Common Bacterial and Viral Infections: Review of Management in the Pregnant Patient

Urinary Tract Infections

UTIs are the most common bacterial infection in pregnancy.^2,3 The incidences of asymptomatic bacteriuria (ASB), cystitis, and pyelonephritis are 2% to 10%, 1% to 2%, and ≤1%, respectively. ⁴ Because of physiological changes in the urinary tract during pregnancy, cystitis and ASB are more likely to result in pyelonephritis than in nonpregnant patients. Any urinary tract bacteriuria (colony count ≥100 000 CFU/mL), including ASB, has been associated with adverse outcomes, including preterm birth, premature rupture of membranes (PROM), triple I (Intrauterine Inflammation or Infection), postpartum fever, and neonatal infection.^2,5-8 Screening and treatment of ASB during pregnancy is currently standard of care, although a recent randomized controlled trial in women with uncomplicated singleton pregnancies did not show that ASB in midtrimester pregnancy was associated with low birthweight or preterm birth but did show an association with pyelonephritis.^9,10

The most common pathogen causing UTIs in pregnancy is Escherichia coli (70%-82%).^2-4,11 Other pathogens include Klebsiella, Enterobacter, Citrobacter, Proteus, Pseudomonas, group B Streptococcus (GBS), and Enterococcus spp. There is no clear consensus in the literature on the preferred antibiotic, so prescribing should be based on drug safety considerations and local resistance patterns.^2,4,5 First-, second-, and third-generation cephalosporins, semisynthetic penicillins with or without β-lactamase inhibitors, and nitrofurantoin are commonly recommended antibiotics.^4,12 A single dose of fosfomycin is also an option, maintaining high concentrations in the urine for 3 days after treatment.^4,11 In addition, pregnant women with GBS UTIs should receive intrapartum prophylaxis to prevent neonatal infection, as discussed later. ² There are limited data on the use of carbapenems in pregnancy, but they could be considered for multidrug-resistant UTIs. ⁴ Nitrofurantoin may be utilized in the second and third trimesters, although there is a low risk of hemolytic anemia, linked to glucose-6-phosphate dehydrogenase deficiency, which may manifest in the neonate at term.^4,13-15 Trimethoprim/sulfamethoxazole (TMP/SMX), although efficacious, should be used with caution in the first trimester because of the risk of congenital defects and avoided after 32 weeks of gestation because of the risk of severe jaundice and kernicterus in the neonate.^1,4 Fluoroquinolones should be avoided because of high risk of teratogenicity and adverse drug events. The typical duration for cystitis and ASB in pregnancy is 3 to 7 days.^4,9,16

Although some data suggest that outpatient or emergency department treatment of pyelonephritis may be considered in select stable pregnant patients, most pregnant patients with pyelonephritis should initially be admitted and treated with intravenous (IV) antibiotics and hydration.^5,17 When possible, blood cultures should be obtained prior to antibiotic administration. Conversion to oral antibiotics may be considered after the patient has been afebrile for 48 hours. Empirical treatment options for pyelonephritis include a cephalosporin such as ceftriaxone or ampicillin plus gentamicin.^2,4,12 The empirical regimen should be tailored to the local resistance patterns and patient factors for resistant pathogens (eg, prior antibiotic use and cultures). Definitive therapy should be optimized based on culture and susceptibilities, although agents such as nitrofurantoin and fosfomycin should be avoided because of lack of effectiveness in pyelonephritis. If no improvement occurs with appropriate definitive treatment, imaging should be considered to rule out renal abscesses, nephrolithiasis, or other structural abnormalities.^4,17 The typical duration of therapy is 7 to 14 days. ⁴

In contrast to nonpregnant patients, follow-up cultures should be obtained after treatment for all UTIs in pregnancy.^4,17 Prophylactic antibiotics (nitrofurantoin 50-100 mg daily or cephalexin 250-500 mg daily) may be considered to reduce the risk of recurrence. ⁴

Pelvic Inflammatory Disease

Pelvic inflammatory disease (PID) is an inflammatory disorder of the upper genital tract, which can lead to infertility, ectopic pregnancy, and chronic pelvic pain. ¹⁸ Although uncommon in pregnancy, PID is most frequently seen during the first trimester. ¹⁹ Women with suspected PID are at high risk for pregnancy complications and should be hospitalized and treated with 14 days of IV antibiotics.^18,20,21 Ideally, therapy should cover Neisseria gonorrhoeae, Chlamydia trachomatis, and anaerobic bacteria. ²⁰ Other potential pathogens include Mycoplasma genitalium, streptococci, staphylococci, Escherichia coli, and Haemophilus influenzae. There are limited data to support any particular antibiotic regimen for use in pregnancy, but potential treatment options are listed in Table 1. Doxycycline should be avoided in pregnancy because of teratogenic effects, including adverse effects on fetal bone health.^1,4 Sexual partners within 60 days of symptom onset should be tested and presumptively treated for gonorrhea and chlamydia. ²¹ If last sexual contact was >60 days prior, the most recent sexual partner should be treated.

OPEN IN VIEWER

Table 1.

