Infectious Disease in Pregnancy
Courtney J. Mitchell
Brenna L. Hughes
Introduction
Pregnancy is a unique condition with regards to infectious disease. Due to pregnancy-induced changes in the immune system, many diseases that may cause no symptoms or mild illness in nonpregnant subjects trigger much more severe maternal affliction. The advent of antibiotics and vaccines has rendered infectious diseases sometimes a less trendy topic, especially in pregnancy. However, novel organisms continue to emerge and present new challenges to managing these new diseases in pregnancy. Additionally, waning uptake of vaccination in the general population provides opportunities to advocate for recommended immunizations in pregnancy. In this chapter, we will review important infections in the context of pregnancy. Much of this chapter provides a review of enduring science pertinent to infectious disease and pregnancy. However, updates to emerging therapies and changes in guidelines are also provided.
Cytomegalovirus
Cytomegalovirus (CMV), otherwise known as human herpes virus 5, is an enveloped double-stranded DNA virus belonging to the Herpesviridae family. It is the most common congenitally acquired infection.1 The name of the virus is derived from the characteristic “owl’s eye” appearance of cells seen in histological sections of tissues which have been infected by the virus; this appearance is due to massive viral cytoplasmic replications, creating distinct viral or cytomegalic inclusions.
Epidemiology
Seroprevalence studies of pregnant and nonpregnant women worldwide have consistently shown wide variations in seropositivity for CMV antibodies. These rates range from 40% to 80%, with higher rates related to geography, lower socioeconomic status, race, and an increase in patient age, gravidity, parity, and number of sexual partners.2,3,4 Studies using polymerase chain reaction (PCR) have shown a cervical excretion rate of CMV of 13% to 40% and a urinary excretion rate of 1% to 13% throughout pregnancy in seropositive patients.5 Viral nucleic acid has been detected in other fluids such as nasopharyngeal secretions, urine, breast milk, and amniotic fluid.6
Congenital infection with CMV occurs at a frequency of approximately 0.5% to 0.7% of all newborns born in the United States.2 In the United States, approximately 40,000 infants are born annually with either clinical or laboratory evidence of CMV infection. Worldwide, it is estimated that 1% of all newborns are infected with CMV.
Transmission
Perinatal transmission of CMV has been demonstrated in cases where the pregnant woman develops either a primary or recurrent CMV infection or when there is acquisition of a new CMV strain. Transmission rates of CMV after primary infection range from 30% to 40% in the first trimester and 30% to 70% in the third trimester,7 whereas vertical transmission occurs in approximately 1% to 3% of cases where there is a recurrent infection in the mother.8,9 Primary CMV infection occurs in 1% to 3% of pregnant women.10,11 In general, the following principles apply to congenital infection with CMV: severe congenital CMV results almost exclusively from primary maternal infection, and clinically evident manifestations in the newborn are more common following primary infection in the mother.
Clinical Presentation
Primary CMV infection has been described as a heterophile-negative, mononucleosis-like syndrome. Patients with CMV may develop fever,
pharyngitis, lymphadenopathy, and other generalized symptoms of viral illness, but 90% of adults are asymptomatic. Following initial primary infection, CMV becomes latent; reactivation of latent infection is often asymptomatic and the factors that control reactivation are poorly understood at present.
pharyngitis, lymphadenopathy, and other generalized symptoms of viral illness, but 90% of adults are asymptomatic. Following initial primary infection, CMV becomes latent; reactivation of latent infection is often asymptomatic and the factors that control reactivation are poorly understood at present.
Major target organ systems for the fetus include the hematopoietic and central nervous system (CNS) and general development. Characteristics of fetal infection that may aid in prenatal diagnosis include fetal growth restriction, cerebral ventriculomegaly, ascites, microcephaly, hydrocephaly, periventricular calcifications, calcifications of the bowel and liver, hepatosplenomegaly, cardiomegaly, placentomegaly, hyperechogenic bowel, and oligohydramnios or polyhydramnios. CMV may cause nonimmune hydrops. CMV has also been implicated in myocarditis; there have been reports of fetal heart block and of fetal supraventricular tachycardia.12
Most infected neonates are asymptomatic at birth, although 10% of these infants present with clinical manifestations at birth. Forty to sixty percent of neonates with symptoms at birth will have permanent sequelae from infection, most commonly, sensorineural hearing loss, followed by cognitive impairment, chorioretinitis, and cerebral palsy13; 10% to 15% of neonates asymptomatic at birth will go on to have sensorineural hearing loss.13 Other common findings in congenital CMV include petechial rash, hepatosplenomegaly, hemolytic anemia, jaundice, interstitial pneumonia, seizures, and microcephaly.
