Antibiotic
Dose
Duration
Notes
Nitrofurantoin
100 mg orally every 12 h
Five to seven days
Does not achieve therapeutic levels in the kidneys so should not be used if pyelonephritis is suspected.
Avoid use during the first trimester if other options are available.
Amoxicillin
500 mg orally every 8 h
Three to seven days
Resistance may limit its utility among gram-negative pathogens.
Amoxicillin-clavulanate
500 mg orally every 8 h
Three to seven days
Cephalexin
500 mg orally every 6 h
Three to seven days
Cefpodoxime
100 mg orally every 12 h
Three to seven days
Fosfomycin
3 g orally as single dose
Does not achieve therapeutic levels in the kidneys so should not be used if pyelonephritis is suspected.
Trimethoprim-sulfamethoxazole
800/160 mg (one double-strength tablet) every 12 h
Three days
Avoid during the first trimester and at term.
The treatment of cystitis in pregnancy is similar to ASB. However, the provider may not have the urine culture results at the time of diagnosis, and empiric antibiotics can be chosen based on coverage of common organisms such as Enterobacteriaceae. Again, a 3–7-day course is recommended with a repeat culture after completing antibiotics to confirm sterilization. Shorter courses of antibiotics have the potential to minimize side effects and complications for the mother such as Clostridium difficile-associated diarrhea and also to decrease antimicrobial exposure for the fetus. According to a recent Cochrane review, there is no significant difference in outcomes for cure rates, recurrent infection rate, and incidence of preterm delivery or rupture of membranes with any one particular antibiotic over another [17]. Please see Table 1 for antimicrobial options during pregnancy. Some antibiotics that are typically used to treat UTI in the nonpregnant patient, including fluoroquinolones and tetracyclines, are contraindicated in pregnancy due to potential effects on musculoskeletal and dental development, respectively.
As described above, pyelonephritis in pregnant women has the potential for serious morbidity and appropriate treatment is paramount. Because of this, initial management of pyelonephritis in the pregnant patient should begin as an inpatient. The case patient above should start parenteral antibiotics and transition to oral antibiotics when afebrile for 24–48 h. Some options for initial therapy could include a parenteral cephalosporin such as cefazolin or ceftriaxone. See Table 2 for additional antibiotic choices. Of note, nitrofurantoin and fosfomycin do not achieve adequate tissue penetration and should not be used for the treatment of pyelonephritis. Because recurrent pyelonephritis can occur in up to 8 % of patients, ongoing suppression with antibiotics such as nitrofurantoin 50–100 mg or cephalexin 250–500 mg daily should be considered for the duration of the pregnancy in cases like our patient [3, 10, 18]. In summary, urinary tract infections are frequently encountered during pregnancy, and risk of progression to upper tract disease is increased. Appropriate workup and treatment is critical to reduce the risk of pyelonephritis and adverse pregnancy outcomes.
Table 2
Parenteral regimens for empiric treatment of pyelonephritis in pregnancy
Antibiotic | Dose, interval |
|---|---|
Mild to moderate pyelonephritis | |
Ceftriaxone | 1 g every 24 h |
Cefepime | 1 g every 12 h |
Aztreonama | 1 g every 8 h |
Ampicillin | 1–2 g every 6 h |
PLUS | |
Gentamicinb | 1.5 mg/kg every 8 h |
Severe pyelonephritis with an impaired immune system and/or incomplete urinary drainage | |
Ticarcillin-clavulanate | 3.1 g every 4 h |
Piperacillin-tazobactam | 3.375 g every 6 h |
Meropenem | 500 mg every 8 h |
Ertapenem | 1 g every 24 h |
Doripenem | 500 mg every 8 h |
Case #2 Influenza and Pregnancy
A 27-year-old woman, currently 20 weeks pregnant, presents to her primary care physician for a routine visit in October. She is offered the flu vaccine but declines, concerned that she always gets “the flu” with the influenza vaccine, and since she is pregnant, she does not want to risk getting sick. She also heard that vaccines might harm her fetus.
