Infections in Pregnancy

C. David Adair, Shawn P. Stallings, and A. Ben Abdu

Despite numerous advances since the time of Semmelweis when infectious complications were the number one cause of maternal mortality, the obstetric community still faces challenges that remain a major cause of morbidity.

URINARY tract infection

Urinary tract infections (UTIs) constitute one of the most common and costly infectious complications of pregnancy, most likely the result of several factors: a relatively short urethra, proximity to the vaginal-anal canal, and physiologic dilatory changes of pregnancy that result in urostasis and reflux. A recent article reported an independent association of maternal UTI with preterm delivery, preeclampsia, intrauterine growth restriction (IUGR), and cesarean delivery (1).

Asymptomatic Bacteriuria

Background

Asymptomatic bacteriuria (ASB) is the presence of bacteria in the urine without concomitant specific urinary tract symptoms. The incidence is not influenced by pregnancy, and the prevalence remains 2% to 7% of all pregnancies, similar to the nonpregnant population, and tends to be more evident in the first trimester (2,3). Certain groups do appear to be at higher risk for ASB. These include patients with lower socioeconomic status, sickle cell trait and disease, diabetes, and chronic urinary retention (2-8).

Diagnosis

The diagnosis is made by bacterial culture revealing ≥10⁵ organisms of a sin­gle species per milliliter of urine without specific UTI symptoms. Because Pyelonephritis may occur with lower colony counts (20k to 50k) in the presence of symptoms or specific isolates such as group B streptococcus or Escherichia coli should be considered positive findings, and patients should be provided treatment based on sensitivity of isolates. A single midstream clean-catch urine culture suffices for the diagnosis. E. coli, Klebsiella, and Enterobacter species account for more than 85% of the isolates. Group B strep­tococcus, although a rare isolate, when identified in the urine, should be aggressively treated to prevent transmission to the neonate and frank progression to pyelonephritis. This patient will also require intrapartum GBS prophylaxis.

By identifying and treating ASB, a significant reduction in symptomatic infections can be achieved. Left untreated, approximately 40% of all cases of ASB will progress to acute symptomatic infection and 25% to acute pyelonephritis (AP) and its increased attendant morbidity. With adequate therapy, the risk is significantly decreased to only 3% (3,4).

Management

Therapy should be directed by specific isolate identification and sensitivity; some authorities do not recommend C&S evaluation on initial positive cultures in uncomplicated pregnant individuals. Drugs that provide successful ASB treatment and have safe fetal profiles include sulfa-based drugs, first-generation cephalosporins, nitrofurantoin, and penicillin-based alternatives. The latter group should not be used empirically but rather for specific isolates with docu­mented sensitivity because E.

Acute Cystitis

Acute cystitis (AC) complicates 0.3% to 1.3% of all pregnancies. One third of the cases represent progression from ASB, and the remainder represent de novo infection and recurrence can be up to 1.3% (8). Patients with AC often present in the second trimester with complaints of urgency, frequency, dysuria, and pelvic pressure discomfort. A lower colony count (i.e., ≥10²) in the presence of the symp­toms is usually sufficient to confirm diagnosis. In general, the same isolates as found in ASB are the culprits in AC such as E. coli, Gram-negative facultative organisms, Group B Streptococcus (GBS), and Staphylococcus saprophyticus. Therapy is largely empiric at first, then it is directed to specific agents as culture and sensitivities of isolates become available. Appropriate first-line therapies include nitrofurantoin macrocrystals or first-generation cephalposporins. Ther­apeutic options are included in Table 9.1. Symptomatic abatement should occur between 48 and 72 hours, and the absence of symptom resolution should prompt reevaluation.

Acute Pyelonephritis

Background

AP disorder complicates more than 1% to 2.5% of all pregnancies (10). Forty percent of pregnant women with AP have antecedent symptoms of lower UTI. Unlike

ASB and AC, pregnancy does seem to predispose to AP. Two thirds of cases arise in women with previously documented positive urine culture results and the remain­der arise de novo. Most cases of AP in pregnant women occur in the second and third trimesters when significant and maximal physiologic changes have occurred (4,10). The disease is thought to result from the significant physiologic changes of the genitourinary system, namely, urethral dilation, mechanical obstruction of the gravid uterus, and significant glucosuria and aminoaciduria.

