Showing papers on "Amniocentesis published in 2020"

The birth of a baby with mosaicism resulting from a known mosaic embryo transfer: a case report

Abstract: Mosaic embryos have the potential to implant and develop into healthy babies. The transfer of mosaic embryos is now considered to be a possible option for women undergoing ART with preimplantation genetic testing for aneuploidies and in the absence of euploid embryos, particularly those with diminished ovarian reserve and/or advanced maternal age. It can aid in avoiding the discard of potentially viable embryos, which might otherwise result in healthy babies. In over 500 studies on mosaicism, there have been no reports of mosaicism in babies born following the transfer of mosaic embryos. Here, we present a case report of a 39-year-old woman with diminished ovarian reserve with only one blastocyst available for trophectoderm biopsy. The transfer of the embryo, which showed 35% mosaicism of monosomy 2, resulted in pregnancy. Amniocentesis revealed a mosaic trisomic mos46,XX(98)/47,XX,+2(2) karyotype. There were no pathological findings in detailed ultrasonography, and the fetus showed a normal fetal growth with no evidence of intrauterine growth retardation. A healthy female baby was born at Week 37. The peripheral blood chromosome analysis validated with fluorescence in situ hybridization showed 2% mosaic monosomy 2 [mos45,XX,-2(2)/46,XX(98)]. This is the first reported case of true fetal mosaicism resulting in a live birth following the transfer of a known mosaic embryo. Worldwide, prenatal diagnosis has shown the depletion of mosaicism in embryos transferred after they have been reported as mosaics. Our case demonstrates the need for close prenatal monitoring and diagnosis by early amniocentesis, preferably at >14 weeks gestation.

Risk of fetal loss following amniocentesis or chorionic villus sampling in twin pregnancy: systematic review and meta-analysis.

Abstract: OBJECTIVE To assess the rate of fetal loss following amniocentesis or chorionic villus sampling (CVS) in twin pregnancy. METHODS MEDLINE, EMBASE and Cochrane databases were searched for studies reporting procedure-related complications following amniocentesis or CVS in twin pregnancy. The primary outcome was the rate of procedure-related fetal loss. The secondary outcomes were fetal loss occurring before 24 weeks of gestation and fetal loss occurring within 4 weeks after the procedure. Head-to-head meta-analyses were used to compare directly each outcome, between women undergoing amniocentesis and those not undergoing amniocentesis and between women undergoing CVS and those not undergoing CVS, and to compute pooled risk differences (RD) between women exposed and those not exposed to each invasive procedure. Additionally, meta-analyses of proportions were used to estimate the pooled rates of each of the three outcomes in women undergoing amniocentesis or CVS and in controls. RESULTS Sixteen studies (3419 twin pregnancies undergoing and 2517 not undergoing an invasive procedure) were included. Head-to-head meta-analyses comparing directly twin pregnancies undergoing and those not undergoing amniocentesis showed a higher risk for overall fetal loss in those undergoing amniocentesis (odds ratio (OR), 1.46 (P = 0.04); RD, 0.013 (P = 0.04)), while there was no difference in the risk of either fetal loss before 24 weeks of gestation (OR, 1.59 (P = 0.06); RD, 0.010 (P = 0.11)) or fetal loss within 4 weeks after the procedure (OR, 1.38 (P = 0.3); RD, 0.003 (P = 0.8)). Overall, the pooled rate of fetal loss was 2.4% (95% CI, 1.4-3.6%) in twin pregnancies undergoing amniocentesis compared with 2.4% (95% CI, 0.9-4.6%) in those not undergoing amniocentesis. Head-to-head meta-analyses directly comparing twin pregnancies undergoing and those not undergoing CVS showed no significant difference in either overall fetal loss (OR, 1.61 (P = 0.5); RD, 0.003 (P = 0.8)) or fetal loss before 24 weeks of gestation (OR, 1.61 (P = 0.5); RD, 0.003 (P = 0.8)). Overall, the pooled rate of fetal loss was 2.0% (95% CI, 0.0-6.5%) in twin pregnancies undergoing CVS compared with 1.8% (95% CI, 0.3-4.2%) in those not undergoing CVS. CONCLUSION The risk of fetal loss following amniocentesis and CVS in twins is lower than reported previously and the rate of fetal loss before 24 weeks of gestation, or within 4 weeks after the procedure, did not differ from the background risk in twin pregnancy not undergoing invasive prenatal testing. These data can guide prenatal counseling for twin pregnancies undergoing invasive procedures. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Non-invasive cell-free fetal DNA testing for aneuploidy: multicenter study of 31 515 singleton pregnancies in southeastern China.

