Influence of maternal BMI on genetic sonography in the FaSTER trial.

OBJECTIVE: We sought to evaluate the influence of maternal body mass index (BMI) on sonographic detection employing data from the FaSTER trial. METHOD: Unselected singleton pregnancies underwent detailed genetic sonogram to evaluate for structural fetal anomalies and soft markers for aneuploidy. BMI (kg/m(2)) were calculated from reported initial visit values. Sensitivity, specificity, false positive and false negative rates (FPR and FNR), likelihood ratio, detection rates, and a missed diagnosis rate (MDR: FNR + marker recorded as 'missing'/N) were calculated. RESULTS: Eight thousand five hundred and fifty-five patients with complete BMI information had detailed genetic sonography. A lower sensitivity with an elevated FNR and MDR was observed in obese women for multiple aneuploid markers (e.g. > or =2 markers 32% sensitivity with 68% FNR among BMI <25 vs 22% and 78% among BMI >30). Similarly, the detection rate for cardiac anomalies among women at BMI <25 was higher (21.6%) at a significantly lower FPR (78.4%; 95% CI 77.3-79.5%) in comparison to obese women (8.3% with FPR 91.7%; 95% CI 90.1-93.2%). In a logistic regression model, maternal obesity significantly decreased the likelihood of sonographic detection of common anomalies (adjusted OR 0.7; 95% CI 0.6-0.9; p = 0.001). CONCLUSION: The performance of second trimester genetic sonography is influenced by obesity, with a significantly higher MDR for multiple minor markers and lower likelihood for detecting common anomalies.

Preconceptional folate supplementation and the risk of spontaneous preterm birth: a cohort study.

BACKGROUND: Low plasma folate concentrations in pregnancy are associated with preterm birth. Here we show an association between preconceptional folate supplementation and the risk of spontaneous preterm birth. METHODS AND FINDINGS: In a cohort of 34,480 low-risk singleton pregnancies enrolled in a study of aneuploidy risk, preconceptional folate supplementation was prospectively recorded in the first trimester of pregnancy. Duration of pregnancy was estimated based on first trimester ultrasound examination. Natural length of pregnancy was defined as gestational age at delivery in pregnancies with no medical or obstetrical complications that may have constituted an indication for delivery. Spontaneous preterm birth was defined as duration of pregnancy between 20 and 37 wk without those complications. The association between preconceptional folate supplementation and the risk of spontaneous preterm birth was evaluated using survival analysis. Comparing to no supplementation, preconceptional folate supplementation for 1 y or longer was associated with a 70% decrease in the risk of spontaneous preterm delivery between 20 and 28 wk (41 [0.27%] versus 4 [0.04%] spontaneous preterm births, respectively; HR 0.22, 95% confidence interval [CI] 0.08-0.61, p = 0.004) and a 50% decrease in the risk of spontaneous preterm delivery between 28 and 32 wk (58 [0.38%] versus 12 [0.18%] preterm birth, respectively; HR 0.45, 95% CI 0.24-0.83, p = 0.010). Adjustment for maternal characteristics age, race, body mass index, education, marital status, smoking, parity, and history of prior preterm birth did not have a material effect on the association between folate supplementation for 1 y or longer and spontaneous preterm birth between 20 and 28, and 28 to 32 wk (adjusted HR 0.31, 95% CI 0.11-0.90, p = 0.031 and 0.53, 0.28-0.99, p = 0.046, respectively). Preconceptional folate supplementation was not significantly associated with the risk of spontaneous preterm birth beyond 32 wk. The association between shorter duration (<1 y) of preconceptional folate supplementation and the risk of spontaneous preterm birth was not significant after adjustment for maternal characteristics. However, the risk of spontaneous preterm birth decreased with the duration of preconceptional folate supplementation (test for trend of survivor functions, p = 0.01) and was the lowest in women who used folate supplementation for 1 y or longer. There was also no significant association with other complications of pregnancy studied after adjustment for maternal characteristics. CONCLUSIONS: Preconceptional folate supplementation is associated with a 50%-70% reduction in the incidence of early spontaneous preterm birth. The risk of early spontaneous preterm birth is inversely proportional to the duration of preconceptional folate supplementation. Preconceptional folate supplementation was specifically related to early spontaneous preterm birth and not associated with other complications of pregnancy.

