Cmv in Pregnancy Reviews in Obstetrics and Gynecology
Rev Obstet Gynecol. 2010 Autumn; 3(4): 172–179.
Cytomegalovirus Infection in Pregnancy: Should All Women Be Screened?
Amanda Carlson
1Department of Obstetrics, Gynecology and Reproductive Sciences, Yale University School of Medicine, New Oasis, CT
Errol R Norwitz
2Louis E. Phaneuf Professor of Obstetrics and Gynecology, Tufts University School of Medicine, Chairman, Department of Obstetrics and Gynecology, Tufts Medical Center, Boston, MA
Robert J Stiller
3Department of Obstetrics and Gynecology, Bridgeport Hospital, Bridgeport, CT
Abstruse
Cytomegalovirus (CMV) is the most common cause of built infection and complicates approximately 1% of all live births. Primary maternal CMV infection carries a 30% to forty% risk of vertical manual to the fetus. In cases where maternal CMV infection is suspected, it is of import to evaluate the risk to the fetus to provide advisable counseling and guidance to parents. This article reviews the published literature and summarizes current diagnostic and direction recommendations to assist answer the question, should all women be screened for CMV infection in pregnancy?
Key words: Cytomegalovirus infection, Pregnancy, Antiviral agents, Hyperimmune globulin, Built infection
Cytomegalovirus (CMV) is the most common cause of congenital infection.ane Moreover, congenital CMV is the most oftentimes identified viral cause of mental retardation and is the leading nongenetic cause of neurosensory hearing loss.2 , three In developed countries, congenital CMV infection occurs in 0.3% to 2.iv% of all live births.4 Infection in the newborn can be acquired through close contact (via contaminated claret, urine, and secretions), vertically through transplacental manual, and postnatally through breast milk.one Most symptomatic neonatal CMV infections occur when a woman is newly infected merely prior to or during pregnancy.five , 6 Master maternal CMV infection in pregnancy carries a 30% to twoscore% risk of vertical transmission.1 Of all pregnancies with confirmed vertical transmission, but ten% to 20% of the fetuses volition accept evidence of clinical infection at nativity.1 As compared with women who are infected in the latter half of pregnancy, women who develop primary CMV infection in the first trimester are more than likely to deliver fetuses with sensorineural hearing loss (24% vs two.5%) or other CNS sequelae, such as mental retardation, cerebral palsy, seizures, or chorioretinitis (32% vs fifteen%).7 Mothers who are CMV seropositive prior to pregnancy tin can also develop a secondary CMV infection either due to reactivation of virus residing at specific sites in the body (primarily the salivary glands) or reinfection with a different viral strain.6 Such infections tend to be less severe and are ordinarily asymptomatic for both mother and newborn. Infants born to such mothers tin likewise accept sequelae of congenital CMV, only this is far less likely (estimated at 0.2% to 2%).8 In cases where maternal CMV infection is suspected, information technology is of import to evaluate the hazard to the fetus of being infected and/or symptomatically affected past CMV to provide appropriate counseling and guidance to parents. We present a case of fetal CMV infection to illustrate and highlight some of the diagnostic and therapeutic bug raised by CMV infection.
Case Study
A good for you 29-year-old woman (G2, P1) with a well-dated spontaneous conception was seen for routine ultrasound exam at 18-0/7 weeks of gestation. The fetus was noted to have echogenic bowel (Figure 1) and intrauterine growth brake (IUGR) with an estimated fetal weight in the 9th percentile. Her past obstetric history was remarkable for severe preeclampsia resulting in an induction of labor and vaginal commitment at 34 weeks of gestation ii years earlier. Maternal serologic tests performed in light of the ultrasound findings revealed elevated CMV IgM and IgG titers. Amniotic fluid was strongly positive for CMV Dna by quantitative existent-time polymerase chain reaction (RT-qPCR). Later on all-encompassing counseling as to the diagnosis of fetal CMV and their options, including pregnancy termination, the couple chose to go on the pregnancy. Subsequently consultation with an infectious disease specialist, CMV allowed globulin (200 U/kg, for a total dose of 10 thousand intravenous [IV]) was recommended starting at 25 weeks of gestation with subsequent doses of v grand IV planned at monthly intervals. Fetal magnetic resonance imaging (MRI) at 25 weeks of gestation showed no evidence of intracranial calcifications or abnormalities.
