Diagnostic accuracy of fundal height and handheld ultrasound-measured abdominal circumference to screen for fetal growth abnormalities.

OBJECTIVE: We sought to compare fundal height and handheld ultrasound-measured fetal abdominal circumference (HHAC) for the prediction of fetal growth restriction (FGR) or large for gestational age. STUDY DESIGN: This was a diagnostic accuracy study in nonanomalous singleton pregnancies between 24 and 40 weeks' gestation. Patients underwent HHAC and fundal height measurement prior to formal growth ultrasound. FGR was defined as estimated fetal weight less than 10%, whereas large for gestational age was defined as estimated fetal weight greater than 90%. Sensitivity and specificity were calculated and compared using methods described elsewhere. RESULTS: There were 251 patients included in this study. HHAC had superior sensitivity and specificity for the detection of FGR (sensitivity, 100% vs 42.86%) and (specificity, 92.62% vs 85.24%). HHAC had higher specificity but lower sensitivity when screening for LGA (specificity, 85.66% vs 66.39%) and (sensitivity, 57.14% vs 71.43%). CONCLUSION: HHAC could prove to be a valuable screening tool in the detection of FGR. Further studies are needed in a larger population.

Screening for fetal aneuploidy: is maternal age relevant?

The process of genetic screening has evolved from a simple notation of maternal age to a complex algorithm incorporating age, maternal serum screening, and sonographic findings. The extent to which each of these variables should contribute to the overall screening result is much debated and deserves continued research. It is clear that maternal age provides useful information when used as part of this equation but should not represent the sole screening modality. The use of genetic screening in a general population should be examined in terms of cost effectiveness without sacrificing patient preference and autonomy.

Clinical and economic evaluation of a proteomic biomarker preterm birth risk predictor: cost-effectiveness modeling of prenatal interventions applied to predicted higher-risk pregnancies within a large and diverse cohort.

OBJECTIVES: Preterm birth occurs in more than 10% of U.S. births and is the leading cause of U.S. neonatal deaths, with estimated annual costs exceeding $25 billion USD. Using real-world data, we modeled the potential clinical and economic utility of a prematurity-reduction program comprising screening in a racially and ethnically diverse population with a validated proteomic biomarker risk predictor, followed by case management with or without pharmacological treatment. METHODS: The ACCORDANT microsimulation model used individual patient data from a prespecified, randomly selected sub-cohort (N = 847) of a multicenter, observational study of U.S. subjects receiving standard obstetric care with masked risk predictor assessment (TREETOP; NCT02787213). All subjects were included in three arms across 500 simulated trials: standard of care (SoC, control); risk predictor/case management comprising increased outreach, education and specialist care (RP-CM, active); and multimodal management (risk predictor/case management with pharmacological treatment) (RP-MM, active). In the active arms, only subjects stratified as higher risk by the predictor were modeled as receiving the intervention, whereas lower-risk subjects received standard care. Higher-risk subjects' gestational ages at birth were shifted based on published efficacies, and dependent outcomes, calibrated using national datasets, were changed accordingly. Subjects otherwise retained their original TREETOP outcomes. Arms were compared using survival analysis for neonatal and maternal hospital length of stay, bootstrap intervals for neonatal cost, and Fisher's exact test for neonatal morbidity/mortality (significance, p < .05). RESULTS: The model predicted improvements for all outcomes. RP-CM decreased neonatal and maternal hospital stay by 19% (p = .029) and 8.5% (p = .001), respectively; neonatal costs' point estimate by 16% (p = .098); and moderate-to-severe neonatal morbidity/mortality by 29% (p = .025). RP-MM strengthened observed reductions and significance. Point estimates of benefit did not differ by race/ethnicity. CONCLUSIONS: Modeled evaluation of a biomarker-based test-and-treat strategy in a diverse population predicts clinically and economically meaningful improvements in neonatal and maternal outcomes.

