Placental DNA methylation changes in detection of tetralogy of Fallot.

OBJECTIVES: To determine whether the methylation level of cytosine nucleotides in placental DNA can be used to predict tetralogy of Fallot (TOF) and provide insights into the developmental mechanism of this condition. METHODS: Tissue sections were obtained from formalin-fixed paraffin-embedded specimens of placental tissue obtained at birth from eight cases with non-chromosomal, non-syndromic TOF and 10 unaffected newborns. The Illumina Infinium HumanMethylation450 BeadChip assay was used to measure cytosine ('CpG' or 'cg') methylation levels at loci throughout the placental genome. Differential methylation was assessed by comparing the ß-values (a measure of the extent of cytosine methylation) for individual CpG loci in fetuses with TOF vs in controls. The most discriminating CpG sites were determined based on a preset cut-off of ≥ 2.0-fold change in the methylation level. The predictive accuracy of CpG loci with significant methylation changes for TOF was determined by the area under the receiver-operating-characteristics curve (AUC). A false-discovery-rate (FDR) P-value < 0.05 was used to define a statistically significant difference in the methylation level. Ingenuity Pathway Analysis (IPA) (Qiagen) was used to identify gene pathways that were significantly overexpressed, and thus altered, in TOF cases compared with controls. RESULTS: We found a total of 165 significantly differentially methylated CpG loci in TOF cases compared with controls, in 165 separate genes. These biomarkers demonstrated from fair to excellent individual predictive accuracy for TOF detection, with AUCs ≥ 0.75 (FDR P-value < 0.001 for all). The following CpG loci (gene) had the highest predictive accuracy: cg05273049 (ARHGAP22; AUC = 1.00; 95% CI, 1.00-1.00), cg02540011 (CDK5; AUC = 0.96; 95% CI, 0.87-1.00), cg08404201 (TRIM27; AUC = 0.95; 95% CI, 0.84-1.00) and cg00687252 (IER3; AUC = 0.95; 95% CI, 0.84-1.00). IPA revealed over-representation (dysregulation) of 14 gene pathways involved in normal cardiac development, including cardiomyocyte differentiation via bone morphogenetic protein receptors, cardiac hypertrophy signaling and role of nuclear factor of activated T cells in cardiac hypertrophy. Cardiac hypertrophy is an important feature of TOF. CONCLUSIONS: Analysis of placental DNA cytosine methylation changes yielded accurate markers for TOF detection and provided mechanistic information on TOF development. Our work appears to confirm the central role of epigenetic changes and of the placenta in the development of TOF. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Artificial intelligence and amniotic fluid multiomics: prediction of perinatal outcome in asymptomatic women with short cervix.

OBJECTIVE: To evaluate the application of artificial intelligence (AI), i.e. deep learning and other machine-learning techniques, to amniotic fluid (AF) metabolomics and proteomics, alone and in combination with sonographic, clinical and demographic factors, in the prediction of perinatal outcome in asymptomatic pregnant women with short cervical length (CL). METHODS: AF samples, which had been obtained in the second trimester from asymptomatic women with short CL (< 15 mm) identified on transvaginal ultrasound, were analyzed. CL, funneling and the presence of AF 'sludge' were assessed in all cases close to the time of amniocentesis. A combination of liquid chromatography coupled with mass spectrometry and proton nuclear magnetic resonance spectroscopy-based metabolomics, as well as targeted proteomics analysis, including chemokines, cytokines and growth factors, was performed on the AF samples. To determine the robustness of the markers, we used six different machine-learning techniques, including deep learning, to predict preterm delivery < 34 weeks, latency period prior to delivery < 28 days after amniocentesis and requirement for admission to a neonatal intensive care unit (NICU). Omics biomarkers were evaluated alone and in combination with standard sonographic, clinical and demographic factors to predict outcome. Predictive accuracy was assessed using the area under the receiver-operating characteristics curve (AUC) with 95% CI, sensitivity and specificity. RESULTS: Of the 32 patients included in the study, complete omics, demographic and clinical data and outcome information were available for 26. Of these, 11 (42.3%) patients delivered ≥ 34 weeks, while 15 (57.7%) delivered < 34 weeks. There was no statistically significant difference in CL between these two groups (mean ± SD, 11.2 ± 4.4 mm vs 8.9 ± 5.3 mm, P = 0.31). Using combined omics, demographic and clinical data, deep learning displayed good to excellent performance, with an AUC (95% CI) of 0.890 (0.810-0.970) for delivery < 34 weeks' gestation, 0.890 (0.790-0.990) for delivery < 28 days post-amniocentesis and 0.792 (0.689-0.894) for NICU admission. These values were higher overall than for the other five machine-learning methods, although each individual machine-learning technique yielded statistically significant prediction of the different perinatal outcomes. CONCLUSIONS: This is the first study to report use of AI with AF proteomics and metabolomics and ultrasound assessment in pregnancy. Machine learning, particularly deep learning, achieved good to excellent prediction of perinatal outcome in asymptomatic pregnant women with short CL in the second trimester. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Metabolomic identification of diagnostic serum-based biomarkers for advanced stage melanoma.

