Congenital cytomegalovirus infection among twin pairs

Objective: The purpose of this study was to describe the fetal/neonatal cytomegalovirus (CMV) status according to chorionicity and outcome in twin pregnancies diagnosed with CMV.

Methods: An opportunistic diagnosis of CMV infection was performed in a tertiary referral center. All cases diagnosed in twin pregnancies (2006–2011) were included. Prenatal diagnosis was performed by CMV-DNA in the amniotic fluid (AF) of both fetuses only on the evidence of sonographic findings in either one or both twins. Neonatal screening was selectively assessed in symptomatic newborns, preterm, and infants born to HIV-infected mothers. Congenital infection was considered in the presence of CMV-DNA in AF, fetal tissues or newborn urine within the first 2 weeks of life, and symptomatic disease with clinical findings at birth or autopsy.

Results: A total of six twin pregnancies with congenital CMV infection were diagnosed, five dichorionic and one monochorionic diamniotic. Only one sibling was infected among dichorionic pregnancies, two diagnosed prenatally, and three after birth. In the monochorionic pregnancy, the diagnosis was performed prenatally and the two fetuses were infected and severely damaged.

Conclusions: Congenital CMV infection in twins might be related, among other factors, to chorionicity, and in DC twins a non-concordant infection can be expected.     

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.     

双胎妊娠产前诊断取样技术评估

产前诊断取样技术对双胎染色体异常的精准诊断必不可少。文章从双胎介入性产前诊断的标识系统、操作要点、术后相关风险及取样技术间的优劣对比等方面进行综述,为临床医生相关咨询及处理提供参考。     

双胎妊娠非整倍体异常的产前筛查与产前诊断

双胎妊娠非整倍体产前筛查较单胎复杂。应在早孕期确定孕周、绒毛膜性并测量颈项透明层厚度。早孕期联合筛查优于中孕期血清学筛查,但检出率明显低于单胎妊娠。无创产前检查用于双胎筛查仍需更多研究数据。双胎之一胚胎停育将影响早孕期筛查的准确性。产前诊断时区分标记双胎是需要注意的重要问题。     

Non-invasive prenatal screening of fetal Down syndrome by maternal plasma DNA sequencing in twin pregnancies

Non-invasive prenatal screening for fetal Down syndrome (NIFTY) by maternal plasma sequencing was performed in 12 subjects with twin pregnancies, including 11 with normal fetuses and 1 with discordant fetal Trisomy 21. For every sample, it was processed, sequenced and reported as soon as it was collected as other clinical samples for singleton pregnancies. The NIFTY test was negative in the 11 pregnancies carried normal fetuses, and was positive (high risk) in the case with discordant fetal Trisomy 21. The sensitivity and specificity were both 100%. This small case series suggested the NIFTY as a screening test for fetal Trisomy 21 is feasible in twin pregnancies.     

DNA-positive,IgM-negative symptomatic congenital cytomegalovirus infection: Two case reports

The characteristics of two newborns that had clinical symptoms of congenital cytomegalovirus have been presented here, whose CMV-DNA was found to be positive by the PCR method, despite serological analysis being negative for CMV IgM. In conclusion, when congenital CMV infection is suspected in newborns, it should not be forgotten that the sensitivity of serological CMV IgM assay is 70% and other methods such as CMV-DNA analysis should be performed in case of negative test results.     

孕期TORCH感染产前筛查、诊断和临床咨询

弓形虫、风疹病毒、巨细胞病毒及疱疹病毒是最常见的引起孕妇感染的病原体,可经胎盘垂直传播导致胎儿宫内感染,最终造成胎儿及新生儿结构的畸形及神经系统的损伤。尽管目前可以对上述先天性感染进行产前筛查和诊断,但尚缺乏统一的临床咨询及诊治指南。文章主要对近年来在上述先天性感染产前筛查、诊断和临床咨询领域的最新进展进行阐述。     

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.     

A comparison of maternal and perinatal outcome between in vitro fertilization and spontaneous dichorionic-diamniotic twin pregnancies

Objective: To compare the maternal and neonatal outcome of dichorionic diamniotic in vitro fertilization (IVF) twin and spontaneous twin pregnancies.

Material and methods: Maternal and fetal data of all consecutive dichorionic-diamniotic twin pregnancies delivered in our institution between January 2009 and May 2015 were abstracted from medical records and pregnancy outcome of IVF twin was compared to spontaneous twin.

Results: Overall 708 twin pregnancies (449 IVF and 259 spontaneous) were included. Women in the IVF group were 2 years older and more frequently nulliparous. The rate of pregnancy induced hypertension and preeclampsia (PIH/PET) was three times higher in the IVF group than in the spontaneous group. The rate of preterm births, before 37 weeks of gestation and the rate of cesarean section were higher in the IVF group. These results were confirmed by multivariate analysis. The neonatal outcome was similar in both the groups except for a lower mean newborn birthweight in the IVF group.

