Several viruses cause severe maternal infections, and some can also cause devastating fetal infections. Of these, cytomegalovirus (CMV) is a ubiquitous DNA herpes virus that eventually infects most humans. CMV is also the most common perinatal infection in the developed world. Specifically, some evidence of fetal infection is found in 0.2 to 2.2 percent of all neonates (American College of Obstetricians and Gynecologists, 2017). The virus is secreted into all body fluids, and person-to-person contact with viral-laden saliva, semen, urine, blood, and nasopharyngeal and cervical secretions can transmit infection. The fetus may become infected by transplacental viremia, or the neonate is infected at delivery or during breastfeeding. Moreover, acquisition continues to accrue. Day-care centers, for example, are a frequent source. Revello and coworkers (2008) reported that amniocentesis in women whose blood is positive for CMV DNA does not result in iatrogenic fetal transmission.
Up to 85 percent of women from lower socioeconomic backgrounds are seropositive by the time of pregnancy, whereas only half of women in higher income groups are immune. Following primary CMV infection, and in a manner similar to other herpesvirus infections, the virus becomes latent with periodic reactivation characterized by viral shedding. This occurs despite high serum levels of anti-CMV IgG antibody. These antibodies do not prevent maternal recurrence, reactivation, or reinfection, nor do they totally mitigate fetal or neonatal infection.
Women who are seronegative before pregnancy, but who develop primary CMV infection during pregnancy, are at greatest risk to have an infected fetus. It is estimated that 25 percent of congenital CMV infections in the United States are from primary maternal infection (Wang, 2011). Most CMV infections are clinically silent, but they can be detected by seroconversion, and this may be as high as 1 to 7 percent annually (Hyde, 2010). Conversely, diagnosis of CMV nonprimary infection is a challenge (Picone, 2017).
Pregnancy does not increase the risk or severity of maternal CMV infection. Most infections are asymptomatic, but 10 to 15 percent of infected adults have a mononucleosis-like syndrome characterized by fever, pharyngitis, lymphadenopathy, and polyarthritis. Immunocompromised women may develop myocarditis, pneumonitis, hepatitis, retinitis, gastroenteritis, or meningoencephalitis. Nigro and associates (2003) reported that most women in a cohort with primary infection had elevated serum aminotransferases or lymphocytosis. Reactivation disease usually is asymptomatic, although viral shedding is common.
Transmission rates for primary infection are 30 to 36 percent in the first trimester, 34 to 40 percent in the second, and 40 to 72 percent in the third trimester (American College of Obstetricians and Gynecologists, 2017; Picone, 2017). In contrast, recurrent maternal infection infects the fetus in only 0.15 to 1 percent of cases. Naturally acquired immunity during pregnancy results in a 70-percent risk reduction of congenital CMV infection in future pregnancies (Fowler, 2003; Leruez-Ville, 2017). However, as noted earlier, maternal immunity does not prevent recurrences, and maternal antibodies do not prevent fetal infection (Ross, 2011).
Newborns with apparent sequelae of in-utero-acquired CMV infection are described as having symptomatic CMV infection. Congenital infection is a syndrome that may include growth restriction, microcephaly, intracranial calcifications, chorioretinitis, mental and motor retardation, sensorineural deficits, hepatosplenomegaly, jaundice, hemolytic anemia, and thrombocytopenic purpura (Cheeran, 2009). An example of periventricular calcifications is shown in Figure 64-1. Of the estimated 40,000 infected neonates born each year, only 5 to 10 percent demonstrate this syndrome (Fowler, 1992). Thus, most infected infants are asymptomatic at birth, but some develop late-onset sequelae. Complications may include hearing loss, neurological deficits, chorioretinitis, psychomotor retardation, and learning disabilities. Infections in dichorionic twins most likely are nonconcordant (Egaña-Ugrinovic, 2016).
Coronal view of cranial sonogram from a neonate with congenital cytomegalovirus infection showing multiple periventricular calcifications.
Routine prenatal CMV serological screening is currently not recommended by the Society for Maternal–Fetal Medicine (2016). An algorithm for management is shown in Figure 64-2. Pregnant women should be tested for CMV if they present with a mononucleosis-like illness or if congenital infection is suspected based on abnormal sonographic findings. Primary infection is diagnosed using CMV-specific IgG testing of paired acute and convalescent sera. CMV IgM does not accurately reflect timing of seroconversion because IgM antibody levels may be elevated for more than a year (Stagno, 1985). Moreover, CMV IgM may be found with reactivation disease or reinfection with a new strain. Thus, specific CMV IgG avidity testing is valuable in confirming primary CMV infection. High anti-CMV IgG avidity indicates primary maternal infection >6 months before testing (Kanengisser-Pines, 2009). Finally, viral culture may be useful, although a minimum of 21 days is required before findings are considered negative.
Algorithm for evaluation of suspected maternal primary cytomegalovirus (CMV) infection in pregnancy. EIA = enzyme immunoassay; IgG = immunoglobulin G; IgM = immunoglobulin M.
Several fetal abnormalities associated with CMV infection may be seen with sonography, computed tomography, or magnetic resonance imaging. In some cases, they are found at the time of routine prenatal sonographic screening, but in others they are part of a specific evaluation in women with CMV infection. Findings include microcephaly, ventriculomegaly, and cerebral calcifications; ascites, hepatomegaly, splenomegaly, and hyperechoic bowel; hydrops; and oligohydramnios (Society for Maternal-Fetal Medicine, 2016). Abnormal sonographic findings seen in combination with positive findings in fetal blood or amnionic fluid are predictive of an approximate 75-percent risk of symptomatic congenital infection (Enders, 2001).
