Twin pregnancy and congenital cytomegalovirus: Case report and review

Primary cytomegalovirus (CMV) infection during pregnancy is the leading infectious cause of congenital neurological disabilities. Diagnosis of maternal primary CMV infection and fetal compromise can be difficult, as well as the fact that most infected child are asymptomatic at birth, which makes binomial CMV and pregnancy challenging. The treatment of pregnant women with CMV hyperimmunoglobulin (CMV-HIG) has shown promising results. However, as far as we know, no randomized trials of immunoglobulin therapy of CMV-infected fetuses are ongoing. We describe CMV-HIG administration for twin pregnancy as maternal and fetal infection early in gestation. The epidemiology, clinical manifestations, prevention strategies and treatment of CMV infections are reviewed.     

Characteristics and serology of pregnant women with cytomegalovirus immunoglobulin G seroconversion during pregnancy in Japan

ObjectiveInvestigate the characteristics and serology of pregnant women with cytomegalovirus (CMV) immunoglobulin (Ig)G seroconversion during pregnancy to understand the risk factors associated with primary CMV infection and the occurrence of fetal congenital CMV infection.Materials and methodsWe retrospectively studied 3202 pregnant women who were CMV IgG-negative in early pregnancy and were retested for IgG in late pregnancy. Characteristics were compared between participants with and without IgG seroconversion, and serological parameters were compared between participants with and without fetal congenital CMV infection.ResultsTwenty-six participants showed CMV IgG seroconversion and fifteen showed fetal congenital CMV infection. Seroconversion rates were significantly higher in teens (5.0%) than in older women (20s: 0.8%; 30s and over: 0.6%) (p < 0.001). Titers of CMV IgM at IgG seroconversion were higher in women without (median 8.66) than with (median 6.54) congenital infection (p = 0.045). The congenital infection rate was high when IgM titers at IgG seroconversion were low (47.1% with 4.00–12.00 titers and 100% with 1.21–3.99 IgM titers) (p = 0.048).ConclusionsNulliparous pregnant teenagers have a high risk of CMV IgG seroconversion and the CMV IgM titer at IgG seroconversion may help predict the occurrence of fetal congenital CMV infection.     

用聚合酶链式反应技术检测孕妇与胎儿巨细胞病毒感染的研究

应用聚合酶链式反应（ＰＣＲ）技术检测了孕妇、羊水及脐血中巨细胞病毒（ＣＭＶ）ＤＮＡ。结果表明，１８６例中正常孕妇９８例血清中ＣＭＶＤＮＡ阳性２例。阳性率为２％，异常妊娠（死胎、胎儿畸形及产前咨询）孕妇８８例血清中ＣＭＶＤＮＡ阳性１４例，阳性率为１５．９％，两者差异有显著性，（Ｐ＜０．０１）。提示孕妇ＣＭＶ感染与死胎、胎儿畸形及异常妊娠史有关。通过检测羊水和脐血中ＣＭＶＤＮＡ，发现９例胎儿ＣＭＶ感染，其中３例畸形，２例死胎，１例自然流产，３例足月分娩。     

Early detection by magnetic resonance imaging of fetal cerebral damage in a fetus with hydrops and cytomegalovirus infection.

We discuss the use of magnetic resonance imaging (MRI) to reveal early fetal neurological involvement of cytomegalovirus (CMV) infection. A woman presented at 21 weeks of pregnancy with active CMV infection. Cerebral ultrasound examination had been normal. An MRI scan revealed a thickened germinal matrix, which was histologically confirmed, associated with underdevelopment of the gyri. Brain MRI proved particularly useful in identifying the findings not disclosed by routine ultrasound during pregnancy and subsequently confirmed at histology.     

Early detection by magnetic resonance imaging of fetal cerebral damage in a fetus with hydrops and cytomegalovirus infection

We discuss the use of magnetic resonance imaging (MRI) to reveal early fetal neurological involvement of cytomegalovirus (CMV) infection. A woman presented at 21 weeks of pregnancy with active CMV infection. Cerebral ultrasound examination had been normal. An MRI scan revealed a thickened germinal matrix, which was histologically confirmed, associated with underdevelopment of the gyri. Brain MRI proved particularly useful in identifying the findings not disclosed by routine ultrasound during pregnancy and subsequently confirmed at histology.     

