B·R·A·H·M·S Biomarkers: Understanding Pre-eclampsia

What you should know about pre-eclampsia

Pre-eclampsia is a serious and life-threatening pregnancy complication which affects about 2-8% of pregnancies.1 This disease can only be cured by the delivery of the baby and contributes largely to maternal and neonatal mortality and morbidity. Pre-eclampsia can start from week 20 and happens up to 6 weeks after delivery 2. Furthermore, pre-eclampsia can have significant consequences after pregnancy.

Key figures on pre-eclampsia burden, as described above.3,15,16,17

Even if the cause of pre-eclampsia is still unknown, the disease is related to a placental dysfunction and associated with an imbalance of angiogenic factors such as Placental Growth Factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1).4 

sFlt-1 is a truncated form of the VEGF receptor Flt-1, circulating freely in the blood. sFlt-1 is produced in the placenta and secreted into the bloodstream, where it binds VEGF and PIGF with high affinity and therefore neutralizes their effects. PIGF belongs to the VEGF family, promoting proliferation and survival of endothelial cells and inducing vascular permeability.4

sFlt-1 acts as a potent antagonist of PIGF and VEGF by adhering to the receptor-binding domains, thus preventing interaction with endothelial receptors and inducing endothelial dysfunction.4

How can biomarkers help improve pre-eclampsia management throughout pregnancy?

Our Thermo Scientific B·R·A·H·M·S Biomarkers offer a wide range of options to cover screening strategies throughout pregnancy. With our solution, you have the flexibility to choose the most suitable biomarkers for your specific screening needs for the best clinical performance. 

 

From first to third trimester of pregnancy, PAPP-A, PlGF and sFlt-1 biomarkers can be used to improve management of early and late-onset pre-eclampsia.

Prevent early onset pre-eclampsia with first trimester pre-eclampsia screening and low dose aspirin

Early-onset pre-eclampsia occurring before week 34 and pre-term pre-eclampsia occurring before week 37 represent 25% of pre-eclampsia cases and contribute largely to fetal and maternal mortality and morbidity.3

 

By combining PlGF and PAPP-A with Maternal Arterial Pressure (MAP) and Uterine Artery Pulsatily Index (UtA-PI), you can assess the risk of developing early onset pre-eclampsia, between week 11+0 and 13+6.

The first trimester screening developed by the Fetal Medicine Foundation identifies 90% of the women at risk of developing early-onset pre-eclampsia and 77% of the women at risk of developing preterm pre-eclampsia.5

With the implementation of first trimester screening and administration of low dose aspirin, the ASPRE (Combined Multimarker Screening and Randomized Patient Treatment with Aspirin for Evidence-Based Pre-eclampsia Prevention) trial has shown an effective 82% reduction  of early-onset pre-eclampsia and 62% reduction of preterm pre-eclampsia.6

Prevent late onset pre-eclampsia with third trimester pre-eclampsia screening and timed birth

Late-onset pre-eclampsia occurring after week 37 is a significant burden with more than 75% of the pre-eclampsia cases and therefore contributes largely to maternal mortality and morbidity.3 

 

By combining PlGF and sFlt-1 with MAP, you can assess the risk of developing late-onset pre-eclampsia between week 35+0 and 36+6.

The third trimester screening developed by the Fetal Medicine Foundation identifies 79% of the women at risk of developing late-onset pre-eclampsia.7

Based on the individual risk, the pregnant woman could be proposed a timed delivery. Timed birth after week 39 could help reduce pre-eclampsia by 35%.3

Improve pre-eclampsia management after week 20 with sFlt-1/PlGF ratio

After week 20, 10% of women may develop clinical signs and symptoms of pre-eclampsia but only 20% will develop pre-eclampsia.8  

The clinical management of women at risk of developing pre-eclampsia remains a challenge for clinicians, as described below.9 

The sFlt-1/PlGF ratio can help the clinician in the early diagnosis, the short-term prediction of pre-eclampsia and the prognosis of maternal adverse outcomes.9

The universal cut-off 66

With the universal cut-off of 66, clinical use of the sFlt-1/PlGF on KRYPTOR for short-term prediction and diagnosis of pre-eclampsia is easy and safe.  