CMV nucleic acid amplification testing (NAAT) of amnionic fluid is considered the gold standard for the diagnosis of fetal infection. Sensitivities range from 70 to 99 percent and depend on amniocentesis timing. Sensitivity is highest when amniocentesis is performed at least 6 weeks after maternal infection and after 21 weeks’ gestation (Azam, 2001; Guerra, 2000). A negative result from amnionic fluid polymerase chain reaction (PCR) testing does not exclude fetal infection and may need to be repeated if suspicion for fetal infection is high.
Management and Prevention
The management of the immunocompetent pregnant woman with primary or recurrent CMV is limited to symptomatic treatment. If recent primary CMV infection is confirmed, amnionic fluid analysis should be offered. Counseling regarding fetal outcome depends on the gestational age during which primary infection is documented. Despite the high infection rate with primary infection in the first half of pregnancy, most fetuses develop normally. However, pregnancy termination may be an option for some.
Currently, no proven treatments are available for CMV infection (Society for Maternal–Fetal Medicine, 2016). Leruez-Ville and associates (2016) recently reported that oral treatment with valacyclovir, 8 g daily, apparently mitigated adverse outcomes in eight of 11 affected fetuses treated beginning at median of 25.9 weeks’ gestation. Kimberlin and colleagues (2015) previously showed that intravenous valganciclovir administered for 6 weeks to neonates with symptomatic central nervous system (CNS) disease prevented hearing deterioration at 6 months and possibly later. Passive immunization with CMV-specific hyperimmune globulin may lower the risk of congenital CMV infection when given to pregnant women with primary disease (Nigro, 2005, 2012; Visentin, 2012). The Maternal–Fetal Medicine Units Network currently is conducting a randomized trial designed to address this.
There is no CMV vaccine, although several clinical trials are underway (Arvin, 2004; Schleiss, 2016). Prevention of congenital infection relies on avoiding maternal primary infection, especially in early pregnancy. Basic measures such as good hygiene and hand washing have been promoted, particularly for women with toddlers in day-care settings (Fowler, 2000). CMV may be sexually transmitted among infected partners, but no data address the efficacy of preventive strategies.
Varicella–zoster virus (VZV) is a double-stranded DNA herpesvirus acquired predominately during childhood, and 90 percent of adults have serological evidence of immunity (Whitley, 2015). The incidence of adult varicella declined by 82 percent after the introduction of varicella vaccination, and this has resulted in a drop in maternal and fetal varicella rates (American College of Obstetricians and Gynecologists, 2017). In the United States between 2003 and 2010, the incidence of maternal varicella among 7.7 million pregnancy admissions was 1.21 per 10,000 (Zhang, 2015).
Primary infection—varicella or chickenpox—is transmitted by direct contact with an infected individual, although respiratory transmission has been reported. The incubation period is 10 to 21 days, and a nonimmune woman has a 60- to 95-percent risk of becoming infected after exposure (Whitley, 2015). Primary varicella presents with a 1- to 2-day flulike prodrome, which is followed by pruritic vesicular lesions that crust after 3 to 7 days. Infection tends to be more severe in adults (Marin, 2007). Affected patients are then contagious from 1 day before the onset of the rash until the lesions become crusted.
Mortality is predominately due to VZV pneumonia, which is thought to be more severe during adulthood and particularly in pregnancy. Although the incidence was once thought to be higher, only 2 to 5 percent of infected pregnant women develop pneumonitis (Marin, 2007; Zhang, 2015). Risk factors for VZV pneumonia include smoking and having more than 100 cutaneous lesions. Maternal mortality rates with pneumonia have decreased to 1 to 2 percent (Chandra, 1998).
Symptoms of VZV pneumonia usually appear 3 to 5 days into the course of illness. Fever, tachypnea, dry cough, dyspnea, and pleuritic pain are characteristic. Nodular infiltrates are similar to other viral pneumonias (Chap. 51, Influenza Pneumonia). Although resolution of pneumonitis parallels that of skin lesions, fever and compromised pulmonary function may persist for weeks.
If primary varicella is reactivated years later, it causes herpes zoster or shingles (Whitley, 2015). This presents as a unilateral dermatomal vesicular eruption associated with severe pain. Zoster does not appear to be more frequent or severe in pregnant women. Congenital varicella syndrome rarely develops in cases of maternal herpes zoster (Ahn, 2016; Enders, 1994). Zoster is contagious if blisters are broken, although less so than with primary varicella.
Fetal and Neonatal Infection
In women with varicella during the first half of pregnancy, the fetus may develop congenital varicella syndrome. Some features include chorioretinitis, microphthalmia, cerebral cortical atrophy, growth restriction, hydronephrosis, limb hypoplasia, and cicatricial skin lesions as shown in Figure 64-3 (Ahn, 2016; Auriti, 2009). Enders and coworkers (1994) evaluated 1373 pregnant women with varicella. When maternal infection developed before 13 weeks, only two of 472 pregnancies—0.4 percent—had neonates with congenital varicella syndrome. The highest risk was between 13 and 20 weeks, during which time seven of 351 exposed fetuses—2 percent—had evidence of congenital varicella. After 20 weeks’ gestation, the researchers found no clinical evidence of congenital infection. Ahn and colleagues (2016) recently described similar findings. That said, sporadic reports have described CNS abnormalities and skin lesions in fetuses who developed congenital varicella in weeks 21 to 28 of gestation (Lamont, 2011a; Marin, 2007).
