Role of Cerebroplacental Ratio in Predicting the Outcome of Pregnancies Complicated by Diabetes.

INTRODUCTION: Our objective was to evaluate the strength of association and diagnostic performance of cerebroplacental ratio (CPR) in predicting the outcome of pregnancies complicated by pre- and gestational diabetes mellitus. METHODS: PubMed, Embase, Cochrane, and Google Scholar databases were searched. Inclusion criteria were pregnancies complicated by gestational or pregestational diabetes undergoing ultrasound assessment of CPR. The primary outcome was a composite score of perinatal mortality and morbidity as defined by the original publication. The secondary outcomes included preterm birth gestational age (GA) at birth, mode of delivery, fetal growth restriction (FGR) or small for GA (SGA) newborn, neonatal birthweight, perinatal death (PND), Apgar score <7 at 5 min, abnormal acid-base status, neonatal hypoglycemia, admission to neonatal intensive care unit (NICU). Furthermore, we aimed to perform a number of sub-group analyses according to the type of diabetes (gestational and pregestational), management adopted (diet insulin or oral hypoglycemic agents), metabolic control (controlled vs. non-controlled diabetes), and fetal weight (FGR, normally grown, and large for GA fetuses). Head-to-head meta-analyses were used to directly compare the risk of each of the explored outcomes. For those outcomes found to be significant, computation of diagnostic performance of CPR was assessed using bivariate model. RESULTS: Six studies (2,743 pregnancies) were included. The association between low CPR and adverse composite perinatal outcome was not statistically significant (p = 0.096). This result did not change when stratifying the analysis using CPR cut-off below 10th (p = 0.079) and 5th (p = 0.545) centiles. In pregnancies complicated by GDM, fetuses with a low CPR had a significantly higher risk of birthweight <10th percentile (OR: 5.83, 95% confidence interval [CI] 1.98-17.12) and this association remains significant when using a CPR <10th centile (p < 0.001). Fetuses with low CPR had also a significantly higher risk of PND (OR: 6.15, 95% CI 1.01-37.23, p < 0.001) and admission to NICU (OR 3.32, 95% CI 2.21-4.49, p < 0.001), but not of respiratory distress syndrome (p = 0.752), Apgar score <7 at 5 min (p = 0.920), abnormal acid-base status (p = 0.522), or neonatal hypoglycemia (p = 0.005). These results were confirmed when stratifying the analysis including only studies with CPR <10th centile as a cut-off to define abnormal CPR. However, CPR showed a low diagnostic accuracy for detecting perinatal outcomes. CONCLUSION: CPR is associated but not predictive of adverse perinatal outcome in pregnancies complicated by gestational diabetes. The findings from this systematic review do not support the use of CPR as a universal screening for pregnancy complication in women with diabetes.

Cell-free DNA analysis of maternal blood in prenatal screening for chromosomal microdeletions and microduplications: a systematic review.

BACKGROUND AND AIM OF THE STUDY: Scientific Societies do not recommend the use of cell-free DNA (cfDNA) testing as a first-tier screening for microdeletion and microduplication syndromes (MMs). The aim of this study was to review the current available literature on the performance of cell-free DNA as a screening for MMs. METHODS: Medline, Embase and the Cochrane Library were searched electronically from 2000 to January 2020 and articles reporting the diagnostic performance of cfDNA screening for MMs in large (>5000 cases) series were included. Between-study heterogeneity and random effect model for screen positive rate (SPR), false positive rate (FPR) and positive predictive value (PPV) were calculated. RESULTS: We identified 42 papers, seven included, for a total of 474,189 pregnancies and 210 cases of MMs. Diagnostic verification of positive cases was available overall in 486 (71.68 %) of 678 cases. The weighted pooled SPR, FPR and PPV were 0.19% (95% CI = 0.09-0.33), 0.07 (95% CI = 0.02-0.15) and 44.1 (95% CI = 31.49-63.07). In conclusion, the pooled PPV of cfDNA testing in screening for MMs was about 40%, ranging from 29% to 91%, for an overall FPR <0.1%. CONCLUSIONS: No confirmatory analysis was available in cases that did not undergo invasive testing, which were the vast majority of cases with a negative test, and therefore, the DR and the negative predictive value cannot be determined.

Diagnostic Accuracy of Doppler Ultrasound in Predicting Perinatal Outcome in Appropriate for Gestational Age Fetuses: A Prospective Study.

