Cytogenetic outcomes following a failed cell-free DNA screen: a population-based retrospective cohort study of 35,146 singleton pregnancies.

BACKGROUND: Cell-free fetal DNA screening is routinely offered to pregnant individuals to screen for aneuploidies. Although cell-free DNA screening is consistently more accurate than multiple-marker screening, it sometimes fails to yield a result. These test failures and their clinical implications are poorly described in the literature. Some studies suggest that a failed cell-free DNA screening result is associated with increased likelihood of cytogenetic abnormalities. OBJECTIVE: This study aimed to assess the association between a failed cell-free DNA test and common aneuploidies. The objectives were to determine: (1) the proportion of test failures on first and subsequent attempts, and (2) whether a failed cell-free DNA screen on first attempt is associated with increased likelihood of common aneuploidies (trisomies 21, 18, and 13, and sex chromosome aneuploidies). STUDY DESIGN: This was a population-based retrospective cohort study using data from Ontario's prescribed maternal and child registry, Better Outcomes Registry and Network Ontario. The study included all singleton pregnancies in Ontario with an estimated date of delivery from September 1, 2016 to March 31, 2019 that had a cell-free DNA screening record in the registry. Specific outcomes (trisomies 21, 18, and 13, and sex chromosome aneuploidies) of pregnancies with a failed cell-free DNA screen on first attempt were compared with those of pregnancies with low-risk cell-free DNA-screening results using modified Poisson regression adjusted for funding status (publicly funded vs self-paid), gestational age at screening, method of conception, and maternal age for autosomal aneuploidies. RESULTS: Our cohort included 35,146 pregnancies that had cell-free DNA screening during the study period. The overall cell-free DNA screening failure rate was 4.8% on first attempt and 2.2% after multiple attempts. An abnormal cytogenetic result for trisomies 21, 18, and 13, or sex chromosome aneuploidies was identified in 19.4% of pregnancies with a failed cell-free DNA screening for which cytogenetic testing was performed. Pregnancies with a failed cell-free DNA screen on first attempt had a relative risk of 130.3 (95% confidence interval, 64.7-262.6) for trisomy 21, trisomy 18, or trisomy 13, and a risk difference of 5.4% (95% confidence interval, 2.6-8.3), compared with pregnancies with a low-risk result. The risk of sex chromosome aneuploidies was not significantly greater in pregnancies with a failed result compared with pregnancies with a low-risk result (relative risk, 2.7; 95% confidence interval, 0.9-7.9; relative difference, 1.2%; 95% confidence interval, -0.9 to 3.2). CONCLUSION: Cell-free DNA screening test failures are relatively common. Although repeated testing improves the likelihood of an informative result, pregnancies with a failed cell-free DNA screen upon first attempt remain at increased risk for common autosomal aneuploidies, but not sex chromosome aneuploidies.

Performance of a universal prenatal screening program incorporating cell-free fetal DNA analysis in Ontario, Canada.

BACKGROUND: The emergence of cell-free fetal DNA (cfDNA) testing technology has disrupted the landscape of prenatal screening for trisomies 21 (T21) and 18 (T18). Publicly funded systems around the world are grappling with how to best integrate this more accurate but costly technology, as there is limited evidence about its incremental value in real-world conditions. The objectives of this study were to describe the population-based performance of Ontario's prenatal screening program, which incorporates publicly funded cfDNA screening for specific indications, and the effect of cfDNA testing on the screening and diagnostic choices made by pregnant people. METHODS: We conducted a retrospective, descriptive cohort study using routinely collected data from Better Outcomes & Registry Network (BORN) Ontario, which captures linked population data for prenatal and neonatal health encounters across Ontario. We included all singleton pregnancies with an estimated due date between Sept. 1, 2016, and Mar. 31, 2019, that underwent publicly funded prenatal screening in Ontario, and a comparison cohort from Apr. 1, 2012, and Mar. 31, 2013. We assessed performance of the screening program for the detection of T21 or T18 by calculating sensitivity, specificity, positive predictive value and negative predictive value against diagnostic cytogenetic results or birth outcomes. We assessed the impact of the program by calculating the proportion of T21 screen-positive pregnancies undergoing subsequent cfDNA screening and invasive prenatal diagnostic testing. RESULTS: The study cohort included 373 682 pregnancies. The prenatal screening program had an uptake of 69.9%, a screen-positive rate and sensitivity of 1.6% and 89.9% for T21, and 0.2% and 80.5% for T18, respectively. The test failure rate for cfDNA screening was 2.2%. Invasive prenatal diagnostic testing decreased from 4.4% in 2012-2013 to 2.4% over the study period; 65.2% of pregnant people who received a screen-positive result from cfDNA testing went on to have invasive prenatal diagnostic testing. INTERPRETATION: This publicly funded screening program, incorporating cfDNA analysis for common aneuploidies, showed robust performance, a substantial reduction in invasive prenatal diagnostic testing and that pregnant people exercise autonomy in their choices about prenatal screening and diagnosis.

