Severe congenital cytomegalovirus infection with fetal hydrops in a cytomegalovirus-seropositive healthy woman

We report the case of a woman whose two consecutive pregnancies resulted in intrauterine fetal death due to severe congenital cytomegalovirus infection. In both pregnancies, congenital cytomegalovirus infection was prenatally diagnosed on the basis of detection of cytomegalovirus DNA and specific IgM in cord blood. This case suggests that severe congenital cytomegalovirus infection can occur even in seropositive healthy women.     

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.     

Nonimmune hydrops fetalis and fulminant fatal disease due to congenital cytomegalovirus infection in a premature infant.

We report a case of fatal congenital cytomegalovirus (CMV) disease in a 695 gm, 29 weeks estimated gestational age premature infant. The newborn presented with hydrops fetalis, an unusual presentation of congenital CMV infection. In spite of ganciclovir therapy, the infant succumbed to his illness. Autopsy findings revealed the presence of widespread CMV disease, including pneumonitis, enteritis, and myocarditis. Congenital CMV infection should be considered in the differential diagnosis of hydrops fetalis.     

Maturation of the immune system in the fetus and the implications for congenital CMV

Congenital cytomegalovirus (CMV) infection is the most prevalent and consequential congenital infection, among others, that affects approximately 0.6% of all live births worldwide. Timing of maternal infection and maternal immune status largely determine the likelihood of a symptomatic infection. However, recent studies suggest that the fetal immune system, long perceived as naïve and immature, may also play a role in deciding the outcome of congenital CMV infection. Here, we review the development of four immune cells most pertinent to CMV control in the human fetus. αβT cells, B cells, natural killer (NK) cells, and γδT cells are all present, mature and partially functional in utero, and are capable of mounting some form of response to congenital CMV infection. Whether this response is negligible, effective, or harmful remains an open question. Expanding our knowledge of normal and abnormal immune development could provide clinicians with more accurate tools for the detection, monitoring, and treatment of congenital CMV infection in fetuses.     

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.     

Intrauterine therapy with cytomegalovirus hyperimmunoglobulin for a fetus congenitally infected with cytomegalovirus

Reported herein is a case of hydrops fetalis in which the cord blood expressed cytomegalovirus (CMV) antigen. Fetal ascites was removed from an infected fetus with hydrops in utero and 2.5 g CMV hyperimmunoglobulin was administered into the fetal abdominal cavity at 28 weeks gestation. After immunoglobulin administration, fetal ascites vanished, preload index of the inferior vena cava decreased and platelet count of the infant increased. However, despite intrauterine therapy and intensive neonatal care, the infant died soon after birth. The expression of CMV antigen in the nucleus of polymorphonuclear leukocytes in fetal cord blood indicated that the fetal hydrops was caused by CMV infection. When symptomatic CMV infection of a fetus is suspected from serological and ultrasound findings, further examinations should be performed for the diagnosis. Intrauterine immunoglobulin therapy could be one of the therapeutic options for the affected fetus.     

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.     

Evidence in a human fetus of micrognathia and cleft lip as potential effects of early cytomegalovirus infection

Human cytomegalovirus (CMV) infection is one of the most frequent congenital infections, affecting 0.2-2% of all live births. Approximately 30-50% of pregnant women are seronegative at the beginning of pregnancy, and 1% will develop primary infection during pregnancy. Fetal CMV infection is associated with a phenotype that has been described to include central nervous system anomalies, hydrops fetalis and oligohydramnios. Impaired first branchial arch development as well as orofacial clefts after CMV infection have been shown in animal models. We present a case in which ultrasound examination at 29 weeks of gestation revealed marked micrognathia and slight cleft lip as well as multiple signs of fetal infection. We focus on the detection of fetal face and skull anomalies.     

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.     

