The effect of 75-g oral glucose tolerance test on maternal and foetal Doppler parameters in healthy pregnancies: a cross-sectional observational study.

Hyperglycaemia can alter placental resistance to blood flow and hyperglycaemia has adverse perinatal outcomes. Oral glucose tolerance testing (OGTT) increases the maternal plasma glucose levels temporarily and mimics metabolic hyperglycaemia. The blood flow of the uterine artery (UtA), umbilical artery (UA), middle cerebral artery (MCA) were assessed before, 1 and 2 h following the OGTT by using Doppler ultrasonography. Z-score of cerebroplacental ratio (CPR), pulsatility index (PI) for three vessels were evaluated separately. All measurements of the MCA, UA, UtA Doppler parameters were not statistically different for fasting, and 1 and 2 h following the 75 g OGTT in the 53 pregnant women with a singleton gestation in the low-risk group. This study results show that acute hyperglycaemia induced by OGTT has no effect on maternal and foetal Doppler parameters in healthy pregnancies.IMPACT STATEMENTWhat is already known on this subject? Foetal glucose is affected by maternal blood glucose concentrations and placental blood flow. Acute hyperglycaemia may have an effect on maternal, and foetal Doppler parameters among healthy pregnanciesWhat do the results of this study add? Our findings indicate that blood flow velocity metric measurements in the UA, MCA and UtA were not affected by the OGTT in healthy pregnant women.What are the implications of these findings for clinical practice and/or further research? Acute hyperglycaemia induced by OGTT does not have any effect on fetomaternal circulation, especially foetal brain blood flow. Other foetal vessels including ductus venosus, renal artery, etc. may be affected by maternal blood glucose levels during the OGTT or in diabetic patients. Future prospective studies consisting of diabetic patients are warranted to verify the exact effect of glucose levels on foetal and maternal circulation.

Cross-modality and in-vivo validation of 4D flow MRI evaluation of uterine artery blood flow in human pregnancy.

OBJECTIVES: Clinical assessment of uterine artery (UtA) hemodynamics is currently limited to Doppler ultrasound (US) velocimetry. We have demonstrated previously the feasibility of applying four-dimensional (4D) flow magnetic resonance imaging (MRI) to evaluate UtA hemodynamics during pregnancy, allowing flow quantification of the entire course of the vessel. In this study, we sought to further validate the physiological relevance of 4D flow MRI measurement of UtA blood flow by exploring its association with pregnancy outcome relative to US-based metrics. METHODS: Recruited into this prospective, cross-sectional study were 87 women with a singleton pregnancy who underwent 4D flow MRI between May 2016 and April 2019 to measure the UtA pulsatility index (MRI-PI) and blood flow rate (MRI-flow, in mL/min). UtA-PI was also measured using US (US-PI). The primary outcome was a composite (COMP) of pre-eclampsia (PE) and/or small-for-gestational-age (SGA) neonate, and secondary outcomes were PE and SGA neonate individually. We assessed the ability of MRI-flow, MRI-PI and US-PI to distinguish between outcomes, and evaluated whether MRI-flow changed as gestation progressed. RESULTS: Following 4D flow postprocessing and exclusions from the analysis, 74 women had 4D flow MRI data analyzed for both UtAs. Of these, 18 developed a COMP outcome: three developed PE only, 11 had a SGA neonate only and four had both. A comparison of the COMP group vs the no-COMP group found no differences in maternal age, body mass index, nulliparity, gravidity or race. For 66 of the 74 subjects, US data were also available. In these subjects, both median MRI-PI (0.95 vs 0.70; P < 0.01) and median US-PI (0.95 vs 0.73; P < 0.01) were significantly increased in subjects in the COMP group compared with those in the no-COMP group. The UtA blood-flow rate, as measured by MRI, did not increase significantly from the second to the third trimester (median flow (interquartile range (IQR)), 543 (419-698) vs 575 (440-746) mL/min; P = 0.77), but it was significantly lower overall in the COMP compared with the no-COMP group (median flow (IQR), 486 (366-598) vs 624 (457-749) mL/min; P = 0.04). The areas under the receiver-operating-characteristics curves for MRI-flow, MRI-PI and US-PI in predicting COMP were not significantly different (0.694, 0.737 and 0.731, respectively; P = 0.87). CONCLUSIONS: 4D flow MRI can yield physiological measures of UtA blood-flow rate and PI that are associated with adverse pregnancy outcome. This may open up new avenues in the future to expand the potential of this technique as a robust tool with which to evaluate UtA hemodynamics in pregnancy. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal cardiac function at 35-37 weeks' gestation in pregnancies that subsequently develop pre-eclampsia.

