Ophthalmic artery Doppler at 36 weeks' gestation in prediction of pre-eclampsia: validation and update of previous model.

OBJECTIVE: To validate and extend a model incorporating maternal ophthalmic artery Doppler at 35-37 weeks' gestation in the prediction of subsequent development of pre-eclampsia (PE). METHODS: This was a prospective validation study of screening for PE (defined according to the 2019 American College of Obstetricians and Gynecologists criteria) by maternal ophthalmic artery peak systolic velocity (PSV) ratio in 6746 singleton pregnancies undergoing routine care at 35 + 0 to 36 + 6 weeks' gestation (validation dataset). Additionally, the data from the validation dataset were combined with those of 2287 pregnancies that were previously used for development of the model (training dataset), and the combined data were used to update the original model parameters. The competing-risks model was used to estimate the individual patient-specific risk of delivery with PE at any time and within 3 weeks from assessment by a combination of maternal demographic characteristics and medical history with PSV ratio alone and in combination with the established PE biomarkers of mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1). We evaluated the predictive performance of the model by examining, first, the ability to discriminate between the PE and non-PE groups using the area under the receiver-operating-characteristics curve and the detection rate (DR) at fixed screen-positive (SPR) and false-positive rates of 10% and, second, calibration by measuring the calibration slope and calibration-in-the-large. McNemar's test was used to compare the performance of screening by a biophysical test (maternal factors, MAP, UtA-PI and PSV ratio) vs a biochemical test (maternal factors, PlGF and sFlt-1), low PlGF concentration (< 10th percentile) or high sFlt-1/PlGF concentration ratio (> 90th percentile). RESULTS: In the validation dataset, the performance of screening by maternal factors and PSV ratio for delivery with PE within 3 weeks and at any time after assessment was consistent with that in the training dataset, and there was good agreement between the predicted and observed incidence of PE. In the combined data from the training and validation datasets, good prediction for PE was achieved in screening by a combination of maternal factors, MAP, UtA-PI, PlGF, sFlt-1 and PSV ratio, with a DR, at a 10% SPR, of 85.0% (95% CI, 76.5-91.4%) for delivery with PE within 3 weeks and 65.7% (95% CI, 59.2-71.7%) for delivery with PE at any time after assessment. The performance of a biophysical test was superior to that of screening by low PlGF concentration or high sFlt-1/PlGF concentration ratio but not significantly different from the performance of a biochemical test combining maternal factors with PlGF and sFlt-1 for both PE within 3 weeks and PE at any time after assessment. CONCLUSION: Maternal ophthalmic artery PSV ratio at 35-37 weeks' gestation in combination with other biomarkers provides effective prediction of subsequent development of PE. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler and biomarkers of impaired placentation at 36 weeks' gestation in pregnancies with small fetuses.

OBJECTIVES: First, to compare ophthalmic artery peak systolic velocity (PSV) ratio and biomarkers of impaired placentation at 36 weeks' gestation in women who delivered a small-for-gestational-age (SGA) or growth-restricted (FGR) neonate, in the absence of hypertensive disorder, with those of women who developed pre-eclampsia (PE) or gestational hypertension (GH) and of women unaffected by SGA, FGR, PE or GH. Second, to examine the associations of PSV ratio, uterine artery pulsatility index (UtA-PI), placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) with birth-weight Z-score or percentile. METHODS: This was a prospective observational study of women with a singleton pregnancy attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination of fetal anatomy and growth, and measurement of maternal ophthalmic artery PSV ratio, UtA-PI, PlGF and sFlt-1. Values of PSV ratio, UtA-PI, PlGF and sFlt-1 were converted to multiples of the median (MoM) or delta values. Median MoM or deltas of these biomarkers in the SGA, FGR, PE and GH groups were compared with those in the unaffected group. Regression analysis was used to examine the relationship of PSV ratio delta, UtA-PI MoM, PlGF MoM and sFlt-1 MoM with birth-weight Z-score, after exclusion of PE and GH cases. RESULTS: The study population of 9033 pregnancies included 7696 (85.2%) that were not affected by FGR, SGA, PE or GH, 182 (2.0%) complicated by FGR in the absence of PE or GH, 698 (7.7%) with SGA in the absence of FGR, PE or GH, 236 (2.6%) with PE and 221 (2.4%) with GH. Compared with unaffected pregnancies, in the FGR and SGA groups, the PSV ratio delta and sFlt-1 MoM were increased and PlGF MoM was decreased; UtA-PI MoM was increased in the FGR group but not the SGA group. The magnitude of the changes in biomarker values relative to the unaffected group was smaller in the FGR and SGA groups than that in the PE and GH groups. In non-hypertensive pregnancies, there were significant inverse associations of PSV ratio delta and UtA-PI MoM with birth-weight Z-score, such that the values were increased in small babies and decreased in large babies. There was a quadratic relationship between PlGF MoM and birth-weight Z-score, with low PlGF levels in small babies and high PlGF levels in large babies. There was no significant association between sFlt-1 MoM and birth-weight Z-score. CONCLUSIONS: Ophthalmic artery PSV ratio, reflective of peripheral vascular resistance, and UtA-PI, PlGF and sFlt-1, biomarkers of impaired placentation, are altered in pregnancies complicated by hypertensive disorder and, to a lesser extent, in non-hypertensive pregnancies delivering a SGA or FGR neonate. The associations between the biomarkers and birth-weight Z-score suggest the presence of a continuous physiological relationship between fetal size and peripheral vascular resistance and placentation, rather than a dichotomous relationship of high peripheral resistance and impaired placentation in small compared to non-small fetuses. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler at 19-23 weeks' gestation in pregnancies that deliver small-for-gestational-age neonates.