INTRODUCTION: Melanoma is a highly aggressive malignancy and is currently one of the fastest growing cancers worldwide. While early stage (I and II) disease is highly curable with excellent prognosis, mortality rates rise dramatically after distant spread. We sought to identify differences in the metabolome of melanoma patients to further elucidate the pathophysiology of melanoma and identify potential biomarkers to aid in earlier detection of recurrence. METHODS: Using 1H NMR and DI-LC-MS/MS, we profiled serum samples from 26 patients with stage III (nodal metastasis) or stage IV (distant metastasis) melanoma and compared their biochemical profiles with 46 age- and gender-matched controls. RESULTS: We accurately quantified 181 metabolites in serum using a combination of 1H NMR and DI-LC-MS/MS. We observed significant separation between cases and controls in the PLS-DA scores plot (permutation test p-value = 0.002). Using the concentrations of PC-aa-C40:3, DL-carnitine, octanoyl-L-carnitine, ethanol, and methylmalonyl-L-carnitine we developed a diagnostic algorithm with an AUC (95% CI) = 0.822 (0.665-0.979) with sensitivity and specificity of 100 and 56%, respectively. Furthermore, we identified arginine, proline, tryptophan, glutamine, glutamate, glutathione and ornithine metabolism to be significantly perturbed due to disease (p < 0.05). CONCLUSION: Targeted metabolomic analysis demonstrated significant differences in metabolic profiles of advanced stage (III and IV) melanoma patients as compared to controls. These differences may represent a potential avenue for the development of multi-marker serum-based assays for earlier detection of recurrences, allow for newer, more effective targeted therapy when tumor burden is less, and further elucidate the pathophysiologic changes that occur in melanoma.

Metabolomic profiling of brain from infants who died from Sudden Infant Death Syndrome reveals novel predictive biomarkers.

OBJECTIVE: Sudden Infant Death Syndrome (SIDS) is defined as the sudden death of an infant <1 year of age that cannot be explained following a thorough investigation. Currently, no reliable clinical biomarkers are available for the prediction of infants who will die of SIDS. STUDY DESIGN: This study aimed to profile the medulla oblongata from postmortem human brain from SIDS victims (n=16) and compare their profiles with that of age-matched controls (n=7). RESULTS: Using LC-Orbitrap-MS, we detected 12 710 features in electrospray ionization positive (ESI+) mode and 8243 in ESI- mode from polar extracts of brain. Five features acquired in ESI+ mode produced a predictive model for SIDS with an area under the receiver operating characteristic curve (AUC) of 1 (confidence interval (CI): 0.995-1) and a predictive power of 97.4%. Three biomarkers acquired in ESI- mode produced a predictive model with an AUC of 0.866 (CI: 0.767-0.942) and a predictive power of 77.6%. We confidently identified 5 of these features (l-(+)-ergothioneine, nicotinic acid, succinic acid, adenosine monophosphate and azelaic acid) and putatively identify another 4 out of the 15 in total. CONCLUSIONS: This study underscores the potential value of metabolomics for studying SIDS. Further characterization of the metabolome of postmortem SIDS brains could lead to the identification of potential antemortem biomarkers for novel prevention strategies for SIDS.

Labor and neonatal outcomes after term induction of labor in gestational diabetes.