Variability in thyroid-stimulating hormone suppression by human chorionic [corrected] gonadotropin during early pregnancy.

OBJECTIVE: The objective of the study was to further explore relationships between human chorionic gonadotropin (hCG), TSH, and free T4 in pregnant women at 11 through 18 wk gestation. STUDY DESIGN: The design of the study was to analyze hCG in comparison with TSH and free T4, in paired first- and second-trimester sera from 9562 women in the First and Second Trimester Evaluation of Risk for Fetal Aneuploidy trial study. RESULTS: hCG is strongly correlated with body mass index, smoking, and gravidity. Correlations with selected maternal covariates also exist for TSH and free T4. As hCG deciles increase, body mass index and percent of women who smoke both decrease, whereas the percent of primigravid women increases (P < 0.0001). hCG/TSH correlations are weak in both trimesters (r2 = 0.03 and r2 = 0.02). TSH concentrations at the 25th and fifth centiles become sharply lower at higher hCG levels, whereas 50th centile and above TSH concentrations are only slightly lower. hCG/free T4 correlations are weak in both trimesters (r2 = 0.06 and r2 = 0.003). At 11-13 wk gestation, free T4 concentrations rise uniformly at all centiles, as hCG increases (test for trend, P < 0.0001), but not at 15-18 wk gestation. Multivariate analyses with TSH and free T4 as dependent variables and selected maternal covariates and hCG as independent variables do not alter these observations. CONCLUSIONS: In early pregnancy, a woman's centile TSH level appears to determine susceptibility to the TSH being suppressed at any given hCG level, suggesting that hCG itself may be the primary analyte responsible for stimulating the thyroid gland. hCG affects lower centile TSH values disproportionately.

First-trimester or second-trimester screening, or both, for Down's syndrome.

BACKGROUND: It is uncertain how best to screen pregnant women for the presence of fetal Down's syndrome: to perform first-trimester screening, to perform second-trimester screening, or to use strategies incorporating measurements in both trimesters. METHODS: Women with singleton pregnancies underwent first-trimester combined screening (measurement of nuchal translucency, pregnancy-associated plasma protein A [PAPP-A], and the free beta subunit of human chorionic gonadotropin at 10 weeks 3 days through 13 weeks 6 days of gestation) and second-trimester quadruple screening (measurement of alpha-fetoprotein, total human chorionic gonadotropin, unconjugated estriol, and inhibin A at 15 through 18 weeks of gestation). We compared the results of stepwise sequential screening (risk results provided after each test), fully integrated screening (single risk result provided), and serum integrated screening (identical to fully integrated screening, but without nuchal translucency). RESULTS: First-trimester screening was performed in 38,167 patients; 117 had a fetus with Down's syndrome. At a 5 percent false positive rate, the rates of detection of Down's syndrome were as follows: with first-trimester combined screening, 87 percent, 85 percent, and 82 percent for measurements performed at 11, 12, and 13 weeks, respectively; with second-trimester quadruple screening, 81 percent; with stepwise sequential screening, 95 percent; with serum integrated screening, 88 percent; and with fully integrated screening with first-trimester measurements performed at 11 weeks, 96 percent. Paired comparisons found significant differences between the tests, except for the comparison between serum integrated screening and combined screening. CONCLUSIONS: First-trimester combined screening at 11 weeks of gestation is better than second-trimester quadruple screening but at 13 weeks has results similar to second-trimester quadruple screening. Both stepwise sequential screening and fully integrated screening have high rates of detection of Down's syndrome, with low false positive rates.

Individualized norms of optimal fetal growth: fetal growth potential.