  • Single KRYPTOR-specific cut-off
  • Clinically validated
  • For all gestational ages
  • Easy implementation in clinical practice
  • Easy interpretation
  • Safe decisions

The sFlt-1/PlGF ratio at cut-off 66 on KRYPTOR has a clinical sensitivity of 82% and a clinical specificity of 91%, as described below.9

B·R·A·H·M·S PlGF plus KRYPTOR and B·R·A·H·M·S sFlt-1 KRYPTOR, the first FDA-cleared assays to stratify pregnant women with pre-eclampsia with severe features

Incidence of pre-eclampsia

The incidence of pre-eclampsia has nearly doubled in the US from 2007 to 2019 with an acceleration since 2014.10

Hypertensive disorders of pregnancy

Close to 16% of pregnant women in the US are suffering from hypertensive disorders of pregnancy,11 with half of them developing pre-eclampsia.12

Maternal deaths and premature births

Pre-eclampsia is the cause of 17% of maternal deaths13 and 15% of premature births in the US.

The FDA approved clinical indication:

*As defined by the American College of Obstetricians and Gynecologists (ACOG) guidelines.

**Preeclampsia, chronic hypertension with or without superimposed preeclampsia, or gestational hypertension.

The evidence from PRAECIS study:

The PRAECIS (Preeclampsia Risk Assessment: Evaluation of cut-offs to Improve Stratification) study is the largest prospective U.S. study to date and included 30% Black and 16% Hispanic women. The PRAECIS study clearly demonstrated that in women hospitalized with a hypertensive disorder of pregnancy presenting between 23 and 35 weeks of gestation, measurement of serum sFlt-1/PlGF provided stratification of the risk of progressing to severe pre-eclampsia (sPE) within the coming fortnight as well as a strong association with adverse outcomes.14

 

Key results

At a cut-off of 40, the clinical performance of the sFlt-1/PlGF ratio is:

  • 65% PPV (95% CI, 59 to 71)
  • 96% NPV (95% CI, 93 to 98)
  • 94% Sensitivity (95% CI, 89 to 96)
  • 75% Specificity (95% CI, 70 to 79)
  • The ratio performed better than standard clinical measures (area under the ROC, 0.92 versus 0.75)
  • Women with a ratio >=40 were at higher risk for adverse maternal outcomes (16.1% versus 2.8%; relative risk, 5.8; 95% CI, 2.8 to 12.2)
Predicting maternal and fetal adverse outcomes
40x Women who developed preeclampsia with severe features had sFlt-1/PIGF ratios approximately 40 times higher than those who did not.14
10x The sFlt-1/PIGF ratio was approximately 10 times higher for women who developed adverse maternal outcomes than for patients who did not.14
30x The sFlt-1/PIGF ratio was approximately 30 times higher in women with an adverse fetal and neonatal outcome compared with those without.14
40 Women with an sFlt-1/PIGF ratio ≥ 40 were more likely to deliver (spontaneously or induced) within 2 weeks compared with women with a ratio <40.14

The measurement of sFlt-1/PIGF can be used to determine if patients require stepped up care or if expectant management per ACOG guidelines should be followed.2 

Interpreting results (US)*

sFlt-1/PlGF < 40 (low risk) sFlt-1/PlGF ≥ 40 (high risk)
If the result of the ratio is lower than 40, the pregnant woman is at low risk for progression to pre-eclampsia with severe features within 2 weeks.  If the result of the ratio is higher or equal to 40, the pregnant woman is at high risk for progression to pre-eclampsia with severe features within 2 weeks.

*Interpretations may differ in regions outside of the US

 

References

1.     L. Ghulmiyyah and B. Sibai, “Maternal Mortality From Preeclampsia/Eclampsia” Semin. Perinatol., vol. 36, no. 1, pp. 56–59, 2012

2.     ACOG practice bulletin 222 (2020)

3.     L. Magee et al. NEJM, 2022

4.     R. Levine et al. 2004

5.     Akolekar R et al. Fetal Diagn Ther 2013; 33 (1): 8-15

6.     Rolnik D et al. N Eng J Med 2017; 377 (7): 613–22

7.     Döbert M et al. Utrasound Obstet Gynecol 2022; 59(1): 69-75

8.     Milne F et al. BMJ 2009; 339: b3129

9.     Andersen LLT et al. J Am Heart Assoc. 2021;10(17):e021376

10.   Cameron et al. (2022). J Am Heart Assoc 11 :e023791

11.   Ford et al. (2022).MMWR CDC 71(17)

12.   Joseph et al (2021). Obstet Gynecol 137 :763-71

13.   Wen et al. (2021). BJOG 00 :1-11

14.   Thadhani et al. (2022). NEJM 2022 :1(12)

15.   Preeclampsia Foundation - Saving Mothers and Babies From Preeclampsia. https://www.preeclampsia.org/

16.   Fingar et al (2017). Statistical Brief 222

17.   Preeclampsia. Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/17952-preeclampsia

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