OBJECTIVE: To elucidate the role of Doppler ultrasound in predicting perinatal outcome in appropriate for gestational age (AGA) fetuses at term. MATERIAL AND METHODS: Prospective study carried out in a dedicated research ultrasound clinic. The inclusion criterion was AGA fetuses, defined as those with an estimated fetal weight between the 10th and 90th percentile, at 36 + 0-37 + 6 weeks of gestation. The primary outcome was a composite score of adverse perinatal outcome including either adverse intrapartum events or abnormal acid-base status at birth. Secondary outcomes were the individual components of the primary outcome. The Doppler parameters explored were umbilical artery (UA) PI, middle cerebral artery (MCA) PI, uterine arteries (UtA) PI and cerebroplacental ratio (CPR). Attending clinicians were blinded to Doppler findings. Logistic regression and ROC curve analyses were used to analyze the data. RESULTS: 553 AGA fetuses were included. There was no difference in mean UA PI (p = 0.486), MCA PI (p = 0.621), CPR (p = 0.832) and UtA PI (p = 0.611) between pregnancies complicated by composite perinatal morbidity compared to those not complicated by composite perinatal morbidity. In pregnancies complicated by adverse intrapartum outcome, the mean MCA PI (1.47 ±â€Š0.4 vs 1.61 ±â€Š0.4, p = 0.0039) was lower compared to the control group, while there was no difference in UA PI (p = 0.758), CPR (p = 0.108), and UtA PI (p = 0.177). Finally, there was no difference in any of the Doppler parameters explored between AGA fetuses with abnormal acid-base status at birth compared to those without abnormal acid-base status at birth. In the logistic regression analysis, UA PI, MCA PI, CPR, UtA PI, EFW and AC percentiles were not independently associated with composite adverse outcome, adverse intrapartum outcome or abnormal acid-base status at birth in non-SGA fetuses. The diagnostic performance of all of these Doppler parameters for predicting composite adverse outcome, adverse intrapartum outcome and abnormal acid-base status was poor. CONCLUSION: Cerebroplacental and maternal Doppler is not associated with or predictive of adverse pregnancy outcome in AGA fetuses close to term.

Reference values for pulsatility index of fetal anterior and posterior cerebral arteries in prolonged pregnancy.

OBJECTIVE: To establish consistent normal reference values for fetal anterior cerebral artery (ACA) and posterior cerebral artery (PCA) pulsatility index (PI) in prolonged pregnancy. METHODS: This prospective cross-sectional observational study included singleton normal prolonged pregnancies into two study groups according to the gestational age: from 40 + 0 to 40 + 6 and from 41 + 0 to 41 + 6 weeks. The PI was assessed in both anatomical segments of ACA (ACA-S1 and ACA-S2) and of PCA (PCA-S1 and PCA-S2) with color Doppler imaging and pulsed Doppler examination, and reference centiles charts were generated. PI values from the two investigated segments of each vessel were also compared. RESULTS: Data were obtained in 771 patients: n = 448 in the 40 + 0 and 40 + 6 weeks group, and n = 323 in the 41 + 0 and 41 + 6 weeks group. A moderate decrease in PI was observed as pregnancy progressed. No differences in PI values were found between the two anatomical segments of ACA and PCA. CONCLUSION: This study provides Doppler reference values for the fetal ACA and PCA PI. It also shows that Doppler examination could be performed indifferently in one of the two anatomical segments of these arteries.

Prenatal imaging features and postnatal outcomes of isolated fetal duplex renal collecting system: A systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review of studies reporting the outcome of fetuses with a prenatal diagnosis of isolated duplex collecting system (DCS). METHODS: Inclusion criteria were studies reporting the outcome of fetuses with a prenatal diagnosis of isolated DCS, defined as DCS not associated with other major structural anomalies at the time of diagnosis. The outcomes observed were: imaging features of DCS on prenatal ultrasound, associated anomalies detected exclusively at prenatal follow-up ultrasound and at birth, abnormal karyotype, symptoms at birth (including vesicoureteral reflux [VUR] and urinary tract infections [UTI]), need for and type of surgical approach, complications after surgery, and accuracy of prenatal ultrasound in correctly identifying this anomaly. RESULTS: Eleven studies (284 fetuses with a prenatal diagnosis of DCS) were included. On ultrasound, DCS was associated with ureterocele in 70.7% and with megaureter in 36.6% of cases. Worsening of pelvic/ureteric dilatation was reported to occur in 41.3% of fetuses. At birth, 4.3% of fetuses affected by DCS showed associated renal anomalies. After birth, VUR and UTI presented in 51.3% and 21.7% of children respectively, while 33.6% required surgery. Prenatal diagnosis of DCS was confirmed in 90.9% of included cases. CONCLUSION: DCS diagnosed prenatally is associated with a generally good outcome. Prenatal ultrasound has a good diagnostic accuracy, while detailed postnatal assessment is required in order to identify associated renal anomalies.

Vaginal birth after caesarean section: a multicentre study on prognostic factors and feasibility.