Eight weeks later, she returns with a fever of 102 F (39 C) and diffuse myalgias for the last 3 days. A point-of-care test for influenza A is positive. She asks about medications that “cure” this disease. Should she be prescribed oseltamivir?
Discussion
Influenza is caused by three members of the family Orthomyxoviridae. They are divided into influenza A, B, and C. Influenza A is the most common cause of severe disease and epidemics. Influenza A viruses are characterized by their hemagglutinin (H) and neuraminidase (N) surface antigens.
Influenza epidemics occur annually to triennially and are of variable severity. Pregnant patients were overrepresented in admissions to hospital and intensive care in the 2009 pandemic [19]. The reasons for this increased severity of disease are unknown, but might include altered immune response and cardiopulmonary physiology.
Influenza is characterized by a febrile respiratory illness that starts abruptly with chills, high fevers (normally >102 F), myalgia, and headaches. Associated respiratory symptoms include cough, nasal discharge, and sore throat, lasting 5 days to a week. Nausea and vomiting seems to be more common in pregnant patients [20]. While influenza is mostly a self-resolving illness, in older patients and in a disproportionate percentage of pregnant patients, it can be complicated by viral pneumonia, myocarditis, and myositis. Secondary bacterial pneumonia (caused by S. aureus, Streptococcus pneumoniae, and H. influenzae) is a feared complication.
Studies done during influenza pandemics reveal that this disease increases the risk for spontaneous abortion and preterm birth [21]. Fetal malformations have also been associated with influenza, but if this is a result of the disease itself or hyperthermia is yet unknown. This is clear only in the vulnerable time of the early first trimester usually less than 10 weeks.
Clinical diagnosis alone in the setting of an epidemic is accurate approximately 80 % of the time. Laboratory diagnosis in the outpatient setting can be made by either a rapid viral antigen with a sensitivity varying between 50 and 80 % or a molecular diagnostic test using PCR amplification with sensitivity of around 90 %.
Influenza Vaccination in Pregnancy
The most effective strategy for preventing influenza in pregnant women is immunization. Benefit to the infant has also been demonstrated as maternal immunization reduces respiratory illnesses with fever in infants in the first 6 months of life [22].
Both the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) and the American College of Obstetricians and Gynecologists recommend that all pregnant adults receive an annual influenza vaccine. An inactivated and a live attenuated vaccine are available. Currently, the inactivated influenza vaccine should be given to pregnant women as soon as it is available, and it can be given at any point during gestation. The live intranasal influenza vaccine is not recommended for pregnant women, but can be given in the postpartum period. In the Northern Hemisphere, influenza occurs from October through May, and vaccines are available as early as late August.
A common misconception about the flu vaccine is that you can get the flu from the vaccine. This has been studied by two blinded, randomized trials that reported no difference between subjects that received the inactivated flu vaccine and placebo in terms of fever, headache, or muscle aches. Differences were seen in soreness and redness at the injection site among people who got the flu shot [22, 23]. The safety of influenza vaccination during pregnancy is supported by a multitude of studies [24, 25]. A second misconception is regarding thimerosal. Thimerosal is a mercury-containing preservative used in multidose vials of the influenza vaccine. There is no scientific evidence that thimerosal-containing vaccines cause adverse effects in children born to women who received vaccines with thimerosal [26]. However, thimerosal-free formulations of the vaccine are also available.
Treatment of Influenza
In the United States, oseltamivir and zanamivir are FDA Pregnancy Category C drugs, a result of the lack of studies to assess safety in pregnant patients. There is no evidence of adverse fetal outcomes with oseltamivir [27]. Expert opinion recommends prompt antiviral treatment for pregnant and postpartum (2 weeks postpartum) women with confirmed or suspected influenza [28]. Treatment should not be delayed pending laboratorial diagnosis. Early treatment within 48 h of symptom onset has been shown to decrease intensive care admission and mortality [29]. While the evidence for the later treatment is not as strong, treatment is still recommended. Based on limited data, the dosing of antiviral therapy for treatment of influenza during pregnancy is 5 days, the same as in nonpregnant adults and nonimmunocompromised patients.
