Dr Fergus McCarthy takes a monthly look at articles just published in the area of hypertension & pre-eclampsia…

The much anticipated ASPRE study was published recently in the New England Journal of Medicine.¹

In this study which is led by Professor Kypros Nicolaides and the Fetal Medicine Foundation, women deemed to be at high risk for pre-eclampsia were randomised to placebo or 150mg aspirin at night. Screening risk was determined using the FMF algorithm which uses Bayes’ theorem to combine the a priori risk from maternal factors with biophysical and biochemical measurements obtained at 11 to 13 weeks of gestation. This algorithm was previously shown to detect 76% of cases of preterm pre-eclampsia and 38% of cases of term pre-eclampsia, at a screen-positive rate of 10%.²

In this double-blind, placebo-controlled trial, women with singleton pregnancies who were at high risk for preterm pre-eclampsia. were administered either aspirin at a dose of 150 mg per day or placebo from 11 to 14 weeks’ gestation until 36 weeks. The trial was conducted at 13 maternity hospitals in the United Kingdom, Spain, Italy, Belgium, Greece, and Israel.

A total of 26,941 women with singleton pregnancies underwent screening. 2971 (11.0%) of them were found to be at high risk for preterm pre-eclampsia. However, 332 of these women (11.2%) were excluded from recruitment to the trial because they did not fulfill the eligibility criteria. Of the 2641 eligible women, 1776 (67.2%) agreed to participate in the trial. After randomization, 152 women (8.6%) withdrew consent. Of the women who participated in the trial, 4 were lost to follow-up. Adherence was good in 1294 of 1620 participants (79.9%), moderate in 241 (14.9%), and poor in 85 (5.2%).

Preterm pre-eclampsia occurred in 13 of 798 participants (1.6%) in the aspirin group, as compared with 35 of 822 (4.3%) in the placebo group (adjusted odds ratio in the aspirin group, 0.38; 95% confidence interval, 0.20 to 0.74; P=0.004).

The size of the treatment effect was consistent across estimated risk groups at the time of screening, across groups defined according to obstetrical history, and across countries of the participating centres. This study provides significant support for the safe use of aspirin in women at high risk of preterm pre-eclampsia and at higher doses to that which many clinicians currently use (75-100mg daily). Questions remain including the relatively poor ability of algorithms to identify women at high risk of pre-eclampsia., the costs of screening, whether a higher dose of 150mg is more efficacious and considering the safety profile of aspirin, should we just consider administering it to all pregnant women?

The US Preventive Services Task Force (USPSTF) recently updated their 1996 statement regarding screening for pre-eclampsia.³ The authors conducted a systematic review and included twenty-one studies (13, 982 participants).⁴ No studies were found which directly compared the effectiveness of pre-eclampsia screening in a screened population compared with an unscreened population. One US trial (n = 2764) found no difference in benefits or harms with fewer prenatal visits but was underpowered for rare, serious outcomes. For harms, a before-after comparison cohort noninferiority study of urine protein screening for specific indications compared with routine screening (n = 1952) did not identify harms with fewer urine screening tests.

Four studies (n = 7123) reported external validation performance of 16 risk prediction models, 5 of which had good or better discrimination (c statistic >0.80) for prediction of pre-eclampsia, and positive predictive values of 4% in the largest, most applicable validation cohorts. Calibration was not reported despite being a key model performance measure. There were no studies of urine screening test performance conducted in asymptomatic primary care populations; 14 studies of protein urine test performance among women being evaluated for suspected pre-eclampsia (n = 1888) had wide-ranging test accuracy (sensitivity, 22%-100%; specificity, 36%-100%) and high statistical and clinical heterogeneity in tests used, eligibility criteria, and proteinuria prevalence (8.7%-93.8%).

The authors concluded that the evidence to estimate benefits and harms of pre-eclampsia screening and the test performance of different screening approaches over the course of pregnancy was limited. However, in their updated recommendation, the USPSTF recommended that given the evidence that treatment can reduce maternal and perinatal morbidity and mortality, and the well-established accuracy of blood pressure measurements, that screening for pre-eclampsia results in a substantial benefit for the mother and infant.

In addition, there was adequate evidence to bound the harms of screening for and treatment of pre-eclampsia as no greater than small. Therefore, the USPSTF concluded with moderate certainty that there is a substantial net benefit of screening for pre-eclampsia in pregnant women with blood pressure measurements throughout pregnancy.

As assessment of blood pressure is generally a standard part of the antenatal care programmes in most developed countries antenatal. This review and recommendation is welcome but perhaps limited and some may have hoped the USPSTF would have gone further and examined additional screening tools rather than blood pressure alone. While many are focusing on first trimester prediction or early detection using models such as that described in the ASPRE study, this review and recommendation follows what many health systems and practitioners already currently advise. Nonetheless, the recommendation is welcome.

Finally, this month, although the translation of research from animal models to humans is fraught with scepticism by some, nonetheless, animal models provide very useful steps in generating hypotheses and testing novel therapeutic targets.

Fushima et al examined the use of the vitamin B3 nicotinamide (Nam) which has been shown to inhibit vasoconstriction by endothelin and is generally considered safe in pregnancy.⁵ Nam also has been shown to alleviate oxidative stress and has been shown to be involved in the pathogenesis of pre-eclampsia. The authors used the reduced uterine perfusion pressure (RUPP) model in mice and administered Nam or water daily by gavage. Nam improved maternal hypertension, proteinuria, and glomerular endotheliosis in RUPP mice. Moreover, Nam prolonged pregnancies and improved survival and growth of the embryos in RUPP pre-eclamptic mice.

 

References

1. Rolnik DL, Wright D, Poon LC, et al. Aspirin versus Placebo in Pregnancies at High Risk for Preterm Preeclampsia. The New England journal of medicine. 2017.
2. Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing risks model in early screening for preeclampsia by biophysical and biochemical markers. Fetal diagnosis and therapy. 2013;33(1):8-15.
3. Force USPST, Bibbins-Domingo K, Grossman DC, et al. Screening for Preeclampsia: US Preventive Services Task Force Recommendation Statement. JAMA. 2017;317(16):1661-1667.
4. Henderson JT, Thompson JH, Burda BU, Cantor A. Preeclampsia Screening: Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2017;317(16):1668-1683.
5. Fushima T, Sekimoto A, Oe Y, et al. Nicotinamide ameliorates a preeclampsia-like condition in mice with reduced uterine perfusion pressure. Am J Physiol Renal Physiol. 2017;312(2):F366-F372.