Diagnosis

The diagnosis of AP is based on the presence of systemic signs and symptoms that include fever, chills, nausea, vomiting, and costovertebral angle tenderness. Almost always, these cases are complicated by a fever and, in some cases, sig­nificant temperature elevation may occur ≥44°C (11). Costovertebral sensitivity tends to be right sided in the predominance of cases but does not exclude the possibility of bilateral or left-sided tenderness.

Laboratory findings usually include an elevated white blood cell count, but occasionally, in mild or early infections, this may be normal. Some investigators have reported decreased hematocrit and transient renal dysfunction (10,12). Sig­nificant pyuria, hematuria, and ultimately positive urine cultures are mainstay findings. It is not unusual for a patient to have “sterile” urine despite having clas­sic symptoms.

Effects ofAP are not limited to the kidney. These include hemolytic anemia, renal dysfunction, and pulmonary dysfunction including transient mild distress to frank adult respiratory distress syndrome (13,14). About 15% to 20% of women with AP also have bacteremia (2). As with any systemic infection combining with the immunocompromised status of pregnancy, septic shock may result. Unlike ASB and AC, AP is associated with increased occurrence of uterine contractions and preterm labor.

Management

The treatment of pyelonephritis consists of aggressive systemic intravenous antibiotics and judicious fluid management. All pregnant patients suspected of having pyelonephritis should be admitted to the hospital for treatment. The i ni- tial antimicrobial selection should be reflective of most common isolates and should be cost sensitive. Several regimens can be employed. These include gen­tamicin and ampicillin or first- or third-generation cephalosporins. A random­ized controlled trial showed 95% efficacy of these regimens (15). This selection of the third-generation cephalosporins allows for the possibility of early dis­charge and outpatient therapy in gestations Maternal mortality is fortunately a rare event. Neonatal morbidity can be significant and can lead to neonatal death. Neonates whose intrapartum course is complicated by IAI are at sig­nificantly increased risks of sepsis, congenital pneumonia, and cerebral palsy (26,27).

Numerous risk factors for the development of IAI have been elucidated. These include preterm labor, preterm rupture of membranes, dysfunctional labor, prolonged rupture of term membranes (>18 hours), meconium-stained amniotic fluid, presence of cervical pathogens, bacterial vaginosis, number of vaginal examinations, and presence of intrauterine fetal monitoring and con­tractile monitors (20,28-40). IAI most commonly is caused by bacteria found in the lower genital tract and is polymicrobial rather than related to a single pathologic isolate.

Management

The treatment of IAI is approached best by preventive measures, for example, by avoiding numerous or unnecessary vaginal examinations and intrauterine monitoring and by identifying and treating cervical pathogens before intrapar­tum presentation. When prevention proves inadequate, systemic antibiotic administration is required. Withholding antibiotics until after delivery is not prudent. IAI complicates both the maternal and the neonatal units. Thus, anti­biotic selection and administration should be considered therapy for both the mother and the fetus. The selection should cover usual vaginal borne patho­gens, especially group B streptococcus and enteric organisms. Although IAI alone is not an indication for cesarean delivery, when c-section is required in the face of IAI, coverage should also include antimicrobial activity directed to anaerobes.

Even though risk factors and common isolate epidemiology are well-known, the optimal “gold standard” therapy remains less well defined. Historically, pen­icillin or ampicillin, paired with the aminoglycoside gentamicin, has been favored. Single broad-spectrum therapeutic agents have also been advocated. The selection is empiric and should be broad enough to cover usual suspected pathogens (20-23).

Some commonly recommended drug regimens in the treatment of IAI are presented in Table 9.2. Again, IAI is not in and of itself an indication for cesarean delivery, but rather the mode of delivery should follow standard obstetric guide­lines. With close fetal monitoring and the provision of good antibiotic coverage, no particular “rush” for delivery is indicated. There is accumulating evidence that respiratory distress syndrome, periventricular leukomalacia, and cerebral palsy are increased in both term and preterm infants. A thorough discussion of this is beyond the scope of this text. Once delivery has occurred, the decision to continue antibiotics postpartum remains controversial. One reasonable approach is to continue antibiotics in the presence of a cesarean delivery or for the patient who appears clinically ill. Otherwise, antibiotic discontinuance and close observation are practical (24).