A 2-year review of publicly funded cell-free DNA screening in Ontario: utilization and adherence to funding criteria.

OBJECTIVE: Ontario offers a publicly funded modified contingent model of prenatal screening for aneuploidy in which cell-free DNA (cfDNA) screening is covered for pregnancies at higher risk of fetal aneuploidy. The objective of this study was to review utilization of provincially funded cfDNA screening and adherence to the criteria laid out in Ontario prenatal screening guidelines. METHODS: This was a descriptive cohort study using data collected by Ontario's prescribed maternal and child registry. The study population included all pregnant individuals who received cfDNA screening from January 2016 to December 2017. RESULTS: The most common criteria for provincially funded cfDNA screening were advanced maternal age ≥40 years (37.7%), positive multiple marker screen (34.1%), modifying risk factors such as ultrasound soft markers (7.1%), and previous aneuploidy (5.5%). The audit demonstrated that 2.9% of funded cfDNA screens tests did not meet funding criteria, and that 11.4% of self-paid cfDNA screens could have been publicly funded. CONCLUSION: Reviewing and auditing the application of criteria for funded cfDNA screening using prescribed registry data allows an opportunity to identify areas where targeted education may improve adherence to standardized screening protocols, and provides a basis for reassessment of the funding model.

Noninvasive Prenatal Testing for Trisomies 21, 18, and 13, Sex Chromosome Aneuploidies, and Microdeletions in Average-Risk Pregnancies: A Cost-Effectiveness Analysis.

OBJECTIVE: The cost effectiveness of noninvasive prenatal testing (NIPT) has been established for high-risk pregnancies but remains unclear for pregnancies at other risk levels. The aim was to assess the cost effectiveness of NIPT in average-risk pregnancies from the perspective of a provincial public payer in Canada. METHODS: A model was developed to compare traditional prenatal screening (TPS), NIPT as a second-tier test (performed only after a positive TPS result), and NIPT as a first-tier test (performed instead of TPS) for trisomies 21, 18, and 13; sex chromosome aneuploidies; and microdeletions in a hypothetical annual population cohort of average-risk pregnancies (142 000 to 148,000) in Ontario, Canada. A probabilistic analysis was conducted with 5000 repetitions. RESULTS: Compared with TPS, NIPT as a second-tier test detected more affected fetuses with trisomies 21, 18, and 13 (188 vs. 158), substantially reduced the number of diagnostic tests (i.e., chorionic villus sampling and amniocentesis) performed (660 vs. 3107), and reduced the cost of prenatal screening ($26.7 million vs. $27.6 million) annually. Compared with second-tier NIPT, first-tier NIPT detected an additional 80 cases of trisomies 21, 18, and 13 at an additional cost of $33 million. The incremental cost per additional affected fetus detected was $412 411. Extending first-tier NIPT to include testing for sex chromosome aneuploidies and 22q11.2 deletion would increase the total screening cost. CONCLUSIONS: NIPT as a second-tier test is cost-saving compared with TPS alone. Compared with second-tier NIPT, first-tier NIPT detects more cases of chromosomal anomalies but at a substantially higher cost.

The Ontario Birth Study: A prospective pregnancy cohort study integrating perinatal research into clinical care.

