Infections During Pregnancy



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Diagnosis and Management of CMV Infection in Pregnancy
   By Patrick Duff, M.D.
   Perinatology 2010; 1:1-6

Clinical Case

A twenty-seven-year-old primigravid woman had an ultrasound examination at twenty-four weeks gestation because her uterus was smaller than expected for dates. Of note, the placenta was moderately thickened, measuring 4.8 cm in diameter. The amniotic fluid volume was in the low-normal range.  The estimated fetal weight was in the 15th percentile for gestational age,  and the fetal bowel was highly echogenic. 

No other abnormalities were noted.  Upon detailed questioning, the patient indicated that she had had a prolonged “flu-like” illness at approximately fourteen weeks’ gestation.  No treatment had been administered for this illness.  The patient presently works as a pre-school teacher. 

What is the most likely explanation for the ultrasound findings noted above?  What are the most appropriate steps in the evaluation of this patient?

Dr. Duff is Professor of Clinical Obstetrics and Gynecology, Division of Maternal-Fetal Medicine at the University of Florida College of Medicine.


Cytomegalovirus is a DNA virus, and humans are its only known host.  Like other members of the herpes virus family, CMV can cause latent infection. 

CMV may be transmitted horizontally as a result of organ donation, blood transfusion, sexual contact, and contact with infected saliva and urine.  At least 50% of women of reproductive age have evidence of prior CMV infection.  The prevalence of prior infection is increased in women of lower socioeconomic status.  Most pregnant women acquire infection as a result of contact with their own younger children or children in a daycare or pre-school setting. 

 Infants may acquire CMV infection by contact with contaminated blood and genital secretions during delivery and via breast milk after delivery.  Fortunately, these two mechanisms of transmission are extremely unlikely to cause any injury to the baby.    However, when a pregnant woman develops primary CMV infection in the first half of pregnancy, the risk of transplacental infection is approximately 40%.  Of these babies,  5 to 15% are acutely symptomatic at birth.  The principal clinical manifestations of severe congenital CMV infection include hepatosplenomegaly, thrombocytopenia with resultant petechiae, intracranial calcifications, intrauterine growth restriction, hepatitis and jaundice, microcephaly, chorioretinitis, hearing loss, mental retardation, and seizures. Of these severely infected infants, up to 30% die, and approximately 80% of the survivors have serious sequelae.      

Eighty-five to 95% of these infected infants are asymptomatic at birth.  Ten to 15% of the initially asymptomatic children subsequently develop neurologic, auditory, visual, and/or dental defects, which become evident as they enter school.
Interestingly, when primary maternal infection occurs in the third trimester of pregnancy, the risk of transplacental transmission is much higher – 75 to 80%.  However, the risk of serious fetal injury is very low.

In contrast to primary maternal infection, recurrent or reactivated maternal infection does not pose nearly so serious a risk to the fetus.  When recurrent or reactivated CMV infection develops during pregnancy, only 5 to 10% of infants become infected.  None of these children are symptomatic at birth.  Late sequela of infection include minor visual and auditory deficits and developmental delays which become apparent as the child enters elementary school.

 Diagnosis of CMV in the Mother

Some women who contract CMV infection will be asymptomatic, and the diagnosis will only be suspected because abnormal fetal ultrasound findings have been identified.    When clinical manifestations are present, they include:  malaise, fever, generalized lymphadenopathy, and hepatosplenomegaly.  Patients who are immunocompromised may develop extremely serious sequelae of infection, including chorioretinitis and pneumonitis.         

A patient with suspected CMV infection should have a serologic assay for IgM and IgG antibody.  Typically, in the acute phase of the infection, the IgM  antibody is positive and the IgG antibody is negative.  As the illness evolves, IgG antibody becomes detectable.  Patients who are acutely infected also will usually test positive by culture or PCR for virus in the blood and urine.2 

Clinicians must be aware that the initial serology for CMV can be confusing because the IgM antibody may remain positive for 9 to 12 months after an acute infection.  Moreover, there can be anamnestic increases in IgM in the face of a recurrent or reactivated infection.  Therefore, IgG avidity testing can be extremely helpful in differentiating between acute and chronic infection.  In the setting of acute infection, the avidity of IgG antibody for the virus is low.  In a recurrent or reactivated infection, IgG avidity is high.2 Table 1 summarizes the key tests for diagnosing CMV infection in the mother.   

