Multiple Marker Screening Research Articles

Outcomes of pregnancies with varying levels of nuchal translucency measurements: A population-based retrospective study in Ontario, Canada.

Nuchal translucency prenatal ultrasound is widely used to screen for chromosomal abnormalities. An elevated nuchal translucency has been associated with adverse outcomes such as pregnancy loss; however, extant studies investigating these associations have had important limitations, including selection bias. This study aimed to investigate the association between nuchal translucency measurements and pregnancy outcome, specifically, a composite of pregnancy loss, termination, stillbirth, or neonatal death. This was a population-based retrospective cohort study conducted with data from the prescribed perinatal registry in Ontario, Canada, Better Outcomes Registry & Network. All singleton pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, and multiple marker screening including a nuchal translucency were included. Pregnancies with measurements 2.0- < 2.5 mm, 2.5- < 3.0 mm, 3.0- < 3.5 mm, 3.5- < 5.0 mm, 5.0- < 6.5 mm, and ≥6.5 mm were compared to a reference group with measurements <2.0 mm. We used multivariable modified Poisson regression models with robust variance estimation to estimate associations between nuchal translucency measurement and pregnancy outcome, with adjustment for age at estimated date of delivery and gestational age at screening. There were 414 268 singleton pregnancies included in the study. The risk of pregnancy loss, termination, stillbirth, or neonatal death increased with increasing levels of nuchal translucency measurements, with an adjusted risk ratio (aRR) of 11.9 (95% confidence interval (CI) 9.9, 14.3) in the group with measurements 3.5- < 5.0 mm. When pregnancies with diagnosed chromosomal abnormalities were excluded, this association remained strong, with an aRR of 6.4 (95% CI 4.8, 8.5). Among pregnancies with a live birth, those with a higher nuchal translucency measurement (>5.0 mm vs. <2.0 mm) were also at increased risk of adverse perinatal outcomes such as admission to the neonatal intensive care unit and APGAR score <7. In this population-based study using robust methods to reduce the risk of selection bias, we found that pregnancies with increased nuchal translucency measurements are less likely to result in a live birth, even with the exclusion of chromosomal abnormalities. Pregnancies with increased nuchal translucency measurements that resulted in a live birth may also be at increased risk of adverse perinatal outcomes.

Pregnancies with ‘double-positive’ multiple marker screening results: a population-based study in Ontario, Canada

BackgroundMultiple marker screening is offered to pregnant individuals in many jurisdictions to screen for trisomies 21 and 18. On occasion, the result is ‘double-positive’—a screening result that is unexpectedly positive for both aneuploidies. Although this occurs rarely, the paucity of available evidence about the outcomes of these pregnancies hinders patient counselling. This study aimed to investigate the association of double-positive results with preterm birth and other adverse perinatal outcomes.MethodsWe conducted a population-based retrospective cohort study of pregnancies with an estimated date of delivery from September 1, 2016, to March 31, 2021, using province-wide perinatal registry data in Ontario, Canada. Pregnancies with double-positive screening results where trisomies 21 and 18 were ruled-out were compared to pregnancies with screen negative results for both aneuploidies. We used modified Poisson regression models with robust variance estimation to examine the association of double positive results with preterm birth and secondary outcomes.ResultsFrom 429 540 pregnancies with multiple marker screening, 863 (0.2%) had a double-positive result; trisomies 21 and 18 were ruled out in 374 pregnancies, 203 of which resulted in a live birth. Among the pregnancies in the double-positive group resulting in a live birth, the risk of preterm birth was increased compared to pregnancies with a screen negative result: adjusted risk ratio (aRR) 2.6 (95%CI 2.0-3.6), adjusted risk difference (aRD) 10.5% (95%CI 5.4–15.7). In a sensitivity analysis excluding all diagnosed chromosomal abnormalities, the risk of preterm birth remained elevated to a similar degree: aRR 2.6 (95%CI 1.9–3.7), aRD 10.0% (95%CI 4.8–15.3). The risk of other adverse perinatal outcomes was also higher, including the risk of chromosomal abnormalities other than trisomies 21 and 18: aRR 81.1 (95%CI 69.4–94.8), aRD 34.0% (95%CI 29.2–38.8). Pregnancies with double-positive results were also less likely to result in a live birth, even when excluding all diagnosed chromosomal abnormalities; and at increased risk of adverse perinatal outcomes for those resulting in a live birth.ConclusionAlthough rare, double-positive multiple marker screening results are associated with an increased risk of preterm birth and other adverse perinatal outcomes, even when excluding all identified chromosomal abnormalities.