Preferred and Alternative Therapy for Common Bacterial and Viral Infections in the Pregnant Patient. ^a

Disease State	Preferred Therapy	Alternative Therapy	Additional Recommendations
Uncomplicated urinary tract infection cystitis/asymptomatic bacteriuria5,12,16	Fosfomycin 3 g orally in a single dose, or narrowest penicillin or cephalosporin if susceptibilities are available, or nitrofurantoin 100 mg orally q12 hours for 5-7 days b	Cephalexin 250-500 mg orally q6 hours for 7 days, or amoxicillin/clavulanate 250/125 mg orally q8 hours for 7 days, or TMP/SMX 1 DS orally q12 hours for 3 days (if contraindication to β-lactams and other preferred therapy)	The choice of antibiotics should be guided by local resistance patterns and altered based on susceptibilities
Pelvic inflammatory disease18,20,21	Ceftriaxone 2 g IV once daily, plus erythromycin lactobionate 50 mg/kg IV once daily or continuous IV infusion (or azithromycin 1 g IV or orally followed by a second dose 1 week later; see comments for preference), plus metronidazole 500 mg IV or orally q8 hours. Treat for 14 days.	Cefotetan 2 g IV q12 hours or cefoxitin IV 2 g q6-8 hours may be considered in replacement of ceftriaxone plus metronidazole to be used in combination with azithromycin or erythromycin (based on regional susceptibilities) Severe penicillin or cephalosporin allergy: infectious diseases consultation recommended	There is insufficient evidence to recommend a specific regimen; however, parenteral therapy is advised. Use of erythromycin vs azithromycin should be determined based on regional susceptibilities for gonorrhea and chlamydia. Maximum daily dose of erythromycin: 4 g. Doxycycline-containing regimens should be avoided
Chlamydia 21	Azithromycin 1 g orally in a single dose	Amoxicillin 500 mg orally 3 times a day for 7 days, or erythromycin base 500 mg orally 4 times a day for 7 days, or erythromycin base 250 mg orally 4 times a day for 14 days, or erythromycin ethylsuccinate 800 mg orally 4 times a day for 7 days, or erythromycin ethylsuccinate 400 mg orally 4 times a day for 14 days	Abstain from intercourse until symptoms are resolved and 7 days, regardless of regimen. Erythromycin estolate is contraindicated during pregnancy. Retest in 3 weeks and 3 months following treatment. Pregnant patients <25 years old or at high risk for infection: retest during third trimester
Uncomplicated gonococcal infections of the cervix, urethra, and rectum 21	Ceftriaxone 250 mg IM in a single dose, plus azithromycin 1 g orally in a single dose	Cefixime 400 mg orally in a single dose, plus azithromycin 1 g orally in a single dose Severe penicillin or cephalosporin allergy: infectious diseases consultation recommended	Abstain from intercourse until symptoms are resolved and 7 days, regardless of regimen. Retest in 3 months High-risk patients: retest during third trimester
Syphilis 21	Early latent syphilis: benzathine penicillin G 2.4 million units IM in a single dose Late latent syphilis or latent syphilis of unknown duration: benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals Tertiary syphilis with normal CSF examination c : benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals Neurosyphilis and ocular syphilis: aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or continuous infusion, for 10-14 days	None recommended Mild or severe penicillin allergy: desensitization is recommended, followed by treatment determined by stage	Providers should be aware of medication differences in formulation, dose, and duration Patients with concurrent HIV infection: refer to CDC treatment guidelines for more information
Bacterial vaginosis 21	Metronidazole 500 mg orally q12 hours for 7 days or metronidazole gel 0.75%, 1 full applicator (5 g) intravaginally, once daily for 5 days, or clindamycin cream 2%, 1 full applicator (5 g) intravaginally at bedtime for 7 days	Clindamycin 300 mg orally q12 hours for 7 days, or clindamycin ovules 100 mg intravaginally once at bedtime for 3 days	Clindamycin ovules may weaken latex or rubber products (condoms or diaphragms) for 5 days following use Abstain from intercourse or use condoms while being treated. Partners do not need to be treated
Chancroid 21	Azithromycin 1 g orally in a single dose or ceftriaxone 250 mg IM in a single dose	Erythromycin base 500 mg orally q8 hours for 7 days	Treat sexual partners if there was contact with patient within 10 days of symptoms
Herpes simplex virus (genital)21,44,48	First clinical episode: acyclovir 400 mg orally 3 times daily for 7-10 days, or acyclovir 200 mg orally 5 times daily for 7-10 days, or valacyclovir 1 g orally twice daily for 7-10 days Episodic therapy (start within 1 day of symptoms): acyclovir 400 mg orally 3 times daily for 5 days, or acyclovir 800 mg orally twice daily for 5 days, or acyclovir 800 mg 3 times daily for 2 days, or valacyclovir 500 mg orally twice daily for 3 days, or valacyclovir 1 g orally once daily for 5 days Suppressive therapy: acyclovir 400 mg orally 3 times daily or valacyclovir 500 mg orally twice daily		Begin suppressive therapy after 36 weeks of gestation and continue until delivery in patients with active genital HSV lesions