OBJECTIVE: To identify the optimal gestational age (GA) for induction of labor (IOL) at term among patients with gestational diabetes (GDMA) according to perinatal outcomes. STUDY DESIGN: The US Natality Database from 2007 to 2010 was reviewed. Inclusion criteria were singleton delivery, IOL at 37 to 42 weeks and GDMA. Exclusion criteria included congenital anomalies, pre-gestational diabetes, hypertensive disorders, previous cesarean, breech presentation and rupture of membranes. Controls were non-GDMA cases delivered in geographic and temporal proximity. Delivery mode, macrosomia and perinatal complications were analyzed. Logistic regression adjusted for confounders was used to calculate odds ratios by GA using 39 weeks non-GDMA as reference. RESULTS: In all, 96,964 cases and 176,079 controls were included. Increased risk for all adverse outcomes among GDMA cases was found. The nadir for intrapartum and neonatal complications was 38 and 40 weeks, respectively, whereas for cesarean and macrosomia was 39 weeks. CONCLUSION: The optimal timing for IOL at term in GDMA appears to be 39 to 40 weeks.

Pregnancy outcomes with increased nuchal translucency after routine Down syndrome screening.

OBJECTIVES: The purpose of this study was to evaluate the outcomes of pregnancies with nuchal translucency greater or equal to 3 mm for routine first trimester screening in unselected populations. METHODS: A total of 2980 pregnant women for first trimester ultrasonography were routinely offered crown-rump length (CRL) and nuchal translucency (NT) for screening for Down syndrome between 11 and 14 weeks' gestation. A complete follow-up was obtained in all cases by a review of medical records. RESULTS: Using a cut-off value of 3 mm, the prevalence of increased fetal NT was 0.7% (n=22). Among the 22 cases, there were five (22.7%) chromosomal abnormalities. Of the 17 chromosomally normal pregnancies, four resulted in fetal demise (spontaneous abortion, intrauterine death or termination of pregnancy due to fetal abnormalities). The remaining 13 pregnancies resulted in live births, including one gestational hypertension and one preterm delivery, respectively. The total incidence of an adverse outcome in the group of increased fetal NT was 45.5%. CONCLUSIONS: In a routine population with first-trimester ultrasonography, fetal NT measuring greater than or equal to 3 mm was associated with a poor pregnancy outcome with not only chromosomal abnormalities and congenital cardiac diseases, but also poor maternal and fetal health or adverse pregnancy outcomes. In addition, this study also demonstrated the necessity for fetal assessment and follow-up in cases where the fetal NT is increased in the first trimester.

Splenic artery Doppler in the prediction of the small-for-gestational age infant.

OBJECTIVES: We hypothesized that, as with other areas of the peripheral circulation, fetal splenic artery blood flow undergoes changes in small-for-gestational age (SGA) fetuses due to a redistribution of cardiac output, and that the Doppler peak systolic velocity (PSV) reflects such changes and thus may be used to predict fetuses being SGA. METHODS: Splenic artery Doppler PSV, end-diastolic velocity (EDV), resistance index (RI) and umbilical artery RI were measured prospectively in fetuses at risk for being SGA at birth. Normal reference data were generated from appropriately grown fetuses delivering at > or = 37 weeks without complications, and SGA was defined as birth weight < 10th percentile. The Doppler indices were expressed as multiples of the normal median (MoM) for gestational age. Using receiver operating characteristic curves, optimal Doppler thresholds for the detection of SGA cases were determined and the areas under the curves calculated. The analysis was limited to singleton pregnancies delivered within 2 weeks of the last Doppler examination. RESULTS: There were 88 study patients of which 60 had SGA babies. The mean gestational age at Doppler examination was 31.4 weeks with a mean interval of 5.6 days from Doppler to delivery. The splenic artery PSV was lower in SGA, compared to normal cases: mean PSV (MoM), 0.93 vs. 1.09, respectively (P = 0.0001). The sensitivity, specificity and area under the curve were 70.0%, 72% and 0.734, respectively (P < 0.003), for the PSV in the prediction of delivery of a SGA fetus. For the splenic artery RI, values were 70%, 46% and 0.539, respectively (not significantly different), and for umbilical artery RI these were 70%, 61% and 0.689, respectively (P < 0.01). Splenic artery EDV was significantly reduced in SGA vs. normally grown fetuses (0.924 MoM vs. 1.145 MoM, P = 0.007). CONCLUSIONS: Fetal splenic artery PSV decreases in SGA infants, and is a strong predictor of the delivery of a SGA infant. It appears to be superior to the standard Doppler index, the RI, in predicting this outcome.