Clinical Assessment
Adult CMV infections usually go unrecognized unless symptoms develop. The presence of CMV-specific immunoglobulin (Ig)G antibodies in the mother confirms a recent or past infection; however, because CMV becomes latent in the mother, previous infection in the mother does not confer immunity against infection in the infant. CMV-specific IgM is detectable in both maternal and neonatal primary infections in 80% of cases.
Shell vial viral culture is the most accurate method of diagnosing CMV infection, although culture positivity cannot distinguish between primary and recurrent infection. Culture sites in the mother include the nasopharynx, cervix, vagina, and urine; in the infant, they include the nasopharynx, conjunctiva, and urine. Modern techniques, such as detection of viral DNA using PCR or in situ hybridization, have also been used in the prenatal diagnosis of CMV.
A number of serologic studies are available for the detection of antibodies to CMV, including indirect hemagglutination assay, enzyme-linked immunsorbent assay (ELISA), neutralization tests, and complement fixation (CF). However, CF assays are often inaccurate because of high false-positive rates due to cross-reactivity with other herpesviruses. CMV-specific IgM antibody tests are helpful but of limited value because 30% of women with primary infections are initially seronegative, and the test result is positive in 10% of women with recurrent infections.11 In addition, 90% of women with IgM-positive and IgG-negative test results are false-positive for infection. Acute and convalescent paired specimens demonstrating a significant increase in titer are suggestive of a primary infection.14
When maternal primary infection is suspected or when there are findings on ultrasonography that are suspicious of congenital CMV infection, prenatal diagnosis can be carried out by amniocentesis. Ideally, prenatal diagnosis among women without ultrasound findings including fetal growth restriction, cerebral ventriculomegaly, ascites, microcephaly, hydrocephaly, periventricular calcifications, calcifications of the bowel and liver, hepatosplenomegaly, cardiomegaly, placentomegaly, hyperechogenic bowel, and oligohydramnios or polyhydramnios should occur beyond 21 weeks’ gestation, as this optimizes the sensitivity of diagnostic tests. PCR and/or viral culture of amniotic fluid can be performed to detect CMV. PCR of amniotic fluid, when combined with viral isolation, has been shown to have a sensitivity of 84% and a specificity of 100%.15,16
Fetal blood can be tested for the presence of CMV-specific IgM after 20 weeks’ gestation and has a sensitivity of 51% to 58% and a specificity of 100%.12 The presence of CMV-specific IgM in fetal cord blood, which is detectable in 60% of infants with congenital infection, establishes the diagnosis.17 It is possible to obtain false-negative IgM titers when cordocentesis is performed early in the course of fetal infection; IgM levels correlate positively with abnormal fetal ultrasound findings and hematologic test results, antigenemia (ie, pp65 [protein antigen associated with CMV]-positive leukocytes; sensitivity 16%-64%),
and messenger RNA (sensitivity 82%).18 On the whole, fetal blood sampling and amniotic fluid analysis has sensitivity, specificity, positive predictive value, and negative predictive value of 80%, 99%, 98%, and 93%, respectively, for CMV.18 However, as fetal blood sampling adds little additional value to amniotic fluid sampling and is associated with a risk of fetal death, it should not be routinely performed.
and messenger RNA (sensitivity 82%).18 On the whole, fetal blood sampling and amniotic fluid analysis has sensitivity, specificity, positive predictive value, and negative predictive value of 80%, 99%, 98%, and 93%, respectively, for CMV.18 However, as fetal blood sampling adds little additional value to amniotic fluid sampling and is associated with a risk of fetal death, it should not be routinely performed.
Pharmacologic Treatment
The treatment of CMV infection in the mother and infant is directed toward the symptoms, when they are present. Agents that have been used to treat maternal symptoms include adenosine arabinoside, cytosine arabinoside, acyclovir, ganciclovir, and foscarnet (phosphonoformic acid). Unfortunately, these agents have had limited success; adenosine and cytosine arabinoside are toxic, and acyclovir, ganciclovir, and foscarnet have only been used in a very small number of studies.