Atrophy of the lower extremity with bony defects and scarring in a fetus infected during the first trimester by varicella. (Reproduced with permission from Paryani SG, Arvin AM: Intrauterine infection with varicella zoster virus after maternal varicella, N Engl J Med. 1986 Jun 12;314(24):1542–1546.)
If the fetus or neonate is exposed to active infection just before or during delivery, and therefore before maternal antibody has been formed, the newborn faces a serious threat. Attack rates range from 25 to 50 percent, and mortality rates approach 30 percent. In some instances, neonates develop disseminated visceral and CNS disease, which is commonly fatal. For this reason, varicella-zoster immune globulin (VZIG) should be administered to neonates born to mothers who have clinical evidence of varicella 5 days before and up to 2 days after delivery.
Maternal varicella is usually diagnosed clinically. Infection may be confirmed by NAAT of vesicular fluid, which is very sensitive. The virus may also be isolated by scraping the vesicle base during primary infection and performing a Tzanck smear, tissue culture, or direct fluorescent antibody testing. Congenital varicella may be diagnosed using NAAT analysis of amnionic fluid, although a positive result does not correlate well with the development of congenital infection (Mendelson, 2006). A detailed anatomical sonographic evaluation performed at least 5 weeks after maternal infection may disclose abnormalities, but the sensitivity is low (Mandelbrot, 2012).
Several aspects of maternal VZV exposure and infection in pregnancy affect management. Exposed gravidas with a negative history for chickenpox should undergo VZV serological testing. At least 70 percent of these women will be seropositive, and thus immune. Exposed pregnant women who are susceptible (seronegative) should be given varicella-zoster immune globulin (VariZIG). Although best given within 96 hours of exposure, its use is approved for up to 10 days to prevent or attenuate varicella infection (Centers for Disease Control and Prevention, 2012, 2013d). Passive immunization appears to be highly effective (Jespersen, 2016). In women with known history of varicella, VariZIG is not indicated.
Any patient diagnosed with primary varicella infection or herpes zoster should be isolated from pregnant women. Because VZV pneumonia often presents with few symptoms, a chest radiograph is recommended by many. Most women require only supportive care, but those who require intravenous (IV) fluids and especially those with pneumonia are hospitalized. IV acyclovir therapy is given to women requiring hospitalization—500 mg/m2 or 10 to 15 mg/kg every 8 hours.
An attenuated live-virus vaccine is recommended for nonpregnant adolescents and adults with no history of varicella. Two doses of Varivax are given 4 to 8 weeks apart, and the seroconversion rate is 98 percent (Marin, 2007). Importantly, vaccine-induced immunity diminishes over time, and the breakthrough infection rate approximates 5 percent at 10 years (Chaves, 2007).
The vaccine is not recommended for pregnant women or for those who may become pregnant within a month following each vaccine dose. That said, a registry of more than 1000 vaccine-exposed pregnancies reports no cases of congenital varicella syndrome or other associated congenital malformations (Marin, 2014; Wilson, 2008). The attenuated vaccine virus is not secreted in breast milk. Thus, postpartum vaccination should not be delayed because of breastfeeding (American College of Obstetricians and Gynecologists, 2016c).
These respiratory infections are caused by members of the family Orthomyxoviridae. Influenza A and B form one genus of these RNA viruses, and both cause epidemic human disease (Cohen, 2015b). Influenza A viruses are subclassified further by hemagglutinin (H) and neuraminidase (N) surface antigens. Influenza outbreaks occur annually, and the most recent epidemic was in 2016 to 2017 caused by an influenza A/H3N2 strain (Shang, 2016).
Maternal and Fetal Infection
Fever, dry cough, and systemic symptoms characterize this infection, which usually is not life-threatening in otherwise healthy adults. However, pregnant women appear to be more susceptible to serious complications, particularly pulmonary involvement (Cohen, 2015b; Mertz, 2017; Rasmussen, 2012). Severe infection has a maternal mortality rate of 1 percent (Duryea, 2015). And from 2009 to 2010, widespread influenza A infection affected pregnant women and caused 12 percent of pregnancy-related deaths (Callaghan, 2015).
No firm evidence links influenza A virus and congenital malformations (Irving, 2000; Zerbo, 2017). Conversely, Lynberg and colleagues (1994) reported higher rates of neural-tube defects in neonates born to women with influenza early in pregnancy. This was possibly associated with hyperthermia. Viremia is infrequent, and transplacental passage is rare (Rasmussen, 2012). Stillbirth, preterm delivery, and first-trimester abortion have all been reported, but usually correlate with the severity of maternal infection (Centers for Disease Control and Prevention, 2011; Fell, 2017; Meijer, 2015).
Influenza may be detected in nasopharyngeal swabs using viral antigen rapid detection assays (Table 64-2). Reverse transcriptase–polymerase chain reaction (RT-PCR) is the more sensitive and specific test, although not widely available (Cohen, 2015b). In contrast, rapid influenza diagnostic tests (RIDTs) are least indicative, with sensitivities of 40 to 70 percent. Decisions to administer antiviral medications for influenza treatment or chemoprophylaxis should be based on clinical symptoms and epidemiological factors. Specifically, the start of therapy should not be delayed pending testing results (Centers for Disease Control and Prevention, 2017e).