OBJECTIVE: To compare fetal cardiac morphology and function between pregnancies that subsequently developed pre-eclampsia (PE) and those that remained normotensive. METHODS: This was a prospective observational study in 1574 pregnancies at 35-37 weeks' gestation, including 76 that subsequently developed PE. We carried out comprehensive assessment of fetal cardiac morphology and function including novel imaging modalities, such as speckle-tracking echocardiography, and measured uterine artery pulsatility index, mean arterial pressure (MAP), serum placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and cerebroplacental ratio (CPR). The findings in the group that subsequently developed PE were compared to those in pregnancies that remained normotensive. RESULTS: In fetuses of mothers who subsequently developed PE, compared to those from normotensive pregnancies, there was a more globular right ventricle, as shown by reduced right ventricular sphericity index, reduced right ventricular systolic contractility, as shown by reduced global longitudinal strain, and reduced left ventricular diastolic function, as shown by increased E/A ratio. On multivariable regression analysis, these indices demonstrated an association with PE, independent of maternal characteristics and fetal size. In pregnancies that subsequently developed PE, compared to those that remained normotensive, MAP, sFlt-1 and the incidence of low birth weight were higher, whereas serum PlGF, CPR and the interval between assessment and delivery were lower. These findings demonstrate that, in pregnancies that develop PE, there is evidence of impaired placentation, reflected in low PlGF and reduced birth weight, placental ischemia, evidenced by increased sFlt-1 which becomes apparent in the interval of 2-4 weeks preceding the clinical onset of PE, and consequent fetal hypoxia-induced redistribution in the fetal circulation, reflected in the low CPR. CONCLUSION: Although the etiology of the observed fetal cardiac changes in pregnancies that subsequently develop PE remains unclear, it is possible that the reduction in right-heart systolic function is the consequence of high afterload due to increased placental resistance, whilst the early left ventricular diastolic changes could be due to fetal hypoxia-induced redistribution in the fetal circulation. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

From Where Does the Uterine Artery Originate? A Prospective, Observational Laparoscopic Anatomic Study.

STUDY OBJECTIVE: To determine and categorize the anatomic variations of the uterine artery (UA) as observed during laparoscopic hysterectomy with retroperitoneal dissection for benign conditions. DESIGN: A prospective, observational study. SETTING: A hospital department of obstetrics and gynecology, Uludag University Hospital, Bursa, Turkey. PATIENTS: A total of 378 female patients who presented with indications for laparoscopic hysterectomy for benign disease. INTERVENTIONS: Laparoscopic hysterectomy with retroperitoneal dissection was performed bilaterally in all patients between March 2014 and October 2018. The vascular anatomy beginning at the bifurcation of the common iliac artery down to the crossing of the UA with the ureter was exposed and subsequently studied. The UA was identified, and its variable branching patterns were recorded. The patterns were then categorized into groups adapted from classic vascular anatomy studies. MEASUREMENTS AND MAIN RESULTS: Retroperitoneal dissections of 756 UAs were performed in 378 female patients. The UA was the first anterior branch of the internal iliac artery in 80.9% of the cases (Model 1; Main Model). Three additional models adequately described other variations of the UA as follows: Model 2 (Cross Model), 3.7%; Model 3 (Trifurcation Model), 3.1%; and Model 4 (Inverted-Y Model), 7.4%. The origin of the UA could not be determined in 7.4% of the cases. CONCLUSION: The UA is the first anterior branch of the internal iliac artery in more than 80% of females. Surgeons should be aware of the anatomic variations of the UA to perform safe and efficient procedures.

First-trimester pre-eclampsia biomarker profiles in Asian population: multicenter cohort study.