Experimental primary cytomegalovirus infection in pregnancy: timing and fetal outcome

In contrast to intrauterine rubella infection, the relationship between timing of maternal cytomegalovirus (CMV) infection and fetal outcome has not been clearly defined. In order to investigate this relationship, a guinea pig model was utilized to assess the fetal consequences of maternal CMV infection during the first, second, or third trimester of pregnancy. Congenital infection occurred in 24 of 35 newborn guinea pigs (69%) delivered to mothers infected during the third trimester, with localization of virus to salivary gland in 17 of the 24 infected newborn guinea pigs. In contrast, only one of 28 (5%) progeny sacrificed following first-trimester maternal infection was congenitally infected (p less than 0.01). Second-trimester maternal infection was associated with an intermediate risk of intrauterine infection with transmission of virus to 17 of 54 progeny (33%) (p less than 0.01). Eight of the 10 fetuses delivered after second-trimester infection had virus in multiple organs including the brain. These data suggest that timing of maternal CMV infection is an important variable affecting fetal outcome, with increased risk of intrauterine infection when maternal infection occurs late in pregnancy. However, if fetal infection occurs earlier in pregnancy, it appears to present a greater threat to the fetus, with the potential for dissemination of virus in multiple fetal tissues, including the brain.     

CMV Infection and Pregnancy

Cytomegalovirus (CMV) occurs in 0.2?% to 2.2?% of all live births and is the most common cause of intrauterine infection and the leading infectious cause of sensorineural hearing loss and mental retardation. This article reviews literature that relate to the pathogenesis, diagnosis, and treatment of this disease for pregnant women and their fetus. Primary maternal CMV infection during pregnancy has a much higher rate of mother-to-fetus transmission and causes symptoms at birth and long-term disability than nonprimary infection. In addition, some research has shown that children with congenital CMV infection following first-trimester maternal infection are more likely to have severe sequelae. The prenatal diagnosis of fetal CMV infection includes serological testing (IgM detection and IgG avidity assay), amniocentesis, and ultrasound examination. The combination of the presence of CMV IgM antibodies and low CMV IgG avidity, along with maternal or fetal symptoms is used for the diagnosis of a primary maternal infection. Amniocentesis should be complemented until approximately 20-21?weeks of gestation to increase the sensitivity. Because ultrasound abnormalities are only found in less than 25?% of infected fetuses, ultrasound is as a relatively poor predictor of symptomatic congenital infection. CMV hyperimmunoglobulin also may be considered when the pregnant women are confirmed as primary CMV infection with low IgG avidity and amniotic fluid is found to contain CMV or CMV DNA. There is no consensus on the benefit of prenatal administration of ganciclovir into the umbilical vein.     

Congenital cytomegalovirus infection in pregnancy: a case report of fetal death in a CMV-infected woman

Objectives The human cytomegalovirus (CMV) is universally distributed among human populations as one of the most common cause of congenital infection with an incidence of about 0.15–2.0% in developed countries. However, controversial data concerning intrauterine fetal death caused by CMV infection exist. Method A case report. Results In this case report we present a stillbirth in the 18th week of pregnancy, caused by a maternal serological and fetal histological congenital CMV infection. Conclusion Every attending physician and obstetrician should be aware of the possibility of a primary or even recurrent congenital CMV infection that could be a reason for sudden unknown congenital fetal death.     

Fetal cytomegalovirus infection associated with cerebral hemorrhage, hydrops fetalis, and echogenic bowel: case report

We describe some fetal ultrasound findings associated with intrauterine cytomegalovirus (CMV) infection. We report a 38-year-old gravida 3, para 2 at 16 weeks of gestation who underwent ultrasound examination for anomaly screening. The scan revealed an extensive irregular echogenic area in the fetal brain, especially at the level of lateral ventricles, suggestive of intraventricular and cerebral hemorrhage. Cardiomegaly, hepatomegaly, and mild ascites as well as an echogenic bowel were demonstrated. Abnormal chromosomes and hemoglobin Bart disease were excluded by analysis of fetal blood. Follow-up ultrasound at 20 weeks of gestation showed frank hydrops fetalis, and termination of the pregnancy was performed based on the couple's decision, giving stillbirth to a male fetus weighing 450 g. Autopsy findings showed intracerebral hemorrhage (right cerebral hemisphere) and hydrops fetalis with hepatosplenomegaly. Microscopic investigation showed typical changes of CMV infection in several organs, including brain, thyroid gland, lung, liver, kidney, heart, pancreas, and placenta. Sonographically, the combination of hydrops fetalis, cerebral hemorrhage, and hyperechoic bowel should raise the possibility of a CMV infection, particularly in cases with no obvious cause of hydrops fetalis.     

