The mechanisms of the immune system alterations and the infectious complications of these alterations are areas of ongoing investigation. Rather than a generalized immunosuppression, pregnancy results in a modulation of immune responses with differential effects depending on pathogen and stage of pregnancy. Concentrations of estradiol and progesterone are elevated during pregnancy, increasing to peak in the third trimester. These hormones may alter T-cell responses, stimulating a shift from Th1- to Th2-skewed immunity.⁸ During pregnancy, regulatory T-cells suppress T-cell and natural killer (NK) cell responses, and those same cells produce less interferon (IFN)-γ, interleukin (IL)-6, and macrophage inflammatory protein (MIP)-1β in response to nonspecific stimulation indicating a shift away from Th1 responses.^9,10 This is concurrent with an increase in the number of phagocytic cells and dendritic cells, as well as an increase in circulating antimicrobial peptides (α-defensins 1-3) that may provide compensatory increases in innate immune defenses.⁹ In addition, the numbers of circulating B-cells are reduced in the third trimester, a likely result of estrogen-driven decreased lymphopoiesis in early pregnancy demonstrated in mouse models.⁹

Beyond the infectious complications that may increase maternal morbidity and mortality, management of infections in pregnant women are complicated by safety concerns. Teratogenic drugs are discussed in Chapter 7, but brief discussions of antimicrobials will be included herein. Additionally, certain perinatal infections cause relatively minor maternal morbidity but severe fetal consequences. Classically referred to as TORCH infections, these infectious agents include toxoplasma, other (syphilis, parvovirus B19, varicella-zoster virus [VZV], Zika virus), rubella, cytomegalovirus, and herpes simplex virus (discussed in detail in Chapter 10). Treatment
and prevention of infection during pregnancy provides profound health improvements by reducing maternal morbidity and mortality and by preventing perinatal transmission that can cause congenital or chronic infection in fetuses and infants.

Immunization should be an integral part of practice for obstetrician-gynecologists to protect adults, pregnant women, and newborns from preventable diseases. Pregnant women are a special population requiring unique recommendations for immunization, as the state of pregnancy is one of both vulnerability and opportunity for disease prevention. Maternal immunization as an intervention is intended to prevent at least one of the following infectious complications: maternal morbidity and mortality, perinatal infections associated with congenital abnormalities, and young infant morbidity and mortality. Vaccine recommendations for pregnant women are often limited by a relative paucity of evidence compared to standard populations. This is driven by the justified concern for an increased risk of vaccination in pregnant women.

Concerns regarding possible reproductive effects include congenital malformations or miscarriage, ineffectiveness, or possible adverse effects of adjuvants. However, of the live attenuated vaccines, only smallpox vaccination has been definitively associated with congenital infection after vaccination.¹¹ Postlicensing studies of adjuvanted influenza vaccination in pregnant women showed no increase in adverse events, but the CpG-adjuvanted hepatitis B vaccination is not yet recommended in pregnant women due to an absence of studies (at the time of this publication).^12,13,14 There remains an ongoing need for interventions to prevent infections associated with increased susceptibility and severity of illness such as malaria and hepatitis E virus, infections associated with congenital abnormalities, such as Zika virus or cytomegalovirus, and infections associated with severe disease in the immunologically immature young infant such as respiratory syncytial virus and group B Streptococcus. Vaccine recommendations and postexposure prophylaxis options are included in Table 39.1.

UTIs are the most common bacterial infections in pregnancy due to increased urinary stasis.
Pregnancy is one of the few times asymptomatic bacteriuria should be treated due to the risk for progression to pyelonephritis and possible association with low birth weight and preterm births^41,42,43,44. Studies in the 1960s to 1980s showed that screening for and treatment of asymptomatic bacteriuria reduced the incidence of subsequent pyelonephritis from 20%-36% to 1%-4%, although current rates for progression to pyelonephritis may be as low as 2.5%.^43,45,46 Screening at one of the initial visits with urine culture allows selection of antimicrobial therapy based on culture and antibiotic susceptibility results.

