The utility of nuchal translucency ultrasound in identifying rare chromosomal abnormalities not detectable by cell-free DNA screening.

OBJECTIVE: To evaluate the utility of nuchal translucency (NT) screening in the detection of rare chromosomal aneuploidies in the setting of cell-free DNA (cfDNA). METHODS: A retrospective cohort study of pregnancies screened through the California Prenatal Screening Program between March 2009 and December 2012. Karyotype analysis was the primary method of chromosomal evaluation during the study period and abnormal chromosomal karyotype results were classified by whether the abnormality would be detectable by cfDNA (nonmosaic trisomy 13, 18, 21 or sex-chromosomal aneuploidy [SCA]). For those rare aneuploidies detectable by karyotype but not cfDNA, the number of cases that had an increased NT and the detection rate and positive predictive value (PPV) of increased NT for rare aneuploidies were determined. RESULTS: A total of 452 901 pregnant women had screening. There were 2572 chromosomally abnormal fetuses, of which 1922 (74.7%) had a common aneuploidy detectable by cfDNA, leaving 450 979 without T13, 18, 21. Of these, 4181 (0.93%) had an NT ≥3.0 mm. There were 649 rare aneuploidies not detectable by cfDNA. Of these, 108 (16.6%) had an NT ≥3.0 mm. The PPV of an NT ≥3.0 mm for rare aneuploidies was 2.6%. In all, 4176 fetuses need to be screened with NT to detect a rare aneuploidy. CONCLUSIONS: The addition of NT to cfDNA screening would detect 16.6% of rare aneuploidies. Increased NT has a low PPV for rare aneuploidies and a large number of women would need NT screening to detect each affected fetus.

Observed Rate of Down Syndrome in Twin Pregnancies.

OBJECTIVE: To evaluate the observed incidence of Down syndrome in twins compared with that expected based on maternal age-matched singletons, which is the current clinical approach. METHODS: This was a retrospective review of California Prenatal Screening Program participants with expected delivery dates between July 1995 and December 2012. Cases confirmed prenatally or postnatally with a genetic imbalance leading to phenotypic Down syndrome (trisomy 21, mosaic trisomy 21, or translocations) were included. Pregnancies conceived with ovum donation and women older than 45 years were excluded. We compared the observed Down syndrome incidence per pregnancy for twins with expected incidence by extrapolating from singleton data and expected zygosity as is the current clinical approach. This extrapolation assumes that monozygotic pregnancies have equivalent Down syndrome risk per pregnancy relative to maternal age-matched singletons and dizygotic pregnancies have twice the risk of at least one affected fetus. Zygosity for affected cases was presumed to be monozygotic with Down syndrome concordance and dizygotic with Down syndrome discordance. Counts were compared using cumulative Poisson distributions. RESULTS: Of 77,279 twin pregnancies, 182 (0.2%) had at least one fetus with Down syndrome confirmed by karyotype. The ratio of observed-to-expected Down syndrome incidence per pregnancy was 33.6%, 75.2%, and 70.0% for monozygotic, dizygotic, and all twins, respectively (P<.001 for all comparisons). Considering maternal age subgroups and twin zygosity, a significantly lower-than-expected Down syndrome incidence was seen for women aged 25 to 45 years with monozygotic pregnancies and overall for women aged 25 to 45 years with dizygotic pregnancies. CONCLUSION: The observed incidence of Down syndrome in twin pregnancies is lower than expected, most notably for monozygotic pregnancies and with increasing maternal age. Risk-based counseling can strongly affect women's choices regarding testing and management during pregnancy, so an understanding of the true Down syndrome risk in twin gestations is crucial.

Racial-ethnic differences in midtrimester maternal serum levels of angiogenic and antiangiogenic factors.