Pregnancy outcome following first-trimester varicella infection.

Varicella infection in the first trimester has been associated with a constellation of congenital abnormalities. The incidence of the congenital varicella syndrome is unknown, although it has been reported to be as high as 9%. In a prospective study performed between 1986-1990, 40 patients were identified who had first-trimester varicella infection. Pregnant patients were referred from physicians in the perinatal regional network after developing the classical picture of varicella infection. Targeted fetal ultrasound examinations were performed between 16-20 weeks' gestation in all cases and neonatal outcome was determined. Of the 40 patients, three had first-trimester losses and another underwent an elective termination of pregnancy after counseling. Of the remaining 36 women, one had fetal omphalocele. Thirty-five pregnancies continued until term, and no infant had features of the congenital varicella syndrome at birth. Other than the case of omphalocele, no major congenital anomalies were identified. This study, the largest series of patients with first-trimester varicella infection, showed an incidence of congenital varicella syndrome of 0% and an incidence of congenital anomalies of 3% (range 0-8% at 95% confidence level).     

A prospective study of primary cytomegalovirus infection during pregnancy: final report

In a 7-year prospective study cytomegalovirus (CMV) was shown to infect approximately twice as many pregnant women as did rubella virus. Fetal loss occurred in 4/26 (15%) early CMV infections which was seven-fold higher than the rate found in controls (16/744; 2.2%). There was no evidence that fetal loss resulted from intrauterine transmission of virus. Fifty-eight women experienced primary CMV infection and congenital infection was found in nine (20%) of the 46 infants from whom clinical samples were obtained. Transmission of virus was found in 20%, 0% and 40% in the first, second and third trimesters respectively. All babies were normal at birth but two have so far developed definite intellectual impairment attributable to cytomegalovirus infection. The mothers of both of these cases were infected after the fetus had become legally viable. We conclude that the lessons learned from studying rubella infection during pregnancy cannot be applied to cytomegalovirus; in particular, we could find no evidence that termination of pregnancy should be offered to women with early CMV infections.     

Transvaginal sonographic detection of embryonic-fetal abnormalities in early pregnancy

OBJECTIVE: To estimate the detection rate of abnormalities by transvaginal ultrasound in early pregnancy. METHODS: We prospectively analyzed records of 3592 sequential pregnant women at 10-16 weeks' (singleton) gestation (mean 13 weeks and 2 days). After exclusion of 114 women, there were 3478 women in the study. Each woman underwent a transvaginal sonographic survey for fetal anomalies as well as biometric measurements. Fetuses diagnosed with malformations were followed to delivery, and those without underwent transabdominal sonography at 18-24 weeks' gestation.Results: The anomaly detection rate by transvaginal ultrasound was 51.6% (33 of 64; 95% confidence interval [CI] 38.7, 64.2) in early pregnancy, and the detection rate by transvaginal ultrasound combined with second-trimester transabdominal ultrasound was 84.4% (54 of 64; 95% CI 73.1, 92.2). Cystic hygroma and fetal hydrops were the anomalies detected most frequently by transvaginal ultrasound. Low detection rates for abnormalities of the face and of the cardiac, skeletal, and urinary systems were found even when both methods were used. CONCLUSION: Transvaginal sonography appears to be an effective way to identify many congenital fetal anomalies in early pregnancy. There is a good probability of diagnosing cystic hygroma and fetal hydrops, although other abnormalities, particularly heart defects, are associated with lower detection rates.     

Neonatal screening for congenital cytomegalovirus infections.

