Screening for preterm preeclampsia

Preeclampsia: is characterised by the development of hypertension during the second half of pregnancy in association with deranged renal, hepatic, haematological or neurological function.^1,2 Some jurisdictions include evidence of placental insufficiency (fetal growth restriction) as a defining characteristic.¹ Preeclampsia may be de-novo or occur in women with a history of chronic preeclampsia (who may have presented with elevated blood pressure earlier in pregnancy). 

Early onset preeclampsia: is a term often used to differentiate women who develop preeclampsia at an early gestation and who are delivered for this primary indication at <34 weeks’ gestation. 

Preterm preeclampsia: is a term often used to differentiate women who develop preeclampsia at an early gestation and who are delivered for this primary indication at <37 weeks’ gestation.

Screening: population-based assessment with the intention of identifying unrecognised disease in a cohort who do not have obvious symptoms or signs of disease.³ 

A number of screening processes for preeclampsia have been proposed. This article is focused on first trimester (11-13+6 week) assessment of risk of preeclampsia using a test that collates features of maternal history with three investigational tools: measurement of maternal blood pressure, ultrasound assessment of uterine artery Doppler and biochemical assessment of placental function (PaPP-A and / or PlGF).    

Preeclampsia: O14.9
 

The prevalence of preeclampsia varies internationally but this condition is generally reported to affect between 3% and 8% of pregnancies.^4,5 
The prevalence of early onset preeclampsia (delivery <34 weeks’ gestation) is approximately 0.3-0.4% (1 in 250 to 1 in 330 pregnancies).
The prevalence of preterm preeclampsia (delivery <37 weeks’ gestation) is approximately 0.7-1.2%. Approximately 20% of pregnancies that develop preeclampsia are delivered preterm in most populations.
The prevalence of preeclampsia is decreasing in many jurisdictions.⁶

Preeclampsia is associated with significant maternal and fetal mortality and morbidity (Figure 1). The WHO estimates that preeclampsia leads to 60,000 maternal and 500,000 fetal / infant deaths each year.¹ Prematurity can have a significant effect on surviving fetuses, and mothers have higher risks of cardiovascular disease in later life.^7,8

Preeclampsia is a disease specific to pregnancy, secondary to placental dysfunction.⁹ Delivery of the placenta, and therefore of the fetus, leads to resolution of the maternal symptoms and signs of this disease. 

Abnormal placental implantation and the development of placental insufficiency appears to be a central part of the pathogenesis of early onset (delivery <34 weeks) disease.¹⁰ Maternal cardiovascular / endothelial dysfunction appears to be more significant for the development of late-onset disease.¹¹ 

Early recognition of these aetiological factors potentially enables prophylactic intervention, resulting in a reduction in prevalence of disease.

The characteristic symptoms and signs of this disease (hypertension and end organ damage) represent the end stage of a disease caused by poor placental implantation and maternal endothelial dysfunction. 

First trimester (11-13+6 weeks) screening is well established for assessment of common forms of fetal chromosomal abnormality. The process of risk assessment; identifying a background ‘a-priori’ risk that is then adjusted to account for investigational findings, was originally developed for aneuploidy screening.¹²

Many national guidelines identify maternal characteristics associated with preeclampsia and recommend that high risk women can be identified on the basis of having one major or two minor risk factors.^13-15 This binary process of risk assessment has very poor specificity committing large portions of the population to increased surveillance and intervention. 

An alternative strategy involves collation of these data for digital analysis, which allows risk to be apportioned more specifically and enables risk reduction. The level of risk may change for a continuous variable, and risks may be reduced, for example in a woman who previously had a pregnancy not affected by preeclampsia. This improves the specificity of screening based on maternal history whilst maintaining sensitivity.

The most common and readily available calculator used to assess risk of preterm preeclampsia is published by the Fetal Medicine Foundation.¹⁶ This calculator includes maternal age, height, weight and ethnicity; maternal medical history including chronic hypertension, diabetes, lupus, antiphospholipid syndrome and a history of smoking; obstetric history including parity and previous preeclamptic outcome(s); mode of conception and plurality. Using maternal characteristics alone, the Fetal Medicine Foundation risk calculator identifies 45% of women as ‘high risk’ for preterm preeclampsia for a 10% screen positive rate.¹⁷  

Maternal blood pressure is recognised as a reliable screening tool for prediction of preeclampsia.¹⁸ Maternal blood pressure changes during the course of pregnancy, reaching a nadir in the second trimester of pregnancy before rising toward term (Figure 2A).¹⁹ Maternal blood pressure is also affected by maternal ethnicity, mode of conception, chronic hypertension and diabetes and smoking history (Figure 2B).¹⁹ In order to use blood pressure in a risk assessment algorithm it is important to ensure that measurements are made with a validated machine following a standardised protocol which includes sitting the patient with their feet on the floor and measuring with the upper arm at the level of the heart.^15,20  