OBJECTIVES: To (i) evaluate the applicability of the European-derived biomarker multiples of the median (MoM) formulae for risk assessment of preterm pre-eclampsia (PE) in seven Asian populations, spanning the east, southeast and south regions of the continent, (ii) perform quality-assurance (QA) assessment of the biomarker measurements and (iii) establish criteria for prospective ongoing QA assessment of biomarker measurements. METHODS: This was a prospective, non-intervention, multicenter study in 4023 singleton pregnancies, at 11 to 13 + 6 weeks' gestation, in 11 recruiting centers in China, Hong Kong, India, Japan, Singapore, Taiwan and Thailand. Women were screened for preterm PE between December 2016 and June 2018 and gave written informed consent to participate in the study. Maternal and pregnancy characteristics were recorded and mean arterial pressure (MAP), mean uterine artery pulsatility index (UtA-PI) and maternal serum placental growth factor (PlGF) were measured in accordance with The Fetal Medicine Foundation (FMF) standardized measurement protocols. MAP, UtA-PI and PlGF were transformed into MoMs using the published FMF formulae, derived from a largely Caucasian population in Europe, which adjust for gestational age and covariates that affect directly the biomarker levels. Variations in biomarker MoM values and their dispersion (SD) and cumulative sum tests over time were evaluated in order to identify systematic deviations in biomarker measurements from the expected distributions. RESULTS: In the total screened population, the median (95% CI) MoM values of MAP, UtA-PI and PlGF were 0.961 (0.956-0.965), 1.018 (0.996-1.030) and 0.891 (0.861-0.909), respectively. Women in this largely Asian cohort had approximately 4% and 11% lower MAP and PlGF MoM levels, respectively, compared with those expected from normal median formulae, based on a largely Caucasian population, whilst UtA-PI MoM values were similar. UtA-PI and PlGF MoMs were beyond the 0.4 to 2.5 MoM range (truncation limits) in 16 (0.4%) and 256 (6.4%) pregnancies, respectively. QA assessment tools indicated that women in all centers had consistently lower MAP MoM values than expected, but were within 10% of the expected value. UtA-PI MoM values were within 10% of the expected value at all sites except one. Most PlGF MoM values were systematically 10% lower than the expected value, except for those derived from a South Asian population, which were 37% higher. CONCLUSIONS: Owing to the anthropometric differences in Asian compared with Caucasian women, significant differences in biomarker MoM values for PE screening, particularly MAP and PlGF MoMs, were noted in Asian populations compared with the expected values based on European-derived formulae. If reliable and consistent patient-specific risks for preterm PE are to be reported, adjustment for additional factors or development of Asian-specific formulae for the calculation of biomarker MoMs is required. We have also demonstrated the importance and need for regular quality assessment of biomarker values. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Third-trimester uterine artery Doppler for prediction of adverse outcome in late small-for-gestational-age fetuses: systematic review and meta-analysis.

OBJECTIVE: To investigate the predictive ability for adverse perinatal outcome of abnormal third-trimester uterine artery Doppler in late small-for-gestational-age (SGA) fetuses. METHODS: A systematic search was performed to identify relevant observational studies and randomized controlled trials evaluating the performance of abnormal third-trimester uterine artery Doppler for the prediction of adverse perinatal outcome in suspected SGA fetuses and SGA neonates. Abnormal uterine artery Doppler was defined as uterine artery pulsatility index > 95th percentile or ≥ 2 SD above the mean, or bilateral uterine artery notching. Hierarchical summary receiver-operating-characteristics (ROC) curves were constructed using random-effects modeling. Bayesian analysis was used to calculate the posterior probability of adverse perinatal outcome following an abnormal or normal uterine artery Doppler assessment. RESULTS: Seventeen observational studies (including 7552 fetuses either diagnosed with suspected SGA (n = 3461) or later diagnosed as a SGA neonate (n = 4091)) met the inclusion criteria; no randomized-controlled trials met the inclusion criteria. Summary ROC curves showed that, among suspected SGA fetuses, the best predictive accuracy of abnormal third-trimester uterine artery Doppler was for perinatal mortality and the worst was for composite adverse perinatal outcome, with areas under the summary ROC curves of 0.90 and 0.66, respectively. The corresponding positive and negative likelihood ratios were 16.5 and 0.6 for perinatal mortality and 2.82 and 0.65 for composite adverse perinatal outcome, respectively. Following an abnormal vs normal uterine artery Doppler assessment, the posterior risks for composite adverse perinatal outcome, admission to the neonatal intensive care unit, Cesarean section for intrapartum fetal compromise, 5-min Apgar score < 7, neonatal acidosis and perinatal death were: 52.3% vs 20.2%, 48.6% vs 18.7%, 23.1% vs 15.2%, 3.59% vs 1.32%, 9.15% vs 5.12% and 31.4% vs 1.64%, respectively. CONCLUSION: Abnormal uterine artery Doppler in the third trimester appears to be moderately useful in predicting perinatal death in pregnancies with suspected SGA. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Doppler uterino en el tercer trimestre para la predicción de resultados adversos en fetos pequeños para la edad gestacional: revisión sistemática y metaanálisis OBJETIVO: Investigar la capacidad de predicción de resultados perinatales adversos del Doppler uterino anómalo en el tercer trimestre en fetos pequeños para la edad gestacional (PEG). MÉTODOS: Se realizó una búsqueda sistemática para identificar estudios observacionales pertinentes y ensayos controlados aleatorizados que hubieran evaluado el comportamiento del Doppler uterino anómalo en el tercer trimestre para la predicción de resultados perinatales adversos en fetos con sospecha de ser PEG y en neonatos PEG. El Doppler uterino anómalo se definió como el índice de pulsatilidad de la arteria uterina >95 percentil o DE ≥2 por encima de la media, o escotadura bilateral de la arteria uterina. Se elaboraron modelos de efectos aleatorizados para la elaboración de una curva jerárquica resumen de las características operativas del receptor (ROC, por sus siglas en inglés). Se utilizó el análisis bayesiano para calcular la probabilidad a posteriori de un resultado perinatal adverso después de una evaluación de Doppler uterino anómalo o normal. RESULTADOS: Diecisiete estudios observacionales (incluidos 7552 fetos diagnosticados como sospechosos de ser PEG (n=3461) o diagnosticados posteriormente como neonatos PEG (n=4091)) cumplieron los criterios de inclusión; ningún ensayo controlado aleatorizado cumplió los criterios de inclusión. Las curvas resumen ROC mostraron que, entre los fetos sospechosos de ser PEG, la mayor precisión predictiva del Doppler uterino anómalo en el tercer trimestre fue para la muerte perinatal y la peor fue para el resultado perinatal adverso compuesto, con áreas por debajo de las curvas resumen ROC de 0,90 y 0,66, respectivamente. Los cocientes de verosimilitud correspondientes, positivo y negativo, fueron de 16,5 y 0,6 para la mortalidad perinatal y de 2,82 y 0,65 para el resultado perinatal adverso compuesto, respectivamente. Los riesgos posteriores a una evaluación de Doppler uterino anómalo vs normal, para el resultado perinatal adverso compuesto, la admisión en la unidad de cuidados intensivos para neonatos, la cesárea por deterioro fetal durante el parto, el test de Apgar a los 5 minutos <7, la acidosis neonatal y la muerte perinatal, fueron: 52,3% vs 20,2%, 48,6% vs 18,7%, 23,1% vs 15,2%, 3,59% vs 1,32%, 9,15% vs 5,12% y 31,4% vs 1,64%, respectivamente. CONCLUSIÓN: El Doppler uterino anómalo en el tercer trimestre parece ser moderadamente útil para predecir la muerte perinatal en embarazos con sospecha de ser PEG.

