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1. 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)

2. 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.

3. 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.

4. 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).

5. 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.

6. 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.

7. 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).

8. 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.

9. 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).

11. 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.

12. 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%.

13. 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.

14. 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.

15. 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?