Currently, there is no proven antenatal treatment of fetal CMV infection recommended outside of research protocols.12 There is a case report of a good outcome with antenatal treatment of CMV-induced hydrops using valganciclovir.19
Because the vast majority of congenital CMV infections occur in instances of maternal primary infection, a reasonable strategy is to vaccinate seronegative women prior to conception. Vaccine development has included investigations into live-attenuated vaccines, recombinant virus vaccines, subunit vaccines, DNA vaccines, and peptide vaccines20; however, there is no current CMV vaccine available to prevent maternal CMV infection or decrease vertical transmission. Routine antepartum serologic screening for CMV is not recommended at this time due to no widely available treatment.2 The detection of maternal CMV antibodies before conception indicates prior infection, but the degree of protection that this immunity provides against congenital infection in subsequent pregnancies is unclear. The implications of a single antibody titer obtained during pregnancy are difficult to interpret. Even in a high-risk environment, the extent of risk for a seronegative pregnant woman by exposure is uncertain. One potentially effective prevention strategy is the use of good handwashing and avoiding contact with bodily fluids in healthcare settings, especially in high-risk settings such as daycare facilities or neonatal intensive care units.
Rubella
Rubella, or German measles, is caused by a single-stranded RNA virus that is a member of the Togaviridae family. Out of all the known teratogenic viruses, infection with rubella results in the most severe congenital malformations. The success of vaccination against rubella, and the subsequent decline of congenital rubella syndrome (CRS), stands as one of the major achievements of twentieth-century perinatal and neonatal medicine. Although congenital rubella infections (CRIs) are rare in the United States, it still is prevalent in developing countries. Despite increasing vaccination hesitancy and decreasing rate of measles-mumps-rubella (MMR) immunization, the rate of congenital rubella is still rare in the United States.
Epidemiology
The US incidence of rubella between ages 0 and 44 is 1/10,000,000, and since 2004, rubella has been considered eradicated in the United States.21 Despite this, an estimated 100,000 neonates are born annually with CRS.22 Efforts are now focused on vaccinating susceptible adults, but opportunities to do so are missed, including in the postpartum period. In mid-1990s, 8% of person aged 15 to 29 years were susceptible to acute rubella infection despite routine and mandatory vaccination programs in children.23 At present, the single most important source of sero-susceptible individuals in the United States are foreign-born immigrants who have not been vaccinated in their countries of origin, primarily Mexico and Central America.24 In addition, specific groups in the United States, such as the Amish communities in Pennsylvania, do not commonly accept the vaccine and have a high sero-susceptibility to rubella. As of 2018, 87% of countries recommend routine vaccination against rubella.25
Transmission
Rubella virus is spread by respiratory droplets. This requires prolonged close exposure. The virus is present in the nasopharynx and spreads via the lymphatics and then blood. It has an 80% attack rate. Fetal infection requires maternal viremia and placental transmission. Viremia has been thought to occur only with primary infection. Rare cases of reinfection leading to CRS have been reported.26 Serologic evidence of fetal exposure to rubella has been documented after inadvertent vaccination in pregnancy. To date, no cases of congenital defects
secondary to CRS have been reported due to the vaccine.27 Nevertheless, vaccine administration is contraindicated in pregnancy because the theoretical risk of CRS after vaccination, although low, may not be zero.28 Although the virus is shed in breast milk, neonatal exposure to rubella during breastfeeding has not been associated with morbidity.29 Prolonged viral shedding from an infant with CRS may be a source of infection. In addition, virus has been isolated in the urine, cerebrospinal fluid, and even the lens of neonates with CRS.
secondary to CRS have been reported due to the vaccine.27 Nevertheless, vaccine administration is contraindicated in pregnancy because the theoretical risk of CRS after vaccination, although low, may not be zero.28 Although the virus is shed in breast milk, neonatal exposure to rubella during breastfeeding has not been associated with morbidity.29 Prolonged viral shedding from an infant with CRS may be a source of infection. In addition, virus has been isolated in the urine, cerebrospinal fluid, and even the lens of neonates with CRS.
