REVIEW URRENT C OPINION

Chorioamnionitis: time for a new approach Tara M. Randis a, Richard A. Polin b, and George Saade c

Purpose of review The association between maternal chorioamnionitis and early-onset sepsis in the newborn has long been recognized, and established guidelines recommend treating all exposed infants with broad-spectrum antibiotics until infection can be ruled out. However, recent data suggest that close observation of well appearing term and late-preterm newborns may be a preferable alternative. The present review addresses the evidence in favor of newly proposed changes to the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis. Potential implications of these new practice guidelines will also be discussed. Recent findings A panel of experts assembled in 2015 to provide updated, evidence-based guidelines for the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis. Revised terminology and diagnostic criteria were proposed as well as changes in the management of newborns of mothers with suspected intrauterine infection, most notably a recommendation to observe (rather than treat) well appearing term and late-preterm newborns. Summary A management strategy consisting of close observation of well appearing term and late-preterm infants exposed to suspected intrauterine infection is preferable to empiric antimicrobial therapy. Large prospective epidemiologic studies will be needed to ascertain the impact of these new practice guidelines on the outcomes of infants exposed to intrauterine infection and/or inflammation. Improved precision in the clinical diagnosis of intrauterine infection should improve both the quality and reproducibility of data generated from future studies. Keywords chorioamnionitis, early-onset sepsis, infection or both (triple I), intra-amniotic infection, intrauterine inflammation

INTRODUCTION One to five percentage of infants greater than 35 weeks’ gestation are born to mothers with chorioamnionitis [1–3], although the reported incidence in the literature varies widely depending upon population studied and the diagnostic criteria used. The association between maternal chorioamnionitis and early-onset sepsis (EOS) of the newborn has long been recognized and current practice guidelines from the American Academy of Pediatrics (AAP) and the Centers for Disease Control (CDC) recommend treating all infants born to mothers with chorioamnionitis with broad-spectrum antibiotics for at least 48 h until infection can be ruled out [4,5]. The rationale for empiric treatment of well appearing term and late-preterm infants exposed to chorioamnionitis has recently been called into question. The perceived balance of benefits and burdens associated with a ‘treat all’ strategy has shifted secondary to several key observations. First,

the overall incidence of EOS in this population has declined dramatically over the last several decades, largely because of the success of obstetrical interventions including administration of antibiotics to women with Group B Streptococcal (GBS) colonization, prolonged rupture of membranes, or suspected chorioamnionitis. Second, the diagnosis of chorioamnionitis is both common and problematic, relying on inconsistently used clinical criteria with poor predictive value. Finally, there is increasing

a

Departments of Pediatrics and Microbiology, New York University School of Medicine, bDepartment of Pediatrics, Columbia University, College of Physicians and Surgeons, New York, New York, USA and c Department of Obstetrics and Gynecology, University of Texas Medical Branch, Galveston, Texas, USA Correspondence to Tara M. Randis, MD, MS, New York University School of Medicine, 550 First Ave, MSB 217A, New York, NY 10016, USA. Tel: +1 646 501 0039; e-mail: [email protected] Curr Opin Pediatr 2017, 29:159–164 DOI:10.1097/MOP.0000000000000466

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KEY POINTS  Chorioamnionitis is common, but the risk of EOS in healthy term and late-preterm newborns is quite low.  A recent workshop endorsed close observation of asymptomatic infants greater than 34 weeks’ gestation born to mothers with suspected (not confirmed) intraamniotic infection rather than initiation of empiric antibiotic therapy.  Refinement of terminology and clinical diagnostic criteria may help identify those mothers and infants with significant risk of infection.  Large prospective epidemiologic studies will be needed to ascertain the impact of these new practice guidelines on the outcomes of infants exposed to intraamniotic infection.

