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The use of race in maternal serum screening is problematic because race is a social construct rather than a distinct biological classifier. Nevertheless, laboratories offering this testing are encouraged to use race-specific cutoff values for maternal serum screening biomarkers to determine the risk of fetal abnormalities. Large cohort studies examining racial differences in maternal serum screening biomarker concentrations have yielded conflicting results, which we postulate may be explained by genetic and socioeconomic differences between racial cohorts in different studies. We recommend that the use of race in maternal serum screening should be abandoned. Further research is needed to identify socioeconomic and environmental factors that contribute to differences in maternal serum screening biomarker concentrations observed between races. A better understanding of these factors may facilitate accurate race-agnostic risk estimates for aneuploidy and neural tube defects. [Display omitted] [ABSTRACT FROM AUTHOR]

• We investigated interference of anti-alkaline phosphatase antibodies (anti-ALP's). • The anti-ALP's interfered with the unconjugated estriol assay for maternal serum screening. • These efforts identified 17 of 160 samples at increased risk for erroneous results. • Four of the 17 had screen interpretations changes using pseudo-risk calculations. Unconjugated estriol (uE3) is an important biomarker in second trimester prenatal screening. Previous studies from our laboratory identified rare interference in the Beckman uE3 assay due to anti-ALP antibodies, which could be mitigated with a scavenger or heat-inactivated ALP (hALP). In the current study, 160 de-identified patient samples previously submitted for the Quad screen with low uE3 multiples of the median (MoM ≤0.50) were investigated for potential interference. A reagent pack spiking strategy with hALP was employed to understand if the interference could be identified and mitigated in a scalable manner. The 160 samples were measured using uE3 lot #920861 previously known to be subject to interference, lot #920861 spiked with hALP, and the vendor reformulated lot #922579. Samples were suspected to have interference if the percent difference in uE3 measurements was >50%. Pseudo-risks were calculated using a test patient environment to understand the screening impact due to the change in uE3 result. Seventeen of the 160 samples had uE3 results that were >50% different between the hALP spiked and non-spiked reagent pack. Both original lot #920861 with hALP and reformulated lot #922579 identified the same 17 patients as having interference in lot #920861. Analysis of screening risks using a test patient environment showed that assay interference could result in false positives for one trisomy 21 and three trisomy 18 post-test risk calculations. Our experiment of reagent pack spiking with hALP produced similar uE3 results to a reformulated reagent designed to address potential interference, demonstrating that this is a feasible strategy to screen for interference in a scalable manner. The vendor-provided reformulation addressed anti-ALP interference and improved the performance of the screen. [ABSTRACT FROM AUTHOR]

Introduction: The rates of syphilis among pregnant women and infants have increased in recent years, particularly in the U.S. South. Although state policies require prenatal syphilis testing, recent screening rates comparable across Southern states are not known. The purpose of this study is to measure syphilis screening among Medicaid enrollees with delivery in states in the U.S. South.Methods: A total of 6 state-university research partnerships in the U.S. South developed a distributed research network to analyze Medicaid claims data using a common analytic approach for enrollees with delivery in fiscal years 2017-2018 and 2018-2019 (combined N=504,943). In 2020-2021, each state calculated the percentage of enrollees with delivery with a syphilis screen test during the first trimester, third trimester, and at any point during pregnancy. Percentages for those with first-trimester enrollment were compared with the percentages of those who enrolled in Medicaid later in pregnancy.Results: Prenatal syphilis screening during pregnancy ranged from 56% to 91%. Screening was higher among those enrolled in Medicaid during the first trimester than in those enrolled later in pregnancy.Conclusions: Despite state laws requiring syphilis screening during pregnancy, screening was much lower than 100%, and states varied in syphilis screening rates among Medicaid enrollees. Findings indicate that access to Medicaid in the first trimester is associated with higher rates of syphilis screening and that efforts to improve access to screening in practice settings are needed. [ABSTRACT FROM AUTHOR]

• Pregnancies with preimplantation genetic testing for aneuploidy (PCT-A) follow standard prenatal screening. • Specificity of the combined screening test decreases in pregnancies conceived through IVF with PGT-A. • Maternal age is the main contributor to risk of trisomy 21 in pregnancies conceived through IVF with PGT-A. How does first-trimester aneuploidy screening perform in pregnancies achieved through IVF with preimplantation genetic testing for aneuploidy (PGT-A) in a medical setting? This retrospective cohort study was undertaken in a single tertiary care centre between January 2013 and June 2022. In total, 20,237 women had prenatal follow-up at the study centre and were included in the study. The women were divided into three groups: singleton pregnancies conceived through the transfer of a PGT-A-screened euploid embryo (n = 510); singleton pregnancies conceived through IVF without PGT-A (n = 3291); and singleton pregnancies conceived naturally (n = 16,436). The conventional combined screening test for pregnancies conceived through IVF with PGT-A had specificity of 91%; sensitivity could not be calculated as there were no cases of fetal aneuploidy in this group. In 89.1% of pregnancies conceived through IVF with PGT-A with high risk for trisomy 21, 18 or 13, the result was related to advanced maternal age (>35 years at time of screening). The current screening strategy for trisomies 21, 18 and 13 can generate unnecessary tests in pregnancies achieved through IVF with PGT-A. A new protocol is needed for these patients, with greater weight given to ultrasound markers. [ABSTRACT FROM AUTHOR]