OBJECTIVE: To demonstrate that individualized optimal fetal growth norms, accounting for physiologic and pathologic determinants of fetal growth, better identify normal and abnormal outcomes of pregnancy than existing methods. METHODS: In a prospective cohort of 38,033 singleton pregnancies, we identified 9,818 women with a completely normal outcome of pregnancy and characterized the physiologic factors affecting birth weight using multivariable regression. We used those physiologic factors to individually predict optimal growth trajectory and its variation, growth potential, for each fetus in the entire cohort. By comparing actual birth weight with growth potential, population, ultrasound, and customized norms, we calculated for each fetus achieved percentiles, by each norm. We then compared proportions of pregnancies classified as normally grown, between 10th and 90th percentile, or aberrantly grown, outside this interval, by growth potential and traditional norms, in 14,229 complicated pregnancies, 1,518 pregnancies with diabetes or hypertensive disorders, and 1,347 pregnancies with neonatal complications. RESULTS: Nineteen physiologic factors, associated with maternal characteristics and early placental function, were identified. Growth potential norms correctly classified significantly more pregnancies than population, ultrasound, or customized norms in complicated pregnancies (26.4% compared with 18.3%, 18.7%, 22.8%, respectively, all P<.05), pregnancies with diabetes or hypertensive disorders (37.3% compared with 23.0%, 28.0%, 34.0%, respectively, all P<.05) and neonatal complications (33.3% compared with 19.7%, 24.9%, 29.8%, respectively, all P<.05). CONCLUSION: Growth potential norms based on the physiologic determinants of birth weight are a better discriminator of aberrations of fetal growth than traditional norms. LEVEL OF EVIDENCE: II.

First- and second-trimester thyroid hormone reference data in pregnant women: a FaSTER (First- and Second-Trimester Evaluation of Risk for aneuploidy) Research Consortium study.

OBJECTIVE: The purpose of this study was to calculate first and second trimester reference ranges and within-woman correlations for TSH, free T4, and thyroid antibodies. STUDY DESIGN: TSH, free T4, and thyroid antibodies were measured in paired sera from 9562 women in the FaSTER trial of Down syndrome screening. RESULTS: The median first trimester TSH (1.05 mIU/L) is lower than the second (1.23 mIU/L); and 98th centile is higher (4.15 vs 3.77 mIU/L). Within-woman paired TSH correlations are moderately strong (r(2) = 0.64). Among women with first trimester TSH values above the 98th centile, second trimester values are over the 95th centile in 68%. Median first trimester free T4 values (1.10 ng/dL) are higher than second (1.01 ng/dL). Paired free T4 measurements correlate weakly (r(2) = 0.23). Among women with first trimester free T4 values below the 2nd centile, second trimester values are below the 5th centile in 32%. Antibody measurements correlate strongly between trimesters (thyroperoxidase r(2) = 0.79, thyroglobulin r(2) = 0.83). CONCLUSION: TSH and free T4 measurements require gestation-specific reference ranges.

Sequential first- and second-trimester TSH, free thyroxine, and thyroid antibody measurements in women with known hypothyroidism: a FaSTER trial study.

OBJECTIVE: The purpose of this study was to examine how closely hypothyroidism management in the general pregnancy population satisfies recently issued guidelines and to determine whether improvements are indicated. STUDY DESIGN: This was an observational study in which women at 5 recruitment centers in the first- and second-trimester evaluation of risk for aneuploidy trial allowed the use of sequentially obtained first- and second-trimester sera for additional research. Three hundred eighty-nine women had hypothyroidism by self-report. Thyroid-related measurements were performed on all samples between July 2004 and May 2005. RESULTS: Forty-three percent of the thyroid-stimulating hormone (TSH) values are at or above recently recommended guidelines in the first trimester (2.5 mU/L), as opposed to 33% of the values in the second trimester (3.0 mU/L). Twenty percent of the TSH values are at or above a less restrictive 98th percentile of normal in the first trimester, as opposed to 23% of the values in the second trimester. Mean TSH levels are higher in women with antibodies. Free thyroxine values are unremarkable. CONCLUSION: Future strategies should focus on more effectively treating women with hypothyroidism who have persistently elevated TSH values.

Prediction of patient-specific risk for fetal loss using maternal characteristics and first- and second-trimester maternal serum Down syndrome markers.