Table 1.    Key Tests for the Diagnosis of CMV Infection in the Mother

Type of Infection

Serum PCR

Urine PCR







Absent on low avidity antibody

Recurrent or Reactivated

Usually negative

May be positive

Usually negative, but secondary response can occur

Positive for high avidity antibody


Diagnosis of Congenital Infection

The single best test for the diagnosis of congenital infection is detection of virus in the amniotic fluid by culture or PCR.  In an important early study, Donner et al3 noted that amniocentesis correctly identified 12 of 13 (92%) infants with congenital CMV infection.     In a subsequent investigation, Lipitz and associates4 noted that amniocentesis was 100% sensitive in diagnosing congenital CMV infection.  In a more recent investigation, Azam and associates5 showed that amniocentesis was 77% sensitive in detecting congenital CMV infection; the specificity was 100%.

Cordocentesis has been suggested as a possible diagnostic test because it permits the assessment of total IgM antibody and IgM-specific antibody in umbilical cord blood.  However, from a technical perspective, this test cannot be performed at a gestational age much less than 20 weeks.  Moreover, the fetus does not develop an immunologic response to viruses such as CMV until approximately 23 to 24 weeks’ gestation.  Therefore, this test is not of practical value in evaluating patients in the critical first half of pregnancy.

Detection of CMV in amniotic fluid by culture or PCR accurately identifies an infected fetus.  However, a comprehensive ultrasound examination is then invaluable in determining the extent of fetal injury.  The principal ultrasound findings associated with congenital CMV infection are placentomegaly, intrauterine growth restriction, microcephaly, ventriculomegaly, periventricular calcifications, isolated serous effusions, and echogenic bowel.

Management of the Patient with Congenital CMV Infection

Once the diagnosis of congenital CMV infection is confirmed, one option is pregnancy termination.  A second proposed option has been treatment of the mother with antiviral agents such as ganciclovir, foscarnet, and cidofovir. These drugs are of moderate effectiveness in treating CMV infection in the adult, particularly the immunocompromised patient.  However, they are not of proven value in preventing or treating congenital CMV infection.

The most promising therapy for congenital CMV infection appears to be hyperimmune globulin.6  In one of the earliest reports of this therapy, Nigro et al7 described the use of hyperimmune globulin for treatment of a mother who had a twin pregnancy, discordant for congenital CMV infection (Level III evidence).  Treatment was administered at 22 weeks’ gestation.  The patient received hyperimmune globulin, 200 units/kg/day intravenously for three days. A separate dose of 400 units of hyperimmune globulin was injected intra-amniotically into the sac of the affected twin.  The authors noted that treatment resulted in decreased placental edema, improvement in fetal growth, an increase in IgG avidity, and an increase in maternal cell-mediated immunity.  At nine months of age, both infants were negative for CMV. 

 In a subsequent widely publicized investigation8, this same group of authors reported a prospective cohort study (Level II evidence) in which patients received either treatment with hyperimmune globulin, prophylaxis with hyperimmune globulin, or no therapy.  The study was performed at eight Italian medical centers and included 157 pregnant women with serologically-confirmed primary CMV infection.  Of these women, 148 were asymptomatic and were identified by routine serologic screening.  Eight women had symptomatic viral infection consistent with CMV, and one was identified because her fetus had abnormal findings on ultrasonography.  Forty-five women had a primary infection more than six weeks before enrollment, underwent amniocentesis, and had CMV detected in amniotic fluid by PCR or culture.  Thirty-one of these women elected to receive intravenous treatment with CMV-specific hyperimmune globulin (200 units/kg of body weight).  Nine of the 31 received one or two additional infusions of hyperimmune globulin into either the amniotic fluid or umbilical cord because of persistent fetal abnormalities on ultrasonography.  Fourteen women with positive amniotic tests (culture or PCR ) for CMV declined treatment.  Seven of these individuals had infants who were symptomatic at delivery.  In contrast, only one of the 31 treated women had an infant with clinical CMV disease at birth (adjusted odds ratio, 0.02; p < 0.001).  This treatment outcome was particularly impressive given that 15 of the women had fetuses with unmistakable ultrasonographic evidence of CMV disease.