labor, which reduces the risk of infection in exposed infants by 82% [7]. This substantially increases the number of healthy, newborns who would need to receive antibiotics to prevent one case of sepsis. A recent prospective surveillance study of EOS revealed that 70–1500 well appearing, full-term infants, born to women with chorioamnionitis would need a sepsis evaluation to identify one case of true early-onset sepsis [9]. Benitz et al. [10 ] noted that ‘these much lower attack rates reflect a landscape that is fundamentally different from that extant when consensus guidelines for neonatal sepsis management were being developed 20 years ago’. Importantly, the risk of EOS in infants born to women with chorioamnionitis is strongly dependent on gestational age. Reported rates of confirmed EOS in infants born at at least 35 weeks’ gestation to mothers with clinical chorioamnionitis range from 0.47 to 1.24% [1,10 ,11,12]. This risk of EOS is further reduced if symptomatic newborns are excluded from analysis [10 ,13]. In contrast, rates of EOS in exposed moderate and extremely preterm infants are 5 – 10 times higher [14– 16], with the vast majority of those infants being symptomatic. &&

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recognition of the unintended adverse consequences of early antibiotic exposure in newborns. In response to these growing concerns, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), American College of Obstetricians and Gynecologists (ACOG), Society for Maternal-Fetal Medicine (SMFM), and AAP organized a workshop of invited experts with a goal of providing updated, evidencebased guidelines for the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis. The present review addresses the evidence in favor of recently proposed changes to the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis. The potential implications of these new practice guidelines will also be discussed.

CHORIOAMNIONITIS AND SEPSIS RISK Epidemiologic data collected in the 1990s demonstrated a strong association between maternal chorioamnionitis and EOS, with a reported odds ratio (OR) of 6.42 (95% CI, 2.32–17.8; ref. [6]). In 1999, a published review of the literature noted that chorioamnionitis was a factor in 88% of the instances in which intrapartum antibiotics had failed to prevent EOS because of GBS [7]. Given these data, empiric treatment of chorioamnionitis exposed infants was appropriately recommended. Over the next two decades, the incidence of EOS declined dramatically likely secondary to widespread implementation of intrapartum prophylaxis for mothers colonized with GBS [8], as well as the treatment of women with chorioamnionitis with antibiotics during 160

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CONSEQUENCES OF EMPIRIC ANTIBIOTICS THERAPY Early exposure of healthy newborns to antibiotics Mounting evidence suggests that exposure to antibiotics, even for brief periods of time early in life, may have significant adverse consequences [17]. Very often, the initiation of what is intended to be a short 48-h course of therapy evolves into prolonged treatment [1]. This commonly occurs when abnormal laboratory values are obtained as part of the initial diagnostic work-up of chorioamnionitis-exposed infants. One retrospective study of infants at least 35 weeks’ gestation born to mother with chorioamnionitis noted that 27.6% had an abnormal immature to total neutrophil ratio and/or CRP at 12 h of age [1]. Jackson et al. [12] noted that 99% of such infants had at least one abnormal finding on the CBC during the first 24 h of life [12]. These abnormal screening tests are exceedingly common and notoriously nonspecific, leading many experts to conclude that laboratory screening tests should not factor into the diagnosis of EOS or determination of duration of antibiotic therapy in asymptomatic, culturenegative neonates who are at least 35 weeks’ gestation [12,18]. Volume 29  Number 2  April 2017

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Separation of mother and infant

A NEW APPRAOCH

In many U.S. hospitals, a sepsis evaluation in a newborn requires admission to a neonatal intensive care unit (NICU), transitional unit or ‘step-down unit’. This results in separation of the mother– infant dyad and disrupts initial bonding as well as the early establishment of breastfeeding [19].

In 2015, the NICHD, ACOG, SMFM, and AAP organized a workshop of invited experts with the goal of providing updated, evidence-based guidelines for the diagnosis and management of women and newborns following a maternal diagnosis of chorioamnionitis [24 ]. Several critical themes emerged: a refinement of the nomenclature and diagnostic criteria used to describe intrauterine infection was needed for both clinicians and researchers alike, reconsideration of management strategies for affected mothers and exposed neonates was warranted, and significant knowledge gaps remained.

Resource utilization Evaluation and management of all chorioamnionitis-exposed newborns is accompanied by significant financial burden and resource utilization. One retrospective study of more than 7000 infants born at at least 35 weeks’ gestation found that an astounding 15% underwent an evaluation for EOS [20]. Two thirds of these evaluations were prompted by the presence of maternal fever and nearly 80% of these infants received empiric antibiotic therapy.

