Multiples Of The Normal Median Research Articles

Extreme βHCG levels in first trimester screening are risk factors for adverse maternal and fetal outcomes

Multiples of the normal median (MoM) of free βHCG is a valuable parameter in evaluation of risk of adverse pregnancy outcomes. In the current retrospective study, we assessed the maternal and fetal outcomes in pregnant women having free βHCG MoM levels < 0.2 or > 5 in their first trimester screening (FTS). Relative risk of trisomy 21 was significantly higher in patients having free βHCG MoM > 5. On the other hand, relative risk of trisomies 13 and 18 and Turner syndrome were higher in those having free βHCG MoM < 0.2. Other chromosomal abnormalities were nearly equally detected between those having free βHCG MoM < 0.2 or > 5. Relative risk of hydrocephaly and hydrops fetalis was higher when free βHCG MoM was below 0.2. On the other hand, relative risk of low birth weight was higher when free βHCG MoM was above 5. Moreover, frequency of gestational diabetes mellitus, preeclampsia, preterm delivery and vaginal bleeding increased with levels of free βHCG MoM. However, polyhydramnios had the opposite trend. Frequencies of premature rupture of membranes and pregnancy induced hypertension were highest among pregnant women having levels of free βHCG MoM < 0.2. The current study indicates importance of free βHCG MoM in identification of at-risk pregnancies in terms of both fetal and maternal outcomes. In fact, βHCG MoM < 0.2 or > 5 can be regarded as risk factors for adverse maternal or fetal outcomes irrespective of the presence of other abnormalities in the FTS results.

Karyotype analysis of amniotic fluid cells and report of chromosomal abnormalities in 15,401 cases of Iranian women

The aim of present study was to assess the karyotypes of amniotic fluid cells and find the frequency of chromosomal abnormalities and their significance in clinical setting. A total of 15,401 pregnant women were assessed from March 2016 to May 2019, and 14,968 amniotic fluid samples were successfully cultured. These fetuses were grouped according to different indications including advanced maternal age, abnormal nuchal translucency (NT) values, positive first/second trimester screening results, high risk NIPT results, very low PAPP-A and free β-hCG multiples of the normal median (MoM) results, abnormal ultrasound findings or previous history of chromosomal abnormalities. Results indicated the presence of normal karyotype in 90.2% (13,497/14,968) of fetuses. Totally, 46.4% (6945/14,968) of fetuses were 46,XX and 43.8% (6552/14,968) had 46,XY chromosome pattern. A total of 1077 abnormal karyotypes were found among 14,968 fetuses, thus the rate of abnormal fetuses was calculated to be 7.2% (1072/14,968). Meanwhile, a total of 394 cases (2.8%) had a normal polymorphism in their karyotype. In other words, abnormal karyotypes were detected in one of 13.9 cases of patients underwent amniocentesis. Down syndrome, Edward’s syndrome, abnormal mosaicisms and Patau’s syndrome were detected in 4.4% (659/14,968), 0.57% (85/14,968), 0.49% (74/14,968) and 0.24% (36/14,968) of cases, respectively. Sex chromosomal abnormalities including Klinefelter syndrome, Turner syndrome and 47,XXX karyotype were detected in 64 cases (0.43%). In this article, the rates of chromosomal abnormalities are compared between different groups of patients based on the advanced maternal age, abnormal NT values, very low PAPP-A and free β-hCG MoMs results, and positive FTS results. The current investigation provides insight into the most appropriate indications for amniocentesis in Iran.

