Maternal sepsis is one of the five leading causes of maternal mortality worldwide. In a population-based, retrospective cohort study of more than 5 million women who delivered in the United States between 1998 and 2008, more than 1500 cases of sepsis were identified. This yielded an incidence of 29.4 cases per 100,000 births and a case fatality rate of 4.4%, with an increase in both incidence of sepsis and sepsis-related mortality across the study period.¹ This increase is thought to be due to complications associated with advanced maternal age and obesity, assisted reproductive technologies, and invasive procedures.²

Since 2004, the Surviving Sepsis Campaign has published and updated international guidelines for the management of severe sepsis and septic shock, emphasizing the utilization of a “sepsis bundle” that includes timely, broad-spectrum antibiotic therapy and early, goal-directed therapy. Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. The use of systemic inflammatory response syndrome (SIRS) criteria to identify those with sepsis has fallen out of favor because of its low specificity. Therefore a combination of clinical, laboratory, radiologic, and microbiologic data is necessary for the diagnosis of sepsis. Patients may present with fever, tachycardia, and tachypnea. Arterial hypotension and signs of organ dysfunction such as altered mental status, oliguria, and skin mottling may indicate severe disease. Taking a careful history may aid in the localization of the source of infection (e.g. a productive cough and shortness of breath may suggest pneumonia, dysuria and flank pain may suggest pyelonephritis, and a painful, purulent wound may indicate soft tissue infection). Laboratory abnormalities may include leukocytosis or leukopenia, bandemia, hypoxemia, thrombocytopenia, hyperbilirubinemia, coagulopathy, acute kidney injury, and lactic acidosis.

Because of the lack of pregnancy-specific data in the management of sepsis, it is recommended that physicians follow treatment guidelines for nonpregnant adults while being cognizant of the physiologic changes in pregnancy.³ Timely, broad-spectrum antibiotic administration after obtaining blood cultures, fluid resuscitation, early, goal-directed therapy, and source control remains the cornerstone of management. It is recommended that empiric, broad-spectrum therapy with one or more antimicrobials to be started within 1 hour of diagnosis of sepsis or septic shock. The choice of antibiotics depends on the site of infection, patient’s history, clinical status, underlying illness, and recent antibiotic exposure. Because the obstetric patient is generally young and healthy, a broad-spectrum beta-lactam such as piperacillin-tazobactam or cefepime is a reasonable starting point. These antibiotics would cover a variety of Gram-positive and -negative bacterial pathogens. Piperacillin-tazobactam also provides anaerobic coverage.

If the patient is presenting with respiratory symptoms, the addition of azithromycin to cover atypical pathogens and oseltamivir to cover influenza during the winter months is reasonable. Vancomycin should be added if the patient is at risk for or has a history of methicillin-resistant Staphylococcus aureus (MRSA). In patients with septic shock, guidelines recommend double coverage for resistant Gram-negative organisms. This is difficult to do safely in the obstetric patient because antibiotics usually used for this purpose are pregnancy Category C or D as per US Food and Drug Administration (FDA) standards. The risks and benefits may need to be assessed and individualized for each patient. The antimicrobial regimen should be reassessed in 48 hours and deescalated based on culture results.

Bloodstream infection (BSI) is associated with a high case-fatality rate (13.5%).⁴ The optimal management of bacteremia is often complex, and the effort to identify and control the source of bacteremia, such as chorioamnionitis, endometritis, urinary source, pneumonia, gastrointestinal (GI), skin soft tissue infection (SSTI), and line infection, is warranted. The incidence of bacteremia in pregnancy might be rare, but it has been associated with 10% fetal mortality. The most common sources of bacteremia in the pregnant population are chorioaminionitis (47%), urinary tract infection (UTI) (30%), and endometritis (10%).⁵ Escherichia coli and Streptococcus agalactiae were the most frequent pathogens.⁶ Up to 25% of Staphylococcus bacteremia is associated with infective endocarditis; therefore echocardiogram is recommended for any S. aureus bacteremia cases.