Background: We developed a decision aid (DA) to help pregnant women and their partners make informed decisions about prenatal screening for trisomy. We aimed to determine its usefulness for preparing for decision-making and its acceptability among end-users.Methods: In this mixed-methods pilot study, we recruited participants in three prenatal care settings in Quebec City. Eligible women were over 18 and more than 16 weeks pregnant or had given birth recently. We asked them about the usefulness of the DA using an interview grid based on the Technology Acceptance Model. We performed descriptive statistics and deductive analysis.Results: Thirty-nine dyads or individuals participated in the study. Mean usefulness score was 86.2 ± 13. Most participants found the amount of information in the DA just right (79.5%), balanced (89.7%), and very useful (61.5%). They were less satisfied with the presentation and the values worksheet and suggested different values clarification methods.Conclusion: Rigorous pilot tests of DAs with patients are an important stage in their development before the more formal assessments that precede scaling up the DA in clinical practice.Practice Implications: The next version of the DA will integrate the suggestions of end-users for better decision-making processes about prenatal screening for trisomy. [ABSTRACT FROM AUTHOR]

Objectives: To assess the cost-effectiveness of the Fetal Medicine Foundation (FMF) combined first-trimester pre-eclampsia (PE) screening algorithm, coupled with low-dose aspirin treatment in high-risk patients, compared to the standard of care (SOC; screening based on maternal risk factors) for nulliparous pregnancies in Belgium.Study Design: A decision analytic model was used to estimate the costs and outcomes for patients screened using the SOC and for those using the FMF screening algorithm, from the Belgian payers' perspective. Where possible, the probabilities and associated costs at each decision point were calculated based on published literature and public databases.Main Outcome Measures: Cost-effectiveness was assessed using an incremental cost-effectiveness ratio. One-way sensitivity analyses were performed to assess the impact of independent variations in each model parameter. A probabilistic sensitivity analysis was used to estimate the impact of the overall uncertainty of the model on the estimated cost-effectiveness.Results: Considering an estimated 51,309 pregnancies in nulliparous women in Belgium per year, the FMF screening algorithm resulted in fewer cases of pre-term PE compared with the SOC (479 versus 816 cases) and a cost saving of €28.67 per patient. The outcome in quality-adjusted life-years was similar for both screening approaches (FMF screening algorithm 1.8521 versus SOC 1.8518). The FMF screening algorithm was cost-saving and more effective in 99.4% of simulations.Conclusions: The FMF screening algorithm coupled with early intervention using low-dose aspirin has the potential to prevent an additional 337 cases of pre-term PE per year compared with the current SOC in this population, along with a cost saving. [ABSTRACT FROM AUTHOR]

Down syndrome screening has been available within clinical practice for over 50 years within which time significant innovation and exciting new advances have improved the accuracy, safety, and choice for women who are considering antenatal screening for Down syndrome. The UK National Screening Committee is responsible for setting the national standards regarding screening and it has steadily and consistently directed and facilitated an increase in the detection rate whilst minimising the screen positive rate. This has reduced the number of false positive results and consequently the number of invasive diagnostic procedures and their related miscarriages. Non-invasive pre-natal testing (NIPT) using cell free DNA is a rapidly evolving field and it will soon be incorporated into the existing NHS antenatal screening programme for aneuploidy. It will be offered to women who receive a 'high risk' result following current screening methods (combined test or quadruple test), and will further reduce the number of invasive tests performed, whilst maintaining current detection rates. [ABSTRACT FROM AUTHOR]

As part of the national screening programme, fetal anomaly screening is offered by the NHS to all women expecting a baby in the UK. The identification of suspected fetal anomalies causes stress and anxiety in the expectant parents. Therefore, a thorough understanding of the issues as described can help alleviate this to a degree. This problem-based review presents two case histories describing issues encountered during first and second trimester screening, and principles behind subsequent management. [ABSTRACT FROM AUTHOR]

Abstract Screening in reproductive healthcare in the UK has expanded rapidly since the introduction of cervical screening by the NHS in 1981. Women are offered comprehensive antenatal care screening for a range of pregnancy complications, including pre-eclampsia and gestational diabetes with the aim of early disease detection and management. With the advances in molecular medicine in recent years, novel biomarkers are being developed that have the potential to accurately predict these diseases long before their clinical onset. Likewise, non-invasive testing in fetal medicine for a variety of genetic conditions may supersede traditional first trimester screening. In oncology, new tools for population screening for ovarian cancer are being sought via prospective samples stored in biobanks. Tracking serial measurements from each patient may optimise the current use of CA125 rather than using predetermined thresholds. These developments highlight the move towards more personalised medicine. However, challenges in implementing new screening will include cost efficacy and ethical considerations such as informed consent. [ABSTRACT FROM AUTHOR]

In 2020, the American College of Obstetricians and Gynecologists recommended noninvasive prenatal testing be offered to all patients. However, current societal guidelines in the United States do not universally recommend a detailed first-trimester ultrasound. This study aimed to determine the additional findings identified through first-trimester ultrasound that would have otherwise been missed if noninvasive prenatal testing was used alone as a first-trimester screening method. This was a retrospective cohort study involving 2158 pregnant patients and 2216 fetuses that were seen at a single medical center between January 1, 2020, and December 31, 2022. All those included underwent both noninvasive prenatal testing and detailed first-trimester ultrasound between 11.0 and 13.6 weeks of gestation. Noninvasive prenatal testing results were categorized as low risk or high risk, and first-trimester ultrasound results were categorized as normal or abnormal. Abnormal first-trimester ultrasounds were further classified as first-trimester screening markers (increased nuchal translucency, absent nasal bone, tricuspid regurgitation, and ductus venosus reverse a-wave) or structural defects (the cranium, neck, heart, thorax, abdominal wall, stomach, kidneys, bladder, spine, and extremities). Descriptive statistics were used to report our findings. Of 2216 fetuses, 65 (3.0%) had a high-risk noninvasive prenatal testing result, whereas 2151 (97.0%) had a low-risk noninvasive prenatal testing result. Of those with a low-risk noninvasive prenatal testing result, 2035 (94.6%) had a normal first-trimester ultrasound, whereas 116 (5.4%) had at least 1 abnormal finding on first-trimester ultrasound. The most common screening marker detected within the low-risk noninvasive prenatal testing group was absent nasal bone (52/2151 [2.4%]), followed by reversed a-wave of the ductus venosus (30/2151 [1.4%]). The most common structural defect in this group was cardiac abnormality (15/2151 [0.7%]). Overall, 181 fetuses were identified as having "abnormal screening" through either a high-risk noninvasive prenatal testing result (n=65) or through a low-risk noninvasive prenatal testing result but abnormal first-trimester ultrasound (n=116). In summary, the incorporation of first-trimester ultrasound screening identified 116 additional fetuses (5.4%) that required further follow-up and surveillance than noninvasive prenatal testing alone would have identified. Detailed first-trimester ultrasound identified more fetuses with a potential abnormality than noninvasive prenatal testing alone. Therefore, first-trimester ultrasound remains a valuable screening method that should be used in combination with noninvasive prenatal testing. [ABSTRACT FROM AUTHOR]