Abstract: OBJECTIVE To analyze the non-invasive prenatal testing (NIPT) for aneuploidy results of 31 515 singleton pregnancies in Fujian province, southeastern China, and assess its performance in low-, moderate- and high-risk pregnancies. METHODS Women were categorized into groups according to whether their risk for fetal abnormality was low, moderate or high. Cell-free plasma DNA extracted from peripheral blood samples was subjected to low-coverage whole-genome sequencing. Standard Z-score analysis of the mapped sequencing reads was used to identify fetal aneuploidy, including the three main trisomies (T21, T18 and T13) and sex chromosome aneuploidy (SCA). NIPT-positive results were confirmed by amniocentesis and karyotyping. The performance of NIPT for detection of T21, T18, T13 and SCA was assessed by calculating the sensitivity and specificity. RESULTS The rate of chromosomal abnormality detected by NIPT in the study population was 1.38%. A higher rate of chromosomal abnormality was found in the high-risk group (1.57%) compared to the moderate-risk (1.05%) and low-risk (1.18%) groups (P < 0.05). Sensitivity and specificity, respectively, were 98.96% (95/96) and 99.94% (31 274/31 292) for detection of T21, 100% (25/25) and 99.96% (31 352/31 363) for T18, 100% (7/7) and 99.97% (31 373/31 381) for T13 and 100% (61/61) and 99.74% (31 245/31 327) for SCA. Positive predictive values were high for T21 (84.07%) and T18 (69.44%) and moderate for T13 (46.67%) and SCA (42.66%). CONCLUSION Our findings support the application of NIPT for reliable and accurate testing of the general population of reproductive-age women for clinically significant fetal aneuploidy. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Microarray and RASopathy-disorder testing in fetuses with increased nuchal translucency.

Abstract: Objectives To determine the incidence of chromosomal abnormalities, submicroscopic chromosomal abnormalities and RASopathy-disorder (RD) pathogenic variants in a cohort of pregnancies with nuchal translucency thickness (NT) ≥ 3.5 mm, and to propose a clinical protocol for surveillance of this group of patients. Methods This was a retrospective chart review of patients referred to The Prenatal Diagnosis and Medical Genetics Program at Mount Sinai Hospital between January 2013 and December 2015, due to NT ≥ 3.5 mm, who underwent chorionic villus sampling or amniocentesis. Patients underwent extensive genetic counseling prior to invasive procedures and testing. Quantitative fluorescence polymerase chain reaction (QF-PCR) was performed as the first-line test for aneuploidy. If the result was negative, patients underwent karyotyping and/or chromosomal microarray analysis (CMA), and if the findings were normal, they had testing for RD pathogenic variants, which included nine known genes. Patients also underwent detailed fetal ultrasound examinations and echocardiography, performed by expert operators. Results A total of 226 eligible patients were identified. In 116/226 (51.3%) patients, QF-PCR identified a chromosomal aneuploidy. The remaining 110/226 (48.7%) patients had further genetic testing. Karyotyping/CMA detected an abnormal/pathogenic cytogenetic result in 9/110 (8.2%) patients, as well as five variants of unknown significance (VOUS). RD testing yielded three pathogenic variants (3/103), giving a detection rate of 2.9%, and one VOUS. The optimal NT cut-off for RD screening was 7.9 mm in this population. In 92/110 (83.6%) patients, the genetic investigations were normal. Of these pregnancies, an early (14-16 weeks' gestation) detailed fetal ultrasound examination identified a structural abnormality in 24 (26.1%), 15 (16.3%) had an abnormal detailed ultrasound examination at 18-22 weeks' gestation and fetal echocardiography showed a cardiac abnormality in nine (9.8%). The birth outcome in the 83 pregnancies that had normal genetic investigations and known outcome included seven (8.4%) cases of termination of pregnancy, seven (8.4%) cases of intrauterine fetal death and 69 (83.1%) cases of live birth. Nine (9.8%) patients were lost to follow-up. Conclusions Both CMA and molecular testing for RD are important investigations in pregnancies with NT ≥ 3.5 mm. The use of genetic testing combined with fetal ultrasound examination provides valuable information that can influence pregnancy outcome, and provide recurrence risks, in this patient population. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

High false-positive non-invasive prenatal screening results for sex chromosome abnormalities: Are maternal factors the culprit?

Abstract: Objective To explore the impact of maternal sex chromosome aneuploidies (SCAs) and copy number variation (CNV) on false-positive results of non-invasive prenatal screening (NIPS) for predicting foetal SCAs. Methods In total, 22 844 pregnant women were recruited to undergo NIPS. Pregnant women with high-risk of SCAs underwent prenatal diagnosis and maternal copy number variation sequencing (CNV-seq). Results Among 117 women with high-risk of SCAs, 72 accepted prenatal diagnosis, 86 accepted maternal CNV-seq, and 21 had maternal sex chromosome abnormalities. The abnormality rate was significantly higher than women at low-risk of SCAs (24.42% vs 3.51%). Using a novel parameter cffDNA (ChrX)/cffDNA, when the ratio was greater than 2, all foetuses had normal karyotype, and 75.0% (6/8) had abnormal maternal chromosome X. If the ratio was less than or equal to 2, only 10% (4/40) of the mothers had chromosome X CNV alterations, while 33.3% (13/40) of their foetuses had sex chromosomes CNV abnormalities. Conclusions Approximately 25% of pregnant women with SCAs predicted by NIPS had sex chromosome abnormalities as determined by CNV-seq. The ratio of cffDNA (ChrX)/cffDNA can tentatively distinguish the maternal or foetal origin of abnormal cell-free DNA. In a reanalysis of previous NIPS data, false-positive results caused by maternal CNV might be elucidated.