BACKGROUND: Little is known about racial-ethnic differences in the distribution of maternal serum levels of angiogenic and antiangiogenic factors and their associations with early-onset preeclampsia. OBJECTIVE: We sought to investigate the distribution of midtrimester maternal serum levels of placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1 and their associations with early-onset preeclampsia in whites, Hispanics, and blacks. STUDY DESIGN: A population-based nested case-control design was used to identify cases and controls of white, Hispanic, and black origin from a 2000 through 2007 live-birth cohort in 5 southern California counties. Cases included 197 women (90 whites, 67 Hispanics, and 40 blacks) with early-onset preeclampsia defined as hypertension and proteinuria with onset <32 weeks according to hospital records. Controls included a random sample of 2363 women without early-onset preeclampsia. Maternal serum specimens collected at 15-20 weeks' gestation as part of routine prenatal screening were tested for placental growth factor, soluble endoglin, and soluble vascular endothelial growth factor receptor 1. Serum levels of the 3 factors were log-normally distributed. Adjusted natural logarithmic means were compared between cases and controls and between racial-ethnic groups. Odds ratios and 95% confidence intervals derived from logistic regression models were calculated to measure the magnitude of the associations. RESULTS: Cases showed lower adjusted logarithmic means of placental growth factor but higher adjusted logarithmic means of soluble endoglin than controls across all 3 groups (P < .05). Cases also had higher adjusted means of soluble vascular endothelial growth factor receptor 1 than controls in whites (7.75 vs 7.52 log pg/mL, P < .05) and Hispanics (7.73 vs 7.40 log pg/mL, P < .05) but not in blacks (7.85 vs 7.69 log pg/mL, P = .47). Blacks were found to have higher levels of placental growth factor in both cases and controls when compared to whites and Hispanics (adjusted means: 4.69 and 5.20 log pg/mL in blacks, 4.08 and 4.78 log pg/mL in whites, and 3.89 and 4.70 log pg/mL in Hispanics, respectively, P < .05). Hispanic cases had the highest adjusted mean of soluble endoglin compared to white and black cases (9.24, 9.05, and 8.93 log pg/mL, respectively, P < .05). The weakest association of early-onset preeclampsia with placental growth factor and soluble endoglin was observed in blacks. The adjusted odds ratio per log pg/mL increase of the 2 analytes were 0.219 (95% confidence interval, 0.124-0.385) and 5.02 (95% confidence interval, 2.56-9.86) in blacks in comparison to 0.048 (95% confidence interval, 0.026-0.088) and 36.87 (95% confidence interval, 17.00-79.96) in whites (P < .05) and 0.028 (95% confidence interval, 0.013-0.060) and 86.68 (95% confidence interval, 31.46-238.81) in Hispanics (P < .05), respectively. As for soluble vascular endothelial growth factor receptor 1, the association was not significantly different among the racial-ethnic groups. CONCLUSION: Racial-ethnic differences were observed in the distribution of midtrimester maternal levels of placental growth factor and soluble endoglin and in the associations with early-onset preeclampsia. These differences should be considered in future studies to improve etiologic and prognostic understanding of early-onset preeclampsia.

Detection Rates for Aneuploidy by First-Trimester and Sequential Screening.

OBJECTIVE: To estimate detection rates for aneuploidy by first-trimester and sequential screening. METHODS: The study included women with singleton pregnancies who participated in the California Prenatal Screening Program with estimated delivery dates from August 2009 to December 2012 who had first- or first- and second-trimester (sequential) screening. Detection rates were measured for target (trisomies 21 and 18) and other aneuploidies identified from the California Chromosome Defect Registry. RESULTS: Of 452,901 women screened, 17,435 (3.8%) were screen-positive for Down syndrome only; 433 (0.1%) for trisomy 18 only; 1,689 (0.4%) for both Down syndrome and trisomy 18; and 2,947 (0.7%) for neural tube defects, Smith-Lemli-Opitz syndrome, or for multiple conditions. The detection rates were Down syndrome-92.9% (95% confidence interval [CI] 91.4-94.2); trisomy 18-93.2% (95% CI 90.5-95.9); trisomy 13-80.4% (95% CI 73.9-86.9); 45,X-80.1% (95% CI 73.9-86.3), and triploidy-91.0% (95% CI 84.2-97.9). Overall, the detection rate for chromosome abnormalities was 81.6% (95% CI 80.0-83.1) at an overall false-positive rate of 4.5%. CONCLUSION: First-trimester and sequential screening are sensitive and specific for the broad range of karyotype abnormalities seen in the population. LEVEL OF EVIDENCE: II.

Risk of critical congenital heart defects by nuchal translucency norms.