PREGNANCY-RELATED GROUP A STREPTOCOCCAL INFECTIONS (PUERPERAL SEPSIS)

During the mid-nineteenth century, up to 15% of women who delivered in hospitals in Paris and Vienna died of “childbed fever,” transmitted on the hands of clinicians.⁷ Group A streptococcal (GAS) (Streptococcus pyogenes) was later proved to be the main cause of puerperal sepsis. In the United States, the annual incidence of GAS postpartum infection is estimated to be 6 per 100,000 live births. Worldwide, it causes 75,000 maternal deaths per year, with a maternal mortality rate of 40% to 60% when associated with toxic shock syndrome.⁸ Pregnant women are at a 20-fold increased risk for invasive GAS infection compared to nonpregnant women, with 85% of infections occurring during the postpartum period.⁹

Risk factors for invasive GAS infection in pregnant or postpartum patients include upper respiratory tract infection with pharyngeal colonization, contact with GAS carriers during pregnancy (notably young children), premature rupture of membranes, mucosal damage, and emergency cesarean section (C-section).¹⁰ Immunologic polymorphism may play a role in the susceptibility of the patient to invasive infections because a much larger number of women are colonized with this organism than develop the disease. In addition, despite the existence of more than 150 different GAS strains, only a handful of strains are associated with invasive GAS infection in pregnant women.

GAS can cause serious invasive infection in the obstetric patient in the form of endometritis, necrotizing fasciitis, or toxic shock syndrome. Patients with puerperal sepsis typically present with nonspecific signs and symptoms of fever, abdominal pain, tachycardia, or leukocytosis, making the diagnosis difficult. Hypotension and organ dysfunction, including renal failure and Adult Respiratory Distress Syndrome (ARDS), may be signs of toxic shock syndrome.¹¹ These signs and symptoms should prompt consideration of GAS infection. Blood and urine cultures should be obtained, a pelvic exam should be performed, and vaginal discharge should be cultured. Postpartum patients should have endometrial aspiration for Gram stain and culture, which is done by extraction of tissue from the uterine lining by suction, following instillation of sterile saline in the endometrial cavity. Computed tomography (CT) scans, magnetic resonance imaging (MRI), and ultrasound may appear normal, or they may show an edematous uterus which is typical of the condition. GAS does not generally form abscesses or produce gas, unlike anaerobic pathogens.

Treatment for pregnancy-related GAS infection includes timely antibiotics and source control. Antibiotic therapy consists of intravenous (IV) penicillin G plus clindamycin. Vancomycin and daptomycin are alternatives to penicillin in allergic patients. Duration of therapy should be individualized, typically at least 14 days for bacteremia, 14 days counting from the last surgical debridement, or both. Source control is critical in this disease that has such potentially catastrophic outcomes, and this may include wound or vulvar debridement, hysterectomy, or both. The clinical efficacy of IV immunoglobulin (IVIG) has been debated in several case reports, small observational cohort studies, case-control studies, and one small, multicenter, placebo-controlled trial that were stopped prematurely due to low enrollment.¹² Although the benefits were not statistically significant, most experts would add IVIG as adjunctive therapy for streptococcal toxic shock syndrome, for which the mortality approaches 60%.

The suppression of immune functions and physiologic changes in pregnancy may increase the patient’s susceptibility to pulmonary infections, while decreasing her ability to compensate for respiratory illnesses. Community-acquired pneumonia is the most common form of pneumonia in pregnancy. In the United States, it is estimated that community-acquired pneumonia complicates about 1 in 1000 pregnancies, making it a relatively common nonobstetric complication of pregnancy.¹³ The causative agent is identified in only about half the cases.¹⁴ In adults, 60% to 80% of community-acquired pneumonia is caused by bacteria, and 10% to 15% is viral. The most common bacterial pathogen is Streptococcus pneumoniae, accounting for 30% to 50% of identified cases.

The symptoms of community-acquired pneumonia in pregnancy are similar to those in nonpregnancy, including productive cough, shortness of breath, and pleuritic chest pain. Physical examination should include evaluation for fever, intravascular volume, respiratory status, and evidence of pulmonary consolidation. A chest radiograph should be done. Findings of lobar consolidation, cavitation, and pleural effusion are more consistent with a bacterial etiology, while a more diffuse interstitial pattern suggests a viral etiology. Of note, viral pneumonia is often complicated by secondary bacterial infection. Notably, S. aureus has been reported to complicate influenza infection.