Upper respiratory tract infections49-52	Acute bacterial rhinosinusitis: amoxicillin/clavulanate 875/125 mg orally q12 hours for 5-7 daysAcute bronchitis and the common cold: antibiotics not recommended	Acute bacterial rhinosinusitis: cefuroxime 250 mg orally q12 hours or cefpodoxime 200 mg orally q12 hours, plus/minus clindamycin 300 mg orally q6-8 hoursSevere penicillin or cephalosporin allergy: azithromycin 500 mg orally ×1, then 250 mg once daily ×4 days	Nonpharmacological management is preferred given the predominance of viral causes
Influenza59-61,63	Treatment: oseltamivir 75 mg orally twice daily for 5 daysProphylaxis: oseltamivir 75 mg orally once daily for 10 days	Treatment: zanamivir 10 mg (2 inhalations) twice daily for 5 daysProphylaxis: zanamivir 10 mg (2 inhalations) once daily for 10 days	Therapy should begin in exposed women without waiting for laboratory confirmation. Oseltamivir may be increased in critically ill to 150 mg, although no direct clinical benefit is documented
Community-acquired pneumonia66,67,69	Otherwise healthy with no recent antimicrobial use: azithromycin 500 mg ×1 orally, then 250 mg orally once daily for 4 daysComorbidities or recent antimicrobial use: azithromycin 500 mg ×1 orally, then 250 mg orally once daily for 4 days plus amoxicillin/clavulanate 875/125 mg orally q12 hoursInpatient, non-ICU admission: azithromycin 500 mg ×1 orally, then 250 mg orally once daily for 4 days plus ceftriaxone 1-2 g IV once daily or ampicillin 1-2 g IV q6 hoursInpatient, ICU admission:Without Pseudomonas risk: ceftriaxone 1-2 g IV once daily or ampicillin/sulbactam 3 g IV q6 hours plus azithromycin 500 mg ×1 IV, then 250 mg IV or orally daily for 4 daysRisk for Pseudomonas: piperacillin/tazobactam 3.375 g IV q8 hours over 4 hours or cefepime 1-2 g IV q8 hours plus aminoglycoside inhaled/IV (if APBL risk factors present) plus azithromycin 500 mg ×1 IV, then 250 mg IV once daily for 4 days	Alternative β-lactams include ceftriaxone 1-2 g IV once daily, or cefpodoxime 200 mg orally q12 hours, or cefuroxime 500 mg orally q12 hours
Acute diarrheal infections71,72	Shigellosis: azithromycin 500 mg orally once daily for 3-5 daysYersiniosis: ceftriaxone 1 g IV once daily or cefixime 400 mg orally once dailySalmonellosis: ceftriaxone 1 g IV once daily or cefixime 400 mg orally once dailyCampylobacteriosis: azithromycin 500 mg orally daily for 3 days	Shigellosis: ceftriaxone 1 g IV once daily (severe disease)Salmonellosis: azithromycin 500 mg orally once daily for 5-7 days after 1 g oral dose or ampicillin 1-2 g IV q6 hours	Most cases are self-limiting, requiring no antibiotics
Clostridioides difficile colitis76,77	Vancomycin 125 mg orally q6 hours for 10 days (increase dose to 500 mg orally if critically ill/fulminant disease)	Potentially fidaxomicin but sparse clinical data	IDSA/SHEA guideline update makes no specific recommendation regarding treatment of pregnant patients but ACG guidelines recommends against metronidazole. If critically ill or fulminant disease, may consider addition of IV metronidazole
Group B Streptococcus 78	Penicillin G 5 million units IV once, then 2.5-3 million units IV q4 hours, or continuous infusion until delivery	Ampicillin 2 g IV once, then 1 g IV q4 hours until deliveryMild penicillin allergy: cefazolin 2 g IV once, then 1 g IV q8 hours until deliverySevere penicillin allergy: vancomycin 1 g IV q12 hours or clindamycin 900 mg IV q8 hours until delivery	Erythromycin is no longer an acceptable alternative treatment option. Refer to local clindamycin resistance rates prior to using empirically
Listeriosis 84	IV ampicillin (minimum dose of 2 g IV q8 hours) for ≥14 days	TMP/SMX 200-320 mg of TMP in divided doses IV or orally once daily for ≥14 days	Gentamicin 2.5 mg/kg/d IV may be considered for synergy with ampicillin
Intrauterine inflammation or infection89-91	Ampicillin 2 g IV q6 hours plus gentamicin 2 mg IV load then 1.5 mg/kg IV q8 hours. Gentamicin 5 mg/kg IV once daily may also be used. For anaerobic coverage, add clindamycin 900 mg IV q8 hours or metronidazole 500 mg IV q6-8 hours	Mild penicillin allergy: gentamicin 2 mg/kg load then 1.5 mg/kg IV q8 hours and cefazolin 2g IV q8 hoursSevere penicillin allergy: clindamycin 900 mg IV q8 hours or gentamicin 2 mg/kg IV load, then 1.5 mg/kg IV q8 hours and vancomycin 1 g IV q 12 hours. Gentamicin 5 mg/kg IV once daily may also be usedOther alternatives: ampicillin-sulbactam 3 g IV q6 hours, piperacillin-tazobactam 3.375 g IV q6 hours or 4.5 g IV q8 hours, cefotetan 2 g IV q12 hours, cefoxitin 2 g IV q8 hours, or ertapenem 1 g IV once daily	Antibiotic selection based on prevalent organisms and institutional susceptibilities. Treatment duration based on resolution of clinical symptoms
Surgical antibiotic prophylaxis 93	Cefazolin 1 g IV 60 minutes prior to procedure	Severe penicillin or cephalosporin allergy: clindamycin 900 mg IV and aminoglycoside 5 mg/kg IVObese patients: cefazolin 2-3g IV	Significant allergy defined in guidelines as anaphylaxis, angioedema, respiratory distress, or urticaria