Asymptomatic bacteriuria is defined as ≥10⁵ colony-forming units without dysuria, urgency, or other symptoms of a UTI.⁴⁴ If symptomatic, empiric antimicrobial therapy based on local antibiograms can begin while awaiting culture results. Escherichia coli is the most common infection isolated from women who have bacteriuria, followed by other Enterobacteriaceae.^41,46 Common antibiotic choices include nitrofurantoin, fosfomycin (with the advantage of single dose treatment), penicillin (eg, amoxicillin-clavulanate), or cephalosporins (eg, cefpodoxime), with a treatment duration of 4 to 7 days depending on the antibiotic chosen.^44,47 If progressed to pyelonephritis, blood cultures should precede antibiotics if possible, and therapy should be initiated with parenteral antibiotics (eg, ceftriaxone) while awaiting culture and susceptibility results. Once a patient has improved clinically, parenteral antibiotics can be transitioned to oral antibiotics based on susceptibility results to complete a 10- to 14-day course.⁴¹

Group B streptococcal (GBS) bacteriuria warrants particular attention as intrapartum colonization is associated with severe neonatal infections, and GBS bacteriuria is a risk factor for GBS intrapartum colonization.⁴⁸ Detection of GBS bacteriuria is an indication for intrapartum prophylaxis with penicillin to prevent neonatal infection. In the case of penicillin allergies, intrapartum cefazolin can be used as second-line treatment if there is a low risk for anaphylaxis, or clindamycin or vancomycin if there is a high risk for anaphylaxis.⁴⁹

Respiratory tract infections compose nearly half of self-reported infections during pregnancy in the United States and are the frequent causes of obstetric hospital admissions.^50,51 In addition to the aforementioned immune modulations that may affect susceptibility to infections, the physiologic changes of pregnancy may increase the severity of respiratory infections. Pregnant individuals are more prone to aspiration pneumonia due to lower esophageal sphincter tone and increased intra-abdominal pressure, more readily develop respiratory acidosis due to decreased buffering ability (with resultant ready hypoxemia), and have increased risk for pulmonary edema.^51,52,53 Therefore, a lower threshold exists for hospitalization of pregnant individuals with respiratory symptoms.

Most upper respiratory tract infections (rhinosinusitis, bronchitis) are viral, although the rare bacterial sinusitis may be treated with amoxicillin-clavulanate for a short (5- to 7-day) course.⁵⁴ Molecular tests capable of identifying multiple viral respiratory pathogens should be used both for rapid diagnosis and to reduce unnecessary antibiotic use (and the associated risk of complications, including Clostridium difficile infections). A prospective surveillance⁵⁵ of viral respiratory illnesses in women in their second and third trimesters who presented to an outpatient urban clinic displayed a striking progression to lower respiratory tract illness (including wheezing, dyspnea, or cyanosis) in up to one-third of cases. Notably, the predominant viruses were rhinovirus, common coronaviruses, and respiratory syncytial virus—all managed with purely supportive care. Insufficient data are available at the time of this publication to evaluate the risks of coronavirus infectious disease 2019 (COVID-19) to pregnant women.

Influenza infections in pregnancy are associated with increased risk for hospitalization, acute respiratory distress syndrome, and death.^56,57,58 Preventive care for pregnant individuals (and up to 2 weeks postpartum) includes vaccination and prophylactic therapy with oseltamivir after known exposure to individuals with influenza (dosed 75 mg daily for 1 week after last known exposure).⁵⁹ Pregnant individuals presenting with influenza symptoms (including fever, cough, rhinorrhea, myalgias, headache, and/or malaise) should begin empiric antiviral therapy even if they had an influenza vaccine that season, as vaccine efficacy is not complete and early therapy is associated with reduced duration of hospitalization or risk of death.^56,60,61 Oseltamivir is an oral neuraminidase inhibitor (NAI) that has extensive safety data in pregnancy and is the preferred antiviral agent for influenza. Zanamivir
(an inhaled NAI) is not preferred due to concerns about lower long volumes and bronchospasm, whereas peramivir (an intravenous NAI) and baloxavir (an oral endonuclease inhibitor) are not preferred due to a lack of pharmacokinetic and safety data in pregnant individuals. Amantadine and rimantadine are no longer used in any population due to the high (>99%) rates of resistance in circulating influenza strains.⁶²

