Is mid-gestational uterine artery Doppler still useful in a setting with routine first-trimester pre-eclampsia screening? A cohort study.

OBJECTIVE: To evaluate whether routine mid-gestational uterine artery Doppler (UtAD) modifies the risk for preterm pre-eclampsia after first-trimester combined pre-eclampsia screening. DESIGN: Retrospective cohort study. SETTING: London Tertiary Hospital. POPULATION: A cohort of 7793 women with singleton pregnancies, first-trimester pre-eclampsia screening using the Fetal Medicine Foundation (FMF) algorithm and UtAD pulsatility index (PI) assessment at the mid-gestation ultrasound. METHODS: Pregnancies were divided into four groups: high risk in both trimesters (H1 H2 ), high risk in the first but not in the second trimester (H1 L2 ), low risk in the first but high risk in the second trimester (L1 H2 ) and low risk in both trimesters (L1 L2 ). MAIN OUTCOME MEASURES: Small for gestational age (SGA), hypertensive disorders of pregnancy (HDP) and stillbirth. RESULTS: In this cohort, 600 (7.7%) and 620 (7.9%) women were designated as being at high risk in the first and second trimesters, respectively. Preterm pre-eclampsia was more prevalent in the H1 L2 group (4.5%) than in women considered at low risk in the first trimester (0.4%, p < 0.0001). The prevalence of preterm pre-eclampsia in the L1 H2 group (3.3%) was significantly lower than that in women considered at high risk in the first trimester (7.0%, p = 0.0076), and was higher than that observed in the L1 L2 group (0.2%, p < 0.0001). The prevalence of SGA and term HDP followed similar trends. CONCLUSIONS: Pre-eclampsia risk after first-trimester FMF pre-eclampsia screening may be stratified through mid-gestational routine UtAD assessment. Pregnancy care should not be de-escalated for low mid-gestational UtAD resistance in women classified as being at high risk in the first trimester. The escalation of care may be justified in women at low risk but with high mid-gestational UtAD resistance.

Assessment of CA-125 First-Trimester Values as a Potential Screening Marker for Pre-Eclampsia.

Background: Pre-eclampsia is a major public health issue. Current screening methods are based on maternal characteristics and medical history, but complex predictive models combining different clinical and biochemical markers have been proposed. However, although their accuracy is high, the implementation of these models in clinical practice is not always feasible, especially in low- and middle-resource settings. CA-125 is a tumoral marker, accessible and cheap, with proven potential as a severity marker in the third trimester of pregnancy in pre-eclamptic women. Assessment of its use as a first-trimester marker is necessary. Methods: This observational study involved fifty pregnant women between 11 and 14 weeks of pregnancy. Clinical and biochemical markers (PAPP-A), known for their value in pre-eclampsia screening, were recorded for every patient as well as first-trimester value of CA-125 and third-trimester data regarding blood pressure and pregnancy outcome. Results: No statistical correlation between CA-125 and first-trimester markers was observed except with PAPP-A, with which it exhibited a positive correlation. Additionally, no correlation was made between it and third-trimester blood pressure or pregnancy outcomes. Conclusions: CA-125 first-trimester values do not represent a valuable marker for pre-eclampsia screening. Further research on identifying an accessible and cheap marker to improve pre-eclampsia screening in low- and middle-income settings is needed.

Changes in ophthalmic artery Doppler during acute blood-pressure control in hypertensive pregnant women.