Abbreviations: ACG, American College of Gastroenterology; APBL, anti-pseudomonal beta-lactam; CDC, Centers for Disease Control and Prevention; CSF, cerebrospinal fluid; DS, double strength; HIV, human immunodeficiency virus; HSV, herpes simplex virus; ICU, intensive care unit; IDSA, Infectious Diseases Society of America; IM, intramuscular; IV, intravenous; SHEA, Society for Healthcare Epidemiology of America; TMP/SMX, trimethoprim/sulfamethoxazole.

a

Mild penicillin allergy: identified as non–IgE-mediated delayed reactions such as urticarial rash following allergy reconciliation. This does not include other serious non–IgE-mediated reactions such as Stevens-Johnson Syndrome, which should preclude use of all related β-lactam antibiotics. Severe penicillin allergy: identified as IgE-mediated or anaphylactoid reaction following allergy reconciliation.

b

Nitrofurantoin is not a preferred therapy in the first trimester or at term. See text for additional trimester-specific and organism-specific comments and for treatment of pyelonephritis.

c

CSF examination is required before treatment. Antibody titers should be minimally repeated at 28 to 32 weeks of gestation and at delivery.

Cervicitis

Cervicitis is most commonly caused by Chlamydia trachomatis and Neisseria gonorrhoeae.^19,21 Other potential causes include actinomycetes, Mycoplasma hominis, Ureaplasma urealyticum, cytomegalovirus, tuberculosis, and other bacteria associated with bacterial vaginosis (BV). Treatment should be based on laboratory confirmation. Presumptive treatment with antibiotics covering C trachomatis and N gonorrhoeae should be given to those at high risk if testing is not possible or with high likelihood of loss to follow-up. In addition, treatment for trichomoniasis (Trichomonas vaginalis) and BV should be initiated if detected. ²¹ The treatment for C trachomatis, N gonorrhoeae, and BV are discussed in the following sections. The recommended regimen for the treatment of trichomoniasis in pregnancy is metronidazole 2 g orally as a single dose. ²¹

Chlamydia

Chlamydia infection (Chlamydia trachomatis) is the most frequently reported sexually transmitted infection (STI) in the United States, with more than 1.5 million cases in 2016. ²² Patients with chlamydia or gonorrhea are at risk for complications such as PID, ectopic pregnancy, and infertility. Patients are largely asymptomatic. If untreated during pregnancy, premature delivery, stillbirth, low birth weight, and neonatal ophthalmia may result. Neonatal pneumonia is also a concern with maternal chlamydia infections. ²²

Prompt treatment is recommended (Table 1). Azithromycin is considered first-line, with demonstrated safety and efficacy during pregnancy.^23-25 In 2 randomized controlled trials comparing amoxicillin with azithromycin, no difference in efficacy was seen.^23,24 In a retrospective cohort study of 277 pregnant women, efficacy was demonstrated with a 7-day negative test-of-cure of 97% (95% CI = 92.9-99.2) for azithromycin, 64% (95% CI = 44.1-81.4) for erythromycin (P < 0.001), and 95% (95% CI = 76.2-99.9) for amoxicillin (P = 0.71). ²⁵ Single-dose azithromycin regimens administered should be directly observed by a health care provider. Doxycycline, a commonly recommended alternative, should be avoided in pregnancy.^1,21 Test-of-cure to document eradication should be performed at 3 to 4 weeks and 3 months following treatment. Pregnant patients <25 years old or at high risk for infection should be retested in the third trimester.

Gonorrhea

Gonococcal infection (N gonorrhoeae) is the second most common reported STI in the United States, with more than 460 000 cases in 2016. ²² As with chlamydia, patients with gonorrhea are largely asymptomatic. If untreated, premature delivery, stillbirth, low birth weight, and neonatal ophthalmia may result.

Dual treatment with ceftriaxone and azithromycin is recommended for pregnant patients (Table 1). In addition to the ease of administration, azithromycin provides a second mechanism of action, has potential to slow the development of resistance, is proven effective against uncomplicated urogenital gonorrhea, and is the treatment of choice for C trachomatis infection (a common coinfection).^22,26,27 Clinicians should be aware of varying susceptibilities by region. Any cephalosporin treatment failure should be reported to the CDC via public health authorities. ²¹ In patients with a severe cephalosporin allergy or other reasons to prohibit recommended treatment, an infectious disease consultation is recommended. Ceftriaxone intramuscular injection is usually provided in the office setting, and coadministration with single-dose azithromycin is recommended. Pharyngeal gonococcal infection treatment should be considered if oral sexual activity has been reported. All treated patients should be retested within 3 months, and high-risk patients should be retested during the third trimester. ²¹ Reinfection may be attributable to treatment failure but is often related to lack of partner treatment. Treatment of all sexual partners is encouraged.