Representative perinatal ultrasound image showing fetal echogenic bowel. Fetal echogenic bowel refers to increased echogenicity or brightness of the fetal bowel noted on 2d trimester ultrasound examination. The diagnosis of echogenic bowel should be reserved for fetuses in which the echogenicity of the bowel is equal to or greater than that of adjacent os. The differential diagnosis of fetal echogenic bowel includes cystic fibrosis, infection with cytomegalovirus or toxoplasmosis, meconium ileus, and chromosomal abnormalities (including Turner syndrome and trisomy 21, 13, or eighteen).
At 30 weeks of gestation, post-obit 2 doses of CMV allowed globulin, the fetal heart-rate tracing was noted to accept absent variability and repetitive belatedly decelerations (category Iii). A biophysical profile was 2/ten (2 points for amniotic fluid book merely) and umbilical avenue Doppler velocimetry showed reversed stop-diastolic catamenia. A viable female babe was delivered by emergent cesarean weighing 920 g with Apgar scores of 2, 7, and 10 at 1, 5, and x minutes, respectively. Cord blood analysis showed an arterial pH of vii.sixteen and base backlog of −12.five and venous of pH seven.29 and base excess of −8.9. The neonate was intubated and admitted to neonatal intensive care. Chest radiography showed footing drinking glass opacities consistent with built CMV pneumonia. Hematologic abnormalities included thrombocytopenia, coagulopathy, elevated transaminase levels, and hyperbilirubinemia. CMV antigenemia was present in the infant's blood, and CMV DNA was identified in urine and cerebrospinal fluid. Placental pathology showed diffuse fibrin deposition and villous edema. Specific immunostaining of the placenta was positive for CMV (Figure 2).
Representative histologic images of a placenta with cytomegalovirus (CMV) infection. (A) Placental histology shows moderate villous edema, intervillous fibrin deposition, amnion hyperplasia, and grade I inflammation. (B) Specific immunostaining confirms the presence of CMV infection.
The infant was treated with Four gancyclovir (6 mg/kg twice daily) with subsequent resolution of laboratory and imaging abnormalities over a 10-day period. Ultrasound examination of the head and abdomen showed no prove of calcifications, ventriculomegaly, or hepatosplenomegaly prior to treatment. Ophthalmologic examination showed no prove of retinitis. Still, the infant failed multiple newborn hearing screens and appeared to have profound bilateral deafness. Antiviral therapy was continued for 6 weeks. The baby was discharged home in stable condition on day of life 55.
Word
CMV infection is very common in the United States, with 50% to lxxx% of reproductive-age women showing serological evidence of previous infection.9 Reproductive-age women of heart and college socioeconomic status are at college take chances for principal CMV, equally approximately half are seronegative for CMV antibodies and are therefore susceptible to infection during pregnancy. In day intendance centers, approximately 80% of young children will develop CMV within 2 years.ten Although these children are typically asymptomatic, they will proceed to shed virus for years after initial acquisition. Many women with exposure to young children will acquire a CMV infection inside i year.1 , 11 Women with dumb cellular response (eg, patients with HIV/acquired immunodeficiency syndrome [AIDS] or those receiving immunosuppressive therapy) are at college risk of acquiring CMV infection and, considering they are less probable to produce neutralizing antibodies, they are as well at college risk of transmitting the virus to their fetuses.5
How Should the Diagnosis Be Confirmed in the Female parent?
Maternal CMV tends to be asymptomatic and patients will rarely be diagnosed past clinical symptoms alone. For most infections, evidence of maternal seroconversion (defined as a conversion from a negative to a positive IgM or a four-fold increment in IgG antibody titer over a 4- to vi-calendar week period) is sufficient to confirm the diagnosis of a main infection. Notwithstanding, the accuracy of maternal anti-CMV IgM to predict primary maternal infection is complicated past the fact that IgM antibodies tin can persist for months or even years after principal infection, and also can be institute in the setting of reactivation or reinfection with a dissimilar strain of CMV.12
Another method of determining the timing of maternal CMV infection is to measure antibody ardor, which refers to the force of antibiotic binding to a target antigen. Equally the immune response to a detail antigen matures over time, ardor increases. Thus, detection of low-ardor anti-CMV IgG early in pregnancy suggests a contempo acute infection, and tin be used to identify pregnant women at increased adventure of having an infected fetus.4 , xiii In contrast, the presence of high-ardor antibodies at 12 to 16 weeks of gestation indicates a by infection, likely prior to conception. Improvement in CMV IgM testing has been reported by performing gel electrophoresis Western blotting of CMV viral polypeptides and may provide the most accurate way to diagnose a main maternal CMV infection.12 Although available in Europe, this test is not bachelor in the U.s..