POSTPARTUM ENDOMETRITIS

Background

Postpartum endometritis (PPE) complicates 1% to 3% of all vaginal deliveries and is much more frequent following cesarean delivery (41-43). This wide range of incidence depends on socioeconomic, delivery route, and labor parameters. PPE can be a continuation of IAI or arise de novo. The microbiologic isolates, like for IAI, the infection tends to be polymicrobial rather arising from a specific spe­cies. A mixed aerobic-anaerobic population is expected, especially after cesar­ean delivery (43,44). Single-species PPE should be suspected when the patient has received the benefit of prophylactic antibiotics (45-48).

Diagnosis

PPE is diagnosed in the patient with fever ≥38°C, uterine tenderness, foul­smelling lochia, abdominal pain, leukocytosis, and, most importantly, the absence of other discernible causes of infection (e.g., pyelonephritis or pneumo­nia). Some cases of IAI, without question, are severe enough that despite delivery of the infected placenta or membrane, persistent infection accompanies the puerperium, particularly in cases complicated by cesarean delivery. In those cases, antibiotic administration should be extended into the puerperium. How­ever, in the patient with low-grade IAI or suspected de novo PPE, a clinical exam­ination and evaluation are mandatory. The temptation to empirically administer antibiotics should be restrained until the diagnosis is firmly established.

Clinical risk factors parallel those of IAI. Chiefly, the factors include the duration of membrane rupture and labor, internal monitoring, numerous vagi­nal examinations, cesarean delivery, IAI, lower socioeconomic status, and the presence of meconium staining (49-62).

Management

The evaluation of the patient includes a detailed history and review of the labor record to ascertain the presence of risk factors and whether the patient has mitigating circumstances, such as antibiotic prophylaxis, immunosuppres­sive disorders, and drugs. A physical examination should exclude other likely sources. Most cases of endometritis are relatively straightforward in diagnosis; occasionally, the clinician encounters a postpartum fever with absent pinpoint focal findings. After thorough evaluation is inconclusive, it is reasonable to provide supportive measures, that is, antipyretics, and to observe the non- ill-appearing patient. However, if the patient’s temperature is ≥38°C, particu­larly when following a cesarean delivery, antibiotics are generally indicated.

Antibiotic selection should be broad enough to cover all of the usual patho­gens and should be aimed at a polymicrobial infection. Several recommended regimens are presented in Table 9.2. With appropriate selection, clinical symp­toms and fever begin to abate in 24 to 48 hours. Blood cultures are generally reserved for patients with complicated underlying medical conditions or very ill appearing. For those with relatively straight forward PPE, omission of blood cul­ture is acceptable. Failure to respond by 72 hours should prompt a reevaluation of the patient and antibiotic coverage to ensure no existence of a therapeutic gap in the chemotherapy. Pelvic ultrasound or computed tomography (CT) scan may assist in identifying hematoma, abscess, and retained placental products or instruments and in excluding septic pelvic thrombophlebitis.

If a hematoma is identified, CT-guided drainage may be beneficial. When septic pelvic thrombophlebitis is present, intravenous heparinization therapy for 7 days is recommended. When confronted with a pelvic abscess, unrespon­sive to antibiotics and nonamenable to needle drainage, surgical intervention is required. The surgical approach must be aggressive, because, left unchecked, the abscess may lead to myonecrosis and subsequent death.

Preventive measures to diminish PPE include several modalities. The fore­most example is that of prophylactic antibiotic administration at the time of the cesarean delivery. Usually, a first-generation cephalosporin such as cefazolin is administered at the time of the cord clamping or in some series administered within 1 hour of surgical incision. For true allergic response to penicillins, those individuals are generally recommended to be treated with both gentamicin and clindamycin. Amnioinfusion has been suggested to reduce PPE in patients under­going cesarean delivery with clear amniotic fluid and membrane rupture of >6 hours’ duration (63,64), although this is not universally embraced. This approach seems to be not beneficial in cases with meconium staining (65).