The Fetal Anomaly Screening Programme (FASP) is a national antenatal screening programme, responsible for two screening pathways: Down's syndrome, Edwards' syndrome, Patau's syndrome and 11 physical conditions at the 18–20 week scan. The core aim is to provide parents with information that supports their choices and values. In the last 19 years screening performances have improved significantly by defining a standardized approach, refining the tests offered, developing e-learning, supporting sonographers and laboratories with a quality assurance programme (Down's syndrome screening Quality Assurance Support Service) and auditing screening performance through the National Congenital Anomaly and Rare Diseases Registration Service. In 2021 FASP will implement non-invasive prenatal testing (NIPT) to screen for T21, T18 and T13 only. This will improve the choices offered to women and reduce the number of women having invasive prenatal diagnosis. In addition FASP is working with the National Institute for Health Research to potentially develop standards for evaluating specific fetal anomalies at 11–14 weeks. [ABSTRACT FROM AUTHOR]

Background: Routine screening for emotional health difficulties in women during pregnancy is now advocated in several countries. There is a need therefore to compare the performance of different self-report measures to accomplish this. This study reports on the comparative performance of two such measures- the well-established PHQ-2, which aims to detect depression, and the more recent MGMQ, which aims to detect a wide array of negative emotions.Method: Women (N = 2292) attending a public hospital antenatal clinic over a 14-month period completed the two measures, either on their own (72%), verbally administered by the midwife (25%), or with an interpreter (3%).Results: Similar rates of women screened positive on each instrument (PHQ-2: 11.6%; MGMQ: 12.3%), but the overlap between the two measures was low. The PHQ-2 only detected 58% of the MGMQ screen positive women, while the MGMQ detected 89.5% of the PHQ-2 screen positive women. No clinically meaningful difference in screen positive rates on either measure was evident for the administration method.Limitations: No demographic data were available apart from gestational age, and only about half the women presenting to the clinic during the time period were screened with the measures.Conclusion: The MGMQ detected a greater proportion of women screening positive on the PHQ-2 than vice-versa. This is part due to the MGMQ's focus on a wider range of negative emotions than just depression. Accumulating evidence for this MGMQ indicates that clinical services can consider using this simple measure if they wish to screen for a broad range of negative emotions during pregnancy and postnatally. [ABSTRACT FROM AUTHOR]

The discovery of cell free fetal DNA in maternal plasma has stimulated a rapid development of non-invasive prenatal testing. The recent advent of massively parallel sequencing has allowed the analysis of circulating cell-free fetal DNA to be performed with unprecedented sensitivity and precision. It is thus expected that plasma DNA-based non invasive prenatal testing will play an increasingly important role in the future of obstetric care. The present review summarizes recent advances in non invasive prenatal testing using cell free fetal DNA. The importance of genetic counseling, the current guidelines for the use of cffDNA screening in pregnancy, as well as specific maternal conditions that can affect the performance of non invasive prenatal testing are also discussed in this review. [ABSTRACT FROM AUTHOR]

Objectives: To examine the costs and outcomes of different screening strategies for Down Syndrome (DS) in singleton pregnancies.Study Design: A decision-analytic model was developed to compare the costs and the outcomes of different prenatal screening strategies. Five strategies were compared for women under 35-year of age: 1A) triple test (TT), 2A); combined test (CT), 3A) Non-invasive Prenatal Screening Test by using cell free fetal DNA (NIPT), 4A) and 5A) NIPT as a second-step screening for high-risk patients detected by either TT, or CT respectively. For women ≥35-year of age, 1B) implementing invasive test (amniocentesis -AC) and 2B) NIPT for all women were compared. Data was analyzed to obtain the outcomes, total costs, the cost per women and the incremental cost-effectiveness ratios (ICERs) for screening strategies.Results: Among the current strategies for women under 35 years old, CT is clearly dominated to TT, as it is more effective and less costly. Although, the current routine practice (2A) is the least-costly strategy, implementing NIPT as a second step screening to high-risk women identified by CT (5A) would be more effective than 2A; leading to a 10.2% increase in the number of detected DS cases and a 96.3% reduction in procedural related losses (PRL). However, its cost to the Social Security Institution that is a public entity would be 17 times higher and increase screening costs by 1.5 times. Strategy 5A would result in an incremental cost effectiveness of 6,873,082 (PPP) US$ when compared to the current one (2A). Strategy 1B-for offering AC to all women ≥35-year of age is dominated over NIPT (2B), as it would detect more DS cases and would be less costly. On the other hand, there would be 206 PRL associated with AC, but NIPT provides clear clinical benefits as there would be no PRL with NIPT.Conclusions: NIPT leads to very high costs despite its high effectiveness in terms of detecting DS cases and avoiding PRL. The cost of NIPT should be decreased, otherwise, only individuals who can afford to pay from out-of-pocket could benefit. We believe that reliable cost-effective prenatal screening policies are essential in countries with low and smiddle income and high birth rates as well. [ABSTRACT FROM AUTHOR]

