Paul Lyons1
(1)
Department of Family Medicine, University of California, Riverside, Riverside, CA, USA
Key Points
1.
2.
3.
4.
Background
Infection presents a particular challenge in pregnancy. Symptoms of infection may be subtle, unusual in presentation, or masked by other pregnancy-related symptoms. Infection may affect both the mother and fetus; antibiotic choices may be limited by concerns related to pregnancy and fetal development. As with most elements of obstetrical care, management of infection in pregnancy ideally begins in the preconception period. The preconception history can provide important data concerning infection risk such as recent exposures (toxoplasmosis, tuberculosis, cytomegalovirus), immunization status (influenza, measles, and varicella), and chronic infectious conditions (HIV, herpes, viral hepatitis). For some of these infections, appropriate preconception planning and risk reduction is the only effective intervention. A thorough physical examination may reveal evidence of such infections as active herpes, gonorrhea, or chlamydia. Preconception screening for HIV, tuberculosis, and syphilis, among other conditions, may allow for treatment prior to pregnancy, thereby decreasing the likelihood of adverse prenatal outcomes.
Infections occurring during the course of pregnancy may have two significant consequences. Direct maternal–fetal transmission may lead to infection not just in the mother but also in the fetus. Such infections may have very serious consequences for the fetus or newborn. Herpetic infection in newborns, for example, is associated with a 50 % mortality rate and significant morbidity among those infants who survive. In addition, some infectious agents are known to cause complications in the course of pregnancy, particularly preterm labor. Although most studies have shown conflicting data concerning the demonstrated benefit of diagnosis and treatment, most authorities recommend screening and treatment.
Symptoms of Infection in Pregnancy
Although diagnosis of infection in pregnancy is critically important, symptoms of infection in prenatal patients may be absent or difficult to detect or interpret. Many infectious etiologies are asymptomatic. Syphilis, latent-phase herpes, HIV, and others may be present without producing any symptoms in the pregnant patient. For these conditions, routine screening is recommended for all pregnant patients by history, physical examination, and/or diagnostic studies.
Some disease processes produce characteristic symptoms, which should be further evaluated whenever present. Such symptoms as fever, chills, bleeding per vagina, severe abdominal pain, or dysuria should lead to prompt evaluation. For other disease processes, the symptoms associated with infection may be difficult to interpret or may be masked by some of the common symptoms associated with pregnancy. Cervical mucus production may be increased during pregnancy and some women may interpret this increased mucus as infectious in cause. By contrast, some women may interpret an abnormal vaginal discharge as “normal” for pregnancy, delaying evaluation or failing to mention such symptoms during the course of prenatal care. Nonspecific abdominal pain is also a relatively common symptom occurring during pregnancy. Providers should be diligent in eliciting suggestive symptoms and should maintain a low threshold for following up such symptoms with appropriate diagnostic tests. As a general rule, women should be screened by history for symptoms that are suggestive of common infectious complications of pregnancy at each prenatal visit. Those patients who report such symptoms should be further evaluated for the possible presence of infection (Table 13.1).
Table 13.1
Antibiotics in pregnancy
|
Infection |
Antibiotics |
|
Gram positive |
Penicillins |
|
First-generation cephalosporins |
|
|
Clindamycin |
|
|
Gram negative |
Aminoglycosides (see text) |
|
Third-generation cephalosporins |
|
|
Anaerobic |
Clindamycin |
|
Special conditions |
|
|
Urinary tract infection |
Cephalosporins |
|
Nitrofurantoin |
|
|
Ampicillin (see text) |
|
|
Sulfisoxazole (see text) |
|
|
Chlamydia |
Erythromycin |
|
Azithromycin |
|
|
Gonorrhea |
Ceftriaxone |
|
Syphilis |
Penicillin |
|
Yeast |
Azole antifungal agents after the first trimester |
|
Bacterial vaginosis |
Clindamycin |
|
Metronidazole after the first trimester |
|
|
Trichomoniasis |
Metronidazole after the first trimester |
|
Herpes |
Acyclovir; cesarean section indicated if present at time of labor |
|
HIV |
See Chap. 16 |
|
Group B strep |
Ampicillin in labor |
Maternal Infection
The primary concern in pregnancy is with the health and welfare of the mother. Timely diagnosis and treatment of infection has direct health consequences for the mother and should be approached in the same manner as in nonpregnant patients. Routine prenatal care includes screening for gonorrhea, chlamydia, syphilis, HIV, hepatitis B, and urine culture for bacteriuria. These tests are performed in all patients regardless of symptoms. It is worth noting that most of these infections are sexually transmitted. Pregnancy can be taken as good evidence of unprotected sexual activity and therefore confers the infection risk associated with unprotected sex. Prenatal patients are also routinely screened for evidence of human papilloma virus through Pap smear screening. Although treatment is generally deferred until the patient is no longer pregnant, documentation of the presence and severity of dysplastic lesions is an important element of the comprehensive care plan. The timing and method of screening for these infectious conditions are reviewed in Chap. 3.
