First‐trimester screening for pre‐eclampsia and fetal growth restriction: a test seeking both a treatment and an optimal timing

Almost a decade has passed since I wrote an Opinion for this Journal, entitled ‘Uterine artery Doppler: time to establish the ground rules’1. This was just before first-trimester uterine artery Doppler made its appearance on the scene, and was at a time when the arguments regarding uterine artery Doppler revolved chiefly around what was an appropriate definition of adverse outcome, what constituted a uterine artery ‘notch’ and whether 20 or 24 weeks was the optimum time to screen women. The concern that I expressed then was that the multiplicity of adverse outcomes reported in studies (pregnancy-induced hypertension, gestational hypertension, pre-eclampsia, small-for-gestational age (SGA), preterm delivery) were often defined in no reproducible way and were often reported as ‘compound’, making more precise analysis difficult. Fortunately, most investigators have now developed an informal consensus that uterine artery Doppler is particularly useful in screening for the early-onset severe outcomes of uteroplacental insufficiency, namely pre-eclampsia and SGA requiring delivery < 34 weeks, and less so for these conditions at term. For example, in a screening study of 1757 women at 23 weeks' gestation the sensitivity using increased uterine artery pulsatility index (PI) (> 95th percentile; screen-positive rate, 5.1%) for early onset pre-eclampsia was 80%, and for pre-eclampsia overall it was 35%2. Thus, in 10 years there has been a paradigm shift. There is now widespread use of a continuous variable to define uterine artery impedance—notably, PI—rather than the more subjective assessment of whether a notch is present. Outcomes in uterine artery Doppler studies are defined more clearly, with a focus on severe and/or preterm complications, and there is an emphasis on models that describe individualized, rather than ‘group’, risk prediction3. The natural next step was to investigate the use of uterine artery Doppler in the first trimester. Early first-trimester uterine artery Doppler screening studies showed disappointing screening performance for pre-eclampsia overall, but relatively good performance for pre 32-week pre-eclampsia: Martin et al.4 reported a 60% detection for a 5% screen-positive rate. The relatively poor predictive value at this gestational age should not come as a surprise as placental development is only part way through by 14 weeks and uterine artery Doppler impedance usually reduces rapidly week by week until it approaches its nadir at 24–26 weeks5. Uterine artery Doppler performed in the late first trimester as a marker of abnormal uteroplacental development cannot therefore be expected to provide a definitive result. Using a continuous variable—uterine artery PI—allowed the next important development: that of risk prediction models in combination with maternal blood tests, blood pressure and other non-invasive vascular indices. These now almost exclusively use either mean6 or lowest7 PI (of the two uterine arteries), the latter having marginally better screening performance for some early-onset complications. In this model, maternal history plus lowest uterine artery PI gave 80% sensitivity for early onset pre-eclampsia at a 10% screen-positive rate. In a further step in the development of a first-trimester screening model, it soon became clear that first-trimester markers of placentation prior to 13 weeks—most notably pregnancy-associated plasma protein-A (PAPP-A)8 and plasma protein 139—are associated individually with a risk of pre-eclampsia. Other markers, including ADAM12, activin, inhibin and placental growth factor (PlGF), have also been described with, in many cases, contradictory findings and associations10. When factors are found to be associated with the subsequent development of pre-eclampsia, though individually their predictive values might not be particularly impressive, it is sometimes the case that in combination with maternal history, blood pressure and uterine artery Doppler they may have an acceptable sensitivity for the detection of early onset pre-eclampsia and fetal growth restriction (FGR). Three studies of this type are reported in this issue of the Journal. Poon et al.11 found that a combination of maternal factors, serum markers and lowest uterine artery PI at 11–13 weeks gave a detection rate of just under 90% for a 5% screen-positive rate for early (< 34 weeks) pre-eclampsia. A variant on the same theme, Foidart et al.12 obtained a particularly high sensitivity for pre-eclampsia requiring delivery before 34 weeks of 97% for a screen-positive rate of 10% by using soluble endoglin in combination with PlGF, lowest uterine artery PI and maternal factors at 11–13 weeks. Khalil6 reports a novel approach to screening: contingency testing at 11 to 13 + 6 weeks, combining a non-invasive vascular measurement (the augmentation index) with plasma protein 13 level and measurement of the mean uterine artery PI. The best screening performance was provided by the combination of all three, with a sensitivity for pre 34-week pre-eclampsia of 93% and, notably, a sensitivity for pre-eclampsia overall of 86% with a screen-positive rate of 10%. A contingency screening model, reducing the number of tests required by almost one half, yielded a slightly lower sensitivity for pre-eclampsia. Nevertheless, and interestingly, the combination of tests in the first trimester