PURPOSE: Vaginal birth after caesarean (VBAC) is an option to avoid major abdominal surgery and many consequences related to repeated caesarean delivery. In the last years, many efforts have been made to increase the number of patients attempting trial of labour after caesarean (TOLAC). The aim of our study was to identify the most important factors associated with the success of VBAC. METHODS: A retrospective study was conducted in two Italian referral centres. Subjects included were singleton and morphologically normal pregnancy with previous C-section. Subjects with an inter-pregnancy interval shorter than 18 months, a large for gestational age baby, a pregnancy complicated with gestational diabetes and a previous unclassified uterine scar were excluded. The characteristics of the subjects were compared and a logistic regression was performed to evaluate variables associated with successful VBAC. RESULTS: Of the 300 patients included, 224 (74.7%) achieved VBAC while 76 (25.3%) underwent C-section after failed TOLAC. The number of previous C-sections was not significantly associated with the success of TOLAC. Factors positively associated with achievement of VBAC were previous vaginal delivery (OR of 6.88 for one and 9.68 for more than one) and oxytocin implementation (OR 3.32). No maternal and neonatal adverse events occurred. CONCLUSION: Our results show that attempting VBAC is a feasible option in referral centres after adequate evaluation of the potential factors affecting the probability of success. A careful record of obstetrical history and management of labour can provide clinicians useful information to counsel women before and during labour.

Fetal Doppler Parameters at Term in Pregnancies Affected by Gestational Diabetes: Role in the Prediction of Perinatal Outcomes.

OBJECTIVE: The timing of delivery for women affected by gestational diabetes (GDM) is still controversial. Good clinical practice often suggests offering induction of labor at term in order to reduce the complications associated with this condition, while recent evidence supports expectant management. Fetal Doppler parameters represent a validated tool for testing fetal well-being at term and can select pregnancies that need increased surveillance. The aim of the present study was to evaluate the role of fetal Doppler parameters at term for the prediction of pregnancy outcomes in patients affected by GDM. METHODS: Prospective cohort study in a single center. Evaluation of umbilical artery (UA) PI, middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR) and umbilical-to-cerebral ratio (UCR) at > 37 weeks of gestation in singleton, morphologically normal pregnancies affected by GDM, was performed in order to estimate the association between ultrasound measurements at term and perinatal outcome. Regression linear analysis was used to estimate the association between fetal Doppler parameters and neonatal pH, neonatal Apgar score, neonatal weight and a composite adverse outcome. The receiver operating characteristic (ROC) curve was used to estimate the possible predictive value of the above association. RESULTS: Our results on 130 women showed MCA PI to be the best predictor of perinatal outcomes in terms of low Apgar score at the 1st minute (p = 0.00), pH (p = 0.02) and composite adverse outcome (p = 0.05). UCR showed a significant correlation with neonatal pH (p = 0.02). No significant correlations for UA PI and CPR MoMs have been demonstrated in our population. However, the small sample size is a limitation of the study. CONCLUSION: Evaluation of MCA Doppler and eventually UCR at term can be a useful tool to discriminate pregnancies affected by GDM that can benefit from IOL before 41 weeks in order to reduce complications related to this condition.

Risk Factors for Coarctation of the Aorta on Prenatal Ultrasound: A Systematic Review and Meta-Analysis.

BACKGROUND: Prenatal diagnosis of coarctation of the aorta (CoA) is still challenging and affected by high rates of false-positive diagnoses. The aim of this study was to ascertain the strength of association and to quantify the diagnostic accuracy of different ultrasound signs in predicting CoA prenatally. METHODS: Medline, Embase, CINAHL, and Cochrane databases were searched. Random-effects and hierarchical summary receiver operating characteristic model meta-analyses were used to analyze the data. RESULTS: Seven hundred ninety-four articles were identified, and 12 (922 fetuses at risk for CoA) articles were included. Mean mitral valve diameter z score was lower (P<0.001) and the mean tricuspid valve diameter z score was higher in fetuses with CoA than in those without CoA (P=0.01). Mean aortic valve diameter z score was lower in fetuses with CoA than in healthy fetuses (P≤0.001), but the ascending aorta diameter, expressed as z score or millimeters, was similar between groups (P=0.07 and 0.47, respectively). Mean aortic isthmus diameter z scores measured either in sagittal (P=0.02) or in 3-vessel trachea view (P<0.001) were lower in fetuses with CoA. Conversely, the mean pulmonary artery diameter z score, the right/left ventricular and pulmonary artery/ascending aorta diameter ratios were higher (P<0.001, P=0.02, and P=0.02, respectively) in fetuses with CoA in comparison with controls, although aortic isthmus/arterial duct diameter ratio was lower in fetuses with CoA than in those without CoA (P<0.001). The presence of coarctation shelf and aortic arch hypoplasia were more common in fetuses with CoA than in controls (odds ratio, 26.0; 95% confidence interval, 4.42-153; P<0.001 and odds ratio, 38.2; 95% confidence interval, 3.01-486; P=0.005), whereas persistent left superior vena cava (P=0.85), ventricular septal defect (P=0.12), and bicuspid aortic valve (P=0.14) did not carry an increased risk for this anomaly. Multiparametric diagnostic models integrating different ultrasound signs for the detection of CoA were associated with an increased detection rate. CONCLUSIONS: The detection rate of CoA may improve when a multiple-criteria prediction model is adopted. Further large multicenter studies sharing the same imaging protocols are needed to develop objective models for risk assessment in these fetuses.