OBJECTIVE: To examine the changes in ophthalmic artery Doppler indices and their association with changes in mean arterial blood pressure (MAP) and systolic (SBP) and diastolic (DBP) blood pressure, following acute antihypertensive treatment in women with hypertensive disorders of pregnancy presenting with high blood pressure. METHODS: This was a prospective cohort study of 31 pregnant women presenting at 30 + 0 to 39 + 6 weeks' gestation for management of their hypertension. Paired maternal blood-pressure and ophthalmic-artery-Doppler measurements were performed prior to and at 30 min and 60 min after starting antihypertensive medication. In patients who did not achieve blood-pressure control (i.e. when blood pressure was < 140/90 mmHg) by 60 min, paired readings were continued up to 120 min. If blood-pressure control was still not achieved at that point, patients were admitted to hospital. Univariate linear regression was performed to determine the association of ophthalmic artery peak systolic velocity (PSV) ratio with SBP, DBP and MAP before treatment and after blood-pressure control. The longitudinal changes in MAP, SBP, DBP and PSV ratio from pretreatment to 30 min and 60 min after commencement of antihypertensives were examined by repeated measure, multilevel, linear mixed-effects analysis. RESULTS: Antihypertensive treatment was associated with a decrease in SBP, DBP, MAP and PSV ratio. At 60 min following antihypertensive treatment, the decrease in SBP, DBP, MAP and PSV ratio was 12.1 mmHg (95% CI, 9.0-15.1 mmHg; P < 0.0001), 9.1 mmHg (95% CI, 6.5-11.5 mmHg; P < 0.0001), 10.0 mmHg (95% CI, 7.6-12.4 mmHg; P < 0.0001) and 0.07 (95% CI, 0.03-0.11 mmHg; P < 0.001), respectively. From the total cohort, 20 (64.5%) women had achieved blood-pressure control at 60 min and another seven (22.6%) by 120 min from commencement of antihypertensive treatment. Four (12.9%) women did not achieve blood-pressure control during this period and were admitted to hospital. The relationship between PSV ratio and SBP, DBP and MAP was assessed before treatment (n = 31) and at the point of blood-pressure control in women in whom this was achieved by 120 min (n = 27). Prior to treatment, there was a significant association between PSV ratio and MAP (P < 0.0001, R2 = 0.39). This was primarily due to the association of PSV ratio with DBP (P < 0.0001, R2 = 0.39) and less so due to its association with SBP (P = 0.02, R2 = 0.16). At the point of achieving blood-pressure control, there was no significant association between PSV ratio and MAP (P = 0.7), DBP (P = 0.5) or SBP (P = 0.7). CONCLUSIONS: Acute blood-pressure control in pregnancy is associated with a concomitant reduction in blood pressure and ophthalmic artery PSV ratio. In hypertensive pregnant women, there is a significant association of PSV ratio with MAP, SBP and DBP, which disappears after blood pressure is reduced to < 140/90 mmHg following antihypertensive treatment. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Maternal hemodynamics in screen-positive and screen-negative women of the ASPRE trial.

OBJECTIVE: To compare maternal hemodynamics and perinatal outcome, in pregnancies that do not develop pre-eclampsia (PE) or deliver a small-for-gestational-age (SGA) neonate, between those identified at 11-13 weeks' gestation as being screen positive or negative for preterm PE, by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index, serum placental growth factor and pregnancy associated plasma protein-A. METHODS: This was a prospective longitudinal cohort study of maternal cardiovascular function, assessed using a bioreactance method, in women undergoing first-trimester screening for PE. Maternal hemodynamics and perinatal outcome were compared between screen-positive and screen-negative women who did not have a medical comorbidity, did not develop PE or pregnancy-induced hypertension and delivered at term a live neonate with birth weight between the 5th and 95th percentiles. A multilevel linear mixed-effects model was used to compare the repeated measures of cardiac variables, controlling for maternal characteristics. RESULTS: The screen-negative group (n = 926) had normal cardiac function changes across gestation, whereas the screen-positive group (n = 170) demonstrated static or reduced cardiac output and stroke volume and higher mean arterial pressure and peripheral vascular resistance with advancing gestation. In the screen-positive group, compared with screen-negative women, birth-weight Z-score was shifted toward lower values, with prevalence of delivery of a neonate below the 35th , 30th or 25th percentile being about 70% higher, and the rate of operative delivery for fetal distress in labor also being higher. CONCLUSION: Women who were screen positive for impaired placentation, even though they did not develop PE or deliver a SGA neonate, had pathological cardiac adaptation in pregnancy and increased risk of adverse perinatal outcome. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

First-trimester prediction of pre-eclampsia: external validity of algorithms in a prospectively enrolled cohort.