Conclusion: Women with IVF twins are at a significantly higher risk of having preterm births, PIH/PET and cesarean section but there was no significant adverse effect on neonatal outcome except for a lower mean newborn birth weight.     

Preeclampsia in twin pregnancies: association with selective intrauterine growth restriction

Objective: To identify the association between preeclampsia (PE) and selective intrauterine growth restriction (sIUGR) in twin pregnancies.

Methods: This was a retrospective cohort study of 1004 twin pregnancies from 2008 to 2014. We specifically compared the incidence, clinical characteristics and outcomes of PE between sIUGR and normal-growth twin pregnancies.

Results: PE occurred more frequently in sIUGR pregnancies [29.0% (51/176)] than in normal-growth twin pregnancies [13.1% (99/756), p?<?0.001, adjusted odds ratio 3.29]. Among sIUGR, the incidence of PE was significantly higher in dichorionic (DC) pregnancies (37.5%, 30/80) than in monochorionic (MC) pregnancies (21.9%, 21/96). The rates of onset at <32 weeks (p?=?0.045) and of severe PE (p?=?0.025) were higher in sIUGR pregnancies with PE. The systolic blood pressure was also higher in sIUGR pregnancies with PE (152.6?±?11.8?mmHg) than in normal-growth pregnancies with PE (148.0?±?8.2?mmHg) (p?=?0.042). Additionally, more sIUGR pregnancies were delivered at 32–36 weeks (p?=?0.001), and fewer were delivered at ≥36 weeks (p?<?0.001). Moreover, the prevalence of severe neonatal asphyxia was higher in sIUGR pregnancies with PE than in normal-growth pregnancies with PE (8.8% versus 2.5%, p?=?0.020).

Conclusions: sIUGR is associated with increased odds of developing severe PE in twin pregnancies, leading to poorer perinatal outcomes.     

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.     

双胎妊娠染色体异常的产前筛查及产前诊断

双胎妊娠发生胎儿畸形、染色体异常的风险较单胎妊娠高。近年来双胎妊娠发生率和高龄产妇数量不断增加,双胎妊娠的早期筛查以及产前诊断十分重要。早孕期,颈项透明层(nuchal translucency,NT)超声筛查是重要手段,不建议单独使用血清学筛查;中孕期超声结构筛查对检出胎儿结构异常有一定意义。无创产前基因检测技术的发展,对降低侵入性产前诊断的风险有重要意义,但由于目前临床证据尚不充分,双胎妊娠行无创基因检测仍需谨慎。     

Prenatal diagnosis of cord entanglement in monoamniotic multiple pregnancies

Monoamniotic (MA) twins occur in about 2-5% of monochorionic (MC) pregnancies. The condition is characterized by late splitting of the developing embryo at around 8-9 days after fertilization and may also occur in higher-order multiples. During the first trimester, ultrasound diagnosis in MC-MA twins is based on visualization of only a single aniotic cavity without an intertwin membrane, and can be confirmed by the presence of only one yolk sac. The visualization of cord entanglement confirms the diagnosis at any stage of pregnancy, and has important implications for further management. Criteria for the proper diagnosis of MC-MA multiple gestation and cord entanglement are given.     

Perinatal outcomes with intrahepatic cholestasis of pregnancy in twin pregnancies

Objective: To describe perinatal outcomes of twin pregnancies complicated by intrahepatic cholestasis of pregnancy (ICP).

Methods: We conducted a retrospective cohort study of women delivered at a large tertiary obstetric center in Shanghai, China from January 2006 to May 2014. Delivery data were abstracted from medical records of all twin gestations delivered at the hospital.

Results: A total of 129/1922(6.7%) twin and 1190/92?273 singleton (1.3%) pregnancies were complicated by ICP. An increased risk of stillbirth among twin pregnancies was observed (3.9% and 0.8% in the ICP and non-ICP groups, respectively; aOR 5.75, 95% CI 2.00–16.6). Stillbirths with ICP and twins occurred between 33 and 35 weeks gestation compared to 36–38 weeks gestation among singletons. ICP in twins was also associated with an increased risk of preterm birth (<37 weeks) with an aOR of 4.17 (95% CI 2.47–7.04) and an aOR of 1.89 (95% CI 1.26–2.85) for delivery <35 weeks. Twin pregnancies complicated by ICP also had increased meconium staining of amniotic fluid and lower birth weight.

Conclusions: Twin pregnancies with ICP have significantly increased risks of adverse perinatal outcomes including stillbirth and preterm birth. Stillbirth occurs at an earlier gestational age in twin gestation compared to singletons, suggesting that earlier scheduled delivery should be considered in these women.     

