries may require transfer to a level 3 or 4 neonatal ICU (NICU).

Transfer depends on the circumstances of the neonatal infection, degree of prematurity, presence of anomalies, and other pathophysiologic states.

Reasons for transfer of the neonate from a level 1 or 2 nursery to a higher-level facility are outlined in Consultations.

Transfer requirements such as oxygen or assisted ventilation, mode of transportation (eg, ambulance, helicopter, fixed wing aircraft), and health care personnel to transport the patient are beyond the scope of this article.

Deterrence/Prevention

Maternal antibiotic chemoprophylaxis is related to urogenital colonization with group B streptococcus (GBS). Mothers are screened for GBS-related colonization at 35-37 weeks' gestation. Preterm labor before 35 weeks' gestation means that knowledge of GBS-related colonization of the urogenital tract is not immediately available. The CDC has published guidelines for "Prevention of Perinatal Group B Streptococcal Disease."[158]

GBS-related chemoprophylaxis is the program of this type related to maternal chorioamnionitis. Treatment bacterial vaginosis to prevent preterm birth has been considered, although its effectiveness is questioned. When a mother has signs and symptoms of chorioamnionitis during the intrapartum period, the administration of antibiotics is warranted to treat not only the mother but also her fetus, which may have acquired infection because of the placental disease.

Complications

For the mother with chorioamnionitis, serious infectious complications include endometritis, localized pelvic infections requiring drainage, and intra-abdominal infections. Maternal chorioamnionitis or other secondary infectious complications may cause thrombosis of pelvic vessels and the potential for pulmonary emboli.

Serious complications, including septic shock, pulmonary hypertension, respiratory failure, and meningitis, occur in early onset bacterial infections of the neonate. The duration of

hospitalization can be quite prolonged in an extremely premature infant because of infectious complications such as maternal chorioamnionitis or congenital pneumonia. Either condition increases the probability of chronic lung disease in prematurely born and term babies.[177, 54, 178]

Prognosis

The outcome of neonatal infections depends on the causative organism, nature of infection, time of infection onset to administration of appropriate therapy, symptoms at time of birth, and gestational age of the infant. Prematurity and birth defects are cofactors that must be considered when a prognosis is offered to parents or caregivers of an infected newborn. When each of these factors is considered, a prognosis may be provided.

Outcome may not be evident during the neonatal period, and long-term follow-up care is indicated in these infected neonates.[14, 45, 48] Thus, referring these infants to a neonatal follow-up clinic after discharge is prudent. Parental permission should be obtained for transfer of health-protected information because records of the maternal and neonatal course assist in delineating neurologic pathophysiology. In addition to potential long-term neurologic insults, chorioamnionitis may increase the risk of childhood asthma.[179]

Patient Education

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

Similarly, 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 NICU.