Objectives 1) To analyze screening performance of second trimester scan for ACC, 2) to evaluate the agreement between ultrasound and MRI and 3) to compare prenatal and postnatal diagnosis. Methods It was a prospective observational study. All patients with fetuses suspected of ACC were referred to prenatal MRI (pMRI). Results One subject was not confirmed by pMRI with the diagnosis of ACC. This case demonstrated partial ACC in neonatal MRI (nMRI). Conclusion Sensitivity of second trimester scan for callosal agenesis of 73% and specificity of 99%. Prenatal MRI and US has similar amount of misdiagnoses. [ABSTRACT FROM AUTHOR]

Down screening has been available within clinical practice for over 50 years during which time significant innovation and exciting new advances have improved the accuracy and safety of screening, and improved choice for women who are considering antenatal screening for Down syndrome. The UK National Screening Committee is responsible for setting the national standards regarding screening and it has steadily and consistently directed and facilitated an increase in the detection rate whilst minimising the screen positive rate of Down syndrome screening. This has reduced the number of false positive results and consequently the number of invasive diagnostic procedures and their related miscarriages. Non-invasive pre-natal testing (NIPT) using cell free DNA is a rapidly evolving field and it will soon be incorporated into the existing NHS antenatal screening programme for aneuploidy. It will be offered to women who receive a ‘high risk’ result following current screening methods (combined test or quadruple test), and will further reduce the number of invasive tests performed, whilst maintaining current detection rates. [ABSTRACT FROM AUTHOR]

/Background : The high rate of obstructive sleep apnea (OSA) in Down Syndrome (DS) is well described in the literature. The impact of the 2011 screening guidelines has not been fully evaluated. The objective of this study is to evaluate the impact of the 2011 screening guidelines on the diagnosis and treatment of obstructive sleep apnea (OSA) in a community cohort of children with Down Syndrome. This is a retrospective, observational study conducted on 85 individuals with DS born between 1995 and 2011 in a nine-county region of southeast Minnesota. The Rochester Epidemiological Project (REP) Database was used to identify these individuals. /Conclusions : Sixty-four percent of the patients with DS had OSA. Post guideline publication, the median age at OSA diagnosis was higher (5.9 years; p = 0.003) and polysomnography (PSG) was used more often to establish the diagnosis. Most children underwent first line therapy with adenotonsillectomy. There was a high degree of residual OSA after surgery (65%). There were trends post guideline publication towards increased PSG use and for consideration of additional therapy beyond adenotonsillectomy. The use of PSG before and after first line treatment for OSA in children with DS is needed due to the high rate of residual OSA. Unexpectedly, in our study, the age at OSA diagnosis was higher after guideline publication. Continued assessment of clinical impact and refinement of these guidelines will be of benefit to individuals with DS given the prevalence and longitudinal nature of OSA in this population. [ABSTRACT FROM AUTHOR]

Objective: Methods for the antenatal detection of small for gestational age babies (SGA) differ between countries. The aim of this study was to compare the diagnostic accuracy of routine versus selective small for gestational age babies screening policy using data from two European Maternity Units.Study Design: This was a retrospective cohort study from Liverpool Women's Hospital, UK, that uses selective third trimester sonography and from the University Hospital Centre Zagreb, Croatia, that uses routine third trimester sonography for SGA detection. Screen positive cases were defined as pregnancies with estimated fetal weight (EFW) <10th centile at the last 3rd trimester scan. True positives had both EFW and birth weight <10th centile. Pregnancy management data and perinatal outcomes were retrieved from hospital electronic data and special care baby unit (SCBU) reports.Results: The proportion of small for gestational age babies was higher in Liverpool (7.8%) compared with Zagreb (4%); P<0.001. Sensitivity for detection of SGA babies in Zagreb was 27% (95%CI 15%-44%) and 33% (95%CI 23%-45%) in Liverpool. The specificity was high in both centres (Zagreb 100% (95%CI); Liverpool 98% (95%CI)). The induction of labour for antenatally diagnosed SGA babies was more common in Liverpool (38.5%) than in Zagreb (9.1%). In both centres, all antenatally diagnosed SGA babies admitted to SCBU were preterm babies. Their indications for admission to SCBU were complications related to prematurity.Conclusion: The effectiveness of selective SGA screening policy is comparable to universal third trimester ultrasound screening. Further prospective evaluations of SGA screening policies are warranted and they should include full cost-effectiveness analysis and assessment of possible harm from increased interventions leading to more preterm births. [ABSTRACT FROM AUTHOR]

