This application uses Bayes theorem to combine the prior risk from maternal factors and medical history with the results of various biophysical and biochemical measurements to estimate the posterior risk for PE. You can obtain risks for PE based on maternal factors alone and in combination with any of the biomarkers.

Clinical application

Screening for PE at 11-14 weeks ¹

• The objective of screening at this stage is the identification of a group at high-risk for preterm-PE (<37 weeks) and the reduction of such risk through the prophylactic use of aspirin (150 mg/day from 11-14 to 36 weeks). The ASPRE trial has shown that in pregnancies at high-risk for PE administration of aspirin reduces the rate of early-PE (<32 weeks) by about 90% and preterm-PE by 60%. Prophylactic use of aspirin does not reduce the incidence of term-PE ².
• Combined screening by maternal factors, uterine artery PI, mean arterial pressure and serum PLGF can predict 90% of early-PE and 75% of preterm-PE, at screen positive rate (SPR) of 10% (

  Table 1. Detection rate at screen positive rate of 10%, of preeclampsia with delivery at <32, <37 and ≥37 weeks’ gestation in screening by maternal factors, biomarkers and their combination at 11⁺⁰ to 14⁺¹ weeks.

  
  

  Method of screening	PE <32 w	PE <37 w	PE ≥37 w
  Maternal factors	53%	45%	34%
  Maternal factors plus
  MAP	61%	51%	38%
  UtA-PI	70%	58%	35%
  PAPP-A	55%	49%	35%
  PLGF	72%	61%	35%
  MAP, UtA-PI	83%	68%	41%
  MAP, PAPP-A	66%	56%	39%
  MAP, PLGF	79%	66%	39%
  UtA-PI, PAPP-A	70%	59%	36%
  UtA-PI, PLGF	81%	67%	37%
  PLGF, PAPP-A	74%	64%	36%
  MAP, UtA-PI, PAPP-A	83%	68%	41%
  MAP, PAPP-A, PLGF	81%	67%	39%
  MAP, UtA-PI, PLGF	90%	75%	41%
  UtA-PI, PAPP-A, PLGF	81%	68%	37%
  MAP, UtA-PI, PAPP-A, PLGF	90%	75%	41%

  Table 1). Inclusion of PAPP-A does not provide significant improvement to any combination of biomarkers which include serum PLGF.
• In a White population, for risk cut-off of 1 in 100 and 1 in 150 the respective SPR’s are about 10% and 16%, the DR’s for early-PE are 88% and 94% and DR’s for preterm-PE are 69% and 81%. It would therefore be reasonable in screening for PE in a setting with a predominantly White population to use a risk cut-off of 1 in 150 to define the high-risk group that would benefit from prophylactic use of aspirin. However, at such risk cut-off it should be anticipated that for Black women the SPR would be about 40% with DR of early- and preterm-PE of 100% and 95%, respectively. This is an inevitable consequence of the fact that the prevalence of preterm-PE is more than three times as high in Black than White women.

Screening for PE at 19-25 weeks ³

Screening at this stage should ideally be by a combination of maternal factors, uterine artery PI, mean arterial pressure and serum PLGF and the risk for PE <32 weeks and PE <36 weeks should be calculated. On the basis of these risks the women are stratified into high-, intermediate- and low-risk management groups. The high-risk group would require close monitoring for high blood pressure and proteinuria at 24-31 weeks. The intermediate-risk group together with the undelivered pregnancies from the high-risk group, would have reassessment of risk for PE at 32 weeks to identify those that would require close monitoring for high blood pressure and proteinuria at 32-35 weeks.

• At risk cut-off of 1 in 25 for PE <32 weeks, 1% of the population would be stratified into the high-risk group which will contain nearly all cases that will develop PE at <32 weeks; these patients need close monitoring at 24-31 weeks.
• At risk cut-off of 1 in 150 for PE <36 weeks, 10% of the population would be stratified into the intermediate-risk group which will contain about 90% of cases that will develop PE at 32-36 weeks; these patients need reassessment at 32 weeks.
• All pregnancies would have reassessment of risk for PE at 35-37 weeks to define the high-risk group for term-PE.

Screening for PE at 30-35 weeks

Screening at this stage should ideally be by a combination of maternal factors, uterine artery PI, mean arterial pressure, serum PLGF and serum sFLT-1.

• At risk cut-off of 1 in 150 for PE <36 weeks, 10% of the population would be stratified into the high-risk group which will contain nearly all cases that will develop PE at 32-36 weeks; these patients need close monitoring for high blood pressure and proteinuria at 32-35 weeks.
• All pregnancies would have reassessment of risk for PE at 35-37 weeks to define the high-risk group for term-PE.

Screening for PE at 35-38 weeks ⁴

Screening at this stage should ideally be by a combination of maternal factors, mean arterial pressure, PLGF and sFLT-1.

• At risk cut-off for PE at <42 weeks of 1 in 30 the detection rate of term-PE is 75% at SPR of 13%. The rationale for such late third-trimester screening is identification of a high-risk group that would benefit from close monitoring to minimize adverse perinatal events for those that develop PE by determining the appropriate time and place for delivery.