We evaluated a screening program for the detection of congenital cytomegalovirus in 3075 unselected pregnant women. From each live-born child urine for CMV culture was collected within 7 days after birth. Each fetus expelled after a spontaneous second trimester abortion and each stillborn infant were also evaluated for a possible congenital CMV infection. For each congenital infection stored maternal sera were analysed to determine whether maternal infection was primary or recurrent. Fifteen out of the 3075 pregnancies studied resulted in a congenitally infected infant (0.49%). Nine maternal CMV infections were primary infections; five were recurrent infections, and in one case the type of infection could not be determined. Three congenital infections resulted in severe sequelae, leading to the termination of pregnancy in two instances and to neonatal death in one case. One of these severe fetal infections was due to a recurrent maternal infection. Follow-up of the other 12 neonates demonstrated hearing disorders in two children. One was born after a primary maternal infection and one after a recurrent maternal infection. We conclude that congenital CMV infections occurs in 0.49% of all pregnancies in the population studied. Twenty percent of the congenitally infected infants present severe sequelae at birth or during pregnancy, and an additional 17% have audiological deficits at 1 year of age. Severe sequelae may occur after both primary and recurrent maternal CMV infection.     

Effective management and intrauterine treatment of congenital cytomegalovirus infection: review article and case series

Abstract

Objective: Human Cytomegalovirus (CMV) infection during pregnancy is the most frequent viral cause of intrauterine infection and responsible for various cerebral and other ultrasound abnormalities of the fetus. It is the leading infectious cause of mental retardation and sensorineural deafness in affected newborns and infants.

We present three cases of primary cytomegalovirus infection in pregnancy and demonstrate three different scenarios of the disease with regard to clinical outcome and therapy options. We first report on CMV related phospho- and glycoprotein-specific antibody reactivities in amnion fluid that have not been reported earlier in literature.

Case presentation: Case 1: A 33-year-old Gravida II Para I was referred for primary CMV infection at 15 weeks gestation presenting with a history of fever. HIG therapy was performed resulting in good neonatal outcome.

Case 2: A 23-year-old Gravida I was referred for targeted ultrasound at 23 weeks of gestation presenting with intrauterine growth retardation, multiple fetal hepatic echodensities and thickened placenta. Termination of pregnancy was initiated.

Case 3: A 29-year-old Gravida II Para I was referred for primary CMV infection at 16 weeks gestation presenting with no clinical symptoms of CMV. HIG therapy was performed, resulting in good neonatal outcome.

Conclusion: We want to stress the potential benefit of an off label use of CMV-specific hyperimmune globulin (HIG) therapy, present an algorithm for the management of affected pregnancies and review current literature on this issue.     

Use of Cytomegalovirus-Specific Hyperimmunoglobulins in Pregnancy: A Retrospective Cohort

Objective

There is no consensus on the use of cytomegalovirus (CMV)–specific hyperimmunoglobulins (CSHIGs) for suspected congenital CMV infections during pregnancy, but this therapy is currently used in some countries. The objectives of this study were to describe tolerability and pregnancy outcome following treatment with monthly intravenous CSHIG and compare rates of positive PCR and postnatal symptoms according to whether CSHIGs were given or not.

Multi-system cytomegalovirus fetopathy by recurrent infection in a pregnant woman with hepatitis B

A pregnant woman with acute hepatitis B virus (HBV) infection had her second pregnancy terminated at 25 weeks' gestation because of fetal ascites and ventriculitis. Meconium peritonitis was also found at autopsy. No HBV DNA but cytomegalovirus (CMV) DNA was detected in the fetal liver and ascitic fluid. Recurrent maternal CMV infection was demonstrated by pre-existing CMV IgG antibodies, high IgG avidity and low IgM levels. After abortion, the patient developed chronic active hepatitis. Nevertheless, having become pregnant again with a new partner, she had an uneventful third pregnancy and gave birth to a healthy boy.     