Right and left uterine arteries provide vascular supply from the lateral aspects of the uterus. The association between vascular impedance, identified through an increased pulsatility index, and placental insufficiency resulting in preeclampsia and/or fetal growth restriction is well recognised. This screening tool was initially applied at 18-22 weeks’ gestation,^21,22 but is equally effective at 11-13+6 weeks,^23,24 and has recently also been shown to have some predictive value in the later part of the third trimester.²⁵

The uterine artery Doppler is assessed using a standardised technique.¹⁵ This differs at 11-13+6 weeks compared to later gestations. At this early stage of pregnancy, the uterine artery is identified with colour Doppler by first locating the cervix, then rocking the probe laterally to identify the ascending branch of the uterine artery at the level of the internal cervical os. The pulse wave gate is used to sample a series (at least three) of waveforms (for consistency) and the peak systolic velocity and pulsatility index are measured. The peak systolic velocity should be at least 60cm/s for accurate sampling (Figure 3). Both right and left uterine arteries are assessed then the mean PI is calculated. 

The observed mean uterine artery pulsatility index value is compared to a predefined normal range accounting for ethnicity, parity and gestational age. The observed result is then described as a multiple of the median (MoM) value - which is used to generate a likelihood ratio for risk calculation.²³

A raised mean uterine artery pulsatility index MoM is associated with an increased risk of preterm preeeclampsia^.23 Conversely, a low MoM value reduces risk of preterm preeclampsia. 

Both pregnancy associated placental protein A (PaPP-A) and placental growth factor (PlGF) are increased in pregnancies that later develop preterm preeclampsia (Figure 4).^26,27 Once again, raw observed data is compared the expected normal range and converted to a MoM value for production of likelihood ratios. Analysis of screening efficacy shows little value in using both biochemical markers.¹⁷ In some studies, PlGF performs better than PaPP-A, although other studies (which may have been underpowered) have not shown this._^28,29 PaPP-A is often readily available as it is used for first trimester aneuploidy screening. PlGF may be used for aneuploidy screening instead of PaPP-A – but there is limited data on screening efficacy to this endpoint.³⁰   
 

The most effective means of screening relies on combining these investigational tools for risk assessment. Screening based on maternal demographic characteristics, maternal mean arterial pressure, ultrasound assessment of uterine artery Doppler and measurement of maternal serum PlGF can identify almost 100% of pregnancies that will develop preeclampsia <32 weeks, 75% of those that develop preterm preeclampsia (<37 weeks) and 45% of those that develop preeclampsia at term.^17,29 

Accurate risk assessment requires careful governance with ongoing audit of all investigational tools and review of pregnancy outcomes in relation to high and risk categorisation at the time of screening. A number of web-based audit tools are available to assist centres with this process.³¹ 
 

Women deemed high risk for preterm preeclampsia should be offered aspirin (150mg PO nocte) as prophylaxis against the development of this disease.³² Aspirin has been shown to reduce the prevalence of preterm preeclampsia (>37 weeks) by 60%.33 It is most effective at reducing the rate of early (<32 or <34 weeks) preeclampsia – where it is 80-90% effective.^33-35 Screening linked to prophylactic treatment has been shown to be associated with a 65% reduction in the number of days of neonatal stay.³⁶ 

Women who have a high risk for preeclampsia are also at increased risk of other adverse pregnancy outcomes. Screening and treatment of the high-risk cohort also appears to reduce prevalence of other adverse outcomes including prevalence of preterm birth, low birthweight and low Apgar scores.³⁷ 

It is unclear whether women deemed high risk for preterm preeclampsia need additional levels of surveillance through pregnancy. Some centres manage high-risk women in an antenatal clinic responsible for hypertensive women. Others recommend that high risk women have additional scans to check growth velocity at 28 and 34 weeks’ gestation. 

Best screening results involve a relatively complex test that is more expensive than the proposed prophylactic treatment (aspirin). Some have advocated prescription of aspirin to all women, but some studies that have trialled this showed no improvement in outcome and compliance with treatment was poor.^38-40 There are a number of published cost economic analyses that demonstrate the value of investing in this screening program.^41,42 The first trimester screening test is cost saving when compared to usual care (screening by maternal history) due to a significant reduction in length of stay for neonatal care. 

The first trimester screening test is based on assessment of markers of poor placentation. The test is very effective at predicting preterm preeclampsia but is not an effective tool for prediction of term preeclampsia.^17,43 

Women who have chronic hypertension appear to be less likely to benefit from prophylaxis with early aspirin.⁴⁴ It is important to ensure adequate blood pressure control of these women as well.^45,46 Women who have low dietary intake of dairy products (a source of calcium) should also be offered calcium supplements for prophylaxis against preeclampsia.⁴⁷

Prophylaxis against preeclampsia is more effective if women take at least 90% of their tablets.⁴⁸
 

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