Ultrasonographic Fetal Nuchal Translucency Measurements and Cytogenetic Outcomes

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. To evaluate the association between different nuchal translucency measurements and cytogenetic outcomes on a population level. 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. Nuchal translucency measurements were identified through multiple-marker screening results. 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. 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). 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.

Cytogenetic Outcomes Following a Failed Cell-Free DNA Screen: A Population-Based Retrospective Cohort Study of 35,146 Singleton Pregnancies

(Abstracted from Am J Obstet Gynecol 2023;229:168.e1–e8) Cell-free DNA (cfDNA) screening is a form of prenatal genetic screening for aneuploidies. This method boasts lower false-positive rates than multiple-marker screening methods and is now commonly recommended.

Implementation of Multiple Marker Screening for Preterm Preeclampsia in a Single Tertiary Obstetric Centre

ObjectivesEarly assessment of pregnant individuals for risk of preterm preeclampsia (PE) is possible at the 11–14 week ultrasound visit using a validated multiple marker algorithm, allowing timely use of preventative low-dose acetylsalicylic acid (LDA) in high-risk patients. With no established early screening program for preterm PE in Canada, our objectives were to assess the acceptability and operational impact of routine screening for preterm PE during the 11–14 week ultrasound visit, evaluate uptake and adherence to LDA when recommended, and assess screening performance. MethodsA prospective implementation study of preterm PE screening among pregnant patients at the ultrasound unit of a tertiary obstetric centre in Toronto, Canada. ResultsA total of 1057 patients were screened, with an acceptance rate of 87.1%. First-trimester ultrasound appointment time increased by a median time of 7 minutes (Interquartile range 6–9). By 16 weeks gestation, 88.7% of high-risk patients had started LDA, with adherence of 88.7%‒94.6% from 16‒36 weeks. Satisfaction with counselling was ≥7/10 in more than 95% of patients. There were 7 cases of preterm PE (0.73%), 3 in the low-risk group (0.35%), and 4 in the high-risk group (4.1%). When accounting for LDA use, the treatment-adjusted detection rate was 78.6%. ConclusionsWe demonstrate successful implementation of a validated, effective screening and prevention program for preterm PE as a first step in the implementation of a broader program adaptable for cultural, access/equity considerations, and marker availability.

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

ObjectivesThe 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. MethodsThe 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 β 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. ResultsThe 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. ConclusionThe adjustment factors generated in this study can adjust the effects of race, smoking, and IDDM on serum markers more accurately.

Prenatal screening for preeclampsia: the roles of placental growth factor and pregnancy–associated plasma protein A in the first trimester and placental growth factor and soluble fms-like tyrosine kinase 1–placental growth factor ratio in the early second trimester