Screening, diagnosis, and management of cytomegalovirus infection in pregnancy

Congenital cytomegalovirus (CMV) is the most common intrauterine infection and the leading infectious cause of sensorineural hearing loss and mental retardation. This article reviews the issues that relate to the diagnosis and management of this disease, detailing the points that led to the recent published guidelines by the Society of Obstetricians and Gynaecologists of Canada. A MEDLINE/Cochrane search of CMV infection, pregnancy, and prenatal diagnosis found 195 studies between 1980 and 2010. Of these, we examined 59 relevant studies. The probability of intrauterine transmission following primary infection is 30% to 40%, but only 1% after secondary infection. About 10% to 15% of congenitally infected infants will have symptoms at birth, and 20% to 30% of them will die, whereas 5% to 15% of the asymptomatic infected neonates will develop sequelae later. Children with congenital CMV infection following first trimester infection are more likely to have central nervous system sequelae, whereas infection acquired in the third trimester has a high rate of intrauterine transmission but a favorable outcome. The prenatal diagnosis of fetal CMV infection should be based on amniocentesis performed 7 weeks after the presumed time of infection and after 21 weeks of gestation. Sonographic findings often imply poor prognosis, but their absence does not guarantee a normal outcome. The value of quantitative determination of CMV DNA in the amniotic fluid is not yet confirmed. The effectiveness of prenatal therapy for fetal CMV is not yet proven, although CMV-specific hyperimmune globulin may be beneficial. Routine serologic screening of pregnant women or newborns has never been recommended by any public health authority. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologist should be better able to evaluate the principles of prenatal diagnosis of congenital CMV infection so doctors will be familiar with the tests and procedures needed, in order to reach a diagnosis of congenital CMV; to assess the natural history and outcome of congenital CMV infection enabling obstetricians to counsel prenatally pregnant women with CMV; and to analyze the prognostic markers for fetal CMV, so managing physicians will be able to predict more accurately the outcomes of fetuses infected by CMV.     

Comparison between ultrasound and magnetic resonance imaging in assessment of fetal cytomegalovirus infection

OBJECTIVE: To evaluate whether fetal brain magnetic resonance imaging (MRI) adds useful information to the one obtained by ultrasound in fetuses with cytomegalovirus (CMV) infection. METHODS: MRI and ultrasonographic findings were analyzed retrospectively in 38 fetuses with proven congenital CMV infection. Both techniques were performed on the same week at a mean gestational age of 33 weeks (24-37). The referral indications were maternal seroconversion (n = 19), and ultrasound findings (n = 19). The results were compared with the fetopathologic examination in cases with fetal death or termination of pregnancy (TOP) or the infant's neurological examination. RESULTS: The 38 cases were classified into three groups, depending on ultrasound findings at referral. Group 1: no ultrasound features (n = 11); group 2: extracerebral features without cerebral abnormalities at ultrasound (n = 13); group 3: presence of cerebral features at ultrasound (n = 14). In group 1, MRI was always normal. In group 2, MRI revealed cerebral features in six cases (46%). In group 3, MRI always confirmed the lesions seen at ultrasound and highlighted other cerebral features. CONCLUSIONS: MRI can provide important additional information with regard to abnormal gyration, cerebellar hypoplasia, or abnormal signal in white matter. It is certainly useful in the assessment of fetuses with extracerebral features without brain abnormalities detected with ultrasounds. If the fetal ultrasound is strictly normal in an infected fetus, MRI may not detect brain anomalies; however, it seems difficult to not perform this noninvasive procedure.     

Prevention of maternal and congenital cytomegalovirus infection

Congenital cytomegalovirus (CMV) infection is an important cause of hearing impairment, mental retardation, and cerebral palsy. Principal sources of infection during pregnancy are young children and intimate contacts. Prevention of maternal and congenital CMV infection depends on counseling women regarding the sources of infection and hygienic measures that might prevent infection. There is currently insufficient evidence to support use of antiviral treatment or passive immunization for postexposure prophylaxis of pregnant women or as a maternal treatment aimed at preventing fetal infection. Vaccines for CMV are under development but it will be a number of years before one is licensed.     

Contribution of transvaginal ultrasonography and fetal cerebral MRI in a case of congenital cytomegalovirus infection

Cytomegalovirus is the most common cause of congenital viral infection. In utero this infection is usually suspected on the basis of ultrasound findings. We present a case in which routine ultrasound examination demonstrated a decrease in fetal cephalic dimensions at 32 weeks' gestation in an asymptomatic patient. Transvaginal ultrasound revealed echogenic vessels in the thalami and lesions in the subependymal region. Suspected diagnosis of fetal cytomegalovirus infection was confirmed by positive titers of anti-cytomegalovirus-IgM antibodies in fetal blood and amniotic-fluid PCR studies. Fetal cerebral MRI demonstrated parenchymal atrophy and polymicrogyria. The parents decided to terminate the pregnancy, and necropsy confirmed the diagnosis. Suspicion of CMV fetal infection should prompt transvaginal ultrasound and fetal brain MRI.