Factors associated with common and atypical chromosome abnormalities after positive combined first-trimester screening in Chinese women: a retrospective cohort study.

BACKGROUND: When cell-free DNA (cfDNA) testing is used as a secondary screening tool following combined first-trimester screening (cFTS), cFTS is used to estimate the prior risk for chromosome abnormalities. This study aimed to assess the factors that are associated with common and atypical abnormalities following cFTS, including cFTS risk, advanced maternal age, increased nuchal translucency (NT) ≥3.5 mm, and abnormal levels of serum markers. METHODS: We reviewed a historical cohort of 1855 Chinese women carrying singleton pregnancies with a positive cFTS [at a threshold of 1:250 for trisomy (T) 21 or 1:180 for T18] in one public hospital over a five-year period. All chromosome abnormalities were confirmed by invasive prenatal diagnosis (IPD) with karyotyping, with or without array comparative genomic hybridization. Using multivariable binary logistic regression analysis, we determined the parameters that were associated with common and atypical abnormalities. RESULTS: Overall, the prevalence of common and atypical abnormalities was 6.2 and 1.2%, respectively, and the prevalence increased with the risk of T21 by cFTS. In pregnancies with a risk of T21 > 1 in 100, a high risk of both T21 and T18, an increased NT, or a pregnancy-associated plasma A (PAPP-A) level <  0.2 multiple of medians (MoM), the prevalence of common abnormalities was 12.2, 64.7, 25.5 and 33.8%, respectively, while that of atypical abnormalities was 1.6, 3.9, 4.2, and 7.4%, respectively. In the multivariable binary logistic regression analysis, out of these four factors, only two (increased NT and PAPP_A <  0.2 MoM) were significant predictors of common and atypical abnormalities, respectively. Of all positive cFTS pregnancies, 50.4% did not have any of these four factors, and the prevalence of common and atypical abnormalities was 1.1 and 0.6%, respectively. There were three atypical abnormalities, all of which were mosaicism, and they were detected among women with IPD alone. The ages of these women were ≥ 35 years. All three pregnancies were continued after proper counseling. After giving birth, only one child had mild abnormalities, while the other two were phenotypically normal. CONCLUSIONS: Our study identified factors associated with common and atypical abnormalities after cFTS. These factors can be used to estimate the prior risk for these abnormalities to help with post-cFTS counseling in terms of choosing between cfDNA testing and IPD.

Prenatal ultrasound monitoring of homozygous α0-thalassemia-induced fetal anemia.

A noninvasive approach by serial ultrasound examination at 12-15, 18, and 30 weeks of gestation can be used to exclude homozygous α0-thalassemia-induced fetal anemia. At 12-15 weeks of gestation, the predictive values for the fetal cardio-thoracic ratio were better than that for the placental thickness. At 16-20 weeks of gestation, measuring middle cerebral artery peak systolic velocity is associated with a low false-positive rate. However, the false-positive rate of this noninvasive approach can be about 3%, requiring an invasive test to confirm the diagnosis. A false-negative may result in a delay in diagnosis. The success of this noninvasive approach depends on an accurate measurement of the fetal cardiothoracic ratio which can be improved by adequate training and subsequent quality control. Currently, there is a lack of data reporting the performance of a noninvasive approach before 12 weeks of gestation.

Effect of non-invasive prenatal testing as a contingent approach on the indications for invasive prenatal diagnosis and prenatal detection rate of Down's syndrome.