OBJECTIVE: The purpose of this study was to compare the performance of first-trimester nuchal translucency (NT) cutoff of ≥3.5 mm with NT percentiles that were calculated for crown-rump length to identify fetuses with critical congenital heart defects (CCHDs). STUDY DESIGN: This was a population-level study of singleton pregnancies in California with NT measurements performed between 11 and 14 weeks of gestation. Eligible cases were those that resulted in live births from 2009-2010 and had information about the presence or absence of CCHDs available in the hospital discharge records through age 1 year (n = 76,089). Logistic binomial regression methods were used to compare the rate of CCHDs by an NT percentile for crown-rump length and millimeter cutpoints. RESULTS: Compared with fetuses with an NT measurement of <90th percentile, fetuses with an NT of ≥99th percentile were >5 times as likely to have a CCHD (1.3% vs 0.2%; relative risk, 5.66; 95% confidence interval, 3.19-10.04) and fetuses with an NT measurement ≥3.5 mm were >12 times as likely to have a CCHD (2.8% vs 0.2%; relative risk, 12.28; 95% confidence interval, 5.11-29.51). NT ≥99th percentile had a sensitivity of 5.8% and a specificity of 98.9% for the detection of CCHDs compared with 2.6% and 99.8% for NT ≥3.5 mm. CONCLUSION: Results show that NT measurements of ≥99th percentile and ≥3.5 mm are not equivalent and that substantial risk for CCHD extends to the less restrictive ≥99th percentile cutpoint. Data suggest that the use of this cutpoint compared with the current standard could double the number of CCHDs that are identified based on NT risk.

Risk of selected structural abnormalities in infants after increased nuchal translucency measurement.

OBJECTIVE: We sought to examine the association between increased first-trimester fetal nuchal translucency (NT) measurement and major noncardiac structural birth defects in euploid infants. STUDY DESIGN: Included were 75,899 singleton infants without aneuploidy or critical congenital heart defects born in California in 2009 through 2010 with NT measured between 11-14 weeks of gestation. Logistic binomial regression was employed to estimate relative risks (RRs) and 95% confidence intervals (CIs) for occurrence of birth defects in infants with an increased NT measurement (by percentile at crown-rump length [CRL] and by ≥3.5 mm compared to those with measurements <90th percentile for CRL). RESULTS: When considered by CRL adjusted percentile and by measurement ≥3.5 mm, infants with a NT ≥95th percentile were at risk of having ≥1 major structural birth defects (any defect, RR, 1.6; 95% CI, 1.3-1.9; multiple defects, RR, 2.1; 95% CI, 1.3-3.4). Infants with a NT measurement ≥95th percentile were at particularly high risk for pulmonary, gastrointestinal, genitourinary, and musculoskeletal anomalies (RR, 1.6-2.7; 95% CI, 1.1-5.4). CONCLUSION: Our findings demonstrate that risks of major pulmonary, gastrointestinal, genitourinary, and musculoskeletal structural birth defects exist for NT measurements ≥95th percentile. The ≥3-fold risks were observed for congenital hydrocephalus; agenesis, hypoplasia, and dysplasia of the lung; atresia and stenosis of the small intestine; osteodystrophies; and diaphragm anomalies.

Obstetric, perinatal, and fetal outcomes in pregnancies with false-positive integrated screening results.

OBJECTIVE: To assess the risk of adverse obstetric, perinatal, and fetal outcomes for pregnant women participating in prenatal sequential integrated screening through the California Prenatal Screening Program who had a false-positive screening result. METHODS: Women who underwent first- and second-trimester prenatal integrated screening plus nuchal translucency measurement with outcome information available were included. Fetuses and neonates with chromosomal or neural tube defects were excluded. We compared the risk of adverse outcomes for all women with a positive screening result compared with a 10% random sample of women with a negative screening result. Logistic binomial regression was used to compare adverse outcomes in screen-positive compared with screen-negative women. RESULTS: We identified 9,051 screen-positive and 30,928 screen-negative pregnancies with outcome information available. Compared with screen-negative pregnancies, screen-positive women were more likely to be diagnosed with preeclampsia, placenta previa, or abruption (7.6% screen-positive, 3.8% screen-negative; relative risk 1.7, 95% confidence interval [CI] 1.6-1.8) or experience fetal loss before 20 weeks of gestation (1.9% screen-positive, 0.2% screen-negative; relative risk 3.5, 95% CI 3.2-3.8). Women with positive results for more than one screened condition were at substantially greater risk of fetal and neonatal mortality (relative risks 33.6-156.7, 95% CIs 21.8-194.4). CONCLUSION: Among pregnancies without chromosomal or neural tube defects, prenatal sequential integrated screening provides information regarding risk across a variety of adverse pregnancy outcomes.