BACKGROUND: Pregnancy and early childhood represent critical periods that impact health throughout the life-course. The Ontario Birth Study (OBS) is a pregnancy cohort study designed as a platform for research on pregnancy complications, maternal and infant health, and the developmental origins of health and disease. METHODS: Pregnant women <17 weeks gestational age were recruited between 2013 and 2015 from antenatal clinics at Mount Sinai Hospital, Toronto, Canada. Life style and diet questionnaires, biospecimens, and clinical data were collected throughout the pregnancy and postpartum period at the time of clinical care. The OBS was integrated into clinical care to reduce participant burden, improve efficiency, and increase research potential. RESULTS: There were 3181 eligible women approached for recruitment and 1374 (43%) participated in the study. Among the 1374 participants, 1272 (93%) delivered a liveborn infant and were followed to 6-10 weeks postpartum. Of the 1272 women who completed the study, 98% had at least one pregnancy blood sample collected, 97% had vaginal swabs collected, 90% completed the prenatal life style questionnaires, and 78% completed the Diet History Questionnaire. Most women (88%) were ≥30 years of age, 55% had no previous children, 24% were overweight or obese pre-pregnancy and 78% of parents had postsecondary education. Most pregnancies were singleton (3% twins), 34% delivered by caesarean section, and 6% preterm (<37 weeks gestation). CONCLUSIONS: The OBS is a contemporary cohort with detailed data including banked biospecimens for studies of pregnancy health and the gene-environment interactions that establish developmental trajectories to health, learning, and social functioning.

Informed Decision-Making in the Context of Prenatal Chromosomal Microarray.

The introduction of chromosomal microarray (CMA) into the prenatal setting has involved considerable deliberation due to the wide range of possible outcomes (e.g., copy number variants of uncertain clinical significance). Such issues are typically discussed in pre-test counseling for pregnant women to support informed decision-making regarding prenatal testing options. This research study aimed to assess the level of informed decision-making with respect to prenatal CMA and the factor(s) influencing decision-making to accept CMA for the selected prenatal testing procedure (i.e., chorionic villus sampling or amniocentesis). We employed a questionnaire that was adapted from a three-dimensional measure previously used to assess informed decision-making with respect to prenatal screening for Down syndrome and neural tube defects. This measure classifies an informed decision as one that is knowledgeable, value-consistent, and deliberated. Our questionnaire also included an optional open-ended question, soliciting factors that may have influenced the participants' decision to accept prenatal CMA; these responses were analyzed qualitatively. Data analysis on 106 participants indicated that 49% made an informed decision (i.e., meeting all three criteria of knowledgeable, deliberated, and value-consistent). Analysis of 59 responses to the open-ended question showed that "the more information the better" emerged as the dominant factor influencing both informed and uninformed participants' decisions to accept prenatal CMA. Despite learning about the key issues in pre-test genetic counseling, our study classified a significant portion of women as making uninformed decisions due to insufficient knowledge, lack of deliberation, value-inconsistency, or a combination of these three measures. Future efforts should focus on developing educational approaches and counseling strategies to effectively increase the rate of informed decision-making among women offered prenatal CMA.

Enhanced First Trimester Screening for Trisomy 21 with Contingent Cell-Free Fetal DNA: A Comparative Performance and Cost Analysis.

OBJECTIVE: Prenatal screening for trisomy 21 is a standard of care. Emerging cell-free fetal DNA (cffDNA) technologies can improve screening performance, but they are expensive. This study was conducted to propose a contingent screening model that would incorporate cffDNA technology, would remain affordable, and could be applied equitably in a publically funded system. METHODS: Using performance and cost parameters from published literature, four prenatal screening strategies were compared. Scenario 1 modelled integrated prenatal screening (first trimester nuchal translucency and biochemical markers from both the first and second trimesters) with no cffDNA. Scenarios 2 and 3 modelled first trimester combined screening (FTS) and "enhanced FTS" (adding serum placental growth factor and alpha fetoprotein to FTS), respectively, with contingent cffDNA following a positive result. Scenario 4 modelled cffDNA as the primary screening test. RESULTS: Scenario 1 provides a known detection rate (DR) of 88%, with a false positive rate (FPR) of 3.3%. Scenarios 2 and 3 result in a DR of 94% and overall FPR of 0.59% and 0.33%, respectively, comparable to the DR of 96% and FPR of 0.1% with primary cffDNA (assuming the published test failure rate of 3%). The total cost, cost per woman screened, and cost per case of trisomy 21 detected were lower with scenario 3 (enhanced FTS with contingent cffDNA) compared with primary cffDNA or scenario 2 (FTS with contingent cffDNA). CONCLUSION: Enhanced FTS with contingent cffDNA following a positive result provides a similar performance to that of primary cffDNA at a substantially lower cost.