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。     

Fetale Virusinfektionen

Infections during pregnancy may adversely affect pregnancy outcome and child health. They may be associated with fetal death, preterm delivery, congenital defects, and an increased risk of perinatal morbidity and mortality. The risk of intrauterine transmission and fetal disease depends on the nature of the pathogen, type of maternal infection (primary, recurrent, or chronic infection), and gestational age at time of fetal infection. The most important viruses that may cause symptomatic fetal infections are human cytomegalovirus (CMV), human parvovirus B19 (B19V), varicella-zoster virus (VZV), and rubella virus (RV). Available preventive measures (e.g., active or passive immunization, exposure or postexposure prophylaxis) and treatment options as well as modern serological and virological diagnostics should be thoroughly used to minimize the risk of sequelae associated with prenatal viral infections..     

Cytomegalovirusinfektion in der Schwangerschaft

Primary infection with cytomegalovirus (CMV) affects about 0.6?% of all pregnant women. In about 80?% of the cases, these women are asymptomatic. Depending on the gestational age, the maternal–fetal transmission rate raises from 30 to 70?%. At the same time, the rate of postnatal sequelae decreases with increasing gestational age. As a consequence, a CMV infection in the first trimester carries the highest risk for an adverse outcome. Among others, postnatal symptoms of a congenital CMV infection include microcephaly and sensorineural hearing loss and are generally associated with a long-term developmental disorder. Treatment focuses on prevention of transmission. This could be realized by detailed hygiene counseling about the common ways of infection. In case of maternal infection, hyperimmunglobulines (HIG) are often used off-label in Germany to avoid maternofetal transmission. If fetal infection is documented, treatment may also involve the application of HIG or alternatively valaciclovir.     

Foscarnet therapy for congenital cytomegalovirus liver fibrosis following prenatal ascites

We report on an infant with multi-system disease including liver fibrosis, right microphthalmia with cataract, interstitial pneumonitis, and hyperechoic lesions in the basal ganglia and in the periventricular and thalamic regions. Prenatal ascites with hepatomegaly concomitantly with detection of cytomegalovirus (CMV) DNA in the amniotic fluid, following recurrent maternal CMV infection, had been shown. Although CMV culture and DNA detection were negative in the urine, the infant was given foscarnet because CMV infection was demonstrated in the liver by DNA detection and immunohistochemical staining. Favorable clinical outcome and absence of CMV in the liver were subsequently shown. Our case suggests that congenital CMV disease following maternal recurrence may not be associated with disseminated infection but only with intracellular infection. The diagnosis should therefore be based on CMV detection in the involved organs. Moreover, this is the first report on the possible efficacy and safety of foscarnet for therapy of immunocompetent infants with congenital CMV disease.     

Foscarnet therapy for congenital cytomegalovirus liver fibrosis following prenatal ascites.

We report on an infant with multi-system disease including liver fibrosis, right microphthalmia with cataract, interstitial pneumonitis, and hyperechoic lesions in the basal ganglia and in the periventricular and thalamic regions. Prenatal ascites with hepatomegaly concomitantly with detection of cytomegalovirus (CMV) DNA in the amniotic fluid, following recurrent maternal CMV infection, had been shown. Although CMV culture and DNA detection were negative in the urine, the infant was given foscarnet because CMV infection was demonstrated in the liver by DNA detection and immunohistochemical staining. Favorable clinical outcome and absence of CMV in the liver were subsequently shown. Our case suggests that congenital CMV disease following maternal recurrence may not be associated with disseminated infection but only with intracellular infection. The diagnosis should therefore be based on CMV detection in the involved organs. Moreover, this is the first report on the possible efficacy and safety of foscarnet for therapy of immunocompetent infants with congenital CMV disease.     