TABLE 64-2Outpatient Influenza A and B Virus Testing Methods ||Download (.pdf) TABLE 64-2 Outpatient Influenza A and B Virus Testing Methods
|Methoda ||Test Time |
|Viral cell culture ||3–10 d |
|Rapid cell culture ||1–3 d |
|Direct (DFA) or indirect (IFA) fluorescent antibody assay ||1–4 hr |
|RT-PCR and other molecular assays ||1–6 hr |
|Rapid influenza diagnostic tests (RIDT) ||<30 min |
Two classes of antiviral medications are currently available. Neuraminidase inhibitors are highly effective for the treatment of early influenza A and B. These include oseltamivir (Tamiflu), which is taken orally for treatment and for chemoprophylaxis; zanamivir (Relenza), which is inhaled for treatment; and peramivir (Rapivab), which is administered intravenously.
The adamantanes include amantadine and rimantadine, which were used for years for treatment and chemoprophylaxis of influenza A. In 2005, influenza A resistance to adamantine was reported to exceed 90 percent in the United States. Thus, its use is not currently recommended. It is possible that these drugs may again be effective for subsequently mutated strains. Patterns of resistance are available at cdc.gov/flu.
Experience with all of these antiviral agents in pregnant women is limited (Beau, 2014; Beigi, 2014; Dunstan, 2014). They are Food and Drug Administration category C drugs and thus used when potential benefits outweigh risks. At Parkland Hospital, we start oral oseltamivir treatment within 48 hours of symptom onset—75 mg twice daily for 5 days. Early administration may reduce length of hospital stays (Meijer, 2015; Oboho, 2016). Prophylaxis with oseltamivir, 75 mg orally once daily for 7 days, is also recommended for significant exposures. Antibacterial medications are added when a secondary bacterial pneumonia is suspected (Chap. 51, Pregnancy Outcome).
Effective vaccines are formulated annually. Vaccination against influenza throughout the influenza season, but optimally in October or November, is recommended by the Centers for Disease Control and Prevention (CDC) (2013a) and the American College of Obstetricians and Gynecologists (2016b) for all women who will be pregnant during the influenza season. This is especially important for those affected by chronic medical disorders such as diabetes, heart disease, asthma, or human immunodeficiency virus (HIV) infection. Inactivated vaccine prevents clinical illness in 70 to 90 percent of healthy adults. Importantly, there is no evidence of teratogenicity or other adverse maternal or fetal events (Chambers, 2016; Fell, 2017; Kharbanda, 2017; Polyzos, 2015; Sukumaran, 2015). Moreover, for mothers vaccinated during pregnancy, several studies found lower rates of influenza in their infants up to 6 months of age (Nunes, 2017; Steinhoff, 2012; Zaman, 2008). Immunogenicity of the trivalent inactivated seasonal influenza vaccine in pregnant women is similar to that in the nonpregnant individual. A live attenuated influenza virus vaccine is available for intranasal use but is not recommended for pregnant women (Cohen, 2015b).
This uncommon adult infection is caused by an RNA paramyxovirus. Because of childhood immunization, up to 90 percent of adults are seropositive (Rubin, 2012). The virus primarily infects the salivary glands but also may involve the gonads, meninges, pancreas, and other organs. It is transmitted by direct contact with respiratory secretions, saliva, or through fomites. Most transmission occurs before and within 5 days of parotitis onset, and droplet isolation is recommended during this time (Kutty, 2010). Treatment is symptomatic, and mumps during pregnancy is no more severe than in nonpregnant adults.
Women who develop mumps in the first trimester may have a greater risk of spontaneous abortion. Infection in pregnancy is not associated with congenital malformations, and fetal infection is rare (McLean, 2013).
The live attenuated Jeryl-Lynn vaccine strain is part of the MMR vaccine—measles, mumps, and rubella. This vaccine is contraindicated in pregnancy according to the CDC (McLean, 2013). No malformations attributable to MMR vaccination in pregnancy have been reported, but pregnancy should be avoided for 30 days after mumps vaccination. The vaccine may be given to susceptible women postpartum, and breastfeeding is not a contraindication.
This is a highly contagious RNA virus of the family Paramyxoviridae that only infects humans. In endemic areas, annual outbreaks of measles, also called rubeola, occur in late winter and early spring, transmission is primarily by respiratory droplets, and the secondary attack rate among contacts exceeds 90 percent (Rainwater-Lovett, 2015). Resurgences in measles have been linked to clusters of vaccine-eligible but unvaccinated individuals (Fiebelkorn, 2010; Phadke, 2016). Fever, coryza, conjunctivitis, and cough are typical symptoms. The characteristic erythematous maculopapular rash develops on the face and neck and then spreads to the back, trunk, and extremities. Koplik spots are small white lesions with surrounding erythema found within the oral cavity. Immediate or delayed neurological sequelae of measles may manifest in several forms, making diagnosis difficult (Buchanan, 2012; Chiu, 2016). Diagnosis of acute infection is most commonly performed by serological evidence of IgM antibodies, although RT-PCR tests are available. Treatment is supportive.
Pregnant women without evidence of measles immunity should be administered passive immunoprophylaxis with immune globulin, 400 mg/kg intravenously (Centers for Disease Control and Prevention, 2017d). Active vaccination is not performed during pregnancy, however, susceptible women can be vaccinated routinely postpartum, and breastfeeding is not contraindicated (Ohji, 2009).