Maternal hemodynamics, fetal biometry and Doppler indices in pregnancies followed up for suspected fetal growth restriction.

OBJECTIVES: To assess whether, in a cohort of patients with a small-for-gestational-age (SGA) fetus with estimated fetal weight ≤ 10th percentile, maternal hemodynamics, fetal biometry and Doppler indices at presentation can predict the subsequent development of an abnormal fetal Doppler index or delivery of a baby with birth weight < 3rd percentile. METHODS: This was a prospective observational cohort study conducted at a specialist clinic for the management of pregnancies with a SGA fetus at King's College Hospital, London, UK. The study population comprised 86 singleton pregnancies with a SGA fetus, presenting at a median gestational age of 32 (range, 26-35) weeks. We measured maternal cardiac function using a non-invasive transthoracic bioreactance monitor, as well as mean arterial pressure, fetal biometry, and umbilical artery (UA), fetal middle cerebral artery (MCA) and uterine artery (UtA) pulsatility indices (PI), and the deepest vertical pool of amniotic fluid. Z-scores of these variables were calculated based on reported reference ranges and the values were compared between pregnancies with evidence of an abnormal fetal Doppler index at presentation (Group 1), those that had developed an abnormal Doppler index at a subsequent visit (Group 2) and those that did not develop an abnormal Doppler index throughout pregnancy (Group 3). Abnormal fetal Doppler was defined as UA-PI > 95th percentile and/or MCA-PI < 5th percentile. Differences in measured variables at presentation were also compared between pregnancies delivering a baby with birth weight < 3rd percentile and those delivering a baby with birth weight ≥ 3rd percentile. Multivariate logistic regression analysis was used to determine significant predictors of birth weight < 3rd percentile and evolution from normal to abnormal fetal Doppler. RESULTS: In the study population, 14 (16%) cases were in Group 1, 19 (22%) in Group 2 and 53 (62%) in Group 3. Birth weight was < 3rd percentile in 39 (45%) cases and ≥ 3rd percentile in 47 (55%). There was decreased cardiac output and stroke volume and increased peripheral vascular resistance compared with a normal population, and the deviations from normal were most marked in Group 1. Pregnancies with birth weight < 3rd percentile, compared with those with birth weight ≥ 3rd percentile, had greater deviations from normal in fetal biometry, maternal cardiac output, stroke volume, heart rate, peripheral vascular resistance and UtA-PI. Multivariate logistic regression analysis demonstrated that, in the prediction of birth weight < 3rd percentile, maternal hemodynamic profile provided significant improvement to the prediction provided by maternal demographics, fetal biometry, UtA-PI, UA-PI and MCA-PI (difference between areas under receiver-operating characteristics curves, 0.18 (95% CI, 0.06-0.29); P = 0.002). In contrast, there was no significant independent contribution from maternal hemodynamics in the prediction of the subsequent development of abnormal fetal Doppler. CONCLUSIONS: In pregnancies with a SGA fetus, there is decreased maternal cardiac output and stroke volume and increased peripheral vascular resistance, and the deviations from normal are most marked in cases of redistribution in the fetal circulation and reduced amniotic fluid volume. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Longitudinal changes in fetal biometry and cerebroplacental hemodynamics in fetuses with congenital heart disease.