Background: Women with a history of previous cesarean delivery, presenting with a placenta previa, have become the largest group with the highest risk for placenta previa accreta.Objective: The objective of the study was to evaluate the accuracy of ultrasound imaging in the prenatal diagnosis of placenta accreta and the impact of the depth of villous invasion on management in women presenting with placenta previa or low-lying placenta and with 1 or more prior cesarean deliveries.Study Design and Data Sources: We searched PubMed, Google Scholar, clinicalTrials.gov, and MEDLINE for studies published between 1982 and November 2016.Study Eligibility Criteria: Criteria for the study were cohort studies that provided data on previous mode of delivery, placenta previa, or low-lying placenta on prenatal ultrasound imaging and pregnancy outcome. The initial search identified 171 records, of which 5 retrospective and 9 prospective cohort studies were eligible for inclusion in the quantitative analysis.Study Appraisal and Synthesis Methods: The studies were scored on methodological quality using the Quality Assessment of Diagnostic Accuracy Studies tool.Results: The 14 cohort studies included 3889 pregnancies presenting with placenta previa or low-lying placenta and 1 or more prior cesarean deliveries screened for placenta accreta. There were 328 cases of placenta previa accreta (8.4%), of which 298 (90.9%) were diagnosed prenatally by ultrasound. The incidence of placenta previa accreta was 4.1% in women with 1 prior cesarean and 13.3% in women with ≥2 previous cesarean deliveries. The pooled performance of ultrasound for the antenatal detection of placenta previa accreta was higher in prospective than retrospective studies, with a diagnostic odds ratios of 228.5 (95% confidence interval, 67.2-776.9) and 80.8 (95% confidence interval, 13.0-501.4), respectively. Only 2 studies provided detailed data on the relationship between the depth of villous invasion and the number of previous cesarean deliveries, independently of the depth of the villous invasion. A cesarean hysterectomy was performed in 208 of 232 cases (89.7%) for which detailed data on management were available. Positive correlations were found in the largest prospective studies between the cumulative rates of the more invasive forms of accreta placentation and the sensitivity and specificity of ultrasound imaging but not with diagnostic odds ratio values. We found no data on the ultrasound screening of placenta accreta at the routine midtrimester ultrasound examination from the nonexpert ultrasound units.Conclusion: Planning individual management for delivery is possible only with accurate evaluation of prenatal risk of accreta placentation in women presenting with a low-lying placenta/previa and a history of prior cesarean delivery. Ultrasound is highly sensitive and specific in the prenatal diagnosis of accreta placentation when performed by skilled operators. Developing a prenatal screening protocol is now essential to further improve the outcome of this increasingly more common major obstetric complication. [ABSTRACT FROM AUTHOR]

The evolution of preimplantation genetic screening (PGS) for aneuploidy to blastocyst biopsy and more sensitive 24-chromosome screening techniques has resulted in a new diagnostic category of PGS results: those classified as mosaic. This diagnosis presents significant challenges for clinicians in developing policies regarding transfer and storage of such embryos, as well as in providing genetic counselling for patients prior to and following PGS. Given the high frequency of mosaic PGS results and the wide range of possible associated outcomes, there is an urgent need to understand how to appropriately counsel patients regarding such embryos. This is the first commentary to thoroughly address pre- and post-test genetic counselling recommendations, as well as considerations regarding prenatal screening and diagnosis. Current data on mosaic PGS results are summarized along with embryo selection considerations and potential outcomes of embryos diagnosed as mosaic. [ABSTRACT FROM AUTHOR]

Purpose To compare overall outcomes of conventional postnatal screening of familial retinoblastoma and prenatal RB1 mutation identification followed by planned early-term delivery. Design Retrospective, observational study. Participants Twenty children with familial retinoblastoma born between 1996 and 2014 and examined within 1 week of birth. Methods Cohort 1 included spontaneously delivered neonates examined within 1 week of birth and confirmed postnatal to carry their family's RB1 mutant allele. Cohort 2 included infants identified by amniocentesis to carry their family's RB1 mutant allele, and therefore scheduled for early-term delivery (36–38 weeks' gestation). Treatment for retinoblastoma was performed at the Hospital for Sick Children, Toronto, Canada. Main Outcome Measures Age at first tumor in each eye, eye stage, treatments given, ocular salvage, treatment success (defined as avoidance of enucleation, external-beam irradiation, or both), visual outcome, number of anesthetics, pregnancy or delivery complications, and estimated treatment burden. Results Vision-threatening tumors were present at birth in 4 of 8 infants in cohort 1 and in 3 of 12 infants in cohort 2. Eventually, all infants demonstrated tumors in both eyes. At the first treatment, 1 of 8 infants in cohort 1 had eyes in stage cT1a/cT1a or cT1a/cT0 (smallest and least vision-threatening tumors), compared with 8 of 12 infants in cohort 2 ( P = 0.02). Null RB1 germline alleles induced earlier tumors than low-penetrance alleles ( P = 0.03). Treatment success was achieved in 3 of 8 children in cohort 1 compared with 11 of 12 children in cohort 2 ( P = 0.002). Acceptable vision (better than 0.2 decimal) was achieved for 8 of 16 eyes in cohort 1 compared with 21 of 24 eyes in cohort 2 ( P = 0.014). Useful vision (better than 0.1, legal blindness) was achieved for 8 of 9 children in cohort 1 compared with 12 of 12 children in cohort 2. There were no complications related to early-term delivery. Median follow-up was 5.6 years, cohort 1 and 5.8 years, cohort 2. Conclusions When a parent had retinoblastoma, prenatal molecular diagnosis with early-term delivery increased the likelihood of infants born with no detectable tumors, better vision outcomes, and less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory planning for both the child and family. [ABSTRACT FROM AUTHOR]

Objectives For beta thalassemia control program in pregnancy, mass screening of the carrier state by determination of the hemoglobin (Hb) A 2 and Hb E proportions and mutation analysis is a preferred method for making prenatal diagnoses. Q Sepharose micro-column chromatography, developed for the determination of Hb A 2 and Hb E for screening purposes, was compared with high performance liquid chromatography (HPLC) to ascertain its relative accuracy and reliability. Design and methods Results using Q Sepharose micro-column chromatography in 350 blood specimens, including 50 samples genetically proven to be beta thalassemia heterozygotes, were compared to HPLC for validation. An additional study was conducted to test a clinical application on a large-scale survey for beta thalassemia in 1581 pregnant women and their spouses. Results The mean (± SD) Hb A 2 proportions in the normal and genetically proven beta thalassemia heterozygotes were 2.70 ± 0.40% and 6.30 ± 1.23%, respectively, as determined by Q-Sepharose micro-column chromatography, and 2.65 ± 0.31% and 5.37 ± 0.96%, respectively, as determined by HPLC. The mean Hb E proportions in the Hb E heterozygotes were 23.25 ± 4.13% and 24.72 ± 3.5% as determined by Q Sepharose micro-column chromatography and HPLC, respectively. In the large-scale survey for beta thalassemia, 23 at risk couples were detected. Seven affected fetuses were identified by prenatal diagnosis. Conclusions Q Sepharose micro-column chromatography was found to be reliable, reproducible and well-suited for large-scale surveys. Additionally, by being reusable and convenient, this simple and economical chromatography method may be an alternative means to screen for beta thalassemia and Hb E carriers in the mass population. [ABSTRACT FROM AUTHOR]