The virus does not appear to be teratogenic (Siegel, 1973). However, rates of spontaneous abortion, preterm delivery, and low-birthweight neonates are increased with maternal measles (Rasmussen, 2015). If a woman develops measles shortly before birth, risk of serious infection developing in the neonate is considerable, especially in a preterm neonate.
This RNA togavirus causes rubella, also called German measles, which is of minor importance in the absence of pregnancy. Rubella infection in the first trimester, however, poses significant risk for abortion and severe congenital malformations. Transmission occurs via nasopharyngeal secretions, and the transmission rate is 80 percent to susceptible individuals. The peak incidence is late winter and spring in endemic areas (Lambert, 2015).
Maternal rubella is usually a mild febrile illness with a generalized maculopapular rash beginning on the face and spreading to the trunk and extremities. That said, 25 to 50 percent of infections are asymptomatic. Other symptoms may include arthralgias or arthritis, head and neck lymphadenopathy, and conjunctivitis. The incubation period is 12 to 23 days. Viremia usually precedes clinical signs by about a week, and adults are infectious during viremia and through 7 days after the rash appears. Up to half of maternal infections are subclinical despite viremia that may cause devastating fetal infection (McLean, 2013).
Rubella virus may be isolated from the urine, blood, nasopharynx, and cerebrospinal fluid for up to 2 weeks after rash onset. The diagnosis is usually made, however, with serological analysis. In one study, 6 percent of nonimmune women seroconverted to rubella virus during pregnancy (Hutton, 2014). Specific IgM antibody can be detected using enzyme-linked immunoassay for 4 to 5 days after onset of clinical disease, but antibody can persist for up to 6 weeks after appearance of the rash. Importantly, rubella virus reinfection can give rise to transient low levels of IgM. With this, fetal infection can rarely occur, but no adverse fetal effects have been described. Serum IgG antibody titers peak 1 to 2 weeks after rash onset. This rapid antibody response may complicate serodiagnosis unless samples are initially collected within a few days after the onset of the rash. If, for example, the first specimen was obtained 10 days after the rash, detection of IgG antibodies would fail to differentiate between very recent disease and preexisting immunity to rubella. IgG avidity testing is performed concomitant with the serological tests above. High-avidity IgG antibodies indicate an infection at least 2 months in the past.
The rubella virus is one of the most complete teratogens, and effects of fetal infection are worst during organogenesis (Adams Waldorf, 2013). Pregnant women with rubella and a rash during the first 12 weeks of gestation have an affected fetus with congenital infection in up to 90 percent of cases (Miller, 1982). At 13 to 14 weeks’ gestation, this incidence is 50 percent, and by the end of the second trimester, it is 25 percent. Defects are rare after 20 weeks’ gestation. Features of congenital rubella syndrome amenable to prenatal diagnosis are cardiac septal defects, pulmonary stenosis, microcephaly, cataracts, microphthalmia, and hepatosplenomegaly (Yazigi, 2017). Other abnormalities include sensorineural deafness, intellectual disability, neonatal purpura, and radiolucent bone disease. Neonates born with congenital rubella may shed the virus for many months and thus be a threat to other infants and to susceptible adults who contact them. Reports of delayed morbidities associated with congenital rubella syndrome may include a rare, progressive panencephalitis, insulin-dependent diabetes mellitus, and thyroid disorders (Sever, 1985; Webster, 1998).
Management and Prevention
There is no specific treatment for rubella. Droplet precautions for 7 days after the onset of the rash are recommended. Postexposure passive immunization with polyclonal immunoglobulin may be of benefit if given within 5 days of exposure (Young, 2015).
Although large epidemics of rubella have virtually disappeared in the United States because of immunization, up to 10 percent of women in the United States are susceptible. Cluster outbreaks during the 1990s mainly involved persons born outside the United States, as congenital rubella is still common in developing nations (Centers for Disease Control and Prevention, 2013f). To eradicate rubella and prevent congenital rubella syndrome completely, a comprehensive approach is recommended for immunizing the adult population (Grant, 2015).
MMR vaccine should be offered to nonpregnant women of childbearing age who do not have evidence of immunity whenever they make contact with the health-care system. Vaccination of all susceptible hospital personnel who might be exposed to patients with rubella or who might have contact with pregnant women is important. Rubella vaccination should be avoided 1 month before or during pregnancy because the vaccine contains attenuated live virus. No observed evidence links the vaccine and induced malformations, although the overall theoretical risk is up to 2.6 percent (McLean, 2013; Swamy, 2015). MMR vaccination is not an indication for pregnancy termination.
Prenatal serological screening for rubella is indicated for all pregnant women. Women found to be nonimmune are offered the MMR vaccine postpartum.
More than 200 antigenically distinct respiratory viruses cause the common cold, pharyngitis, laryngitis, bronchitis, and pneumonia. Rhinovirus, coronavirus, and adenovirus are major causes of the common cold. The RNA-containing rhinovirus and coronavirus usually produce a trivial, self-limited illness characterized by rhinorrhea, sneezing, and congestion. The DNA-containing adenovirus is more likely to produce cough and lower respiratory tract involvement, including pneumonia.