Renal artery Doppler investigation of the etiology of oligohydramnios in postterm pregnancy.

OBJECTIVE: To investigate the etiology of oligohydramnios in postterm pregnancy using Doppler velocimetry. METHODS: Renal and umbilical artery Doppler velocimetry were performed in women with singleton postterm (287 days' or more gestation) pregnancies. The renal and umbilical artery Doppler resistance index (RI) and end-diastolic velocity were measured. Stepwise logistic regression and the two-tailed t test were used to determine whether the Doppler indices correlated with oligohydramnios (amniotic fluid index less than 5 cm). RESULTS: We studied 147 well-dated, singleton, postterm pregnancies, of which 21 (14.3%) had oligohydramnios. For the study cohort, the mean (+/-standard deviation) gestational age at Doppler was 41.4 +/- 0.45 weeks and at delivery 41.8 +/- 0.47 weeks. Stepwise logistic regression using renal and umbilical artery Doppler indices found the renal RI to be the only significant predictor of oligohydramnios: beta = -10.4186, P <.05 (odds ratio [95% confidence interval (CI)] = 0, 0.88). The renal artery RI was significantly higher in cases with oligohydramnios (RI: mean (+/-standard error) = 0.8843 +/- 0.11 versus 0.8601 +/- 0.05, P

The role of hyperglycosylated hCG in trophoblast invasion and the prediction of subsequent pre-eclampsia.

OBJECTIVE: Hyperglycosylated hCG (HhCG) is the predominant form of chorionic gonadotrophin in states characterized by aggressive trophoblast invasion such as early pregnancy or choriocarcinoma. Pre-eclampsia may be the result of failed or inadequate trophoblast invasion. We investigated whether low levels of maternal urine HhCG levels would predict subsequent pre-eclampsia. STUDY DESIGN: Mid-trimester urine (14-21 weeks) was collected and frozen from non-hypertensive women undergoing genetic amniocentesis. Inclusion criteria were: normal singleton pregnancies without a prior history of pre-eclampsia, hypertension, diabetes or other vascular disorders. The specimens were subsequently thawed, and HhCG levels standardized to urine creatinine were measured. Maternal charts were reviewed after delivery to determine the development of pre-eclampsia. There were a total of 568 study subjects. RESULTS: Pre-eclampsia developed in 26 (4.6%) women. There was a significant correlation between low urine HhCG and subsequent pre-eclampsia (Mantel-Haenszel test of linear association: Chi-square 10.52, p=0.001). The mean HhCG level (ng/mg creatinine) was significantly greater in normals than in those destined to develop pre-eclampsia: 42.7 versus 20.3, p=0.002 (Mann-Whitney U-test). There was a progressive increase in the risk of subsequent pre-eclampsia as HhCG levels fell: HhCG < or =0.9 MoM RR (95% CI)=1.51 (1.15-1.98) compared with < or =0.1 MoM 10.42 (2.0-54.3). CONCLUSION: Low maternal mid-trimester urine HhCG predicted subsequent pre-eclampsia. This appears to support the view that pre-eclampsia results at least in part from poor trophoblast invasion. Thus, HhCG may play a role in trophoblast invasion and measurement of this in urine identifies women at high risk for developing pre-eclampsia.

Intraplacental smooth muscle tumor. A case report.

BACKGROUND: Chorioangioma is the leading diagnosis for circumscribed placental lesion noted on ultrasound. Other rare intraplacental tumors may have a significant clinical impact on the mother and fetus. CASE: An intraplacental, hypoechoic area consistent with chorioangioma was noted on ultrasound examination at 17 weeks' gestation. The lesion remained stable in size throughout gestation, with no evidence of fetal hydrops or polyhydramnios. At term, a live-born male infant was delivered vaginally, followed by spontaneous expulsion of the placenta. Histologic examination of the placenta revealed an intraplacental, potentially malignant smooth muscle tumor. Six weeks postpartum, total abdominal hysterectomy and pelvic node sampling were performed. No residual disease was found on the final histologic examination. CONCLUSION: Although ultrasound differentiation is difficult, rare nontrophoblastic tumors should be considered in the differential diagnosis of placental masses. To our knowledge, this is the first report of such a lesion in the placenta.