Potential role of biochemical placentation markers - pregnancy associated plasma protein-A and human chorionic gonadotropin for early gestational diabetes screening - a pilot study.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications. The universal screening for GDM is usually performed between 24-28 weeks' gestation. This often delays the diagnosis and could increase the risk of adverse pregnancy outcomes. Some of the biochemical placental markers - pregnancy associated plasma protein A (PAPP-A) and free-β human chorionic gonadotropin (hCG), probably could provide a diagnostic value for GDM. The aim of our study was to assess if PAPP-A and hCG values were different among pregnant women with and without GDM and respectively, to tested their place in the early GDM screening. We conducted a retrospective, case-control study by reviewing the clinical database records of 662 pregnant women. The analysis includes the data for a two-year period. The patients included in the observation were divided into two groups - GDM group (n = 412) and Euglycemic group (n = 250). Early screening for GDМ between 9-12 weeks' gestation was performed in 173 of the women in the interventional group due to: registered fasting plasma glucose (FPG) above 5.1 mmol/L, obesity, macrosomia in previous pregnancies or family history for diabetes mellitus. The remaining 239 women underwent universal screening at 24-28 weeks' gestation. Mean serum levels of PAPP-A, hCG, FPG, and body mass index (BMI) were measured between 10-13 gestational weeks. Serum levels of PAPP-A and hCG are presented as multiples of the normal median (MoM), adjusted by maternal baseline characteristics and demographics. In patients who developed GDM during pregnancy, compared with the control group, we have found significantly lower MoM values of PAPP-A (p < 0.0001), higher levels of FPG (р < 0.0001) and higher BMI (р < 0.0001). Median hCG MoM was similar in both group of pregnant women. Our findings suggest that low-normal to low reference range values of PAPP-A might be associated with higher risk for GDM. PAAP-A levels can be used as an additional factor to recommend early screening for GDM.

Are the first-trimester levels of PAPP-A and fb-hCG predictors for obstetrical complications in diabetic pregnancy?

Objective To assess the levels of pregnancy-associated plasma protein-A (PAPP-A) and β-human chorionic gonadotropin (fb-hCG) in cases of diabetic pregnancy, to determine whether these biomarkers can be considered significant predictors for macrosomia, preeclampsia (PE), intrauterine growth restriction (IUGR), and preterm birth in mothers with different types of pregestational diabetes mellitus (DM). Methods It was a retrospective cohort study. Study groups were presented: type 1 DM (n = 100), type 2 DM (n = 50), and controls (n = 25). At 11 + 0 to 13 + 6 week’s gestation, we recorded maternal characteristics and medical history, and performed a combined test for the detection of risk of chromosomal abnormalities. To assess the performance of the markers in the prediction of the main obstetrical complications (PE, IUGR, preterm birth, and macrosomia), receiver-operating characteristic (ROC) curves were produced and area under the curves was calculated. Results The study has shown that DM is associated with a high rate of perinatal complications: PE, IUGR, macrosomia, and preterm birth. The median level of PAPP-A was significantly lower in case of type 1 DM- 0.89 (inter quartile range (IQR), 0.51–1.1), and type 2 DM-0.88 (IQR, 0.42–1.15) compared to the unaffected group 1.03 (IQR, 0.96–1.12; p = .025). There were no significant differences in the fb-hCG multiples of the normal median (MoM; p = .14) between the diabetic and unaffected groups. More significant results were obtained when calculated by percentile: in diabetic pregnancies, PAPP-A and fb-hCG MoMs values were lower in the 5–10% ranges and higher in the 95% range, compared to the control group. ROC-analysis did not show any significant data that first-trimester PAPP-A and fb-hCG serum levels are predictors for PE, IUGR, macrosomia, and preterm birth. Conclusion The routine first-trimester serum screening of fetal Down syndrome cannot be used as a tool of risk identification for PE, IUGR, macrosomia, and preterm birth in case of diabetic pregnancy.

Fetal renal blood flow velocimetry and cerebro-placental ratio in patients with isolated oligohydramnios

ObjectiveIt’s proposed that oligohydramnios is caused by decreased renal perfusion due to redistribution of fetal blood at fetal growth restriction. Isolated oligohydramnios refers to the presence of oligohydramnios without fetal structural and chromosomal abnormalities, without fetal growth restriction, without intrauterine infection, and in the absence of known maternal disease. It’s unknown whether the redistribution or decreased renal perfusion cause isolated oligohydramnios. The aim of the study was to evaluate fetal renal artery Doppler blood velocimetry and cerebro-placental ratio (CPR) among women with isolated oligohydramnios between 25–40 weeks of gestational age. Study designThe middle cerebral artery, umbilical artery and, renal artery pulsatility index (PI) values were measured in 45 fetuses with isolated oligohydramnios and 65 fetuses with normal amniotic fluid. Oligohydramnios was defined as deepest vertical amniotic fluid being measured lower than 1cm. The CPR (middle cerebral artery PI/umbilical artery PI) and renal artery PI values were expressed as multiples of the normal median (MoM) and were compared between the two groups. ResultsThere was no difference in MoM of CPR PI (p=0.167) and MoM of renal artery PI values (right p=0.253, left p=0.353) between the groups. ConclusionThe renal artery Doppler velocimetry and CPR were not significantly different in the women with isolated oligohydramnios, compared to the women with normal amniotic fluid.