Professional societies have recommended universal first trimester screening for preeclampsia and a second or third trimester soluble fms-like tyrosine kinase-1-placental growth factor ratio test to assess for preeclampsia and its severity. However, it may not be feasible to implement the most optimal screening protocol for preeclampsia in the first trimester which uses a combination of maternal characteristics, maternal biophysical and biochemical markers due to limitations in the access to uterine artery doppler ultrasound. There are inconsistent findings on how early in the second trimester the fms-like tyrosine kinase-1-placental growth factor ratio begins to provide useful information in preeclampsia prediction. This study aimed to assess the accuracy of (1) a combination of maternal characteristics, maternal serum pregnancy-associated plasma protein A, and placental growth factor in the screening for preeclampsia in the first trimester; and (2) placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio in the prediction of preeclampsia in the early second trimester. This retrospective case-control study used frozen residual blood samples from women who had aneuploidy screening and delivered at a tertiary center. The case group included pregnancies with gestational hypertension or preeclampsia (further classified as early-onset [birth at <34 weeks' gestation] and preterm preeclampsia [birth at <37 weeks' gestation]). Each case was matched with 3 control pregnancies by date of blood sample draw, gestational age at first blood sample draw, maternal age, maternal ethnicity, type of multiple-marker screening, and amount of residual sample. Mann-Whitney U tests were used to assess the associations between serum markers and the risk of preeclampsia. Logistic regressions were used to assess if the risk of preeclampsia can be predicted using a combination of maternal characteristics and serum markers. The case group included 146 preeclampsia and 295 gestational hypertension cases. Compared with the controls, preeclampsia cases had significantly lower first-trimester pregnancy-associated plasma protein A and placental growth factor. At a 20% false-positive rate, 71% of early-onset and 58% of preterm preeclampsia cases can be predicted using maternal characteristics, pregnancy-associated plasma protein A, and placental growth factor. Preeclampsia cases had lower second-trimester placental growth factor and a higher soluble fms-like tyrosine kinase-1-placental growth factor ratio. At a 10% false-positive rate, 80% and 53% of early-onset preeclampsia can be predicted using maternal characteristics and placental growth factor or soluble fms-like tyrosine kinase-1-placental growth factor ratio, respectively. The current first-trimester aneuploidy screening programs may be expanded to identify women at increased risk of developing preeclampsia. Early in the second trimester, placental growth factor alone provided better prediction for preeclampsia compared with the soluble fms-like tyrosine kinase-1-placental growth factor ratio.

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

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. 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). 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. 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). 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.

Extending the provision of cell-free DNA screening for trisomy21.

It is now 12 years since the discovery that fetal cfDNA fragments in maternal plasma can be used to detect Down syndrome. This single marker has a detection rate above 99% and a false-positive rate below 0.2%, a performance greatly exceeding conventional multiple serum and ultrasound marker screening tests. Nevertheless, there has not been widespread replacement of conventional screening by cfDNA. Commercial providers report annual cfDNA testing totaling millions but this covers only a few percent of pregnancies worldwide.

Diagnostic accuracy of maternal serum multiple marker screening for early detection of gestational diabetes mellitus in the absence of a gold standard test

BackgroundGestational diabetes mellitus (GDM) is associated with adverse diabetic complications for both mother and child during pregnancy. The common Gold Standard (GS) for diagnosis of GDM is 75 g oral glucose tolerance test (OGTT) during 24–28 gestational weeks which seems a little late for any proper intervention. This study aimed to employ the Bayesian latent class models (LCMs) for estimating the early diagnostic power of combination of serum multiple marker in detecting GDM during 14–17 weeks of gestation.MethodsData from a sample of 523 pregnant women who participated in gestational diabetes screening tests at health centers affiliated to Shahid Beheshti University of Medical Sciences in Tehran, Iran from 2017 to 2018 were used. The beta-human chorionic gonadotropin (β-hCG), unconjugated estriol (uE3), and alfa-fetoprotein (AFP) values were extracted from case records for all participants. The Bayesian LCMs were applied for estimating sensitivity, specificity, and area under receiver operating characteristic curve (AUC) of combining the three biomarkers’ results in the absence of GS, adjusting for maternal age and body mass index.ResultsThe mean (standard deviation) maternal age of the participants was 28.76 (±5.33) years. Additionally, the mean (standard deviation) BMI was 24.57 (±3.22) kg/m2. According to the Bayesian model, the cSensitivity, cSpecificity, and cAUC for the optimal composite diagnostic test were estimated as 94% (95% credible interval (CrI) [0.91–0.99]), 86% (95% CrI [0.80–0.92]), and 0.92 (95% CrI [0.87–0.98]), respectively.ConclusionsOverall, the findings revealed that the combination of uE3, AFP, and β-hCG results might be considered as an acceptable predictor for detecting GDM with a rather high level of accuracy in the early second trimester of pregnancy without a GS.