OBJECTIVE: To develop and evaluate a method of estimating patient-specific risk for fetal loss by combining maternal characteristics with serum markers. STUDY DESIGN: Data were obtained on 36,014 women from the FaSTER trial. Separate likelihood ratios were estimated for significant maternal characteristics and serum markers. Patient-specific risk was calculated by multiplying the incidence of fetal loss by the likelihood ratios for each maternal characteristic and for different serum marker combinations. RESULTS: Three hundred eighteen women had fetal loss < 24 weeks (early) and 103 > 24 weeks (late). Clinical characteristics evaluated included maternal age, body mass index, race, parity, threatened abortion, previous preterm delivery, and previous early loss. Serum markers studied as possible predictors of early loss included first-trimester pregnancy-associated plasma protein A and second-trimester alpha-fetoprotein, and unconjugated estriol. A risk assessment for early loss based on all of these factors yielded a 46% detection rate, for a fixed 10% false-positive rate, 39% for 5% and 28% for 1%. The only significant marker for late loss was inhibin A. The detection rate was 27% for a fixed 10% false-positive rate and only increased slightly when clinical characteristics were added to the model. CONCLUSION: Patient-specific risk assessment for early fetal loss using serum markers, with or without maternal characteristics, has a moderately high detection. Patient-specific risk assessment for late fetal loss has low detection rates.

First- and second-trimester evaluation of risk for Down syndrome.

OBJECTIVE: To investigate the differences in costs and outcomes of Down syndrome screening using data from the First and Second Trimester Evaluation of Risk (FASTER) Trial. METHODS: Seven possible screening options for Down syndrome were compared: 1) Triple Screen-maternal serum alpha fetoprotein, estriol, and hCG; 2) Quad-maternal serum alpha fetoprotein, estriol, hCG, and Inhibin A; 3) Combined First-nuchal translucency, pregnancy-associated plasma protein A (PAPP-A), free beta-hCG; 4) Integrated-nuchal translucency, PAPP-A, plus Quad; 5) Serum Integrated-PAPP-A, plus Quad; 6) Stepwise Sequential-Combined First plus Quad with results given after each test; and 7) Contingent Sequential-Combined First and only those with risk between 1:30 and 1:1,500 have Quad screen. The detection rates for each option were used given a 5% false-positive rate except for Contingent Sequential with a 4.3% false-positive rate. Outcomes included societal costs of each screening regimen (screening tests, amniocentesis, management of complications, and cost of care of Down syndrome live births), Down syndrome fetuses identified and born, the associated quality-adjusted life years, and the incremental cost-utility ratio. RESULTS: Based on the screening results derived from the 38,033 women evaluated in the FASTER trial, the Contingent Sequential screen dominated (lower costs with better outcomes) all other screens. For example, the Contingent Sequential cost 32.3 million dollars whereas the other screens ranged from 32.8 to 37.5 million dollars. The Sequential strategy led to the identification of the most Down syndrome fetuses of all of the screens, but at a higher cost per Down syndrome case diagnosed ($719,675 compared with $690,427) as compared with the Contingent Sequential. Because of the lower overall false-positive rate leading to fewer procedure-related miscarriages, the Contingent Sequential resulted in the highest quality-adjusted life years as well. The Contingent Sequential remained the most cost-effective option throughout sensitivity analysis of inputs, including amniocentesis rate after positive screen, rate of therapeutic abortion after Down syndrome diagnosis, and rate of procedure-related miscarriages. CONCLUSION: Analysis of this actual data from the FASTER Trial demonstrates that the Contingent Sequential test is the most cost-effective. This information can help shape future policy regarding Down syndrome screening.

Nuchal translucency and the risk of congenital heart disease.