Small fetal thymus and adverse obstetrical outcome: a systematic review and a meta-analysis.

INTRODUCTION: The aim of this study was to explore the association between small fetal thymus on ultrasound and adverse obstetrical outcome. MATERIAL AND METHODS: Medline, Embase, Cochrane and Web of Science databases were searched. Primary outcome was the risk of preterm birth before 37 and 34 weeks of gestation in fetuses with, compared to those without, a small thymus on ultrasound. SECONDARY OUTCOMES: occurrence of chorioamnionitis, intrauterine growth restriction, neonatal sepsis, gestational age at birth, birthweight, neonatal morbidity and preeclampsia. RESULTS: Twelve studies including 1744 fetuses who had ultrasound assessment of thymus during pregnancy were included. Women with preterm premature rupture of the membranes or with preterm labor were at higher risk of preterm birth before 37 weeks (p = 0.01), or before 34 weeks (p < 0.001) for fetuses with a small fetal thymus compared to those without a small thymus, and the risk of chorioamnionitis was higher when the thymus was small (p < 0.001). Fetuses with small thymus were not at higher risk of intrauterine growth restriction (p = 0.3). A small thymus increased the risk of neonatal sepsis (p = 0.007) and morbidity (p = 0.003), but not the risk of preeclampsia (p = 0.9). CONCLUSIONS: A small fetal thymus is associated with a higher risk of preterm birth, chorioamnionitis, neonatal sepsis and morbidity, but not with intrauterine growth restriction and preeclampsia.

Diagnostic accuracy of magnetic resonance imaging in detecting the severity of abnormal invasive placenta: a systematic review and meta-analysis.

INTRODUCTION: Accurate prenatal diagnosis of abnormally invasive placenta (AIP) is fundamental because it significantly reduces maternal morbidities. MATERIAL AND METHODS: Medline, Embase, CINAHL and the Cochrane databases were searched. The primary aim of the present review was to elucidate the diagnostic accuracy of prenatal magnetic resonance imaging (MRI) in recognizing the severity of AIP, defined as the depth and topography of invasion. The secondary aim was to ascertain the strength of association between each MRI sign and the depth of placental invasion and to test their individual predictive accuracy in detecting such invasion. Inclusion criteria were studies on women who had prenatal MRI for ultrasound suspicion or the presence of clinical risk factors for AIP. Estimates of sensitivity, specificity, positive and negative likelihood ratios and diagnostic odds ratio were calculated using the hierarchical summary receiver characteristics curve model, and individual data random-effect logistic regression was used to calculate OR. RESULTS: Twenty studies (1080 pregnancies undergoing MRI mainly for the ultrasound suspicion of AIP) were included. MRI showed a sensitivity of 94.4% [95% confidence interval (CI) 15.8-99.9], 100% (95% CI 75.3-100) and 86.5% (95% CI 74.2-94.4) for detection of placenta accreta, increta and percreta, respectively; the corresponding values for specificity were 98.8% (95% CI 70.7-100), 97.3% (95% CI 93.3-99.3), 96.8% (95% CI 93.5-98.7). MRI identified 100% of cases with S1 and 100% of those with S2 invasion confirmed at surgery. Among the different MRI signs, intra-placental dark bands showed the best sensitivity for the detection of placenta accreta, increta and percreta; as well as abnormal intra-placental vascularity, uterine bulging was associated with a higher risk of increta and percreta, exophitic mass and bladder tenting with placenta percreta. CONCLUSION: Prenatal MRI has an excellent diagnostic accuracy in identifying the depth and the topography of placental invasion. However, these findings come mainly from studies in which MRI was performed as a secondary imaging tool in women already screened for AIP on ultrasound and might not reflect its actual diagnostic performance in detecting the severity of these disorders.

Diagnostic accuracy of ultrasound in detecting the depth of invasion in women at risk of abnormally invasive placenta: A prospective longitudinal study.