INTRODUCTION: In Hong Kong, universal combined first-trimester screening for Down's syndrome was started as a 'free service' in July 2010. Non-invasive prenatal testing was available as a self-financed item in August 2011. This study aimed to determine whether the introduction of non-invasive prenatal testing as a contingent approach influenced the indications for invasive prenatal diagnosis and the consequent prenatal detection of Down's syndrome. METHODS: This historical cohort study was conducted at the Prenatal Diagnosis Clinic of Queen Elizabeth Hospital in Hong Kong. We compared the indications for invasive prenatal diagnosis and prenatal detection of Down's syndrome in singleton pregnancies 1 year before and 2 years following the availability of non-invasive prenatal testing as a contingent test after a positive aneuploidy test. All pregnant women who attended our hospital for counselling about universal Down's syndrome screening between August 2010 and July 2013 were recruited. RESULTS: A total of 16 098 women were counselled. After the introduction of non-invasive prenatal testing, the invasive prenatal diagnosis rate for a positive aneuploidy screening reduced from 77.7% in 2010-11 to 68.8% in 2012-13. The new combined conventional plus non-invasive prenatal testing strategy was associated with a lower false-positive rate (6.9% in 2010-11 vs 5.2% in 2011-12 and 4.9% in 2012-13). There was no significant increase in invasive prenatal diagnosis for structural anomalies over the years. There was no significant trend in the overall prenatal detection rate of Down's syndrome (100% 1 year before vs 89.1% 2 years after introduction of non-invasive prenatal testing). Four (2.6%) of 156 women who underwent non-invasive prenatal testing for a screen-positive result had a high-risk result for trisomy 21, which was subsequently confirmed by invasive prenatal diagnosis. There were no false-negative cases. CONCLUSION: The introduction of non-invasive prenatal testing as a contingent approach reduced the invasive prenatal diagnosis rate for a positive aneuploidy screening without affecting the invasive prenatal diagnosis rate for structural anomalies or the overall detection rate of fetal Down's syndrome.

An Unusual Hydrops Fetalis Associated with Compound Heterozygosity for Krüppel-like Factor 1 mutations.

Hydrops fetalis is commonly due to Hb Bart's (γ4) disease in South East Asia. Here, we report an unusual case of hydrops fetalis due to congenital dyserythropoietic anemia (CDA) associated with compound heterozygosity for Krüppel-like factor 1 (KLF1) gene mutations. Fetal cardiomegaly was first detected on routine mid-trimester scan in a pregnant woman with normal mean corpuscular volume (MCV) and Rhesus positive status. The fetus subsequently developed hydrops fetalis, and cordocentesis showed severe fetal anemia with a hemoglobin (Hb) level of 3.4 g/dL. Common causes of fetal anemia including Hb Bart's disease, parvovirus infection, and red cell antibodies were excluded. In view of the marked increase in erythroblasts at various stages of erythropoiesis, the diagnosis of CDA was suspected. We screened the couple for previously reported KLF1 gene mutations, showing that the mother was heterozygous for the c.525_526insCGGCGCC, p.Gly176Argfs*179 mutation, and her husband heterozygous for c.1012C>A, p.Pro338Thr mutation. The fetus was a compound heterozygote for these two KLF1 mutations. After counseling, repeated intrauterine transfusions were given at 27, 29, and 34 weeks' gestation; the hydrops fetalis was resolved. The baby was delivered at 34 weeks' gestation and required monthly blood transfusions but was otherwise thriving. Bone marrow aspiration at 10 months of age showed the features of ineffective erythropoiesis, compatible with CDA. In conclusion, hydrops fetalis can rarely be due to CDA associated with a compound heterozygous mutation for KLF1 gene mutations, and be managed by repeated intrauterine transfusions. Our present report adds to the wide clinical spectrum of KLF1 mutations.

Uptake of Noninvasive Prenatal Testing in Chinese Women following Positive Down Syndrome Screening.

OBJECTIVES: To investigate how the introduction of noninvasive prenatal testing (NIPT) influenced women's testing choices following a positive Down syndrome screening. METHODS: A retrospective study was conducted to compare differences in the uptake rates of invasive prenatal diagnosis (IPD) or no testing in one public hospital 1 year before (pre-NIPT) and 1 and 2 years after the introduction of NIPT in private in August 2011 using descriptive analysis and a χ² test. Conventional screening was funded publicly, but NIPT was not. Multivariable binary logistic regression was used to determine factors affecting choices. RESULTS: In pre-NIPT and in years 1 and 2 after the introduction of NIPT, 306, 362 and 401 women who screened positive were seen, respectively. In year 1 and year 2, 12.6 and 26.7% of them underwent NIPT while IPD was decreased by 16.3 and 25.6%, respectively (p < 0.001). Both chorionic villus sampling and amniocentesis decreased in year 1, but only the former in year 2. However, the rate of declining further testing was similar before and after NIPT (p = 0.213). In multivariable analysis, first trimester screening, nulliparity and working women were significant predictors of accepting NIPT, while only nulliparity was a predictor of declining IPD (OR = 0.61). CONCLUSIONS: Introduction of NIPT resulted in a significant decrease in IPD for 2 consecutive years..

