PCR vs karyotype for CVS and amniocentesis—the experience at one tertiary fetal medicine unit

Purpose Despite the rise of non-invasive screening tests for fetal aneuploidy, invasive testing during pregnancy remains the definitive diagnostic tool for fetal genetic anomalies. Results are rapidly available with polymerase chain reaction (PCR) tests, but cases have been reported whereby initial results were not confirmed after pregnancy termination and the fetal karyotype was ultimately normal. We sought to examine the potential discordance between PCR and karyotype for fetal aneuploidy. Methods The results from all amniocentesis and CVS tests performed over a 6-year period in a large tertiary level fetal medicine unit were reviewed. The results of PCR and karyotype were recorded and discrepancies examined. Pregnancy outcomes were also recorded. Results A total of 1222 invasive tests were performed (716 amniocentesis and 506 CVS). Within the cohort having amniocentesis, 11 had discrepant results (normal QF-PCR result but with a subsequent abnormal karyotype). There was 1 case among this group which QF-PCR should have identified. Within the CVS group, 7 patients had discrepant results. All had a diploid QF-PCR and would not have been identified as abnormal by it. Conclusion PCR can be reliably used to determine aneuploidy of chromosomes 13, 18, and 21. However, in cases of sex chromosome aneuploidy, its performance is less reliable and warrants waiting for a complete karyotype. Given such discordance, we advise waiting for karyotype for all invasive tests performed in the presence of a normal ultrasound before advising a patient of a diploid QF-PCR result or potentially terminating a normal pregnancy.

Isolated Upward Rotation of the Fetal Cerebellar Vermis (Blake’s Pouch Cyst) Is a Normal Variant: An Analysis of 111 Cases

<b><i>Introduction:</i></b> The objective of the study was to provide more detailed data about fetal isolated upward rotation of the cerebellar vermis rotation (Blake’s pouch cyst) in particular regarding pregnancy outcome. <b><i>Methods:</i></b> This is a retrospective study of all cases of fetal isolated upward rotation of the cerebellar vermis (URCV) diagnosed in 3 referral centers in Italy from January 2009 to November 2019. Whenever possible, prenatal magnetic resonance imaging (MRI) was performed and a fetal karyotype was obtained. A detailed follow-up was obtained by consultation of medical records, interview with the parents, and the pediatricians. <b><i>Results:</i></b> Our study population included 111 patients with a prenatal diagnosis of isolated URCV made at a median gestational age of 21 weeks +3 days (interquartile range (IQR) 21 + 0–22 + 2). The median brain stem-vermis (BV) angle was 27° (IQR 24–29°). In 37.9% of the cases, a regression of the finding with restoration of normal anatomy was noted at a follow-up scan or at postnatal checks. A BV angle of 25° or less predicted regression with a probability in excess of 90%. MRI was performed in utero or at birth in 101 patients and always confirmed sonographic diagnosis. Fetal CGH array and/or karyotype was available in 97 cases and was always normal, but in 1 case. A postnatal follow-up was available in 102 infants (mean 7 months, range 0–10 years of age) and documented a normal neurologic development in all the cases. <b><i>Conclusions:</i></b> Isolated URCV is most likely a normal variant of fetal anatomy without clinical consequences, at least at an early follow-up. A BV angle of 25° or less predicts intrauterine regression of the finding, but the outcome is good in all the cases. When a confident sonographic diagnosis is made, MRI is not mandatory. The risk of a chromosomal anomaly in these cases is probably low.

Prenatal Screening of Trisomy 21: Could Oxidative Stress Markers Play a Role?

Despite significant progress in trisomy 21 (T21) diagnostic tools, amniocentesis is still used for the confirmation of an abnormal fetal karyotype. Invasive tests carry the potential risk of miscarriage; thus, screening biomarkers are commonly used before undergoing invasive procedures. In our study, we investigated the possible application of oxidative stress markers in the prenatal screening of trisomy 21. The DNA/RNA oxidative stress damage products (OSDPs), advanced glycation end (AGE) products, ischemia-modified albumin (IMA), alfa-1-antitrypsin (A1AT), asprosin, and vitamin D concentrations were measured in both maternal plasma and amniotic fluid in trisomy 21 (T21) and euploid pregnancies. The obtained results indicated increased levels of DNA/RNA OSDPs and asprosin with simultaneous decreased levels of vitamin D and A1AT in the study group. The diagnostic utility of the plasma measurement based on the area under the received operative characteristic (ROC) curve (AUC) calculation of asprosin (AUC = 0.965), IMA (AUC = 0.880), AGE (AUC = 0.846) and DNA/RNA OSDPs (AUC = 0.506) in T21 screening was demonstrated. The obtained results indicate a potential role for the application of oxidative stress markers in the prenatal screening of T21 with the highest screening utility of plasma asprosin.