INTRODUCTION: The aim of this study was to assess the diagnostic accuracy of ultrasound in detecting the depth of abnormally invasive placenta in women at risk. MATERIAL AND METHODS: Prospective longitudinal study including women with placenta previa and at least one prior cesarean delivery or uterine surgery. Depth of abnormally invasive placenta was defined as the degree of trophoblastic invasion through the myometrium and was assessed with histopathological analysis. The ultrasound signs explored were: loss of clear zone, placental lacunae, bladder wall interruption, uterovesical hypervascularity, and increased vascularity in the parametrial region. RESULTS: In all, 210 women were included in the analysis. When using at least one sign, ultrasound had an overall sensitivity of 100% (95% CI 96.5-100) and overall specificity of 61.9 (95% CI 51.9-71.2) for all types of abnormally invasive placenta. Using two ultrasound signs increased the diagnostic accuracy in terms of specificity (100%, 95% CI 96.5-100) but did not affect sensitivity. When stratifying the analysis according to the depth of placental invasion, using at least one sign had a sensitivity of 100% (95% CI 93.7-100) and 100% (95% CI 92.6-100) for placenta accreta/increta and percreta, respectively. Using three ultrasound signs improved the detection rate for placenta percreta with a sensitivity of 100% (95% CI 92.6-100) and a specificity of 77.2% (95% CI 69.9-83.4). CONCLUSION: Ultrasound has a high diagnostic accuracy in detecting the depth of placental invasion when applied to a population with specific risk factors for anomalies such as placenta previa and prior cesarean delivery or uterine surgery.

Diagnostic accuracy of ultrasound in detecting the severity of abnormally invasive placentation: a systematic review and meta-analysis.

INTRODUCTION: Our objective was to elucidate the overall diagnostic accuracy of ultrasound in detecting the severity of abnormally invasive placentation (AIP). MATERIAL AND METHODS: Medline, Embase, CINAHL and The Cochrane databases were searched. The ultrasound signs explored were: loss of hypoechoic (clear) zone in the placental-uterine interface, placental lacunae, bladder wall interruption, myometrial thinning, focal exophitic mass, placental lacunar flow, subplacental vascularity, and uterovesical hypervascularity. RESULTS: Twenty studies (3209 pregnancies) were included. Ultrasound had an overall good diagnostic accuracy in identifying the depth of placental invasion with sensitivities of 90.6%, 93.0%, 89.5%, and 81.2% for placenta accreta, increta, accreta/increta, and percreta, respectively; the corresponding specificities were 97.1%, 98.4%, 94.7%, and 98.9%. Placental lacunae had sensitivities of 74.8%, 88.6%, and 76.3% for the detection of placenta accreta, increta, and percreta, respectively. Sensitivity and specificity of loss of the clear zone in identifying placenta accreta were 74.9% and 92.0%, whereas the corresponding figures for placenta increta and percreta were 91.6% and 76.9%, and 88.1% and 71.1%. Lacunar flow had sensitivities of 81.2%, 84.3%, and 45.2% for the detection of placenta accreta, increta, and percreta respectively; the corresponding figures for specificity were 84.0%, 79.7%, and 75.3%. Sensitivity of uterovesical hypervascularity was low for the detection of placenta accreta (12.3%) but high for placenta increta (94.4%) and percreta (86.2%); the corresponding figures for specificity were 90.8%, 88.0% and 88.2%, respectively. CONCLUSIONS: Ultrasound has an overall good diagnostic accuracy in recognizing the depth and the topography of placental invasion.

Fetal Tricuspid Regurgitation in the First Trimester as a Screening Marker for Congenital Heart Defects: Systematic Review and Meta-Analysis.

BACKGROUND: Assessment of tricuspid flow has been reported to improve the performance of screening for aneuploidies and congenital heart defects (CHD). However, the performance of tricuspid regurgitation (TR) as a screening marker for CHD in euploid fetuses is yet to be established. The main aim of this meta-analysis was to establish the predictive accuracy of TR for CHD. METHODS: MEDLINE, Embase, and the Cochrane Library were searched electronically utilizing combinations of the relevant medical subject heading for "fetus," "tricuspid regurgitation," and "first trimester." The outcomes explored were prevalence of TR in an euploid population, strength of association between TR and CHD, and predictive accuracy of TR for CHD in euploid fetuses. Summary estimates of sensitivity, specificity, positive and negative likelihood ratios, and diagnostic odds ratio for the overall predictive accuracy of TR for the detection of CHD were computed using the hierarchical summary receiver-operating characteristics model. RESULTS: A total of 452 articles were identified; 60 were assessed with respect to their eligibility for inclusion and a total of 4 studies were included in the study. TR was associated with an increased risk of CHD (RR: 9.6, 95% CI 2.8-33.5; I2: 92.7%). The strength of association between TR and CHD persisted when considering fetuses at risk for CHD, such as those with increased nuchal translucency (RR: 7.2, 95% CI 5.2-9.8; I2: 0%), while TR did not show any association with CHD when detected in a population at low risk for cardiac defects (RR: 9.3, 95% CI 0.8-111.8; I2: 93%). The overall diagnostic performance of TR in detecting CHD was poor in detecting CHD (sROC: 0.684, SE: 0.61) with a sensitivity of 35.2% (95% CI 26.9-44.1) and a specificity of 98.6% (95% CI 98.5-98.7). Detection of TR at the 11-14 weeks' scan showed a positive likelihood ratio of 7.2 (95% CI 5.3-9.8) in detecting CHD when applied to a population at risk for CHD such as fetuses with an increased nuchal translucency. CONCLUSION: The detection of TR in the first trimester increases the risk of CHD. However, isolated TR in the first trimester does not seem to be a strong predictor for CHD.