In addition to antivirals, control of fever is essential in the treatment of influenza in this patient population as fever has been associated with worse fetal outcomes, especially in the first trimester. Of all antipyretics, acetaminophen has a long history of safe use in pregnancy and is widely used.
Infection Control in the Outpatient Setting
When visiting their healthcare providers, pregnant women with suspected or confirmed influenza infection should be given facemasks and instructed on precautions to decrease transmission.
Healthy newborns of mothers with confirmed or suspected influenza should be considered exposed and should follow hospital infection control guidelines. In the wake of the 2009 H1N1 pandemic, the CDC recommends temporary separation of a mother with suspected or confirmed influenza from her newborn until all criteria were met: the mother had received antiviral medications for at least 48 h, was afebrile without antipyretics for 24 h, and is able to control her cough and respiratory secretions. Once the mother and infant are able to initiate close contact, standard precautions and respiratory hygiene apply. The mother’s milk should be fed to the newborn by a healthy caregiver until criteria are met for close contact. Unlike other body fluids and secretions, human milk is not considered a body fluid to which standard, droplet, or contact precaution recommendations apply. Milk from an infected mother is not considered infectious. Antiviral medication use by the mother is not a contraindication to breastfeeding. Antiviral chemoprophylaxis of the infant is currently not recommended, due to limited data on safety and efficacy [30] (Fig. 1).
Fig. 1
Common antivirals active against influenza A and B
Case #3 TORCH Infections
Ms. B. is a 33-year-old G2P2 13-week pregnant woman that presents to an urgent care center in August with a history of 3 days of sore throat with cervical lymphadenopathy, cough, fever, and malaise. She reports that she has been febrile up to 100.6 F (38 °C). She denies any rashes, recent travel, raw food ingestion, or sick contacts. She has two small cats that were adopted about 3 months ago. She is a kindergarten teacher. Per the patient, a prenatal screen for human immunodeficiency virus (HIV) and syphilis was negative. She is immune against rubella. She is concerned about toxoplasmosis, as her obstetrician had counseled her about this condition and the risk for fetal disease. What tests should be obtained? What is the risk for the fetus? What are some of the other infections associated with congenital syndromes and fetal abnormalities?
Congenital and Perinatal Infections
Congenital and perinatal infections are important causes of fetal mortality and child morbidity. They are grouped in an acronym, TORCH, that reflects a group of infections with common disease manifestations in the fetus and newborn that includes dermal, ocular, and neurological manifestations such as jaundice, purpura, and visual and hearing loss. The TORCH complex encompasses Toxoplasma gondii, syphilis, rubella, cytomegalovirus, and herpes simplex virus.
Congenital Toxoplasmosis
Toxoplasma gondii is a protozoan intracellular parasite acquired from ingestion of infected bradyzoites in undercooked, cured, or raw meat or from using kitchen supplies contaminated with raw meat. Soil and water can also be infected by cat feces which can contain oocysts. Because cats develop immunity after primary infection and oocysts are only shed in a primary infection, kittens are a particular risk to susceptible hosts such as pregnant women and patients with immunodeficiencies.
If toxoplasmosis is acquired for the first time during pregnancy, vertical transmission to the fetus via the placenta occurs during the acute parasitemic phase. Symptoms of acute maternal infection can vary from none to fever, headache, malaise, and myalgias, mimicking a mononucleosis-like illness.