The yield of blood cultures in community-acquired pneumonia is relatively low, while the yield of respiratory cultures is variable. Hence, these should be considered when clinically indicated. Pregnant patients hospitalized with community-acquired pneumonia should be empirically treated with a beta-lactam (ceftriaxone, cefotaxime, or ampicillin-sulbactam) and a macrolide (azithromycin). According to the Infectious Diseases Society of America (IDSA)/American Thoracic Society (ATS) guidelines on community-acquired pneumonia, this empiric regimen would cover the most common pathogens (S. pneumoniae, Haemophilus influenzae, S. aureus) that cause severe community-acquired pneumonia, all the atypical pathogens (including the Legionella species), and most of the relevant Enterobacteriaceae species (Klebsiella pneumoniae, E. coli). For those patients at risk for MRSA, vancomycin should be added. Patients with suspected Pseudomonas aeruginosa pneumonia should be treated with an antipseudomonal beta-lactam (piperacillin-tazobactam, cefepime, imipenem, or meropenem).¹⁵ Empiric regimens should be deescalated if a specific pathogen is isolated based on susceptibility results. The recommended duration of treatment for uncomplicated, community-acquired pneumonia is a minimum of 5 days.

Most cases of viral pneumonia during pregnancy are caused by influenza viruses. Influenza is spread by respiratory droplets. Infection is prevalent during the winter months (December–March). Reports from the 2009 H1N1 pandemic demonstrated that pregnant women were four times more likely than the general population to be hospitalized with the infection. In the United States, 8% to 16% of all deaths from H1N1 infection occurred in pregnant women, while this group represented only 1% of the population.¹⁶

Clinical presentation in pregnant women is the same as in nonpregnant patients, with an incubation period of 1–4 days, followed by a syndrome of malaise, myalgias, fever, rhinorrhea, cough, headache, and sore throat. A thorough physical examination should be performed as described previously, looking for fever, signs of respiratory failure, and bacterial superinfection. A nasopharyngeal swab should be sent for influenza polymerase chain reaction (PCR) testing. Pneumonia, both primary viral or secondary bacterial superinfection, is the most common complication, developing in about 12% of pregnant women with influenza. Preterm delivery and C-section were reported up to 30%, due to severe maternal illness.¹⁷ Oseltamivir is recommended for pregnant women with influenza. Nonetheless, the best way to prevent influenza is through vaccination.¹⁸

Fungal pneumonias are usually opportunistic infections that occur in immunocompromised hosts. There is a fungal pneumonia that deserves special mention with respect to the pregnant patient. Pregnancy is one of the most commonly identified risk factors for the development of severe and disseminated coccidioidomycosis, especially in late pregnancy and the immediate postpartum period.¹⁹ Coccidioides spp. are endemic to regions in the Western hemisphere, namely in the southwestern United States, parts of Mexico, and Central and South America.²⁰ Diagnosis for Coccidioides spp. is by serology.

The treatment of coccidioidomycosis during pregnancy is complicated by the potential teratogenicity of azole antifungals observed in a small number of cases in the first trimester of pregnancy. The IDSA recommends IV amphotericin B for the management of nonmeningeal coccidioidal infection during the first trimester of pregnancy. Fluconazole may be considered after the first trimester, or amphotericin B can be administered throughout pregnancy.²¹ Practically, a liposomal preparation of amphotericin B is often used in the place of conventional amphotericin B to decrease the risk of nephrotoxicity.

Urinary tract infections (UTIs) are defined as either acute cystitis or acute pyelonephritis. It is thought that the smooth muscle relaxation and subsequent ureteral dilation taking place due to pregnancy facilitate the ascent of bacteria from the bladder to the kidneys. Pressure on the bladder by the gravid uterus may also play a role. The immunosuppression associated with pregnancy may also contribute to the risk of infection. As in nonpregnant patients, E. coli is the most common uropathogen found in UTIs in pregnant women.²² Differential diagnosis includes vaginitis and urethritis. If not already performed, testing for sexually transmitted infections (e.g. chlamydia, gonorrhea) should be done.

Acute cystitis should be suspected when the patient complains of dysuria. Urinary frequency and urgency may be symptoms of cystitis, but they also can occur as a result of normal physiologic changes of pregnancy. Hematuria and pyuria are often seen on urinalysis. Systemic symptoms such as fevers and chills are generally absent. These signs, in addition to flank pain and costovertebral tenderness, should alert the clinician for possible acute pyelonephritis. In patients with recurrent cystitis, prophylaxis should be considered. If cystitis is thought to be sexually related, postcoital prophylaxis is reasonable, or it can be taken continuously. The choice of antibiotic should be based on the susceptibility of the isolated bacteria strain.