Mid-pregnancy fetal biometry, uterine artery Doppler indices and maternal demographic characteristics: role in prediction of small-for-gestational-age birth.

INTRODUCTION: The aim of this study was to evaluate the role of mid-trimester fetal biometry, uterine artery Doppler indices and maternal demographics in prediction of small-for-gestational-age (SGA) birth. MATERIALS AND METHODS: We conducted a retrospective cohort study in a single referral center. The study included 23 894 singleton pregnancies scanned between 19 and 24 weeks of gestation. Maternal demographics included age, body mass index and ethnicity. Fetal biometry, birthweight and uterine artery pulsatility index values were converted into centiles. Multivariable logistic regression analysis was performed and the predictive accuracy was assessed using receiver operating characteristic curve analysis. The main outcome measure was prediction of delivery of preterm and term SGA neonates defined as a birthweight in the lowest centile groups (<10th, <5th and <3rd centiles). RESULTS: Maternal ethnicity, fetal biometry and uterine artery Doppler indices were significantly associated with the risk of SGA <5th centile (p < 0.01). Maternal factors or fetal biometry alone showed poor to moderate performance in prediction of term and preterm SGA <5th centile at a 10% false-positive rate. Uterine artery pulsatility index alone was able to predict 25, 60 and 77% of SGA <5th centile delivering at >37, <37 and <32 weeks of gestation respectively at a 10% false-positive rate; maternal factors, fetal biometry and uterine artery Doppler combined detected 40, 66 and 89% of term, preterm and very preterm SGA <5th centile at a 10% false-positive rate. CONCLUSIONS: Second-trimester screening can identify the majority of pregnancies at high risk of SGA birth and showed a higher performance for earlier gestational ages at birth and lower birthweight centiles.

Mid-pregnancy fetal growth, uteroplacental Doppler indices and maternal demographic characteristics: role in prediction of stillbirth.

INTRODUCTION: To evaluate the relative value of mid trimester fetal growth, uterine artery Doppler indices and maternal demographics in prediction of stillbirth. MATERIAL AND METHODS: Retrospective cohort study; 23 894 singleton pregnancies routinely scanned between 19 and 24 weeks' gestation. Maternal characteristics included age, body mass index, ethnicity and medical history. Fetal biometry indices, birthweight and uterine artery pulsatility index values were converted to percentiles and multivariable logistic regression analysis was performed. The predictive accuracy was assessed using receiver operating characteristic curves analysis. The main outcome was prediction of preterm and term stillbirths. RESULTS: Non-Caucasian ethnicity, femur length centile and uterine artery pulsatility index were significantly associated with the risk of stillbirth (all p < 0.01). The detection rate of screening by maternal factors alone was 19% for all stillbirths, and 12 and 14% for term and preterm stillbirth at a 10% false positive rate, respectively. Using femur length centile alone, the detection rates were 27 and 23%, respectively. Uterine artery pulsatility index alone was able to predict 24 and 31% of term and preterm stillbirths. Screening by combining maternal factors, femur length centile and uterine artery Doppler detected 27 and 35% of term and preterm stillbirths at a 10% false positive rate. CONCLUSIONS: Second trimester ultrasound assessment offers an opportunity to identify pregnancies at the highest risk of stillbirth occurring as a consequence of placental dysfunction. This information may be useful to improve pregnancy outcome by identifying women who may benefit from increased ultrasound surveillance and/or timely intervention.

Sensitivity of first-trimester ultrasound in the detection of congenital anomalies in twin pregnancies: population study and systematic review.

INTRODUCTION: The first aim of this study was to ascertain the diagnostic performance of first-trimester ultrasound in detecting congenital anomalies in twins. The secondary aim was to explore the strength of association between different pregnancy characteristics and early detection of structural anomalies in a large unselected population of twin pregnancies. A systematic review of the published literature was also carried out. MATERIAL AND METHODS: Retrospective analysis of prospectively collected data from consecutive twin pregnancies booked for antenatal care between 1996 and 2014. Predictive accuracy of those covariates independently associated with the occurrence of fetal anomalies was assessed with logistic regression analysis and receiver operating characteristics curves. RESULTS: In all, 1064 twin pregnancies (820 dichorionic and 264 monochorionic) were included in the analysis. Forty-two pregnancies had one or more fetuses with structural abnormalities. Detection of structural abnormalities using ultrasound was possible in the first trimester in 27.3% (95% confidence interval 15.0-42.8) of twin pregnancies. Monochorionicity (odds ratio 2.3, 95% confidence interval 1.1-4.7) and discordance in crown-rump length and nuchal translucency were associated with an increased risk of fetal anomalies. However, their predictive accuracy was only moderate (areas under the curve 0.67, 95% confidence interval 0.6-0.8 and 0.68, 95% confidence interval 0.6-0.8, for crown-rump length and nuchal translucency discrepancy, respectively). CONCLUSIONS: First-trimester detection of structural abnormalities in twin pregnancies is possible in 27.3% (95% confidence interval 15.0-42.8) of cases. The likelihood for first-trimester detection of structural anomalies in twins was maximum for cranial vault, midline brain and abdominal wall defects. Monochorionicity and increasing discrepancy in crown-rump length and nuchal translucency were associated with fetal structural abnormalities, although their predictive performance was only moderately good.