OBJECTIVES: To determine the longitudinal behavior of fetal biometric measures and cerebroplacental hemodynamics throughout gestation in fetuses with congenital heart disease (CHD). METHODS: Fetal biometry and Doppler hemodynamics (uterine artery (UtA), umbilical artery (UA) and fetal middle cerebral artery (MCA)) were measured serially in a cohort of consecutive fetuses diagnosed with CHD. Evaluations were made at various time points, from diagnosis (20-25 weeks) to delivery, with at least two measurements per fetus that were at least 2 weeks apart. Fetuses were classified into three groups according to the pattern of blood supply to the brain (placental vs systemic) that would be expected on the basis of the type of CHD. All parameters were transformed into Z-scores. A linear mixed model to analyze repeated measurements was constructed for each parameter to assess its behavior throughout gestation. RESULTS: Four hundred and forty-four ultrasound examinations were performed in 119 CHD fetuses, with a median of two measurements per fetus. The fetuses presented a small head at diagnosis (biparietal diameter (BPD) Z-score, -1.32 ± 0.99; head circumference (HC) Z-score, -0.79 ± 1.02), which remained small throughout gestation. UtA and UA pulsatility indices (PI) showed a significant increase towards the end of pregnancy, whereas no significant changes were observed in MCA-PI or cerebroplacental ratio (CPR) with gestational age. Both MCA and CPR presented significant differences in longitudinal behavior between CHD groups, while BPD and HC did not. CONCLUSIONS: CHD fetuses have a relatively small head from the second trimester of pregnancy, regardless of the type of CHD anomaly, and increasing resistance in the UtA and UA as pregnancy progresses, suggestive of increasing degree of placental impairment. Our findings indicate the early onset of mechanisms that could lead to poorer neurodevelopment later in life. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Consensus definition of fetal growth restriction: a Delphi procedure.

OBJECTIVE: To determine, by expert consensus, a definition for early and late fetal growth restriction (FGR) through a Delphi procedure. METHOD: A Delphi survey was conducted among an international panel of experts on FGR. Panel members were provided with 18 literature-based parameters for defining FGR and were asked to rate the importance of these parameters for the diagnosis of both early and late FGR on a 5-point Likert scale. Parameters were described as solitary parameters (parameters that are sufficient to diagnose FGR, even if all other parameters are normal) and contributory parameters (parameters that require other abnormal parameter(s) to be present for the diagnosis of FGR). Consensus was sought to determine the cut-off values for accepted parameters. RESULTS: A total of 106 experts were approached, of whom 56 agreed to participate and entered the first round, and 45 (80%) completed all four rounds. For early FGR (< 32 weeks), three solitary parameters (abdominal circumference (AC) < 3(rd) centile, estimated fetal weight (EFW) < 3(rd) centile and absent end-diastolic flow in the umbilical artery (UA)) and four contributory parameters (AC or EFW < 10(th) centile combined with a pulsatility index (PI) > 95(th) centile in either the UA or uterine artery) were agreed upon. For late FGR (≥ 32 weeks), two solitary parameters (AC or EFW < 3(rd) centile) and four contributory parameters (EFW or AC < 10(th) centile, AC or EFW crossing centiles by > two quartiles on growth charts and cerebroplacental ratio < 5(th) centile or UA-PI > 95(th) centile) were defined. CONCLUSION: Consensus-based definitions for early and late FGR, as well as cut-off values for parameters involved, were agreed upon by a panel of experts. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Bedside diagnosis of two major clinical phenotypes of hypertensive disorders of pregnancy.