Patients with suggestive symptoms may also be screened for other infectious conditions. Patients with vaginal discharge should be evaluated for the presence of bacterial vaginosis and trichomoniasis in addition to gonorrhea and chlamydia. The presence of bacterial vaginosis has been associated with an increased risk of preterm contractions and preterm labor. Treatment of bacterial vaginosis or trichomoniasis is recommended after the first trimester. Patients with urinary symptoms such as dysuria or hematuria should be evaluated for possible urinary tract infection (UTI).
Fetal Infection
In addition to maternal considerations, many infectious processes have health consequences for the developing fetus. Infection in pregnancy may result in three related fetal complications: direct infection of the fetus or newborn, alteration in the normal course of pregnancy, and alteration of fetal development. Many maternal infections can be transmitted to the fetus either during pregnancy or at the time of delivery. Syphilis, gonorrhea, group B strep (GBS), and HIV, among others, all have demonstrated maternal–fetal transmission. Syphilis is associated with neonatal long bone infection; gonorrhea may cause neonatal ophthalmological disease; GBS is a significant contributor to neonatal febrile illness including meningitis; maternal–fetal transmission of HIV remains a critical source of new HIV infections in many parts of the world.
Infectious agents may result in pregnancy complications even in the absence of direct fetal infection. Maternal infections, such as bacterial vaginosis or GBS, may affect the course of pregnancy resulting in such complications as preterm labor and delivery. Universal or directed screening of prenatal patients can identify a significant number of patients at risk. Several infectious complications have been associated with significant developmental abnormalities in fetuses. Cytomegalovirus, toxoplasmosis, and measles all have potentially serious effects on fetal development. Appropriate screening for exposure and/or timely vaccination can reduce the risk for these complications.
Antibiotic Use in Pregnancy
Antibiotic choice in pregnancy is complicated by the fact that several commonly used classes of antibiotics are contraindicated or should be used with caution in pregnancy. Prior to the use of any antibiotic in pregnancy, providers should review its safety and efficacy in pregnancy. If questions concerning safety remain, consultation with a maternal–fetal expert is recommended. A more complete review of the use of medications in pregnancy can be found in Chap. 4.
Although microbial sensitivity to antibiotics is important in the management of any patient, it is of particular importance in pregnant patients. The potentially limited number of available choices makes culture and sensitivity studies critical in pregnancy. Allergies to such common antibiotics as penicillin may further limit antibiotic choices. In such circumstances, providers may be considering third- or fourth-line antibiotic choices. Under such circumstances, knowing the specific microbe and its sensitivity to available antibiotics is often very helpful.
Although a comprehensive review of all antibiotic classes is beyond the scope of this text, a few key classes should be reviewed (a review of the risk classification for drugs used in pregnancy can be found in Chap. 4).
Sulfonamides
Sulfonamides are most commonly used as sulfamethoxazole in combination with trimethoprim. This antibiotic is routinely used for respiratory tract and UTIs in nonpregnant patients. Sulfonamides readily cross the placenta and levels persist in newborns for several days postpartum. Sulfonamides are a category B drug early in pregnancy but are category D near term. Complications include jaundice and hemolytic anemia. Currently available data do not suggest teratogenesis with the use of sulfonamides. Trimethoprim also crosses the placenta freely. Trimethoprim acts as a folate antagonist and may theoretically contribute to congenital abnormalities if used in the first trimester. There is no definitive data linking trimethoprim to congenital defect; however, because of its mechanism of action and some data to suggest a possible increased risk, trimethoprim is a category C drug.
Fluoroquinolones
This class of drugs includes such agents as ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, and ofloxacin. These are used for a wide variety of infections including UTIs and respiratory tract infections. Ciprofloxacin has been associated with cartilaginous defects in some animal studies. Data from human studies does not demonstrate a consistent pattern of congenital abnormalities. In general, safer alternatives to fluoroquinolones exist for most conditions. Fluoroquinolones are generally a category C drug.