The potential teratogenic effects of respiratory viruses are controversial. In a case-control study using data from the Finnish Register of Congenital Malformations, 393 gravidas with a common cold had a four- to fivefold greater risk of fetal anencephaly (Kurppa, 1991). In another population study of California births from 1989 to 1991, low attributable risks for neural-tube defects were associated with many illnesses in early pregnancy (Shaw, 1998). Adams and colleagues (2012) performed amnionic fluid viral PCR studies in 1191 women undergoing amniocentesis for fetal karyotyping. Viral PCR was positive in 6.5 percent, with adenovirus being the virus most frequently identified. There was an association with fetal-growth restriction, nonimmune hydrops, foot/hand abnormalities, and neural-tube defects. Adenoviral infection is a known cause of childhood myocarditis. Towbin (1994) and Forsnes (1998) and their associates used PCR tests to identify and link adenovirus to fetal myocarditis and nonimmune hydrops.
These RNA viruses are members of the family Bunyaviridae. They are associated with a rodent reservoir, and transmission involves inhalation of virus excreted in rodent urine and feces. Outbreaks of hantaviruses including Sin Nombre virus and Seoul virus have been reported in the United States, the most recent in early 2017 (Centers for Disease Control and Prevention, 2017b). Hantaviruses are a heterogenous group of viruses with low and variable rates of transplacental transmission. Howard and associates (1999) reported the Hantavirus pulmonary syndrome to cause maternal death, fetal demise, and preterm birth. They found no evidence of vertical transmission of the causative Sin Nombre virus.
These viruses are a major subgroup of RNA picornaviruses that include coxsackievirus, poliovirus, and echovirus. They are trophic for intestinal epithelium but can also cause widespread maternal, fetal, and neonatal infections that may include the CNS, skin, heart, and lungs. Most maternal infections are subclinical yet can be fatal to the fetus–neonate (Tassin, 2014). Hepatitis A is an enterovirus that is discussed in Chapter 55 (Chronic Viral Hepatitis).
Coxsackievirus infections with group A and B are usually asymptomatic. Symptomatic infections—usually with group B—include aseptic meningitis, polio-like illness, hand foot and mouth disease, rashes, respiratory disease, pleuritis, pericarditis, and myocarditis. No treatment or vaccination is available (Cohen, 2015a). Coxsackievirus may be transmitted by maternal secretions to the fetus at delivery in up to half of mothers who seroconverted during pregnancy (Modlin, 1988). Transplacental passage has also been reported (Ornoy, 2006).
Congenital malformation rates may be slightly increased in fetuses of pregnant women who had serological evidence of coxsackievirus (Brown, 1972). Viremia can cause fetal hepatitis, skin lesions, myocarditis, and encephalomyelitis, all of which may be fatal. Some have reported higher rates of cardiac anomalies and of low-birthweight, preterm, and small-for-gestational-age newborns (Chen, 2010; Koro’lkova, 1989). Maternal–fetal infection has been associated with massive perivillous fibrin deposition and fetal death (Yu, 2015). Finally, a rare association between maternal coxsackievirus infection and insulin-dependent diabetes in offspring has been described (Viskari, 2012).
Polioviruses cause highly contagious infections that are subclinical or mild. The virus is trophic for the CNS, and it can cause paralytic poliomyelitis (Cohen, 2015a). Siegel (1955) demonstrated that pregnant women not only were more susceptible to polio but also had a higher death rate. Perinatal transmission has been observed, especially when maternal infection developed in the third trimester (Bates, 1955). Inactivated subcutaneous polio vaccine is recommended for susceptible pregnant women who must travel to endemic areas or are placed in other high-risk situations. Live oral polio vaccine has been used for mass vaccination during pregnancy without harmful fetal effects (Harjulehto, 1989).
This B19 virus causes erythema infectiosum, or fifth disease. It is a small, single-stranded DNA virus that replicates in rapidly proliferating cells such as erythroblast precursors (Brown, 2015). This can lead to anemia, which is its primary fetal effect. Only individuals with the erythrocyte globoside membrane P antigen are susceptible. In women with severe hemolytic anemia‒for example, sickle-cell disease‒parvovirus infection may cause an aplastic crisis.
The main mode of parvovirus transmission is respiratory or hand-to-mouth contact, and the infection is common in spring months. The maternal infection rate is highest in women with school-aged children and in day-care workers, but not in schoolteachers. An infected person develops viremia 4 to 14 days after exposure, and an otherwise immunocompetent individual is no longer infectious at the onset of the rash. By adulthood, only 40 percent of women are susceptible. The annual seroconversion rate is 1 to 2 percent but is >10 percent during epidemic periods (Brown, 2015). The secondary attack rate approaches 50 percent.
In 20 to 30 percent of adults, infection is asymptomatic. Fever, headache, and flulike symptoms may begin in the last few days of the viremic phase. Several days later, a bright red rash with erythroderma affects the face and gives a slapped-cheek appearance. The rash becomes lacelike and spreads to the trunk and extremities. Adults often have milder rashes and develop symmetrical polyarthralgia that may persist several weeks. Mayama and associates (2014) described a pregnant woman in whom B19 infection was associated with hemophagocytic lymphohistiocytosis. No evidence suggests that parvovirus infection is altered by pregnancy. With recovery, IgM antibody is generated 7 to 10 days postinfection, and production persists for 3 to 4 months. Several days after IgM is produced, IgG antibody is detectable and persists for life with natural immunity (American College of Obstetricians and Gynecologists, 2017).
