(UOG Editor for Trainees) UOG Journal Club: June 2018 ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm L. C. POON, D. L. ROLNIK, M. Y. TAN, J. L. DELGADO, T. TSOKAKI, R. AKOLEKAR , M. SINGH, W. ANDRADE, T. EFETURK, J. C. JANI, W. PLASENCIA, G. PAPAIOANNOU, A. R. BLAZQUEZ, I. F. CARBONE, D. WRIGHT and K. H. NICOLAIDES Volume 51, Issue 6, Pages 738–742 Journal Club slides prepared by Dr Yael Raz (UOG Editor for Trainees)

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Introduction The current approach to screening for pre-eclampsia (PE) is to identify risk factors from maternal demographic characteristics and medical history (NICE, ACOG criteria). This approach treats each maternal risk factor as a separate screening test with a cumulative detection rate (DR) and screen-positive rate. The Fetal Medicine Foundation (FMF) approach, allows estimation of individual patient-specific risks of PE requiring delivery before a specified gestational age. This approach combines the a-priori risk from maternal factors with the results of various combinations of biophysical and biochemical measurements.

Introduction – High risk for PE ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Introduction – High risk for PE National Institute for Health and Care Excellence (NICE), UK: One high-risk factor: Hypertensive disease in previous pregnancy, chronic hypertension, chronic renal disease, diabetes mellitus or autoimmune disease. or Two moderate-risk factors: Nulliparity, age ≥ 40 years, body mass index (BMI) ≥ 35 kg/m2, family history of PE or interpregnancy interval > 10 years.

Introduction – High risk for PE ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Introduction – High risk for PE American College of Obstetricians and Gynecologists (ACOG), USA: Any of the following factors: PE in previous pregnancy, chronic hypertension, chronic renal disease, diabetes mellitus, systemic lupus erythematosus, thrombophilia, nulliparity, age >40 years, BMI ≥30 kg/m2, family history of PE or conception by IVF The Fetal Medicine Foundation (FMF) assessment of risk for PE by: Maternal demographic factors MAP (mean arterial pressure). UtA-PI (uterine artery pulsatility index). PAPP-A (serum pregnancy-associated plasma protein-A). PlGF (serum placental growth factor).

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Aim of the study To report the incidence of preterm PE in women who are screen positive according to the criteria of NICE and ACOG and compare the incidence with that in those who are screen positive or screen negative by the FMF algorithm, in the total screened population of the ASPRE study.

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Methods Secondary analysis of women recruited during the two phases of the ASPRE study, a prospective, multicenter study in singleton pregnancies at 11 + 0 to 13 + 6 weeks’ in 13 maternity hospitals in the UK, Spain, Italy, Belgium, Greece and Israel. Two phases of the ASPRE study: First phase: screening by the FMF algorithm but no intervention (8775 women, 59 developed preterm PE). Second phase: randomized control trial of use of aspirin vs placebo for prevention of preterm PE in the high-risk group (25 798 women were screened,159 developed preterm PE). In the subgroup of patients allocated to aspirin, an adjustment was made for the incidence of preterm PE.

Methods Outcome measure was preterm PE. ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Methods Outcome measure was preterm PE. PE was diagnosed based on the criteria of the International Society for the Study of Hypertension in Pregnancy: Systolic blood pressure ≥ 140 mmHg and/or diastolic blood pressure ≥ 90 mmHg on at least two occasions 4 h apart developing after 20 weeks of gestation in previously normotensive women. Proteinuria of ≥ 300mg in 24 h or two readings of at least ++ on dipstick analysis of midstream or catheter urine specimens if no 24-h collection is available. Superimposed PE - significant proteinuria (as defined above) should develop after 20 weeks of gestation in women with known chronic hypertension (history of hypertension before conception or presence of hypertension at the booking visit before 20 weeks’ gestation in the absence of trophoblastic disease).

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Methods In the ACOG and NICE screen-positive patients, the incidence of preterm PE was estimated separately for those who were screen positive and those who were screen negative by the FMF algorithm, using a risk cut-off of 1 in 100 for preterm PE, and the relative incidence of preterm PE in the screen-negative to the screen-positive group was calculated.

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Results At least one ACOG risk criterion was present in 22,287 (64.5%) women. The incidence of preterm PE in FMF negative pregnancies was 0.25% (1:400) . At least one NICE high risk criterion was present in 1392 (4%) women. The incidence of preterm PE in FMF negative pregnancies was 0.65% (1:150). At least two NICE moderate risk criteria was present in 2360 (6.8%) women. The incidence of preterm PE in FMF negative pregnancies was 0.42% (1:240).

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Discussion In the ASPRE population, the incidence of preterm PE was 0.7% and this increased in women with risk factors described by ACOG and NICE. The highest risk factors were chronic hypertension (15-fold), history of PE in a previous pregnancy (7-fold) and diabetes mellitus (7-fold). There was also a 2-fold increase in incidence of preterm PE associated with obesity, family history of PE and conception by in-vitro fertilization. Nulliparity and increased maternal age did not significantly increase the incidence of preterm PE.

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Discussion In women who were screen positive by ACOG or NICE criteria, the incidence of preterm PE increased substantially in those who were also screen positive by the FMF algorithm, whereas in the FMF negative group, the incidence was reduced to within or below background levels. In women fulfilling any one of the ACOG criteria, the incidence of preterm PE in the subgroup of FMF screen-negative pregnancies was 95% lower than in the screen-positive group. Similarly, in women fulfilling any one of the NICE high-risk criteria, the incidence of preterm PE in the subgroup of FMF screen-negative pregnancies was 92% lower than in the screen-positive group, and for those with any two or more moderate-risk factors the reduction was 91%.

Strengths Limitations ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Strengths Large prospective study. Participants are women attending for routine care. Gestational age range at enrollment is widely used for diagnosis of major fetal defects and screening for fetal trisomies. Measurement of all biomarkers was recorded in all cases. Consistency in data collection was maintained throughout the study period (standardized protocols, regular UCL-CCTU monitoring). Limitations Low number of cases of women with certain risk factors ( APLA, SLE ). Small number of cases of preterm PE leading to wide CIs obtained for relative risks.

Implications for practice ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Implications for practice The performance of screening for preterm PE, and therefore appropriate selection of the patients that would benefit from prophylactic use of aspirin, is by far superior if the FMF algorithm is used than the method advocated by ACOG and NICE. In women that fulfill the ACOG or NICE screening criteria but are screen negative by the FMF method, the incidence of preterm PE is reduced to within or below background levels. Therefore, they should not be advised to take aspirin. ACOG and NICE guidelines should be updated to reflect recent scientific evidence that the screening target should be preterm PE, the best way to identify the high-risk group is by a combination of maternal factors and biomarkers, aspirin should be started before 16 weeks’ gestation and the daily dose should be higher than 100 mg.

ASPRE trial: incidence of preterm pre-eclampsia in patients fulfilling ACOG and NICE criteria according to risk by FMF algorithm Poon et al., UOG 2018 Points for discussion What is the incidence of term and preterm severe PE/HELLP in women who are screen positive according to the criteria of NICE and ACOG and screen positive or screen negative by the FMF algorithm in the study population? In populations in which serum biomarkers are not available for any reason – which criteria should be applied? Given the fact that PE background levels depend on the country of origin, will the stratification of the analysis according to countries change the results of the analysis?