How Should the Diagnosis Exist Confirmed in the Fetus?
In cases of confirmed maternal CMV infection, it is important to evaluate the gamble of fetal infection to provide appropriate counseling and guidance to parents. Perinatal ultrasound tin can aid in identifying structural or growth abnormalities that may suggest symptomatic fetal infection. These abnormalities include echogenic bowel, IUGR, ventriculomegaly, placental thickening, brain calcifications, evidence of hydrops fetalis, and/or aberrant amniotic fluid volume14 , 15 (Table one). These ultrasound findings are not specific for congenital CMV infection, and there may be other causes for these findings16 (Tabular array 2). Moreover, only 15% of CMV-infected fetuses will brandish ultrasound abnormalities.xiv However, the presence of ultrasound abnormalities in a significant woman with confirmed master maternal CMV infection is strongly suggestive of fetal infection.14
Table 1
Ultrasound Features of Congenital Cytomegalovirus Infection
| • Cerebral ventriculomegaly |
| • Microcephaly |
| • Hyperechogenic fetal bowel |
| • Hepatosplenomegaly |
| • Cerebral periventricular echogenicity/intracranial calcifications |
| • Intrauterine growth restriction |
| • Abnormal amniotic fluid volume |
| • Placental enlargement |
| • Ascites and fetal hydrops |
Table 2
Differential Diagnosis of Built Cytomegalovirus Infection
| • Rubella |
| • Toxoplasmosis |
| • Syphilis |
| • Herpes simplex virus |
| • Enterovirus |
Amniocentesis may be performed to confirm fetal infection, and is recommended in situations where maternal primary or undefined CMV infection is detected in the kickoff half of pregnancy or in cases where sonographic fetal abnormalities are suggestive of infection. Amniotic fluid should be sent for viral culture and for polymerase concatenation reaction (PCR) testing for the CMV genome. False-negative results may occur if amniocentesis is performed prior to 21 weeks of gestation because the virus is slow growing and may non be excreted past the fetal kidneys in sufficient quantities for detection in early on pregnancy.4 If viral culture and PCR for CMV are both negative, built CMV can be effectively excluded at that time; if positive, this suggests the presence of fetal infection, although the impact on the fetus cannot be adamant. Further evaluation by series ultrasound examinations for signs of fetal encephalon involvement (intracranial calcifications, ventriculomegaly, microcephaly) or DNA quantification by RT-qPCR may provide boosted prognostic information.17 Fetal thrombocytopenia detected by fetal claret sampling has besides been reported to be an contained predictor of poor fetal outcome,xviii but is non by and large recommended.
Following birth, CMV infection in the newborn should be confirmed by isolating the virus in the urine and/or saliva in the first 2 to iii weeks of life. Thereafter, PCR can discover the viral genome in the newborn's blood with equal sensitivity and specificity. CMV IgM antibodies are present in only 70% of infected infants and do not finer rule out congenital infection.four Infants with built CMV infection should undergo farther testing (including a detailed physical examination and boosted radiologic and hematologic tests) to determine whether the infection should be classified as symptomatic.
What Is the Prognosis for the Fetus?
A diagnosis of fetal CMV infection does not equate to an affected fetus, every bit lxxx% to 90% of fetuses with built CMV infection are asymptomatic at birth. For the ten% to 20% of fetuses who are symptomatic at nascence, nevertheless, outcomes are by and large poor.1 , v , xix Signs and symptoms may include neurologic deficits (eg, seizures, chorioretinitis, hypotonia, hearing loss, microcephaly, and intracranial calcifications) besides equally hematologic abnormalities (eg, petechiae, thrombocytopenia, and evidence of liver affliction as manifested by jaundice, transaminitis, hyperbilirubinemia, and hepatosplenomegaly). Infants may as well testify prove of growth restriction and failure to thrive. Of CMV-infected children who are asymptomatic at nascency, 8% to 15% volition develop hearing loss and psychomotor delay subsequently in life.20
Should CMV Hyperimmune Globulin or Antiviral Agents Be Recommended in Pregnancy?
Because of the poor prognosis associated with primary maternal CMV diagnosed early in pregnancy, elective termination should be discussed as an selection. Women who wish to continue the pregnancy may be offered one of several medical therapies; yet, these should all still be regarded as investigational.