Syphilis

Caused by Treponema pallidum, syphilis is classified by stage (e.g. primary, secondary, and tertiary) based on clinical presentation and timing of infection. ²¹ Latent syphilis lacks clinical symptoms and is not considered sexually transmitted. Neurosyphilis can develop if the central nervous system is involved and requires additional testing (eg, lumbar puncture and cerebral spinal fluid examination) to confirm diagnosis. The risk of fetal infection exists at all stages, but the highest risk is during the primary and secondary stages. Fetal risk includes death, preterm birth, and congenital infection resulting in future disabilities. ²² Treatment during pregnancy is recommended to prevent congenital syphilis. ²⁸ Rising or consistently high antibody titers may suggest treatment failure or reinfection, and retreatment should be considered. ²¹ An evaluation of congenital syphilis should occur if the patient is diagnosed during the second half of pregnancy, and treatment should begin immediately in the neonate.

Although parenteral penicillin G is the treatment of choice for any diagnosis of syphilis, the formulation, dose, and duration differ. ²¹ Providers should be aware of the indications for each formulation (benzathine, aqueous procaine, or aqueous crystalline) in order to help prevent medication errors (Table 1). Counseling should include the possibility of a Jarisch-Herxheimer reaction, a cytokine-mediated acute febrile response accompanied by headache and myalgias, that usually occurs within 24 hours of treatment initiation. In pregnant patients, this reaction is associated with early labor and fetal distress.

While penicillin G is the only known effective antimicrobial for preventing disease transmission to the fetus, little is known about the optimal dose or duration in pregnant patients.^21,29-33 Antibody titers should be repeated, at a minimum, at 28 to 32 weeks gestation and at delivery; however, some cases may require monthly serological assessment. ²¹ Limited data exist to guide therapy decisions for pregnant patients with latent syphilis. Available data are of low quality, with small sample sizes, lack of disease information, and no evidence of adverse reactions or other therapeutic factors. ³⁴ The goal of therapy is to prevent fetal transmission and maternal complications. ²¹ If patients do receive treatment during the latent stage, a single missed dose requires the patient to repeat the entire course of therapy.

Although some alternative treatment regimens have been used in nonpregnant patients, only penicillin G is recommended to treat syphilis during pregnancy. ²¹ Desensitization should occur in patients with syphilis of any stage who have a documented penicillin allergy, unless they have a history of severe non–IgE-mediated reactions (eg, Stevens-Johnson syndrome, hemolytic anemia), in which they should avoid any use of penicillin. ²¹ Skin testing or oral graded penicillin dose challenge may be considered for other patients in a controlled setting in which treatment for adverse reactions is available. Patients with a negative penicillin allergy skin test (PAST) may receive penicillin, and patients with a positive skin test should be desensitized. Further detailed recommendations can be found in the CDC’s Sexually Transmitted Diseases Guidelines. ²¹

If benzathine penicillin G is not available or in patients with a penicillin allergy in which desensitization is not possible, the World Health Organization 2016 guidelines suggest that erythromycin or ceftriaxone may be considered with caution; however, this recommendation was not supported by the CDC 2015 guidelines.^21,34 Doses and schedules can be found in Table 1 for early and late syphilis. It is important to note that neither of these medications cross the placental barrier completely, and therefore, the fetus will not be treated. If either of these therapies is used, infants will require treatment after delivery. ³⁴ Doxycycline, a potential alternative, should be avoided during pregnancy. ¹

Bacterial Vaginosis

The most common cause of vaginal discharge in women of childbearing age is BV. ²¹ The National Health and Nutrition Examination Survey (NHANES) determined a prevalence of 29% in the general population of women 14 to 49 years old and 52% in African Americans. ³⁵ BV is a polymicrobial infection resulting from a change in the vaginal flora caused by increased anaerobic bacteria. ²¹ Pregnant women with BV are at high risk for a variety of complications, including spontaneous abortion, intra-amniotic infection, PROM, preterm labor, preterm birth, and postpartum endometritis.^21,35

All symptomatic pregnant patients should be treated with metronidazole or clindamycin. ²¹ Cure rates are similar between medications. ³⁶ Oral and vaginal preparations are equally efficacious.^21,37 Although concerns of metronidazole use during the first trimester of pregnancy exist, multiple studies have not demonstrated teratogenicity.^1,38 Screening and treatment of BV in asymptomatic pregnant women is controversial but is not currently supported by recent evidence.^21,39 Furthermore, a Cochrane meta-analysis determined that treatment of symptomatic or asymptomatic BV during pregnancy did not reduce preterm birth or PROM. ⁴⁰ Tinidazole, an alternative BV treatment in nonpregnant women, should be avoided during the first trimester because of risk demonstrated in animal data. ⁴¹