Spontaneous calcification process in primary renal cells from a medullary sponge kidney patient harbouring a GDNF mutation.

Medullary nephrocalcinosis is a hallmark of medullary sponge kidney (MSK). We had the opportunity to study a spontaneous calcification process in vitro by utilizing the renal cells of a patient with MSK who was heterozygous for the c.-27 + 18G>A variant in the GDNF gene encoding glial cell-derived neurotrophic factor. The cells were obtained by collagenase digestion of papillary tissues from the MSK patient and from two patients who had no MSK or nephrocalcinosis. These cells were typed by immunocytochemistry, and the presence of mineral deposits was studied using von Kossa staining, scanning electron microscopy analysis and an ALP assay. Osteoblastic lineage markers were studied using immunocytochemistry and RT-PCR. Staminality markers were also analysed using flow cytometry, magnetic cell separation technology, immunocytochemistry and RT-PCR. Starting from p2, MSK and control cells formed nodules with a behaviour similar to that of calcifying pericytes; however, Ca2PO4 was only found in the MSK cultures. The MSK cells had morphologies and immunophenotypes resembling those of pericytes or stromal stem cells and were positive for vimentin, ZO1, αSMA and CD146. In addition, the MSK cells expressed osteocalcin and osteonectin, indicating an osteoblast-like phenotype. In contrast to the control cells, GDNF was down-regulated in the MSK cells. Stable GDNF knockdown was established in the HK2 cell line and was found to promote Ca2PO4 deposition when the cells were incubated with calcifying medium by regulating the osteonectin/osteopontin ratio in favour of osteonectin. Our data indicate that the human papilla may be a perivascular niche in which pericyte/stromal-like cells can undergo osteogenic differentiation under particular conditions and suggest that GDNF down-regulation may have influenced the observed phenomenon.

Highly purified hMG versus recombinant FSH plus recombinant LH in intrauterine insemination cycles in women ≥35 years: a RCT.

STUDY QUESTION: Is the treatment with recombinant FSH (rFSH) plus recombinant LH (rLH) more effective than highly purified (HP)-hMG in terms of ongoing pregnancy rate (PR) in women ≥35 years of age undergoing intrauterine insemination (IUI) cycles? SUMMARY ANSWER: The ongoing PR was not significantly different in women treated with rFSH plus rLH or with HP-hMG. WHAT IS KNOWN ALREADY: Although previous studies have shown beneficial effects of the addition of LH activity to FSH, in terms of PR in patients aged over 34 years having ovulation induction, no studies have compared two different gonadotrophin preparations containing LH activity in women ≥35 years of age in IUI cycles. STUDY DESIGN, SIZE, DURATION: A single-centre RCT was performed between May 2012 and September 2013 with 579 women ≥35 years of age undergoing IUI cycles. The patients were randomly assigned to one of the two groups, rFSH in combination with rLH group or HP-hMG (Meropur) group, by giving them a code number from a computer generated randomization list, in order of enrolment. The randomization visit took place on the first day of ovarian stimulation. PARTICIPANTS/MATERIALS, SETTING, METHODS: Five hundred and seventy-nine patients with unexplained infertility or mild male factor undergoing IUI cycles were recruited in a university hospital setting. All women were enrolled in this study only for one cycle of treatment. Five hundred and seventy-nine cycles were included in the final analysis. Two hundred and ninety patients were treated with rFSH in combination with rLH and 289 patients were treated with HP-hMG. The ovarian stimulation cycle started on the third day of the menstrual cycle and the starting gonadotrophin doses used were 150 IU/day of rFSH plus 150 IU/day of rLH or 150 IU/day of HP-hMG. The drug dose was adjusted according to the individual follicular response. A single IUI per cycle was performed 34-36 h after hCG injection. MAIN RESULTS AND THE ROLE OF CHANCE: The main outcome measures were ongoing PR and number of interrupted cycles for high risk of ovarian hyperstimulation syndrome (OHSS). Ongoing pregnancy rates were 48/290 (17.3%) in the recombinant group versus 35/289 (12.2%) in the HP-hMG group [(odds ratio (OR) 1.50, 95% CI 0.94-2.41, P = 0.09]. The number of interrupted cycles for high risk of OHSS was 13/290 (4.5%) in the rFSH plus rLH group and 2/289 (0.7%) in the HP-hMG group (OR 6.73, 95% CI 1.51-30.12, P = 0.013). LIMITATIONS, REASONS FOR CAUTION: One of the limitations of this study was the early closure and the ongoing PR could be overestimated. Both patient and gynaecologist were informed of the assigned treatment. WIDER IMPLICATIONS OF THE FINDINGS: Our results demonstrated the lack of differences in terms of ongoing PR between recombinant product and HP-hMG, in women ≥35 years undergoing controlled ovarian stimulation for IUI cycles. HP-hMG was safer than recombinant gonadotrophin concerning the risk of OHSS. STUDY FUNDING/COMPETING INTERESTS: None. TRIAL REGISTRATION NUMBER: NCT01604044.