Ganciclovir has been used extensively in newborns with symptomatic CMV infections. In such newborns, a 6-week grade of Four ganciclovir has been shown to significantly reduce the incidence of hearing loss, although some newborns volition experience neutropenia.21 Information on the safety and efficacy of ganciclovir in pregnancy, however, is extremely limited. Animal data have shown an increased risk of fetal malformations when ganciclovir was used in higher than normal doses in pregnancy, although case reports in humans suggest no increased risk of malformations.5
In a small airplane pilot study, oral valacyclovir was administered to 21 pregnant women with confirmed CMV-symptomatic fetuses. The medication was well tolerated and a subtract in CMV viral load was noted in the cord claret of the treated fetuses; however, given the small sample size, no clear improvement in perinatal outcome could be demonstrated.22 Further studies are necessary to determine the safety and efficacy of antiviral agents in the treatment of CMV during pregnancy.
In vitro and animal studies suggest that CMV hyperimmune globulin (HIG) may be effective in minimizing the impairment caused past CMV infection. For example, when meaning guinea pigs were exposed to CMV followed by administration of a neutralizing antisera, fetal survival increased significantly as compared with those animals who did not receive passive immunization, and a similar reduction was noted in fetal infection, placental inflammation, and IUGR.23 , 24 CMV HIG consists of enriched CMV-specific immunoglobulins and has been studied extensively in post-transplant patients for CMV prophylaxis.25 , 26 Information technology is marketed in the United States every bit Cytogam® (CSL Behring, King of Prussia, PA).
Nigro and colleagues27 conducted a multicenter, prospective study of 181 pregnant women with primary CMV infection. Of these women, 79 underwent amniocentesis and 55 were constitute to have CMV-positive amniotic fluid. Of these, 31 women elected to receive 200 U/kg CMV HIG administered monthly, 14 women elected not to receive HIG, and ten women elected to terminate the pregnancy. Only 3% (1/31) of fetuses who received HIG were symptomatic at nativity every bit compared with 50% (vii/14) of the infants whose mothers declined HIG. In this nonrandomized study, administration of HIG to the mother and the presence of fetal ultrasound abnormalities prior to treatment were important predictors of fetal outcome. In a second study by the aforementioned investigators, three women with CMV-associated fetal cerebral abnormalities received HIG infusions during pregnancy. In all three cases, the fetal ventriculomegaly regressed, other associated abnormalities resolved, and the 3 infants were reportedly developing normally by age five.28
Additional case reports from other investigators have suggested that antenatal assistants of CMV HIG may be associated with more favorable outcomes in fetuses suspected of having congenital CMV infection.29 – 32 CMV HIG has been given by maternal IV injection, intra-amniotic injection, intraperitoneal injection into the fetus, and past straight IV injection into the umbilical vein. The optimum dosage, route of assistants, and indications for its utilize, along with confirmation of its efficacy in randomized, prospective clinical studies, still need to be identified. However, the use of CMV HIG and/or antiviral agents such as valacyclovir in fetuses with confirmed CMV infection may be an option for women who plan to go along the pregnancy.
Is At that place a Vaccine Available Against CMV?
In 1999, the Establish of Medicine report entitled, Vaccines for the 21st Century: A Tool for Decision Making, stated that development of a CMV vaccine was the highest priority for new vaccines.33 Recently, a vaccine targeted toward CMV envelope glycoprotein B, an antigen that typically induces a serum antibody response, entered phase 2 clinical trial.34 This vaccine has already been shown to be immunogenic with an acceptable risk profile. In this trial, CMV infection occurred in 18 of 225 subjects in the vaccine grouping (viii%) and in 31 of 216 subjects in the placebo group (14%). 4 built CMV infections occurred as a result of maternal infection during pregnancy. In that location were three congenitally infected infants in the placebo grouping (1 of which went on to develop severe neurologic sequelae) and 1 congenitally infected babe in the vaccine grouping (who was asymptomatic).34 Although these numbers are also small to support any definitive conclusions, they are consistent with our knowledge of decreased CMV transmission in women who behave protective antibodies. Future studies are necessary to demonstrate the safety and efficacy of this vaccine earlier information technology tin can be used for principal prevention of congenital CMV.
