Learning Objectives:After participating in this continuing professional development activity, the provider should be better able to:
1. Evaluate the common causes of intrapartum fever.
2. Synthesize the existing literature regarding the diagnosis and management of intraamniotic infection.
3. Explain antibiotic stewardship for parturients and their neonates using evidence-based diagnostic criteria and recommended treatment.
Intrapartum fever is relatively common and affects approximately 2% to 7% of laboring patients.1 It can be difficult to identify the specific cause during the intrapartum period due to the many causes of fever. There are negative consequences of fever and infection for maternal and neonatal well-being, and therefore women with intrapartum fever and their neonates often receive broad-spectrum antibiotics. Although emphasizing the treatment of puerperal infection is extremely important, extensive utilization of broad-spectrum antibiotics has its own risks. Antibiotic-resistant organisms are a worsening public health problem, and antibiotics themselves can have adverse effects for mothers and infants.
For these reasons it is important to understand the latest diagnostic criteria and recommended treatment regimens for intrapartum infection to minimize unnecessary antibiotic exposure. In addition, research to allow timelier and more microbiologically specific diagnosis of intraamniotic infection (IAI) is necessary. High-quality research is needed to delineate the ideal treatment regimen for women when IAI is suspected. It is the responsibility of obstetricians to be stewards of antibiotic use for women and infants now and in the future.
Antibiotic Resistance and Side Effects
In 1942, Ann Miller became the first American patient saved by penicillin, when it was used to treat her postabortive Streptococcal sepsis. With the golden age of antibiotic discovery from the 1930s to 1940s, some experts predicted the end of bacterial infection as a clinical problem. However, it was quickly realized that almost as quickly as new agents were created, organisms with the ability to resist their effects emerged. Antibiotic resistance mechanisms are widespread in nature and selected for with exposure to broad-spectrum antibiotics.
Antibiotics have been misused in both humans and livestock, continuously exacerbating the problem of antimicrobial resistance. It is estimated that 30% of all antibiotic prescriptions are unnecessary, and of the remaining 70% there is room for improvement in drug selection, dosing, and duration.2 Currently in the United States, greater than 2.8 million antibiotic-resistant infections occur each year, and more the 35,000 patients die annually as a result.2 A recent large cross-sectional analysis in the United States showed that 30.6% of women who received antibiotics during labor and delivery did so without an evidence-based indication such as preterm prelabor rupture of membranes, endometritis, chorioamnionitis, Group B Streptococcus (GBS) colonization, or other infectious complications such as urinary tract infection (UTI), pneumonia, or sepsis.3
In addition to antimicrobial resistance, it is important to recognize that antibiotics themselves are not harmless. Antibiotics most often given to women in labor include clindamycin, [beta]-lactams such as penicillin and ampicillin, and aminoglycosides such as gentamicin. The severe risks from these specific antibiotic classes include allergic reactions, acute kidney injury, and Clostridium difficile infection.4
While rare (2.7 cases per 100,000 deliveries), maternal anaphylaxis represents an acute emergency and can cause hypoxic-ischemic encephalopathy in the neonate secondary to maternal hypotension and desaturation.5 Although these more severe maternal outcomes are relatively uncommon, it is also important to consider other possible adverse neonatal outcomes secondary to antibiotic exposure. Perinatal and early-life exposure to antibiotics can have a lasting impact on the neonatal microbiome, which has been linked to the development of asthma and obesity later in life.5,6
Intrapartum Infectious Morbidity and Mortality
Infection continues to be a major cause of maternal mortality contributing to 12.5% of maternal deaths, most commonly in the first week postpartum.7 Infection also contributes to maternal and neonatal morbidity. Although IAI alone is not an indication for cesarean delivery, it increases the risk for arrest of labor and cesarean delivery. In addition, risks for postpartum hemorrhage, hysterectomy, endometritis, wound infection, septic pelvic thrombophlebitis, pelvic abscess, sepsis, acute respiratory distress syndrome, and intensive care unit admission are all increased in the setting of IAI.8 For neonates, IAI can have short- and long-term consequences including early-onset sepsis, pneumonia, meningitis, bronchopulmonary dysplasia, and cerebral palsy.9
Body Temperature and Fever
Normal body temperature varies by person, site of measurement, and time of day. Although the upper limit of normal can vary from person to person, 38.0[degrees]C (100.4[degrees]F) and above is widely accepted as the diagnosis of fever. Fever is a nonspecific sign of systemic inflammation caused by both exogenous and endogenous pyrogens. Examples of exogenous pyrogens include bacterial endotoxins, viral RNA, and fungal sugars. Endogenous pyrogens include cytokines such as interleukin-6, tumor necrosis factor, and interferon, which are released from many different tissues in response to certain stimuli. Both endogenous and exogenous pyrogens result in increased prostaglandin E2, which travels to the hypothalamus and raises the body's temperature setpoint. With the change in setpoint, peripheral processes result in a rise in body temperature.10
Causes of Intrapartum Fever
There are many infectious and noninfectious causes of fever during labor and the immediate postpartum period. It is important to consider all possible sources when intrapartum fever is encountered.