Doppler ultrasound velocimetry for timing the second intrauterine transfusion in fetuses with anemia from red cell alloimmunization.

OBJECTIVE: Middle cerebral artery peak systolic velocity has been successfully used for timing the first cordocentesis in fetuses who are at risk for anemia because of maternal red cell alloimmunization. The effects on Doppler velocimetry after the intrauterine transfusion of adult blood to these fetuses are unknown. The objective of this study was to assess the applicability of Doppler methods for the prediction of severe anemia in fetuses who had undergone 1 previous intrauterine transfusion. STUDY DESIGN: Doppler examination of middle cerebral artery peak systolic velocity was performed before cordocentesis in 64 fetuses who had undergone 1 previous intrauterine transfusion. Timing of the second intrauterine transfusion was based on traditional criteria. Anemia was defined as mild (hemoglobin value between 0.84 and 0.65 multiples of the median), moderate (hemoglobin value <0.65-0.55 multiples of the median), and severe (hemoglobin value <0.55 multiples of the median). Receiver operator characteristic curves were created to select threshold values to identify the 3 degrees of anemia with a sensitivity of 100%. RESULTS: Gestational age at the Doppler study ranged from 19 to 36 weeks. Forty-six fetuses (72%) were not or mildly anemic; 7 fetuses (11%) were moderately anemic, and 11 fetuses (17%) were severely anemic. Middle cerebral artery peak systolic velocity for the prediction of severe, moderate, and mild anemia at a sensitivity of 100% showed false-positive rates of 6%, 37%, and 70%, respectively. CONCLUSION: In fetuses who have undergone 1 previous intrauterine transfusion because of maternal red cell alloimmunization, timing the second intrauterine transfusion can be determined noninvasively by Doppler ultrasonography on the basis of an increase in the peak velocity of systolic blood flow in the middle cerebral artery.

The effect of steroids on the biophysical profile and Doppler indices of umbilical and middle cerebral arteries in healthy preterm fetuses.

OBJECTIVE: To examine the effect of antenatal steroids on the biophysical profile and the Doppler parameters of umbilical and middle cerebral arteries of healthy fetuses. STUDY DESIGN: Thiry-five singleton pregnancies between the gestational ages of 28 and 34 weeks, who received two consecutive doses of betamethasone 24h apart to accelerate pulmonary maturation were prospectively studied. Fetal biophysical profile and Doppler assessment were performed at 0 (pre-steroid), 24, 48, 72, 96 and 120 h after the administration of first dose. We compared the percentage of the fetuses with biophysical parameters present for each of the five components of the biophysical profile and the Doppler indices, using Cochran's Q-test, Friedman's test and one way analysis of variance of repeated measures where appropriate. The statistical significance was defined as P<0.05. RESULTS: The mean delivery time was 36.9(+/-1.8) weeks. There was a statistically significant difference in the frequency of the following findings in the pre- compared to post-steroid measurements: absence of body movements (48 h, P<0.05), non-reassuring fetal heart rate tracings (24, 48 and 72 h, P<0.05) and absence of breathing movements (24, 48 and 72 h, p<0.05). Initially none of the biophysical profile score was

Perinatal morbidity and mortality rates in severe twin-twin transfusion syndrome: results of the International Amnioreduction Registry.