The variable risk of CRS at different gestational ages has long been recognized. Rubella infection before implantation has been implicated in spontaneous abortion, stillbirth, neonatal death, and CRS. Enders and co-workers30 reported that rubella occurring from 12 days to 12 weeks after the last menstrual period (LMP) resulted in an 81% to 90% fetal infection rate. No infection was noted if the rash appeared before the LMP or up to 11 days after the LMP. Cradock-Watson and Ridehalgh31 reviewed rates of rubella infection after the first trimester. The overall rate of CRI (seropositivity, with or without clinical disease) was 29% based on presence of rubella-specific IgM and 49% based on persistence of rubella-specific IgG after 8 months of age. Gestational age-specific rates of CRI ranged from 12% when infection occurred at 24 to 28 weeks to 58% at 36 to 40 weeks.
Clinical Presentation
Maternal
Acquired rubella presents as a mild or asymptomatic infection. The incubation period is 14 to 21 days, with viral shedding beginning 1 week before the onset of a fine “rubelliform” rash which starts on the face and neck and then extends to the trunk and extremities. The rash is macular and lasts 3 days, hence the name 3-day measles. Malaise, fever, and postauricular and suboccipital adenopathy are also common. Arthralgias are common in adult women; arthritis, neuritis, encephalitis, and thrombocytopenia are rare. Because these symptoms are nonspecific, diagnosis should be made on serologic rather than clinical grounds.32
Fetal and Neonatal
The pathogenesis of congenital defects due to rubella infection includes impairment in organogenesis due to decreased mitosis and damage secondary to scarring and persistent infection.33 Abnormalities resulting from impaired organogenesis occur with maternal infection in the first trimester. Other abnormalities, such as progressive hearing loss and pulmonic or aortic stenosis, are due to ongoing damage caused by persistent infection and immune response. Congenital infection may be divided into three categories based on its manifestations: CRS, extended CRS, and delayed CRS. Newborn rubella, or CRS, and extended CRS are apparent at birth. Delayed manifestations of congenital infection may not be apparent for years or decades.
Four major defects in CRS, in order of decreasing frequency, are deafness, cognitive impairment, cardiac lesions, and ophthalmologic abnormalities. Congenital manifestations of rubella are summarized in Table 10.1 with hearing loss the most common clinical finding in newborns. Types of malformation are gestational age-specific. Cataracts and cardiac lesions are present when infection occurs before 8 weeks. Deafness occurs with infection before 16 weeks and retinopathy with infection before 18 weeks. Sever and associates,34 in the Collaborative Perinatal Research Study (CPRS) of 1964, reported that deafness was the most common single defect and was present in 100% of infants with multiple defects resulting from first trimester infection. Conversely, eye defects, with cataracts and glaucoma being most frequent, were present only with other abnormalities. Cardiac lesions include ventricular septal defect, patent ductus arteriosus, and peripheral pulmonic stenosis. Thrombocytopenic purpura (blueberry muffin rash), hepatosplenomegaly, osseous lesions, meningoencephalitis, and rubelliform rash may also be present in CRS. Abnormalities (including developmental delay, hearing loss, growth retardation, pulmonic stenosis, and thrombocytopenia) have been found in 15 out of 24 infants exposed to rubella at between 14 and 31 weeks’ gestation.33
The spectrum of extended CRS includes cerebral palsy, mental retardation, developmental and language delay, seizures, cirrhosis, growth restriction, and immunologic disorders (eg, hypogammaglobulinemia). Delayed manifestations of CRS include endocrinopathies, late-onset deafness and ocular damage, renovascular hypertension, and encephalitis. Long-term follow-up of CRS patients revealed a 20% incidence of diabetes mellitus by the age of 35 years.34 Other endocrinopathies include
thyroid dysfunction and growth hormone deficiency. Deafness and ocular and vascular damage may be due to ongoing infection with scarring and inflammation.
thyroid dysfunction and growth hormone deficiency. Deafness and ocular and vascular damage may be due to ongoing infection with scarring and inflammation.
Table 10.1 Clinical Manifestations of Rubella Infection in Newborns and Adults | |||||||||||
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Delayed manifestations of CRS are thought to be due to circulating immune complexes.35 Delayed manifestations occur in more than 20% of those with initially symptomatic CRS.34 The incidence of delayed defects in those with asymptomatic CRI and their gestational age-related risk are not clear. Data from the CPRS showed delayed effects in almost two-thirds of those infected in the third trimester.36 Although major malformations due to infection in the first trimester may be devastating, the adverse effects from later infection are clearly not minor.