OBJECTIVE: To investigate the hypothesis that fetal abdominal circumference (AC) and uterine artery (UtA) Doppler pulsatility index (PI) could be used to select two homogeneous subgroups of women affected by hypertensive disorders of pregnancy (HDP), characterized by the coexistence of maternal hypertension with and without intrauterine growth restriction (IUGR). METHODS: This was a multicenter retrospective study of cases affected by HDP in whom fetal AC and UtA-PI had been measured at admission to fetomaternal medicine units. Maternal characteristics, pregnancy complications and outcome were recorded. These data allowed us to model the characteristics of fetal growth in cases affected by HDP, and to design composite indicators of risk factors for maternal metabolic syndrome and of severity for maternal functional organ damage. RESULTS: Measurements of fetal AC and UtA-PI allowed us to define a group of HDP cases with appropriate-for-gestational-age (AGA) fetuses (HDP-AGA), diagnosed by normal fetal AC and UtA-PI (n = 205), and a group of HDP cases with IUGR fetuses (HDP-IUGR), diagnosed by fetal AC < 5(th) centile and UtA-PI > 95(th) centile (n = 124). Curves fitted to the birth weights of these two groups were significantly different, but gestational age at admission for HDP (< 34 or ≥ 34 weeks) did not show an independent association with birth weight. When birth weight was expressed as a Z-score with respect to local reference charts, the average corresponded to the 6(th) and 48(th) centiles, respectively. The occurrence of HDP-AGA (as compared with HDP-IUGR) was significantly associated with risk factors for maternal metabolic syndrome (odds ratio, 2.79 (95% CI, 1.57-4.97)), independent of gestational age. The same risk factors yielded non-significant odds ratios for the development of late-onset (vs early-onset) HDP. Women with HDP-IUGR had worse clinical outcomes. CONCLUSIONS: This study provides new information based on simple prenatal bedside examinations that might help to differentiate HDP-IUGR from HDP-AGA fetuses. These groups are associated with different fetal growth patterns and risk factors, independent of gestational age at onset of the disease. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.

An integrated model with classification criteria to predict small-for-gestational-age fetuses at risk of adverse perinatal outcome.

OBJECTIVE: To develop an integrated model with the best performing criteria for predicting adverse outcome in small-for-gestational-age (SGA) pregnancies. METHODS: A cohort of 509 pregnancies with a suspected SGA fetus, eligible for trial of labor, was recruited prospectively and data on perinatal outcome were recorded. A predictive model for emergency Cesarean delivery because of non-reassuring fetal status or neonatal acidosis was constructed using a decision tree analysis algorithm, with predictors: maternal age, body mass index, smoking, nulliparity, gestational age at delivery, onset of labor (induced vs spontaneous), estimated fetal weight (EFW), umbilical artery pulsatility index (PI), mean uterine artery (UtA) PI, fetal middle cerebral artery PI and cerebroplacental ratio (CPR). RESULTS: An adverse outcome occurred in 134 (26.3%) cases. The best performing predictors for defining a high risk for adverse outcome in SGA fetuses was the presence of a CPR < 10th centile, a mean UtA-PI > 95th centile or an EFW < 3rd centile. The algorithm showed a sensitivity, specificity and positive and negative predictive values for adverse outcome of 82.8% (95% CI, 75.1-88.6%), 47.7% (95% CI, 42.6-52.9%), 36.2% (95% CI, 30.8-41.8%) and 88.6% (95% CI, 83.2-92.5%), respectively. Positive and negative likelihood ratios were 1.58 and 0.36. CONCLUSIONS: Our model could be used as a diagnostic tool for discriminating SGA pregnancies at risk of adverse perinatal outcome.

Predictive value of sequential models of uterine artery Doppler in pregnancies at high risk for pre-eclampsia.

OBJECTIVE: To evaluate the performance of models described previously for the prediction of pre-eclampsia (PE), based on the sequential evaluation of uterine artery resistance at 11-13 weeks and 19-22 weeks, in a high-risk population. METHODS: This was a prospective study in 135 women with singleton pregnancies and at least one of the following high-risk conditions: PE and/or intrauterine growth restriction in a previous pregnancy, chronic hypertension, pregestational diabetes, renal disease, body mass index > 30 kg/m(2) , autoimmune disease (systemic lupus erythematosus, antiphospholipid syndrome or rheumatoid arthritis) and thrombophilia. Mean uterine artery pulsatility index (mUtA-PI) at 11-13 and at 19-22 weeks' gestation was measured and analyzed according to quantitative and semi-quantitative models, to predict late PE (resulting in delivery ≥ 34 weeks) and early PE (delivery < 34 weeks). RESULTS: Late PE developed in 21 (15.6%) pregnancies and early PE in six (4.4%). Using mUtA-PI, the detection rates of late and early PE for a false-positive rate of 10% were 14.3% and 33.3%, respectively, at 11-13 weeks, and 19.0% and 66.7%, respectively, at 19-22 weeks. Using a semi-quantitative approach, the group of pregnant women with mUtA-PI ≥ 90(th) percentile at both 11-13 and 19-22 weeks had a greater risk for early PE (odds ratio, 21.4 (95% CI, 2.5-184.7)) compared with the group with mUtA-PI < 90(th) percentile at both periods. Using a quantitative approach, there was relative worsening in the mUtA-PI (multiples of the median) from the first to the second trimester in all cases of early PE. CONCLUSION: The application of semi-quantitative and especially quantitative models to evaluate sequential changes in uterine artery Doppler findings between the first and second trimesters could be of additional value in assessing high-risk women regarding their true risk of developing early PE.