Intrauterine Infection
The amniotic cavity is normally sterile during pregnancy and thus any organism identified within the cavity is evidence of microbial invasion. Organisms can gain access to the amniotic cavity by ascending from the vagina and cervix, hematogenous dissemination through the placenta, retrograde seeding from the peritoneal cavity through the fallopian tubes, or introduction from invasive procedures such as amniocentesis.8
Extrauterine Infection
Infections outside the amniotic cavity can also cause fever during labor and the immediate postpartum period. UTIs are common in pregnant women and can complicate labor. As in nonpregnant women, Escherichia coli is the most common organism identified, accounting for approximately 70% of cases of UTIs in pregnancy.11 Other, less common causes of UTIs include Klebsiella, Enterobacter, Proteus, and gram-positive organisms such as GBS.
Another common infectious cause of intrapartum fever is respiratory tract infection. Many respiratory tract infections including the common cold, bronchitis, pharyngitis, and rhinosinusitis are particularly common in the winter months and often present with low-grade temperatures. These infections are caused by viruses and do not warrant antibiotic treatment.
Labor
Normal labor is an inflammatory event and is associated with the acute-phase response.12 Along with several other factors that can lead to the febrile response during labor and the immediate postpartum period, the inflammatory cascade associated with normal parturition makes fevers, especially low-grade fevers, difficult to interpret. Maternal response to exertion during pushing in the second stage is, in fact, the most likely cause of an isolated low-grade fever in an otherwise normal parturient.
Epidural Anesthesia
Approximately 15% to 20% of women with an epidural will experience a fever. However, studies have shown no increased risk of infection with epidural. Epidemiologic studies suggest that 90% of fevers occurring during labor are attributable to epidural analgesia and are not related to infection.13 Despite this, women with an epidural are more likely to receive intrapartum antibiotics.14 Although the pathophysiology of epidural-related fever is not completely understood, the possible mechanisms include noninfectious systemic inflammation and thermoregulatory alterations.
Drug Fever
Another noninfectious cause of fever is drug-related fever. This is seen commonly with misoprostol. The risk of fever after misoprostol depends on the dose, route, and likely genetic variation among ethnic groups. There is a typical pattern of misoprostol-induced fever, which includes shivering and fever onset at less than 20 minutes after administration, fever peak at 1 to 2 hours after administration, and then spontaneous decline within 3 hours.15
A meta-analysis sought to estimate the incidence and risk of misoprostol-induced fever at various doses and routes when used to prevent postpartum hemorrhage and demonstrated the incidence is highest with the sublingual route (15%), followed by the oral route (11.4%), and then followed by the rectal route (4%).16 There is no research regarding the risk of fever with lower doses of misoprostol used for cervical ripening during the induction of labor.
Ambient Temperature
Laboring in an overheated hospital room can be a source of noninfectious fever. If the temperature in the delivery room is greater than that of the mother's skin, the body is unable to lose heat as it should by radiation or conduction. Instead, the body gains heat from the environment, which can cause a fever.1
Dehydration
Labor requires physical effort, which generates heat within the body. In a normal physiologic state, sweat is produced to increase heat loss from the body to decrease body temperature. If the mother is dehydrated, she does not have enough fluid reserves to produce sufficient sweat to offset the amount of heat generated during labor and a fever can develop.1
Physiologic Response to Surgery
In response to stress from surgery, inflammatory pyrogenic cytokine mediators are released. One study that included patients who underwent abdominal surgery, such as cesarean delivery, demonstrated that postoperative body temperature elevations correlated with interleukin-6 levels, suggesting that a postoperative rise in temperature can be related to recent surgery rather than infection.17
Management of Intrapartum Fever
It is important to be vigilant to monitor for signs of IAI and start antibiotics promptly when indicated, as there is good evidence that intrapartum treatment of IAI with antibiotics improves maternal and neonatal outcomes.18 However, the diagnosis of IAI is based on clinical factors and can only be confirmed with pathologic and microbiologic studies. The specificity of clinical factors used to diagnose IAI is poor, and the diagnostic criteria vary. Furthermore, once IAI is diagnosed and the decision is made to start antibiotics, the literature supporting the appropriate choice of antibiotics and the duration of treatment is of low or very low quality.19Figure 1 illustrates a diagnosis and management algorithm of isolated maternal temperature and suspected or confirmed IAI.