Clinical Assessment
Maternal
Clinical diagnosis of postnatal infection is unreliable and must be confirmed by serology. Rubella-specific IgM can be detected 1 week after the onset of the rash and typically persists for up to 8 to 12 weeks; it is detectable by culture of nasopharyngeal swabs, urine, blood, amniotic fluid, placenta, and synovial fluid.37 Diagnosis of acute rubella infection is also made by the observation of a fourfold rise in acute and convalescent titers of rubella-specific IgG over a period of 3 to 4 weeks.
Commercially available enzyme immunoassays for rubella IgM and IgG are routinely performed by most laboratories.38 Indirect antibody assays are more prone to false-positive IgM results, due in part to cross-reactivity with other IgM antibodies or with rheumatoid factor; hence, a second confirmatory test for rubella IgM by a different modality should be performed, especially before 20 weeks’ gestation.
Fetal and Neonatal
Prenatal diagnosis of CRI is possible. The presence of rubella-specific IgM in fetal blood confirms infection.37 Fetal blood sampling to detect IgM must be delayed until 20 to 22 weeks’ gestation. There are currently no reverse transcription polymerase chain reaction (RT-PCR) assays approved by the US Food and Drug Administration (FDA) for rubella but is available in commercial and public health laboratories.
Rubella-specific IgM is detectable for up to 6 months in infected newborns, and rubella IgG may remain elevated beyond this 6-month period. As in the mother, rubella is detectable by culturing infant blood, stools, cerebrospinal fluid, and urine. Because rubella has been considered eliminated in the United States, new cases are reportable. Providers should contact local or state health officials for proper follow-up.
Management of Rubella Infection in Pregnancy
Prevention of in utero rubella infection requires the acquisition of immunity by all persons before the childbearing years. Immunity against rubella is considered to be lifelong given the stability of the viral genome and the protective effect of IgG antibody; the humoral-mediated response confers immunity
against future reinfection. The American College of Obstetricians and Gynecologists (ACOG) currently recommends all prenatal patients be tested for rubella IgG; and all pregnant women identified as being susceptible to rubella should be advised about the potential risk of CRI and be vaccinated after delivery; however, pregnant women should not be vaccinated.39 These guidelines also recommend that breastfeeding is not a contraindication to vaccine administration.
against future reinfection. The American College of Obstetricians and Gynecologists (ACOG) currently recommends all prenatal patients be tested for rubella IgG; and all pregnant women identified as being susceptible to rubella should be advised about the potential risk of CRI and be vaccinated after delivery; however, pregnant women should not be vaccinated.39 These guidelines also recommend that breastfeeding is not a contraindication to vaccine administration.
There is no specific antiviral therapy for rubella infection. If in utero exposure to rubella virus is documented, the woman should be counseled as to the risks and consequences of CRI. With the potentially devastating effects of first trimester infection, a patient may choose to terminate the affected pregnancy if the diagnosis is made in a timely manner.
The treatment of acute rubella in adults and children is based on the symptoms. Most adults have complete recovery from the rash and lymphadenopathy within a week, although one-third may develop late-onset arthralgias. At present, there is no standard method of treating acute CRIs with antiviral therapy.
Varicella Zoster Virus
Varicella zoster virus (VZV) is a DNA virus and a member of the human herpesvirus group that exhibits viral latency. As a highly contagious disorder, before widespread vaccination, VZV infection was acquired by most children in the United States as chickenpox before reproductive age and was generally a self-limited disease characterized by skin lesions. There are two major concerns if VZV infection occurs during pregnancy. The first is the risk that the infection imposes upon the mother; the second is the risk of either teratogenesis or perinatal acquisition by the neonate.
Epidemiology
Chickenpox is one of the most contagious infectious diseases of childhood. Since 2007, coverage with 1 or more doses of varicella vaccine among 19 to 35-month-old children in the United States has been >90%.40 The average varicella incidence from 2013 to 2014 was 3.9 per 100,000 people with 55% of these cases occurring in people who had previously received the vaccine.41 As the majority of children are vaccinated against varicella and the incidence of wild-type varicella decreases, a greater proportion of varicella cases are occurring in immunized people as breakthrough disease.40 The incidence of primary VZV during pregnancy is only 0.013% to 0.07%.42 VZV infection may present later in life as shingles by reactivation of a latent viral infection; this is more frequent in older individuals.
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