PPE is more common after cesarean delivery than vaginal delivery. Because of the increased cesarean rates, PPE has become one of the most common causes of maternal morbidity. However, the use of single-dose perioperative antibiotic prophylaxis is likely the single greatest intervention to reduce the rates of post­cesarean pelvic infections in the past 25 years (66). Prevention is the most pru­dent approach to PPE morbidity. However, when simple measures fail and active infection occurs, aggressive therapy aimed at the most common isolates is indi­cated. The clinician should be cognizant of the polymicrobial nature of PPE and, if therapy becomes unresponsive, more serious etiologies should be considered.

HERPES INFECTION

Herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella are specific viral pathogens that all belong to the family Herpesidae, all contain double­stranded DNA, and all have significant adverse maternal and fetal/neonate effects.

Herpes Simplex Virus

Background

HSV-1 and -2 serotypes invade neural roots through mucosal membrane defects. Infection may be primary or, after acquisition, may remain dormant with recur­rent episodic outbreaks. Acquisition can be by genital:genital, oral:genital, or anal:genital sexual contact. Serotypes previously were site specific, but each serotype may be associated with acute or recurrent HSV infection at oral, geni­tal, or nongential sites. However, HSV-2 is more likely to be associated with recurrence regardless of site selection (67-69). Approximately 45 million ado­lescent and adult Americans are infected with HSV (70). Therefore, it may be a frequently encountered issue to be addressed in the pregnant female.

Diagnosis

The diagnosis of HSV infection is largely clinical. A history of vesicular, painful, burning ulcers prompts the decision to seek medical evaluation. During this evaluation, the clinician should attempt to distinguish primary from recurrent HSV infection. Primary HSV acquisition is associated with flulike symptoms, lymphadenopathy, fever, and malaise. These viral syndrome symptoms typically are absent with recurrent HSV flare-ups. Exposure to onset of viral disease is >2 to 7 days (67,71).

Viral culture may be of assistance in providing absolute confirmation. However, clinically, if primary HSV infection is suspected, therapy should not be withheld pending culture results. Serum immunoglobulin M (IgM) and IgG anti­bodies may be of assistance in confirming the absence of previous infection. Papanicolaou smear test and Tzanck test have also been used to suggest HSV infection by identification of viral cytologic effects, but they lack sensitivity to be used for routine clinical care.

Recent evidence has suggested important prognostic values of primary ver­sus recurrent HSV infection in pregnancy. Pregnancy per se does not influence the course of HSV infection, either in primary or recurrent episodes; however, both may result in hepatitis, meningitis, or pneumonia. Systemic manifestations require prolonged intravenous therapy with acyclovir. Disseminated HSV infec­tion is associated with increased risk of maternal and neonatal mortality.

Neonatal vertical transmission remains the paramount concern for HSV infection complicating pregnancy. Most significant neurologic and severe adverse outcomes develop in those neonates with infection at or near the time of maternal primary disease, whereas infants born to mothers with recurrent dis­ease have the least chance of acquisition and less morbidity (72).

Management

Obstetric management remains supportive and directed to symptomatic man­agement. The clinician should counsel women on possible transmission to part­ners and screen for other sexually transmitted diseases. Cesarean delivery is necessary for the patient in labor who has active disease or has the prodromal symptoms in cases of known recurrence. Cesarean delivery will not necessarily provide 100% prevention of HSV transmission to the neonate. Approximately 25% of affected neonatal cases were delivered by cesarean delivery (67,73,74). Vertical transmission rates are 30% to 60% when there is a primary HSV out­break at the time of delivery (75). The rates are 3% if having a recurrent genital outbreak at the time of delivery, and only 2 per 10,000 in a patient with a history of HSV but no active lesions at the time of delivery (76).

