Effect of routine first-trimester combined screening for pre-eclampsia on small-for-gestational-age birth: secondary interrupted time series analysis.

OBJECTIVE: To evaluate the impact of a first-trimester combined screening program for pre-eclampsia, based on the Fetal Medicine Foundation (FMF) algorithm, on the rate of small-for-gestational age (SGA) at birth and adverse pregnancy outcome. METHODS: This was a retrospective cohort study of data obtained from a London tertiary hospital between January 2017 and March 2019. The data were derived from a secondary analysis of the cohort evaluated in a clinical-effectiveness study on the implementation of a first-trimester screening program for pre-eclampsia. The cohort included 7720 women screened according to the UK National Institute for Health and Care Excellence (NICE) risk-based approach and 4841 women screened by the FMF multimodal approach, which combines maternal risk factors, blood pressure, pregnancy-associated plasma protein-A and uterine artery Doppler indices. The care package for the FMF-screened group included 150-mg aspirin prophylaxis, ultrasound scans at 28 and 36 weeks' gestation and scheduled delivery at 40 weeks. Outcome measures included the rates of SGA neonates at birth, admission to the neonatal unit, intrauterine demise, neonatal death and hypoxic-ischemic encephalopathy assessed by interrupted time series analysis (ITSA). RESULTS: There was no significant difference in the rates of intrauterine demise, neonatal death and hypoxic-ischemic encephalopathy between the FMF-screened and NICE-screened cohorts. ITSA showed a significant reduction in the rate of term SGA birth < 10th percentile at 21 months following implementation of the FMF screening program, with a relative effect reduction of 45.1% (P = 0.004). However, there was no significant relative effect reduction in term SGA birth < 5th or < 3rd percentile. CONCLUSIONS: First-trimester combined screening for pre-eclampsia based on the FMF algorithm accompanied by a care package including serial ultrasound scans for growth evaluation and elective birth from 40 weeks' gestation resulted in a significant 45% relative effect reduction in term SGA birth < 10th percentile but did not affect term SGA birth < 5th or < 3rd percentile. Further screening strategies to detect and improve the outcome of cases with SGA birth < 5th percentile need to be considered. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Implementation of routine first trimester combined screening for pre-eclampsia: a clinical effectiveness study.

OBJECTIVE: Evaluate clinical effectiveness of the first trimester combined (FMF) pre-eclampsia screening programme when implemented in a public healthcare setting. DESIGN: Retrospective cohort study. SETTING: London tertiary hospital from January 2017 to March 2019. METHODS: 7720 women screened for pre-eclampsia according to National Institute for Health and Care Excellence (NICE) risk-based guidance and 4841 by the Fetal Medical Foundation (FMF) algorithm which combined maternal risk factors, blood pressure, PAPP-A and uterine artery Doppler indices in the first trimester. High risk was defined by standard NICE criteria in the pre-intervention cohort (prescribed 75 mg aspirin) or a risk of ≥1:50 for preterm pre-eclampsia from the FMF algorithm in the post-intervention cohort (prescribed 150 mg aspirin). MAIN OUTCOME MEASURES: Screening effectiveness, rates of pre-eclampsia. RESULTS: The FMF screening programme resulted in a significant reduction in the screen-positive rate (16.1 versus 8.2%, odds ratio [OR] 0.50, 95% confidence interval [CI] 0.41-0.53) with a concurrent increase in targeted aspirin use in women classified as high risk for pre-eclampsia (28.9 versus 99.0%, OR 241.6, 95% CI 89.6-652.0). Screening indices were uniformly improved for the FMF algorithm with receiver operating characteristic (ROC) analysis demonstrating excellent discrimination for preterm pre-eclampsia (area under the curve [AUC] = 0.846, 95% CI 0.778-0.915, P value <.001). Interrupted time series analysis showed that the FMF screening programme resulted in a significant 21-month relative effect reduction of 80% (P = .025) and 89% (P = .017), for preterm and early pre-eclampsia, respectively. CONCLUSIONS: First trimester combined screening for pre-eclampsia is both feasible and effective in a public healthcare setting. Such an approach results in a two-fold de-escalation of risk, doubling of pre-eclampsia detection, near total physician compliance of aspirin use and a significant reduction in the prevalence of preterm pre-eclampsia. TWEETABLE ABSTRACT: Implementation of 1st trimester combined pre-eclampsia screening effectively reduces prevalence of the disorder.