Chancroid

Chancroid is a less common cause of genital, anal, or perianal ulcers, mostly associated with sporadic outbreaks. ²¹ Although the prevalence of chancroid is declining, it remains a risk factor for the transmission of HIV infection. There are no reports of chancroid directly affecting pregnancy outcomes. Haemophilus ducreyi, a gram-negative, anaerobic, coccobacillus, is the causative agent. Diagnosis is primarily clinical because H ducreyi testing is not commonly available. Empirical treatment options include azithromycin or ceftriaxone because of their single-dose regimens. Ciprofloxacin or erythromycin are alternatives; however, fluoroquinolones should generally be avoided in pregnancy. ¹

Herpes Simplex Virus

According to the NHANES study from 2005 to 2010, 53.9% of adults aged 14 to 49 years are seropositive for HSV-1, whereas 15.7% are seropositive for HSV-2. ⁴² In pregnancy, the overall seroprevalence of HSV is 72%. ⁴³ Most commonly, genital tract viral shedding at the time of vaginal delivery may lead to neonatal transmission during or after delivery. ⁴² In the neonate, HSV can result in several clinical syndromes, including skin, eye, and mouth disease (45%); disseminated disease (25%), with a mortality rate of almost 30%; and central nervous system disease (30%), with a mortality rate of 4%. ⁴²

Because routine testing does not predict HSV viral shedding at delivery, intervention is currently only recommended for pregnant women with active genital lesions during the third trimester. ⁴⁴ Clinical trials with acyclovir and valacyclovir treatment after 36 weeks of gestation significantly reduced recurrences in pregnant women, without an increase in fetal or maternal toxicities.^45-47 Although these trials have not all significantly reduced the incidence of recurrence or cesarean delivery and suppressive therapy has not always decreased neonatal HSV infection, the American College of Obstetricians and Gynecologists (ACOG) recommends antiviral therapy in patients with active genital lesions beginning at 36 weeks of gestation with acyclovir or valacyclovir (Table 1).^21,44,48 In addition, the CDC recommends that women with active, recurrent genital herpetic lesions at the onset of delivery should undergo cesarean section to reduce risk of neonatal transmission. ²¹

Upper Respiratory Tract Infections

Upper respiratory tract infections (URTIs) comprise a variety of illnesses, the most prevalent of which include the common cold, acute rhinosinusitis, and acute bronchitis. The common cold is primarily viral with symptomatic management using analgesics and cough suppressants as the best strategy.^49,50 Nonpharmacological management with steam humidifiers or vaporizers may also be considered. Rates of acute rhinosinusitis are 6-fold higher than rates observed in nonpregnant patients. ⁵¹ Current guidelines support the use of antibiotics in bacterial rhinosinusitis only, although a viral etiology is more common.^52,53 Amoxicillin-clavulanate is considered first-line therapy, with a shorter course (5-7 days) having effectiveness comparable to that of longer courses (Table 1). ⁵² Nasal decongestants may provide symptomatic relief; however, overuse leads to rhinitis medicamentosa. ⁵¹ Acute bronchitis is caused by a virus in more than 90% of cases. ⁵⁴ Thus, routine use of antibiotics is not recommended. Symptomatic management similar to what is recommended for the common cold is considered the best therapeutic approach, and over-the-counter medicines are commonly used in pregnancy. ⁵⁵ Cough suppressants such as dextromethorphan and guaifenesin may be used in pregnancy, whereas codeine-containing products should likely be avoided late in pregnancy because of the potential increased likelihood of cesarean delivery and postpartum hemorrhage.^49,56 Decongestants, such as pseudoephedrine and phenylephrine, and antihistamines, including diphenhydramine, are considered safe in pregnancy and may be used for symptom relief in the common cold. ⁴⁹

Pertussis is another URTI that deserves mention with regard to pregnancy. ACOG recommends that pregnant women receive the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine between 27 and 36 weeks of gestation during each pregnancy. ⁵⁷ Partners and family members should also receive the Tdap vaccine at least 2 weeks before coming in contact with the newborn.

Influenza

Pregnant women are at especially high risk of morbidity and mortality resulting from influenza infection, both during seasonal periods and pandemics. ⁴³ Mortality rates during pandemics have been reported to be between 20% and 50% in pregnant women, and complications (severity of illness, risk of hospitalization, duration of hospitalization) have been found to be up to 5 times higher in pregnant women.^43,58 Influenza in pregnant women has been associated with spontaneous abortion, preterm birth, and birth defects. ⁴³