Number of episodes of reduced fetal movement at term: association with adverse perinatal outcome.

OBJECTIVE: The aims of this study were evaluation of the association of reduced fetal movements (RFM) and small-for-gestational-age (SGA) birth at term and to explore if fetal and maternal outcomes are different with single vs repeated episodes of RFM and normal fetal assessment test results. STUDY DESIGN: This was a retrospective cohort study of all singleton pregnancies referred for RFMs at a tertiary fetal medicine unit from January 2008 through September 2014. Ultrasound and Doppler indices were obtained from a computerized ultrasound database and pregnancy outcome was collected from hospital records. RESULTS: Of the 21,944 women with a singleton pregnancy booked for maternity care during the study period, 1234 women (5.62%) reported RFMs >36+0 weeks. Of these, 1029 women (83.4%) reported a single episode of RFM and 205 (16.6%) had ≥2 presentations for RFM. Women with repeated RFMs had a significantly higher mean uterine artery pulsatility index in the second trimester. The prevalence of SGA baby at birth in women presenting with a single episode as compared to repeated episodes of RFM was 9.8% and 44.2%, respectively (odds ratio, 7.3; 95% confidence interval, 5.1-10.4; P < .05). CONCLUSION: Repeated episodes of RFMs at term are more likely to occur in women with high second-trimester uterine artery Doppler resistance indices and are strongly associated with the birth of SGA infants. Women presenting with repeated episodes of RFM should be treated as being at high risk of placental dysfunction irrespective of the results of prenatal ultrasound and Doppler assessment.

Discordance in fetal biometry and Doppler are independent predictors of the risk of perinatal loss in twin pregnancies.

OBJECTIVE: Impaired fetal growth might be better evaluated in twin pregnancies by assessing the intertwin discordance rather than the individual fetal size. The aim of this study was to investigate the prediction of perinatal loss in twin pregnancy using discordance in fetal biometry and Doppler. STUDY DESIGN: This was a retrospective cohort study in a tertiary referral center. The estimated fetal weight (EFW), umbilical artery (UA) pulsatility index (PI), middle cerebral artery (MCA) PI, cerebroplacental ratio (CPR), and their discordance recorded at the last ultrasound assessment before delivery or demise of one or both fetuses were converted into centiles or multiples of the median (MoM). The discordance was calculated as the larger value-smaller value/larger value. A logistic regression analysis was performed to identify, and adjust for, potential confounders. The predictive accuracy was assessed using receiver-operating characteristic curve analysis. RESULTS: The analysis included 620 (464 dichorionic diamniotic and 156 monochorionic diamniotic) twin pregnancies (1240 fetuses). Perinatal loss of one or both fetuses complicated 16 pregnancies (2.6%). The combination of EFW discordance and CPR discordance had the best predictive performance (area under the curve, 0.96; 95% confidence interval, 0.92-1.00) for perinatal mortality. The detection rate, false-positive rate, positive likelihood ratio, and negative likelihood ratio were 87.5%, 6.7%, 13.08, and 0.13, respectively. The EFW centile, EFW below the 10th centile (small for gestational age), UA PI discordance, MCA PI discordance, and MCA PI MoM were significantly associated with the risk of perinatal loss on univariate analysis, but these associations became nonsignificant after adjusting for other confounders (P = .097, P = .090, P = .687, P = .360, and P = .074, respectively). The UA PI MoM, CPR MoM, EFW discordance, and CPR discordance were all independent predictors of the risk of perinatal loss, even after adjusting for potential confounders (P = .022, P = .002, P < .001, and P = .010, respectively). CONCLUSION: EFW discordance and CPR discordance are independent predictors of the risk of perinatal loss in twin pregnancies. Their combination could identify the majority of twin pregnancies at risk of perinatal loss. These findings highlight the importance of discordance in Doppler indices of fetal hypoxia, as well as fetal size, in assessing the risk of perinatal mortality.