Aminoglycosides
This class of drugs includes such agents as gentamicin, used widely for serious Gram-negative infections. Although aminoglycosides are used when indicated in pregnancy, there are several issues that should be considered prior to their use. Aminoglycosides cross the placenta and are present at significant but reduced levels (compared with maternal serum levels). Gentamicin is associated with nephrotoxicity in laboratory animals, although only one possible case of possible prenatal gentamicin-associated renal disease has been reported in the literature. Ototoxicity has also been reported with gentamicin use, although no cases associated with in utero exposure have been reported. Aminoglycosides are generally considered class C drugs in pregnancy.
Vaginitis/Vaginosis
Background
A number of infectious agents may result in significant discharge per vagina during pregnancy. Many of the etiologic agents have significance in pregnancy; therefore, a search for the cause and appropriate treatment is particularly important in pregnant patients. In the presence of a significant host inflammatory response, this condition is referred to as vaginitis. In other circumstances, the presence of discharge in the absence of inflammation is referred to as vaginosis. Alteration in the normal vaginal environment including change in pH or elimination of normal flora with the use of some antibiotics allows for proliferation of such abnormal flora as Gardnerella, Trichomonas, or Candidaspecies.
Bacterial vaginosis has been associated with a variety of complications in pregnancy including amniotic fluid infection, chorioamnionitis, postpartum endometritis, premature rupture of membranes (rupture of membranes prior to the onset of labor), preterm labor, preterm delivery, and low birth weight. Complications associated with yeast vaginitis are less clearly defined. In addition to the complications just noted, infection with gonorrhea or chlamydia has been associated with maternal–fetal transmission at the time of delivery.
History
A careful history will often assist in elucidation of the underlying cause for symptoms of vaginitis. The most common, and often most prominent symptom, is discharge per vagina. Patients should also be questioned concerning systemic symptoms such as fever, nausea, vomiting, change in bowel habits, or urinary symptoms. Recent sexual contact should be reviewed (in addition to prior laboratory studies for gonorrhea, chlamydia, urinalysis, urine culture, or wet mount studies). Symptoms in the partner should also be elicited. A review of recent medications and a past history of similar complaints may yield additional information.
Physical Examination
In addition to the routine elements of a prenatal physical examination, a focused exam should be performed to identify key findings consistent with vaginitis or, less commonly, significant peritoneal infections. On abdominal examination, providers should note pain rebound or guarding. On the pelvic examination, a note should be made of external or internal erythema or edema, discharge (including the quality and quantity of such discharge), blood, vaginal or cervical lesions, cervical motion tenderness, and adnexal masses or tenderness.
Laboratory Studies
Further testing is warranted when discharge is noted on exam. Patients should be screened for gonorrhea and chlamydia, especially in the presence of significant mucopurulent discharge. In addition, a sample of discharge should be obtained and tested for pH, KOH (potassium hydroxide) “whiff,” and microscopic examination with saline and KOH solutions.
pH Testing
pH paper placed directly in discharge may be useful in screening for abnormalities. A pH greater than 4.5 is consistent with bacterial vaginosis or trichomoniasis. A pH less than 4.5 is consistent with yeast.
KOH “Whiff”
KOH mixed with a sample of the discharge can be helpful in diagnosing bacterial vaginosis. A positive “whiff” test reveals a foul or fishy odor when the KOH is added.
Microscopic Examination
One slide prepared with saline and discharge; one slide prepared with KOH and discharge. The saline-prepared slide may show evidence of bacterial vaginosis (clue cells) or trichomoniasis (flagellated protozoa). KOH will lyse most cellular elements within the discharge, leaving only yeast on the slide. The presence of fungal elements on a KOH-prepared slide is evidence of candidal infection.
Treatment
When an infectious agent is identified, most authorities recommend treatment. The benefits of treatment may include reduction of pregnancy-related complications and/or symptomatic relief for the patient. Care should be exercised to select agents with a good safety profile and proven efficacy in pregnancy. If appropriate treatment is unclear, consultation with a maternal–fetal expert is recommended.
Bacterial Vaginosis
Patients with bacterial vaginosis present with mild or no pruritus, minimal pain, thin gray discharge, pH greater than 4.5, positive whiff test, and clue cells on microscopic examination. Bacterial vaginosis may be treated with clindamycin 2 % cream or oral clindamycin 300 mg by mouth twice a day for 7 days. After the first trimester, metronidazole is an alternative (0.75 % gel 5 g daily for 5 days or 250 mg by mouth three times daily or 500 mg by mouth twice daily for 7 days).