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

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. 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. 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. 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.

Trends in the use of prenatal testing services for fetal aneuploidy in Ontario: a descriptive study.

In 2014, Ontario augmented its publicly funded multiple-marker screening program for prenatal aneuploidy by incorporating cell-free fetal DNA (cffDNA) analysis for high-risk pregnancies. We assessed trends in the use of multiple-marker screening, cffDNA screening and prenatal diagnostic testing before and after implementation of public funding. We conducted a descriptive study based on data from the Better Outcomes Registry & Network (BORN) Ontario. The study population included all pregnant women in Ontario with a singleton pregnancy and an expected date of delivery between July 1, 2012, and Mar. 31, 2016, with pregnancy data captured in BORN. Pregnancy losses and terminations before 20 weeks' gestation not captured in BORN were excluded. We generated descriptive statistics to show trends and regional variations in use. The study sample included 534 210 singleton pregnancies. After cffDNA screening was funded for specific indications, uptake of multiple-marker screening increased slightly, from 66.5% to 68.1% (p < 0.001). Uptake of cffDNA screening among women with a positive multiple-marker screening result increased substantially, from 3.2% to 48.8% (p < 0.001). In contrast, the rate of prenatal diagnostic testing in this group decreased from 54.8% to 30.8% (p < 0.001). Although women aged 40 years or older are eligible for primary cffDNA screening, only a small decrease in the use of multiple-marker screening was observed in this group. The greatest use of cffDNA screening and greatest decline in prenatal diagnostic testing were seen in women with a level of risk for trisomy 21 of 1:101-1:200 based on multiple-marker screening. After public funding of cffDNA screening was implemented in Ontario, there was a significant increase in cffDNA screening and a significant decrease in prenatal diagnostic testing among women with a positive multiple-marker screening result. These changing patterns show the significant impact of public policy and funding decisions on women's choices regarding prenatal testing.

Sociodemographic and attitudinal predictors of simultaneous and redundant multiple marker and cell-free DNA screening among women aged ⩾35 years.

ObjectiveTo identify characteristics associated with undergoing cell-free DNA (cfDNA) and multiple marker screening (MMS) simultaneously or redundantly (after receiving negative results from the first screening test) among women aged 35 and older.Study DesignParticipants presenting for prenatal testing completed a questionnaire which included measures of pregnancy worry and attitudes toward potential testing outcomes; data on prenatal test use was obtained via medical record review. We used multivariable logistic regression to identify factors associated with redundant or simultaneous screening.ResultAmong 164 participants, 69 (42.1%) had cfDNA redundantly (n=51) to, or simultaneously (n=18) with, MMS. Compared to the 46 MMS-negative women who did not undergo further testing, those who underwent redundant or simultaneous cfDNA/MMS screening were more likely to have annual family incomes >$150,000, to feel having a miscarriage would be worse than having an intellectually disabled child, to desire comprehensive testing for intellectual disability, and to have more pregnancy worry.ConclusionProviders who counsel patients on prenatal aneuploidy screening tests should explain the appropriate utilization of these screening tests to avoid unnecessary or minimally informative use of multiple tests.