Clinical Utility of Increased Nuchal Translucency at 11–13 Weeks of Gestation in Twin Pregnancies Based on the Chorionicity

To assess clinical implications of increased nuchal translucency (INT) in twin pregnancies based on the chorionicity. This was a retrospective review of the twin pregnancies who underwent first trimester ultrasound with nuchal translucency (NT) measurement at 11–13 weeks of gestation from January 2006 to December 2014. Data were collected using the OB database and the chart review. Pregnancy outcomes, including gestational weeks at the delivery, abnormal fetal karyotypes, fetal structural anomalies, and twin-specific complications, were analyzed. A total of 1622 twin pregnancies with INT ≥ 95th percentile in one or both fetuses were identified. In all twin pregnancies with INT, abnormal fetal karyotypes were identified in 17 (8.6%) patients (odds ratio = 13.28, CI = 5.990–29.447, p = 0.000) and twin-specific complications were identified in 23 (11.6%) patients (odds ratio = 2.398, CI = 1.463–3.928, p = 0.001) compared to those with normal NT. Among the INT group, when the groups were subdivided into monochorionic (MC) and dichorionic (DC) pregnancies, 14.8% and 29.6% of the MC pregnancies had structural anomalies in one or both fetuses (odds ratio = 5.774, 95% CI = 1.445–23.071, p = 0.01) and twin-specific complications (odds ratio = 4.379, 95% CI = 1.641–11.684, p = 0.03), respectively, compared to DC pregnancies with 2.9% for structural anomalies and 8.8% for twin-specific complications. The prevalence of abnormal fetal karyotypes was not statistically different in patients with INT when compared between MC and DC pregnancies (p = 0.329). INT was associated with a higher rate of twin-specific complications and fetal structural anomalies in MC twin pregnancies rather than abnormal fetal karyotype. Therefore, NT measurement in MC twin pregnancies can be a useful tool for predicting adverse pregnancy outcomes. Appropriate counseling and surveillance based on the chorionicity are imperative in the prenatal care of twin pregnancies.

Clinical Significance of Non-Invasive Prenatal Screening for Trisomy 7: Cohort Study and Literature Review

Trisomy 7 is the most frequently observed type of rare autosomal trisomies in genome-wide non-invasive prenatal screening (NIPS). Currently, the clinical significance of trisomy 7 NIPS-positive results is still unknown. We reviewed two independent cohorts from two laboratories where similar NIPS metrics were applied. A total of 70,441 singleton cases who underwent genome-wide NIPS were analyzed, among which 39 pregnancies were positive for trisomy 7, yielding a screen-positive rate of 0.055% (39/70,441). There were 28 cases with invasive testing results available; the positive predictive value (PPV) was 3.6% (1/28). We then searched the published NIPS studies to generate a large cohort of 437,873 pregnancies and identified 247 cases (0.056%) that were screened positive for trisomy 7. The overall PPV was 3.4% (4/118) in the combined data. The presence of uniparental disomy 7 was not detected in the NIPS trisomy 7-positive pregnancies with normal fetal karyotype. Among the 85 cases with pregnancy outcome available in combined data, 88.2% were normal live births, 14.1% had intrauterine growth restriction, preterm birth or low birth weight, 3.5% presented with ultrasound abnormality, and no fetal loss was observed. Our data provide valuable information for counseling and management of trisomy 7-positive NIPS pregnancies.

Clinical Utility of Increased Nuchal Translucency at 11-13 weeks of Gestation in Twin Pregnancies based on the Chorionicity

Objectives: To assess clinical implications of increased nuchal translucency (INT) in twin pregnancies based on the chorionicity. Methods: This was a retrospective review of the twin pregnancies who underwent first trimester ultrasound with nuchal translucency (NT) measurement at 11-13 weeks of gestation from January 2006 to December 2014. Data were collected using the OB database and the chart review. Pregnancy outcomes including gestational weeks at the delivery, abnormal fetal karyotypes, fetal structural anomalies, twin specific complications were analyzed. Results: A total of 1,622 twin pregnancies with INT&ge;95th percentile in one or both fetuses were identified. In all twin pregnancies with INT, abnormal fetal karyotypes were identified in 17 (8.6%) patients (odds ratio=13.28, CI=5.990-29.447, P=0.000) and twin-specific complications were identified in 23 (11.6%) patients (odds ratio=2.398, CI=1.463-3.928, P=0.001) compared to those with normal NT. Among the INT group, when the groups were subdivided into monochorionic (MC) and dichorionic (DC) pregnancies, 14.8% and 29.6% of the MC pregnancies had structural anomalies in one or both fetuses (odds ratio=5.774, 95% CI=1.445-23.071, P=0.01) and twin-specific complications (odds ratio=4.379, 95% CI=1.641-11.684, P=0.03), respectively, compared to DC pregnancies. The prevalence of abnormal fetal karyotypes was not statistically different in patients with INT when compared between MC and DC pregnancies (P=0.329). Conclusions: INT was associated with a higher rate of twin-specific complications and fetal structural anomalies in MC twin pregnancies rather than abnormal fetal karyotype. Therefore, NT measurement in MC twin pregnancies can be a useful tool for prediction of adverse pregnancy outcomes. Appropriate counseling and surveillance based on the chorionicity is imperative in prenatal care of twin pregnancies.