Objective: This study examines trends in total and live birth prevalence of trisomy 21 (T21) with regard to increasing maternal age and the introduction of prenatal diagnosis in Bosnia and Herzegovina.Method: The prenatal detection was introduced in January 2008 in 3 hospitals and assessed until December 31, 2015. In this study, 99 fetuses and 330 babies were diagnosed with T21 in the studied period.Results: On average, each year 33 T21 individuals were born and 13 T21 fetuses were diagnosed prenatally. The calculated incidence for the live born T21 individuals in Bosnia is 1:999. The live-birth prevalence of T21 was 9.6 per 10,000 births and the total prevalence of T21 was 19.1. The total T21 prevalence increases exponentially with the advanced maternal age. Prenatal T21 prevalence is 1.29 per 10,000 births for mothers <35, but increases exponentially with increasing age (32 for >40 years). The most common indications for invasive prenatal testing were ultrasound screening combined with biochemical serum analysis followed by the advanced maternal age.Conclusion: The prevalence of liveborn Down syndrome children remained constant. Despite the fact that increasing maternal age in the last decade contributed to the rise in the total T21 prevalence, the effect of the introduction of prenatal diagnosis on the live-birth T21 prevalence of T21 was minimal, leading to the conclusion that the prenatal screening has to be improved in developing countries. [ABSTRACT FROM AUTHOR]

Aims: To evaluate the utility of glycated hemoglobin A1c (HbA1c) for screening gestational diabetes mellitus (GDM) and analyze its association with adverse pregnancy outcomes in a cohort of pregnant women.Methods: Women with singleton pregnancies, who completed a 2h oral glucose tolerance test (OGTT) and HbA1c test at gestational week 24-28 were enrolled in this retrospective study. Clinical information was obtained and statistical analyses were performed to assess the diagnostic value of HbA1c for GDM and the association of HbA1c with adverse pregnancy outcomes.Results: Of the 1959 pregnant women enrolled in the study, 413 were diagnosed with GDM. A HbA1c cutoff value <4.8% (29mmol/mol) showed adequate sensitivity to exclude GDM (85.0%) but low specificity (31.8%). While HbA1c cutoff value ≥5.5% (37mmol/mol) presented adequate specificity (95.7%) but low sensitivity (14.8%) in diagnosing GDM. Adoption of HbA1c as a screening test for GDM could eliminate the need for an OGTT in 34.7% women in our study, however, with 6.5% being wrongly diagnosed. HbA1c level was significantly associated with the risk of preterm delivery, neonatal hyperbilirubinemia, and neonatal asphyxia.Conclusions: Whether adoption of HbA1c as a screening test for GDM would benefit pregnant women remains to be determined. However, HbA1c might be a useful tool to predict patients at increased risk of several adverse pregnancy outcomes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate first trimester pregnancy-associated plasma protein-A (PAPP-A) and birth weight percentile.Study Design: Included were women who underwent first trimester prenatal screening through the California Prenatal Screening Program with expected dates of delivery between August 2009 and December 2010, linked birth certificate and hospital discharge records, known birth weight, and no chromosomal abnormality (n=134.105). PAPP-A results were reported as multiples of the median. The frequency of small or large for gestational age (SGA, ≤10%; LGA, ≥90%) versus appropriately grown for gestational age birth was examined by PAPP-A percentile. Patterns were studied by gestational age at delivery. Relative risks (RRs) and their 95% confidence intervals were adjusted for race/ethnicity.Results: Women with PAPP-A ≤10th percentile and an infant born after 32 weeks were increasingly more likely to have an SGA infant (adjRRs 1.5-4.6) as the PAPP-A percentile declined, and were increasingly less like to have an LGA infant born at term (adjRRs 0.5-0.7) compared to women with PAPP-A measurement >10th to <90th percentile. PAPP-A ≥90th percentile was protective for SGA among infants born after 32 weeks gestation (adjRRs 0.3-0.7) and was associated with LGA among infants born at term (adjRRs 1.2-8.2).Conclusion: Women with PAPP-A ≤10th percentile are more likely to have an SGA infant at all gestational ages. PAPP-A ≥90th percentile is protective against SGA and is associated with an increased risk of LGA for infants born after 32 weeks gestation. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether first trimester combined screening for major fetal trisomies is influenced by assisted reproduction techniques from blastocyst transfer, with or without cryopreservation.Study Design: retrospective case-control analysis involving 298 singleton pregnancies with euploid fetuses recruited between 2012 and 2014. Forty-seven women conceived with fresh blastocysts from in vitro fertilization cycles (fresh-blasto), 51 with frozen-thawed blastocysts (frozen-blasto) and 200 were natural conceptions (controls). All cases underwent ultrasound assessment at 11(+0)-13(+6) weeks with measurements of crown rump length, nuchal translucency, free β-hCG and PAPP-A concentrations. The outcome of pregnancy was recorded (gestational age at birth, birth weight, obstetric complications).Results: Baseline characteristics and pregnancy outcomes did not differ substantially among the study groups. The median delta nuchal translucency was significantly higher both in frozen-blasto group (median: 0.27mm; Interquartile Range [IQR]: 0.02-0.44; p<0.001) and in fresh-blasto group (median: 0.17mm; IQR: 0.04-0.39; p=0.014) as compared to control group (median: 0.06mm; IQR: -0.08 to 0.20), whereas it was not different in the frozen-blasto compared to the fresh-blasto group. The median free β-hCG multiples of the median (MoMs) was significantly higher both in frozen-blasto group (median 1.15; IQR 0.83-2.11; p=0.001) and in fresh-blasto group (median 0.95; IQR 0.52-1.48; p=0.001) as compared to control group (median 0.99; IQR 0.57-1.26), and it was also higher in frozen-blasto group compared to fresh-blasto group (p<0.001). The three groups showed no significant differences in the median PAPP-A MoMs. The median delta crown rump length was also not significantly different among the three groups.Conclusions: in assisted reproduction technique pregnancies from blastocyst transfer, with or without cryopreservation, both the nuchal translucency measurement and free β-hCG concentration are higher as compared to spontaneous conceptions, whereas PAPP-A does not show any significant difference. These features are apparently unrelated to the outcome of pregnancy and may be due to alterations or delays in embryogenesis or placentation with potential relevance for the screening test performance. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing (NIPT) through the analysis of cell free (cf)DNA is revolutionizing prenatal screening for fetal aneuploidy. Current methods used in clinical practice include shotgun massively parallel sequencing (s-MPS); targeted (t-MPS); and an approach that takes advantage of single nucleotide polymorphism (SNP) differences between mother and fetus. Efficacy of cfDNA testing for the common autosomal trisomies far exceeds that of conventional screening. Depending on the methodology used, reasons for discordancy between cfDNA results and fetal karyotype can include true fetal mosaicism, confined placental mosaicism, presence of a maternal karyotype abnormality, insufficient counting due to low fetal fraction, and a vanishing twin. Among the possible cfDNA strategies a Primary test has the highest performance but is expensive, while a Contingent cfDNA test can achieve high performance at a relatively low cost. Practicalities to be considered in the provision of testing include pretest counseling about the scope and accuracy of the testing, the interpretation of results when there is a low fetal fraction and follow-up studies for positive test results. The role of first trimester nuchal translucency measurement and conventional biochemical testing needs to be reassessed in the context of the use of cfDNA. [ABSTRACT FROM AUTHOR]