Secondary non-invasive prenatal screening for fetal trisomy: an effectiveness study in a public health setting.

OBJECTIVE: To evaluate the effectiveness of secondary screening using non-invasive prenatal testing (NIPT) in a routine NHS setting including test performance, turn-around times (TATs) and no-call (failure to obtain result) rates. To examine the influence of maternal and fetal characteristics on test performance. DESIGN: Retrospective cohort. SETTING: London teaching hospital. SAMPLE: A total of 8651 pregnancies undergoing screening for fetal trisomy using NIPT provided by an NHS cell-free DNA screening laboratory - the SAFE laboratory. METHODS: Screening test evaluation and TATs. Univariate and multivariate logistic regression analysis to identify significant predictors of no-call results and reported by low fetal fraction (<2%), very high fetal fraction (>40%) and processing failure. MAIN OUTCOME MEASURES: Test performance, TATs and no-call rates, factors affecting no-call results. RESULTS: Average TAT was 4.0 days (95% CI 4.0-4.2 days). Test sensitivities for trisomies 21 and 13/18 were 98.9% (95% CI 95.9-99.9%) and 90.4% (95% CI 80.0-96.8%), respectively. The overall no-call rate was 32/8651 (0.37%, 95% CI 0.26-0.52%). The overall risk of a no-call result was influenced by gestational age, dichorionic twin pregnancy, history of malignancy and pregnancies affected by trisomy 13/18, but not by maternal weight or use of low-molecular-weight heparin. CONCLUSIONS: High-throughput NIPT can be effectively embedded into a public health NHS setting. TATs of 4 days and no-calls of <0.5% were well within clinically desirable tolerances. Gestational age, maternal weight, assisted reproductive techniques, use of low-molecular-weight heparin and past history of malignancy did not have major impacts on test no-call rates and should not constitute reasons for withholding the option of NIPT from women. TWEETABLE ABSTRACT: Turn-around times of 4 days, no-call (test failure) rates of 0.37% and highly accurate NIPT can be successfully embedded in the NHS.

Routine first-trimester combined screening for pre-eclampsia: pregnancy-associated plasma protein-A or placental growth factor?

OBJECTIVE: To compare the screening performance of serum pregnancy-associated plasma protein-A (PAPP-A) vs placental growth factor (PlGF) in routine first-trimester combined screening for pre-eclampsia (PE), small-for-gestational age (SGA) at birth and trisomy 21. METHODS: This was a retrospective study nested in pregnancy cohorts undergoing first-trimester combined screening for PE and trisomy 21 using The Fetal Medicine Foundation (FMF) algorithm based on maternal characteristics, nuchal translucency thickness, PAPP-A, free beta-human chorionic gonadotropin, blood pressure and uterine artery Doppler. Women at high risk for preterm PE (≥ 1 in 50) received 150 mg of aspirin per day, underwent serial fetal growth scans at 28 and 36 weeks and were offered elective birth from 40 weeks of gestation. PlGF was quantified retrospectively from stored surplus first-trimester serum samples. The performance of combined first-trimester screening for PE and SGA using maternal history, blood pressure, uterine artery pulsatility index and either PAPP-A or PlGF was calculated. Similarly, the performance of combined first-trimester screening for trisomy 21 was calculated using either PAPP-A or PlGF in addition to maternal age, nuchal translucency thickness and free beta-human chorionic gonadotropin. RESULTS: Maternal serum PAPP-A was assayed in 1094 women, including 82 with PE, 111 with SGA (birth weight < 10th centile), 53 with both PE and SGA and 94 with fetal trisomy 21. PlGF levels were obtained retrospectively from 1066/1094 women. Median serum PlGF multiples of the median was significantly lower in pregnancies with PE (1.0 (interquartile range (IQR), 0.8-1.4); P < 0.01), SGA (1.0 (IQR, 0.8-1.3); P < 0.001) and trisomy 21 (0.6 (IQR, 0.5-0.9); P < 0.0001) compared to in controls (1.2 (IQR, 0.9-1.5)). There was no significant difference in the performance of first-trimester screening using PAPP-A vs PlGF for either preterm PE (area under the receiver-operating-characteristics curve (AUC), 0.78 vs 0.79; P = 0.55) or term PE (AUC, 0.74 vs 0.74; P = 0.60). These findings persisted even after correction for the effect of targeted aspirin use on the prevalence of PE. Similarly, there were no significant differences in sensitivity and specificity of combined screening for SGA or trisomy 21 when using PAPP-A vs PlGF. CONCLUSIONS: Using either PlGF or PAPP-A in routine first-trimester combined screening based on maternal characteristics, blood pressure and uterine artery Doppler does not make a significant clinical difference to the detection of PE or SGA. Depending on the setting, biomarkers should be chosen to achieve a good compromise between performance and measurement requirements. This pragmatic clinical-effectiveness study suggests that combined screening for PE can be implemented successfully in a public healthcare setting without changing current protocols for the assessment of PAPP-A in the first trimester. © 2021 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of 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.