OBJECTIVES: First, to explore hemodynamic differences between pregnancies delivering a small-for-gestational-age (SGA) neonate in the absence of hypertensive disorders and those that develop pre-eclampsia (PE) or gestational hypertension (GH), by comparing the ophthalmic artery peak systolic velocity (PSV) ratio and first (PSV1) and second (PSV2) PSV at 19-23 weeks' gestation, and second, to compare these pregnancies for markers of placental perfusion and function. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for assessment of fetal anatomy and growth, and measurement of maternal ophthalmic artery PSV ratio, PSV1, PSV2, mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI) and serum placental growth factor (PlGF). The values of PSV ratio, PSV1, PSV2, MAP, UtA-PI and PlGF were converted to multiples of the median (MoM) or deltas. Mean MoMs or deltas of these biomarkers in the SGA, PE and GH groups were compared with those in the unaffected group. The definition of SGA was birth weight below the 10th percentile in the absence of PE or GH. RESULTS: The study population of 5214 pregnancies contained 4375 (83.9%) that were unaffected by SGA, PE or GH, 563 (10.8%) complicated by SGA, 157 (3.0%) with PE and 119 (2.3%) with GH. There were three main findings of the study. First, in the SGA, PE and GH groups, compared with unaffected pregnancies, the PSV ratio delta, PSV2 MoM, MAP MoM and UtA-PI MoM were increased and PlGF MoM was decreased; however, the magnitude of most changes was smaller in the SGA group than in PE and GH groups. Second, in the PE and GH groups, but not in the SGA group, PSV1 MoM was increased. Third, in general, in the pathological pregnancies, the magnitude of deviation of biomarkers from unaffected pregnancies was greater for those delivering at < 37 than at ≥ 37 weeks' gestation. CONCLUSION: In mid-gestation, pregnancies that subsequently develop hypertensive disorders and those delivering a SGA neonate, compared with unaffected pregnancies, have abnormal uteroplacental measurements and increased maternal ophthalmic artery PSV ratio. These data suggest similar pathophysiology in the two conditions, with evidence of placental dysfunction and increased peripheral vascular resistance, but the magnitude of abnormalities is greater in hypertensive disorders. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Ophthalmic artery Doppler in combination with other biomarkers in prediction of pre-eclampsia at 35-37 weeks' gestation.