still does not reach the sensitivity and false-positive rate of uterine artery Doppler alone performed in the late second trimester. Outside the relatively few ‘early adopter’ groups from whom most research in this area arises, there remains scepticism over the usefulness of first-trimester screening13. Thus, the issue of timing of the screening test remains as pertinent now as it was a decade ago. ‘Bundling together’ a multiplicity of blood- and ultrasound-based investigations at one visit in order to give one combined, instantaneous risk is appealing—not least in terms of the convenience it offers patients. The most obvious parallel is with the model for first-trimester combined nuchal and PAPP-A/free beta-human chorionic gonadotropin (β-hCG) screening for Down syndrome. However, in this context there is a trade-off between convenience and screening performance; for example, if for Down screening the PAPP-A blood test were performed at 9 weeks, the nuchal translucency scan at 12 weeks and the hCG blood test at 14 weeks, the combination would likely achieve a higher sensitivity for a lower false-positive result14. What would a screening test for pre-eclampsia and FGR look like if we were to take a purist approach to screening? In aiming to design the best screening model using currently available tests, one might combine, for example, first-trimester PAPP-A and plasma protein 13 with early second-trimester hCG, and uterine artery Doppler and PlGF at 22–24 weeks, the latter two recently having been reported in combination15. Whether by chance or celestial design, the serum predictors for pre-eclampsia, FGR and Down syndrome seem to perform best at the same gestational ages, raising the intriguing prospect of multi-part combined Down syndrome and pre-eclampsia/FGR screening, with a Down syndrome risk given at around 16 weeks and that for pre-eclampsia at 22–24 weeks. This strategy is likely to lead to the highest sensitivity with the lowest false-positive rate for early-onset conditions, and has been suggested as a potentially useful approach based on review of existing data16 and on a recent study in which first-trimester serum markers were combined with second-trimester uterine artery Doppler17. The counter arguments to this approach are: (1) that a screening test should be simple and convenient, and (2) that the information regarding risk should be obtained as early as possible in pregnancy. Taking the first point, multiple clinic visits a few weeks apart might lead to poor compliance and attendance at follow-up visits. This has not, however, been borne out by those studies reporting the integrated test or a variant form for Down syndrome screening which required three visits rather than one; high (> 98%) compliance with the screening protocols were observed, with particularly low screen-positive rates18, 19. The second point is more difficult to argue, irrespective of the gestational age at which screening is carried out. The adapted Wilson criteria20 for screening require that: there is an accepted treatment recognized for the disease; treatment is more effective if started early; there is a policy on who should be treated; and diagnosis and treatment are cost-effective. None of these criteria is true for pre-eclampsia (or, indeed, FGR). There is no prophylactic treatment for the clinical condition of pre-eclampsia; the most recent studies using vitamins C and E21 and aspirin22 respectively, show either no or only a modest benefit in their use for prophylaxis of pre-eclampsia. Nor is there clear evidence that antihypertensive drugs, if started early, improve pregnancy outcome in pre-eclampsia. Furthermore, uterine artery Doppler is not recommended by the UK National Institute for Clinical Excellence for low-risk women. It is perhaps surprising that, in this era of carefully controlled healthcare resources on both sides of the Atlantic, no studies have examined comprehensively the cost-effectiveness and clinical value of uterine artery Doppler. Resources could be allocated according to the level of risk, for example by streaming women into high-, intermediate- and low-risk care, with blood pressure checks, ultrasound scans and biochemical investigations targeted at those with most need. If we are serious about identifying those at risk of pre-eclampsia, then we must also be serious about developing the models that work best. Why, therefore, give a woman a possibly less precise risk assessment in the first trimester, when nothing can or will be done, if a more precise risk assessment might be performed later? After all, pre-eclampsia is extremely rare prior to 24 weeks and early knowledge might only heighten anxiety while allowing the woman no prospect of her knowledge modifying that outcome. It is only when the outcome of women with abnormal uterine artery Doppler is modified by prophylactic agents and/or intensive follow-up that Doppler screening models, including those published in this issue of the Journal, will have come of age. They do, however, represent a sound starting point for assigning individualized risk in order to test new prophylactic agents and to develop clinical management strategies. Furthermore, as the best candidates for serum markers, vascular tests and Doppler indices become known, the possibility of improving their predictive value by moving towards a model that combines tests performed at their optimum gestational age might represent the next major step forwards in risk prediction.