Prenatal diagnosis and outcome of congenital cytomegalovirus infection in twin pregnancies

OBJECTIVE: To study the outcome of 20 twin pregnancies with evidence of primary or recurrent cytomegalovirus (CMV) infection during pregnancy. DESIGN: Observational study. SETTING: Two tertiary perinatal departments in Israel. POPULATION: Twenty women with twin pregnancies who were referred because of serologic investigation indicating CMV infection. Seventeen women had evidence of primary CMV infection, and three women appeared to have recurrent CMV infection. METHODS: Prenatal diagnosis was made by amniocentesis of both sacs after 21 weeks of gestation. CMV isolation was performed by culture on fibroblasts, shell vial technique and polymerase chain reaction (PCR) amplification of CMV DNA. After birth, the neonatal urine and saliva were cultured for CMV. MAIN OUTCOME MEASURES: Intrauterine CMV infection defined as positive PCR at amniotic fluid analysis and congenital CMV infection defined as positive CMV cultures after birth. RESULTS: Except for one, all women underwent amniocentesis of both gestational sacs. In 14 (70%) women, no evidence of vertical transmission to any of the 28 fetuses was found and none of the newborns had evidence of congenital CMV infection. Intrauterine infection was detected by amniocentesis in five women and by ultrasound findings with positive maternal serology in one. In three women, CMV was detected in only one amniotic sac. In five of our six total cases, both twins were found to have congenital CMV infection at birth, all of whom had dichorionic-diamniotic placentation, three fused and two separate. CONCLUSIONS: In twin gestations, as in singletons, intrauterine and congenital CMV infection occurs in about 30% of women with primary or recurrent infection. The placenta type did not predict if one or both twins would be infected. Our data do not exclude the possibility that intrauterine transmission of the virus from one fetus to the other can occur.     

Prenatal diagnosis of congenital cytomegalovirus infection

OBJECTIVE: To assess prospectively the diagnostic reliability and prognostic significance of prenatal diagnosis of cytomegalovirus (CMV) infection. METHODS: One hundred ten pregnant women (four with twin pregnancies) with a risk of congenital CMV infection were investigated. Prenatal diagnosis was carried out by amniocentesis and fetal blood sampling (n = 75) or amniocentesis alone (n = 35). Serial ultrasonographic examinations were performed from time of referral until pregnancy end. All infected neonates were given long-term follow-up. Autopsy was performed in all cases of termination of pregnancy. RESULTS: Nearly 23% (26 of 114) of fetuses were infected and prenatal diagnosis was positive in 20 cases. Sensitivity of prenatal diagnosis was 77% and specificity 100%. In eight cases, parents requested termination of pregnancy on the basis of abnormal ultrasonographic findings and/or biologic abnormalities in fetal blood. In 12 cases, parents decided to proceed with the pregnancy. In this group, one intrauterine and one neonatal death were observed. In one case, prenatal diagnosis revealed an abnormal cerebral sonography and the infant had bilateral hearing loss at birth. In 15 cases (nine positive and six false-negative prenatal diagnoses), no apparent lesion was present at birth, nor did it develop during the follow-up period (mean 31 months). In 88 (77.2%) of 114 infants, no evidence of vertical transmission was found during the pre- or postnatal period. CONCLUSION: Prenatal diagnosis provides the optimal means for both diagnosing fetal infection (amniocentesis) and identifying fetuses at risk of severe sequelae (ultrasound examination, fetal blood sampling), thus allowing proper counseling.     

Prenatal diagnosis of symptomatic congenital cytomegalovirus infection

OBJECTIVE: The aim of this study was to evaluate whether the amniotic viral load of mothers with primary cytomegalovirus infection correlate with fetal or neonatal outcomes. STUDY DESIGN: Sixty-eight of 138 pregnant women with primary infection defined by immunoglobulin G seroconversion or the presence of immunoglobulin M with low immunoglobulin G avidity accepted amniocentesis. Polymerase chain reaction and quantitative polymerase chain reaction were used to detect amniotic fluid cytomegalovirus. Cytomegalovirus infection in neonates was determined by means of urinary viral isolation during the first week after birth or the histologic examination of tissue from aborted fetuses. RESULTS: Cytomegalovirus infection was found in 16 fetuses and neonates (23%), 5 of whom had symptoms. Quantitative polymerase chain reaction showed that the presence of >/=10(3) genome equivalents predicted mother-child infection with 100% probability; >/=10(5) genome equivalents predicted the development of a symptomatic infection. CONCLUSION: Fewer than expected cytomegalovirus-infected fetuses are at risk for development of cytomegaloviral disease, and this fact may be useful in counseling pregnant women with primary cytomegalovirus infection.     