Joint SOGC-CCMG Opinion for Reproductive Genetic Carrier Screening: An Update for All Canadian Providers of Maternity and Reproductive Healthcare in the Era of Direct-to-Consumer Testing.

OBJECTIVE: This guideline was written to update Canadian maternity care and reproductive healthcare providers on pre- and postconceptional reproductive carrier screening for women or couples who may be at risk of being carriers for autosomal recessive (AR), autosomal dominant (AD), or X-linked (XL) conditions, with risk of transmission to the fetus. Four previous SOGC- Canadian College of Medical Geneticists (CCMG) guidelines are updated and merged into the current document. INTENDED USERS: All maternity care (most responsible health provider [MRHP]) and paediatric providers; maternity nursing; nurse practitioner; provincial maternity care administrator; medical student; and postgraduate resident year 1-7. TARGET POPULATION: Fertile, sexually active females and their fertile, sexually active male partners who are either planning a pregnancy or are pregnant (preferably in the first trimester of pregnancy, but any gestational age is acceptable). OPTIONS: Women and their partners will be able to obtain appropriate genetic carrier screening information and possible diagnosis of AR, AD, or XL disorders (preferably pre-conception), thereby allowing an informed choice regarding genetic carrier screening and reproductive options (e.g., prenatal diagnosis, preimplantation genetic diagnosis, egg or sperm donation, or adoption). OUTCOMES: Informed reproductive decisions related to genetic carrier screening and reproductive outcomes based on family history, ethnic background, past obstetrical history, known carrier status, or genetic diagnosis. SOGC REPRODUCTIVE CARRIER SCREENING SUMMARY STATEMENT (2016): Pre-conception or prenatal education and counselling for reproductive carrier screening requires a discussion about testing within the three perinatal genetic carrier screening/diagnosis time periods, which include pre-conception, prenatal, and neonatal for conditions currently being screened for and diagnosed. This new information should be added to the standard reproductive carrier screening protocols that are already being utilized by the most responsible maternity provider through the informed consent process with the patient. (III-A; GRADE low/moderate) SOGC OVERVIEW OF RECOMMENDATIONS QUALITY AND GRADE: There was a strong observational/expert opinion (quality and grade) for the genetic carrier literature with randomized controlled trial evidence being available only for the invasive testing. Both the Canadian Task Force on Preventive Health Care quality and classification and the GRADE evidence quality and grade are provided. EVIDENCE: MEDLINE; PubMed; government neonatal screening websites; key words/common reproductive genetic carrier screened diseases/previous SOGC Guidelines/medical academic societies (Society of Maternal-Fetal Medicine [SMFM]; American College of Medical Genetics and Genomics; American College of Obstetricians and Gynecologists [ACOG]; CCMG; Royal College Obstetrics and Gynaecology [RCOG] [UK]; American Society of Human Genetics [ASHG]; International Society of Prenatal Diagnosis [ISPD])/provincial neonatal screening policies and programs; search terms (carrier screening, prenatal screening, neonatal genetic/metabolic screening, cystic fibrosis (CF), thalassemia, hemoglobinopathy, hemophilia, Fragile X syndrome (FXS), spinal muscular atrophy, Ashkenazi Jewish carrier screening, genetic carrier screening protocols, AR, AD, XL). SEARCH PERIOD: 10 years (June 2005-September 2015); initial search dates June 30, 2015 and September 15, 2015; completed final search January 4, 2016. Validation of articles was completed by primary authors RD Wilson and I De Bie. BENEFITS, HARMS, AND COST: Benefits are to provide an evidenced based reproductive genetic carrier screening update consensus based on international opinions and publications for the use of Canadian women, who are planning a pregnancy or who are pregnant and have been identified to be at risk (personal or male partner family or reproductive history) for the transmission of a clinically significant genetic condition to their offspring with associated morbidity and/or mortality. Harm may arise from having counselling and informed testing of the carrier status of the mother, their partner, or their fetus, as well as from declining to have this counselling and informed testing or from not having the opportunity for counselling and informed testing. Costs will ensue both from the provision of opportunities for counselling and testing, as well as when no such opportunities are offered or are declined and the birth of a child with a significant inherited condition and resulting morbidity/mortality occurs; these comprise not only the health care costs to the system but also the social/financial/psychological/emotional costs to the family. These recommendations are based on expert opinion and have not been subjected to a health economics assessment and local or provincial implementation will be required. GUIDELINE UPDATE: This guideline is an update of four previous joint SOGC-CCMG Genetic Screening Guidelines dated 2002, 2006, 2008, and 2008 developed by the SOGC Genetic Committee in collaboration with the CCMG Prenatal Diagnosis Committee (now Clinical Practice Committee). 2016 CARRIER SCREENING RECOMMENDATIONS.