OBJECTIVE: Serial aggressive amnioreduction is the most widely used therapy for pregnancies that are complicated by twin-twin transfusion syndrome. Survival rates reported with this therapy are 33% to 83%, the wide range attributable to the small number of patients in these case series. Similarly, data on morbidity in survivors are imprecise. We instituted the international twin-twin transfusion syndrome registry to determine the perinatal survival and morbidity rates and the factors that influence perinatal outcome in patients with twin-twin transfusion syndrome who were treated with serial aggressive amnioreduction from 1990 to 1998. STUDY DESIGN: A total of 223 sets of twins who were diagnosed with twin-twin transfusion syndrome before 28 weeks' gestation from 20 fetal medicine referral centers were analyzed, with follow-up data until 4 weeks after birth. RESULTS: Three hundred forty-six twins (78%; 182 recipients and 164 donors) were born alive. Two hundred sixty-six twins (60%; 144 recipients and 122 donors) were alive 4 weeks after birth. Both fetuses survived to 4 weeks in 108 pregnancies (48.4%), whereas, at least 1 fetus survived in 158 pregnancies (70.8%). The interval between the last amnioreduction and delivery ranged from zero to 138 days (median, 17.5 days). In the infants who survived to 4 weeks after birth, abnormalities on neonatal cranial scan were diagnosed in 24% of recipients and in 25% of donors. Logistic regression analysis indicated that the survival rate was significantly related to gestational age at diagnosis, presence of end-diastolic blood flow in the umbilical artery velocity waveforms, presence of hydrops, mean volume of amniotic fluid removed per week, larger birth weight, and gestational age at delivery. The hemoglobin level difference at birth was the only significant parameter to predict abnormal cranial ultrasonography in newborns. CONCLUSION: These data document perinatal survival and neonatal morbidity rates in severe twin-twin transfusion syndrome that were treated by serial aggressive amnioreduction. Outcome was influenced by several perinatal risk factors, which may be used to counsel patients before and during therapy.

Ratio of nuchal thickness to humerus length for Down syndrome detection.

OBJECTIVE: Ultrasonographic biometry markers are now being used clinically to adjust Down syndrome risk. The limitations are that the definitions of "abnormal" measurements used are arbitrary, thus reducing screening performance, and also that patient-specific Down syndrome risks cannot be calculated. We report a new ultrasonographic algorithm that is sensitive for Down syndrome detection and that estimates individual risk. STUDY DESIGN: Overall in fetal populations with Down syndrome the humerus length is decreased, whereas the nuchal thickness is increased relative to that of a normal population. The nuchal thickness/humerus length ratio therefore shows an even greater increase and magnifies the separation between Down syndrome and healthy groups. Prospective data were collected in midtrimester amniocentesis cases. A regression equation for the median nuchal thickness/humerus length ratio based on biparietal partial diameter was generated. The Down syndrome likelihood ratio, or the odds on the basis of the nuchal thickness/humerus length ratio (multiples of the median), was multiplied by the age-related risk to give the posterior Down syndrome risk. Charts for rapid estimation of individual Down syndrome risk on the basis of maternal age and the nuchal thickness/humerus length ratio were constructed. RESULTS: There were 94 cases of Down syndrome and 4700 cases in which the karyotype was normal. The mean (+/-SD) gestational age of the study population was 16.1 +/- 1.6 weeks. Thirty-three fetuses with Down syndrome and 68 karyotypically normal fetuses had gross anomalies. The equation for the expected median nuchal thickness/humerus length ratio was as follows: 10e(1.7163 - 0.0292) x BPD + 0.0003 x BPD2, where BPD is the biparietal diameter. In the overall study population the nuchal thickness/humerus length ratio and maternal age had a 79.8% detection rate at a 22.1% false-positive rate, compared with maternal age plus humerus length (sensitivity, 55.1%) or maternal age plus nuchal thickness (sensitivity, 66.7%) at the same false-positive rate. For women > or =35 years old the values were 80% and 22.0%, respectively. CONCLUSIONS: We report an ultrasonographic biometry algorithm that, in combination with maternal age, detects 79.6% of Down syndrome cases in a high-risk group. Individual Down syndrome risk can be quickly calculated at the bedside and made available to women who desire this information before making a decision on amniocentesis. On the basis of published standards, ultrasonographic biometry as described would be a cost-effective alternative to amniocentesis in this high-risk group.

Comparison of urinary hyperglycosylated human chorionic gonadotropin concentration with the serum triple screen for Down syndrome detection in high-risk pregnancies.