Prenatal diagnosis of congenital cytomegalovirus infection in 189 pregnancies with known outcome

Prenatal diagnosis (PD) of fetal cytomegalovirus (CMV) infection was performed in 242 pregnancies, with known outcome in 189 cases. In 141/189 pregnancies, PD was carried out on account of suspicious maternal CMV serology up to gestational week (WG) 23, and in 48 cases on account of abnormal ultrasonic findings detected between WG 18 and 39. Chorionic villus samples (n = 6), amniotic fluid (AF, n = 176) and/or fetal blood specimens (n = 80) were investigated for detection of virus by cell culture, shell vial assay, PCR and/or CMV-specific IgM antibodies. Of 189 fetuses correctly evaluated by CMV detection either in fetal tissue following therapeutic abortion/stillbirth (n = 24) or in urine of neonates within the first 2 weeks of life (n = 33), 57 were congenitally infected. In women with proven or suspected primary infection, the intrauterine transmission rates were 20.6% (7/34) and 24.4% (10/41), respectively. Of the congenitally infected live-born infants, 57.6% (19/33) had symptoms of varying degree. The overall sensitivity of PD in the serologic and ultrasound risk groups was 89.5% (51/57). A sensitivity of 100% was achieved by combining detection of CMV-DNA and CMV-specific IgM in fetal blood or by combined testing of AF and fetal blood for CMV-DNA or IgM antibodies. There was no instance of intrauterine death following the invasive procedure. The predictive value of PD for fetal infection was 95.7% (132/138) for negative results and 100% (51/51) for positive results. Correct results for congenital CMV infection by testing AF samples can be expected with samples obtained after WG 21 and after a time interval of at least 6 weeks between first diagnosis of maternal infection and PD. In case of negative findings in AF or fetal blood and the absence of ultrasound abnormalities at WG 22-23, fetal infection and neonatal disease could be excluded with high confidence. Positive findings for CMV infection in AF and/or fetal blood in combination with CMV suspicious ultrasound abnormalities predicted a high risk of cytomegalic inclusion disease (CID). Furthermore, detection of specific IgM antibodies in fetal blood was significantly correlated with severe outcome for the fetus or the newborn (p = 0.0224). However, normal ultrasound of infected fetuses at WG 22-23 can neither completely exclude an abnormal ultrasound at a later WG and the birth of a severely damaged child nor the birth of neonates which are afflicted by single manifestations at birth or later and of the kind which are not detectable by currently available ultrasonographic techniques.     

TORCH test for fetal medicine indications: only CMV is necessary in the United Kingdom

OBJECTIVES: To review the indications and value of TORCH testing (toxoplasma, rubella, cytomegalovirus, herpes) for fetal medicine reasons. METHODS: Analysis of all maternal and fetal TORCH tests requested from a busy Fetal Medicine Unit during nearly a 10-year period. The main ultrasound findings considered as possibly caused by congenital fetal infections were analysed. Pregnancy outcomes for cases with confirmed maternal or fetal infections were studied. RESULTS: Four hundred and sixty-two maternal TORCH tests were performed. Of those, TORCH tests were also performed on fetal samples (amniotic fluid or fetal blood) in 67 cases. Fourteen fetal tests without maternal testing were identified, making the total number of patients tested 476. There were 11 cases of maternal CMV infection (2.3%), 10 cases of fetal CMV infection, and none of the other viruses. Indications for testing included fetal hyperechogenic bowel, hydrops, cerebral ventriculomegaly, echogenic foci, oligohydramnios, polyhydramnios, and IUGR. The most common findings to be actually associated with fetal infections were hyperechogenic bowel, ascites, cardiomegaly, and oligohydramnios. No cases were associated with polyhydramnious, while both IUGR and ventriculomegaly were always associated with other more relevant features. CONCLUSION: In the United Kingdom, complete maternal TORCH testing because of fetal findings on detailed scans is often not necessary. Testing can be limited only to CMV, particularly since other infectious agents, including toxoplasmosis, are uncommon in the United Kingdom. More understanding of the relevance of the different ultrasound features to congenital infections is also important.     

