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).