Reproductive Screening SIG Update - October 2017
This year we have seen the publication of one of the most important studies in relation to screening and prevention of preeclampsia.
Preeclampsia is an important cause of maternal and perinatal mortality and morbidity. There is extensive evidence that the risk of adverse outcome in relation to preeclampsia is much higher when the disease is severe and of early onset requiring delivery before 37 weeks’ gestation (preterm preeclampsia), than at term. A major challenge in modern obstetrics is early identification of pregnancies at high-risk of preeclampsia and undertaking the necessary measures to improve placentation and reduce the prevalence of the disease.
Extensive research in the last 20 years, mainly as a consequence of the shift in screening for aneuploidies from the second to the first-trimester of pregnancy, has identified a series of early biophysical and biochemical markers of impaired placentation. A combination of maternal demographic characteristics, including medical and obstetric history, uterine artery pulsatility index (PI), mean arterial pressure (MAP) and maternal serum pregnancy associated plasma protein-A (PAPP-A) and placental growth factor (PlGF) at 11-13 weeks’ gestation could identify 75% of pregnancies at high-risk for preterm preeclampsia, at 10% false positive rate (https://fetalmedicine.org/education/preeclampsia-screening
). In relation to the prevention of this complication, evidence has shown that low-dose aspirin started at 16 weeks’ or earlier is associated with a significant reduction in the relative risk for preterm preeclampsia. On the basis of the available evidence, the ASPRE consortium embarked on a study that aimed to provide evidence to support first-trimester screening and prevention of preterm preeclampsia.
Project ASPRE (Project #601852; EudraCT number 2013-003778-29; ISRCTN13633058; www.aspre.eu
), which was funded by the European Commission 7th Framework Programme (https://ec.europa.eu/research/fp7/index_en.cfm
), was designed with two components – a screening quality study followed by a double blind, randomized controlled trial (RCT) of aspirin vs. placebo in the prevention of preterm preeclampsia.
The aim of the screening quality study was to establish systems that would monitor quality in a more detailed, formalized manner at sites and use these systems to assess quality, identify areas for improvement and, where required, implement strategies to improve quality (e.g. re-training). This is based on the DQASS system that has been successful for improving the quality of the ultrasound and biochemical measurements in the NHS fetal anomaly screening programme in the United Kingdom.
During the screening quality study (between February and July 2015), a total of 10,445 women who attended for the 11-13 weeks scan were assessed for eligibility, of which 309 (3.0%) were excluded as they did not fulfill the inclusion criteria and 714 (6.8%) declined participation. 9,422 eligible women agreed to first-trimester combined screening for preterm preeclampsia, whilst an additional 381 women (4.0%) were not screened for various reasons (crown-rump length <45 mm or >84mm, detection of major fetal defect on scan, miscarriage or multiple pregnancy). 9,041 underwent screening, of which 266 were further excluded for reasons identified during the evaluation (2.9%). In the remaining 8,775 women, 239 developed preeclampsia (2.7%), including 17 (0.2%), 59 (0.7%) and 180 (2.0%) at <32, <37 and >37 weeks, respectively.
In combined screening by maternal factors, MAP, uterine artery PI and serum PlGF and PAPP-A the detection rates were 100% (95% confidence interval [CI] 80-100) for preeclampsia at <32 weeks, 80% (95% CI 67-89) for preeclampsia at <37 weeks and 43% (95% CI 35-50) for preeclampsia at >37 weeks, at 10% false positive rate. These detection rates were comparable to the estimated rates in the dataset used for development of the model.
