Steve Rad

Utilization of noninvasive prenatal testing: impact on referrals for diagnostic testing

OBJECTIVE Since the introduction of noninvasive prenatal testing (NIPT), a marked decrease in prenatal diagnostic testing (chorionic villus sampling [CVS] and amniocentesis) has been observed with unknown potential effects on genetic diagnosis of these pregnancies. The purpose of this study was to understand the impact of NIPT on genetics counseling referrals, diagnostic testing with CVS/amniocentesis, and appropriate use of NIPT. STUDY DESIGN A retrospective cohort study was performed on all women referred for genetic counseling and prenatal testing during the 2 years preceding the introduction of NIPT (pre-NIPT) and 2 years following (post-NIPT). The primary outcome was the difference in the number of women referred for genetic counseling and prenatal diagnosis during the pre-NIPT period compared with the post-NIPT period. The secondary outcome was the difference in the number of women referred who were not considered candidates for NIPT between the 2 study periods. RESULTS There was a statistically significant reduction in the number of referrals for genetic counseling and diagnostic testing in the post-NIPT compared with the pre-NIPT period (2824 vs 3944, P = .001), a reduction of 28.4%. During the post-NIPT period there was a significant reduction in referrals of women who would not be candidates for NIPT (467 pre-NIPT vs 285 post-NIPT, P = .043). In women who had diagnostic testing with CVS during the study period, 32.4% of the aneuploidies identified would not have been detected by NIPT. CONCLUSION There was a significant reduction in the number of patients referred for genetic counseling and prenatal diagnosis following the introduction of NIPT. In addition, there was a significant reduction in the number of patients referred for counseling and testing who would not be candidates for NIPT. This suggests that an increasing number of potential patients are being offered NIPT screening instead of diagnostic testing, including those at risk for fetal single gene disorders and aneuploidies not detectable by NIPT, potentially leading to misdiagnosis.

Attitudes and practices of healthcare providers regarding gestational diabetes: results of a survey conducted at the 2010 meeting of the International Association of Diabetes in Pregnancy Study Group (IADPSG).

Diabet. Med. 28, 976–986 (2011)

Differentially expressed genes in adipocytokine signaling pathway of adipose tissue in pregnancy

Objective To profile the differential gene expression of the KEGG Adipocytokine Signaling pathway in omental compared to subcutaneous tissue in normal pregnancy. Study Design Subjects included 14 nonobese, normal glucose tolerant, healthy pregnant women. Matched omental and subcutaneous tissue were obtained at elective cesarean delivery. Gene expression was evaluated using microarray and validated by RT-PCR. Differential gene expression was defined as ≥1.5 fold increase at p < 0.05. Results Six genes were significantly downregulated with two upregulated genes in omental tissue. Downregulation of Adiponectin and Insulin Receptor substrate, key genes mediating insulin sensitivity, were observed with borderline upregulation of GLUT-1. There were downregulations of CD36 and acyl-CoA Synthetase Long-chain Family Member 1which are genes involved in fatty acid uptake and activation. There was a novel expression of Carnitine palmitoyltransferase 1C. Conclusion Differential gene expression of Adipocytokine Signaling Pathway in omental relative to subcutaneous adipose tissue in normal pregnancy suggests a pattern of insulin resistance, hyperlipidemia, and inflammation.

Predictors of eclampsia in California

Abstract Objective: Eclampsia is a rare yet dangerous complication of the hypertensive disorders of pregnancy. The objective was to elucidate the predictors of eclampsia in a large cohort of pregnant women with gestational hypertension or preeclampsia. Methods: This was a retrospective cohort study of 143 093 pregnancies with preeclampsia or gestational hypertension in California during 2005–2008 of which 1719 had eclampsia. Predictors included race/ethnicity, parity, chronic hypertension (CHTN), diabetes mellitus, gestational diabetes mellitus (GDM), preterm delivery <32 weeks, maternal age ≥ 35, maternal age ≤ 20, socioeconomic status, education, and <5 prenatal visits. Univariate and multivariate analyses were performed. Results: Factors that increased the risk of eclampsia included Black (OR 1.46 [1.19–1.80]) and Hispanic race (OR 1.56 [1.35–1.79]), nulliparity (OR 1.59 [1.42–1.77]), maternal age ≤ 20 (OR 1.85 [1.61–2.11]), preterm delivery <32 weeks (OR 1.41 [1.16–1.70]), and <5 prenatal care visits (1.74 [1.46–2.07]). Factors that decreased the risk of eclampsia included CHTN (OR 0.06 [0.03–0.10]), GDM (OR 0.80 [0.67–0.96]), maternal age ≥ 35 (OR 0.70 [0.59–0.82]), and college education (OR 0.83 [0.74–0.94]). Conclusions: Black and Hispanic race, nulliparity, maternal age ≤ 20, preterm delivery <32 weeks, and <5 prenatal care visits increase the risk of eclampsia while CHTN, GDM, maternal age ≥ 35, and college education are protective. The protective effect of CHTN is the most striking. The mechanisms are likely different and warrant further investigation.