Prevention of CMV in Pregnant Women
Given the limited success of vaccine prevention of CMV, attention has been directed at patient didactics as a means of preventing the acquisition of infection (Tabular array three). Considering fifteen% to seventy% of children in day care learn CMV infection, attempts at prevention take focused primarily on mothers of small-scale children. Information technology has been shown that CMV-seronegative women take a 5- to 25-fold increased risk of developing CMV if exposed to children in twenty-four hour period intendance.11 In a study of 166 seronegative women with a young child in twenty-four hours care, women given data concerning handwashing, gloves for diaper changes, and avoiding sure types of intimate contact (sharing utensils, kissing on the lips) were compared with those not given this information.35 Both groups showed an overall seroconversion rate of 7.8%. However, CMV-seronegative mothers who knew their infant's serostatus and were significant had a lower risk of seroconversion (five.viii%) as compared with those who were non pregnant (41.6%), suggesting that cognition of their infant's condition and the motivation during pregnancy to avoid becoming infected led to a subtract in acquiring CMV. This besides suggests that personal cognition of a woman's own susceptibility to CMV through screening may be useful when designing and implementing prevention strategies.
Table three
Strategies to Prevent CMV Infection in Women Who Are or Will Go Meaning
| • Educate women with young children or who work with young children that they are at increased take chances and that attending to hygiene volition help prevent cytomegalovirus (CMV) transmission |
| • Careful handing of potentially infected articles, such as diapers |
| • Thorough hand washing when around young children or immunocompromised individuals |
| • Avoiding sharing utensils |
| • Avoid kissing children < 6 years on the oral cavity or cheek |
Currently, the American Higher of Obstetricians and Gynecologists (ACOG) recommends that all women be educated about the ways that CMV infection may be caused in pregnancy.36 They recommend careful handling of potentially infected articles, such as diapers, and thorough handwashing when around young children or immunocompromised individuals. The Centers for Disease Control and Prevention (CDC) confirms the ACOG recommendations, merely also adds that meaning women with children nether the age of vi should avert sharing utensils and kissing their children on the lips or cheek.37 Despite these recommendations, a contempo survey report by ACOG of 305 obstetrician-gynecologists reported that only 44% routinely counsel their patients about CMV prevention.38
Should All Patients Be Screened for CMV?
Although ACOG recommends that meaning women be educated about CMV prevention, they have non endorsed routine screening in pregnancy.36 The CDC as well acknowledges that screening for CMV in pregnant women is not currently recommended. Nonetheless, they add together that, for women planning to become pregnant, routine CMV screening tin can assist them to empathise how careful they must be to forbid infection.37 The reasons given for not recommending routine screening accept included the difficulties in accurate diagnosis given the loftier false-positive rate of commercial IgM testing, the lack of effective treatment of infection during pregnancy, and the possibility of reinfection or virus reactivation in a seropositive woman. In a recent determination-analytic model evaluating options for maternal CMV screening, Cahill and colleagues39 noted that universal screening was cost constructive as long as CMV HIG achieved at least a 47% reduction in neonatal affliction. In countries such equally Italian republic where CMV screening is more widespread, the high incidence of false-positive CMV IgM has been studied. In a series of 1857 pregnant women with a reported positive CMV IgM exam, only 26% were idea to represent a true primary CMV infection as confirmed by additional testing with IgG avidity and CMV immunoblot technology, whereas 54% of cases were believed to stand for previous infection without active disease, and 20% were thought to be reactivation/secondary infection.twoscore Such studies underscore the need for appropriate confirmatory testing to make up one's mind the true fetal take chances as well every bit appropriate specialists to provide counseling for the heightened patient anxiety that could result from more widespread screening. Even so, with improvements in serologic testing (eg, IgG ardor or IgM immunoblot technology) coupled with constructive treatments (CMV HIG, antiviral agents, or vaccination), it is hoped that the introduction of more than widespread screening of women for CMV serostatus prior to or at the onset of pregnancy will lead to significant improvements in clinical outcome.
Conclusions
CMV is an important cause of congenital infection and can result in significant perinatal morbidity and health care expense. Although existing data suggest a benefit to HIG prophylaxis, additional clinical trials are needed to confirm these observations. Until and then, the use of HIG and other antiviral agents for treatment remains experimental. In the absence of proven therapies for built CMV infection, prevention is critical. Nigh importantly, patients, especially those exposed to immature children, should be counseled about the importance of conscientious mitt hygiene practices, an intervention that has been proven to decrease the risk of principal CMV infection and subsequent fetal transmission.
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