Has GnRH a direct role in amh regulation?

It’s proposed that oligohydramnios is caused by decreased renal perfusion due to redistribution of fetal blood at fetal growth restriction. Isolated oligohydramnios refers to the presence of oligohydramnios without fetal structural and chromosomal abnormalities, without fetal growth restriction, without intrauterine infection, and in the absence of known maternal disease. It’s unknown whether the redistribution or decreased renal perfusion cause isolated oligohydramnios. The aim of the study was to evaluate fetal renal artery Doppler blood velocimetry and cerebro-placental ratio (CPR) among women with isolated oligohydramnios between 25–40 weeks of gestational age.The middle cerebral artery, umbilical artery and, renal artery pulsatility index (PI) values were measured in 45 fetuses with isolated oligohydramnios and 65 fetuses with normal amniotic fluid. Oligohydramnios was defined as deepest vertical amniotic fluid being measured lower than 1 cm. The CPR (middle cerebral artery PI/umbilical artery PI) and renal artery PI values were expressed as multiples of the normal median (MoM) and were compared between the two groups.There was no difference in MoM of CPR PI (p = 0.167) and MoM of renal artery PI values (right p = 0.253, left p = 0.353) between the groups.The renal artery Doppler velocimetry and CPR were not significantly different in the women with isolated oligohydramnios, compared to the women with normal amniotic fluid.

Is it possible to predict late antepartum stillbirth by means of cerebroplacental ratio and maternal characteristics?

Objective: To examine the potential value of fetal ultrasound and maternal characteristics in the prediction of antepartum stillbirth after 32 weeks’ gestation.Methods: This was a retrospective multicenter study in Spain. In 29 pregnancies, umbilical artery pulsatility index (UA PI), middle cerebral artery pulsatility index (MCA PI), cerebroplacental ratio (CPR), estimated fetal weight (EFW), and maternal characteristics were recorded within 15 days prior to a stillbirth. The values of UA PI, MCA PI, and CPR were converted into multiples of the normal median (MoM) for gestational age and the EFW was expressed as percentile according to a Spanish reference range for gestational age. Data from the 29 pregnancies with stillbirths and 2298 control pregnancies resulting in livebirths were compared and multivariate logistic regression analysis was used to determine significant predictors of stillbirth.Results: The only significant predictor of stillbirth was CPR (OR = 0.161, 95% confidence interval [CI] 0.035, 0.654; p = .014); the area under the receiver operating characteristics curve was 0.663 (95% CI 0.545, 0.782) and the detection rate (DR) was 32.14% at a 10% false-positive rate (FPR). In addition, when we included MCA and UA PI MoM instead of CPR, only MCA PI MoM was significant (OR = 0.104, 95% confidence interval [CI] 0.013, 0.735; p = .029), with similar prediction abilities (area under the curve (AUC) 0.645, DR 28.6%, FPR 10%).Conclusions: The CPR and MCA PI are predictors of late stillbirth but the performance of prediction is poor.

Impaired placental perfusion and major fetal cardiac defects.