Noninvasive prenatal testing compared with invasive diagnostic testing in the setting of an abnormal state aneuploidy screen.

INTRODUCTION: To describe the abnormal results of invasive prenatal diagnostic testing performed for the indication of positive state aneuploidy screening at our institution and to further identify among those results the genetic abnormalities that would not have been detected by noninvasive (cell-free fetal DNA) prenatal testing. METHODS: This was a retrospective review of all patients that underwent invasive prenatal genetic testing (chorionic villus sampling, amniocentesis, or both) for the indication of positive state aneuploidy screening from June 2012 to June 2013 at a single, large academic medical center. Abnormal results were identified. Abnormalities that would not be detected by noninvasive cell- free DNA testing were further noted. RESULTS: There were 84 chorionic villus sampling and 38 amniocentesis procedures (total n=122) performed for the indication of positive state aneuploidy screening during this period. No karyotypic abnormality was detected in 89 (73%). Abnormalities detected included: 22 (18%) trisomy 21, three (2%) trisomy 18, two (2%) 45, X, and two (2%) 47, XYY. The remaining two were abnormalities that are not detected by current commercially available noninvasive tests: a balanced translocation and a loss of an oligonucleotide on the X chromosome. CONCLUSION: Most patients undergoing invasive testing for positive state screen results had aneuploidies that would have been detectable by current available noninvasive tests. However, some of the abnormalities would not have been identified by noninvasive prenatal testing. These limitations should be taken into account when counseling patients who test positive on state prenatal screening programs. Larger studies are needed to validate these findings.

Defining fetal growth restriction: abdominal circumference as an alternative criterion.

Abstract Purpose: The purpose of this study is to determine if using abdominal circumference percentile (AC) to define fetal growth restriction (FGR) improves ultrasound at ≥36 weeks as a screening test for small for gestational age (SGA). Materials and methods: All non-anomalous singletons undergoing ultrasound at a single center at ≥36 weeks during 12/2008–5/2014 were included. FGR was defined as (estimated fetal weight) estimated fetal weight (EFW) and/or abdominal circumference (AC) < 10 for gestational age (GA). The primary outcome was SGA (birthweight ≤10th percentile for GA). Data were stratified by maternal race/ethnicity and BMI. Sensitivity, specificity, false-positive rate (FPR), positive- and negative-predictive values (positive-predictive value (PPV), negative-predictive value (NPV)), and areas under the receiver-operating characteristic (ROC) curve (AUC were calculated. Results: There were 1594 ultrasounds. Median (IQR) ultrasound GA was 37.3 (36.6–38.0), days to delivery 10.6 (5.0–18.4), and delivery GA 39.29 (38.6–39.9). EFW <10 had the following characteristics: sensitivity 50.6%, FPR 2.0%, PPV 83.8%, and AUC 0.743. Using AC <10, these were 64.0, 2.9, 81.3, and 0.806, respectively. Using AC or EFW <10, these were 67.5, 3.3, 80.3, and 0.821, respectively; this criterion has the largest AUC (p < .008). This finding persisted when stratified by maternal race/ethnicity and BMI. Conclusions: AC <10 is more sensitive and has a similar PPV compared with EFW <10 for SGA. Using AC <10 or EFW <10 has the best balance of sensitivity and specificity as a screening test and has a low FPR. AC may be a reasonable alternative criterion to EFW for FGR diagnosis.

Demographic and Obstetric Outcomes of Pregnancies conceived by Assisted Reproductive Technology (ART) compared to Non-ART Pregnancies.