Antepartum Screening for Maternal Infection and Immune Status: Is it Time to Broaden Our Routine?

Maternal infections with PVB19, HCV, CMV, and HIV during the antepartum period are important health problems for which the technological capacities for screening and diagnosis during the antepartum period are available. Each of these viruses requires individual consideration for inclusion in screening and for the method of screening during the antepartum period. The availability of efficacious treatments for HCV and CMV, with demonstrable benefits to the mother or fetus, is required before antepartum screening for these infections can be justified. Screening for parvovirus B19 presents a greater concern because it meets most of the features of a screening test (Wilson's criteria) endorsed by the WHO. There is insufficient evidence to argue strongly for implementation of antepartum PVB19 screening, but the available evidence indicates a need for large studies of potential effectiveness and costs of routine PVB19 screening, either for all pregnant woman or for those at high risk of exposure to PVB19. While the technology to screen for HCV, PVB19, and CMV certainly exists, there must be careful consideration of the downstream implications of routine screening at the level of the individual patient, the general population, and other health care resources, including laboratory infrastructure, before recommending that these infections be screened for routinely in the antepartum period. A strategy for national adoption of an opt-out screening strategy for HIV should be considered.

Ultrasonographic Fetal Nuchal Translucency Measurements and Cytogenetic Outcomes.

Importance: Ultrasonographic measurement of fetal nuchal translucency is used in prenatal screening for trisomies 21 and 18 and other conditions. A cutoff of 3.5 mm or greater is commonly used to offer follow-up investigations, such as prenatal cell-free DNA (cfDNA) screening or cytogenetic testing. Recent studies showed a possible association with chromosomal anomalies for levels less than 3.5 mm, but extant evidence has limitations. Objective: To evaluate the association between different nuchal translucency measurements and cytogenetic outcomes on a population level. Design, Setting, and Participants: This population-based retrospective cohort study used data from the Better Outcomes Registry & Network, the perinatal registry for Ontario, Canada. All singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, were included. Data were analyzed from March 17 to August 14, 2023. Exposures: Nuchal translucency measurements were identified through multiple-marker screening results. Main Outcomes and Measures: Chromosomal anomalies were identified through all Ontario laboratory-generated prenatal and postnatal cytogenetic tests. Cytogenetic testing results, supplemented with information from cfDNA screening and clinical examination at birth, were used to identify pregnancies without chromosomal anomalies. Multivariable modified Poisson regression with robust variance estimation and adjustment for gestational age was used to compare cytogenetic outcomes for pregnancies with varying nuchal translucency measurement categories and a reference group with nuchal translucency less than 2.0 mm. Results: Of 414 268 pregnancies included in the study (mean [SD] maternal age at estimated delivery date, 31.5 [4.7] years), 359 807 (86.9%) had a nuchal translucency less than 2.0 mm; the prevalence of chromosomal anomalies in this group was 0.5%. An increased risk of chromosomal anomalies was associated with increasing nuchal translucency measurements, with an adjusted risk ratio (ARR) of 20.33 (95% CI, 17.58-23.52) and adjusted risk difference (ARD) of 9.94% (95% CI, 8.49%-11.39%) for pregnancies with measurements of 3.0 to less than 3.5 mm. The ARR was 4.97 (95% CI, 3.45-7.17) and the ARD was 1.40% (95% CI, 0.77%-2.04%) when restricted to chromosomal anomalies beyond the commonly screened aneuploidies (excluding trisomies 21, 18, and 13 and sex chromosome aneuploidies). Conclusions and Relevance: In this cohort study of 414 268 singleton pregnancies, those with nuchal translucency measurements less than 2.0 mm were at the lowest risk of chromosomal anomalies. Risk increased with increasing measurements, including measurements less than 3.5 mm and anomalies not routinely screened by many prenatal genetic screening programs.