Two unusual cases of haemoglobin Bart's hydrops fetalis due to uniparental disomy or non-paternity.

The authors present 2 unusual cases of haemoglobin (Hb) Bart's hydrops fetalis and highlight the problem of a screening system for α-thalassaemia which focuses on maternal and paternal mean corpuscular volume (MCV) alone. Normal paternal MCV may not preclude fetal Hb Bart's disease because of the rare occurrence of maternal uniparental disomy or non-paternity. During a mid-trimester anomaly scan, with fetal cardiomegaly or hydrops in a woman with low MCV but normal paternal MCV, obstetricians should remain alert for fetal Hb Bart's disease. This is very important and relevant for national screening systems in South-East Asia, where a routine mid-trimester scan may not be available. A routine mid-trimester anomaly scan should therefore be implemented and in high prevalence areas, sonographers should be sensitive to the cardio-thoracic ratio even if screening shows that pregnancy is unlikely to be at risk.

Fetal biometry in ethnic Chinese: biparietal diameter, head circumference, abdominal circumference and femur length.

OBJECTIVES: To construct new reference charts and equations for fetal biometry in the Hong Kong ethnic Chinese population, and to compare them with existing references from different populations. METHODS: This was a prospective observational study involving 709 women with singleton pregnancies and confirmed gestational age. For the purposes of this study, each woman was scanned once only, between 12 and 40 completed weeks of gestation, and the following fetal biometric measurements were recorded: biparietal diameter, head circumference, abdominal circumference and femur length. For each measurement, regression models were fitted to estimate the mean and SD at each gestational age. For comparison, the fetal biometric measurements of other populations at each gestation were expressed as Z-scores calculated with our reference equations. Results were presented graphically across the different gestational ages to allow visual comparison. RESULTS: New charts and reference equations are reported in this Hong Kong Chinese population for fetal outer-inner and outer-outer biparietal diameter, head circumference, abdominal circumference and femur length. Equations for dating of pregnancy are presented. Our charts were very similar to those of the Singaporean population for most parameters. The main difference in our fetal biometric measurements compared with those of the UK and French populations was in FL. CONCLUSIONS: Our new set of reference centiles for fetal biometric measurements and equations for dating of pregnancy in a Hong Kong Chinese population are ready for clinical use and research in appropriate ethnic Chinese groups.

Cervical length at 18-22 weeks of gestation for prediction of spontaneous preterm delivery in Hong Kong Chinese women.

OBJECTIVE: To assess the value of a single cervical length measurement by transvaginal sonography (TVS) at the time of mid-trimester anomaly scan for predicting spontaneous preterm delivery (SPD) among Chinese women. METHODS: A prospective observational study was carried out involving 2880 subjects with singleton pregnancies and confirmed gestational age. Cervical length was measured at 18-22 weeks of gestation. RESULTS: The incidence of SPD < 34 weeks and < 37 weeks were 0.7% and 3.7%, respectively. Women with SPD < 34 weeks and SPD < 37 weeks had shorter median cervical lengths (32.6 mm and 36.2 mm, respectively) than those with term deliveries (37.6 mm) (P = 0.006 and 0.025, respectively). The predictive performance of cervical length was better for SPD < 34 weeks compared with < 37 weeks. A cervical length < or = 27 mm, which corresponded to the 4th centile, occurred in 36.8%, 62.5% and 100% of those with SPD < 34, < 30 and < 26 weeks, respectively. The positive likelihood ratio (LR) of a cervical length < or = 27 mm in predicting SPD < 34 weeks was 9.8. Using logistic regression, both short cervix and funneling were independent predictors for SPD < 34 weeks of gestation. The coexistence of funneling and a cervical length < or = 27 mm gave a positive predictive value (PPV) and LR of SPD < 34 weeks of 14.7% and 26.0, respectively. CONCLUSIONS: Mid-trimester cervical length is predictive of SPD in Chinese women. However, given the low PPV of a short cervical length, its clinical utility is still limited in low-risk populations.