There is vertical transmission to the fetus in up to a third of maternal parvovirus infections (de Jong, 2011; Lamont, 2011b). Fetal infection has been associated with abortion, nonimmune hydrops, and stillbirth (Lassen, 2012; Mace, 2014; McClure, 2009). According to the American College of Obstetricians and Gynecologists (2017), the rate of fetal loss with serologically proven parvovirus infection is 8 to 17 percent before 20 weeks’ gestation, and 2 to 6 percent after midpregnancy. Currently, no data support evaluating asymptomatic mothers and stillborn fetuses for parvovirus infection.
Hydrops develops in only approximately 1 percent of fetuses of women infected with parvovirus (American College of Obstetricians and Gynecologists, 2017; Pasquini, 2016; Puccetti, 2012). Still, it is the most frequent infectious agent of nonimmune hydrops in autopsied fetuses (Rogers, 1999). Hydrops usually stems from infection in the first half of gestation. In one report, more than 80 percent of hydrops cases were found in the second trimester, with a mean gestational age of 22 to 23 weeks (Yaegashi, 2000). At least 85 percent of cases of fetal infection developed within 10 weeks of maternal infection, and the mean interval was 6 to 7 weeks. The critical period for maternal infection leading to fetal hydrops was estimated to be between 13 and 16 weeks’ gestation, which coincided with the period in which fetal hepatic hemopoiesis is greatest.
An algorithm for diagnosis of maternal parvoviral infection is illustrated in Figure 64-4. Diagnosis is generally made by maternal serological testing for specific IgG and IgM antibodies (Bonvicini, 2011; Brown, 2015). Viral DNA may be detectable by PCR in maternal serum during the prodrome and persist for months to years after infection. Fetal infection is diagnosed by detection of B19 viral DNA in amnionic fluid or IgM antibodies in fetal serum obtained by cordocentesis (de Jong, 2011; Weiffenbach, 2012). Fetal and maternal viral loads do not predict fetal morbidity and mortality (de Haan, 2007).
Algorithm for evaluation and management of human parvovirus B19 infection in pregnancy. CBC = complete blood count; IgG = immunoglobulin G; IgM = immunoglobulin M; MCA = middle cerebral artery; PCR = polymerase chain reaction; RNA = ribonucleic acid.
Most cases of parvovirus-associated hydrops develop in the first 10 weeks after infection. Thus, serial sonography every 2 weeks should be performed in women with recent infection (see Fig. 64-4). As discussed in Chapter 10 (Ductus Arteriosus), middle cerebral artery (MCA) Doppler interrogation can also be used to predict fetal anemia (Chauvet, 2011). Fetal blood sampling is warranted with hydrops to assess the degree of fetal anemia. Comorbid fetal myocarditis may induce hydrops with lesser degrees of anemia.
Depending on gestational age, fetal transfusion for hydrops may improve outcome in some cases (Enders, 2004). Mortality rates as high as 30 percent have been reported in hydropic fetuses without transfusions. With transfusion, 94 percent of hydrops cases resolve within 6 to 12 weeks, and the overall mortality rate is <10 percent. Most fetuses require only one transfusion because hemopoiesis resumes as infection resolves. Concurrent fetal thrombocytopenia worsens the prognosis (Melamed, 2015).
Reports describing neurodevelopmental outcomes in fetuses transfused for B19 infection-induced anemia are conflicting. In one review of 24 transfused hydropic fetuses, abnormal neurodevelopment was noted in five of 16 survivors—32 percent—at 6 months to 8 years (Nagel, 2007). Outcomes were not related to severity of fetal anemia or acidemia, and these investigators hypothesized that the infection itself induced cerebral damage. In another study of 28 children treated with intrauterine transfusion, 11 percent had neurodevelopmental impairment during evaluation at a median age of 5 years (de Jong, 2012). Conversely, Dembinski (2003) found no significant neurodevelopmental delay despite severe fetal anemia.
Currently, no parvovirus vaccine is available, and no evidence suggests that antiviral treatment prevents maternal or fetal infection. Decisions to avoid higher-risk work settings are complex and require assessment of exposure risks. Pregnant women should be counseled that risks for infection approximate 5 percent for casual, infrequent contact; 20 percent for intense, prolonged work exposure such as for teachers; and 50 percent for close, frequent interaction such as in the home. Workers at day-care centers and schools need not avoid infected children because infectivity is greatest before clinical illness. Finally, infected children do not require isolation.
This mosquito-borne RNA flavivirus is a human neuropathogen. It has become the most common cause of arthropod-borne viral encephalitis in the United States (Centers for Disease Control and Prevention, 2017f; Krow-Lucal, 2017). West Nile viral infections are typically acquired through mosquito bites in late summer or perhaps through blood transfusion. The incubation period is 2 to 14 days, and most persons have mild or no symptoms. Fewer than 1 percent of infected adults develop meningoencephalitis or acute flaccid paralysis (Granwehr, 2004). Presenting symptoms may include fever, mental status changes, muscle weakness, and coma (Stewart, 2013).
Diagnosis of West Nile infection is based on clinical symptoms and the detection of viral IgG and IgM in serum and IgM in cerebrospinal fluid. There is no known effective antiviral treatment, and management is supportive. The primary strategy for preventing exposure in pregnancy is the use of insect repellant containing N,N-diethyl-m-toluamide (DEET). This is considered safe for use among pregnant women (Wylie, 2016). Avoiding outdoor activity and stagnant water and wearing protective clothing are also recommended.