Risk of Miscarriage following Amniocentesis or Chorionic Villus Sampling: Systematic Review of Literature and Updated Meta-analysis

Abstract: Objectives: To estimate the procedure-related risks of miscarriage after amniocentesis and trans-abdominal chorionic villus sampling (CVS) based on a systematic review of the literature and an updated meta-analysis. Methods: A search of MEDLINE, EMBASE, and The Cochrane Library was carried out to identify studies reporting complications following CVS or amniocentesis. The inclusion criteria for the systematic review were studies reporting results from large controlled studies and those reporting data for pregnancy loss prior to 24 weeks’ gestation. Study authors were contacted when required to identify additional necessary data. Data for cases that had invasive procedure and controls groups were inputted in contingency tables and risk of miscarriage was estimated for each study. Summary statistics based on a fixed and random effects model were calculated after taking into account the weighting for each study included in the systematic review. Procedure-related risk of miscarriage was estimated as a weighted risk difference from the summary statistics for cases and controls. A subgroup analyses according to the similarity risk levels in the invasive testing and control groups was performed. Heterogeneity was assessed using Cochrane’s Q and I2 statistic. Egger Bias was estimated to assess reporting bias in published studies. Summary statistics for procedure-related risk of miscarriage were graphically represented in Forest plots. Results: The electronic search from the databases yielded 2,943 potential citations, from which, we selected 20 controlled studies for inclusion in the systematic review to estimate the procedure-related risk of miscarriage from invasive procedures. There were a total of 580 miscarriages from 63,273 amniocentesis procedures with a weighted risk of pregnancy loss of 0.91% (95%CI: 0.73 to 1.09). In the control group, there were 1,726 miscarriages in 330,469 pregnancies with a loss rate of 0.58% (95CI%: 0.47 to 0.70). The weighted procedure-related risk of miscarriage was 0.30% (95%CI: 0.11 to 0.49, I2=70.1%). There were a total of 163 miscarriages from 13,011 CVS procedures with a risk of pregnancy loss of 1.39% (95%CI: 0.76 to 2.02). In the control group, there were 1,946 miscarriages in 232,680 pregnancies with a loss rate of 1.23% (95CI%: 0.86 to 1.59). The weighted procedure-related risk of miscarriage following CVS was 0.20% (95%CI: -0.12 to 0.52, I2=51.9%). However, when only studies with similar risk profiles between the intervention and control groups were considered, the procedure related risk for amniocentesis became 0.03% (95%CI -0.08 to 0.14, I2=0%) and for CVS -0.38 (95% CI -1.12 to 0.36, I2=0%). Conclusion: The procedure-related risks of miscarriage following amniocentesis and CVS are lower than currently quoted to women. The risk appears to be negligible when these interventions are compared to control groups of the same risk profile.

The current and future impact of genome-wide sequencing on fetal precision medicine

Abstract: Next-generation sequencing and other genomic technologies are transforming prenatal and reproductive screening and testing for fetal genetic disorders at an unprecedented pace. Original approaches of screening and testing for fetal genetic and genomic disorders were focused on a few more prevalent conditions that were easily diagnosable with pre-genomic era diagnostic tools. First, chromosomal microarray analysis and then next-generation sequencing brought technology capable of more detailed genomic evaluation to prenatal genetic screening and diagnosis. This has facilitated parallel introduction of a variety of new tests on maternal blood samples, including expanded carrier screening and cell-free DNA-based non-invasive screening for fetal aneuploidy, selected copy number variants, and single-gene disorders. Genomic tests on fetal DNA samples, obtained primarily through amniocentesis or chorionic villus sampling, include chromosomal microarray analysis and gene panel and exome sequencing. All these form the diagnostic pillar of the emerging field of fetal precision medicine, but their implementation is associated with ethical, counseling and healthcare resource utilization challenges. We discuss where in the reproductive and prenatal care continuum these exciting new technologies are integrated, along with associated challenges. We propose areas of priority for research to gain the data in support of their responsible implementation into clinical reproductive and prenatal care.

New approach for estimating risk of miscarriage after chorionic villus sampling.