Prenatal diagnosis of congenital cytomegalovirus infection: two decades later

Cytomegalovirus is the most common cause of congenital infection in the United States, yet there has been little progress in the prenatal diagnosis of this intrauterine infection. We present evidence that viral culture of amniotic fluid may be a useful adjunct procedure, when performed as part of the antenatal evaluation of suspected fetal cytomegalovirus infection.     

Prenatal diagnosis of congenital malformations in 500 pregnancies

The organization, techniques used and diagnostic findings of 500 prenatal diagnoses are reported in detail. In 15 cases the pregnancy was terminated because of abnormal laboratory findings. Follow-up of the remaining pregnancies revealed a perinatal mortality of 1.7%, and the risk of an abortion induced by amniocentesis, performed in the 15–16th wk, to be 1–2%. Serious counseling problems arose in 2 cases with trisomy X, in 2 instances of a balanced chromosome translocation and in 1 case of a de novo translocation.     

Prenatal diagnosis of human cytomegalovirus by culture and polymerase chain reaction: 98 pregnancies leading to congenital infection.

Human cytomegalovirus (HCMV) is the most common cause of viral intra-uterine infection. The experience with prenatal diagnosis remains limited and is based on few reports of small numbers of cases. It is thus difficult to compare the accuracy of the different tests because the groups studied were small and heterogeneous. We describe here our experience on a series of 98 pregnancies leading to HCMV congenital infection, among which 71 have been tested by amniotic fluid (AF) sampling followed by culture and/or polymerase chain reaction (PCR). Independently of the delay between AF sampling and the first HCMV IgM positive result, the mean sensitivity of both culture and PCR was around 70 per cent. The best sensitivity (95.5 per cent) was obtained after a delay > or = 6 weeks in late pregnancy (> or = 23 weeks). The present study demonstrated clearly that the delay between AF puncture and the presumed date of seroconversion is more important for sensitivity than the technique used for the diagnosis (PCR or culture). However, even in the best diagnostic conditions, negative results of HCMV culture or PCR in AF cannot formally exclude intra-uterine infection.     

Prenatal diagnosis of fetal primary cytomegalovirus infection

Objective To determine the reliability of prenatal diagnosis for congenital cytomegalovirus in women with primary infection.
Design Retrospective analysis of case records between 1992 and 1997.
Setting Fetal medicine unit of a large teaching hospital.
Population Forty-two pregnant women with primary cytomegalovirus infection.
Methods Fetal diagnosis was made by amniocentesis for viral culture and amplification of cytomegalovirus DNA by polymerase chain reaction (   n = 37  ), or by cordocentesis for the detection of cytomegalovirus -specific IgM antibodies (   n = 13  ). All patients had serial ultrasonographic scans in order to detect those fetuses with abnormalities that could be associated with cytomegalovirus infection.
Results Fourteen pregnancies (33.3%) had evidence of vertical transmission. Nine out of 14 (64.3%) had positive amniotic fluid culture, while 11 (78.6%) had positive polymerase chain reaction results. The combination of both tests allowed antenatal diagnosis in 12 of the 14 infected fetuses (sensitivity 85.7%). All women who underwent cordocentesis for the detection of cytomegalovirus-specific IgM antibodies had negative results, but in two cases cytomegalovirus infection was detected by amniotic fluid studies. In five of the infected fetuses there were abnormal ultrasonographic findings. All pregnancies with evidence of vertical transmission were terminated and the remainder proceeded normally to term.
Conclusions Our data showed that amniotic fluid studies, preferably polymerase chain reaction amplification of viral DNA, are the best diagnostic tools for the detection of vertical transmission in pregnancies with primary cytomegalovirus infection. For women with positive amniotic fluid studies who elect to continue their pregnancies, cordocentesis and serial ultrasound scans may be useful for assessment of fetal status.     

Prenatal diagnosis of fetal cytomegalovirus infection.