To investigate the relationship between fetal congenital heart defects (CHD) and placental perfusion assessed by uterine artery pulsatility index (UtA-PI), in relation to development of pre-eclampsia (PE). This was a prospective screening study of singleton pregnancies at 19-24 weeks' gestation. Transvaginal ultrasound was used to measure UtA-PI and the values were converted into multiples of the normal median (MoM). Median MoM values in pregnancies with a fetus with isolated major CHD were compared to those without CHD, in relation to development of PE. The 91 407 singleton pregnancies fulfilling the entry criteria included 206 (0.23%) with isolated major fetal CHD and 91 201 without CHD. The prevalence of PE was 4.4% in pregnancies with fetal CHD and 2.7% in those without CHD (relative risk (RR), 1.6 (95% CI, 0.84-3.04); P= 0.150); the respective values for preterm PE with delivery at < 37 weeks' gestation were 2.4% and 0.7% (RR, 3.4 (95% CI, 1.42-8.09); P= 0.006). In the total population, median UtA-PI MoM was significantly higher in those that developed PE compared to those without PE (1.22 (interquartile range (IQR), 0.94-1.57) vs 1.00 (IQR, 0.84-1.19); P< 0.0001) and, in the PE group, the median UtA-PI MoM was inversely related to gestational age at delivery (r= -0.458; P< 0.0001). The same pattern of inverse relationship between UtA-PI MoM and gestational age at delivery with PE was observed in pregnancies with and those without CHD, but, in the CHD group, compared to those without CHD, UtA-PI was significantly higher both in pregnancies with and in those without PE. In pregnancies both with and without fetal CHD that develop PE, impedance to flow in the UtAs is increased and this increase is particularly marked in those with preterm PE. The prevalence of preterm PE is more than three times higher in pregnancies with than those without fetal major CHD, and the prevalence of major CHD in pregnancies with preterm PE is also more than three times higher than in those without PE. However, > 97% of pregnancies with fetal CHD do not develop preterm PE and > 99% of pregnancies with preterm PE are not associated with fetal CHD. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Fetal major cardiac defects and placental dysfunction at 11-13 weeks' gestation.

To investigate the relationship between fetal major cardiac defects and markers of placental perfusion and function. This was a prospective screening study in singleton pregnancies at 11-13 weeks' gestation. Uterine artery pulsatility index (UtA-PI), serum pregnancy-associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) were measured and the values were converted into multiples of the normal median (MoM). Median MoM values in fetuses with isolated major cardiac defects were compared with those in fetuses without major defects. The 50 094 singleton pregnancies fulfilling the entry criteria included 49 898 pregnancies with normal cardiac anatomy and 196 (0.39%) with major congenital cardiac defects: 73 (37.2%) with conotruncal defects, 63 (32.1%) with left ventricular outflow tract defects and 60 (30.6%) with valvular defects. In the group with cardiac defects, compared with controls, there was lower median PAPP-A MoM (0.81 vs 1.00, P < 0.0001) and PlGF MoM (0.78 vs 1.00, P < 0.0001) but no significant difference in UtA-PI MoM (1.01 vs 1.00, P = 0.162). In pregnancies with isolated fetal major cardiac defects, there is evidence of placental dysfunction in the absence of impaired placental perfusion. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

Maternal cardiac function at 35-37 weeks' gestation: relationship with birth weight.

To evaluate the relationship between maternal cardiovascular parameters and neonatal birth weight and examine the potential value of these parameters in improving the prediction of small-for-gestational-age (SGA) and large-for-gestational-age (LGA) neonates provided by maternal characteristics and medical history. In 2835 singleton pregnancies maternal characteristics and medical history were recorded and maternal cardiovascular parameters were measured. The observed measurements of cardiovascular parameters were expressed as multiples of the normal median (MoM) values after adjustment for those characteristics found to provide a substantial contribution to their measurement. Regression analysis was used to determine the significance of association between the normalized values of the cardiovascular parameters with birth-weight Z-score. Multivariable logistic regression analysis was then used to determine if the maternal factors, fetal biometry and maternal cardiovascular parameters had a significant contribution to predicting SGA and LGA neonates. The performance of screening was determined by the area under receiver-operating characteristics curves (AUC). In the study population there were significant positive associations between maternal cardiac output and heart rate with neonatal birth-weight Z-score, and significant negative associations between total peripheral resistance and mean arterial pressure (MAP) with neonatal birth-weight Z-score. In pregnancies delivering SGA neonates (n = 249 (8.8%)), cardiac output and heart rate were lower and total peripheral resistance and MAP were higher, whereas in pregnancies delivering LGA neonates (n = 292 (10.3%)) cardiac output and heart rate were higher and total peripheral resistance and MAP were lower. The performance of screening for delivery of SGA neonates achieved by maternal characteristics and fetal biometry was not improved by the measurement of maternal cardiovascular parameters. There was a small but significant improvement in the performance of screening for delivery of LGA neonates by maternal factors and fetal biometry with the addition of maternal heart rate (comparison of AUC, P = 0.0095). There are significant associations between maternal cardiac output, heart rate, total peripheral resistance and MAP and neonatal birth-weight Z-score; such findings reflect the close relationship between maternal cardiac function and fetal demands. However, assessment of these parameters at 35-37 weeks' gestation is unlikely to improve substantially the performance of screening for SGA or LGA neonates provided by a combination of maternal factors and fetal biometry. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal serum alpha-fetoprotein and free beta-human chorionic gonadotropin in the second trimester: implication for high risk of down’s syndrome in the ghanaian population