Abstract: OBJECTIVE To estimate the risk of miscarriage associated with chorionic villus sampling (CVS). METHODS This was a retrospective cohort study of women attending for routine ultrasound examination at 11 + 0 to 13 + 6 weeks' gestation at one of eight fetal-medicine units in Spain, Belgium and Bulgaria, between July 2007 and June 2018. Two populations were included: (1) all singleton pregnancies undergoing first-trimester assessment at Hospital Clinico Universitario Virgen de la Arrixaca in Murcia, Spain, that did not have CVS (non-CVS group); and (2) all singleton pregnancies that underwent CVS following first-trimester assessment at one of the eight participating centers (CVS group). We excluded pregnancies diagnosed with genetic anomalies or major fetal defects before or after birth, those that resulted in termination and those that underwent amniocentesis later in pregnancy. We used propensity score (PS) matching analysis to estimate the association between CVS and miscarriage. We compared the risk of miscarriage of the CVS and non-CVS groups after PS matching (1:1 ratio). This procedure creates two comparable groups balancing the maternal and pregnancy characteristics that are associated with CVS, in a similar way to that in which randomization operates in a randomized clinical trial. RESULTS The study population consisted of 22 250 pregnancies in the non-CVS group and 3613 in the CVS group. The incidence of miscarriage in the CVS group (2.1%; 77/3613) was significantly higher than that in the non-CVS group (0.9% (207/22 250); P < 0.0001). The PS algorithm matched 2122 CVS with 2122 non-CVS cases, of which 40 (1.9%) and 55 (2.6%) pregnancies in the CVS and non-CVS groups, respectively, resulted in a miscarriage (odds ratio (OR), 0.72 (95% CI, 0.48-1.10); P = 0.146). We found a significant interaction between the risk of miscarriage following CVS and the risk of aneuploidy, suggesting that the effect of CVS on the risk of miscarriage differs depending on background characteristics. Specifically, when the risk of aneuploidy is low, the risk of miscarriage after CVS increases (OR, 2.87 (95% CI, 1.13-7.30)) and when the aneuploidy risk is high, the risk of miscarriage after CVS is paradoxically reduced (OR, 0.47 (95% CI, 0.28-0.76)), presumably owing to prenatal diagnosis and termination of pregnancies with major aneuploidies that would otherwise have resulted in spontaneous miscarriage. For example, in a patient in whom the risk of aneuploidy is 1 in 1000 (0.1%), the risk of miscarriage after CVS will increase to 0.3% (0.2 percentage points higher). CONCLUSIONS The risk of miscarriage in women undergoing CVS is about 1% higher than that in women who do not have CVS, although this excess risk is not solely attributed to the invasive procedure but, to some extent, to the demographic and pregnancy characteristics of the patients. After accounting for these risk factors and confining the analysis to low-risk pregnancies, CVS seems to increase the risk of miscarriage by about three times above the patient's background risk. Although this is a substantial increase in relative terms, in pregnancies without risk factors for miscarriage, the risk of miscarriage after CVS remains low and similar to, or slightly higher than, that in the general population. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Application of chromosome microarray analysis in prenatal diagnosis

Abstract: To explore the application value of chromosomal microarray analysis (CMA) in prenatal diagnosis. The results of chromosome karyotype analysis and CMA of 477 cases undergoing amniocentesis were analyzed. The results of the no ultrasound abnormality group and the ultrasound abnormality group were compared separately. Within the ultrasound abnormality group, the results of the ultrasound structural malformation group, the ultrasound soft index abnormality group, and other ultrasound abnormality (including abnormal amniotic fluid volume and fetal growth restriction) groups were compared. Abnormal chromosome and CMA results were found in a total of 71 cases (15.88%, 71/447), which can be broken down into a total of 23 karyotype abnormalities (5.15%, 23/447), consisting of 18 cases of aneuploidy (4.03%, 18/447), 2 cases of unbalanced chromosome rearrangements (0.44%, 2/447), and 3 cases of chimerism (0.67%, 3/447); 17 cases with detection of pathogenic copy number variations (pCNVs) (3.80%, 17/447); and 31 cases of detection of clinical variants of unknown significance (VOUS) (6.93%, 31/447). CMA detected 3.8% more genetic abnormalities than karyotype analysis (in addition to the abnormalities detected simultaneously by karyotype analysis). Between the no ultrasound abnormality group and the ultrasound abnormality group, there was an extremely significant difference in the detection rate of an abnormal chromosomal karyotype (P 0.05). Comparing the ultrasound structural malformation group, the ultrasound soft index abnormality group, and the other ultrasound abnormality group, there were no significant differences in the detection rate of abnormal chromosomal karyotypes (P > 0.05), pCNV (P > 0.05) or VOUS (P > 0.05). The detection rate of chromosomal karyotype abnormalities in prenatal diagnosis in cases with no ultrasound abnormalities was higher. For cases with fetal ultrasound structural abnormalities, when compared with traditional karyotype analysis, CMA can improve the detection rate of fetal genetic abnormalities. However, the no ultrasound abnormality group also had a high VOUS abnormality detection rate, so it is necessary to strictly define the CMA indications.

Application value of NIPT for uncommon fetal chromosomal abnormalities.

Abstract: To investigate the clinical value of noninvasive prenatal testing (NIPT) for fetal chromosomal deletion, duplication, and sex chromosome abnormalities. The study included 6239 pregnant women with singletons in the first and second trimester of pregnancy who received NIPT from December 2017 to June 2019. For pregnant women at high risk of deletion, duplication, and sex chromosome abnormalities indicated by NIPT, amniocentesis was recommended for karyotype analysis and chromosome copy number variation detection to verify the NIPT results and analyze chromosome abnormalities. Women at low risk and with no other abnormal results continued with their pregnancies. Among the 6239 pregnant women who received NIPT, there were 15 cases of chromosomal deletion (12 cases confirmed by amniocentesis), 16 cases of chromosomal duplication (9 cases confirmed by amniocentesis), and 17 cases of sex chromosome abnormalities (11 cases confirmed by amniocentesis). Of these cases, 32 were finally confirmed by amniotic fluid cell karyotype analysis. The coincidence rate was 66.7% (32/48). There were no abnormalities found for the remaining low risk pregnant women during follow-up. NIPT has good application value in predicting fetal chromosomal deletion, duplication, and sex chromosome abnormalities. It can improve the detection rate of fetal chromosomal abnormalities, but further prenatal diagnosis is needed.