QUAD versus cfDNA in an urban population in the second trimester for detection of trisomy 21: a cost sensitivity analysis

Objective: To compare the unit cost of noninvasive prenatal testing (cell-free DNA [cfDNA]) in an urban population who did not have first-trimester screening as a primary screening tool for trisomy 21 (T21) to multiple marker screening (QUAD).Methods: Retrospective study of all QUAD screens performed at a single center from 2013 to 2015. All QUAD screen performed between 15 and 21 weeks were included in the study. Exclusion criteria were patients without anatomy scans or delivery information. Utilizing our population characteristics, we extrapolated to determine the cost of QUAD with additional screening (cfDNA and amniocentesis) versus QUAD for this entire population.Results: 590 QUAD screens were performed during the study time period. After ultrasound correction of gestational age, 5.9% (35) were screen positive. Within this cohort, 51.4% (18) patients underwent cfDNA and 11.4% (4) had invasive testing. No cases of T21 were identified. It would be cost equivalent to offer cfDNA as a primary screen for T21 at less than $360.54 to the entire population regardless of a priori risk status. Invasive procedures were reduced by 55.4%.Conclusions: cfDNA is an acceptable option for second-trimester screening and as a primary screen eliminates the need for multi-step screening preserving valuable healthcare resources.

Preferences regarding contemporary prenatal genetic tests among women desiring testing: implications for optimal testing strategies.

To compare utilities for prenatal testing outcomes among women inclined to continue their pregnancy despite abnormal results versus those inclined to terminate and to analyze how differences affect optimal prenatal testing strategies. Time tradeoff utilities for 23 outcomes were elicited from 281 women. We compared utilities based on termination inclination and applied them to a decision-analytic framework. Of participants, 46.6% indicated that they would 'definitely' or 'probably' continue their pregnancy despite results indicating an intellectual disability. These women assigned higher utilities to abnormal testing results and having a child with an intellectual disability than women who would probably or definitely terminate. Primary cell-free DNA screening had the most quality-adjusted life years for women inclined to continue their pregnancy but yielded an incremental cost-effectiveness ratio (ICER) of $1 685 449. Multiple marker screening with either cell-free DNA or diagnostic testing as follow-up had an ICER of $9037. Primary diagnostic testing resulted in the most quality-adjusted life years for women inclined to terminate, with an ICER of $111 776. Women seeking testing vary in prenatal testing outcome preferences and termination inclinations in the context of results indicating an intellectual disability. How they envision utilizing prenatal testing information impacts their optimal testing strategy. © 2016 John Wiley & Sons, Ltd.

Prenatal Testing in the Genomic Age: Clinical Outcomes, Quality of Life, and Costs.

To use a decision-analytic model to assess a comprehensive set of outcomes of prenatal genetic testing strategies among women of varying ages. We assessed outcomes of six testing strategies incorporating diagnostic testing with chromosomal microarray, multiple marker screening, cell-free DNA screening, and nuchal translucency screening alone, in combination, or in sequence. Clinical outcomes included prenatal detection or birth of a neonate with a significant chromosomal abnormality and diagnostic procedures performed. Other outcomes included maternal quality-adjusted life-years and costs. Sensitivity analyses were conducted to examine the robustness of the findings. At all ages assessed, screening strategies starting with multiple marker screening offered the highest detection rate when all chromosomal abnormalities were considered. Incorporating cell-free DNA as an optional secondary screen decreased the number of diagnostic procedures, but also decreased the number of abnormalities diagnosed prenatally, resulting in a similar number of procedures per case diagnosed at age 30 years; the option of secondary cell-free DNA screening becomes more favorable at older ages. Multiple marker screening with optional follow-up diagnostic testing was the most effective (highest quality-adjusted life-years) and least expensive strategy at ages 20-38 years. At age 40 years or older, cell-free DNA screening was optimal with an incremental cost-effectiveness ratio of $73,154 per quality-adjusted life-year. When considering all detectable chromosome problems as well as patient preferences and baseline risks, multiple marker screening with the option of diagnostic testing for screen-positive results is the optimal strategy for most women. At age 40 years and older, cell-free DNA as a primary screen becomes optimal and is cost-effective. II.

