Infections in Pregnancy and the Perinatal Period
Amanda Guedes de Morais
Jonathan P. Moorman
INTRODUCTION
Pregnancy is by no means considered a pathologic state, and throughout history, the ability to conceive has been considered synonymous with good health. However, there are well-described physiologic and hormonal changes that make the gestational and the perinatal periods very unique from the medical standpoint. The goal of this chapter is to concisely review the most important infections that are associated with this period.
VIRAL DISEASES
Genital Herpes Simplex (HSV 1 and HSV2)
20% to 30% of women may be infected with herpes simplex virus type 2 (HSV2), the serotype responsible for approximately 85% of cases of genital herpes infections.
It is estimated that 30 million people are currently infected in the United States.
Transmission is usually through sexual contact with mucosal membranes or eroded skin.
Viral shedding can occur even during the prodromal stage, when the patient has neuralgia/tingling/itching, but the skin lesions are not yet visible.
In discordant couples, the only way to prevent disease transmission is wearing condoms consistently.
Clinical diagnosis is often inaccurate, as the lesions may present atypically. The Tzanck smear showing intranuclear inclusions and multinucleated giant cells has a sensitivity of only 65%. The commercially available serologic assays are not reliable to differentiate the serotypes 1 and 2. Western blot and PCR are more specific techniques, but are not widely distributed.
Primary genital HSV infection is the development of genital herpes lesions in a patient with no preexisting antibodies to either HSV1 or HSV2. If a patient develops compatible lesions for the first time, but is known to have positive herpes serology (latent disease), the appropriate term to be used is first-episode, nonprimary infection. Recurrent episodes can be painless and therefore go unnoticed.
Pregnant women are at increased risk of acquiring HSV due to hormonal changes. They can present with a more severe course of a primary HSV infection than nonpregnant females, including development of disseminated disease, with meningitis or hepatitis. If the infection is acquired in the first trimester, there is an increased risk of spontaneous abortion, but no embryopathy has been described. When acquired in the second/third trimesters, infection has been associated with preterm labor, intrauterine growth restriction (IUGR) and neonatal infection.
This risk of transmission to the infant during vaginal delivery is variable.
If the mother has a symptomatic first episode lesion (primary or nonprimary), it is approximately 50%.
If the first episode is asymptomatic, the risk drops to 33%.
If there is fetal exposure to a recurrent lesion, the risk falls to 4%.
If there are no identifiable lesions or symptoms, the risk is as low as 0.04%.
Currently, abdominal delivery is recommended by the American College of Obstetrics and Gynecology (ACOG) in the setting of any active genital lesion or reported prodromal symptoms.
Neonatal herpes presents as disseminated disease in 20% of the newborns, which carries a 50% mortality rate. The disease is limited to the central nervous system (CNS) in 35% of the cases and is limited to skin and mucous membranes in 45%. The latter carries the best prognosis, with 100% survival and 5% sequelae.
Antiviral management is indicated for females with more than six recurrences per year and for females whose initial herpes diagnosis happened during pregnancy. The drug of choice is still acyclovir 400 mg orally three times daily. There are currently no vaccines approved for prevention of HSV infections.
Varicella (Varicella-Zoster Virus)
Varicella-zoster virus (VZV) is a DNA virus from the herpes family; primary infection presents as a diffuse exanthema termed varicella or chickenpox. After rash resolution, VZV remains latent in the sensory ganglia and can secondarily reactivate, usually following a dermatomal pattern and termed herpes zoster or shingles.
This virus is highly contagious through contact with skin lesions and respiratory droplets.
The incubation period is 10 to 21 days.
The prodomes are fever, headache, and malaise followed by a widespread typical rash (macules→ papules → vesicles → crusts). The rash occurs in waves, with skin lesions in different stages at a given time, or “lesion polymorphism.”
The disease lasts 6 to 10 days, but the contagious period starts 2 days before the first skin lesion appears till complete crusting of all lesions.
The diagnosis is clinical, based on the characteristic skin lesions. All primary infections are thought to confer immunity.
Varicella in pregnancy is relatively rare in the United States, (˜5 cases/10,000 gestations), but the complications can be devastating, including maternal pneumonia, disseminated disease, fetal malformations, and neonatal infection.
In case of exposure, pregnant females without a positive history of chickenpox should be tested for antibody detection. Most patients will have a positive antibody, but if the result is negative or no antibody test is available, it is recommended to administer varicella-zoster immunoglobulin (VZIG) within 96 hours of exposure. The dose is 125 U (1 vial) per 10 kg, with a maximum of 625 U administered.
If a pregnant woman is diagnosed with varicella, she should be isolated from other potentially nonimmune persons. The live attenuated varicella vaccine is not recommended in pregnancy.
If there is development of pneumonia symptoms and signs (tachydyspnea, cough, hemoptysis, cyanosis, chest pain, chest x-ray with classical bilateral nodular infiltrates) or the skin lesions are not appropriately crusting, hospitalization is recommended to start antiviral therapy with acyclovir 7.5 mg/kg intravenously every 8 hours.