Identification and management of congenital parvovirus B19 infection.

Abstract: Parvovirus B19 (B19V) infection is well known for its mild, self-limiting clinical presentations in children, such as erythema infectiosum. Approximately 40% of women of childbearing age are susceptible to B19V infection. While maternal B19V infection usually has a good prognosis, B19V can cause severe fetal anaemia and pregnancy loss due to its ability to suppress erythroid progenitor cells. Non-invasive ultrasound monitoring for fetal anaemia is usually performed if maternal seroconversion occurs in the first 20 weeks of gestation, with amniocentesis for fetal infection reserved for those who first present with fetal anaemia or hydrops of unknown cause. Intrauterine transfusion is the standard treatment for severe fetal anaemia and is associated with a significant improvement in survival. However, survivors of hydrops fetalis may have a higher rate of long-term neurodevelopmental complications compared with non-hydropic survivors. This review aims to synthesise published data on the diagnosis, surveillance and outcomes of congenital parvovirus infection to assist clinicians in diagnosing and managing this important condition.

Fetal cardiac rhabdomyomas treated with maternal sirolimus.

Abstract: Objective To review the pathophysiology of rhabdomyomas and the emerging option of prenatal treatment of fetal cardiac rhabdomyomas. Methods We present a case of fetal rhabdomyomas causing significant hemodynamic compromise that received in utero treatment of maternal sirolimus. Genetic amniocentesis confirmed a TSC2 mutation. A treatment program was initiated with a 10-mg loading dose titrated to a goal maternal trough of 10 to 15 ng/dL. In order to follow fetal cardiac function, a sophisticated method of speckle tracking echocardiography was used before and after treatment. Obstetric ultrasound was used to monitor fetal growth, and clinical surveillance, echocardiography, and brain MRI were used to monitor postnatal growth and development through 6 months of neonatal life. Results Sirolimus was initiated from 28 to 36 weeks of gestation with improvement of cardiac status. During this period, intrauterine growth restriction developed. Postnatally, the infant has had stable rhabdomyomas and cardiac function without reinitiating sirolimus. Brain MRI demonstrated scattered cortical tubers and subependymal nodules, and the infant has not had seizure-like activity. At 6 months of age, the infant has achieved appropriate developmental milestones. Conclusion In counseling cases of prenatal onset large obstructing rhabdomyomas and cardiac compromise, in utero sirolimus treatment can be considered.

Maternal Consistency in Recalling Prenatal Experiences at 6 Months and 8 Years Postnatal

Abstract: Objective Mothers are known to be reliable reporters of smoking during pregnancy, type of delivery, and birth weight when compared with medical records. Few studies have considered whether the timing of retrospective collection affects the mother's retrospective self-report. We examined the consistency of maternal retrospective recall of prenatal experiences, behaviors, and basic birth outcomes between 6 months and 8 years postpartum. Method We examined 117 mothers (62% White, 44% living in a committed relationship, median high school education) from the Early Growth and Development Study (EGDS). EGDS is a longitudinal adoption study that includes birth mothers of children born between 2003 and 2009 who were involved in a domestic adoption. Using the modified life history calendar and a pregnancy screener, mothers reported on their prenatal health behaviors, prenatal substance use, and labor and delivery at 6 months and 8 years postpartum. Cohen κ was calculated to examine consistency, and χ tests were used to test differences by parity and maternal education. Results Mothers' recall was very good for recall of the type of delivery and good for smoking during pregnancy, medicine used for labor induction, and specific medical problems (i.e., pre-eclampsia, sexually transmitted infections, and kidney infections). Recall consistency was poor for illicit drug use, specific prenatal tests performed (i.e., amniocentesis and emergency room visits), and using drugs other than an epidural during delivery. Conclusion This study provides support for using retrospective collection of maternal self-report on some prenatal experiences up to 8 years postpartum and offers a potential way to more accurately collect self-reported prenatal experiences.