Integrated and first trimester prenatal screening in California: program implementation and patient choice for follow-up services.

OBJECTIVES: The California Prenatal Screening Program serves over 350,000 women annually. This study examines utilization rates for the various screening options and patient choices regarding follow-up services. METHODS: The study tracked patients with first trimester positive results for Down syndrome to examine patient decisions regarding follow-up services and/or additional screening and to identify determinants of patient decisions. For first trimester screen positive women who elected further screening, second trimester integrated screening results were analyzed. The Genetic Disease Screening Program Chromosome Registry was used to identify Down syndrome cases. RESULTS: Ethnicity, but not age, was a strong predictor of acceptance of prenatal diagnosis. Approximately 47% of first trimester screen positive women opted for further screening. Among these women, 46% percent received an integrated screen negative result. All but one confirmed Down syndrome case in this cohort were still screen positive. CONCLUSIONS: Data from the California Prenatal Screening Program indicate that all of the major screening modalities continue to be utilized. The wide range of choices made by women with screen positive results demonstrate the importance of including multiple options within the Program. Providing integrated screening to first trimester Down syndrome screen positive women reduced the number of unnecessary invasive procedures.

The California Prenatal Screening Program: "options and choices" not "coercion and eugenics".

The California Prenatal Screening Program is designed to make prenatal screening available to the state's large and diverse population. The Program provides information to women which will allow them to make informed choices regarding prenatal screening and prenatal diagnosis. Since the Program's inception in 1986, women in California have had the option to participate in prenatal screening or to decline prenatal screening. The California Program offers prenatal diagnostic services to women whose screening tests indicate an increased risk for birth defects, including Down syndrome. Women can decline any or all of these follow-up services. Genetic counseling, diagnostic services, and the presentation of diagnostic results are performed by medical professionals (not State staff) who follow established guidelines for nondirective counseling. Program data clearly demonstrate that women in California have a wide range of options and make a wide range of choices regarding prenatal screening and prenatal diagnosis. California's comprehensive Prenatal Screening Program promotes optimal care for all women within all options and choices. The important and necessary communication among organizations and stakeholders involved in prenatal screening and diagnosis, and in related care for pregnant women and for people with Down syndrome, is not served by misrepresentation and inflammatory rhetoric.

Detection rate of quadruple-marker screening determined by clinical follow-up and registry data in the statewide California program, July 2007 to February 2009.

OBJECTIVE: To evaluate the efficiency of California's quadruple-marker screening program and construct receiver-operating characteristic (ROC) curves. METHODS: This study included the screening records of 552 941 women during July 2007 to February 2009. The screen-positive women received clinical follow-up services at state-approved centers. We used the California Chromosome Defect Registry which includes clinical, laboratory, and demographic data from the prenatal diagnostic centers, cytogenetic laboratories, hospitals, and prenatal care providers. Risk calculations, screen-positive rates (SPRs), detection rates (DRs) for chromosomal abnormalities, and 95% confidence intervals (95% CIs) were determined. ROC curves comparing the quadruple-marker to triple-marker screening were constructed. RESULTS: The DR and SPR for trisomy 21 (N = 827) during the quadruple-marker time period were 75.7% (95% CI 72.8-78.6%) and 3.75% (95% CI 3.70-3.80%) compared with 77.4% (95% CI 75.0-79.7%) and 5.4% during the triple-marker phase. The DRs were 78.2% (95% CI 75.0-81.4%) with ultrasound dating and 66.9% (95% CI 59.7-74.0%) for last-menstrual-period-dated pregnancies. For trisomy 18, triploidy, and trisomy 13, the DRs were 84.3, 95.7, and 43.5%, respectively. CONCLUSIONS: The DR for trisomy 21 in California's statewide quadruple-marker screening is very similar to the Program's previously reported DR using triple-marker screening. However, this was achieved at a lower SPR, demonstrating improved screening performance.