Measurement of biomarkers

• Technique for measurement of mean arterial pressure: please
  • Blood pressure should be taken by validated automated devices, which are calibrated at regular intervals. Mercury sphygmomanometers should not be used because of concerns for both the clinical performance and safety of these instruments.
  • The recordings should be made by healthcare professionals who had received appropriate training on the use of these machines.
  • The women should be in a sitting position and their legs should not be crossed. Crossing of the legs may raise the MAP.
  • The arms of the patient should be supported at the level of their heart. If the upper arm is below the level of the right atrium the MAP is over-estimated and if the arm is above the level of the heart the MAP is under-estimated.
  • A small (<22 cm), normal (22-32 cm) or large (33-42 cm) adult cuff should be used depending on the mid-arm circumference of the patient. If the cuff is too large the MAP is under-estimated and if the cuff is too small the MAP is over-estimated.
  • After rest for five minutes, two measurements of MAP should be taken from each arm simultaneously and the average of the four measurements should be used . Large inter-arm differences in MAP are common in certain pathological conditions, such as dissection or coarctation of the aorta and peripheral vascular disease, but they are also found in normal healthy individuals.
  click here.
• Technique for measurement of uterine artery PI: please

  UTPI can be measured by either transabdominal or transvaginal sonography.
  
  

  Transabdominal scan in the first trimester

  • A mid-sagittal section of the uterus should be obtained and the cervical canal identified.
  • The ultrasound probe should be gently tilted from side to side and color Doppler should be used to identify each uterine artery along the side of the uterus at the level of the internal os.

  Transabdominal scan in the second or third trimester

  • The ultrasound probe should be placed in turn on the left and right lower lateral quadrant of the abdomen just above the inguinal ligament to visualise the external iliac artery.
  • Each uterine artery is identified using color Doppler as a vessel crossing the external iliac artery
  • The pulsed wave sample volume should be placed on the uterine artery about 1 cm above the cross-over of the vessels to avoid contamination from iliac artery

  Transvaginal scan in any trimester

  • The bladder must be empty.
  • The woman should be placed in the dorsal lithotomy position.
  • The ultrasound probe should be placed in turn into the left and right lateral fornix.
  • The uterine arteries are identified using color Doppler at the level of the internal cervical os.

  
  

  After identification of each uterine artery

  • Use pulsed wave Doppler.
  • The sampling gate should be 2 mm so that it covers the whole vessel.
  • The angle of insonation should be <30º.
  • The peak systolic velocity should be >60 cm/s to ensure that the uterine artery, rather than the arcuate artery, is being examined.
  • When three similar consecutive waveforms are obtained the PI should be measured. This can be done by automatic or manual tracing of the waveform.
  • Please record the UTPI of the left and right arteries. The application uses the average value of the two.
  click here.
• Measurement of biochemical markers requires validated equipment and reagents. At present these are provided by DelfiaXpress from PerkinElmer, Kryptor from ThermoFisher and Elecsys from Roche.
• All measurements for biophysical and biochemical markers are expressed as multiples of the normal median (MoMs), adjusting for maternal factors that provide substantive contribution to their value. This application allows calculation of MoMs from the measurements of biomarkers. In the case of biochemical markers you may prefer to record the MoM values obtained from your laboratory.

Audit of results

To ensure that the service you provide is of high quality it is important that you audit the distribution of your mean arterial pressure and uterine artery PI measurements and MoM values of PAPP-A, PLGF and sFLT-1 at regular intervals.

• To audit the distribution of mean arterial pressure measurements please click here.
• To audit the distribution of uterine artery PI measurements please click here.
• To audit the distribution of MoM values of PAPP-A please click here.
• To audit the distribution of MoM values of PLGF please click here.
• To audit the distribution of MoM values of sFLT-1 please click here.

The median MoM value for each biomarker should be approximately 1.0 MoM. The audit function will highlight whether your values are outside acceptable limits:

• In the case of mean arterial pressure and uterine artery PI, you may need to retrain in taking appropriate measurements.
• In the case of biochemical markers, you should review the process of collection and transportation of samples to the laboratory and whether the laboratory uses the appropriate software and adjustments in the calculation of MoMs.

To use the application please click here.

References

1. Tan MY, Syngelaki A, Poon LC, Rolnik DL, O'Gorman N, Delgado JL, Akolekar R, Konstantinidou L, Tsavdaridou M, Galeva S, Ajdacka U, Molina FS, Persico N, Jani JC, Plasencia W, Greco E, Papaioannou G, Wright A, Wright D, Nicolaides KH. Screening for pre-eclampsia by maternal factors and biomarkers at 11-13 weeks' gestation. Ultrasound Obstet Gynecol 2018; 52: 186-195.
2. 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. Aspirin versus placebo in pregnancies at high risk for preterm preeclampsia. N Engl J Med 2017; 377: 613-622.
3. Litwinska M, Syngelaki A, Wright A, Wright D, Nicolaides KH. Management of pregnancies after combined screening for pre-eclampsia at 19-24 weeks' gestation. Ultrasound Obstet Gynecol. 2018; 52: 365-372.
4. Panaitescu A, Ciobanu A, Syngelaki A, Wright A, Wright D, Nicolaides KH. Screening for preeclampsia at 35–37 weeks’ gestation. Ultrasound Obstet Gynecol 2018; 52: 501-506.