OBJECTIVE: To estimate whether nuchal translucency assessment is a useful screening tool for major congenital heart disease (CHD) in the absence of aneuploidy. METHODS: Unselected patients with singleton pregnancies at 10(3/7) to 13(6/7) weeks of gestation were recruited at 15 U.S. centers to undergo nuchal translucency sonography. Screening characteristics of nuchal translucency in the detection of major CHD were determined using different cutoffs (2.0 or more multiples of the median [MoM], 2.5 or more MoM, 3.0 or more MoM). RESULTS: A total of 34,266 euploid fetuses with cardiac outcome data were available for analysis. There were 224 cases of CHD (incidence 6.5 per 1,000), of which 52 (23.2%) were major (incidence 1.5 per 1,000). The incidence of major CHD increased with increasing nuchal translucency: 14.1 per 1,000, 33.5 per 1,000, and 49.5 per 1,000 at 2.0 or more MoM, 2.5 or more MoM, and 3.0 or more MoM cutoffs, respectively. Sensitivity, specificity, and positive predictive values were 15.4%, 98.4%, and 1.4% at 2.0 or more MoM; 13.5%, 99.4%, and 3.3% at 2.5 or more MoM; and 9.6%, 99.7%, and 5.0% at 3.0 or more MoM. Nuchal translucency of 2.5 or more MoM (99th percentile) had a likelihood ratio (95% confidence interval) of 22.5 (11.4-45.5) for major CHD. Based on our data, for every 100 patients referred for fetal echocardiography with a nuchal translucency of 99th percentile or more, three will have a major cardiac anomaly. CONCLUSION: Nuchal translucency sonography in the first trimester lacks the characteristics of a good screening tool for major CHD in a large unselected population. However, nuchal translucency of 2.5 or more MoM (99th percentile or more) should be considered an indication for fetal echocardiography. LEVEL OF EVIDENCE: II.

The contribution of birth defects to preterm birth and low birth weight.

OBJECTIVE: To assess the impact of birth defects on preterm birth and low birth weight. METHODS: Data from a large, prospective multi-center trial, the First and Second Trimester Evaluation of Risk (FASTER) Trial, were examined. All live births at more than 24 weeks of gestation with data on outcome and confounders were divided into two comparison groups: 1) those with a chromosomal or structural abnormality (birth defect) and 2) those with no abnormality detected in chromosomes or anatomy. Propensity scores were used to balance the groups, account for confounding, and reduce the bias of a large number of potential confounding factors in the assessment of the impact of a birth defect on outcome. Multiple logistic regression analysis was applied. RESULTS: A singleton liveborn infant with a birth defect was 2.7 times more likely to be delivered preterm before 37 weeks of gestation (95% confidence interval [CI] 2.3-3.2), 7.0 times more likely to be delivered preterm before 34 weeks (95% CI 5.5-8.9), and 11.5 times more likely to be delivered very preterm before 32 weeks (95% CI 8.7-15.2). A singleton liveborn with a birth defect was 3.6 times more likely to have low birth weight at less than 2,500 g (95% CI 3.0-4.3) and 11.3 times more likely to be very low birth weight at less than 1,500 g (95% CI 8.5-15.1). CONCLUSION: Birth defects are associated with preterm birth and low birth weight after controlling for multiple confounding factors, including shared risk factors and pregnancy complications, using propensity scoring adjustment in multivariable regression analysis. The independent effects of risk factors on perinatal outcomes such as preterm birth and low birth weight, usually complicated by numerous confounding factors, may benefit from the application of this methodology, which can be used to minimize bias and account for confounding. Furthermore, this suggests that clinical and public health interventions aimed at preventing birth defects may have added benefits in preventing preterm birth and low birth weight. LEVEL OF EVIDENCE: II.

First- and second-trimester screening: detection of aneuploidies other than Down syndrome.