OBJECTIVE: To evaluate the performance of published first-trimester prediction algorithms for pre-eclampsia (PE) in a prospectively enrolled cohort of women. METHOD: A MEDLINE search identified first-trimester screening-prediction algorithms for early-onset (requiring delivery < 34 weeks) and late-onset (requiring delivery ≥ 34 weeks) PE. Maternal variables, ultrasound parameters and biomarkers were determined prospectively in singleton pregnancies enrolled between 9 and 14 weeks. Prediction algorithms were applied to this population to calculate predicted probabilities for PE. The performance of the prediction algorithms was compared with that in the original publication and evaluated for factors explaining differences in prediction. RESULTS: Six early and two late PE prediction algorithms were applicable to 871-2962 women, depending on the variables required. The prevalence of early PE was 1.0-1.2% and of late PE was 4.1-5.0% in these patient subsets. One early PE prediction algorithm performed better than in the original publication (80% detection rate (DR) of early PE for 10% false-positive rate (FPR)); the remaining five prediction algorithms underperformed (29-53% DR). Prediction algorithms for late PE also underperformed (18-31% DR, 10% FPR). Applying the screening cut-offs based on the highest Youden index probability scores correctly detected 40-80% of women developing early PE and 71-82% who developed late PE. Exclusion of patients on first-trimester aspirin resulted in DRs of 40-83% and 65-82% for early and late PE, respectively. CONCLUSION: First-trimester prediction algorithms for PE share a high negative predictive value if applied to an external population but underperform in their ability to correctly identify women who develop PE. Further research is required to determine the factors responsible for the suboptimal external validity.

External validity of first-trimester algorithms in the prediction of pre-eclampsia disease severity.

OBJECTIVE: To compare disease features in women with pre-eclampsia between those who are correctly identified (true positive) and those who are missed (false negative) when applying first-trimester prediction algorithms for pre-eclampsia to a prospectively enrolled population. METHOD: Six first-trimester early (requiring delivery < 34 weeks' gestation) pre-eclampsia algorithms were applied to a prospective cohort of singleton pregnancies enrolled at first-trimester screening. Maternal outcomes, neonatal outcomes and severity parameters for pre-eclampsia were compared between true-positive and false-negative predictions. RESULTS: Twenty of 2446 (0.8%) women developed early pre-eclampsia, with 65% of these developing severe features and 20% HELLP syndrome. At enrollment, true-positive cases were more likely to be African-American and chronically hypertensive, while false-negative cases were more likely to be Caucasian. At delivery, true-positive cases were more likely to have pre-eclampsia superimposed on hypertension, severely elevated blood pressure and creatinine level > 1.1 mg/dL. False-negative cases were more likely to have HELLP syndrome (all P < 0.05). CONCLUSION: In an urban population with a high prevalence of chronic hypertension, patients who are correctly identified by first-trimester screening models are more likely to develop pre-eclampsia superimposed on chronic hypertension with severely elevated blood pressure and evidence of renal failure. In contrast, patients who are missed by these algorithms are more likely to have HELLP syndrome. Further research is needed to confirm these findings and the algorithm adjustments that may be necessary to better predict pre-eclampsia phenotypes.

Impact of different types of hypertensive disorders of pregnancy and their duration on incident post-partum risk of diabetes mellitus: Results from the French nationwide study CONCEPTION.

AIMS: To evaluate the impact of onset time, duration, and severity of various types of hypertensive disorders of pregnancy (HDP) on the risk of incident DM. METHODS: We used data from the ongoing French nationwide prospective cohort study CONCEPTION. We included all primiparous women in CONCEPTION who delivered between 2010 and 2018 (n = 2,816,793 women). Follow-up spanned from childbirth to 31 December 2021. HDP and incident DM onset during follow-up were identified using algorithms combining ICD-10 coded diagnoses during hospitalization and/or medication dispensing. We used Cox models to assess the associations between incident DM and preexisting chronic hypertension, gestational hypertension (GH), and various phenotypes of pre-eclampsia. RESULTS: Pre-eclampsia and GH alone occurred in 2.6 % and 4.6 % of the population, respectively. During follow-up (mean = 4.5 years), 16,670 women had incident DM. The cumulative incidences of DM were 15.8 % and 1.8 % in women who had pre-eclampsia during pregnancy with and without concomitant gestational diabetes, respectively. The risk of DM was higher after HDP (all types) irrespective of gestational diabetes status during pregnancy. In women without gestational diabetes, compared with those who had no HDP, the risk of incident DM was higher in women who had GH (adjusted hazard ratio, aHR = 1.97 [1.81-2.16]), pre-eclampsia (aHR = 2.42 [2.21-2.65]), and preexisting chronic hypertension prior to pregnancy (aHR = 3.35 [3.03-3.70]). Pre-eclampsia duration was significantly associated with a higher risk of DM. CONCLUSION: Women who experienced an HDP had twice the risk of developing DM. Early blood glucose assessment and blood pressure monitoring should be more widely recommended after HDP diagnosis.