Eighty-four additional women did not undergo amniocentesis because their infection occurred within six weeks before enrollment, their gestational age was less than 20 weeks, or they declined the procedure.  Thirty-seven of these women received 100 units of hyperimmune globulin/kg every month until delivery; the range of infusions was four to six.  Forty-seven women declined treatment.  Among the treated women, 6 delivered infected infants as compared with 19 of the untreated women (adjusted odds ratio, 0.32; p = 0.04).  No adverse effects of hyperimmune globulin were noted in either group receiving immunotherapy.

These results are clinically impressive and biological plausible.  However, this investigation had several weaknesses.9  The design of the study was not optimal.  Although prospective, the study was not randomized and controlled.  The lack of a strict prospective randomized protocol resulted in a curious blend of two cohorts—a treatment group and a prevention group.  The regimens of hyperimmune globulin were quite different in the two groups.  In actual fact, women in the prevention group received more intensive therapy (that is, higher cumulative doses of hyperimmune globulin) than those in the treatment group.
 The authors also did not address the financial and logistic issues associated with screening large populations for CMV infection, triaging patients with inevitable false-positive results, offering amniocentesis and comprehensive ultrasound examinations to women who seroconvert, and then treating at-risk women with hyperimmune globulin.  The wholesale acquisition cost of hyperimmune globulin at our facility is $850 for a 2.5 g vial.  At a dose of 200 units (mg)/kg, a 70 kg patient will require 14 grams of hyperimmune globulin for a single treatment dose ($4760)  and 7 grams for a prophylactic dose ($2380).
 In a follow-up investigation, members of the same laboratory reported a retrospective cohort study10  (Level II evidence) of 32 women in the previous investigation who had received hyperimmune globulin.  For women both with, and without, an obviously injured baby, treatment with hyperimmune globulin resulted in statistically significant reductions in placental thickness.  This response to treatment is of considerable importance, given the authors’ postulate that placental thickening, leading to uteroplacental insufficiency, is the major mechanism for fetal injury with congenital CMV infection.

Prevention of CMV Infection

Pregnant women who are susceptible to CMV infection should be advised of the importance of careful handwashing and cleansing of environmental surfaces when interacting with young children. Women who work in a day care or preschool setting should particularly be urged to wear gloves when changing the diapers of children and to wash their hands carefully after each diaper change.  They also should wash their hands after handling any toys or other objects that the children might have placed in their mouths.  Pregnant women who require blood transfusions should always receive CMV-negative blood, and this same blood type should be used for any intrauterine transfusion. In addition, because of the possibility of CMV transmission through sexual intercourse, pregnant women should be urged to adopt safe sexual practices if they are not engaged in a mutually faithful monogamous relationship.

Clearly, development of an effective vaccine for prevention of CMV infection would be of great importance.  In this light, the recent publication by Pass et al11 is extremely encouraging.  These authors conducted a Phase II placebo-controlled, randomized, double blind trial (Level I evidence) of a new CMV vaccine.  This vaccine was prepared by recombinant technology and contained envelope glycoprotein B along with the MF 59 adjuvant.  Women were eligible for the study if they were seronegative for CMV antibody, in good health, fourteen to forty years old, and not pregnant or lactating.  Participants received three doses of vaccine or placebo at 0, 1, and 6 months.  The women then underwent serologic testing for CMV infection every three months for up to 42 months.  The serologic assay tested for IgG antibodies directed against viral proteins other than glycoprotein B.  Infection was confirmed by viral culture or immunoblotting.  The primary endpoint of the study was time until detection of CMV infection. 