孕妇与胎儿巨细胞病毒感染的血清学研究

测定了１７３例孕妇及８１例胎儿血清ＣＭＶ抗体。结果：１７３例孕妇血清中ＣＭＶ－ＩｇＧ阳性率为７０．５％（１２２／１７３），ＣＭＶ－ＩｇＭ阳性率为０．５８％（１／１７３），孕妇早、中、晚孕期ＣＭＶ感染率分别为５２％、７２．９％，７４．４％，妊娠次数≥４次的孕妇ＣＭＶ感染率较高。８１例脐血血清中ＣＭＶ－ＩｇＧ阳性率为５４．３％（４４／８１），ＣＭＶ－ＩｇＭ阳性率为６．２％（５／８１），５例先天性ＣＭＶ感染儿分别为４例胎儿畸形及１例产前咨询者，后者取脐血查到ＩｇＭ阳性后１个月，胎死宫内。提示脐血中一旦查到ＣＭＶ－ＩｇＭ阳性，胎儿有严重后果。因此，产前诊断胎儿ＣＭＶ感染，早期发现ＣＭＶ感染儿，是非常重要的。     

Intracranial hemorrhage progressing to porencephaly as a result of congenitally acquired cytomegalovirus infection--an illustrative report

OBJECTIVE: To report ultrasound and magnetic resonance imaging (MRI) findings in a fetus with intracranial hemorrhage and porencephaly, presumed secondary to intrauterine cytomegalovirus (CMV) infection. METHODS: A 20-year-old, G2, P1 woman presented at 28.6 weeks' gestation after ultrasound examination demonstrated apparently isolated fetal ascites. Evaluation included maternal serology, amniocentesis, and repeated ultrasound examinations. Fetal MRI evaluation was also performed. The infant was born at 35 weeks' gestational age. RESULTS: Maternal serology was positive for CMV IgG. Intrauterine CMV infection was confirmed using polymerase chain reaction (PCR). At 31.6 weeks' gestation, ultrasound demonstrated borderline lateral cerebral ventriculomegaly. MRI of the fetal brain on the same day demonstrated parenchymal hemorrhage in the right posterior temporal and parietal regions along with mild ventricular enlargement. Sonography one day before delivery revealed brain parenchymal cystic change consistent with porencephaly of the right posterior temporal and parietal region. Postnatal ultrasound, computed tomography (CT), and MRI confirmed the diagnosis of a porencephalic cyst communicating with the posterior body of the right lateral ventricle. Placental pathology was consistent with CMV infection. CONCLUSION: This case report illustrates that fetal MRI is a useful adjunct in the evaluation of intrauterine infection with CMV.     

Cytomegalovirus (CMV) glycoprotein B genotype and CMV DNA load in the amniotic fluid of infected fetuses

OBJECTIVE: To assess the value of both cytomegalovirus (CMV) DNA quantification in amniotic fluid (AF) and CMV glycoprotein B (gB) genotype as prognostic factors in CMV congenital infection. METHODS: Quantification of CMV DNA was performed prospectively by real-time PCR and gB genotypes were analysed by gene sequencing analysis in the amniotic fluid of 42 fetuses infected by CMV. These were correlated with clinical data on fetal anomalies and outcome. RESULTS: The proportion of severely symptomatic fetuses was similar in each gB genotype group. Median CMV DNA load was higher in the group of symptomatic fetuses but this difference was not significant and high and low viral loads were found in both groups. CONCLUSION: Neither gB genotype nor CMV DNA load in AF correlate with the severity of CMV congenital infection and these markers are unlikely to prove useful for the management of congenital infection.     

Virus detection in the fetal tissue of a premature delivery with a congenital varicella syndrome. A case report

Cases of congenital varicella syndrome have been published, to date, a single case reports. Isolation attempts of Varicella-Zoster virus from fetal tissues have, thus far, been unsuccessful. This is a first report of detection of Varicella-Zoster virus in fetal tissue by means of DNA hybridization technique in a typical case of congenital varicella syndrome in a premature delivery of the 27th gestational week. The case is documented anamnestically, sonographically, pathologically and virologically. In women with primary varicella infection during pregnancy good sonographical controls are recommended. In cases with sonographically characteristical signs prenatal diagnosis with puncture of the umbilical vein cord and placentocentesis may be considered. The varicella DNA detection should be supplemented, however, by the polymerase chain reaction.