Clinical Diagnosis of Intrapartum Infection
Infection or inflammation of the amniotic fluid, membranes, and/or placenta has been referred to as chorioamnionitis, IAI, and triple I (intrauterine infection or inflammation). The term "chorioamnionitis" should be abandoned as it is not descriptive and may lead to unnecessary intervention with antimicrobial agents. What defines IAI varies in the literature and is primarily based on 2 different sets of criteria.
Historically, the Gibbs criteria were used to diagnose IAI. By the Gibbs criteria, IAI can be diagnosed with the presence maternal fever plus 2 or more of the following findings: maternal tachycardia, fetal tachycardia, uterine tenderness, foul odor of the amniotic fluid, or maternal leukocytosis.20 Thus, the Gibbs criteria for IAI are primarily a clinical diagnosis. The Gibbs criteria have a high specificity of more than 98% but a low sensitivity of 15%, indicating that the Gibbs criteria make a poor screening tool but a strong diagnostic test.21
In 2016, another set of criteria for diagnosing IAI was suggested by a National Institute of Child Health and Human Development (NICHD) expert panel.22 These guidelines separated triple I into 3 distinct categories: isolated maternal fever, suspected triple I, and confirmed triple I. By these criteria, a diagnosis of suspected triple I can be made in a woman with fever plus one or more of the following: fetal tachycardia, maternal leukocytosis (generally >15,000 white blood cells), or purulent cervical drainage. Importantly, the NICHD criteria do not include fundal tenderness or maternal tachycardia as the Gibbs criteria do. A confirmed diagnosis of triple I can only be made in women who meet all the suspected triple I criteria plus one or more of the following objective laboratory findings: gram stain, glucose level, or culture consistent with amniotic infection or placental pathology with histopathologic evidence of infection or inflammation. The sensitivity and specificity of the suspected triple I criteria to predict confirmed triple I are 72% and 41%, respectively.23 Thus, NICHD diagnostic criteria may miss febrile women at risk for triple I and clinically significant maternal and neonatal outcomes.
Although the American College of Obstetricians and Gynecologists (ACOG) has endorsed the NICHD definition of IAI for research settings, the college states that, in clinical practice, women who have a fever above 39.0[degrees]C (102.4[degrees]F) should be included in the suspected IAI group and started on antibiotic therapy.8 In this way, the ACOG is valuing increased sensitivity to capture more patients at risk of IAI given the risk of untreated IAI to parturients and their neonates.
Emerging Biomarkers to Help Distinguish Intrapartum Infection
Serum biomarkers are often used to aid in the diagnosis and monitoring of infections in nonpregnant patients. Until recently, it was unknown whether there were useful biomarkers of infection in pregnant and postpartum women. A recent meta-analysis demonstrated that certain biomarkers do have diagnostic value in peripartum patients including interleukin-6, C-reactive protein, procalcitonin, insulin-like growth factor-binding protein 1, tumor necrosis factor-[alpha], calgranulin B, neopterin, and interferon-[gamma] inducible protein 10.24 In the future, with more research, obtaining these biomarkers may help distinguish infectious from noninfectious etiologies of fever in the peripartum period.