OBJECTIVE: To evaluate the performance of first- and second-trimester screening methods for the detection of aneuploidies other than Down syndrome. METHODS: Patients with singleton pregnancies at 10 weeks 3 days through 13 weeks 6 days of gestation were recruited at 15 U.S. centers. All patients had a first-trimester nuchal translucency scan, and those without cystic hygroma had a combined test (nuchal translucency, pregnancy-associated plasma protein A, and free beta-hCG) and returned at 15-18 weeks for a second-trimester quadruple screen (serum alpha-fetoprotein, total hCG, unconjugated estriol, and inhibin-A). Risk cutoff levels of 1:300 for Down syndrome and 1:100 for trisomy 18 were selected. RESULTS: Thirty-six thousand one hundred seventy-one patients completed first-trimester screening, and 35,236 completed second-trimester screening. There were 77 cases of non-Down syndrome aneuploidies identified in this population; 41 were positive for a cystic hygroma in the first trimester, and a further 36 had a combined test, of whom 29 proceeded to quadruple screening. First-trimester screening, by cystic hygroma determination or combined screening had a 78% detection rate for all non-Down syndrome aneuploidies, with an overall false-positive rate of 6.0%. Sixty-nine percent of non-Down syndrome aneuploidies were identified as screen-positive by the second-trimester quadruple screen, at a false-positive rate of 8.9%. In the combined test, the use of trisomy 18 risks did not detect any additional non-Down syndrome aneuploidies compared with the Down syndrome risk alone. In second-trimester quadruple screening, a trisomy 18-specific algorithm detected an additional 41% non-Down syndrome aneuploidies not detected using the Down syndrome algorithm. CONCLUSION: First-trimester Down syndrome screening protocols can detect the majority of cases of non-Down aneuploidies. Addition of a trisomy 18-specific risk algorithm in the second trimester achieves high detection rates for aneuploidies other than Down syndrome. LEVEL OF EVIDENCE: II.

The effect of low body mass index on the development of gestational hypertension and preeclampsia.

OBJECTIVES: To evaluate the relationship between low maternal body mass index (BMI) as calculated in the first trimester and the risk of preeclampsia and gestational hypertension. METHODS: Patients enrolled in the First And Second Trimester Evaluation of Risk for aneuploidy (FASTER) trial were grouped into three weight categories: low BMI (BMI <19.8 kg/m2), normal BMI (BMI 19.8 - 26 kg/m2), and overweight BMI (26.1 - 29 kg/m2). The incidences of gestational hypertension and preeclampsia were ascertained for each group. Tests for differences in crude incidence proportions were performed using Chi-square tests. Multiple logistic regression was used to adjust for maternal age, race, parity, obesity, use of assisted reproductive technology (ART), in vitro fertilization (IVF), gestational diabetes, pre-gestational diabetes, cocaine use, and smoking. RESULTS: The proportion of patients having gestational hypertension in the low BMI group was 2.0% compared to 3.2% for normal BMI and 6.0% for overweight BMI (p < 0.0001). Women with low BMI were also less likely to develop preeclampsia, 1.1% vs. 1.9% for normal BMI and 2.8% for overweight BMI (p < 0.0001). CONCLUSIONS: We found that women with low BMI in the first trimester were significantly less likely to develop gestational hypertension or preeclampsia than women with a normal BMI.

ACR Appropriateness Criteria® Multiple Gestations.

Women with twin or higher-order pregnancies will typically have more ultrasound examinations than women with a singleton pregnancy. Most women will have at minimum a first trimester scan, a nuchal translucency evaluation scan, fetal anatomy scan at 18 to 22 weeks, and one or more scans in the third trimester to evaluate growth. Multiple gestations are at higher risk for preterm delivery, congenital anomalies, fetal growth restriction, placenta previa, vasa previa, and velamentous cord insertion. Chorionicity and amnionicity should be determined as early as possible when a twin pregnancy is identified to permit triage of the monochorionic group into a closer surveillance model. Screening for congenital heart disease is warranted in monochorionic twins because they have an increased rate of congenital cardiac anomalies. In addition, monochorionic twins have a higher risk of developing cardiac abnormalities in later gestation related to right ventricular outflow obstruction, in particular the subgroups with twin-twin transfusion syndrome or selective intrauterine growth restriction. Monochorionic twins have unique complications including twin-to-twin transfusion syndrome, twin embolization syndrome, and acardius, or twin-reversed arterial perfusion sequence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Comparison of serum markers in first-trimester down syndrome screening.