Adverse effects of West Nile viremia on pregnancy are unclear. Animal data suggest that embryos are susceptible, and a case report of human fetal infection at 27 weeks’ gestation described chorioretinitis and severe temporal and occipital lobe leukomalacia (Alpert, 2003; Julander, 2006). In 77 maternal infections initially reported to the West Nile Virus Pregnancy Registry, there were four miscarriages, two elective abortions, and 72 live births, 6 percent of which were preterm (O’Leary, 2006). Three of these 72 newborns were shown to have West Nile infection, and it could not be established conclusively that infection was acquired congenitally. Of three major malformations possibly associated with viral infection, none was definitively confirmed. Similar conclusions were reached by Pridjian and colleagues (2016), who analyzed data from the CDC West Nile Virus Registry. Transmission of West Nile virus through breastfeeding is rare.
These are single-stranded RNA viruses that are prevalent worldwide. In 2002, an especially virulent strain of coronavirus—severe acute respiratory syndrome (SARS–CoV) was first noted in China. It rapidly spread throughout Asia, Europe, and North and South America. The case-fatality rate approached 10 percent in the nonpregnant population and was as high as 25 percent in pregnant women (Lam, 2004; Wong, 2004). Although no additional cases have been confirmed since 2004, the CDC (2013b) now lists SARS-CoV as a “select agent” that has the potential to pose a severe threat to public health and safety.
Another novel regional coronavirus with a high case-fatality rate was detected in 2012—Middle East respiratory syndrome coronavirus (MERS-CoV) (Arabi, 2017). Although experience with MERS-CoV is sparse in pregnancy, infection has been reported to cause maternal and perinatal deaths (Assiri, 2016).
A member of the RNA Filoviridae family, the Ebola virus is transmitted by direct person-to-person contact (Kuhn, 2015). Infection produces a severe hemorrhagic fever with pronounced immunosuppression and disseminated intravascular coagulopathy. Treatment is supportive, and the mortality rate approaches 50 percent.
Data are few concerning Ebola viral infection in pregnancy (Beigi, 2017; Money, 2015; Oduyebo, 2015). The CDC concludes that pregnant women are at increased risk for severe illness and death (Jamieson, 2014). That said, no evidence suggests that pregnant women are more susceptible to Ebola virus infection. One report described trophoblast infection (Muehlenbachs, 2017).
This RNA virus of the Flavivirdae family has recently been recognized as the first major mosquito-borne teratogen (Rasmussen, 2016). Although Zika virus is primarily transmitted by mosquito bite, sexual transmission is also possible, and the virus may be detected in body fluids for months following acute infection (Hills, 2016; Joguet, 2017; Paz-Bailey, 2017).
Reminiscent of the rubella epidemic in the 1960s, in adults Zika infection may be asymptomatic or cause mild symptoms of rash, fever, headache, arthralgia, and conjunctivitis lasting a few days. Virus is typically detectable in blood around the time of symptom onset and may persist days to months in pregnant women (Driggers, 2016; Meaney-Delman, 2016). Serum IgM antibodies typically become detectable within the first two weeks after symptom onset and remain a median of four months (Oduyebo, 2017). Rarely, Guillain-Barré syndrome may develop following infection (da Silva, 2017; Parra, 2016).
The fetus can be severely infected whether or not the mother is symptomatic. Honein and coworkers (2017) describe a 6-percent overall fetal infection rate. In one report of 134 women with positive RT-PCR results, fetal mortality was 7 percent (Brasil, 2016). Among live births, the rate of fetal birth defects ranges from 5 percent—among women with possible Zika infection—to 15 percent among pregnant women with laboratory-confirmed infection in the first trimester (Reynolds, 2017). In the most severely affected fetuses, a congenital Zika syndrome has been described that includes microcephaly, lissencephaly, ventriculomegaly, intracranial calcifications, ocular abnormalities, and congenital contractures (Honein, 2017; Moore, 2017; Soares de Oliveira-Szejnfeld, 2016). Sonographic findings from a Zika-infected fetus are shown in Figure 64-5.
Sonographic transverse view of the cranium from a fetus with congenital Zika infection. Findings shown include a thin cerebral cortex, increased extraaxial space (E), dilated ventricles (F,T), and absent cavum septum pellucidum. (Reproduced with permission from Driggers RW, Ho CY, Korhonen EM, et al: Zika virus infection with prolonged maternal viremia and fetal brain abnormalities, N Engl J Med. 2016 Jun 2;374(22):2142–2151.)
Diagnosis of this infection in pregnant women is made with detection of Zika virus RNA in blood or urine or by serological testing. Detection of Zika virus RNA by PCR confirms infection. Serological assays for Zika IgM antibodies may cross react with other flaviviruses. Thus, a positive assay result is followed by another assay containing virus-specific neutralizing antibodies (Oduyebo, 2017). Testing recommendations and interpretation have evolved for pregnant women who are symptomatic and those who are asymptomatic but have ongoing exposure risk. This risk includes living in or traveling to an area with active local transmission. Large-scale screening programs have been described to identify women at high risk for travel-associated Zika infection (Adhikari, 2017).
Currently, no specific treatment or vaccine is available for Zika infection, although several vaccine candidates are in development (Beigi, 2017; World Health Organization, 2017). Prophylaxis includes protective netting and insect spray to control the vector mosquito and avoidance of sexual contact with partners recently exposed. The CDC has established a pregnancy hotline (770–488–7100) and U.S. Zika Pregnancy Registry (ZikaPregnancy@cdc.gov) for clinicians with concerns related to management of women with Zika infection or exposure.