In accordance with the CDC and the ACOG recommendations, the best prevention for influenza and its complications is yearly vaccination.^59,60 Women who are pregnant or planning to be pregnant should receive the influenza vaccine as soon as available during the influenza season. ⁶¹ Pregnant women should receive either the trivalent or quadrivalent inactivated vaccine and may be vaccinated during any trimester. The live, attenuated vaccine is not recommended during pregnancy but may be used postpartum. ⁶⁰ In women with or exposed to influenza, antiviral treatment with oseltamivir or zanamivir should be started as soon as possible, without waiting for laboratory confirmation, in order to maximize benefit. ⁵⁹ Both agents are generally considered to have higher benefit in pregnancy than risk, and safety has been demonstrated in previous reports.^59,62,63 Efficacy data are lacking, but oseltamivir is generally preferred for treatment, especially in women at higher risk of adverse effects with zanamivir (ie, those with underlying respiratory disorders). ⁵⁹ One pharmacokinetic study found that the oseltamivir active metabolite was reduced by 30% in pregnant women versus nonpregnant women, likely because of the physiological changes in pregnancy. ⁶³ Ariano et al ⁶⁴ found that the average plasma concentration of oseltamivir carboxylate was more than 2000- to 4000-fold higher than the documented 50% maximal inhibitory concentration of the pandemic H1N1 influenza virus strain with an oseltamivir regimen of 75 mg twice daily, suggesting that the standard dosing regimen is sufficient even if absorption is reduced, such as in pregnancy. The CDC recommendations are consistent with adult dosing recommendations (Table 1).^59,63

Community-Acquired Pneumonia

CAP occurs at similar rates in pregnant and nonpregnant patients, although it may cause more severe infection during pregnancy because of physiological changes.^65,66 Hospital admission criteria should be more lenient for pregnant patients because of their reduced ability to tolerate hypoxemia. ⁶⁶ CAP has been associated with higher rates of preterm delivery and lower birth weight compared with pregnancies without such infection.^67,68

In otherwise healthy outpatients with no recent antimicrobial use, empirical azithromycin monotherapy is appropriate (Table 1). When comorbidities are present or the patient has received antibiotics within the past 3 months, azithromycin plus a β-lactam is recommended.^67,69 Fluoroquinolones are often used in nonpregnant patients for CAP but are not recommended in pregnancy.^1,66 In pregnant patients with CAP requiring intensive care unit admission who have risk factors for Pseudomonas aeruginosa, treatment should include an antipseudomonal β-lactam plus azithromycin; use of combination therapy with an aminoglycoside should be based on multidrug resistance risk. ⁶⁶

Acute Diarrheal Infections

Diarrhea is a common occurrence in pregnancy, especially in the third trimester. Most episodes are self-limiting and treatment is not required. ⁷⁰ Preventive measures such as consumption of pasteurized milk only; thoroughly cooking meat, poultry, and shellfish; and good handwashing (including after touching surfaces contaminated by raw foods) are key. Most cases of acute diarrhea are of viral etiology; however, diarrhea can also be caused by bacterial pathogens such as Campylobacter, Shigella, Escherichia coli, Yersinia, and Salmonella and may require treatment in certain circumstances. Evaluation is warranted if the diarrhea is persistent or if alarm symptoms such as weight loss and malnutrition develop. The treatment of acute diarrhea involves conservative management with oral rehydration and correction of electrolyte abnormalities if indicated. Most people infected with Campylobacter will recover without antibiotics; however, people with weakened immune systems, such as in pregnancy, are at increased risk for severe infections. Although not mandatory, pregnant patients may be treated with azithromycin. ⁷¹ Shigella species are highly infectious and can result in serious complications, including bacteremia and seizures, if left untreated once isolated. Ampicillin was considered first-line treatment; however, azithromycin as well as ceftriaxone are now being utilized secondary to resistance.^71,72 Local susceptibilities should guide empirical therapy because azithromycin resistance is also increasing. The CDC recommends against antimicrobial treatment of diarrheagenic shiga toxin–producing E coli because of lack of evidence of efficacy, and antibiotic use may increase the risk of hemolytic uremic syndrome, a potentially life-threatening complication of E coli. No specific treatment recommendations are made for pregnant patients. Yersinia and Salmonella infections typically resolve on their own without antibiotics; however, severe or complicated infections may require antibacterial use. Third-generation cephalosporins are recommended for treatment of both, but azithromycin or ampicillin may also be used to treat Salmonella.^72-74

Clostridioides difficile Infection

Clostridioides difficile, formerly Clostridium difficile, infection (CDI) is another cause of infectious diarrhea, secondary to gut microbiome alterations most often caused by systemic antibiotics. CDI has historically been generally considered a nosocomial infection and, as such, associated with lower incidence in pregnancy; however, emerging data suggest an increased risk in pregnancy, especially severe disease. ⁷⁵ The recently updated IDSA/Society for Healthcare Epidemiology of America guidelines do not make specific recommendations for pregnant patients; however, metronidazole is no longer a first-line option for initial treatment in adults.^76,77 American College of Gastroenterology guidelines continue to recommend against metronidazole because of association with potential increased risk of cleft lip with or without cleft palate via placental transmission.^70,77 Oral vancomycin, therefore, is the drug of choice at standard doses normally used in nonpregnant adult patients. No specific recommendation exists for severe or complicated disease where oral vancomycin is dosed at 500 mg 4 times daily in conjunction with IV metronidazole in nonpregnant patients. Fidaxomicin may be an alternative option to vancomycin because of low systemic absorption, but no published data are available on its use in pregnancy.