OBJECTIVE: To estimate patterns of total hCG and inhibin A levels in the late first trimester of Down syndrome pregnancies, compare them with that of free beta-hCG, and assess screening performance of these markers individually and in combination with pregnancy-associated plasma protein-A (PAPP-A) and nuchal translucency. METHODS: Seventy-nine matched case-control sets of maternal serum samples (each Down syndrome case matched to 5 controls) from 11 through 13 completed weeks of gestation were taken from the sample bank of the First and Second Trimester Evaluation of Risk Consortium, a population-based study, and assayed for levels of free beta-hCG, total hCG, and inhibin A. Distribution characteristics and correlations of the multiples of the median values were estimated in cases and controls. Screening performance for each marker, alone and in combination with PAPP-A, nuchal translucency, and maternal age, was calculated. RESULTS: Median multiples of the median levels of free beta-hCG, total hCG, and inhibin A in cases were more elevated as gestation increased from 11 to 13 weeks, with univariate detection rates of 31%, 23%, and 29%, respectively, at a 5% false-positive rate. At 12 weeks, the multivariate detection rates at a 5% false-positive rate for nuchal translucency and PAPP-A (with maternal age) with either free beta-hCG, total hCG, or inhibin A were 84%, 83%, and 85%, respectively. The improvement in performance from nuchal translucency and PAPP-A to any of the three-marker tests was significant, while performance of any of the three-marker combinations was not significantly different from each other. CONCLUSION: Although levels of free beta-hCG in affected pregnancies were higher earlier than the levels of either total hCG or inhibin A, there was no significant difference in screening performance when either of the three markers was used with nuchal translucency and PAPP-A at 11-13 weeks of pregnancy. LEVEL OF EVIDENCE: II-2.

Is there a nuchal translucency millimeter measurement above which there is no added benefit from first trimester serum screening?

OBJECTIVE: The purpose of this study was to evaluate whether there is a nuchal translucency (NT) measurement, independent of gestational age, above which immediate diagnostic testing should be offered without waiting for first trimester serum markers. STUDY DESIGN: Thirty-six thousand one hundred twenty patients had successful measurement of simple NT at 10 3/7 to 13 6/7 weeks and had first trimester serum screening. No risks were reported until second trimester serum screening was completed. RESULTS: Thirty-two patients (0.09%) had NT > or = 4.0 mm; the lowest combined first trimester trisomy 21 risk assessment in euploid cases was 1 in 8 and among aneuploidy cases was 7 in 8. One hundred twenty-eight patients (0.3%) had simple NT > or = 3.0 mm: the lowest combined first trimester trisomy 21 risk assessment of any patient in this group was 1 in 1479 and the lowest risk assessment among aneuploid cases was 1 in 2. Ten patients (8%) had first trimester trisomy 21 risk assessments lowered to less that 1:200 and none of these 10 cases had an abnormal outcome. CONCLUSION: During first trimester Down syndrome screening, whenever an NT measurement of 3.0 mm or greater is obtained there is minimal benefit in waiting for serum screening results, and no benefit for NT of 4.0 mm or greater. Differentiation between cystic hygroma and enlarged simple NT (> or = 3.0 mm) is now a moot point as both are sufficiently high risk situations to warrant immediate CVS.

First-trimester screening.

Screening for fetal chromosome abnormalities, particularly for trisomy 21, has made dramatic advances. Better screening demonstrates that "high-risk" patients--particularly over age 35--can have lower risk of defects than younger unscreened women. This has caused reduction of amniocentesis for older patients and made screening available for younger patients who have the universal 2% to 3% risk. This means lower procedural-related losses of normal fetuses, and better resource allocation. The trend toward first-trimester detection of structural defects continues; a normal survey is reassuring and helps exclude major defects. Based on screening results, patients can be triaged into early follow-up and possible amniocentesis as 14 to 16 weeks, or a later detailed anatomic survey at 18 to 20 weeks.

ACR Appropriateness Criteria Assessment of Fetal Well-Being.