Natural killer cell-triggered vascular transformation: maternal care before birth?

Natural killer (NK) cells are found in lymphoid and non-lymphoid organs. In addition to important roles in immune surveillance, some NK cells contribute to angiogenesis and circulatory regulation. The uterus of early pregnancy is a non-lymphoid organ enriched in NK cells that are specifically recruited to placental attachment sites. In species with invasive hemochorial placentation, these uterine natural killer (uNK) cells, via secretion of cytokines, chemokines, mucins, enzymes and angiogenic growth factors, contribute to the physiological change of mesometrial endometrium into the unique stromal environment called decidua basalis. In humans, uNK cells have the phenotype CD56(bright)CD16(dim) and they appear in great abundance in the late secretory phase of the menstrual cycle and early pregnancy. Gene expression studies indicate that CD56(bright)CD16(dim) uterine and circulating cells are functionally distinct. In humans but not mice or other species with post-implantation decidualization, uNK cells may contribute to blastocyst implantation and are of interest as therapeutic targets in female infertility. Histological and genetic studies in mice first identified triggering of the process of gestation spiral arterial modification as a major uNK cell function, achieved via interferon (IFN)-γ secretion. During spiral arterial modification, branches from the uterine artery that traverse the endometrium/decidua transiently lose their muscular coat and ability to vasoconstrict. The expression of vascular markers changes from arterial to venous as these vessels dilate and become low-resistance, high-volume channels. Full understanding of the vascular interactions of human uNK cells is difficult to obtain because endometrial time-course studies are not possible in pregnant women. Here we briefly review key information concerning uNK cell functions from studies in rodents, summarize highlights concerning human uNK cells and describe our preliminary studies on development of a humanized, pregnant mouse model for in vivo investigations of human uNK cell functions.

Reference ranges for Doppler assessment of uterine artery resistance and pulsatility indices in dichorionic twin pregnancies.

OBJECTIVES: To construct reference ranges of uterine artery Doppler parameters against gestation in twin pregnancies and to present charts of the pulsatility index (PI) and resistance index (RI) for clinical use. METHODS: This was an observational study of the uterine circulation in 557 women with dichorionic twin pregnancies at 17-38 weeks' gestation. Uterine artery measurements were performed by color and pulsed Doppler imaging. The uterine artery PI and RI were calculated as a mean of both sides. Reference ranges were constructed by regression of each index on gestational age. For this purpose, a regression model with fractional polynomials was fitted to the data. Furthermore, the presence of uterine artery notching was recorded. RESULTS: New reference curves and tables of percentiles of the uterine artery PI and RI are presented. The calculated indices both showed a significant decrease with gestational age. Compared with singleton values, mean twin PI values were lower during the whole course of pregnancy. The prevalence of bilateral notching was 4.6% at 17-19 weeks' gestation and 3.1% at 20-24 weeks. CONCLUSIONS: Uterine artery Doppler indices in twin pregnancies are lower than in singleton pregnancies. Therefore, the use of uterine artery reference ranges adapted to twin gestations seems more appropriate for identifying low- and high-risk groups.

Assessing the 'at-risk' fetus: Doppler ultrasound.

PURPOSE OF REVIEW: Doppler ultrasound has become an indispensable tool in evaluating pregnancies at risk for conditions such as preeclampsia, intrauterine growth restriction, fetal anemia, and umbilical cord abnormalities. Use of umbilical artery, middle cerebral artery, and uterine artery Doppler has been the mainstay of assessment. RECENT FINDINGS: Recent findings promote the use of ductus venosus Doppler to aid in timing delivery of severely growth-restricted fetuses. Whereas initially it appeared that abnormalities in ductus venosus waveform were the endpoint for pregnancies afflicted with intrauterine growth restriction, newer data suggest that these abnormalities may plateau prior to further fetal deterioration as witnessed by changes in the biophysical profile. SUMMARY: In this review, we will discuss current ultrasound Doppler literature and the recommendations of the experts. We observe that the best algorithm for incorporation of the ductus venosus into intrauterine growth restriction management is yet to be determined. This remains a subject of intense research aimed at optimizing pregnancy outcomes and will be important to follow to provide up-to-date care of our patients.

