Early-Onset
Pre-eclampsia

Pre-eclampsia (PE)

PE, a multi-system disorder associated with hypertension, can occur in any pregnancy. The incidence is increasing with the global rise in maternal age, obesity, and the use of assisted reproductive techniques, along with all known co-morbidities that predispose sufferers to PE during pregnancy (see Table 1). Thus, preventing PE would bring substantial improvements to maternal and perinatal health.^5-8

Pre-eclampsia is a spectrum disorder^2,3,4 that can be sub-classified into:

• Early-Onset PE (with delivery at <34⁺⁰ weeks ofgestation)
• Pre-Term PE (with delivery at <37⁺⁰ weeks of gestation)
• Late-Onset PE (with delivery at ≥34⁺⁰ weeks of gestation)
• Term PE (with delivery at ≥37⁺⁰ weeks of gestation)

These sub-classifications are not mutually exclusive.

Pre-eclampsia is more common than aneuploidies^5,6,7,8

PE affects 2-8% of pregnancies globally.⁷ The prevalence of PE and related conditions (fetal growth restriction and pre-term birth) is much higher than that of Down syndrome. Unlike Down syndrome, PE (especially EO-PE) is associated with a much higher risk of short- and long-term maternal and perinatal morbidity and mortality.^2,3,4

PE definition update

In 2021, the International Society for the Study of Hypertension in Pregnancy (ISSHP) broadened the definition of PE to provide further clarity by including additional examples of maternal organ dysfunction^1,27 (see Table 1). This was adopted by the Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG),^25,28 and international guidelines, NICE and ACOG, as PE is considered a major cause of maternal death and morbidity. In the absence of proteinuria, the finding of maternal organ dysfunction is sufficient to make the diagnosis of PE.¹

Table 1. International Society for the Study of Hypertension in Pregnancy (ISSHP) Revised Definition of PE, 2021

Quoted from L.A. Magee et al., 2022.

Placental growth factor (PlGF)

PlGF, a glycoprotein expressed in the villous syncytiotrophoblast that belongs to the vascular endothelial growth factor (VEGF) subfamily, is a potent angiogenic factor. PIGF, together with VEGF, regulates the development of the placental vasculature.^13,14,15

Biochemical markers are reduced in preeclampsia^9,10

Biochemical markers that reflect placental function, such as PlGF and pregnancy-associated plasma protein-A (PAPP-A), are significantly reduced in the first trimester and throughout pregnancy in patients who will later present with pre-term PE, with delivery before 37 weeks’ gestation, contributing to many adverse obstetric outcomes.^13,14,15 Of these two markers, PlGF is a better PE screening marker (PPV 56%) than PAPP-A (PPV 16%)—i.e. it has higher sensitivity.^9,10

PlGF 1-2-3™ for early-onset pre-eclampsia (EO-PE) screening^{13,14,15,22,23}

A systematic review and meta-analysis demonstrated that PlGF is superior to the other biomarkers for predicting PE.²⁴ The serum PlGF biomarker can identify up to 75% of women who develop pre-term PE with delivery at <37 weeks’ gestation, and 90% of those with early PE at <32 weeks, at a screen-positive rate of 10%. Women with suspected pre-eclampsia who have low circulating maternal PlGF concentrations (<5th centile or ≤ 100 pg/ml) have a high sensitivity (96%) and negative predictive value (98%) in diagnosing pre-eclampsia that requires delivery within 14 days.^13,14,15

The COMPARE¹⁶ Study

COMPARE states that the high negative predictive values (NPV) support the role of PlGF-based tests as ‘rule-out’ tests for PE. Among the tests compared, the DELFIA Xpress® PlGF 1-2-3™ assay has the highest NPV.

ASPRE Study¹⁷

Using the PlGF 1-2-3™ assay (PerkinElmer) in PE screening, ASPRE was the largest prospective, randomised, placebo controlled trial showing that the use of aspirin was associated with a significant 62% reduction in the incidence of pre-term PE (<37 weeks’ GA) and an 82% reduction in EO-PE (<34 weeks’ GA). Studies^15,18,19,20 have shown that the administration of aspirin in pregnancies at high risk of PE reduces the length of stay in the neonatal intensive care unit (NICU) by about 70%, mainly through the prevention of EO-PE.

Guidelines recommend early screening for pre-eclampsia^9,10,11,12

The NHMRC recommends an assessment of all women for clinical risk factors for PE early in pregnancy.²⁶

In July 2021, the International Federation of Gynecology and Obstetrics (FIGO) updated the 2019 guidelines to raise global public awareness on managing and monitoring PE by adopting and supporting the Fetal Medicine Foundation (FMF) position that all pregnant women should be offered screening for pre-term PE, performed at 11-13⁺⁶ weeks’ gestation. Screening should involve a combination of maternal demographic characteristics and medical history, as well as biophysical markers, including mean arterial blood pressure (MAP), the mean uterine artery pulsatility index (UTPI) and measurements of the PlGF biochemical marker as a one-step procedure.^{4,9,10,11,12,29}

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