Aspirin delays the development of preeclampsia

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.BACKGROUND: In the Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Preeclampsia Prevention (ASPRE) trial risks of preterm preeclampsia (PE) were obtained from the competing risk model. Consenting women with risks of greater than 1 in 100 were randomised to treatment with aspirin or placebo. The trial showed strong evidence of an effect (odds ratio 0.38, 95% confidence interval 0.20 to 0.74) on the incidence of preterm-PE, which was the primary outcome of ASPRE. There was a small and insignificant effect on the incidence of term-PE which was one of the secondary outcomes (odds ratio 0.95, 95% CI 0.64 to 1.39). These differential effects on term and preterm-PE could reflect a mechanism in which the action of aspirin is to delay the delivery with PE thereby converting what would, without treatment, be preterm-PE to term-PE. OBJECTIVE: To examine the hypothesis that the effect of aspirin is to delay the time of delivery with PE. STUDY DESIGN: This was an unplanned exploratory analysis of data from the ASPRE trial. The delay hypothesis predicts that in groups for which preterm-PE, without aspirin, were infrequent relative to term-PE, a reduction in term-PE would be expected because few cases of preterm-PE would be converted to term-PE. In contrast, in groups for which preterm-PE were frequent relative to term-PE, the conversion of preterm-PE to term-PE by aspirin would reduce or even reverse any effect on the incidence term-PE. This is examined using the ASPRE trial data by analysis of the effect of aspirin on the incidence of term-PE stratified according to the risk of preterm-PE at randomization. Given that women were included in ASPRE with risks of preterm PE > 1 in 100, a risk cut-off if 1 in 50 was used to define higher risk and lower risk strata. A statistical model in which the effect of aspirin is to delay the gestational age at delivery was fitted to the ASPRE trial data and the consistency of the predictions from this model with the observed incidence was demonstrated. RESULTS: In the lower risk group (<1 in 50), there was a reduction in the incidence of term-PE (odds ratio 0.62, 95% confidence interval 0.29 to 1.30). In contrast, in the higher risk group (≥1 in 50) there was a small increase in the incidence of term-PE (odds ratio 1.11, 95% confidence interval 0.71 to 1.75). Although these effects fail to achieve significance, they are consistent with the delay hypothesis. Within the framework of the aspirin-related delay hypothesis, the effect of aspirin was to delay the gestational age at delivery with PE by an estimated 4.4 weeks (95% CI 1.4 to 7.1 weeks) for those that in the placebo group would be delivered at 24 weeks and the effect decreased by an estimated 0.23 weeks (95% CI 0.021 to 0.40 weeks) for each week of gestation so that at 40+0 weeks the estimated delay was by 0.8 weeks (95% confidence interval -0.03 to 1.7 weeks). CONCLUSIONS: The ASPRE trial data are consistent with the hypothesis that aspirin delays the gestational age at delivery with PE.National Institute for Health Research (NIHR

Performance of screening for aneuploidies by cell-free DNA analysis of maternal blood in twin pregnancies

Objectives To report clinical implementation of cell‐free DNA (cfDNA) analysis of maternal blood in screening for trisomies 21, 18 and 13 in twin pregnancies and examine variables that could influence the failure rate of the test. Methods cfDNA testing was performed in 515 twin pregnancies at 10–28 weeks' gestation. The failure rate of the test to provide results was compared with that in 1847 singleton pregnancies, and logistic regression analysis was used to determine which factors among maternal and pregnancy characteristics were significant predictors of test failure. Results Failure rate of the cfDNA test at first sampling was 1.7% in singletons and 5.6% in twins. Of those with a test result, the median fetal fraction in twins was 8.7% (range, 4.1–30.0%), which was lower than that in singletons (11.7% (range, 4.0–38.9%)). Multivariable regression analysis demonstrated that twin pregnancy, higher maternal weight and conception by in‐vitro fertilization provided significant independent prediction of test failure. Follow‐up was available in 351 (68.2%) of the twin pregnancies and comprised 334 with euploid fetuses, 12 discordant for trisomy 21 and five discordant for trisomy 18. In all 323 euploid cases with a result, the risk score for each trisomy was &lt; 1:10 000. In 11 of the 12 cases with trisomy 21 and in the five with trisomy 18, the cfDNA test gave a high‐risk result, but in one case of trisomy 21, the score was &lt; 1:10 000. Conclusion In twin pregnancies screening by cfDNA testing is feasible, but the failure rate is higher and detection rate may be lower than in singletons

Cervical length at 23 weeks' gestation - relation to demographic characteristics and previous obstetric history in South African women