There is currently no universally accepted screening guideline for HSV in pregnancy. Therapy is with any of the synthetic acyclic purine nucleoside ana­logues such as acyclovir, valacyclovir, and famciclovir. These agents (Category B) have no evidence of teratogenic or adverse effects on the human fetus. They should be used in doses similar to those used in a nonpregnant patient. Prophy­lactic suppression has been reputed to be successful in reducing recurrence of HSV infection at term. Generally, prophylaxis is initiated at 36 weeks (77,78). ACOG currently recommends offering suppressive viral therapy for women with active recurrent genital herpes at or beyond 36 weeks’ gestation (79). However, a recent Cochrane review suggests that the overall risk of neonatal herpes is low, and there is insufficient evidence to determine if antiviral prophylaxis reduces the incidence of neonatal herpes (80).

Cytomegalovirus

Background

CMV is the most common perinatally transmitted viral infection, occurring in 1% to 2% of all neonates. Like HSV, it can be transmitted to the fetus by either primary or reactivation of CMV infection. More than 85% of patients in low socioeconomic status have evidence ofprevious CMV infection and about 50% of the adult sexually active population. Fetal transmission in these cases is is fairly straightforward. Most patients have a his­tory of recent exposure of acute vesicular maculopapular rash of the scalp and trunk with progression to the extremities and other body areas. These lesions are commonly accompanied by flulike symptoms, myalgia, headaches, and fever. Each new lesion has active viral shedding for 6 days with “crusting” persisting for 1 week. Fever generally persists until cessation of lesion formation.

VZ infection usually is self-limiting and treatment is thus largely symptom­atic. VZ infection complicating pregnancy, however, presents unique challenges to the clinician. Complications are usually more frequent and severe when accompanying pregnancy. These include meningitis, encephalitis, arthritis, acute glomerulonephritis, and pneumonia. Pneumonia is the most frequent com­plication and is of the most concern. Varicella pneumonia may result in respira­tory insufficiency, edema emphysema, superimposed bacterial infections, and even death. Pulmonary insult and injury lead to maternal and fetal hypoxia.

Varicella has been associated with an embryopathy (91). However, no increased adverse perinatal outcome has been reported, such as spontaneous abortion, prematurity, growth restriction, or death (92-95). The embryopathy syndrome was originally described by LaForest and Lynch (91). Characteristics are skin scarring, limb hypoplasia, and CNS and eye abnormalities. Developmen­tal abnormalities appear to be limited to exposure at 12 weeks or less and occur in 2% to 3% of pregnancies.

The risk of congenital anomalies occurring secondary to varicella has been estimated to be approximately 2% (94-99). These anomalies include cicatrix skin deformities, ocular scarring, cataracts, chorioretinitis, and limb shortening (91,93,96,100-102).

The exposure to varicella requires documenting the antibody status of women who have uncertain varicella history. The majority of women who have no prior history of varicella infection will have serologic evidence of varicella exposure and IgG conversion. The patient who has negative IgG titers should receive VZ immunoglobulin (VZIG). The dose is 125 units∕10kg intramuscu­larly with a maximum of 625 units or five vials intramuscularly and is ideally administered within 96 hours of exposure. Once varicella infection is estab­lished, care is directed at symptomatic relief, prevention of community spread, especially to other pregnant women, and close surveillance for com­plications of disease progression. Acyclovir can be used to provide some symptom relief in mild to moderate cases, although this is largely an empiric treatment. Cases of severe disease of pneumonia mandates intravenous acy­clovir at 10mg∕kg administered every 8 hours. The patient with any pulmo­nary complaint should be given acyclovir and observed closely in a negative airflow room.

Labor, whether it is preterm or term, frequently accompanies severe vari­cella infection. Caution should be used in administering tocolytics and gluco­corticosteroids. Maternal viremia results in antibody production within 4 to 5 days of rash development. Thus, the infant at highest risk of neonatal varicella acquisition is born within 2 to 5 days of rash development. If labor begins during this interval, consideration of tocolysis may be prudent until 5 days after the appearance of the rash, even in term fetuses. Neonates born during this time interval have the highest risk of adverse complication and should therefore receive VZIG and acyclovir (92,103,104). Of interest is the increasing number of varicella vaccinated females that are approaching reproductive age and how the vaccine will impact varicella in pregnancy.

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