Diagnostic difficulties Clinical chorioamnionitis is traditionally diagnosed by the presence of fever and at least two of the following criteria: maternal tachycardia, maternal leukocytosis, uterine tenderness, fetal tachycardia, and foul-smelling amniotic fluid [21]. Although fever is present in 95–100% of cases of chorioamnionitis, the other criteria have variable sensitivity and generally low specificity for chorioamnionitis. Furthermore, there is significant practice variation and the diagnosis of clinical chorioamnionitis is often made in presence of maternal fever alone (26%) or with the presence of only one additional criterion (61%) [22]. This lack of precision in the diagnosis of chorioamnionitis remains a challenge for clinicians and investigators alike. Recent studies show that only 54% of patients with the diagnosis of clinical chorioamnionitis at term have bacteria in the amniotic fluid [23 ] and evidence of intraamniotic inflammation [23 ]. In a recent retrospective study, Romero et al. [23 ] summarized the difficulty in identifying women at term with proven intra-amniotic infection using common clinical criteria. In this study, the sensitivity of maternal and fetal tachycardia or maternal leukocytosis ranged from 75 to 90%, though the specificity was poor (<30%). In contrast, foul-smelling amniotic fluid and uterine tenderness had a high specificity (95%) but a low sensitivity (8 and 12%, respectively). Altogether, the diagnostic accuracy for each clinical criterion ranged between 46.7 and 57.8%. The combination of fever with three or more clinical criteria did not further improve the diagnostic accuracy. &&

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New terminology Chorioamnionitis is most strictly defined as inflammation limited to the chorion and amnion layers of the fetal membranes. However, this histologic description has now evolved into a blanket term commonly used to describe a heterogeneous group of conditions including sterile (i.e. noninfectious) inflammation of maternal–fetal membranes, microbial invasion of intrauterine space of varying degrees of severity and fetal involvement, and in some cases, merely the presence of maternal fever during labor. ‘Intrauterine inflammation, infection or both (triple I)’ is the terminology proposed by the expert panel to replace ‘chorioamnionitis’. The new verbiage represents a more precise description of this clinical entity and reflects the current understanding of pathophysiology, whereby inflammation does not always equal infection. Whether these new terms become embedded in everyday practice remains to be seen. The ‘term isolated maternal fever’ was also put forth as an entity distinct from triple I, and includes fever secondary to epidural anesthesia, dehydration, excess ambient heat or other noninfectious causes. This new categories allows clinicians to note the presence of fever without making a diagnosis of infection.

Refined diagnostic criteria The panel recommended that suspected triple I be diagnosed in the presence of maternal fever without a clear source and any of the following: baseline fetal tachycardia, maternal white blood cell count greater than 15 000 per mm3 in the absence of corticosteroids, or definite purulent fluid from the cervical os. Notably, these criteria de-emphasized use of maternal tachycardia and fundal tenderness for clinical diagnosis, which had been used the past. More importantly, this new terminology stressed that without objective evidence of

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infection/inflammation, the diagnosis is merely suspected. This paradigm change allows clinicians to consider various management strategies rather than be boxed into a definitive diagnosis. Confirmed triple I is diagnosed when criteria are met for suspected triple I and objective laboratory findings of infection in amniotic fluid (positive Gram stain for bacteria, low amniotic fluid glucose, high white blood cell count in the absence of a bloody tap, or positive amniotic fluid culture results), or histopathologic evidence of infection or inflammation or both in the placenta, fetal membranes, or the umbilical cord vessels. Given that these tests are often not performed or their results not available until after delivery, the vast majority of triple I is expected to be in the suspected category.

Recommended changes in management Proposed guidelines for the management of infants exposed to triple I are depicted in Fig. 1. The most notable change is the recommendation to observe (rather than treat) well appearing term and latepreterm newborns born to mothers with isolated fever or suspected Triple I. Infants born to mothers with confirmed Triple I should probably receive empiric therapy as previously advised until neonatal infection is excluded. In addition, it was noted that

there is essentially no evidence to support the use of antibiotics beyond 48 h in well appearing newborns, especially when blood cultures are negative, irrespective of results of screening laboratory tests. Observation of these neonates does not need to be in a NICU setting, and the newborn may even remain in the room with the mother. The approach to antimicrobial treatment in the mother is similar to the one for the neonate. In the presence of isolated fever, it is appropriate to avoid antimicrobial agents and monitor the patient for additional signs or symptoms of infection.