Objectives. To determine the distribution of cervical length in a routine population of singleton  pregnancies; to examine the relationship between cervical length, demographic characteristics, and previous obstetric history; and to compare these data with data from a similar study undertaken in the UK.Patients and methods. The study was conducted among women attending routine antenatal clinics at  Coronation, Johannesburg General and Chris Hani Baragwanath hospitals. Cervical length was measured by means of transvaginal ultrasound at 23 weeks' gestation in women with singleton pregnancies attending these clinics, as part of a multicentre randomised trial investigating the value of cerclage in a short cervix. The distribution of cervical length was determined and the significance of differences in median cervical lengths between subgroups was calculated according to maternal age, ethnic origin, maternal body mass index (BMI), cigarette smoking, alcohol intake, and previous obstetric history.Results. Cervical screening was offered to women (N = 2 173) attending clinics for a 23-week scan during the study period (July 1999- September 2002). Most women (N = 1 920) accepted, while 253 declined. Complete outcomes (date and mode of delivery; gestation at delivery, birth weight, Apgar scores,  maternal blood loss, whether the patient was cerclaged or not, and any complications) were obtained for 1 603 women who accepted screening. Cervical length was measured successfully in all cases. Median cervical length was 33.7 mm and in 64 cases (3.3%) the length was 15 mm or less. Significantly shorter cervical lengths were found in those with a history of previous miscarriage, preterm delivery, those aged less than 20 years and those with an abnormal BMI. Cervical length was not significantly shorter in black women than in coloured and white women.Conclusions. At 23 weeks' gestation the median cervical length in a South African population was 33.2 mm. In 3.3% of the population the length was 15 mm. There was an association between cervical length, demographic characteristics and previous obstetric history

Study protocol for the randomised controlled trial: combined multimarker screening and randomised patient treatment with ASpirin for evidence-based PREeclampsia prevention (ASPRE)

This is the final version of the article. Available from BMJ Publishing Group via the DOI in this record.INTRODUCTION: Pre-eclampsia (PE) affects 2-3% of all pregnancies and is a major cause of maternal and perinatal morbidity and mortality. Prophylactic use of low-dose aspirin in women at risk for PE may substantially reduce the prevalence of the disease. Effective screening for PE requiring delivery before 37 weeks (preterm PE) can be provided by a combination of maternal factors, uterine artery Doppler, mean arterial pressure, maternal serum pregnancy-associated plasma protein A and placental growth factor at 11-13 weeks' gestation, with a detection rate of 75% at a false-positive rate of 10%. We present a protocol (V.6, date 25 January 2016) for the ASpirin for evidence-based PREeclampsia prevention (ASPRE) trial, which is a double-blinded, placebo-controlled, randomised controlled trial (RCT) that uses an effective PE screening programme to determine whether low-dose aspirin given to women from 11 to 13 weeks' gestation will reduce the incidence of preterm PE. METHODS AND ANALYSIS: All eligible women attending for their first trimester scan will be invited to participate in the screening study for preterm PE. Those found to be at high risk of developing preterm PE will be invited to participate in the RCT. Further scans will be conducted for assessment of fetal growth and biomarkers. Pregnancy and neonatal outcomes will be collected and analysed. The first enrolment for the pilot study was in April 2014. As of April 2016, 26 670 women have been screened and 1760 recruited to the RCT. The study is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry. TRIAL REGISTRATION NUMBER: ISRCTN13633058.This study is supported by grants from the European Union 7th Framework Programme—FP7-HEALTH-2013-INNOVATION-2 (ASPRE Project # 601852) and the Fetal Medicine Foundation (FMF) (Charity No: 1037116)

The effect of parity on longitudinal maternal hemodynamics.

BACKGROUND: Parous women have a lower risk for pregnancy complications, such as preeclampsia or delivery of small-for-gestational-age neonates. However, parous women are a heterogeneous group of patients because they contain a low-risk cohort with previously uncomplicated pregnancies and a high-risk cohort with previous pregnancies complicated by preeclampsia and/or small for gestational age. Previous studies examining the effect of parity on maternal hemodynamics, including cardiac output and peripheral vascular resistance, did not distinguish between parous women with and without a history of preeclampsia or small for gestational age and reported contradictory results. OBJECTIVE: The objective of the study was to compare maternal hemodynamics in nulliparous women and in parous women with and without previous preeclampsia and/or small for gestational age. STUDY DESIGN: This was a prospective, longitudinal study of maternal hemodynamics, assessed by a bioreactance method, measured at 11+0 to 13+6, 19+0 to 24+0, 30+0 to 34+0, and 35+0 to 37+0 weeks' gestation in 3 groups of women. Group 1 was composed of parous women without a history of preeclampsia and/or small for gestational age (n = 632), group 2 was composed of nulliparous women (n = 829), and group 3 was composed of parous women with a history of preeclampsia and/or small for gestational age (n = 113). A multilevel linear mixed-effects model was performed to compare the repeated measures of hemodynamic variables controlling for maternal characteristics, medical history, and development of preeclampsia or small for gestational age in the current pregnancy. RESULTS: In groups 1 and 2, cardiac output increased with gestational age to a peak at 32 weeks and peripheral vascular resistance showed a reversed pattern with its nadir at 32 weeks; in group 1, compared with group 2, there was better cardiac adaptation, reflected in higher cardiac output and lower peripheral vascular resistance. In group 3 there was a hyperdynamic profile of higher cardiac output and lower peripheral vascular resistance at the first trimester followed by an earlier sharp decline of cardiac output and increase of peripheral vascular resistance from midgestation. The incidence of preeclampsia and small for gestational age was highest in group 3 and lowest in group 1. CONCLUSION: There are parity-specific differences in maternal cardiac adaptation in pregnancy

Predictive performance of the competing risk model in screening for preeclampsia.