Effect of change in posture on maternal functional hemodynamics at 35-37 weeks' gestation.

OBJECTIVES: To evaluate the effect of posture change from the supine to the sitting position and before and after passive leg raising on maternal functional hemodynamics in pregnant women at 35-37 weeks' gestation, and to compare the changes in pregnancies that subsequently developed pre-eclampsia (PE) or gestational hypertension (GH) with those that remained normotensive. METHODS: In 2764 singleton pregnancies at 35-37 weeks' gestation, maternal cardiovascular parameters were measured using an automated non-invasive cardiac monitor. The hemodynamic response to a change from the supine to the sitting position and before and after passive leg raising in the left lateral position was examined and compared between women who subsequently developed PE or GH and those who remained normotensive. RESULTS: In normotensive singleton pregnancies at 35-37 weeks' gestation, both change from the supine to the sitting position and passive leg raising were associated with an increase in cardiac index and stroke volume index and a decrease in total peripheral resistance index; there was a small increase in mean arterial pressure with both postural changes and a slight decrease in heart rate with passive leg raising. In pregnancies that subsequently developed PE or GH, compared with normotensive pregnancies, cardiac index and stroke volume index were lower and total peripheral resistance index was higher. In general, change from the supine to the sitting position and passive leg raising were associated with similar but less marked changes in cardiovascular parameters as in normotensive pregnancies. CONCLUSIONS: Paradoxically, in late third-trimester normal pregnancy, both change from the supine to a sitting position and passive leg raising may result in an increase in preload with a consequent increase in cardiac and stroke volume indices and a decrease in total peripheral resistance index. In pregnancies that develop PE or GH, the effects of postural change on cardiovascular parameters are similar but less marked than in normotensive pregnancies. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

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

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

Maternal cardiovascular function at 35-37 weeks' gestation: relation to maternal characteristics.

OBJECTIVE: To examine the possible effects of maternal characteristics and obstetric and medical history on maternal cardiovascular parameters at 35-37 weeks' gestation. METHODS: In 3013 singleton pregnancies at 35-37 weeks, maternal characteristics and medical history were recorded; uterine artery pulsatility index, mean arterial pressure (MAP) and maternal cardiovascular parameters were measured. Multivariable regression analysis was used to determine significant predictors of the cardiovascular parameters among gestational age (GA), maternal characteristics and medical history. RESULTS: Multivariable regression analysis demonstrated that significant independent prediction of log10 cardiac output and log10 cardiac power was provided by GA, maternal age, weight, weight gain from the first trimester, height, racial origin, smoking, assisted conception and previous neonatal birth-weight Z-score in parous women. For log10 total peripheral resistance, significant prediction was provided by GA, maternal age, height, racial origin, chronic hypertension, diabetes mellitus, assisted conception, previous neonatal birth-weight Z-score and prior pre-eclampsia (PE) in parous women. For log10 stroke volume, significant prediction was provided by maternal age, height, racial origin, smoking, chronic hypertension and diabetes mellitus. For heart rate, significant prediction was provided by GA, weight, weight gain, height, racial origin, chronic hypertension, previous neonatal birth-weight Z-score and prior PE in parous women. For log10 MAP, significant prediction was provided by maternal weight, racial origin, family history of PE, chronic hypertension and diabetes mellitus. For log10 thoracic fluid capacity, significant prediction was provided by GA, maternal age, weight, height, racial origin and systemic lupus erythematosus or antiphospholipid syndrome. For log10 ventricular ejection time, significant prediction was provided by GA, weight, height and racial origin. CONCLUSION: Maternal cardiovascular parameters are affected by maternal characteristics and medical and obstetric history, and they should therefore be converted into multiples of the normal median adjusted for significant independent predictors before their inclusion in combined screening for PE. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Maternal cardiac function at 35-37 weeks' gestation: prediction of pre-eclampsia and gestational hypertension.