Research gaps Several key areas in need of further investigation were identified during the workshop. Most notable was perhaps the need for the discovery and validation of biomarkers to assist with risk assessment and guidance of therapy for maternal and neonatal infections. Scoring systems, like that proposed by Puopolo and Escobar [13,25] were also highlighted as potentially useful tools. Such algorithms, which combine a rigorous assessment of risk factors together with clinical presentation, may best identify mothers and neonates most at-risk. Improved precision in the clinical diagnosis of triple I should enhance the quality and reproducibility of data generated from future studies.

FIGURE 1. Proposed algorithm for neonatal management. 162

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IMPLICATIONS OF NEW GUIDELINES Large prospective epidemiologic studies will be needed to ascertain the impact of these new practice guidelines on the outcomes of infants born to mothers diagnosed with triple I. Undoubtedly, the number of healthy infants exposed to broad-spectrum antibiotics is expected to decrease, as will the number of NICU admissions. Other anticipated and/or hypothesized clinical implications following the implementation of the new management guidelines are addressed below.

and hesitancy to disrupt feedings are all barriers to a proper physical assessment of the newborn. However, many units have adopted strategies to ensure proper assessment including the use of observation nurseries, specific training of care providers, and the development of checklists. The reliance on physical exam rather than empiric antimicrobial therapy or screening laboratory testing was found to be a well tolerated and effective way to identify infected infants and was associated with decreased antibiotic use [30 ,31].

Potential delay in therapy for infected infants

Allocation of resources

Early recognition of neonatal sepsis and prompt initiation of antimicrobial therapy are believed to improve outcomes. Delayed antibiotic administration in infected infants that are initially asymptomatic may negatively impact patient outcomes. Numerous investigations confirm that the incidence of confirmed EOS in asymptomatic infants is exceedingly low [26–29]. However, a recent multicenter, prospective surveillance for EOS performed by Wortham et al. [9] found that although the majority of chorioamnionitis-exposed infants with culture-confirmed EOS displayed signs and/or symptoms of infection within 6 h of birth, 13% were initially asymptomatic and 21 (9%) remained asymptomatic during the first 72 h after birth [9]. Vigilance will be required to ensure that changes in clinical management of infants born to mothers diagnosed with suspected triple I are not accompanied by an increase in sepsis-related morbidities or mortality. It is important to note the majority of neonatal infections are culture-negative. Yet, our current practices for management of chorioamnionitisexposed infants is to treat until the blood culture is documented as negative. This brief antimicrobial course may potentially mask symptoms in an infected infant. One may argue that 48 h of close observation to exclude infection in an infant who has not received antibiotics would be more reassuring than the immediate discharge of an infant who recently completed empiric antibiotics.

It is anticipated that adoption of these new guidelines will reduce the number of NICU admissions, which is a desirable outcome. However, at the current time, infants exposed to chorioamnionitis comprise a significant proportion of the patient census in many NICUs. Implementation of new policies and practices may result in significant shifts in staffing needs and allocation of other hospital resources.

Observation of at-risk newborns

Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest

Observation is recommended for asymptomatic term infants born to mother’s with suspected triple I. Traditional newborn nurseries are uncommon and have been largely replaced by mother–infant units in many hospitals. ‘Rooming-in’ practices offer significant benefit to mothers and infants alike. However, they present a challenge for frequent physical assessment of infants by clinicians. A darkened room, reluctance to wake a sleeping mother/infant

&

CONCLUSION Close observation of well appearing term and latepreterm infants born to mothers with suspected intrauterine infection is a preferable alternative to empiric antibiotic therapy. Improved precision in the clinical diagnosis of intrauterine infection may better identify mothers and infants most at risk for infection and enhance both the quality and reproducibility of data generated from future clinical studies. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

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