Twelve fetuses were evaluated with a combination of ultrasonography, amniocentesis, and blood sampling for possible cytomegalovirus infection. In seven the mother had a documented primary cytomegalovirus infection. All seven women had normal ultrasonographic findings and one fetus was found to be infected. In the other five cases fetal cytomegalovirus infection was diagnosed in association with abnormal ultrasonographic findings. There was no history of maternal infection in the latter group. All positive and negative diagnoses were confirmed and none of the six infected fetuses survived. In this series, the most reliable parameters of infection were the isolation of the virus from amniotic fluid and elevations of total immunoglobulin M and gamma-glutamyl transpeptidase in fetal blood. In the majority of infected fetuses cytomegalovirus-specific immunoglobulin M was not detected in blood. Prenatal diagnosis of fetal cytomegalovirus infection is possible with a combination of amniocentesis and fetal blood sampling.     

Prenatal diagnosis of fetal cytomegalovirus infection after primary or recurrent maternal infection

OBJECTIVE: To determine the reliability of prenatal diagnosis of cytomegalovirus infection in women with primary or recurrent infection. METHODS: Amniotic fluid (AF) samples from 117 pregnant women were evaluated for cytomegalovirus culture and cytomegalovirus-DNA detection. Neonatal and postnatal samples also were examined to confirm or exclude transmission of maternal-fetal cytomegalovirus infection. RESULTS: Of 25 women with primary cytomegalovirus infection, 13 (52%) had cytomegalovirus-positive AF samples by polymerase chain reaction (PCR), nine of which also were diagnosed by culture. All eight neonates born to mothers whose AF was cytomegalovirus-positive by PCR and culture were cytomegalovirus infected, and three were symptomatic. One aborted fetus had cytomegalovirus-DNAemia. Of four women with cytomegalovirus-positive AF samples by PCR only, two delivered asymptomatic cytomegalovirus-infected neonates and two aborted (one fetus had cytomegalovirus encephalopathy). Of 45 mothers with recurrent infection, two with AF cytomegalovirus-positive by PCR and culture, and another with cytomegalovirus-positive AF samples by PCR only, aborted cytomegalovirus-DNA-positive fetuses. Of the other seven women with cytomegalovirus-positive AF samples by PCR only, two delivered asymptomatic cytomegalovirus-infected neonates, two delivered neonates cytomegalovirus-positive by PCR only (one was symptomatic), and three delivered infants cytomegalovirus-negative by PCR and culture. All 47 mothers with nonactive cytomegalovirus infection and cytomegalovirus-negative AF samples had uninfected neonates. Polymerase chain reaction was superior to viral culture in sensitivity and negative predictive value (100% compared with 57% and 94%, respectively) but was lower in specificity and positive predictive value (97% and 83%, respectively, compared with 100%). CONCLUSION: Prenatal diagnosis of fetal cytomegalovirus infection should include PCR in addition to viral culture, particularly for congenital cytomegalovirus infections following maternal recurrence.     

Prenatal diagnosis and outcome of multiple pregnancies with reversed arterial perfusion (TRAP-sequence)

Objectives

We analyse the prenatal detection and pregnancy outcome of twin reversed arterial perfusion syndrome (TRAP-sequence) in monochorionic twin pregnancies.

Methods

We included all cases in which the prenatal diagnosis of a TRAP-sequence had been established and reviewed the prenatal, obstetrical, and pathological records of the acardiac twin as well as the neonatal/pediatric records of the donor twin. Minimal follow-up for the donor twin after birth was 6?months.

Results

We detected six cases of TRAP-sequence in 412 examined monochorionic multiple pregnancies (incidence 1.46%) Mean gestational age at diagnosis was 20.4 (13.1?C28.0) gestational weeks. All donor twins survived without detectable mid- or long-term sequelae. There was neither missed prenatal diagnosis nor a false-positive diagnosis of TRAP-sequence. Mean birthweight of the acardiac twins was 1,400?g (830?C2800?g). There was an uneventful medical history in the maternal records of all included women. Fetal karyotype was available for 5/6 twin-pairs, all revealing a normal distribution of the chromosomes. All acardiac twins had post-mortem examination with specification of the subtypes of acardiac twin displaying 3/6 acardius acephalus, 2/6 acardius amorphus, and 1/6 acardius anceps.