Treatment for community-acquired pneumonia is minimally changed in pregnant women compared to nonpregnant patients. Fluoroquinolones (such as levofloxacin) are generally avoided in pregnancy due to concerning cartilage toxicity in animal models, although a meta-analysis of fluoroquinolone exposures in pregnancy demonstrated no significant association with congenital abnormalities or adverse pregnancy outcomes.⁶³ For clinically stable pregnant individuals without recent hospitalization, azithromycin monotherapy (500 mg daily for 3 days) is appropriate. If hospitalized, antimicrobials should expand to include a beta-lactam antibiotic (eg, ceftriaxone or ampicillin/sulbactam) for coverage of potentially macrolide-resistant Streptococcus pneumoniae, and a history of recent antibiotics or hospitalization may necessitate the addition of an antipseudomonal beta-lactam (eg, piperacillin-tazobactam).^47,64

Listeria monocytogenes is a gram-positive rod bacterium with a predilection for causing illness in pregnancy, with estimates of a 17- to 100-fold (or higher) increased risk over the baseline adult population.^65,66 Although it rarely manifests as a gastrointestinal illness, most infections are foodborne and may occur in sporadic outbreaks. Historic outbreaks in the 1980s and 1990s were associated with delicatessen meats, with more recent outbreaks also associated with soft cheeses or produce such as cantaloupe.^67,68 Invasive listeriosis results in bacteremia, meningitis, and, in a survey of US cases, progression to fetal loss or neonatal death.^66,69 Maternal infections may present as fever or influenza-like illnesses, and Listeria is readily identified in blood culture.⁷⁰ In cases of meningitis or encephalitis, cerebrospinal fluid (CSF) analysis may show a neutrophilic or monocytic pleocytosis, Gram stain is often negative, and CSF culture sensitivity may be lower.⁷¹ Treatment includes high-dose ampicillin (minimum 2 g every 8 hours), with addition of gentamicin for synergy in severe illness (eg, meningitis). For patients with a penicillin allergy, ampicillin is substituted with trimethoprim/sulfamethoxazole (TMP/SMX) (10-20 mg/kg/d of trimethoprim component divided every 6 or every 12 hours).^72,73,74 There have been concerns that TMP/SMX may be associated with congenital abnormalities due to interference with folate metabolism, although a meta-analysis showed no significant increase above the general population.^75,76,77 Duration of therapy is a minimum of 2 weeks, with possible extension if the fetus survives.⁷² Prevention relies on supply chains reducing contamination of food products and avoidance for pregnant individuals.

In areas in which hepatitis E virus (HEV) is endemic (including Southeast Asia and northern Africa), genotypes 1 and 2 are predominant, associated with waterborne transmission, and infection is associated with more severe illness.⁷⁸ Genotypes 3 and 4 are responsible for sporadic cases in developed countries associated with undercooked meat (usually pork), tend to cause less severe illness, and tend to infect older men or individuals on immunosuppressive medications.⁷⁹ A more detailed discussion of HEV infection and liver disease is provided in Chapter 34, Liver Diseases.