OBJECTIVE Use of assisted reproductive technology has increased steadily, yet multiple socioeconomic and demographic disparities remain between the general population and those with infertility. Additionally, both mothers and infants experience higher rates of adverse outcomes compared to their non-ART counterparts. METHODS Using International Classification of Diseases, Ninth Revision (ICD-9) coding, we performed a retrospective review of all ART-conceived deliveries in California in 2009. A total of 551 ART pregnancies were compared to Non-ART pregnancies (n=406,885). RESULTS The majority of ART deliveries belonged to women of advanced maternal age (AMA) and Caucasian or Asian race. Nearly half of all ART deliveries were multiple gestations. Compared to non-ART deliveries, ART pregnancies were associated with placenta previa, placental abruption, mild preeclampsia, and fetal growth restriction. CONCLUSION While not powered to detect all outcomes, our study highlights significant racial and ethnic disparities between ART and Non-ART pregnancies.

Predictors for Choosing Array-Comparative Genomic Hybridization for Prenatal Diagnosis

INTRODUCTION: The objective of this study was to investigate the indications for which women choose to have prenatal diagnosis with array-comparative genomic hybridization. METHODS: This is a retrospective review of the invasive prenatal diagnostic testing procedures (chorionic villus sampling and amniocentesis) with array-comparative genomic hybridization testing that were performed from December 2012 to June 2013 at a single, large academic medical center. The indications for testing were evaluated to determine the predictors for electing to have array-comparative genomic hybridization testing performed among this cohort of women. RESULTS: During this time period, there were 479 patients who underwent invasive testing. Of these, 162 (34%) women chose to have array-comparative genomic hybridization testing. In this group, 132 (81%) were of advanced maternal age. Advanced maternal age was the only indication for array-comparative genomic hybridization in 100 (62%) of the women. Other indications included: 14 (8%) advanced maternal age with multiple gestation, 22 (14%) ultrasound abnormalities (15 increased nuchal translucency, three first-trimester cystic hygroma, four second-trimester fetal anomalies); seven (4%) abnormal prenatal state screening; six (3.5%) prior aneuploidy; six (3.5%) maternal or paternal carriers of genetic abnormalities; and eight (5%) for maternal concern. Of these, two women were surrogates. Of this cohort, 34 (21%) had an abnormal array-comparative genomic hybridization result. Of these, only three were karyotypic abnormalities. CONCLUSIONS: The most common predictor of choosing array-comparative genomic hybridization was advanced maternal age followed by ultrasound abnormalities. Almost one fourth of abnormalities would not have been identified on routine karyotype. Pretest counseling and appropriate selection of pregnancies for testing continues to be important in this setting. Larger studies are needed to validate these findings.

OP02.03: Intracranial morphometry of the first trimester fetus with chromosomal anomalies

centile) 2) Control group (n = 88) included patients whose infants were appropriate for gestational age (birth weight > 10th centile). Poor neurodevelopmental outcome was defined as the presence of hearing impairment or severe developmental delay and was compared between the two groups. Results: Primary CMV infection occurred during the first trimester in 5 (33%) of the IUGR cases and 26 (29%) of the control cases (P = 0.8). The mean birth weight in the study group was 2460 gr compared to 3180 gr among the control patients (P < 0.01). The median age of children at follow-up was 2 years (range 3 months–8 years). The rate of poor neurodevelopmental outcome was similar among the two groups: Two (13%) infants in the study group had hearing impairment whereas 8 (9%) of the infants in the control group were diagnosed with hearing impairment (7) or developmental delay (1) on post-natal follow-up (P = 0.6). Conclusions: The outcome of congenital CMV infection does not seem to be affected by the presence of isolated IUGR. Therefore, the prognostic value of IUGR as a sole finding in fetuses infected by CMV is limited.

OP14.02: Posterior brain in fetuses with open spina bifida at 11 to 13 weeks gestation

area were significant univariate predictors, and remained significant in multivariate models for clinical and sonographic recurrence, with ROC analysis showing an area under the curve of 0.65 and 0.73 respectively. Avulsion was associated with an OR of 2.95 for recurrence; hiatal area on valsalva conveyed an additional 7% per cm2 for likelihood of recurrence. Predicted individual probability of recurrence varied from 12% to 95%. Conclusions: Recurrence risk after AC is largely determined by the state of the patient’s pelvic floor. The likelihood of recurrence may vary enormously between patient with a given degree of cystocele, depending on avulsion and hiatal ballooning. Both should be determined prior to prolapse surgery, especially if mesh use is contemplated.