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this record.BACKGROUND: The established method of screening for preeclampsia (PE) is to identify risk factors from maternal demographic characteristics and medical history; in the presence of such factors the patient is classified as high-risk and in their absence as low-risk. However, the performance of such approach is poor. We developed a competing risks model which allows combination of maternal factors (age, weight, height, race, parity, personal and family history of PE, chronic hypertension, diabetes mellitus, systemic lupus erythematosus or antiphospholipid syndrome, method of conception and interpregnancy interval), with biomarkers to estimate the individual patient-specific risks of PE requiring delivery before any specified gestation. The performance of this approach is by far superior to that of the risk scoring systems. OBJECTIVE: To examine the predictive performance of the competing risks model in screening for PE by a combination of maternal factors, mean arterial pressure (MAP), uterine artery pulsatility index (PI), and serum placental growth factor (PLGF), referred to as the triple test, in a training dataset for development of the model and two validation studies. STUDY DESIGN: The data for this study were derived from three previously reported prospective non-intervention multicenter screening studies for PE in singleton pregnancies at 11+0 - 13+6 weeks' gestation. In all three studies, there was recording of maternal factors and biomarkers and ascertainment of outcome by appropriately trained personnel. The first study of 35,948 women, which was carried out between February 2010 and July 2014, was used to develop the competing risks model for prediction of PE and is therefore considered to be the training set. The two validation studies comprised of 8,775 and 16,451 women, respectively and they were carried out between February and September 2015 and between April and December 2016, respectively. Patient-specific risks of delivery with PE at 0.95, >0.90 and >0.80, respectively, demonstrating a very high discrimination between affected and unaffected pregnancies. Similarly, the calibration slopes were very close to 1.0 demonstrating a good agreement between the predicted risks and observed incidence of PE. In the prediction of early-PE and preterm-PE the observed incidence in the training set and one of the validation datasets was consistent with the predicted one. In the other validation dataset, which was specifically designed for evaluation of the model, the incidence was higher than predicted presumably because of better ascertainment of outcome. The incidence of all-PE was lower than predicted in all three datasets because at term many pregnancies deliver for reasons other than PE and therefore pregnancies considered to be at high-risk for PE that deliver for other reasons before they develop PE can be wrongly considered to be false positives. CONCLUSIONS: The competing risks model provides an effective and reproducible method for first-trimester prediction of early-PE and preterm-PE, as long as the various components of screening are carried out by appropriately trained and audited practitioners. Early prediction of preterm-PE is beneficial because treatment of the high-risk group with aspirin is highly effective in the prevention of the disease.Fetal Medicine Foundatio

Incorporating DNA Sequencing into Current Prenatal Screening Practice for Down's Syndrome

PMCID: PMC3604109This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

The development and application of a new tool to assess the adequacy of the content and timing of antenatal care

Abstract Background: Current measures of antenatal care use are limited to initiation of care and number of visits. This study aimed to describe the development and application of a tool to assess the adequacy of the content and timing of antenatal care. Methods: The Content and Timing of care in Pregnancy (CTP) tool was developed based on clinical relevance for ongoing antenatal care and recommendations in national and international guidelines. The tool reflects minimal care recommended in every pregnancy, regardless of parity or risk status. CTP measures timing of initiation of care, content of care (number of blood pressure readings, blood tests and ultrasound scans) and whether the interventions were received at an appropriate time. Antenatal care trajectories for 333 pregnant women were then described using a standard tool (the APNCU index), that measures the quantity of care only, and the new CTP tool. Both tools categorise care into 4 categories, from ‘Inadequate’ (both tools) to ‘Adequate plus’ (APNCU) or ‘Appropriate’ (CTP). Participants recorded the timing and content of their antenatal care prospectively using diaries. Analysis included an examination of similarities and differences in categorisation of care episodes between the tools. Results: According to the CTP tool, the care trajectory of 10,2% of the women was classified as inadequate, 8,4% as intermediate, 36% as sufficient and 45,3% as appropriate. The assessment of quality of care differed significantly between the two tools. Seventeen care trajectories classified as ‘Adequate’ or ‘Adequate plus’ by the APNCU were deemed ‘Inadequate’ by the CTP. This suggests that, despite a high number of visits, these women did not receive the minimal recommended content and timing of care. Conclusions: The CTP tool provides a more detailed assessment of the adequacy of antenatal care than the current standard index. However, guidelines for the content of antenatal care vary, and the tool does not at the moment grade over-use of interventions as ‘Inappropriate’. Further work needs to be done to refine the content items prior to larger scale testing of the impact of the new measure