Maternal serum screening during pregnancy for adverse changes in levels of alpha-fetoprotein (AFP) and free beta- Human Chorionic Gonadotropin (free β-HCG) in the second trimester to assess risk of Down’s syndrome (DS) is a rare obstetric practice in Ghana. The aim of this study was to determine changes in the levels of these markers, and assess for risk of DS and adverse pregnancy outcomes in the Ghanaian population. Levels of AFP and free β-HCG were determined in maternal serum samples from eighty one women with singleton pregnancy collected at recruitment (12-13 gestational weeks), and in the second trimester (16 gestational weeks). AFP and free β-HCG markers were expressed in multiples of the normal median (MoM) for gestation. Delivery outcomes and features of the new born at delivery were also noted. The mean age of subjects at recruitment was 33.9±3.2 years. AFP levels at recruitment and in the second trimester were 18.8 ± 7.5 ng/ml (mean ± SD) and 30.9 ± 9.8 ng/ml (mean ± SD) respectively. Similarly, free β-HCG at recruitment and in the second trimester were 47.2 ± 12.2 ng/ml (mean ± SD) and 29.8 ± 11.3 ng/ml (mean ± SD) respectively. The differences in the serum levels of AFP and free β-HCG between the first and second trimesters were significant (p<0.0001: 95% CI -14.9-(-9.3) and p<0.0001: 95% CI 13.6-21.2). Whilst the AFP level did not correlate with weight, free β-HCG weakly correlated with maternal weight (p=0.29 and r 2 =0.017; p=0.08 and r 2 =0.055 respectively), but not age in the second trimester. There were no cases of DS observed in the study population. The mean concentrations of free β-HCG in adverse pregnancies were higher than in normal pregnancies (38.4 ± 6.6; 29.3 ± 10.6) but not for AFP (p=0.059, and p=0.477 respectively). Although no DS was seen for comparison, free b-HCG appears to be a useful marker for risk assessments of poor pregnancy outcomes in the population.

Plasma MIC-1 and PAPP-A Levels Are Decreased among Women Presenting to an Early Pregnancy Assessment Unit, Have Fetal Viability Confirmed but Later Miscarry

BackgroundWe have recently shown first trimester Macrophage inhibitory cytokine-1 (MIC-1) and Pregnancy Associated Plasma Protein-A (PAPP-A) serum concentrations are depressed among asymptomatic women destined to miscarry. Here we examined whether plasma levels of MIC-1 and PAPP-A are depressed among women presenting to an Early Pregnancy Assessment Unit (EPAU), noted to have a confirmed viable fetus, but subsequently miscarry.MethodsWe performed a prospective cohort study, recruiting 462 women in the first trimester presenting to EPAU and had fetal viability confirmed by ultrasound. We obtained plasma samples on the same day and measured MIC-1, PAPP-A and human chorionic gonadotrophin (hCG), grouping the cohort according to whether they later miscarried or not. To correct for changes in analyte levels across gestation, we expressed the data as Multiples of the normal Median (MoMs).ResultsWe recruited 462 participants presenting to EPAU at 5-12 weeks gestation. Most (80%) presented with symptoms of threatened miscarriage (e.g. abdominal pain, vaginal bleeding). 34 (7.4%) subsequently miscarried. Median plasma MIC-1 levels among those who miscarried were 50% of those with ongoing pregnancies (Miscarriage cohort MoM 0.50 (25th-75th centiles: 0.29-1.33) vs ongoing pregnancies MoM 1.00 (0.65-1.38); p=0.0025). Median plasma PAPP-A MoMs among those who miscarried was 0.57 (0.00-1.12), significantly lower than those with ongoing pregnancies (MoMs 1.00 (0.59-1.59); p=0.036). Plasma hCG levels were also significantly depressed among those who miscarried compared to those with ongoing pregnancies. However, the performance of MIC-1 as a diagnostic marker to predict miscarriage in this cohort was modest, and not improved with the addition of hCG.ConclusionMIC-1 and PAPP-A levels are significantly depressed in women presenting to EPAU with ultrasound evidence of fetal viability, but later miscarry. While they are unlikely to be useful as predictive biomarkers in this clinical setting, they probably play important roles in the maintenance of early pregnancy.