The impact of maternal weight discrepancies on prenatal screening results for Down syndrome.

OBJECTIVE: This study aimed to assess the quantitative impact of maternal weight discrepancy on the screen result for Down syndrome when using Integrated Prenatal Screening and First Trimester Combined Screening. METHODS: The study population consisted of 78,165 women undergoing prenatal screening in Ontario, Canada, and 158 pregnancies affected with Down syndrome at one Ontario center. The study assessed quantitative alterations of the multiple of the median values of first and second-trimester serum markers and the risks of Down syndrome at a set of theoretical weight discrepancies. RESULTS: Weight discrepancies have the greatest impact on screening results when the initial risk is close to the risk cut-off. When the weight discrepancy is 5 lb or greater and the denominator of the initial risk is within 50 of the risk cut-off, the chance that a screen result will change from positive to negative or from negative to positive is 47-55% for women undertaking Integrated Prenatal Screening. This chance is 33-43% for women undertaking First Trimester Combined Screening. CONCLUSION: A weight discrepancy of five or more pounds has a significant impact on the risk of Down syndrome; correction of maternal weight would improve the accuracy of the screening test.

First and second trimester maternal serum markers for prenatal aneuploidy screening: An update on the adjustment factors for race, smoking, and insulin dependent diabetes mellitus.

OBJECTIVES: The concentrations of maternal serum markers for aneuploidy screening are influenced by maternal characteristics such as race, smoking, insulin dependent diabetes mellitus (IDDM), and in vitro fertilization (IVF). Accurate risk estimation requires adjustment of initial values for these characteristics. This study aims to update and validate adjustment factors for race, smoking, and IDDM. METHODS: The study included singleton pregnancies that received multiple marker screening in Ontario, Canada between January 2012, and December 2018, and had their information collected in the Better Outcomes Registry & Network (BORN) Ontario. Serum markers assessed included first trimester pregnancy-associated plasma protein A (PAPP-A), free ß and total human chorionic gonadotropin (hCG), placental growth factor (PlGF) and αlpha-fetoprotein (AFP); second trimester AFP, unconjugated estriol (uE3), total hCG and inhibin A. The Mann-Whitney U test was used to assess the differences in the median multiple of the median (MoM) of serum markers between study and reference groups. New adjustment factors were generated by dividing the median MoM of a particular race, individuals who smoke tobacco, or have IDDM by those of the reference groups. RESULTS: The study included 624,789 pregnancies. There were statistically significant differences in serum marker concentrations among pregnant individuals who were Black, Asian, or First Nations compared to a White group, those who smoked compared to Non-smoking individuals, and those with IDDM compared to Non-IDDM group. New adjustment factors for race, smoking, and IDDM were validated by comparing median MoM of serum markers corrected using the current adjustment factors and new adjustment factors generated in this study. CONCLUSION: The adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Combinations of maternal serum markers to predict preeclampsia, small for gestational age, and stillbirth: a systematic review.