Following the external validation of the first-trimester combined test, the main RCT was carried out. The aim of the RCT was to evaluate whether intake of low-dose aspirin during pregnancy reduces the risk of preterm preeclampsia. The ASPRE trial was a multicenter, double-blind, placebo-controlled trial, including 13 maternity units across England, Spain, Italy, Belgium, Greece and Israel. Screening for preeclampsia and recruitment to the trial was during the period from July 2015 through April 2016. A total of 26,941 singleton pregnancies had screening and 2,971 (11.0%) were found to be at high-risk (an estimated risk for preterm preeclampsia of >1 in 100), but 332 (11.2%) of these were excluded from recruitment to the trial because they did not fulfil the eligibility criteria. Of the 2,641 eligible women, 1,776 (67.2%) agreed to participate in the trial. After randomization 152 (8.6%) women withdrew consent and in those that participated there was loss to follow-up in 4 cases. Consented women were randomly assigned, in a 1:1 ratio, to receive aspirin, at a dose of 150 mg per night, or placebo, from 11 to 14 weeks’ gestation until 36 weeks. The primary outcome was delivery with preeclampsia before 37 weeks’ gestation.
The RCT demonstrated that preterm preeclampsia occurred in 13/798 (1.6%) participants in the aspirin group and in 35/822 (4.3%) in the placebo group (odds ratio in the aspirin group 0.38; 95% CI 0.20 to 0.74; p=0.004). Adherence was good, with reported intake of >85% of the required number of tablets in 80% of participants. There were no significant between-group differences in adverse events.
In a secondary analysis of data from the ASPRE trial, the influence of adherence on the beneficial effect of aspirin in prevention of preterm preeclampsia was evaluated. The proportion of prescribed tablets taken was used as an overall measure of adherence. The choice of cut-off for good compliance was re-defined as >90%, which was based on an exploratory analysis of the treatment effect. Preterm preeclampsia occurred in 5/555 (0.9%) participants in the aspirin group with adherence ≥90%, in 8/243 (3.3%) of participants in the aspirin group with adherence <90%, in 22/588 (3.7%) of participants in the placebo group with adherence ≥90%, and in 13/234 (5.6%) of participants in the placebo group with adherence <90%. The odds ratio in the aspirin group for preterm preeclampsia was 0.24 (95% CI 0.09-0.65) for adherence >90% and 0.59 (95% CI 0.23-1.53) for adherence <90%. The beneficial effect of aspirin in preventing preterm-PE is dependent on adherence.
Project ASPRE is definitive proof that effective screening for preterm preeclampsia can be achieved with a combined test of maternal factors and biomarkers at 11-13 weeks and that high-risk women can take aspirin at 150 mg per night from the first trimester of pregnancy to significantly reduce their chances of developing preterm preeclampsia.
Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. Rolnik DL, Wright D, Poon LC, O'Gorman N, Syngelaki A, de Paco Matallana C, Akolekar R, Cicero S, Janga D, Singh M, Molina FS, Persico N, Jani JC, Plasencia W, Papaioannou G, Tenenbaum-Gavish K, Meiri H, Gizurarson S, Maclagan K, Nicolaides KH. N Engl J Med. 2017 Aug 17;377(7):613-622. doi: 10.1056/NEJMoa1704559. Epub 2017 Jun 28.
Aspirin for Evidence-Based Preeclampsia Prevention trial: influence of compliance on beneficial effect of aspirin in prevention of preterm preeclampsia. Wright D, Poon LC, Rolnik DL, Syngelaki A, Delgado JL, Vojtassakova D, de Alvarado M, Kapeti E, Rehal A, Pazos A, Carbone IF, Dutemeyer V, Plasencia W, Papantoniou N, Nicolaides KH. Am J Obstet Gynecol. 2017 Sep 6. pii: S0002-9378(17)31097-9. doi: 10.1016/j.ajog.2017.08.110. [Epub ahead of print]
Accuracy of competing-risks model in screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation. O'Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, Wright A, Akolekar R, Cicero S, Janga D, Jani J, Molina FS, de Paco Matallana C, Papantoniou N, Persico N, Plasencia W, Singh M, NicolaidesKH. Ultrasound Obstet Gynecol. 2017 Jun;49(6):751-755. doi: 10.1002/uog.17399. Epub 2017 May 14.