First‐trimester Down syndrome screening using additional serum markers with and without nuchal translucency and cell‐free DNA

This study aimed to evaluate serum-only four-marker first trimester (1T-Quad) Down syndrome screening, alone or contingently to select 10-20% with highest risk for nuchal translucency (NT) or cell-free (cf)DNA. Stored maternal serum samples (-80 °C) from 90 pregnancies with fetal Down syndrome and 1607 controls were retrieved and measured for placental growth factor, α-fetoprotein, pregnancy-associated plasma protein and free β-human chorionic gonadotropin. Samples were from singleton pregnancies (9-13 + 6 weeks), and NT was measured between 11 and 13 + 6 weeks. Markers were expressed in multiples of the normal median (MoM) for gestation. Gaussian models were fitted to the distribution of log MoMs by using observed parameters, standardized maternal age distribution (mean 27, SD 5.5) and published cfDNA results. The model-predicted detection rate (DR) for 1T-Quad was 74% [5% false-positive rate (FPR)]. When used contingently to select for NT, the DR was 89% at 5%. When used to select for cfDNA, the DR was 91% (FPR < 0.05%). The 1T-Quad test can achieve a similar DR to a second-trimester Quad test. When used contingently to select for NT, the DR is similar to the Combined test. Used contingently to select for cfDNA would achieve even higher detection.

Maternal serum tumour necrosis factor receptor 1 (TNF-R1) at 30–33 weeks in the prediction of preeclampsia

Objective: To investigate the potential value of maternal serum concentration of tumour necrosis factor receptor 1 (TNF-R1) at 30–33 weeks’ gestation in the prediction of preeclampsia (PE) developing at or after 34 weeks.Methods: Serum TNF-R1 was measured at 11–13 and at 30–33 weeks’ gestation in a case-control study of 50 cases that developed PE at or after 34 weeks and 250 unaffected controls. The measured values of TNF-R1 were converted into multiples of the normal median (MoM) and the MoM values in the PE and control groups were compared.Results: The median MoM TNF-R1 was significantly increased at both 11–13 weeks (1.094 MoM versus 1.003 MoM) and at 30–33 weeks (1.101 MoM versus 1.006 MoM). In screening for PE by a combination of maternal characteristics and serum TNF-R1 at 30–33 weeks, the estimated detection rates of PE at false positive rates of 5% and 10% were 32.0% and 40.0%, respectively.Conclusion: Screening by maternal characteristics and serum TNF-R1 at 30–33 weeks could be effective in identifying some of the cases that will subsequently develop PE.

590: Successfully overcoming barriers to genetic counseling through national telephone genetic counseling service