Background High Resolution Melting (HRM) Analysis is a validated, robust, low-cost, high throughput CF screening method. Here, we report the development and retrospective evaluation of the diagnostic value of a novel multiplex HRM, genotyping and haplotyping method for CF prenatal diagnosis (generic HRM/haplotyping). Methods 80 study samples from 20 carrier couples referred for PND (whole blood in EDTA and CVS or amniotic fluid) were genotyped retrospectively using the suggested protocol. Results All DNA samples (variable sources, extraction methods and unknown concentrations) were successfully amplified by the 1st and 2nd round PCR. The Se, Sp, NPV and PPV for the generic HRM/haplotyping method are calculated at 100%. Conclusions This generic protocol for PND using HRM, facilitates the simultaneous analysis of DNA samples from various sources in a fast, robust and efficient way. It can be easily adapted and applied for any genetic condition. [ABSTRACT FROM AUTHOR]

Background: Chromosomal microarray analysis detects a clinically significant amount of copy number variants in approximately 1% of low-risk pregnancies. As the constantly growing use of noninvasive prenatal screening has facilitated the detection of chromosomal aberrations, defining the rate of abnormal chromosomal microarray analysis findings following normal noninvasive prenatal screening is of importance for making informed decisions regarding prenatal testing and screening options.Objective: To calculate the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening.Study Design: The chromosomal microarray results of all pregnancies undergoing amniocentesis between the years 2013 and 2021 in a large hospital-based laboratory were collected. Pregnancies with sonographic anomalies, abnormal maternal serum screening, or multiple fetuses were excluded. Clinically significant (pathogenic and likely pathogenic) copy number variants were divided into the following: 3-noninvasive prenatal screening-detectable (trisomies 13, 18, and 21), 5- noninvasive prenatal screening-detectable (including sex chromosome aberrations), 5-noninvasive prenatal screening and common microdeletion-detectable (including 1p36.3-1p36.2, 4p16.3-4p16.2, 5p15.3-5p15.1, 15q11.2-15q13.1, and 22q11.2 deletions), and genome-wide noninvasive prenatal screening-detectable (including variants >7 Mb). The theoretical residual risk for clinically significant copy number variants was calculated following the exclusion of noninvasive prenatal screening-detectable findings.Results: Of the 7235 pregnancies, clinically significant copy number variants were demonstrated in 87 cases (1.2%). The residual risk following theoretically normal noninvasive prenatal screening was 1.07% (1/94) for 3-noninvasive prenatal screening, 0.78% (1/129) for 5- noninvasive prenatal screening, 0.74% (1/136) for 5- noninvasive prenatal screening including common microdeletions, and 0.68% (1/147) for genome-wide noninvasive prenatal screening. In the subgroup of 4048 pregnancies with advanced maternal age, the residual risk for clinically significant copy number variants following theoretically normal noninvasive prenatal screening ranged from 1.36% (1/73) for 3- noninvasive prenatal screening to 0.82% (1/122) for genome-wide noninvasive prenatal screening. In 3187 pregnancies of women <35 years, this residual risk ranged from 0.69% (1/145) for 3- noninvasive prenatal screening to 0.5% (1/199) for genome-wide noninvasive prenatal screening.Conclusion: The residual risk of clinically significant copy number variants in pregnancies without structural sonographic anomalies is appreciable and depends on the noninvasive prenatal screening extent and maternal age. This knowledge is important for the patients, obstetricians, and genetic counselors to facilitate informed decisions regarding prenatal testing and screening options. [ABSTRACT FROM AUTHOR]