Acute pyelonephritis is a common nonobstetric indication for antepartum hospitalization, complicating up to 2% of all pregnancies in the United States. A total of 80% to 90% of cases are diagnosed in the second and third trimesters, and nearly 25% of women have more than one recurrence during the same pregnancy. In a retrospective cohort study reviewing more than 500,000 singleton pregnancies over an 18-year period (1993–2010), women with acute pyelonephritis during pregnancy were noted to have significantly increased risk of anemia, septicemia, acute renal failure, respiratory failure, spontaneous preterm birth, and low-birth-weight infants.²³ E. coli was found to be the most frequently isolated uropathogenic bacteria, accounting for 82.5% of positive cultures. For hospitalized pregnant patients without history of infection with multidrug-resistant organisms (MDROs), empiric IV ceftriaxone is an appropriate choice while awaiting the results of blood and urine cultures. Duration of treatment for acute, uncomplicated pyelonephritis is 10 to 14 days.²⁴

Data from the 1960s and 1970s noted that women with asymptomatic bacteriuria in early pregnancy are 20 to 30 times more likely to develop pyelonephritis during pregnancy, and these women were more likely to have premature delivery and low-birth-weight infants. Subsequent clinical trials have consistently demonstrated that treatment of asymptomatic bacteriuria during pregnancy decreases the risk of pyelonephritis from 20% to 35% to 1% to 4% and decreases the frequency of low-birth-weight infants and preterm deliveries. Hence routine screening for and treatment of asymptomatic bacteriuria during pregnancy has become the standard of care in many developed countries.²⁵ The recommended screening test is a urine culture because screening for pyuria has a low sensitivity (only about 50%). The optimal frequency of screening is not well defined. Although the most appropriate treatment course for bacteriuria in pregnant women has not been established, the IDSA recommends a duration of 3 to 7 days. The choice of antibiotics is determined by culture results.

Acute gastroenteritis is a diarrheal disease of rapid onset, lasting less than 2 weeks, and may be accompanied by nausea, vomiting, fever, and/or abdominal pain. Respiratory symptoms may be present in 10% of patients.²⁶ It is a common illness; about 179 million cases occur in the United States annually, and most cases are viral. Norovirus is the most common cause of acute gastroenteritis and the second most common cause of hospitalization for acute gastroenteritis in the United States.²⁷ Other common viral pathogens include rotavirus, enteric adenovirus, and astrovirus. Occurring most commonly in the winter and spring, viral gastroenteritis does not typically cause bloody diarrhea. In addition to patients with alarm symptoms of severe dehydration, abnormal electrolytes or renal function, and bloody stool, pregnant patients should be hospitalized and undergo evaluation for other potential causes of diarrhea. If the patient was hospitalized or prescribed antibiotics in the last 3 months, Clostridium difficile testing is reasonable to perform. Stools should be submitted for bacterial culture. Ovum and parasite testing should be done based on exposure history (e.g. travel, hiking, or oral-anal sexual activity). If bloody diarrhea is present, stool should be submitted for E. coli O157:H7 and Shiga toxin testing.

Treatment for acute gastroenteritis is generally supportive, especially if the etiology is clearly viral. For those with severe disease that may be bacterial, pregnant patients may be treated with azithromycin. In stable patients with bloody diarrhea and suspicion for enterohemorrhagic E. coli (EHEC) infection, it is reasonable to hold antibiotics until EHEC is ruled out, as antimicrobial therapy and antimotility drugs enhance toxin release and increase the risk of hemolytic uremic syndrome in these patients.

Listeria monocytogenes causes invasive foodborne illness mainly in elderly, newborn, and immunocompromised patients. In pregnancy-related listeriosis, the mother often develops nonspecific symptoms 1 to 14 days prior to fetal distress, leading to fetal-disseminated disease, with a high mortality rate of about 30%.²⁸ In the United States, the average annual incidence of listeriosis was 0.29 per 100,000 people in 2009 to 2011, and 14% of those cases were pregnancy related. Compared with the general population, rates were 4 times higher for adults 65 years and older, 10 times higher for pregnant women, and 24 times higher for pregnant Hispanic women.²⁹ It is the second-highest cause of foodborne mortality, responsible for 30% of fatal foodborne cases between 1996 and 2005, with a case fatality rate of almost 17%. Outbreaks were often associated with soft cheeses, deli meats, and raw produce items. The treatment of choice for listeriosis is ampicillin; the duration is at least 14 days for bacteremia, and the regimen should be individualized, taking into consideration the location of infection, immune status, drug allergies, and renal and hepatic functions. Patients who are allergic to penicillin should be desensitized or treated with trimethoprim-sulfamethoxazole. However, trimethoprim-sulfamethoxazole should be avoided during the first trimester and the last month of pregnancy, during which time vancomycin is an acceptable alternative.