Prenatal diagnosis of mosaicism for trisomy 12 in a single colony at amniocentesis in a pregnancy with a favorable outcome

Abstract: Objective We present prenatal diagnosis of mosaicism for trisomy 12 in a single colony at amniocentesis with a favorable outcome. Case report A 36-year-old woman underwent amniocentesis at 18 weeks of gestation because of advanced maternal age. Amniocentesis revealed a karyotype of 47,XY,+12[1]/46,XY[14]. In 15 colonies of cultured amniocytes, all three cells in one colony had the karyotype of 47,XY,+12, while the rest 14 colonies had the karyotype of 46,XY. The parental karyotypes were normal. Prenatal ultrasound findings were unremarkable. Polymorphic DNA marker analysis using the DNAs extracted from cultured amniocytes and parental bloods excluded uniparental disomy (UPD) 12. At 37 weeks of gestation, a healthy 2,828-g male baby was delivered with no phenotypic abnormality. The cord blood had a karyotype of 46,XY in 40/40 lymphocytes. Postnatal interphase fluorescence in situ hybridization (FISH) analysis on buccal cells and urinary cells revealed normal signals in 72/72 buccal cells, and trisomy 12 signals in 1/47 (2.1%) urinary cells compared with 0% (0/75 cells) of trisomy 12 signals in the normal control. Conclusion Mosaicism for trisomy 12 in a single colony at amniocentesis without UPD 12 and fetal ultrasound abnormalities can be associated with a favorable outcome.

Chromosomal microarray analysis in prenatal diagnosis: ethical considerations of the Belgian approach

Abstract: Detection of genetic aberrations in prenatal samples, obtained through amniocentesis or chorion villus biopsy, is increasingly performed using chromosomal microarray (CMA), a technique that can uncover both aneuploidies and copy number variants throughout the genome. Despite the obvious benefits of CMA, the decision on implementing the technology is complicated by ethical issues concerning variant interpretation and reporting. In Belgium, uniform guidelines were composed and a shared database for prenatal CMA findings was established. This Belgian approach sparks discussion: it is evidence-based, prevents inconsistencies and avoids parental anxiety, but can be considered paternalistic. Here, we reflect on the cultural and moral bases of the Belgian reporting system of prenatally detected variants.

Clinical chorioamnionitis criteria are not sufficient for predicting intra-amniotic infection.

Abstract: Aim: To evaluate the diagnostic performance of three conventional clinical chorioamnionitis criteria; including Gibbs, Lencki, and suspected triple I; for the prediction of intra-amniotic infection...

Next-generation sequencing: a follow-up of 36,913 singleton pregnancies with noninvasive prenatal testing in central China.

Abstract: To evaluate the noninvasive prenatal testing (NIPT) results of 36,913 cases in Jiangxi province of central China and explore its application value in prenatal screening and diagnosis. This retrospective analysis included 36,913 singleton pregnant women who underwent NIPT because of moderate-/high-risk pregnancy or voluntary requirements between January 2017 and December 2019 in our hospital. Chromosomal abnormalities such as trisomies 21, 18, and 13 (T21, T18, T13) and sex chromosome aneuploidies (SCAs) were judged by standard Z-score analysis. Positive NIPT results were confirmed by amniocentesis and karyotyping. Pregnancy outcomes were followed up via telephone interview. A total of 1.01% (371/36,913) positive cases were detected by NIPT, comprising 137, 46, 31, and 157 cases of T21, T18, T13, and SCAs, respectively. A total of 116 of T21, 27 of T18, 13 of T13, and 51 of SCAs were confirmed to be true positive; all normal cases that had been followed up were verified to be true negative. The NIPT sensitivity in T21, T18, T13, and SCAs was 100.00% individually, whereas the specificity was 99.94% (36,488/36,509), 99.95% (36,579/36,598), 99.95% (36,594/36,612), and 99.72% (36,472/36,574), respectively. Furthermore, the negative predictive values of T21, T18, T13, and SCAs were all 100%, while the positive predictive values were 84.67%, 58.70%, 41.94%, and 33.33%, respectively. NIPT is highly sensitive and has a low false positive rate in testing clinically significant fetal aneuploidies of general reproductive women. However, this technique cannot substitute for amniocentesis and karyotyping, and detailed genetic counseling is also essential for the high-risk group of NIPT.

Chromosomal abnormalities after ICSI in relation to semen parameters: results in 1114 fetuses and 1391 neonates from a single center.