The vaccine was administered to 234 patients, and 230 women received placebo.  Eighteen infections occurred in the vaccine group, compared with 31 in the placebo group.  Vaccinated women were more likely to remain uninfected during the follow-up period (p = .02).  The observed efficacy of the vaccine was 50%; the 95% confidence interval was 7 to 73%. One of 81 infants (1%) subsequently born to mothers in the vaccinated group had congenital CMV infection compared with three of 97 (3%) infants born to infants in the placebo group (p = .41).  One infant in the placebo group had severe infection that was evident at birth.  The other three infants were asymptomatic at birth and free of sequelae three to five years later. 

The goal of a large scale vaccination program is to ensure that women enter reproductive age with pre-existing immunity to CMV infection.  In that light, the study by Pass and colleagues11 is only partially encouraging.  Despite vaccination, 18 infections occurred, and the follow-up period was relatively short.  We do not yet know whether the protective effect of the vaccine will be of extended duration.  Moreover, it was discouraging to note that one vaccinated mother delivered an infant who actually had congenital CMV infection. 


The patient presented in the clinical case at the beginning of this article should have a serologic assay for IgM and IgG antibody.  IgG avidity testing also should be performed.  In addition, she should have a culture or PCR test for virus in serum and urine.  She should also have an amniocentesis, and the amniotic fluid should be tested for CMV by either culture or PCR.  Given that there already are ultrasound findings suggestive of CMV infection, I believe that treatment with hyperimmune globulin, at a dose of 200 units (mg)/kg should be administered.  A follow-up ultrasound examination should be performed in approximately two weeks.  If the abnormal ultrasound findings have resolved, no additional treatment with hyperimmune globulin is indicated.  However, if the ultrasound findings persist, an additional dose of hyperimmune globulin should be given. 

 A detailed algorithm for diagnosis and management of CMV infection in pregnancy is presented in Figure 1.

 Figure 1. Algorithm for the Diagnosis and
Management of Congenital CMV Infection

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1. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA. The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 1992;326:663-7.PMID: 1310525
2. Duff P. A thoughtful algorithm for the accurate diagnosis of primary CMV infection in pregnancy. Am J Obstet Gynecol March 2007, pp. 196-7.
3. Donner C, Liesnard C, Content J, Busine A, Aderca J, Rodesch F. Prenatal diagnosis of 52 pregnancies at risk for congenital cytomegalovirus infection. Obstet Gynecol 1993;82:481-6.
4. Lipitz S, Yagel S, Shalev E, Achiron R, Mashiach S, Schiff E. Prenatal diagnosis of fetal primary cytomegalovirus infection. Obstet Gynecol 1997;89:763-7.
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6. Adler SP, Nigro G, Pereira L. Recent advances in the prevention and treatment of congenital cytomegalovirus infections. Semin Perinatol 2007;31:10-18.
7. Nigro G, LaTorre, Anceschi MM, Mazzocco M, Cosmi EV. Hyperimmunoglobulin therapy for a twin fetus with cytomegalovirus infection and growth restriction. Am J Obstet Gynecol 1999;180:1222-6.
8. Nigro G, Adler SP, LaTorre R, Best AM. Passive immunization during pregnancy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1350-62.
9. Duff P. Immunotherapy for congenital cytomegalovirus infection. N Engl J Med 2005;353:1402-4.
10. LaTorre R, Nigro G, Mazzocco M, Best AM, Adler SP. Placental enlargement in women with primary maternal cytomegalovirus infection is associated with fetal and neonatal disease. Clin Infect Dis 2006;43:994-1000.
11. Pass RF, Zhang C, Evans A, Simpson T, Andrews W, Huang ML, et al. Vaccine prevention of maternal cytomegalovirus infection. N Engl J Med 2009;360:1191-9.

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