Conclusions

The antenatal diagnosis of TRAP-sequence is feasible and can be established during the first-trimester-screening. The discrimination of the adequate time to end the pregnancy, though a crucial concern, remains a challenging question. Future studies should address this topic.     

Prenatal diagnosis in multiple pregnancies.

Multiple pregnancy, with its high rate of fetal loss and increasing incidence, merits greater clinical attention and research. Prenatal diagnosis in multiple pregnancy poses particular difficulties in terms of safety and technique of invasive procedures, interpretation of laboratory results, and the human dilemmas produced by the demonstration of discordant abnormality. Recent applications of ultrasound, including Doppler ultrasound, are also discussed in the context of the monochorionic placenta, prediction of preterm labor, and detection of intrauterine growth retardation.     

Prenatal diagnosis for multiple pregnancies

In multiple pregnancies, first trimester ultrasound is crucial to diagnose chorionicity, to detect major structural defects, and to screen for chromosomal abnormalities based on nuchal translucency measurement. The efficacy of nuchal translucency measurement screening in twins might be improved when combined with first trimester maternal serum screening. In twins as in singletons, the risk of fetal loss attendant to chorionic villi sampling and to amniocentesis are similar. When an invasive procedure is indicated in twins, chorionic villi sampling has, over amniocentesis, the advantage of allowing selective termination to be performed in the first trimester, when the procedure related risk of miscarriage is minimal. It has the disadvantage of leading to ambiguous results in up to 2% of cases. While chorionic villi sampling is the choice technique in pregnancies at very high risk, amniocentesis is still indicated in cases at more moderate risk. In monochorionic pregnancies, selective termination can now be performed using a variety of techniques including bipolar or monopolar cord coagulation, and, in acardiac twins, alcohol ablation. However, selective termination remains more hazardous in monochorionic than in dichorionic pregnancies. The outcome of the twin-to-twin transfusion syndrome has been substantially improved by laser photocoagulation of placental shunts and by amniodrainage, but randomized trials are needed to establish the optimal therapeutic strategy, and further pathophysiologic research might result in new treatments.     

Prenatal screening and diagnosis in multiple pregnancies

Multiple pregnancies account for 1.5% of pregnancies in the UK and both aneuploidies and structural anomalies occur more frequently in twins, compared to singletons. Comprehensive, individualised counselling is key in these challenging situations, requiring clinicians to communicate their knowledge of prenatal screening effectively.Prenatal screening and diagnosis is not straightforward in multiple pregnancies with variable performance of screening tests, choices to be made on diagnostic techniques and sampling, limited robust data on procedure-related risks and potentially complex decision-making in light of results. In this article we will address these issues and provide an up-to-date evidence summary derived from national guidance and published literature.     

先天性巨细胞病毒感染的围生儿预后

目的探讨先天性巨细胞病毒(HCMV)感染围生儿的预后.方法 1996年1月至2004年8月,中山大学附属二院对HCMV活动性感染孕妇的23例先天感染儿及35例非感染儿,于出生时至8岁进行体格和神经系统发育的随访.1、6个月时应用聚合酶链反应(PCR)检测尿HCMV DNA.结果 HCMV先天感染儿畸形、发育商(DQ)落后、听力(BAEP)异常率显著高于非先天感染儿(P<0.05).结论先天性HCMV感染可能导致胎儿畸形,并对智力及听力有远期影响.应加强围生期管理,减少先天感染儿出生,随访感染儿并及早干预.     

Prenatal ultrasound diagnosis, follow-up, and outcome of congenital varicella syndrome

OBJECTIVES: To report on a case of fetal varicella infection following the diagnosis of maternal infection at 16 weeks of gestation. METHODS: Diagnosis was based on serology testing and prenatal ultrasound, confirmed by DNA detection in amniotic fluid (Lightcycler-PCR). Serial ultrasound examinations were performed. RESULTS: Sonographic anomalies included borderline ventriculomegaly, intracerebral, intrahepatic and myocardial calcifications, limb deformities, articular effusions, and intrauterine growth retardation (confirmed postpartally). The newborn showed a severe encephalopathy and could not be stabilized sufficiently. The child died 23 days after birth. CONCLUSION: The outcome of an affected fetus may be very serious and prenatal ultrasound is a helpful tool to recognize the severity of the infection.     