Diagnosis is based on serological conversion from negative to positive IgG or IgM antibodies for T. gondii. While this is possible in countries where prenatal and serial Toxoplasma serologies are obtained, there is no current recommendation for prenatal Toxoplasma serologies in the United States. Reasons for this include the low incidence of congenital toxoplasmosis and the low specificity of the T. gondii serological testing. Some states recommend newborn testing for T. gondii IgM [31]. A more common clinical scenario that might confront a physician practicing in the United States is a positive isolated IgM in the context of an unknown prior serological status in a pregnant patient. IgM reactions can be nonspecific or reflect prior infection as it may persist for more than 1 year. In the case of an isolated positive IgM with a negative IgG and unknown prior immune status, a repeat serology should be obtained in 2 weeks to assess if there is IgG seroconversion, hence eliminating the possibility of a nonspecific IgM reaction. If the repeat test is positive for IgM and IgG, seroconversion is documented and treatment should be initiated. In patients with initial positive IgM and IgG or a persistent positive IgM, a reference laboratory should confirm the positive serology.
The risk for congenital toxoplasmosis increases with gestational age at the time of acute disease with a risk of transmission of around 15 % at 13 weeks and 71 % at 35 weeks [32]. Treatment is advocated for pregnant women with probable or definite seroconversion, and the regimen recommended depends on the gestational age and/or signs of fetal involvement. Fetal ultrasonography should also be obtained to assess for fetal abnormalities (hydrocephalus, brain or hepatic calcifications, splenomegaly, and ascites). Amniocentesis at 18 weeks with amniotic fluid PCR for T. gondii is recommended, but risk and benefits of this procedure should be discussed with the patient. For all cases of suspected congenital toxoplasmosis, consultation with a national expert is recommended (PAMF-TSL, Palo Alto Medical Foundation Toxoplasma Serology Laboratory or the National Collaborative Treatment Trial Study, in the US) [33].
Treatment with spiramycin is recommended by many investigators in the United States and Europe during the first 18 weeks of pregnancy. In the United States, spiramycin can be obtained after discussion with the Food and Drug Administration via a “compassionate use [IND]” program. This medication will not act on the fetus and will only clear the placenta of the parasite. It should be continued until delivery unless there is any evidence (ultrasound, amniotic fluid PCR) or suspicion of fetal involvement, which requires a switch from spiramycin to pyrimethamine and sulfadiazine on week 18 in order to prevent fetal disease. This regimen is avoided in the first 18 weeks due to the risk of teratogenicity from pyrimethamine. Folic acid (25 mg daily p.o.) should be given to prevent hematological toxicities. Weekly complete blood counts should be monitored and treatment discontinued if significant myelotoxicity.
Congenital Syphilis
Syphilis is caused by the spirochete, Treponema pallidum, and it can remain latent for years. Because this organism cannot be cultured using conventional techniques, diagnosis is based on clinical and serological data. Untreated syphilis during pregnancy, especially early syphilis, can lead to stillbirth, neonatal death, or infant disorders such as deafness, neurologic impairment, and bone deformities. Congenital syphilis (CS) can be prevented by early detection of maternal infection and treatment at least 30 days before delivery [34].
A recent report by the Centers for Disease Control and Prevention (CDC) warned of the increased rate in CS during the period 2005–2008 after years of steady decline. Multiple professional organizations, including the American College of Obstetricians and Gynecologists (ACOG) and the CDC, have recommended syphilis screening within the scope of a prenatal visit [34]. In high-incidence populations (sex workers, use of illicit drugs, human immunodeficiency virus infection, and no prenatal care), retesting during the third trimester (28th–30th week) is recommended. All patients who have syphilis should be offered testing for HIV infection.
Penicillin remains the mainstay of treatment, but duration and dosage depends on the phase at which syphilis is diagnosed. Syphilis can be classified as primary, secondary, and tertiary, based on initial symptom presentation. If asymptomatic (latent), it can be divided into early (less than 1 year since negative titers) or late (more than 1 year). Screening tests for syphilis are traditionally non-treponemal specific and include RPR (rapid plasma reaction) and VDRL (venereal disease research laboratory). Positive non-treponemal testing should be followed by confirmatory treponemal testing such as TPPA (T. pallidum particle agglutination assay) or FTA-ABS (fluorescent treponemal antibody absorption). If treponemal testing is negative, this may represent a transient biological false positive which can occur in pregnancy.