Trichomoniasis
Trichomoniasis presents as mild pruritus, minimal pain, copious yellow thin discharge, pH greater than 4.5, negative whiff test, and flagellated protozoa on microscopic examination. It may be treated after the first trimester with oral metronidazole. Some experts recommend against treating asymptomatic trichomoniasis in pregnancy as studies do not demonstrate improved outcomes. Topical metronidazole is associated with a higher rate of treatment failure and/or recurrence. Treatment is 500 mg of oral metronidazole twice a day for 7 days. An alternative regimen is 2 g of oral metronidazole as a single dose. This regimen is associated with a higher recurrence rate and increased gastrointestinal side effects. Tinidazole is effective in nonpregnant patients but safety data in pregnancy is limited and therefore it is not currently recommended.
Yeast Vaginitis
Patients with yeast vaginitis present with mild-severe pruritus, perineal irritation or pain, thick “curd-like” whitish discharge, pH less than 4.5, negative whiff test, and fungal elements on KOH-prepared microscopic examination. Yeast vaginitis may be treated with topical vaginal antifungal preparations, many of which are now available over the counter (OTC). Because of the desirability of obtaining a clear diagnosis and of minimizing the use of unnecessary medications during pregnancy, most patients should be cautioned against self-treating with OTC preparations without consulting their provider.
Gonorrhea/Chlamydia
Gonorrhea/chlamydia should be treated in the usual manner to prevent maternal and/or fetal complications. In pregnancy, the use of quinolones and most variants of tetracyclines should be avoided. Gonorrhea should be treated with dual therapy including ceftriaxone and azithromycin. In the case of cephalosporin allergy, recommendations include either (1) desensitization followed by treatment with cephalosporin or (2) azithromycin 2 g orally. This treatment is also effective for chlamydia but has lower efficacy against gonorrhea and therefore should be followed by a test of cure. Treatment for chlamydia is either azithromycin 1 g orally as a single dose or amoxicillin 500 mg orally three times daily for 7 days. Because treatment efficacy is reduced in pregnancy, a test of cure is recommended no sooner than 3 weeks following treatment.
Urinary Tract Infections
Background
Infections of both the lower and upper urinary tracts are more common in pregnancy. Anatomic and hormonal changes associated with pregnancy increase urinary stasis and may enhance ascending bacterial seeding. The increase in size of the uterus combined, later in pregnancy, with the presence of fetal body parts yields a functional partial obstruction of the outflow tract thereby increasing urinary stasis. Increased progesterone may yield ureteral smooth muscle relaxation, thus increasing the risk for ascending bacterial seeding and proliferation. Such changes appear to peak late in the second trimester or early in the third trimester. UTIs are associated with an increased risk of preterm delivery and low birth weight. In addition, the bacterial seeding can have serious consequences for the mother, including cystitis and pyelonephritis.
Women often report increased urinary frequency during the course of pregnancy. However, bacteriuria and its sequelae are also common during pregnancy. Approximately 5–10 % of all pregnant women develop asymptomatic bacteriuria (with higher prevalence among some at-risk populations). Of these, approximately one-third will develop clinically significant UTIs if not treated. Cystitis complicates about 1 % of all pregnancies with an additional 1–2 % of all pregnant women developing pyelonephritis. Commonly occurring pathogens include E. coli (80 %), Klebsiella, Proteus, and Staphylococcus saprophyticus. GBS is an uncommon cause of UTIs but is of particular significance in pregnancy because of its association with an increased risk for preterm labor and neonatal infection.
Diagnosis
The challenge, then, in pregnancy is to distinguish “normal” pregnancy-related urinary frequency from the urinary symptoms (including frequency) associated with UTIs.
History
Many patients may be asymptomatic. Others may report urinary frequency, urgency, dysuria, hematuria, fever, abdominal pain, cramping or contractions, and flank or back pain. Although frequency and urgency may be normal in pregnancy, the presence of the other symptoms should always prompt further evaluation. A change in baseline frequency or urgency should also prompt reevaluation. Because of the subtle or potentially confusing nature of the patients’ presenting complaints, providers should maintain a high index of suspicion for UTI. The presence of any symptoms should generally prompt evaluation and treatment if indicated.
Physical Examination
The physical examination should focus on physical signs of infection and/or signs of ascending infection. Key elements of the physical examination should include temperature, abdominal pain, rebound or guarding, and costovertebral angle tenderness. A pelvic examination is indicated for patients who present with abdominal or back symptoms or for those who report bleeding, contractions, or cramping.
Laboratory Examination
Urine culture remains the gold standard for diagnosis of UTIs. More than 100,000 colony-forming units per milliliter are considered a positive urine culture. In addition to assisting with the diagnosis, culture may also be useful in identifying the bacterial etiology and the antibiotic sensitivities of the isolated organism. More rapid assessment is often necessary, however, and a variety of additional tests are available that can provide results while the patient is still in the office (or within a few hours). Formal urinalysis performed in a laboratory may be helpful in assisting in diagnosis.