Abstract: STUDY QUESTION Is there a relationship between karyotype abnormalities in fetuses and children conceived by ICSI and their father's semen parameters? SUMMARY ANSWER The de novo chromosomal abnormality rate in pre- and postnatal karyotypes of ICSI offspring was higher than in the general population and related to fathers' sperm parameters. WHAT IS KNOWN ALREADY Several studies have reported a higher rate of de novo chromosomal anomalies in ICSI fetuses but recent data from large cohorts are limited. Overall, reported prevalences of non-inherited karyotype aberrations are increased in fetuses conceived after ICSI and vary between 1.6% and 4.2%. Only a few studies focus on the relation between karyotype anomalies in ICSI offspring and semen parameters of their fathers. Furthermore, an increased incidence of abnormal karyotypes in ICSI neonates has been described, but the rates vary widely across studies. STUDY DESIGN, SIZE, DURATION We report on karyotype results from prenatal testing by means of chorionic villus sampling and amniocentesis and results from postnatal blood sampling in offspring conceived by ICSI in a single center. Ongoing pregnancies resulting from an oocyte retrieval between January 2004 and December 2012 and after transfer of fresh ICSI embryos obtained using ejaculated or non-ejaculated sperm (fresh or frozen-thawed) were considered. Pregnancies following frozen embryo transfer, oocyte or sperm donation, IVF, preimplantation genetic testing and IVM were excluded. All abnormal prenatal results after sampling are reported irrespective of the outcome of the pregnancy. PARTICIPANTS/MATERIALS, SETTING, METHODS From the 4816 ongoing ICSI pregnancies, information on pregnancy outcome was available for 4267 pregnancies. Prenatal testing was performed in 22.3% of the pregnancies, resulting in a diagnosis in 1114 fetuses. A postnatal karyotype was obtained in 29.4% of the pregnancies in which no invasive prenatal diagnosis was performed, resulting in a total of 1391 neonates sampled. The prevalence of chromosomal anomalies according to maternal age and semen quality was analyzed with logistic regression. For definitions of normal semen quality, the World Health Organization reference values for human semen characteristics were adopted. MAIN RESULTS AND THE ROLE OF CHANCE An abnormal fetal karyotype was found in 29 singletons and 12 multiples (41/1114; 3.7%; 95% CI 2.7-4.9%): 36 anomalies were de novo (3.2%; 95% CI 2.3-4.4), either numerical (n = 25), sex (n = 6) or structural (n = 5), and five were inherited. Logistic regression analysis did not show a significant association between maternal age and a de novo chromosomal fetal abnormality (odds ratio (OR) 1.05; 95% CI 0.96-1.15; P = 0.24). In all but one case, fetuses with an abnormal karyotype were conceived by ICSI using ejaculated sperm.Abnormal karyotypes were found in 14 (1.0%; 95% CI 0.6-1.7) out of 1391 postnatal samples of children born after ICSI who were not tested prenatally: 12 were de novo anomalies and two were inherited balanced karyotypes. The 14 abnormal karyotypes were all found in children born after ICSI using ejaculated sperm.The odds of a de novo karyotype aberration increased with maternal age when combining pre- and postnatal data (OR 1.11; 95% CI 1.04-1.19). A higher rate of de novo chromosomal abnormalities was found in fetuses and children of couples with men having a sperm concentration <15 million/ml (adjusted OR (AOR) 2.10; 95% CI 1.14-3.78), sperm concentration <5 million/ml (AOR 1.9; 95% CI 1.05-3.45) and total sperm count <10 million (AOR 1.97; 95% CI 1.04-3.74). LIMITATIONS, REASONS FOR CAUTION We cannot exclude that the observation of a higher prevalence of karyotype anomalies in ICSI offspring compared to literature data in the general population is due to enhanced surveillance after ART given the lack of a control group. Although we did not find more chromosomal anomalies after ICSI with non-ejaculated sperm, the small numbers do not allow firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS The observed increased risk of a de novo karyotype anomaly after ICSI conception in couples with poor sperm warrants continued counseling toward prenatal testing.The current and widespread use of innovative non-invasive prenatal testing will result in larger datasets, adding to a balanced estimation of the prevalence of karyotype anomalies in ICSI offspring. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by the Methusalem grants issued by the Vrije Universiteit Brussel. All authors declared no conflict of interest related to this study. TRIAL REGISTRATION NUMBER N/A.

Revisiting short- and long-term outcome after fetal first-trimester primary cytomegalovirus infection in relation to prenatal imaging findings

Abstract: OBJECTIVE To determine the short- and long-term outcome of pregnancies with proven first-trimester fetal cytomegalovirus (CMV) infection in a large prospective cohort. METHODS This was a prospective cohort study of pregnancies with documented primary maternal CMV infection in the first trimester and evidence of fetal infection, referred for further evaluation between January 2011 and January 2018. Maternal serological diagnosis of primary CMV infection was documented by seroconversion. Vertical CMV transmission was identified by amniocentesis with polymerase chain reaction (PCR) for the CMV genome. After birth, fetal infection was re-tested by PCR in neonatal urine or saliva samples. All patients underwent serial prenatal ultrasound scans and fetal magnetic resonance imaging (MRI) at 32-33 weeks' gestation. All neonates underwent ocular fundus examination, an ultrasound brain scan and hearing evaluation, and were followed periodically for a median of 2 years (range, 6 months to 10 years). Follow-up information was obtained from hospital charts and by telephone interviews with parents. The CMV-associated outcomes assessed were sensorineural hearing loss (SNHL), neurodevelopmental abnormality, composite clinical outcome (including SNHL and neurodevelopmental abnormality) and composite outcome (additionally including termination of pregnancy (TOP)). The association between prenatal ultrasound or MRI findings and abnormal outcome was assessed. RESULTS Primary CMV infection in the first trimester occurred in 123 patients. The rate of an abnormal ultrasound finding was 30.9%, and the rate of an abnormal MRI finding was 30.1% overall and 14.1% in the subgroup of patients with normal ultrasound. Of the 85 patients with normal ultrasound, 12 had an abnormal MRI finding, of whom five (5.9%) had true anatomical findings. Fifteen patients decided to terminate the pregnancy owing to abnormal prenatal findings on either ultrasound or MRI. Overall, the rate of CMV-associated postnatal and childhood sequelae was 27.8%, with a rate of 16.7% for SNHL and 11.1% for neurodevelopmental abnormalities, mostly slight motor or verbal delay. Approximately half of the cases with CMV-associated sequelae did not have any abnormal prenatal imaging findings. Abnormal prenatal findings on ultrasound were not associated significantly with SNHL, neurodevelopmental delay or composite clinical outcome (P = 0.084, 0.109 and 0.176, respectively), but they were associated with the composite outcome including TOP (P < 0.001). We identified a non-significant trend for a higher rate of SNHL in the group with abnormal ultrasound than in those with normal ultrasound. For abnormal MRI findings, we found a correlation only with neurodevelopmental abnormality and composite outcome (P = 0.014 and P < 0.001, respectively). CONCLUSIONS The risk of childhood sequelae after first-trimester fetal CMV infection is most often associated with abnormal prenatal imaging findings. However, normal imaging does not rule out the development of SNHL and minor neurodevelopmental abnormalities. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Vaginal metabolome: towards a minimally invasive diagnosis of microbial invasion of the amniotic cavity in women with preterm labor