Preterm birth, defined as delivery before 37 weeks' gestation, is the leading cause of illness and death in newborns. In the United States, more than 10% of infants are born prematurely, and this rate is substantially higher in lower-income, inner-city and Black populations. Prematurity associates with greatly increased risk of short- and long-term medical complications and can generate significant costs throughout the lives of affected children. Annual U.S. health care costs to manage short- and long-term prematurity complications are estimated to exceed $25 billion.Clinical interventions, including case management (increased patient outreach, education and specialist care), pharmacological treatment and their combination can provide benefit to pregnancies at higher risk for preterm birth. Early and sensitive risk detection, however, remains a challenge.We have developed and validated a proteomic biomarker risk predictor for early identification of pregnancies at increased risk of preterm birth. The ACCORDANT study modeled treatments with real-world patient data from a racially and ethnically diverse U.S. population to compare the benefits of risk predictor testing plus clinical intervention for higher-risk pregnancies versus no testing and standard care. Measured outcomes included neonatal and maternal length of hospital stay, associated costs and neonatal morbidity and mortality. The model projected improved outcomes and reduced costs across all subjects, including ethnic and racial minority populations, when predicted higher-risk pregnancies were treated using case management with or without pharmacological treatment. The biomarker risk predictor shows high potential to be a clinically important component of risk stratification for pregnant women, leading to tangible gains in reducing the impact of preterm birth.

Genetic screening in a university clinic: impact of primary language.

OBJECTIVE: To contrast Spanish-speaking (S) with English-speaking (E) obstetric patients regarding utilization of genetic screening, motivation for undergoing/declining screening, pregnancy-related anxiety, knowledge about genetic conditions, and printed information as an adjunct to counseling. METHOD: Paper surveys were given to patients (n = 121) in an academic OB/GYN clinic or placed in charts (n = 271) over a 4-week period. Comparisons were evaluated with Chi-square and Fisher's exact tests. RESULTS: Completed surveys were returned from 245 gravidas (response rate 63%, S 48%, and E 67%). Uptake of genetic screening was similar between the groups (S 69% vs. E 57%, p = 0.13). No significant differences were noted in patients' motivation regarding screening, source of screening information, or self-assessed pregnancy-related anxiety. Familiarity of genetic disorders other than Down syndrome differed between the S and E groups (p < 0.003). Perceived positive utility of printed information differed significantly when groups were analyzed by language (S 85% vs. E 47%, p < 0.001) and by uptake of screening(screened 62% vs. not screened 44%, p = 0.006). CONCLUSION: A majority of study participants (n = 147, 60%) chose genetic screening; uptake and motivation were similar across language groups. Familiarity with genetic conditions was deficient and screening terminology confusing regardless of primary language. The perceived positive utility of printed information (S > E) highlights the importance of clear and early counseling.

Performance of a proteomic preterm delivery predictor in a large independent prospective cohort.

BACKGROUND: Preterm birth remains a common and devastating complication of pregnancy. There remains a need for effective and accurate screening methods for preterm birth. Using a proteomic approach, we previously discovered and validated (Proteomic Assessment of Preterm Risk study, NCT01371019) a preterm birth predictor comprising a ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin. OBJECTIVE: To determine the performance of the ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin to predict both spontaneous and medically indicated very preterm births, in an independent cohort distinct from the one in which it was developed. STUDY DESIGN: This was a prospective observational study (Multicenter Assessment of a Spontaneous Preterm Birth Risk Predictor, NCT02787213) at 18 sites in the United States. Women had blood drawn at 170/7 to 216/7 weeks' gestation. For confirmation, we planned to analyze a randomly selected subgroup of women having blood drawn between 191/7 and 206/7 weeks' gestation, with the results of the remaining study participants blinded for future validation studies. Serum from participants was analyzed by mass spectrometry. Neonatal morbidity and mortality were analyzed using a composite score by a method from the PREGNANT trial (NCT00615550, Hassan et al). Scores of 0-3 reflect increasing numbers of morbidities or length of neonatal intensive care unit stay, and 4 represents perinatal mortality. RESULTS: A total of 5011 women were enrolled, with 847 included in this planned substudy analysis. There were 9 preterm birth cases at <320/7 weeks' gestation and 838 noncases at ≥320/7 weeks' gestation; 21 of 847 infants had neonatal composite morbidity and mortality index scores of ≥3, and 4 of 21 had a score of 4. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was substantially higher in both preterm births at <320/7 weeks' gestation and there were more severe neonatal outcomes. The ratio of insulin-like growth factor-binding protein 4 to sex hormone-binding globulin ratio was significantly predictive of birth at <320/7 weeks' gestation (area under the receiver operating characteristic curve, 0.71; 95% confidence interval, 0.55-0.87; P=.016). Stratification by body mass index, optimized in the previous validation study (22

