METHODS
This is a secondary analysis of a previously published data, which was
used to test the Gaussian algorithm for early-onset PE
prediction3. That study was conducted in a prospective
fashion at Vall d’Hebron University Hospital (Barcelona) from October
2015 to September 2017. The local ethics committee (CEIC-VHIR
PR(AMI)265/2018) approved the study protocol. A total of 3,777
unselected singleton pregnant women attending their routine
first-trimester scan (from 11+0 to 13+6 weeks of gestation) were invited
to participate, and 2,946 women agreed and provided their written
informed consent. Of those, 305 participants (10.4%) had to be excluded
due to the following reasons: missing outcome data (n=86), major fetal
defects or chromosomopathies (n=13), miscarriage or fetal death
<24 weeks (n=15), and insufficient remaining blood sample to
measure PLGF (n=191). Before the implementation of the first-trimester
combined screening for PE in 2018, no PE screening was performed at the
Vall d’Hebron University Hospital; therefore, none of the remaining
2,641 participants received aspirin at any time during their pregnancy.
Neonatal birthweight was not available for 158 participants; therefore,
predictive accuracies for SGA were calculated with 2,483 participants.
Gestational age was confirmed by fetal crown-rump length measurement
during the first-trimester scan13. Maternal
characteristics and medical and obstetric history were recorded at the
first-trimester ultrasound scan via a patient questionnaire. The
following maternal characteristics were recorded: age (years); height
(centimetres); weight (kilograms); ethnicity (white European, South
American, black, Asian, South-East Asian, and others); smoking during
pregnancy (yes/no); and conception method (spontaneous/assisted
reproductive technology/ovulation drugs). Medical history variables
included the presence of chronic hypertension (yes/no), diabetes
mellitus (Type 1/Type2/no), renal disease (yes/no), systemic lupus
erythematosus (yes/no), and antiphospholipid syndrome (yes/no).
Obstetric history variables included parity (nulliparous, defined as no
previous deliveries before 24 weeks vs multiparous), gestational age at
birth (weeks) in the last pregnancy, interval between the last delivery
and the beginning of the current one (years), and personal or family
history of PE (yes/no). Biochemical markers, including serum PAPP-A and
PlGF, were measured at the first-trimester routine blood test for
aneuploidy screening (from 8+0 to 13+6 weeks) by the fully automated
Elecsys assays for PAPP-A and PlGF on an immunoassay platform (cobas e
analyzers; Roche® Diagnostics, Rotkreuz, Switzerland). Biophysical
markers, including MAP and UtAPI, were assessed at the first-trimester
scan. Blood pressure was measured automatically using a calibrated
device according to a standard procedure: a single measurement in one
arm (right or left) while women were seated and after a 5-minute rest.
MAP was calculated as: diastolic blood pressure + (systolic-diastolic
blood pressure)/3. UtAPI was measured following the recommendations of
the FMF14. All examiners were certified by the FMF for
PE risk assessment and Doppler ultrasound assessment.
Small-for-gestational-age newborns were defined as having a birthweight
below the 10th centile according to customized local
charts15. Indication for elective delivery was based
on Doppler ultrasound findings and conventional cardiotocogram
interpretation, according to the current protocol16.
Newborns were classified as early SGA if delivery occurred before 32
weeks and as preterm SGA if delivery occurred before 37 weeks.
PE was defined according to the guidelines of the International Society
for the Study of Hypertension in Pregnancy: systolic blood pressure of
140 mm Hg or higher and/or diastolic blood pressure of 90 mm Hg or
higher, confirmed by repeated measurements over a few hours, developing
after 20 weeks in previously normotensive women, accompanied by
proteinuria of 300 mg or higher in 24 h, spot urine protein/creatinine
ratio of 0.3 mg/mg or higher, or dipstick urinalysis of 1+ or higher
when a quantitative method was not available17.
Early-onset and preterm PE were defined as PE requiring delivery before
34 and 37 weeks, respectively.
For the Gaussian algorithm, multiples of the median (MoMs) for each
marker were calculated according to the methodology described in a
previous study3. For the FMF algorithm, MoMs were
obtained using the batch calculation tool provided in the FMF
website18. We then coded the variables required for
the prediction formulas according to the description provided in the
corresponding published articles1,3. For the Gaussian
algorithm, the prenatal screening software SsdwLab 6 (SBP Soft 2007 S.L,
Girona, Spain) was used to calculate early-onset PE probability scores.
For the FMF algorithm, the risk calculation tool provided in the FMF
website was used19.
Besides the “a priori” risks, the 4 markers (PAPP-A, PlGF, MAP and
UtAPI) can be incorporated alone or in combination of 2, 3 or 4 for risk
calculation, depending on the markers available in the clinical
practice. Therefore, there are 15 possible marker combinations.
Nevertheless, only the 7 most clinically relevant have been investigated
in this study (MAP alone, MAP + PlGF, MAP + UtAPI, MAP + PAPP-A, MAP +
UtAPI + PAPP-A, MAP + UtAPI + PlGF, and MAP + UtAPI + PlGF + PAPP-A).