Prevention and treatment of fetal cytomegalovirus infection with cytomegalovirus hyperimmune globulin: a multicenter study in Madrid

Introduction: Cytomegalovirus (CMV) is the leading cause of congenital infection worldwide. Data about the management of CMV infection in pregnant women are scarce, and treatment options are very limited. The aim of the study is to investigate the effectiveness of cytomegalovirus hyperimmune globulin (CMV-HIG) for the prevention and treatment of congenital CMV (cCMV) infection.

Materials and methods: A retrospective observational study was conducted in three tertiary hospitals in Madrid. In the period 2009–2015, CMV-HIG (Cytotect^® CP Biotest, Biotest) treatment was offered to all pregnant women with primary CMV infection and/or detection of CMV-DNA in amniotic fluid in participating centers. Women were divided into prevention and treatment groups (PG and TG, respectively). Those with primary CMV infection who had not undergone amniocentesis comprised the PG and received monthly CMV-HIG (100 UI/kg). If CMV-DNA was subsequently detected in amniotic fluid, one extra dose of CMV-HIG (200 UI/kg) was given 4 weeks after the last dose. Those women were considered to be part of the PG group despite detection of CMV-DNA in amniotic fluid. In the case of a negative result in CMV-DNA detection in amniotic fluid or if amniocentesis was not performed, monthly HIG was given up to the end of the pregnancy.

Results: Thirty-six pregnant women were included. Median gestational age at birth was 39 weeks (interquartile range: 38–40) and two children (5.5%) were premature (born at 28 and 34 weeks’ gestation). Amniocentesis was performed in 30/36 (83.4%) pregnancies and CMV PCR was positive in 21 of them (70%). One fetus with a positive PCR in amniotic fluid that received one dose of HIG after amniocentesis presented a negative CMV-PCR in urine at birth, and was asymptomatic at 12 months of age. Twenty-four children were infected at birth, and 16/21 (76.2%) presented no sequelae at 12 months, while two (9.5%) had a mild unilateral hearing loss and three (14.3%) severe hearing loss or neurological sequelae. Seventeen women were included in the PG and 19 in the TG. In the PG 7/17 (41%) fetuses were infected, one pregnancy was terminated due to abnormalities in cordocentesis and one showed a mild hearing loss at 12 months of age. In the TG, 18/19 children (95%) were diagnosed with cCMV, while the remaining neonate had negative urine CMV at birth. Eight out of the 19 fetuses (42.1%) showed CMV related abnormalities in the fetal US before HIG treatment. Complete clinical assessment in the neonatal period and at 12 months of age was available in 16 and 15 children, respectively. At birth 50% were symptomatic and at 12 months of age, 4/15 (26.7%) showed a hearing loss and 3/15 (20%) neurologic impairment. Fetuses with abnormalities in ultrasonography before HIG presented a high risk of sequelae (odds ratios: 60; 95%CI: 3–1185; p?=?.007).

Discussion: Prophylactic HIG administration in pregnant women after CMV primary infection seems not to reduce significantly the rate of congenital infection, but is safe and it could have a favorable effect on the symptoms and sequelae of infected fetuses. The risk of long-term sequelae in fetuses without US abnormalities before HIG is low, so it could be an option in infected fetuses with normal imaging. On the other hand, the risk of sequelae among infected fetuses with abnormalities in fetal ultrasonography before HIG despite treatment is high.     

Prenatal diagnosis and cesarean section in a large,population-based birth defects registry

Objective.?To describe the patterns of cesarean section (CS) and vaginal delivery by type of birth defect and determine whether prenatal diagnosis predicts a higher or lower likelihood of CS for selected defect categories.

Methods.?Data from a large population-based registry were analyzed to determine percentages of vaginal versus CS delivery for each of 49 categories of birth defects. Odds ratios and statistical significance were computed to determine if a record of prenatal diagnosis (PND) predicted delivery mode. Cases were liveborn children with any of these defects born in Texas between 1997 and 2005.

Results.?Forty-three percent of infants in the study were delivered by CS, with a range of 25.3% (aniridia) to 62.4% (spina bifida). A record of prenatal diagnosis of the primary assigned birth defect was found in 43.0% of all records but varied substantially by defect category. PND significantly predicted higher CS percentages for spina bifida without anencephaly, encephalocele, hydrocephaly, transposition of the great vessels, ventricular septal defect, pulmonary valve atresia/stenosis, craniosynostosis, diaphragmatic hernia, gastroschisis, and trisomy 21. Vaginal delivery was predicted by PND of anencephaly, agenesis, aplasia, or hypoplasia of the lung, renal agenesis or dysgenesis, and trisomy 18.

Conclusion.?Texas children with birth defects are more likely to have been delivered by CS than the population in general. For several types of defects, prenatal diagnosis is predictive of higher odds of CS; for others, especially fatal defects, PND predicts lower CS likelihood.     

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.