Primary syphilis is normally characterized by a painless chancre, involving the genital, perineal, anorectal areas, throat/lips, or hands. This normally occurs about 2–4 weeks postexposure and heals spontaneously. Treatment is benzathine penicillin G (BPG) 2.4 million units intramuscularly once. Secondary syphilis can have a broad range of systemic symptoms including rash that involves palms and soles, headache, fever, pharyngitis, and lymphadenopathy. It occurs about 2–8 weeks post resolution of the initial chancre. Treatment is identical to primary syphilis. The hallmark of tertiary syphilis is the formation of gummas (granulomatous lesions). These can occur anywhere but typical lesions involve the heart or large vessels and the central nervous system. Treatment for tertiary syphilis is with BPG 2.4 million units intramuscularly weekly for 3 weeks. If neurosyphilis is suspected, a 10- to 14-day course with aqueous penicillin G 18–24 million units IV is recommended.
The most likely presentation to primary care is for prenatal screening of an asymptomatic patient. Positive screening results in pregnancy even if asymptomatic should prompt a search for prior syphilis testing and for occult symptoms. If by clinical exam there are no signs or symptoms suggestive of symptomatic syphilis, care should be taken to determine how long this latent infection has been present. Treatment with a single injection of BPG as the above is acceptable for primary, secondary, as well as early latent syphilis if clear documentation of negative testing within a year is available. Some experts recommend a second dose of benzathine penicillin G 1 week later in pregnant patients especially in the third trimester tertiary, and late latent syphilis requires weekly penicillin injection for three doses. Severe allergies such as hives or angioedema to penicillin require desensitization as alternatives to penicillin are not recommended because of potential fetal toxicity or failure of treatment to cross the placenta.
While a possibility in any patient receiving treatment for syphilis, the Jarisch-Herxheimer reaction (immune over-reactivation from treponemal destruction) has particular importance in the pregnant patient as it can lead to induction of early labor or fetal distress. Pregnant women should be aware of this potential risk. The non-treponemal test titer or RPR should be repeated at 1, 3, 6, 12, and 24 months with a fourfold titer reduction by 6 months post therapy to ensure resolution.
Most cases of congenital syphilis occur from transmission to the fetus during early syphilis (primary, secondary, and early latent). The frequency of vertical transmission increases as gestation advances, but the severity of fetal infection decreases with infection later in pregnancy. Seventy to 100 % of infants born to untreated mothers will be infected compared to 1–2% of those born to women adequately treated during pregnancy. Therefore, screening for syphilis at the first prenatal visit and repeat testing later in pregnancy for those at highest risk is critical for the prevention of congenital syphilis and its potential adverse fetal outcomes.
Rubella
Rubella, also known as German measles, is a member of the Togavirus family, genus Rubivirus. Rubella is a childhood disease that prior to a generalized vaccination plan occurred in 6-year cycles, usually in the late winter. Rubella during pregnancy can result in spontaneous abortion, intrauterine growth restriction, and fetal malformations. Vaccination greatly reduced the incidence of rubella and congenital rubella syndrome. Acute rubella is normally a self-limited disease associated with a maculopapular rash similar to scarlet fever that begins on the face and quickly spreads to the trunk and extremities. Other nonspecific symptoms such as low-grade fever, sore throat, cough, headache, and malaise may also be present. Classically, rubella is associated with tender suboccipital and postauricular lymphadenopathy. Treatment is supportive.
Congenital rubella infection can be catastrophic, not only resulting in spontaneous abortion, intrauterine growth, and congenital defects (classically valvular abnormalities, hearing and visual impairment) but also more subtle late manifestations such as intellectual disability, diabetes mellitus, and thyroid abnormalities. Maternal-fetal transmission is the highest if infection occurs in the first 16 weeks of pregnancy. The incidence of defects may be as high as 80–85 % if maternal rubella is acquired during the first trimester. Little if any risk for congenital rubella syndrome occurs after 18–20 weeks’ gestation.