Outcome of pregnancies with vertical transmission of primary cytomegalovirus infection

OBJECTIVE: To study the outcome of 50 pregnancies with documented vertical transmission of cytomegalovirus infection. METHODS: We recruited 50 pregnant women (51 fetuses) with primary cytomegalovirus infection and confirmed in utero transmission. Prenatal evaluation included diagnostic amniocentesis and repeated ultrasound examinations. Fetal diagnosis was made after 21 weeks' gestation by amniocentesis and based on virus isolation by culture, shell vial, and polymerase chain reaction (PCR). Cytomegalovirus infection in neonates was determined by urinary viral isolation after birth or histologic examination of tissue from aborted fetuses. Cerebral ultrasound, hearing assessment, and psychomotor development were investigated for all 18 live-born neonates. RESULTS: Thirty-three of the 50 women (66%) elected termination of pregnancy. Ultrasonographic abnormalities associated with in utero fetal infection were observed in 11 (21.5%) fetuses. Two of them continued to term; both were congenitally infected, and one had neurologic abnormalities. The positive predictive values of the PCR and virus isolation assessments performed in all 50 pregnancies (51 gestational sacs) were 92% and 93.7%, respectively. Seventeen pregnancies (18 fetuses) continued to term: four fetuses had neurologic abnormalities, of which three had normal prenatal ultrasound findings. The remaining 14 had normal neonatal assessments. CONCLUSION: Positive isolation of cytomegalovirus accompanied by positive PCR values in amniotic fluid provided approximately 94% certainty of in utero cytomegalovirus infection. The risk of postnatal neurologic abnormalities was 19% (three of 16) when there were no prenatal ultrasonographic abnormalities.     

Treatment of symptomatic congenital cytomegalovirus infection with valganciclovir

Cytomegalovirus (CMV) is the most common cause of congenital infection in humans. Some congenitally infected infants will develop sequelae later in life, especially sensorineural hearing loss (SNHL) and mental retardation. There is no generally accepted antiviral therapy for the treatment of symptomatic congenital CMV infections yet. We present a neonate with symptomatic congenital CMV infection, who was treated with intravenous (iv) ganciclovir (GCV) during 18 days and subsequently with oral valganciclovir (VGCV) for 5.5 months, in an attempt to prevent development of SNHL. GCV was given intravenously 10 mg/kg/day in two doses and VGCV doses ranged from 280-850 mg/m2 bidaily (bid). Our experience shows that it is not possible to give a fixed dosing regime for VGCV in neonates and that continuous adaptation of dose is necessary to achieve stable target levels of GCV and to keep the viral load in urine at undetectable level. At 18 months of age no hearing deterioration has occurred. While the current findings are encouraging, the limitations of a single case report with a relatively short follow-up emphasizes the need for further prospective randomized studies to evaluate pharmacokinetics, efficacy and safety of VGCV therapy in neonates with congenital CMV infection.     

Prenatal diagnosis of congenital toxoplasmosis

Ninety-three pregnant women with Toxoplasma gondii seroconversion during pregnancy underwent prenatal diagnosis of fetal toxoplasmosis. The following tests were used: (1). amniocentesis for mouse inoculation (93 subjects), (2). amplification of T. gondii DNA by polymerase chain reaction (PCR) (79 subjects), and (3). cordocentesis for the detection of T. gondii-specific IgM antibodies (13 subjects). All patients had serial ultrasonographic scans to detect those fetuses with abnormalities that could be associated with congenital toxoplasmosis. Eighteen pregnancies (19.4%) had evidence of vertical transmission. A total of 11/18 (61.1%) had positive amniotic mouse inoculation test, while 10/12 (83.3%) had positive PCR results. The combination of both tests allowed the prenatal diagnosis in 17/18 infected fetuses (94.4%). All patients who underwent cordocentesis for the detection of T. gondii-specific IgM antibodies had negative results. However, in two of the above cases fetal toxoplasmosis was detected by amniotic fluid studies. In five of the infected fetuses there were abnormal ultrasonographic findings. All pregnancies with evidence of vertical transmission were terminated, whereas the remaining pregnancies proceeded normally to term. The present data showed that amniotic fluid studies, preferably PCR amplification of T. gondii DNA, are the best diagnostic tools for the detection of vertical transmission in pregnancies with seroconversion during pregnancy.