Pre-eclampsia screening in the first trimester - preemptive action to prevent the peril.

Pre-eclampsia complicating 2-5% of pregnancies is an obstetrical syndrome associated with deleterious short-and long-term consequences to the gravid women, the fetus and the neonate. Majority of the obstetrical complications occur in early pre-eclampsia (requiring delivery <34 weeks). The risk factor based approach recommended by the professional organizations for pre-eclampsia screening has shown suboptimal clinical performance. The combined multimarker screening for pre-eclampsia encompassing documentation of maternal medical history, measurement of mean arterial pressure, estimation of the maternal serum levels of placental growth factor, pregnancy associated plasma protein-A, and recording the Uterine artery mean pulsatility index, performed in the first trimester between 11 and 13 + 6 weeks has proven to be an effective screening strategy. The a-priori risk is determined by multivariate analysis of the factors from history, while the other parameters are converted to log 10 transformed multiple of median values. Bayes' theorem is used to calculate the final risk. The above model has shown to detect 77% of preterm pre-eclampsia (<37 weeks), 96% of early preterm pre-eclampsia (<34 weeks), 38% of term pre-eclampsia and 54% of all pre-eclampsia, at a false positive rate of 10%. Uterine artery Doppler is key to pre-eclampsia screening. Currently a risk of >1:100 for pre-eclampsia developing before 37 weeks (preterm pre-eclampsia) is regarded as screen positive. Aspirin at a dose of 150 mg at bedtime given to screen positive subjects is associated with a significant reduction of preterm pre-eclampsia and early pre-eclampsia. The intervention is now supported by a well conducted randomized trial and metanalysis data. Aspirin acts by diminishing stores of constitutive cyclooxygenase enzyme in the non-nucleated platelets without disturbing systemic prostaglandin production. Selective use of aspirin in screen positive women is associated with a very low incidence of adverse maternal, fetal and neonatal side effects. The screening protocol can be applied to twin pregnancies albeit minor differences. Hence, screening for pre-eclampsia in first trimester, which is now endorsed by the federation of international obstetrical and gynecological societies, should be offered universally to all women at 11 to 13 + 6 weeks of gestation, followed by the administration of aspirin and serial maternal-fetal surveillance in the screen positive woman.

Early prediction of hypertension during pregnancy in a low-resource setting.

OBJECTIVE: To evaluate the role of maternal factors, biomarkers, and uterine-artery Doppler in the prediction of hypertension during pregnancy. METHODS: A prospective cohort study was performed between December 2012 and November 2014. All singleton pregnancies between 11 weeks and 13 weeks, 6 days of pregnancy were included. Patients had their body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters), mean arterial pressure, uterine-artery Doppler pulsatility index, and pregnancy-associated plasma protein A (PAPP-A) and free ß-human chorionic gonadotropin levels recorded. Any patients diagnosed with hypertension during follow-up were assigned to the case cohort; all other patients were assigned to the control group. RESULTS: Hypertension during pregnancy was observed in 198 (9.7%) of 2042 patients that attended follow-up. The mean BMI, mean arterial pressure, uterine-artery Doppler pulsatility index, and the PAPP-A level at study enrollment were all significantly correlated with the later development of hypertension (P<0.001 for all variables). The combined sensitivity, specificity, positive predictive value, and negative predictive value of using the investigated parameters to predict hypertension was 76%, 80%, 31%, and 93%, respectively. CONCLUSION: Patient BMI, mean arterial pressure, PAPP-A, and pulsatility index were found to be effective predictors of hypertension during pregnancy. Combining these predictors may be beneficial in selecting individuals for close monitoring and early intervention during pregnancy.