As there is no treatment, prevention and early fetal diagnosis is essential. The CDC recommends documentation of rubella immunity at the first prenatal visit. If the woman is nonimmune, MMR vaccine should be given postpartum since this live vaccine is contraindicated during pregnancy.
In patients with no evidence of immunity and clinical features suggestive of rubella infection, acute rubella can be documented by one of the following: a greater than fourfold increase in IgG rubella titers in convalescent versus acute serum, the presence of rubella-specific IgM, or a positive rubella culture. In all pregnant patients with acute rubella, fetal infection should be sought by chorionic villous or amniotic fluid sampling with a rubella-specific polymerase chain reaction assay.
Due to the catastrophic effects of congenital rubella infection in early pregnancy, women should be counseled on the risk of maternal-fetal transmission and offered pregnancy termination, especially if congenital infection happens in the first trimester.
Cytomegalovirus
Cytomegalovirus (CMV) is a DNA herpes virus that is the most common congenital viral infection. Maternal infection can be either primary, when a nonimmune woman is primarily infected, or secondary, when maternal immunity was present prior to conception and may be due to reactivation of latent virus versus reinfection. Maternal immunity is more prevalent in the lower socioeconomical status and older and multiparous women.
Adult primary infection resembles a mononucleosis-like syndrome with low-grade fever, myalgia, headaches, rhinitis, pharyngitis, and malaise. About a quarter of all congenital CMV infection occurs after maternal primary infection [35]. Fetal CMV disease presents with a wide variety of manifestations and appears to be more severe if infection is acquired in the first trimester. Clinical manifestations include intrauterine growth restrictions, CNS abnormalities such as microcephaly or chorioretinitis, hepatosplenomegaly, and thrombocytopenia [35]. Mortality is around 5 % of all the newborn affected and long-term morbidity is typically related to neurological involvement [36]. Treatment with antiviral medication during pregnancy has not been proven to be beneficial, and the effects of medications such as ganciclovir, foscarnet, and cidofovir on the early fetus have not been established. Treatment of the neonate for CMV end organ disease is however recommended.
While recommended in many European countries, there is no consensus on baseline prenatal screening for immunity to CMV in the United States. In general, women with a febrile illness or clinical features suggestive of mononucleosis-like illness should be screened for primary CMV infection. As with Toxoplasma, the diagnosis of acute primary CMV is dependent on a fourfold increase in IgG titers between acute and convalescent serum, with IgM titers not helpful as they can remain elevated for prolonged periods.
If acute primary CMV is confirmed, prenatal diagnosis should be offered to pregnant women, given the risk of fetal infection. Fetal infection can be established by amniotic fluid sampling for CMV DNA-specific polymerase chain reaction. Fetal prognosis depends on ultrasound assessment of stigmata of CMV infection. There is evidence that CMV hyperimmunoglobulin might be helpful in decreasing the rate of fetal infection with primary maternal infection.
Herpes Simplex Virus
Genital herpes is the result of infection with either herpes simplex virus (HSV) type 1 or 2. HSV is a DNA virus that belongs to the family Herpesviridae. While classically genital herpes is associated with HSV-2 infection, more recent data shows that HSV-1 appears to be an important cause of genital herpetic lesions as well [37]. Seroprevalence for both HSV-1 and HSV-2 is higher with lower socioeconomical status and multiple sexual partners and among black women. Unlike CMV, HSV transmission happens mostly through direct contact in the birth canal and perineal area during labor and delivery. Rarely, there is in utero transplacental transmission. There are no current recommendations in the United States to screen couples for HSV infection.
The presentation and treatment of genital herpes differs whether it is a primary infection or a recurrence. In primary infection, the presentation is normally more symptomatic and has the potential to be severe. Genital and/or perineal pustular lesions with blistering and ulceration are normally present in primary infection. They last for about 2 weeks. Local pruritus with dysuria that can progress to urinary retention might also be present. Systemic signs such as fever and lymphadenopathy are more commonly present in primary infection. Only about one-third of patients with primary genital herpes are symptomatic [38].
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