Microbiology and Antibiotic Resistance Patterns
Many cases of IAI are polymicrobial vaginal flora, with the most common organisms isolated being Ureaplasma urealyticum, Mycoplasma hominis, and Gardnerella vaginalis. Organisms that cross from maternal circulation via the placenta are more likely to be nonpolymicrobial and include organisms such as Listeria monocytogenes and Staphylococcus aureus.8
Management of intrapartum fevers has long-term consequences for current and future patients. For example, overuse of antibiotics has led to resistant strains of E. coli, which is now the most commonly isolated organisms in early-onset sepsis in preterm infants after universal screening and intrapartum prophylaxis of GBS began.25 Erythromycin and clindamycin-resistant GBS strains have been increasing,26 necessitating use of broad-spectrum antibiotics and further exacerbating the problem. In total, overtreatment of intrapartum fever has led to antibiotic resistance responsible for up to 30% of neonatal deaths from sepsis worldwide.27
Treatment of IAI
Standard management of women with suspected or confirmed IAI is broad-spectrum antibiotics and delivery. Although antimicrobial therapy provides intraamniotic and fetal bactericidal concentrations soon after IV infusion, delivery is important to the resolution of infection. This can be achieved through induction or augmentation of labor, as IAI alone is not an indication for cesarean delivery.
Broad-spectrum antibiotics aim to cover the common pathogens implicated in IAI. The recommended antibiotic regimen from the ACOG is ampicillin 2 g IV every 6 hours plus gentamicin 5 mg/kg IV once daily, or gentamicin 2 mg/kg IV loading dose followed by 1.5 mg/kg IV every 8 hours. For those with mild penicillin allergies, cefazolin and gentamicin are recommended. Those with severe penicillin allergies should receive clindamycin or vancomycin plus gentamicin. Alternative regimens include ampicillin-sulbactam, piperacillin-tazobactam, cefotetan, cefoxitin, and ertapenem.8 In women undergoing a cesarean delivery, clindamycin or metronidazole is added to these regimens preoperatively to reduce the risk of postsurgical infections due to anaerobes. A recent review compared the different types and doses of antibiotics for treatment of IAI and most studies did not show any difference in maternal or neonatal outcomes between regimens, suggesting that one regimen is not superior to another.28
The optimal duration of antibiotic therapy after delivery has also not clearly been established. Importantly, a recent review demonstrated no difference in outcomes when antibiotics were given in one dose before delivery or multiple doses into the postpartum period.29 Further, there is no evidence that oral antibiotics provide any benefit after discontinuation of parenteral therapy.30 For these reasons, the ACOG recommends that additional doses of antibiotics are not required after vaginal delivery whereas at least one additional dose, plus one dose of clindamycin or metronidazole, should be given after cesarean delivery. In patients who display signs of ongoing infection, the ACOG recommends choosing an antibiotic duration according to individual patients' clinical signs and symptoms.8
Ways to Avoid Antibiotic Exposure
To avoid unnecessary antibiotic exposure to mothers and their newborns, the following considerations can be taken. First, consider repeating the temperature determination when an elevated temperature is identified in an intrapartum patient with a low-grade fever. A repeated recording may demonstrate that the temperature was elevated due to a warm environment, dehydration, or another noninfectious etiology. Second, for intrapartum patients with fevers suggestive of IAI, use the shortest effective duration of therapy (ie, discontinue antibiotics after vaginal delivery and provide only one additional dose for those undergoing cesarean delivery). Taking these steps will provide necessary treatment to those mothers and neonates who need it while preventing antibiotic resistance and overtreatment.
Conclusion
It is the responsibility of the obstetrician to practice and promote antibiotic stewardship. Antibiotics have a clear benefit to pregnant patients and their neonates when IAI is suspected; however, broad-spectrum antibiotics should never be used without a clear indication. Misuse of antibiotics contributes greatly to the creation of resistant strains of bacteria that are responsible for neonatal mortality and increasing antibiotic resistance.
Practice Pearls
* Diagnosis of suspected IAI requires a maternal temperature of more than 39.0[degrees]C or 38.0[degrees]C to 38.9[degrees]C with one additional risk factor: fetal tachycardia, maternal leukocytosis, or purulent cervical discharge.
* In the absence of other risk factors, consider expectant management in patients with an isolated or persistent maternal fever of less than 39.0[degrees]C.
* All febrile episodes, regardless of etiology, should be treated with antipyretics.
* Consider alternative sources of fever in peripartum patients before starting antibiotics for suspected IAI including epidural, warm ambient temperature, dehydration, physiologic response to surgery, and drug fever from misoprostol.
* After a vaginal delivery, discontinuing antibiotics for suspected IAI is appropriate for most patients.
* After a cesarean delivery, patients should receive one dose of predelivery antibiotic regimen plus one dose of clindamycin or metronidazole to cover anaerobes.
* In the rare case of persistent signs of infection after delivery, antibiotic duration should be determined based on clinical signs and symptoms.
References