Doppler velocimetry of the uterine, umbilical and fetal middle cerebral arteries in pregnant women undergoing tocolysis with oral nifedipine.

OBJECTIVES: To evaluate Doppler velocimetry (resistance index (RI) and peak systolic velocity (PSV)) in the maternal-fetal circulation before and 5 and 24 h after tocolysis with oral nifedipine. METHODS: This was a prospective, observational, analytic cohort study performed in 47 pregnant women undergoing nifedipine tocolysis, each subject acting as her own control. Doppler assessment of uterine, umbilical and fetal middle cerebral (MCA) arteries was performed before and 5 and 24 h after an initial 20-mg sublingual dose, which was repeated twice at 20-min intervals if contractions failed to diminish. The maintenance dose consisted of 20 mg orally every 6 h for 24 h up to a total of 100-120 mg nifedipine. We analyzed whether there was a time effect and compared values at the different time-points. RESULTS: The MCA-RI had decreased significantly after 24 h of tocolysis (0 h = 0.85; 5 h = 0.85; 24 h = 0.81; P = 0.001), with no differences in uterine or umbilical arteries or in the MCA to umbilical artery ratio. The MCA-PSV had reduced significantly after 5 h (0 h = 41.5 cm/s; 5 h = 34.7 cm/s; P = 0.001), returning close to baseline levels between 5 and 24 h. The PSV increased significantly between 5 and 24 h in the right uterine artery (5 h = 55.1 cm/s; 24 h = 65.0 cm/s; P = 0.037) and in the umbilical artery (5 h = 28.4 cm/s; 24 h = 33.1 cm/s; P = 0.038). CONCLUSIONS: Nifedipine tocolysis is associated with a reduction in RI in the MCA but not in the uterine or umbilical arteries, a reduction in PSV in the MCA after 5 h but returning to baseline within 24 h, and an increase in PSV between 5 and 24 h in the umbilical and right uterine arteries.

Trophoblast-mediated spiral artery remodelling: a role for apoptosis.

In the first 20 weeks of pregnancy a number of important changes take place in the maternal uterine vasculature. Vascular endothelial and smooth muscle cells are lost from the spiral arteries and are replaced by fetal trophoblast cells. The resulting increase in blood flow to the intervillous space ensures that the fetus receives the nutrients and respiratory gases required for growth. Failure of the vessels to remodel sufficiently is a common feature of pregnancy pathologies such as early pregnancy loss, intrauterine growth restriction and pre-eclampsia. Although there is evidence to suggest that some vascular changes occur prior to trophoblast invasion, it is clear that in the absence of trophoblast invasion the remodelling of the spiral arteries is reduced. The cellular and molecular mechanisms by which trophoblasts influence vessel structure have been little studied. Trophoblasts synthesize and release a plethora of cytokines and growth factors including members of the tumour necrosis factor family such as tumour necrosis factor alpha, Fas-ligand and tumour necrosis factor-related apoptosis-inducing ligand. Recent studies suggest that these factors may be important in regulating the remodelling process by inducing both endothelial cell and vascular smooth muscle cell apoptosis.

Oxygen as modulator of trophoblast invasion.

At the time of blastocyst implantation the uterine spiral arteries have already undergone morphological changes in the absence of any extravillous trophoblast invasion. Only 2 weeks after implantation, extravillous trophoblast cells develop and come into first contact with decidual tissues. Invading through the decidual interstitium, extravillous trophoblasts potentially reach and transform spiral arteries into uteroplacental arteries. Spiral arterial erosion starts at about mid-first trimester, whereas flow of maternal blood into the intervillous space is continuously established only at the beginning of the second trimester. One key regulator of the number of extravillous trophoblasts is oxygen. The steep gradient in oxygen concentration within the first trimester placenta is diminished with the onset of maternal blood flow. This gradient is used by the trophoblast to generate a large number of invasive cells to adapt the arterial vasculature in the placental bed to the growing needs of the fetus. Changes in oxygen concentrations or other factors leading to alterations in the rates of proliferation and/or apoptosis of extravillous trophoblast clearly impact on the remodelling of the vessels. The respective consequences of a failure in trophoblast invasion are growth restrictions of the baby and perhaps other pregnancy complications.