Other office-based tests are very specific but not sensitive. Dipstick leukocyte esterase testing is approximately 20 % sensitive and a 95 % specific. Dipstick nitrite is approximately 57 % sensitive and 95 % specific. Urine microscopy with more than ten white blood cells per high-powered field on a spun urine sample is about 25 % sensitive and 99 % specific. These tests can be very useful if positive but may need to be followed up with urine culture if negative.
Treatment
Because of the potentially significant complications of untreated UTIs, treatment is recommended regardless of patient symptoms. There are several treatment options but, as always, each treatment option should be reviewed for safety and efficacy in pregnancy. Ampicillin has traditionally been the treatment of choice for UTIs during pregnancy. Its safety profile is excellent and it has been used widely during pregnancy. However, emerging ampicillin resistance in E. coli (more than one-third resistant in some regions) has led many providers to use alternatives as first-line therapy. Among the options for treatment are the following:
· Cephalexin (category B, 250–500 mg orally, twice a day)
· Nitrofurantoin (category B, 50–100 mg orally, twice a day)
· Sulfa drugs (sulfisoxazole 1 g orally, four times a day, TMP/SMZ 160/180 mg orally, twice a day; they may be used in the second trimester but should be avoided in either first or third trimester)
· Fosfomycin (category B; 3 g single dose)
With the exception of fosfomycin, all treatment should be for 7–10 days for lower tract infections and up to 2 weeks for pyelonephritis.
Group B Strep
Background
GBS (most commonly Streptococcus agalactiae) are normal colonic flora. Under appropriate conditions, GBS colonize in the vagina, complicating pregnancy and the early neonatal course. Of all pregnant women, 10–30 % are colonized with GBS in either the vaginal or rectal areas. GBS is a common and significant cause of prenatal and neonatal morbidity. GBS is associated with preterm labor, premature rupture of membranes, and preterm delivery. Less commonly, GBS is associated with UTIs. It is also associated with neonatal infection, including meningitis. Infants born to colonize women often develop early onset invasive disease, 80 % within the first 7 days of life. The prevalence of invasive disease is about 0.6 per 1000 live births. In the United States, GBS is responsible for about 2000 neonatal infections and 100 fatalities annually.
Treatment of GBS has been shown to decrease the incidence of such complications. The use of intrapartum antibiotic therapy to treat women at increased risk for transmission to their newborns can significantly reduce peripartum transmission and neonatal infection. Treatment of invasive GBS infection is associated with a reduction in rates of premature rupture of membranes and preterm delivery. The key to successful management is identification and treatment of those patients who are at risk for preterm complications or peripartum transmission.
Diagnosis
Diagnosis of GBS can be challenging. Most patients do not consistently demonstrate colonization throughout the course of pregnancy. Early GBS cultures do not correlate well with GBS status at the time of delivery. In addition, patients colonized with GBS are generally asymptomatic. For this reason, authorities recommend universal screening of prenatal patients regardless of risk or symptoms near term (35–37 weeks’ gestation). For patients who present with suggestive signs or symptoms, GBS testing should be performed. High-risk conditions include preterm labor, premature rupture of membranes, or evidence of GBS UTI. Those patients with a past history of premature rupture of membranes, preterm delivery, or neonatal strep infection should also be considered high risk.
Universal Screening
All patients are screened during the course of pregnancy with treatment reserved for those who have positive cultures or who are at high risk.
· GBS testing is performed on all women at 35–37 weeks’ gestation (the results of which more nearly correlate with intrapartum GBS status than cultures obtained earlier in pregnancy).
· In the absence of GBS culture results, all patients with fever, prolonged rupture of membranes (>18 h), or gestational age less than 37 weeks should be presumed GBS positive.
· In the absence of GBS cultures, all patients with a past history of GBS UTI or neonatal GBS infection should be presumed GBS positive.
· In patients with preterm premature rupture of membranes, GBS cultures should be obtained. Patients may be presumed GBS positive until culture results are available.
Treatment
Penicillin is the gold standard treatment for GBS in patients without penicillin allergy. Acceptable penicillin-based regimens include penicillin G intravenous, five million units loading dose followed by 2.5 million intravenous units every 4 h until delivery or 2 g of ampicillin intravenous loading dose followed by 1 g intravenously every 4 h.
For patients with a nonserious penicillin sensitivity, cefazolin 2 g IV once and then 1 g IV every 8 h until delivery is recommended. Alternatives for patients with more significant penicillin allergies include clindamycin (if sensitivity data is available and indicates clindamycin sensitivity) or vancomycin 20 mg/kg every 12 h (max 2 g dose).