Placental Nkx2-5 and target gene expression in early-onset and severe preeclampsia.

OBJECTIVE: Preeclampsia (PE) affects 2-8% of pregnancies worldwide and is a significant source of maternal and neonatal morbidity and mortality. However, the mechanisms underlying PE are poorly understood and major questions regarding etiology and risk factors remain to be addressed. Our objective was to examine whether abnormal expression of the cardiovascular developmental transcription factor, Nkx2-5, was associated with early onset and severe preeclampsia (EOSPE). METHODS: Using qPCR and immunohistochemical assay, we examined expression of Nkx2-5 and target gene expression in EOSPE and control placental tissue. We tested resulting mechanistic hypotheses in cultured cells using shRNA knockdown, qPCR, and western blot. RESULTS: Nkx2-5 is highly expressed in racially disparate fashion (Caucasians > African Americans) in a subset of early EOSPE placentae. Nkx2-5 mRNA expression is highly correlated (Caucasians > African Americans) to mRNA expression of the preeclampsia marker sFlt-1, and of the Nkx2-5 target and RNA splicing factor, Sam68. Knockdown of Sam68 expression in cultured cells significantly impacts sFlt-1 mRNA isoform generation in vitro, supporting a mechanistic hypothesis that Nkx2-5 impacts EOSPE severity in a subset of patients via upregulation of Sam68 to increase sFlt-1 expression. Expression of additional Nkx2-5 targets potentially regulating metabolic stress response is also elevated in a racially disparate fashion in EOSPE. CONCLUSIONS: Expression of Nkx2-5 and its target genes may directly influence the genesis and racially disparate severity, and define a mechanistically distinct subclass of EOSPE.

Costs and clinical outcomes of noninvasive fetal RhD typing for targeted prophylaxis.

OBJECTIVE: To examine the cost and clinical outcomes of noninvasive RhD typing with cell-free fetal DNA to selectively deliver antenatal and postnatal prophylaxis with anti-D immune globulin for prevention of alloimmunization in RhD-negative women. METHODS: We developed a decision tree to compare the costs and clinical outcomes of three strategies in an RhD-negative nonalloimmunized population as follows: 1) routine antenatal anti-D immune globulin prophylaxis and postpartum prophylaxis guided by cord blood typing (the current approach in most of the United States); 2) noninvasive fetal RhD typing with prophylaxis guided by test results; and 3) no screening or prophylaxis. Costs were estimated for testing and treatment algorithms using hospital billing records and information from the manufacturer of the fetal RhD genotyping test. Probability estimates were derived from published literature. The decision tree and sensitivity analyses were constructed and performed with Microsoft Excel. RESULTS: We estimated the cost of the current approach to prevention of alloimmunization to be $351 per pregnancy, and we estimated the cost of noninvasive determination of fetal RhD status to be $682. Assuming essentially perfect test performance, threshold analysis found the cost must decrease to $119 to break even. The gap widened in favor of routine prophylaxis in most other circumstances (increased false-negative test rate and decreasing prevalence of RhD negativity). CONCLUSION: Unless the cost of noninvasive fetal RhD typing is reduced substantially, routine antenatal anti-D immune globulin prophylaxis with postpartum prophylaxis guided by cord blood typing is less costly than noninvasive determination of fetal RhD status.