2 The diagnostic tests | PLGF-based testing to help diagnose suspected preterm pre-eclampsia | Guidance

Clinical need and practice

2.1

Pre-eclampsia is a potentially serious complication of pregnancy, thought to be related to problems with the development of the placenta. It requires referral to a specialist and hospital admission to monitor the mother and unborn baby, and is only cured by the birth of the baby. Pre-eclampsia is characterised by high blood pressure (hypertension) and proteinuria, which is when the kidneys leak protein into the urine. Either, on its own indicates a risk of developing pre-eclampsia. Other symptoms include headache, visual disturbances, right upper quadrant abdominal (epigastric) pain, oedema (swelling of the hands, face or feet) and oliguria (low urine output).

2.2

If pre-eclampsia is not diagnosed and closely monitored, it can lead to potentially life-threatening complications including eclampsia, HELLP syndrome (haemolysis, elevated liver enzymes and low platelets), disseminated intravascular coagulation, stroke or organ dysfunction. Women who have hypertension or pre-eclampsia during pregnancy may have a higher risk of placental abruption. Gestational hypertension and pre-eclampsia may also affect the unborn baby by slowing growth or leading to premature birth.

2.3

This is a full update of NICE's diagnostics guidance on placental growth factor (PLGF)-based testing to help diagnose suspected pre-eclampsia (DG23), which was published in 2016. The original guidance recommended the Triage PLGF Test and the Elecsys immunoassay sFlt‑1/PLGF ratio, used with standard clinical assessment and subsequent clinical follow up, to help rule out pre-eclampsia. Further research was recommended on using these tests to rule in pre-eclampsia. The DELFIA Xpress PLGF 1‑2‑3 test and BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio were not recommended for routine adoption in the NHS.

The diagnostic and care pathway

Identifying and managing the risk of developing pre-eclampsia

2.4

Recommendations on management of pre-eclampsia in NICE's guideline on antenatal care include measuring blood pressure and doing urinalysis for protein at each antenatal visit to check for pre-eclampsia. The guideline also recommends determining risk factors for pre-eclampsia at the booking appointment (by 10 weeks of pregnancy). NICE's guideline on hypertension in pregnancy describes risk factors for pre‑eclampsia. It defines pre-eclampsia as new-onset hypertension (over 140 mmHg systolic or over 90 mmHg diastolic) after 20 weeks of pregnancy plus 1 or more new-onset conditions. If a woman presents with some but not all of these criteria, they are considered to have suspected pre-eclampsia. If they are under 37 weeks of pregnancy, this would be suspected preterm pre-eclampsia.

Managing pregnancy with gestational hypertension with or without pre-eclampsia

2.5

NICE's guideline on hypertension in pregnancy includes recommendations on managing gestational hypertension and pre-eclampsia in pregnancy, including timing the birth in women with pre-eclampsia.

The interventions

Triage PLGF Test (Quidel)

2.6

The Triage PLGF Test can be used at the point of care and in the laboratory. The test is used with other clinical information to help diagnose preterm pre-eclampsia, and as an aid in the prognosis of birth, in women who are between 20 weeks and 35 weeks pregnant with signs and symptoms of pre-eclampsia. The Triage PLGF kit costs £1,000 (excluding VAT) and can do 25 tests. The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £49.58.

**Table 1 Recommended cut-offs for the Triage PLGF Test**
Result	Classification	Interpretation
Placental growth factor (PLGF) less than 12 pg/ml	Test positive – highly abnormal	Highly abnormal and suggestive of patients with severe placental dysfunction and at increased risk of preterm birth
PLGF between 12 pg/ml and 99 pg/ml	Test positive – abnormal	Abnormal and suggestive of patients with placental dysfunction and at increased risk of preterm birth
PLGF 100 pg/ml or more	Test negative – normal	Normal and suggestive of patients without placental dysfunction and unlikely to progress to birth within 14 days of the test

Elecsys immunoassay sFlt‑1/PLGF ratio (Roche)

2.7

The Elecsys immunoassay sFlt‑1/PLGF ratio is formed by combining the results from 2 electrochemiluminescence immunoassays (the Elecsys PLGF and Elecsys sFlt‑1 assays), which are compatible with the Roche Cobas e automated clinical chemistry analysers. The sFlt‑1/PLGF ratio is intended to help diagnose pre-eclampsia, together with other diagnostic and clinical information. The sFlt‑1/PLGF ratio is also intended to help predict pre-eclampsia in the short term (rule out and rule in) in pregnant women with suspected pre-eclampsia, together with other diagnostic and clinical information. The Elecsys sFlt‑1 reagent kit and the Elecsys PLGF reagent kit cost £3,310.78 each and can do 100 tests. They are intended to be used together, with each sFlt‑1/PLGF ratio test costing £66.21 (excluding VAT). The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £79.23.