Even in the setting of appropriated therapy, up to 40% of the patients with varicella pneumonia may progress to respiratory failure requiring ventilator support.
Congenital varicella presents with CNS lesions, limb hypoplasia, joint contractures, skin scarring, hypopigmented lesions, and other miscellaneous changes. The contamination is transplacental. If the mother develops the rash within 5 days before delivery up to 2 days after, there is increased likelihood of transmission due to a lack of maternal IgG production. All neonates delivered within this period should receive VZIG 125 U as an attempt to prevent the disease.
There are no reports of congenital varicella in the setting of maternal herpes zoster. If the eruption does not involve the breast, breast-feeding is considered safe.
Cytomegalovirus
Cytomegalovirus (CMV) is a DNA virus in the herpes family. It has the ability to remain latent after the primary infection, which allows it to be endemic.
50% of the pregnant females are seropositive for CMV antibodies and maternal immunity does not protect against recurrences or transmission to the fetus.
CMV is the most common cause of congenital viral infection in the United States, affecting 40,000 infants per year.
Transmission among adults happens in the setting of close contact. Fetal transmission is thought to be transplacental, but it can also be acquired during breast-feeding.
The risk of transmission to the fetus is higher if the mother acquires the primary infection during pregnancy (˜30% to 40%)
If the mother experiences a reactivation, the risk of transmission drops to 0.2% to 1.8%.
Due to high prevalence, most neonatal infections are acquired during reactivation; however, the ones secondary to primary infection are more severe.
Only 10% of the infected neonates are symptomatic at birth.
Present with microcephaly, ventriculomegaly, periventricular calcifications, pneumonia, hepatosplenomegaly, high bilirubin, retinitis, and IUGR
Mortality rate is high among symptomatic newborns, reaching 20% to 30%, and the ones who survive usually have CNS sequelae.
Diagnosis in an immunocompetent adult is difficult, as most patients are asymptomatic.
May present as a mononucleosis-like syndrome (fever, myalgias, arthralgias, and enlarged lymph nodes) or rarely as a more disseminated disease
Diagnosis is confirmed by serology, usually ELISA, with specimens collected 4 weeks apart to detect an IgG rise.
IgM titer can also be checked, but it can persist for up to 18 months, and it is not as specific, with 20% of the primary infections negative for IgM to CMV.
The use of PCR to detect the viral DNA has become more available and is a very reliable diagnostic tool.
Viral cultures have been used in the past but demand too much time and trained personnel.
Currently, there is no well-studied, effective treatment for CMV during pregnancy. Also, there is no way to predict the clinical severity of the neonatal disease. Elective abortions are not recommended, even in the case of proven maternal primary infection. It is not recommended to routinely screen the pregnant population to CMV immunity. Women of childbearing age should be educated about CMV infection and contact hygiene precautions, particularly if there is exposure to immunocompromised hosts or young children.
Parvovirus B19
Parvoviruses are the smallest DNA virus that can affect mammals.
It is a causative organism for aplastic crisis in sickle cell patients, and it is linked to erythema infectiosum or fifth disease in children.
Parvovirus infection in the pregnant population has been associated with nonimmune hydrops fetalis and fetal death.
It is a common childhood infection, which confers immunity. As opposed to the herpes family viruses, there are no reports of recurrence.
It is very contagious, spreads by respiratory and mouth secretions contact. Infected blood products can also be a source. It is more prevalent in spring months (March to May), and epidemics occur cyclically every 4 to 5 years.
The symptoms of erythema infectiosum are usually mild, including fever, headache, coryza, nausea, and diarrhea, followed by the classic “slapped cheek rash” in 2 to 5 days. A maculopapular body rash may then appear.
Adult females may present with severe polyarthropathy that can last for months.
Acute anemia is not uncommon, although rarely symptomatic, unless there is an underlying hemoglobinopathy. In those cases, a transient aplastic crisis may occur.
If infection occurs during pregnancy, asymptomatic transmission to the fetus happens in 1/4 to 1/3 of the cases. On follow-up, most of these infants did well, with no associated sequelae. Up to 5% of fetuses may develop a transient aplastic crisis, which can be severe given their shortened fetal red blood cell life span and accelerated red blood cell production. They become severely anemic, develop a high output heart failure, hydrops, and possibly death. Second trimester pregnancies are particularly vulnerable.
If a gravida is exposed to a patient with parvovirus infection, she should have her IgM and IgG antibody titers checked.
If both are positive, this indicates that exposure was over the past 6 months.
If IgG is positive and IgM is negative, this female is previously immune.
If both antibody subclasses are negative, this patient is at risk, and a repeat IgM titer should be drawn in 3 to 4 weeks to detect acute infection.
PCR may be useful in immunocompromised patients who cannot mount an antibody response or in the fetal blood.
An elevation of the maternal serum alphafetoprotein may be a diagnostic clue to anticipate development of fetal hydrops.
Once a gestational infection is confirmed, serial weekly obstetric ultrasounds should be done for 8 weeks to look for early signs of hydrops: If no signs of hydrops, the pregnancy should be uneventful. If it develops, intrauterine blood transfusion through cordocentesis and IVIG may be indicated.