Although there is limited evidence that antepartum testing decreases the risk for fetal death in low-risk pregnancies, women with high-risk factors for stillbirth should undergo antenatal fetal surveillance. The strongest evidence supporting antepartum testing pertains to pregnancies complicated by intrauterine fetal growth restriction secondary to uteroplacental insufficiency. The main ultrasound-based modalities to determine fetal health are the biophysical profile, modified biophysical profile, and duplex Doppler velocimetry. In patients at risk for cardiovascular compromise, fetal echocardiography may also be indicated to ensure fetal well-being. Although no single antenatal test has been shown to be superior, all have high negative predictive values. Weekly or twice-weekly fetal testing has become the standard practice in high-risk pregnancies. The timing for the initiation of assessments of fetal well-being should be tailored on the basis of the risk for stillbirth and the likelihood of survival with intervention. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer-reviewed journals and the application of well-established methodologies (the RAND/UCLA Appropriateness Method and the Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Impact of maternal age on obstetric outcome.

OBJECTIVE: To estimate the effect of maternal age on obstetric outcomes. METHODS: A prospective database from a multicenter investigation of singletons, the FASTER trial, was studied. Subjects were divided into 3 age groups: 1) less than 35 years, 2) 35-39 years, and 3) 40 years and older. Multivariable logistic regression analysis was used to assess the effect of age on outcomes after adjusting for race, parity, body mass index, education, marital status, smoking, medical history, use of assisted conception, and patient's study site. RESULTS: A total of 36,056 women with complete data were available: 28,398 (79%) less than 35 years of age; 6,294 (17%) 35-39 years; and 1,364 (4%) 40 years and older. Increasing age was significantly associated with miscarriage (adjusted odds ratio [adjOR]2.0 and 2.4 for ages 35-39 years and age 40 years and older, respectively), chromosomal abnormalities (adjOR 4.0 and 9.9), congenital anomalies (adjOR 1.4 and 1.7), gestational diabetes (adjOR 1.8 and 2.4), placenta previa (adjOR 1.8 and 2.8), and cesarean delivery (adjOR 1.6 and 2.0). Patients aged 35-39 years were at increased risk for macrosomia (adjOR 1.4). Increased risk for abruption (adjOR 2.3), preterm delivery (adjOR 1.4), low birth weight (adjOR 1.6), and perinatal mortality (adjOR 2.2) was noted in women aged 40 years and older. CONCLUSION: Increasing maternal age is independently associated with specific adverse pregnancy outcomes. Increasing age is a continuum rather than a threshold effect.

First-trimester septated cystic hygroma: prevalence, natural history, and pediatric outcome.

OBJECTIVE: To estimate prevalence, natural history, and outcome of septated cystic hygroma in the first trimester in the general obstetric population, and to differentiate this finding from simple increased nuchal translucency. METHODS: Patients at 10.3-13.6 weeks of gestation underwent nuchal translucency sonography as part of a multicenter clinical trial. Septated cystic hygroma cases were offered chorionic villi sampling for karyotype, and targeted fetal anatomical and cardiac evaluations. Survivors were followed up for fetal and long-term pediatric outcome (median 25 months, range 12-50 months). Cases of septated cystic hygroma were also compared with cases of simple increased nuchal translucency. RESULTS: There were 134 cases of cystic hygroma (2 lost to follow-up) among 38,167 screened patients (1 in 285). Chromosomal abnormalities were diagnosed in 67 (51%), including 25 trisomy-21, 19 Turner syndrome, 13 trisomy-18, and 10 others. Major structural fetal malformations (primarily cardiac and skeletal) were diagnosed in 22 of the remaining 65 cases (34%). There were 5 cases (8%) of fetal death and 15 cases of elective pregnancy termination without evidence of abnormality. One of 23 (4%) normal survivors was diagnosed with cerebral palsy and developmental delay. Overall, survival with normal pediatric outcome was confirmed in 17% of cases (22 of 132). Compared with simple increased nuchal translucency, cystic hygroma has 5-fold, 12-fold, and 6-fold increased risk of aneuploidy, cardiac malformation, and perinatal death, respectively. CONCLUSION: First-trimester cystic hygroma was a frequent finding in a general obstetric screening program. It has the strongest prenatal association with aneuploidy described to date, with significantly worse outcome compared with simple increased nuchal translucency. Most pregnancies with normal evaluation at the completion of the second trimester resulted in a healthy infant with a normal pediatric outcome.