NSGC Practice Guideline: Prenatal Screening and Diagnostic Testing Options for Chromosome Aneuploidy

The BUN and FASTER studies, two prospective multicenter trials in the United States, validated the accuracy and detection rates of first and second trimester screening previously reported abroad. These studies, coupled with the 2007 release of the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin that endorsed first trimester screening as an alternative to traditional second trimester multiple marker screening, led to an explosion of screening options available to pregnant women. ACOG also recommended that invasive diagnostic testing for chromosome aneuploidy be made available to all women regardless of maternal age. More recently, another option known as Non-invasive Prenatal Testing (NIPT) became available to screen for chromosome aneuploidy. While screening and testing options may be limited due to a variety of factors, healthcare providers need to be aware of the options in their area in order to provide their patients with accurate and reliable information. If not presented clearly, patients may feel overwhelmed at the number of choices available. The following guideline includes recommendations for healthcare providers regarding which screening or diagnostic test should be offered based on availability, insurance coverage, and timing of a patient's entry into prenatal care, as well as a triage assessment so that a general process can be adapted to unique situations.

First‐trimester maternal vitamin D status and risk for gestational diabetes (GDM) a nested case‐control study

Vitamin D deficiency may contribute to impaired glucose metabolism. There are sparse data regarding vitamin D and the development of gestational diabetes (GDM). The objective of this study was to assess if first-trimester vitamin D deficiency is more prevalent in women later diagnosed with GDM compared with women with uncomplicated pregnancies. We conducted a nested case-control study of pregnant women who had previously given blood for routine genetic multiple marker screening and subsequently delivered at a tertiary hospital between November 2004 and July 2009. From an overall cohort of 4225 women, 60 cases of GDM were matched by race/ethnicity with 120 women delivering at term (≥37 weeks) with uncomplicated pregnancies. Banked maternal serum was used to measure maternal 25-hydroxyvitamin D [25(OH)D]. The prevalence of first-trimester maternal vitamin D deficiency (defined as 25(OH)D < 50 nmol/L) was comparable among women with GDM compared with controls (5/60 vs 8/120, p = 0.90). The median 25(OH)D level for all subjects was 89 nmol/L (interquartile range, 73-106 nmol/L). Seventy three percent (117/160) of the cohort had 25(OH)D levels ≥75 nmol/L. In a cohort of pregnant women with mostly sufficient levels of serum 25(OH)D, vitamin D deficiency was not associated with GDM. Further studies are warranted with larger cohorts, especially in populations with lower levels of vitamin D.