OBJECTIVE: To examine the potential value of maternal ophthalmic artery Doppler at 35-37 weeks' gestation in combination with the established biomarkers of pre-eclampsia (PE), including mean arterial pressure (MAP), uterine artery pulsatility index (UtA-PI), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 35 + 0 to 36 + 6 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, ultrasound examination for fetal anatomy and growth, assessment of flow velocity waveforms from the maternal ophthalmic arteries, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE at any time and at < 3 weeks after assessment by a combination of maternal demographic characteristics and medical history with biomarkers. The area under the receiver-operating-characteristics curve and detection rate (DR) of delivery with PE, at a 10% false-positive rate (FPR), in screening by combinations of maternal factors with ophthalmic artery second to first peak of systolic velocity ratio (PSV ratio), MAP, UtA-PI, serum PlGF and serum sFlt-1 were determined. The modeled performance of screening for PE was also estimated. RESULTS: The study population of 2287 pregnancies contained 60 (2.6%) that developed PE, including 19 (0.8%) that delivered with PE at < 3 weeks after assessment. The PSV ratio improved the prediction of PE with delivery at any stage after assessment provided by maternal factors alone (from 25.4% to 50.6%), maternal factors and MAP (54.3% to 62.7%), maternal factors, MAP and PlGF (68.3% to 70.8%) and maternal factors, MAP, PlGF and sFlt-1 (75.7% to 76.7%), at a FPR of 10%. The PSV ratio also improved the prediction of PE with delivery at < 3 weeks after assessment provided by maternal factors alone (from 31.0% to 69.4%), maternal factors and MAP (74.1% to 83.4%), maternal factors, MAP and UtA-PI (77.1% to 85.0%) and maternal factors, MAP and PlGF (84.8% to 88.6%). The empirical results for DR at a 10% FPR were consistent with the modeled results. Screening by a combination of maternal factors with MAP and PSV ratio also detected 59.4% (95% CI, 58.6-82.5%) of cases of gestational hypertension with delivery at any stage after assessment, and 86.7% (95% CI, 82.4-100%) of those with delivery at < 3 weeks after assessment. CONCLUSION: Ophthalmic artery Doppler could potentially improve the performance of screening for PE at 35-37 weeks, especially imminent PE with delivery within 3 weeks after assessment, but further studies are needed to validate this finding. © 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.

Maternal cardiac function at 19-23 weeks' gestation in prediction of pre-eclampsia.

OBJECTIVES: First, to examine the factors from maternal characteristics and medical history that affect maternal cardiovascular indices, and, second, to examine the potential value of maternal cardiovascular indices at 19-23 weeks' gestation, on their own and in combination with maternal factors and the established biomarkers of pre-eclampsia (PE), including uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP), serum placental growth factor (PlGF) and serum soluble fms-like tyrosine kinase-1 (sFlt-1), in the prediction of subsequent development of PE. METHODS: This was a prospective observational study in women attending for a routine hospital visit at 19 + 1 to 23 + 3 weeks' gestation. This visit included recording of maternal demographic characteristics and medical history, assessment of maternal E/A ratio, E/e' ratio, myocardial performance index, global longitudinal systolic strain, left ventricular ejection fraction, peripheral vascular resistance, left ventricular cardiac output and left ventricular mass indexed for body surface area, and measurement of MAP, UtA-PI, serum PlGF and serum sFlt-1. The measurements of the eight maternal cardiac indices were standardized to remove the effects of maternal characteristics and elements from the medical history. The competing-risks model was used to estimate the individual patient-specific risks of delivery with PE and determine the detection rate, at a 10% false-positive rate, in screening by a combination of maternal demographic characteristics and medical history with biomarkers. RESULTS: The study population of 2853 pregnancies contained 76 (2.7%) that developed PE. In pregnancies that subsequently developed PE, there was evidence of altered cardiac geometry, impaired myocardial function and increased peripheral vascular resistance. All maternal cardiovascular indices were affected significantly by maternal demographic characteristics and elements of medical history known to be associated with an increased risk for subsequent development of PE. After adjustment for maternal demographic characteristics and medical history, the only cardiovascular index that was affected significantly by subsequent development of PE was peripheral vascular resistance. Peripheral vascular resistance multiples of the median (MoM) was correlated with MAP MoM, which is not surprising because blood pressure is involved in the estimation of both. There were weak correlations between several cardiovascular indices and MAP MoM, but none was correlated with MoM values of UtA-PI, PlGF or sFlt-1. The performance of screening for delivery with PE at < 37 weeks' gestation or delivery with PE at any gestational age in screening by maternal demographic characteristics and medical history or combinations of maternal factors with MAP, UtA-PI, PlGF and sFlt-1 was not improved by the addition of peripheral vascular resistance. CONCLUSION: Assessment of maternal cardiovascular function provides information on the pathophysiology of PE but is not useful in the prediction of PE. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.