Compared to hepatitis A, which similarly causes an acute but self-resolving hepatitis with a mortality rate less than 2%, the mortality rate for HEV is 1% to 4% in nonpregnant adults and 10-fold higher in pregnancy.⁷⁸ A systematic review of adverse outcomes following HEV in pregnancy found a median case fatality rate of 26%, with the caveat that most studies are hospital based.⁸⁰ Prevention remains in the realm of good sanitation, despite a promising vaccine with >95% efficacy that has not yet progressed to approval.⁷⁸ Pregnant travelers should be advised as to the risks of HEV and the importance of hand hygiene and clean drinking water. Management is purely supportive, requiring a high degree of suspicion to diagnose (with positive IgM serology, rising IgG, or polymerase chain reaction [PCR]-based RNA detection).⁸¹

Lyme disease, caused by the spirochete Borrelia burgdorferi, is a tick-borne disease usually presenting as a rash (erythema migrans) but with rare complications including Lyme carditis, neuroborreliosis, or
late manifestations of arthritis.⁸² No clear association exists between Lyme disease in pregnancy and adverse birth outcomes.⁸³ In areas endemic for Lyme disease, nonpregnant individuals can receive prophylaxis for Lyme after a tick bite, but only doxycycline has demonstrated efficacy. Amoxicillin may be used for treatment of mild illness (500 mg three times daily for 14 days), and ceftriaxone may be used for meningitis.⁸² Importantly, persistent fevers despite treatment for Lyme disease warrant evaluation for alternate etiologies, including complete blood counts and blood smears to evaluate for coinfections, such as Babesia microti or Anaplasma phagocytophilum, that are transmitted by the same vector.

Although rickettsial infections, such as Rocky Mountain spotted fever (RMSF), anaplasmosis, or ehrlichia, do not appear to have increased susceptibility or severity in pregnancy, these are potentially life-threatening infections. Fever, headache, thrombocytopenia, and a history of tick bite are common for each of the rickettsial diseases.

The rash of RMSF often appears 2 to 4 days after the fever and may start as a blanching maculopapular rash before progressing to petechial involving the palms and soles. However, rash presentations may vary, thrombocytopenia may be delayed, and abdominal pain and vomiting may mimic gastroenteritis to delay diagnosis.^84,85 For ehrlichia and anaplasma, rashes are rarer and variable. Serology is particularly sensitive 2 to 3 weeks after onset, with variable utility in acute illness, and therefore, both acute and convalescent specimens should be collected. PCR detection from whole blood is useful for ehrlichia and anaplasma, although less sensitive for RMSF. Blood smears or buffy coat preparations may identify ehrlichia or anaplasma, although not RMSF.⁸⁴ First-line therapy is doxycycline (100 mg twice daily) and has been used successfully in a few cases of RMSF, ehrlichia, or anaplasma in pregnancy without evident sequelae in surviving cases.^84,86,87,88 Initiation of doxycycline should be based on clinical suspicion, as delays in diagnosis are associated with increased mortality and most confirmatory tests are not rapid. A member of the tetracycline family, doxycycline is usually contraindicated in pregnancy as extended courses of tetracyclines were associated with of musculoskeletal and dental abnormalities in the fetus and fatty liver in the mother.⁸⁹ However, a systematic review of doxycycline in pregnancy demonstrated that therapeutic doses of doxycycline were not associated with any increased risk to the fetus or mother.⁹⁰ Doxycycline is the only therapy effective for Ehrlichia chaffeensis or Anaplasma phagocytophilum, and the alternate agent chloramphenicol, used for RMSF, is not as effective and is associated with increased mortality.^84,91,92

The prolonged and intimate relationship between humans and their STIs was predicted to end with 20th century advances in antimicrobials. However, steady increases in the incidence of notable STIs (syphilis, chlamydia, gonorrhea) since the turn of the century have belied that hope. Routine screening for STIs has increased during pregnancy due to the deleterious effects on both the pregnant woman and the fetus. The combined incidence of nationally reportable STIs have increased 31% from 2013 to 2017, reaching historic highs and with concomitant increases in congenital infections.⁹³

In addition to being younger than 25 years, individual risk factors for STI acquisition include new or multiple sex partner(s), a partner with other concurrent partners, a sex partner with a known STI diagnosis, coexisting STI(s), or a history of transactional sex. Importantly, several screening recommendations are adjusted based on local STI surveillance data, requiring clinicians to be aware of STI trends in the immediate communities they serve.