505: Prediction of preterm birth in triplet pregnancy

Lidewij van de Mheen, Anita Ravelli, Maria van Pampus, Christianne de Groot, Eva Pajkrt, Ben Willem Mol Onze Lieve Vrouwe Gasthuis Amsterdam, Obestetrics and Gynaecology, Amterdam, Netherlands, Academic Medical Center, Medical Informatics, Amsterdam, Netherlands, Onze Lieve Vrouwe Gasthuis, Obestetrics and Gynaecology, Amsterdam, Netherlands, VU Medical Centre, Obstetrics and Gynaecology, Amsterdam, Netherlands, Academic Medical Center, Department of Obstetrics and Gynaecology, Amsterdam, Netherlands, Dutch consortium AMPHIA trial, ., ., Netherlands OBJECTIVE: Some clinicians advise prophylactic administration of antenatal steroids for fetal lung ripening in women with a triplet pregnancy, irrespective of the development of signs and symptoms that announce preterm delivery. The aim of this study was to assess the natural course of triplet pregnancies by calculating the risk of delivery in a particular time frame during gestation. STUDY DESIGN: We collected data on all triplet pregnancies in the Netherlands from 1999-2007 from the Dutch Perinatal Registration (PRN). From these data, we constructed a Kaplan Meier curve for time to delivery, and calculated the risk of delivery within two weeks for different gestational ages. RESULTS: Between 1999 and 2007, there were 575 triplet pregnancies in the Netherlands, of which 367 after artificial reproductive techniques and 208 after spontaneous conception. The mean gestational age at delivery was 32.8 weeks (SD 3.8 weeks) (figure 1), Artificially conceived triplets were on average 0.4 weeks longer pregnant (data not shown). There were 22 pregnancies (4%) that ended before 24 weeks. At a gestational age of 24 weeks, the change to deliver within the next two weeks was 2%. For 26, 28, 30 and 32 weeks these risks were 5%, 6%,13% and 31%, respectively (table 1). The probability to continue the pregnancy until a gestational age of 37 weeks was approximately 7%. CONCLUSION: Mean gestational age for triplet pregnancies in The Netherlands was 32.8 weeks. Before 32 weeks of gestation, prophylactic administration of steroids is not indicated. At a gestational age of 32 weeks, prophylactic antenatal corticosteroids could be considered in a triplet pregnancy. 506 Midtrimester Vitamin D status is not associated with spontaneous preterm birth prior to 35 weeks Luisa Wetta, Joseph Biggio, Suzanne Cliver, Adi Abramovici, Stephen Barnes, Alan Tita University of Alabama at Birmingham, Obstetrics & Gynecology, Birmingham, AL, University of Alabama at Birmingham, Department of Pharmacology and Toxicology, Birmingham, AL OBJECTIVE: Preterm birth (PTB) has been associated with deficient maternal vitamin D status in some studies. Measurement methodologies, patient populations, and seasonal variation may all affect results. We evaluated whether midtrimester serum vitamin D levels are associated with spontaneous(S) PTB prior to 35 weeks gestation. STUDY DESIGN: We conducted a nested case-control study of 100 women with SPTB prior to 35 weeks gestation (cases) and 200 healthy women who delivered at 39-40 weeks (controls). Stored remnant serum specimens from a midtrimester sample drawn between 15-21 weeks gestation for multiple marker screening were tested for total 25-hydroxy vitamin D levels (25-OH D) using a validated liquid chromatography-tandem mass spectrometry method considered the gold standard for 25-OH D quantitation. We compared mean 25-OH D levels as well as prevalence of vitamin D insufficiency (25-OH D level 30 ng/mL) and vitamin D deficiency (25-OH D 15 ng/mL). Logistic regression was used for multivariable adjustments. RESULTS: A total of 90 SPTB cases and 177 controls had remnant specimens with valid measurements. Data are provided in the Table. African Americans were more likely to be vitamin D deficient than other races (24.5% versus 3.7%, p 0.0001) as were women with specimens drawn between Oct and Apr (20.9% versus 9.2%, p 0.011). Mean midtrimester 25-OH D levels were similar between cases and controls. After adjusting for age, race, parity, weight, and season of specimen collection, neither vitamin D insufficiency (Adjusted OR: 0.8; 0.4-1.4) www.AJOG.org Doppler Assessment, Fetus, Prematurity Poster Session III

Copy-number changes in prenatal diagnosis

Until recently, the prenatal detection of genetic disease was available to only a subset of the pregnant population deemed to be at an increased risk for chromosomal abnormalities or, more rarely, other genetic disorders, based on family history, multiple-marker screening or ultrasound findings. Guided by recent data that indicate that screening for Down syndrome has improved and that risks of invasive procedures are smaller than previously ascertained, the American College of Obstetricians and Gynecologists has recommended that all women have access to invasive prenatal diagnosis. The parallel development of newer genetic diagnostic technologies, such as chromosomal microarray analysis, has made it feasible to simultaneously test for more conditions than was possible with standard karyotype analysis complemented by targeted fluorescence in situ hybridization or mutation detection for specific conditions. In the pediatric and adult population, chromosomal microarray analysis has already been thoroughly evaluated and is now recommended as a first-line diagnostic test for clinically suspected genetic disorders. In this article, we review the current status of array-based comparative genomic hybridization use for prenatal diagnosis and predict that, in the future, it will replace karyotyping as a first-line test for detecting chromosomal abnormalities in the prenatal setting.