OBJECTIVE: Abnormal serum screening markers have been associated with adverse pregnancy outcomes. We sought to review the performance of combined abnormal first and/or second trimester maternal serum markers used in prenatal screening for aneuploidy and open neural tube defects for predicting preeclampsia (PET), small for gestational age (SGA), and stillbirth beyond 24 weeks' gestation. DATA SOURCES AND STUDY SELECTION: Medline, EMBASE, and Cochrane Library databases were searched for studies from 1970 to May 2010 that analyzed predictive abilities of combined serum markers for defined outcomes. DATA EXTRACTION AND SYNTHESIS: Data were extracted independently by two authors, and 15 studies were included. Eight studies of 115,290 pregnancies, 11 studies of 144 853 pregnancies, and seven studies of 80 274 pregnancies examined PET, SGA, and stillbirth respectively. Because of the heterogeneity of marker combinations and thresholds, outcome definitions, and analytic methods, limited meta-analysis was possible for the outcomes of PET and SGA only. Three relatively homogeneous studies on prediction of PET, and two on prediction of SGA were meta-analyzed. Several single studies demonstrated utility in combining markers to predict adverse outcome; however, this effect was not confirmed after meta-analysis. The most common combination of markers evaluated was alpha fetoprotein and human chorionic gonadotrophin for all outcomes. The highest positive likelihood ratios for predicting PET (5.68; 95% CI 0.73 to 43.97) and SGA (6.18; 95% CI 1.84 to 20.85) were seen with combined alpha fetoprotein and human chorionic gonadotrophin (> 2.5 multiples of the median). CONCLUSIONS: Currently, no identifiable combination of serum markers performs well as a screening test for preeclampsia, small for gestational age, and stillbirth beyond 24 weeks. Large cohort studies with standardized screening test parameters and outcomes are needed.

Fetal anatomic survey using three-dimensional ultrasound in conjunction with first-trimester nuchal translucency screening.

OBJECTIVE: To determine the visualization rates of fetal anatomic structures by three-dimensional ultrasound (3DUS) at 12-13 weeks of gestation. STUDY DESIGN: This was a prospective observational study of women presenting for nuchal translucency ultrasound. Five 3D volumes of the fetus were acquired transabdominally. Two investigators independently reviewed the stored volumes offline following a standardized protocol. RESULTS: One hundred singleton fetuses were examined. The mean time for 3D volumes acquisition was 4.8 min; and for 3D review 17 min. Anatomic structures were seen as follows: cranium, lateral cerebral ventricles and abdominal wall 100%; stomach, vertebrae, upper and lower limbs >or= 94%; face 71%, bladder 58%, both kidneys 39%, skin overlying spine 26% and heart 18%. Agreement between two observers ranged from 100% (for head, abdominal wall and lower limbs) to 43% (for visualization of skin overlying spine). A complete basic anatomic survey was achieved in 11.4% of the 12-week fetuses and 33.3% of the 13-week fetuses (p-value = 0.038). CONCLUSIONS: First-trimester transabdominal 3DUS was adequate for assessment of the head, abdominal wall, stomach, limbs and vertebral alignment. It was less effective for evaluating the heart and intactness of the skin over the spine.

An assessment of women's knowledge of and views on the reporting of ultrasound soft markers during the routine anatomy ultrasound examination.

OBJECTIVE: To assess women's knowledge of and views on the evaluation and reporting of ultrasound soft markers. METHODS: A prospective survey of 263 women undergoing 18 to 20 week anatomy ultrasound examination at Mount Sinai Hospital, a level 3 perinatal referral centre for a multi-ethnic population of approximately 2.5 million. RESULTS: Prior to reading an information pamphlet provided in the context of this survey, 30% of women (79/263) reported having heard of the term soft marker and 59% of these women (47/79) had discussed soft markers with their caregiver. When asked their preferences about the reporting of ultrasound soft markers, 53% of women said that soft markers should be reported routinely, 20% said they should be reported when the caregiver thinks it necessary, and 23% preferred they be reported only when they have been discussed prior to the ultrasound examination. A minority of respondents (8%) had not participated in prenatal screening for aneuploidy. All of these women preferred that soft markers be reported only after pre-screening discussion. CONCLUSION: The study demonstrates that most women have little prior knowledge about routine examination for soft markers during the anatomy ultrasound examination and emphasizes the importance of expanding counselling and informed consent to include this aspect of prenatal screening.