Abstract: Microbial invasion of the amniotic cavity (MIAC) is only identified by amniocentesis, an invasive procedure that limits its clinical translation. Here, we aimed to evaluate whether the vaginal metabolome discriminates the presence/absence of MIAC in women with preterm labor (PTL) and intact membranes. We conducted a case-control study in women with symptoms of PTL below 34 weeks who underwent amniocentesis to discard MIAC. MIAC was defined as amniotic fluid positive for microorganisms identified by specific culture media. The cohort included 16 women with MIAC and 16 control (no MIAC). Both groups were matched for age and gestational age at admission. Vaginal fluid samples were collected shortly after amniocentesis. Metabolic profiles were analyzed by nuclear magnetic resonance (NMR) spectroscopy and compared using multivariate and univariate statistical analyses to identify significant differences between the two groups. The vaginal metabolomics profile of MIAC showed higher concentrations of hypoxanthine, proline, choline and acetylcholine and decreased concentrations of phenylalanine, glutamine, isoleucine, leucine and glycerophosphocholine. In conclusion, metabolic changes in the NMR-based vaginal metabolic profile are able to discriminate the presence/absence of MIAC in women with PTL and intact membranes. These metabolic changes might be indicative of enhanced glycolysis triggered by hypoxia conditions as a consequence of bacterial infection, thus explaining the utilization of alternative energy sources in an attempt to replenish glucose.

Identifying the potential protein biomarkers of preterm birth in amniotic fluid.

Abstract: Objective Preterm birth severely threatens neonatal health and life. Although the detailed mechanism of preterm birth is not well understood, accurately predicting preterm birth can help people make preparations in advance, greatly reducing the subsequent health risk of neonates. Therefore, in this study, we aimed to identify potential protein biomarkers of preterm birth in amniotic fluid (AF). Materials and methods We first enrolled pregnant subjects and collected their AF samples when they underwent amniocentesis at the second trimester of gestation. After delivery, the collected AF samples were classified into a full-term birth (sample size n = 21) set or preterm birth (n = 36) set, followed by 2-D DIGE and MS/MS assays. Results By doing so, we identified seven potential protein biomarkers of preterm birth, three of which were further validated in all samples with ELISA, including Apolipoprotein A-IV (Apoa4), Lumican (Lum) and Kininogen-1 (Kng1). As a result, all three potential biomarkers were significantly differently expressed between preterm and full-term birth AF samples. Furthermore, without prior classification, we found that these three biomarkers were positively correlated with gestation age (correlation coefficient ranging from 0.25 to 0.38) and were able to predict the occurrence of preterm birth. Conclusion In this study, by examining amniotic fluid, we identified three biomarker proteins that may facilitate the identification of preterm birth. There three proteins were never reported to be related to preterm birth. Their pathogenesis roles in preterm birth deserve further investigations by using in vitro cell model or in vivo animal model assays.

Genetic diagnosis in the fetus.

Abstract: Many genetic disorders are detectable in the prenatal period, and the capacity to identify them has increased remarkably as molecular genetic testing techniques continue to improve and become incorporated into clinical practice. The indications for prenatal genetic testing vary widely, including follow-up of an anomaly found by routine ultrasound or maternal aneuploidy screening, a family history of genetic disease, advanced maternal or paternal age, or evaluation of a low-risk pregnancy due to parental concern. The interpretation of genetic variants identified in the prenatal period poses unique challenges due to the lack of ability for deep phenotyping as well as the option to make critical decisions regarding pregnancy continuation and perinatal management. In this review, we address the various modalities currently available and commonly used for genetic testing, including preimplantation genetic testing of embryos, cell-free DNA testing, and diagnostic procedures such as chorionic villous sampling, amniocentesis, or percutaneous umbilical blood sampling, from which samples may be sent for a wide variety of genetic tests. We discuss the difference between these modalities for the genetic diagnosis of a fetus, their strengths and weaknesses, and strategies for their optimal use in order to direct perinatal care.