**Table 2 Recommended cut-offs for the Elecsys immunoassay sFlt‑1/PLGF ratio**
Intended use	Stage of pregnancy	Decision rule	sFlt‑1/PLGF ratio
To help diagnose pre-eclampsia	Week 20 to week 33 plus 6 days	Rule out cut-off	33
To help diagnose pre-eclampsia	Week 20 to week 33 plus 6 days	Rule in cut-off	85
To help diagnose pre-eclampsia	Week 34 to birth	Rule out cut-off	33
To help diagnose pre-eclampsia	Week 34 to birth	Rule in cut-off	110
Short-term prediction of pre-eclampsia	Week 24 to week 36 plus 6 days	Rule out pre-eclampsia for 1 week	38 or less
Short-term prediction of pre-eclampsia	Week 24 to week 36 plus 6 days	Rule in pre-eclampsia within 4 weeks	Over 38

DELFIA Xpress PLGF 1-2-3 test and DELFIA Xpress sFlt-1 kit (PerkinElmer)

2.8

The DELFIA Xpress PLGF 1‑2‑3 can be used on its own or with the DELFIA Xpress sFlt‑1 kit. The tests are intended to help diagnose pre‑eclampsia and for short-term prediction of suspected pre-eclampsia together with other biochemical and clinical information.

2.9

The company specifies threshold values for the DELFIA Xpress PLGF 1‑2‑3 test when used alone (see table 3):

**Table 3 DELFIA Xpress PLGF 1‑2‑3 cut-offs**
Intended use	Stage of pregnancy	Decision rule	PLGF cut-off
To help diagnose pre-eclampsia	Week 20 to week 33 plus 6 days Week 34 or more	Rule in cut-off	Less than 50 pg/ml
To help diagnose pre-eclampsia	Week 20 to week 33 plus 6 days Week 34 or more	Rule out cut-off	150 pg/ml or more
Short-term prediction of pre-eclampsia	Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more	Rule out pre-eclampsia within 1 week	150 pg/ml or more
Short-term prediction of pre-eclampsia	Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more	Rule out pre-eclampsia within 4 weeks	150 pg/ml or more

2.10

The company specifies threshold values for DELFIA Xpress 1‑2‑3 used with the DELFIA Xpress sFlt‑1 (see table 4):

**Table 4 DELFIA Xpress sFlt‑1/PLGF ratio cut-offs**
Intended use	Stage of pregnancy	Decision rule	sFlt‑1/PLGF ratio
To help diagnose pre-eclampsia	Week 20 to week 33 plus 6 days	Rule in cut-off	70 or over
To help diagnose pre-eclampsia	Week 34 or more	Rule in cut-off	90 or over
Short-term prediction of pre-eclampsia	Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more	Rule out pre-eclampsia within 1 week	50 or less
Short-term prediction of pre-eclampsia	Week 20 to week 41 Week 20 to week 33 plus 6 days Week 34 or more	Rule out pre-eclampsia within 4 weeks	50 or less

2.11

The DELFIA Xpress PLGF 1‑2‑3 kit costs £722 (excluding VAT) and the DELFIA Xpress sFlt‑1 kits costs £944 (excluding VAT). Each can do 96 tests (that is 96 PLGF tests alone or 96 sFlt‑1/PLGF ratio tests). The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £37.41 for DELFIA Xpress PLGF 1‑2‑3 and £71.41 for the DELFIA Xpress sFlt‑1/PLGF ratio.

BRAHMS sFlt-1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio (ThermoFisher)

2.12

The BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is formed by combining the results from the BRAHMS sFlt‑1 Kryptor and BRAHMS PLGF plus Kryptor assays. The assays are compatible with the BRAHMS Kryptor compact plus analyser and the Kryptor Gold immunoanalyser. The BRAHMS sFlt‑1 Kryptor/BRAHMS PLGF plus Kryptor PE ratio is intended to be used to confirm or exclude a diagnosis of pre-eclampsia after 20 weeks of pregnancy. The BRAHMS sFlt‑1 Kryptor and BRAHMS PLGF plus Kryptor kits cost £825 each and can do 75 tests. The cost per test used in the economic model (incorporating additional cost components such as machine costs, reagents, service charges, training and staff costs) was £52.28.

2.13

The company says that a ratio of more than 85 suggests pre-eclampsia and a high-risk pregnancy. At consultation on the draft guidance, it said that updated instructions for use will be released later in 2022 (see section 3.6).

The comparator

The comparator is no further assessment beyond clinical assessments already done, such as blood pressure measurement, urinalysis and fetal monitoring, to help diagnose preterm pre-eclampsia and make decisions about care.