Predictive value of aberrant right subclavian artery for fetal Chromosome aneuploidy in women of advanced maternal age

Background: In entire population, aberrant right subclavian artery ( ARSA) was in closely association with chromosomal abnormalities. The risk of fetal chromosomal abnormalities increased with the maternal age exponentially. This situation in advanced maternal age ( AMA )group is uncertain. This study aimed to establish the incidence of ARSA in Chinese AMA and non-AMA women and to determine the frequency of aneuploidy among AMA and non-AMA women with ARSA.Methods: The retrospective study included 13,690 singleton pregnancies which were divided into AMA and non-AMA groups. Integrated obstetric ultrasonic screening, biochemical screening, noninvasive prenatal screening and fetal karyotype analysis were analyzed.Results: 1. The overall incidence of ARSA was 0.69 % with no difference in both age groups. 2. The incidence rate of chromosomal abnormalities in AMA group ( 37 / 2,860 ) was much higher than that in non-AMA group. The risk of chromosomal abnormalities significantly increased with both ARSA detected and additional ultrasound findings. 3. With combined ARSA detected in AMA ones, the lilelihood of the incidence of chromosomal abnormalities increased. 4. Additionally, a case with chimeric ( 45X / 46XX ) was found with isolated ARSA in AMA pregnancy.Conclusion: There is a high prevalence of chromosomal abnormalities in AMA fetuses. ARSA would increase the risk of chromosomal abnormalities in both age groups, especially combined ARSA. Moreover, when combined ARSA is found in AMA ones, it confers a high likelihood of chromosomal abnormalities.

Prenatal diagnosis of congenital high airway obstruction syndrome: our experience from a tertiary care center

Congenital high airway obstruction syndrome (CHAOS) is an extremely rare and life-threatening condition. It occurs due to obstruction in fetal respiratory tract and is characterized by typical ultrasonographic findings. Risk of recurrence is low, so antenatal diagnosis can help in counselling regarding risk of recurrence. A retrospective record review of all cases referred to our institution for antenatal ultrasound over a period of 5 years from January, 2014 to December, 2018 was done. Cases diagnosed as CHAOS were reviewed in detail regarding the radiological findings, information regarding delivery, fetal karyotype and postnatal/ fetal examination. Between the period of 2014 to 2018 three fetuses with CHAOS were identified. All of them had characteristic radiological features. Two of them were associated with hydrops and one fetus had oligohydramnios. All the pregnancies were terminated after antenatal diagnosis. Amniocentesis was done in 2 out of 3 cases and fetal karyotype was found to be normal. Fetal autopsy was done in one case and site of upper airway obstruction was identified. Confirmation of diagnosis by antenatal ultrasound and if possible, by post-mortem examination is essential for providing estimation of risk of recurrence to the family and genetic counselling.

Predictive value of aberrant right subclavian artery for fetal chromosomal in women of advanced maternal age

Background: In entire population, aberrant right subclavian artery ( ARSA ) was in closely association with chromosomal abnormalities. The risk of fetal chromosomal abnormalities increased with the maternal age exponentially. While, the situation in advanced maternal age ( AMA ) group is uncertain. This study aimed to establish the incidence of ARSA in Chinese AMA and non-AMA women and to determine the frequency of aneuploidy among AMA and non-AMA women with ARSA. Methods: The retrospective study included 13,690 singleton pregnancies which were divided into AMA and non-AMA groups. Integrated obstetric ultrasonic screening, biochemical screening, noninvasive prenatal screening and fetal karyotype analysis were analyzed. Results: 1. The overall incidence of ARSA was 0.69 % with no difference in both groups. 2. The prevalence rate of chromosomal abnormalities in AMA group ( 37 / 2,860 ) was much higher than that in non-AMA group. The risk of chromosomal abnormalities significantly increased with both ARSA detected and additional ultrasound findings. 3. With ARSA detected, the incidence increased to 20.00 % and 10.00 % in AMA and non-AMA cases, respectively. 4. Additionally, a case with chimeric Turner syndrome ( 45X / 46XX ) was found with isolated ARSA in AMA pregnancy. Conclusion: There is a high prevalence of chromosomal abnormalities in AMA fetuses. Both isolated and nonisolated ARSA would increase the risk of chromosomal abnormalities. Moreover, when ARSA is found in AMA ones, it confers a sharp increase in the incidence of chromosomal abnormalities.