589 First-trimester prediction of preeclampsia using soluble P-selectin,follistatin-related protein 3, complement 3a, soluble TNF receptor type 1, PAPP-A, AFP, inhibin A, placental growth factor, uterine artery Doppler and maternal characteristics Lorraine Dugoff, Howard Cuckle, Nicholas Behrendt, Darleen Cioffi-Ragan, Leslie Myers, John Hobbins University of Pennsylvania, Obstetrics and Gynecology, Philadelphia, PA, Columbia University Medical Center, Obstetrics and Gynecology, New York, NY, University of Colorado, Obstetrics and Gynecology, Aurora, CO OBJECTIVE: To estimate the efficiency of first-trimester serum markers and uterine artery Doppler (UtA) in the prediction of severe preeclampsia (SPE). STUDY DESIGN: This is a prospective cohort study of patients presenting for aneuploidy screening between 11-14 weeks’ gestation. Maternal serum levels of soluble P-selectin, follistatin-related protein 3, complement 3a, soluble TNF receptor type 1, PAPP-A, AFP, inhibin A(inhA) and placental growth factor(PlGF) were measured by immunoassay and mean UtA resistance indices(RI) were calculated. The primary outcome was SPE. A secondary outcome of all PE including mild preeclampsia was also evaluated. Marker levels were expressed in multiples of the normal median (MOM), adjusting for gestation, weight, smoking and ethnicity. Logistic regression analysis was used to model performance. Maternal characteristics identified as significant in a univariate analysis were included in the models. Predicted sensitivity, specificity, and area under the receiver-operating characteristic curves were used to compare the screening efficiency of the models. RESULTS: Of 1028 patients, 26(2.5%) had SPE and 56(5.4%) had PE. Median PlGF levels were lower in patients with SPE (0.83 MoM vs 0.98 MoM, P 0.05) and PE(0.90 MoM vs 0.98 MoM, P 0.05) compared to those without PE. AFP was significantly higher (1.15 MoM vs 1.00 MoM, P 0.05; 1.20 MoM vs 0.99 MoM, P 0.01). Median RI was significantly increased in PE (1.05 MoM vs 1.00 MoM, P 0.05) but not in SPE; similarly for inhA (1.09 MoM vs 0.99 MoM, P 0.05). For a fixed false positive rate of 20%, PlGF and AFP identified 49% of patients with SPE; combining these with prior risk factors did not improve the model efficiency. The detection rate for PE was 44% modeling with PlGF, AFP, inhA and RI. CONCLUSION: First-trimester PlGF and AFP are each modestly predictive of SPE, but combining both improves detection.

Model predicted Down syndrome detection rates for nuchal translucency screening in twin pregnancies

To estimate the Down syndrome detection rate for nuchal translucency (NT) screening in twins when fetus-specific risk allows for between-fetus NT correlation. The between-fetus correlation coefficient of log NT, in multiples of the median (MoM), was estimated from a series of 977 unaffected twins scanned at a single centre. Results were expressed in multiples of the normal median using a curve derived from 515 unaffected singleton pregnancies at the same centre. A screening result was classified as positive if the risk for at least one fetus exceeded the cut-off. Detection rates were estimated for a fixed 1-5% false-positive rate, at different gestational weeks, separately for risk calculation using an algorithm which takes account of between-fetus NT correlation or not. The correlation coefficient in unaffected pregnancies was 0.43 (P < 0.0001) and estimated to be 0.23 and 0.11 in discordant and concordant twins. At 12 weeks of gestation, the model predicted detection rate for a 3% false-positive rate was 68% when between-fetus correlation is not taken into account, increasing to 73% when it is applied. Similarly, for other false-positive rates and gestational weeks there was a predicted 4-6% increase in detection. Using a fetus-specific Down syndrome risk algorithm leads to a worthwhile increase in detection.

Maternal thyroid function at 11–13 weeks of gestation in fetal trisomies 21 and 18

To examine the association between maternal serum levels of thyroid stimulating hormone (TSH) and free β-human chorionic gonadotrophin (free β-hCG) in trisomy 21, trisomy 18 and euploid pregnancies at 11-13 weeks and investigate the potential value of TSH in first-trimester screening for aneuploidies. Maternal serum TSH and free β-hCG levels at 11-13 weeks in 25 trisomy 21 and 25 trisomy 18 pregnancies were compared with levels in 3592 unaffected pregnancies. Only women with no history of thyroid disease and negative for antithyroid antibodies were included. Serum TSH in the trisomy 21 pregnancies was lower [0.76 multiples of the normal median (MoM), interquartile range (IQR) 0.46-1.09 MoM] and in trisomy 18 it was higher (1.25 MoM, IQR 0.88-1.98 MoM) than in unaffected pregnancies (1.01 MoM, IQR 0.61-1.51 MoM). There were significant associations between TSH and free β-hCG in the unaffected pregnancies (r = - 0.214, p < 0.0001), but not in those with trisomy 21 (r = - 0.157, p = 0.452) or trisomy 18 (r = - 0.176, p = 0.401). hCG, rather than TSH, may be the primary thyrotropic factor in early pregnancy. Measurement of TSH does not improve the performance of screening for trisomies 21 and 18 provided by nuchal translucency, free β-hCG and pregnancy-associated plasma protein-A.