OBJECTIVE: To investigate the potential value of combining maternal factors with multiples of the normal median values of maternal cardiovascular parameters at 35-37 weeks' gestation in the prediction of pre-eclampsia (PE) and gestational hypertension (GH). METHODS: In 2764 singleton pregnancies maternal characteristics and medical history were recorded; uterine artery pulsatility index (UtA-PI), mean arterial pressure (MAP) and maternal cardiovascular parameters were measured. Multivariable logistic regression analysis was then used to determine if the maternal factors and maternal cardiovascular parameters made a significant contribution to predicting PE and GH. The performance of screening was determined by the area under receiver-operating characteristics curves. RESULTS: In pregnancies that subsequently delivered with PE or GH, total peripheral resistance and MAP were higher and maternal cardiac output was lower, mainly owing to a decrease in heart rate in PE and a decrease in stroke volume in GH. The increases in total peripheral resistance and MAP were inversely related to gestational age at delivery. The performance of screening for PE and GH achieved by maternal characteristics and medical history was improved by the inclusion of MAP, but not by UtA-PI or maternal cardiovascular parameters. CONCLUSIONS: In women developing term PE total peripheral resistance and MAP are increased and maternal cardiac output is reduced. However, assessment of maternal cardiac function at 35-37 weeks' gestation is unlikely to improve the performance of screening for PE provided by maternal factors and MAP alone. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

An unusual complication in a gravida with factor IX deficiency: case report with review of the literature.

Factor IX deficiency (hemophilia B, Christmas disease) is an X-linked recessive coagulation disorder. It occurs in one out of every 25,000-30,000 male births and requires even rarer genetic circumstances for phenotypic expression in females. We report the occurrence of a large, late-trimester subchorionic hematoma in a gravida with factor IX deficiency and with laboratory evidence of consumptive coagulopathy during treatment. The patient was managed conservatively and had a successful outcome at term. The only four reported cases of antepartum management of factor IX deficiency in the English literature are reviewed.

Vibroacoustic stimulation evokes human fetal micturition.

OBJECTIVE: To examine the effect of vibroacoustic stimulation on fetal voiding as a measure of stress. METHODS: Fetal bladder volumes were examined serially by ultrasound 5 and 1 minutes before and 1 and 5 minutes after vibroacoustic stimulation (21 cases) or sham stimulation (20 cases). RESULTS: In the stimulated group, the mean (+/- SD) bladder volume decreased from 21.7 +/- 11.3 mL 1 minute before stimulation to 12.8 +/- 9.4 mL 1 minute after vibroacoustic stimulation, a statistically significant difference (P < .001). There was no significant decrease in bladder volume in the sham-stimulated fetuses. The correlations between bladder volume 1 minute before and 1 and 5 minutes after vibroacoustic stimulation were statistically significant (P < .01 and P < .001, respectively). CONCLUSION: Vibroacoustic stimulation induces fetal voiding, which may reflect a response to stress.

Ultrasonographic evaluation of uteroplacental blood flow patterns of abnormally located and adherent placentas.

Transvaginal ultrasonography was used to evaluate antepartum bleeding in a group of 76 patients at varying gestational ages with suspected placenta previa. The clinical outcome of 16 patients with persistent placenta previa was documented. Nine of the 16 patients had placental lacunar blood flow. Two of the nine patients were lost to follow-up. At cesarean section the seven patients with lacunar flow had a higher incidence of blood loss, transfusion requirements, abnormally implanted placenta, and cesarean hysterectomy than the six patients in whom no lacunar flow patterns were seen (p = 0.002). The finding of these flow patterns with abnormally located placentas suggests the anticipation of significant blood loss and probable extension of operative procedures to stop the blood loss.