Non-invasive prenatal testing on the basis of cell-free DNA of placental origin (NIPT) changed the landscape of prenatal care and is seen as superior to all other up to now implemented prenatal screening procedures - at least in the high-risk population. NIPT has spread almost worldwide commercially, but only in a few countries the costs of NIPT are covered by insurance companies. Such financial barriers in prenatal testing can lead to significant restrictions to the average range of opportunities of pregnant women and couples, which on an intersubjective level can be defined as unfair discrimination and on an individual level weakens reproductive autonomy. Given that enabling reproductive autonomy is the main ethical justification for offering prenatal (genetic) testing, these barriers are not only an issue of justice in health care, but are potentially counteracting the primary purpose of these testing procedures. [ABSTRACT FROM AUTHOR]

Health Technology Assessment (HTA) uses explicit methods to determine the value of a health technology. This typically results in several claims regarding the effects that are expected to follow from the use of a health technology in a particular context. These claims seem to capture conclusions based solely on facts, but they often combine empirical information with normative presuppositions. Claims that have this character reflect (implicit) value judgments and have been labelled mixed claims. Not recognizing these normative components of such claims risks value inattention and value imposition , presenting results as self-evident and not in need of any moral justification. As proposed by Anna Alexandrova, to avoid these risks of value inattention and imposition we need rules to deal with mixed claims. According to her, when producing and evaluating mixed claims we need to unearth the invoked value presuppositions and check whether these presuppositions are invariant to disagreements. By applying these rules, the robustness of mixed claims can be checked: it can be evaluated whether their truth value is independent from the way in which their components, involving normative presuppositions, are conceptualized. This paper aims to illustrate the role of mixed claims in HTA, and expand upon the work by Alexandrova, by analyzing claims and recommendations presented in an HTA report on the introduction of Non-Invasive Prenatal Testing (NIPT) in The Netherlands. Our results show that the report contains mixed claims, and that a normative analysis of these claims can help to clarify the normativity of HTA and evaluate the robustness of claims on alleged effects of a health technology. • HTA examines claims on potential effects of health technology. • Conceptualizing these effects may invoke value judgments. • Causal claims invoking value judgments have been described as mixed claims. • We analyzed mixed claims in an HTA report on Non-Invasive Prenatal Testing. • This showed that normative analysis helps evaluating the robustness of these claims. [ABSTRACT FROM AUTHOR]

Background: Noninvasive prenatal screening has become an increasingly prevalent choice for women who desire aneuploidy screening. Although the test characteristics are impressive, some women are at increased risk for noninvasive prenatal screen failure. The risk of test failure increases with maternal weight; thus, obese women may be at elevated risk for failure. This risk of failure may be mitigated by the addition of a paternal cheek swab and screening at a later gestational age.Objective: The purpose of this study was to evaluate the association among obesity, gestational age, and paternal cheek swab in the prevention of screening failure.Study Design: A retrospective cohort study was performed for women who were ≥35 years old at delivery who underwent screening at NorthShore University HealthSystem, Evanston, IL. Maternal weight, body mass index, gestational age, and a paternal cheek swab were evaluated in univariate and multivariable logistic regression analyses to assess the association with failed screening.Results: Five hundred sixty-five women met inclusion criteria for our study. The mean body mass index was 25.9 ± 5.1 kg/m(2); 111 women (20%) were obese (body mass index, ≥30 kg/m(2)). Forty-four women (7.8%) had a failed screen. Obese women had a failure rate of 24.3% compared with 3.8% in nonobese women (P < .01). Gestational age was not associated with failure rate (mean ± standard deviation, 13 ± 3 weeks for both screen failure and nonfailure; P = .76). The addition of a paternal cheek swab reduced the failure rate from 10.2% in women with no swab to 3.8% in women with a swab (P < .01). In multivariable analysis, obesity and lack of a paternal cheek swab were independent predictors of screen failure (odds ratio, 9.75; 95% confidence interval, 4.85-19.61; P < .01; and odds ratio, 3.61; 95% confidence interval, 1.56-8.33; P < .01, respectively).Conclusion: The addition of a paternal cheek swab significantly improved noninvasive prenatal screen success rates in obese women. However, delaying testing to a later gestational age did not. [ABSTRACT FROM AUTHOR]

Objective: The purpose of the study was to evaluate pregnancy outcomes of hypothyroidism that were identified in a population-based prenatal screening program.Study Design: This is a secondary analysis of a prospective prenatal population-based study in which serum thyroid analytes were obtained from November 2000 to April 2003. Initial screening thresholds were intentionally inclusive (thyroid-stimulating hormone [TSH], >3.0 mU/L; free thyroxine, <0.9 ng/dL); those who screened positive were referred for confirmatory testing in a hospital-based laboratory. Hypothyroidism was identified and treated if TSH level was >4.5 mU/L and if fT4 level was <0.76 ng/dL. Perinatal outcomes in these women and those who screened positive but unconfirmed to have hypothyroidism were compared with women with euthyroidism. Outcomes were then analyzed according to initial TSH levels.Results: A total of 26,518 women completed initial screening: 24,584 women (93%) were euthyroid, and 284 women (1%) had abnormal initial values that suggested hypothyroidism. Of those referred, 232 women (82%) underwent repeat testing, and 47 women (0.2% initially screened) were confirmed to have hypothyroidism. Perinatal outcomes of women with treated overt hypothyroidism were similar to women with euthyroidism. Higher rates of pregnancy-related hypertension were identified in the 182 women with unconfirmed hypothyroidism when compared with women with euthyroidism (P < .001); however, this association was seen only in women with initial TSH >4.5 mU/L (adjusted odds ratio, 2.53; 95% confidence interval, 1.4-4.5).Conclusion: The identification and treatment of overt hypothyroidism results in pregnancy outcomes similar to women with euthyroidism. Unconfirmed screening results suggestive of hypothyroidism portend pregnancy risks similar to women with subclinical hypothyroidism, specifically preeclampsia; however, this increased risk was seen only in women with initial TSH levels of >4.5 mU/L and suggests that this is a more clinically relevant threshold than 3.0 mU/L. [ABSTRACT FROM AUTHOR]