Group B Streptococcal Disease

GBS, a gram-positive coccus, is a frequent cause of maternal infections. Colonization, a primary risk factor for GBS infections, occurs in the genitourinary or gastrointestinal tracts in approximately 10% to 30% of pregnant women.^78,79 Women may experience asymptomatic colonization or illnesses such as UTIs, postpartum endometritis, or sepsis. Invasive GBS infections may result in spontaneous abortions or preterm delivery. Infants may acquire GBS during delivery; vertical transmission rates are 60%. ⁴¹ Intrapartum antibiotics prior to delivery decrease the transmission of GBS. ⁸⁰ Maternal vaccination against GBS could be a future prevention strategy. ⁸¹

Because early-onset GBS infection remains a leading cause of morbidity and mortality in the newborn, all pregnant women should have vaginal and rectal cultures evaluated at 35 to 37 weeks of gestation. ⁷⁸ If screening is positive, treatment is indicated at the time of labor or rupture of membranes, unless a cesarean delivery is planned. The CDC guidelines provide specific information on indications for intrapartum antibiotic use to prevent early-onset GBS infection. ⁷⁸

Penicillin G is the drug of choice for intrapartum prophylaxis (Table 1). ⁷⁸ Ampicillin is an alternative. Patients who are allergic to penicillin but not at high risk for anaphylaxis or other severe reactions may receive cefazolin. If a patient is at high risk for anaphylaxis from β-lactam antibiotics, clindamycin or vancomycin may be used. In vitro resistance rates to clindamycin have increased, so it is important to note local susceptibility patterns. ⁷⁸ Women with a penicillin allergy are often given non–guideline-recommended alternatives, stressing the need for appropriate allergy reconciliation. Antibiotic administration should be at least 4 hours prior to delivery.^78,80 When ampicillin, cefazolin, or penicillin were administered in this period, prophylaxis demonstrated 78% (95% CI = 44-91) efficacy in preventing early-onset GBS in the neonate. ⁷⁸ Additional studies have found 86% to 89% efficacy for preventing early-onset GBS infection with intrapartum antibiotics.^82,83 Only IV antimicrobials are indicated for intrapartum prophylaxis.

Listeriosis

Listeriosis, a foodborne illness with gastrointestinal and influenza-like symptoms, is caused by the gram-positive bacillus Listeria monocytogenes. The incidence of listeriosis is 13 times higher during pregnancy, and most infections occur in previously healthy pregnant women. ⁸⁴ Complications include preterm labor, fetal loss or infections, and a perinatal mortality rate of 29%.^84,85 Prevention is key. The CDC recommends that pregnant women avoid eating foods with a high risk of contamination such as hot dogs, cold cuts, lunch meats (chilled or at room temperature), or unwashed raw produce.^84,86 Treatment of symptomatic, febrile pregnant patients includes high-dose IV ampicillin as the drug of choice for ≥14 days (Table 1). ⁸⁴ The addition of gentamicin for synergy is controversial, with limited data to support outcomes.^87,88 TMP/SMX is an alternative for patients allergic to penicillin but should be used with caution during pregnancy and avoided in the first trimester because of risk of congenital malformations and after 32 weeks of gestation because of the fetal risk of kernicterus.^1,84

Intrauterine Inflammation or Infection (Triple I)

Traditionally, chorioamnionitis referred to the inflammation or infection of the chorion, amnion, or both. ⁸⁹ In 2016, an expert panel recommended that “intrauterine inflammation or infection or both (Triple I)” replace the term chorioamnionitis. Infection likely occurs from ascending aerobic and anaerobic organisms from the lower genital tract flora. Common organisms isolated are Escherichia coli, GBS, Bacteroides, or Clostridium spp. ⁴¹ Potential maternal complications include prolonged labor, postpartum hemorrhage, postpartum endometritis, sepsis, or hysterectomy.^89,90 For suspected or confirmed Triple I, IV ampicillin plus gentamicin are the recommended empirical treatment (Table 1).^89-91 Metronidazole or clindamycin should be added for anaerobic coverage or if delivery is via cesarean section to lower the risk of endometritis. ⁸⁹ For a vaginal delivery, treatment may be discontinued after the infant is born. A single antimicrobial dose postpartum had similar rates of treatment failure as prolonged therapy: 4.6% versus 3.5% (P = 0.639), respectively. ⁹² The majority of patients in this study had vaginal deliveries. Additional outcome analyses found no difference when evaluating specifically vaginal or cesarean delivery. Clinical resolution may guide the treatment duration in those who deliver via cesarean section.

Surgical Prophylaxis

Surgical prophylaxis will vary per procedure, but general concepts for pregnant women remain the same. Specific guidelines from the ACOG for antibiotic recommendations and timing in labor and delivery recommend a narrow-spectrum antibiotic, such as cefazolin, within 1 hour for cesarean delivery prophylaxis. ⁹³ Patients with a documented, significant penicillin allergy (eg, IgE mediated or anaphylactoid) may be administered a single dose of clindamycin plus an aminoglycoside unless the patient’s allergy can be reconciled or ruled out following a negative PAST. Preoperative skin cleansing is indicated with an alcohol-based solution, such as chlorhexidine alcohol, before a cesarean delivery. A povidone-iodine or chlorhexidine gluconate solution may be considered for vaginal cleaning prior to cesarean delivery. ⁹³