OBJECTIVE: Both modest screening performance and declining patient and physician acceptance have stimulated interest in alternative markers to the triple screen for the detection of Down syndrome. Our purpose was to compare the concentration of a single urinary analyte, hyperglycosylated human chorionic gonadotropin, with the serum triple screen (alpha-fetoprotein, human chorionic gonadotropin, and unconjugated estriol concentrations combined with age) for second-trimester Down syndrome detection. STUDY DESIGN: Urine and blood were obtained from pregnant women in the second trimester undergoing genetic amniocentesis. Urinary hyperglycosylated human chorionic gonadotropin concentration and serum triple-screen values were measured. Individuals undergoing amniocentesis because of abnormal triple-screen results were excluded. Individual Down syndrome risks on the basis of urinary hyperglycosylated human chorionic gonadotropin concentration plus maternal age and on the basis of the triple-screen results were calculated. For each algorithm the sensitivity and false-positive rate for Down syndrome detection at different risk thresholds were determined. From these values receiver operating characteristic curves were constructed, and the area under the curve was determined for each algorithm. Finally, the performance of a new combination in which urinary hyperglycosylated human chorionic gonadotropin concentration replaced serum human chorionic gonadotropin concentration in the triple screen was ascertained. RESULTS: We studied 24 pregnancies complicated by Down syndrome and 500 unaffected pregnancies between 14 and 22 weeks' gestation in a mostly white (93.5%) population undergoing amniocentesis primarily because of advanced maternal age. The sensitivity and false-positive rate for urinary hyperglycosylated human chorionic gonadotropin concentration were 75. 0% and 5.6%, respectively, whereas those for the triple screen were 75.0% and 33.2%, respectively. Urinary hyperglycosylated human chorionic gonadotropin concentration was superior to the triple screen (area under the curve, 0.9337 vs 0.7887; P =.02). The substitution of urinary hyperglycosylated human chorionic gonadotropin concentration for serum human chorionic gonadotropin concentration in the triple screen resulted in a 91.7% sensitivity at a 10.0% false-positive rate, versus a 54.2% sensitivity for the traditional triple screen at the same false-positive rate. CONCLUSION: The performance of urinary hyperglycosylated human chorionic gonadotropin concentration was statistically superior to that of the serum triple screen in a high-risk population. The use of urinary hyperglycosylated human chorionic gonadotropin concentration as an alternative test or substitution of this measurement for serum human chorionic gonadotropin concentration in the triple screen would improve diagnostic accuracy and address many current concerns related to the triple screen.

Middle cerebral artery Doppler velocimetric deceleration angle as a predictor of fetal anemia in Rh-alloimmunized fetuses without hydrops.

OBJECTIVE: The purpose of this study was to evaluate the screening performance of a new middle cerebral artery Doppler velocimetric index for the prediction of fetal anemia. STUDY DESIGN: Doppler velocimetry of the middle cerebral artery was performed before cordocentesis in 24 Rh-alloimmunized fetuses without hydrops on 52 occasions. The angle between the line describing the average slope during the diastolic phase of the cardiac cycle and the vertical, the middle cerebral artery standardized deceleration angle, was measured. The deceleration angle values were expressed in multiples of the median for gestational age. The screening performances of deceleration angle for the prediction of anemia (difference between expected mean hemoglobin level and measured value >/=2 g/dL) and severe anemia (hemoglobin deficit >/=5 g/dL) were determined. RESULTS: The mean (+/-SD) gestational age at cordocentesis was 28.6 +/- 5.7 weeks' gestation. The risk of fetal anemia increased with decreasing deceleration angle values. The sensitivity and false-positive rate for the detection of anemia in cases with no previous transfusions (one measurement per patient) were 72.0% and 13.3%, respectively; among those with one previous transfusion the values were 90.0% and 0.0%, respectively. For severe anemia the corresponding values were 100% and 0%, respectively, among those with no previous transfusions and 100.0% and 16.7%, respectively, among those with one previous transfusion. There was no risk of severe anemia when the angle was >0.9 multiples of the median. The risk of anemia was significantly reduced with an angle greater than the median for gestational age (deceleration angle >1.0 multiples of the median; relative risk, 0.09; 95% confidence interval, 0.02-0.37). The risk was significantly increased with an angle less than the median for gestational age (deceleration angle <1.0 multiples of the median; relative risk, 30.0; 95% confidence interval, 5.9-158.4). CONCLUSION: The risk of fetal hydrops is remote in the absence of severe anemia. With a new Doppler velocimetric index in the middle cerebral artery the risk of severe anemia was found to be low when the deceleration angle was >0.9 multiples of the median. Anemia can also be predicted with this index. The high sensitivities and acceptable false-positive rates support the potential clinical applicability of the method to reduce the reliance on cordocentesis in Rh alloimmunization. Our findings appear to validate the utility of the deceleration angle for the prediction of fetal anemia.