During epidemics, it may be appropriate to screen females of childbearing age who work with small children and possibly relocate the seronegative gravid women, but otherwise, there is no role for universal female screening.
There are currently no vaccines to prevent parvovirus infections. Avoidance of contact with small children if at all possible remains the best prevention strategy.
German Measles (Rubella)
Rubella virus is a unique virus from the Togavirus family. It is the only one transmitted via the respiratory route and causes rubella or German measles. It is highly contagious, but the incidence of rubella in North America has decreased markedly since the introduction of routine childhood rubella vaccination.
In the absence of pregnancy, it is usually a mild, self-limited infection of childhood. However, during pregnancy, the virus can have devastating effects on the developing fetus, being directly responsible for congenital malformations.
The incubation period for rubella is 12 to 23 days. The infectious period is from 7 days before to 5 to 7 days after rash onset.
Asymptomatic in 25% to 50% of cases, but some patients may have mild prodromal symptoms such as low-grade fever, conjunctivitis, sore throat, coryza, headaches, malaise, and tender lymphadenopathy.
The typical scarlatiniform rash is mildly pruritic and usually starts on the face and spreads to trunk and extremities, following 1 to 5 days after the prodrome.
Resolves within 3 days in the same order in which it appeared
Polyarthritis and polyarthralgia are potential sequelae, developing mostly in adolescent and adult women (60% to 70%) about 1 week after the rash, and may last for 4 weeks.
Other rare manifestations are tenosynovitis, carpal tunnel syndrome, thrombocytopenia, postinfectious encephalitis, myocarditis, hepatitis, hemolytic anemia, and hemolytic uremic syndrome.
Congenital rubella syndrome (CRS) is fetal infection acquired hematogenously, and the rate of transmission varies with the gestational age at which maternal infection occurs.
If the exposure happens in the first trimester, fetal infection rates are near 80%, but only 25% in the late second trimester and varies from 35% at 27 to 30 weeks’ gestation to nearly 100% beyond 36 weeks’ gestation.
The risk of congenital defects is primarily limited to exposure in the first 16 weeks. After the first 20 weeks, the fetus can present with IUGR.
After infecting the placenta, the rubella virus spreads through the vascular system of the developing fetus, causing cytopathic damage to blood vessels and ischemia in developing organs.
The most common congenital defects associated with rubella are audiologic anomalies including deafness, cardiac defects (pulmonary stenosis, patent ductus arteriosus, ventricular septal defect), ophthalmic defects (retinopathy, cataracts, microphthalmia, glaucoma), and CNS defects (mental retardation, microcephaly, meningoencephalitis).
Later, the child may develop diabetes mellitus, thyroiditis, growth hormone deficit, and behavioral problems.
If a pregnant woman develops signs or symptoms of a rubella-like illness or has recently been exposed to rubella, gestational age should be determined as well as her state of immunity.
1. Known immune >12 weeks of gestation: no further testing is necessary. CRS has not been reported after maternal reinfection beyond 12 weeks’ gestation.
2. Known immune <12 weeks of gestation: if these women demonstrate a significant rise in rubella IgG antibody titer without detection of IgM antibody, they should be informed that reinfection is likely to have occurred. Fetal risk for congenital infection after maternal reinfection during the first trimester has been estimated at 8%. Appropriate counseling should be provided.
3. Nonimmune or immunity unknown:
a. Gestational age ≤16 weeks: acute and convalescent IgG and IgM should be obtained. If IgM antibodies are positive or if there is significant increase in IgG titers 2 to 4 weeks apart, it indicates rubella infection and counseling should be provided.
b. Gestational age between 16 and 20 weeks: CRS between 16 and 20 weeks’ gestation are rare (<1%) and may be manifested by sensorineural deafness (often severe) in the newborn. Appropriate counseling is indicated.
c. Gestational age ≥20 weeks: no studies have documented CRS after 20 weeks. Reassurance is recommended.
Currently, there is no effective treatment for rubella. The Centers for Disease Control recommend limiting the use of rubella immunoglobulin to women with known rubella exposure who decline pregnancy termination.
Prevention through vaccination remains the key to avoid CRS.
The recommendations of the Society of Obstetricians and Gynaecologists of Canada (SOGC) Clinical Guidelines on rubella and pregnancy from 2008 are summarized below:
1. Since the effects of CRS vary with the gestational age at the time of infection, accurate gestational dating should be established, as it is critical to counseling.
2. The diagnosis of primary maternal infection should be made by serologic testing.
3. In a pregnant woman who is exposed to rubella or who develops signs or symptoms of rubella, serologic testing should be performed to determine immune status and risk of congenital rubella syndrome.
4. Rubella immunization should not be administered in pregnancy but may be safely given postpartum.
5. Women who have been inadvertently vaccinated in early pregnancy or who become pregnant immediately following vaccination can be reassured that there have been no cases of CRS documented in these situations.
6. Women wishing to conceive should be counseled and encouraged to have their antibody status determined and undergo rubella vaccination if needed.
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