First-Trimester Uterine Artery Doppler and Serum Pregnancy-Associated Plasma Protein-A in Preeclampsia and Chromosomal Defects

Objective: We examined the potential value of the uterine artery pulsatility index (PI) in pregnancies with fetal aneuploidies and in those that developed preeclampsia (PE) with the aim of distinguishing between these complications in pregnancies with low pregnancy-associated plasma protein-A (PAPP-A). Methods: Uterine artery PI and serum PAPP-A at 11–13 weeks were measured in 165 cases of PE, including 33 that required delivery before 34 weeks (early PE) and 132 with late PE, and in 301 cases with aneuploidies, including 200 with trisomy 21. Each case of aneuploidy and PE was matched with 4 unaffected controls. Results: Serum PAPP-A was lower in early PE (0.58 multiples of the normal median, MoM) and in trisomy 21 (0.54 MoM), trisomy 18 (0.22 MoM) and Turner syndrome (0.51 MoM) – but not in late PE (0.90 MoM) – than in controls (1.01 MoM). Uterine artery PI was higher in early PE (1.52 MoM), late PE (1.20 MoM), trisomy 18 (1.20 MoM) and Turner syndrome (1.29 MoM) – but not in trisomy 21 (1.02 MoM) – than in controls (1.0 MoM). Conclusion: The uterine artery PI at 11–13 weeks may be useful in distinguishing between low PAPP-A due to trisomy 21 and early PE.

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

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. 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. 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). 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.

Activin A and activin receptors in gestational tissue from preeclamptic pregnancies.

Maternal serum activin A levels are elevated in women with preeclampsia. To explore whether this could be due, at least in part, to increased production by the gestational tissues, we have measured activin A in the serum of women with (n=23) or without preeclampsia (n=62) at 29-40 weeks of gestation and in placenta and fetal membranes from preterm preeclamptic (PT-PE, n=8), term preeclamptic (T-PE, n=10) and healthy term controls (T-C, n=10). We have also explored if there are associated changes in activin receptor Alk2, ActRII and ActRIIB in these tissues. The relative amounts of receptor proteins were measured by densitometry on Western blots and receptors and activin beta(A) subunit localised by immunohistochemistry in PT-PE, T-PE and T-C gestational tissues (n=8-10/group). Maternal serum activin A levels were significantly elevated in women with preeclampsia (multiples of the normal median (MoM)=3.5, P<0.0001, Mann-Whitney U test) compared with healthy women (median MoM=1.0). Compared with control tissues, the activin A content was significantly higher in preeclamptic placentae (P=0.001 and P=0.0005 for PT-PE and T-PE respectively, Mann-Whitney U test), but significantly lower in the amnion (P=0.005 and P=0.014 for PT-PE and T-PE respectively) and choriodecidua (P=0.009 for T-PE). The maternal serum activin A level in women with preeclampsia was significantly correlated with elevated placental production (P=0.01, Pearson's correlation). Receptor Alk2 protein levels were significantly elevated in T-PE placentae (P=0.0006, Mann-Whitney U test), ActRIIB levels were significantly lower in PT-PE placentae (P=0.01) and ActRII levels were significantly lower in PT-PE choriodecidua (P=0.0002) compared with controls. There were no apparent differences in the distribution of the beta(A) subunit and receptors Alk2, ActRII and ActRIIB between control and preeclamptic tissues. These findings suggest that elevated levels of activin A in the maternal circulation in association with preeclampsia are due, at least in part, to increased placental production, and that the regulation of activin synthesis in placenta and fetal membranes is differentially regulated. Further, the differences in activin receptor protein levels between preeclamptic and control placenta and choriodecidua suggest that activin A-induced regulation may be altered in preeclampsia.