Dr Fergus McCarthy takes a look at the news this month…

Placental growth factor (PlGF) first described in 1991 by Italian scientist Dr Maria Graziella Persico, has since been investigated for its use in the prediction (both long term and short term) of pre-eclampsia. The road to clinical implementation of new diagnostic or predictive tests is challenging but Duhig et al in conducting a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial, have provided definitive answers to the question as to whether PlGF integrated with a clinical management algorithm, decreased the time for clinicians to make a diagnosis in women with suspected pre-eclampsia, and whether this approach reduced subsequent maternal or perinatal adverse outcomes.

In this clinical trial recently published in the Lancet,1 the researchers enrolled and assessed 1035 women with suspected pre-eclampsia. Suspected pre-eclampsia was defined as new-onset or worsening of existing hypertension, dipstick proteinuria, epigastric or right upper-quadrant pain, headache with visual disturbances, fetal growth restriction, or abnormal maternal blood tests that were suggestive of disease (such as thrombocytopenia or hepatic or renal dysfunction). The maternity units, representing the clusters, were randomly allocated to blocks. Blocks represented an intervention initiation time, which occurred at equally spaced 6-week intervals throughout the trial.

At the start of the trial, all units had usual care (in which PlGF measurements were also taken but were concealed from clinicians and women). At the initiation time of each successive block, a site began to use the intervention (in which the circulating PlGF measurement was revealed and a clinical management algorithm was used). Enrolment of women continued for the duration of the blocks either to concealed PlGF testing, or after implementation, to revealed PlGF testing. The primary outcome was the time from presentation with suspected pre-eclampsia to documented pre-eclampsia in women enrolled in the trial who received a diagnosis of pre-eclampsia by their treating clinicians. 576 (56%) women were assigned to the intervention (revealed testing) group, and 447 (44%) women were assigned to receive usual care with additional concealed testing (concealed testing group). The median time to pre-eclampsia diagnosis was 4·1 days with concealed testing versus 1·9 days with revealed testing (time ratio 0·36, 95% CI 0·15-0·87; p=0·027). Maternal severe adverse outcomes were reported in 24 (5%) of 447 women in the concealed testing group versus 22 (4%) of 573 women in the revealed testing group (adjusted odds ratio 0·32, 95% CI 0·11-0·96; p=0·043), but there was no evidence of a difference in perinatal adverse outcomes (15% vs 14%, 1·45, 0·73-2·90) or gestation at delivery (36·6 weeks vs 36·8 weeks; mean difference -0·52, 95% CI -0·63 to 0·73).

The availability of PlGF test results substantially reduced the time to clinical confirmation of pre-eclampsia. Where PlGF was implemented, there was a lower incidence of maternal adverse outcomes, consistent with adoption of targeted, enhanced surveillance, as recommended in the clinical management algorithm for clinicians. Since publication, adoption of PlGF testing in women with suspected pre-eclampsia has been supported by the NHS. Whether costings may influence this decision and the cost effectiveness of widespread implementation of PlGF remains to be determined.

Serrano et al investigated the association of pre-eclampsia risk with maternal levels of folate, homocysteine and vitamin B12 in Colombia using a case-control study.2 Maternal serum concentrations of folate, homocysteine, and vitamin B12 have been associated with pre-eclampsia. Nevertheless, reported studies involve limited number of cases to reliably assess the nature of these associations. The authors conducted a case-control study in which cases of pre-eclampsia and healthy pregnant controls were recruited at the time of delivery from eight different Colombian cities between 2000 and 2012. 2978 cases and 4096 controls were studied. Maternal serum concentrations of folate, homocysteine, and vitamin B12 were determined in 1148 (43.6%) cases and 1300 (31.7%) controls. Also, self-reported folic acid supplementation was recorded for 2563 (84%) cases and 3155 (84%) controls. After adjusting for potential confounders in logistic regression models, the OR for pre-eclampsia was 0.80 (95% CI: 0.72, 0.90) for 1SD increase in log-folate, 1.16 (95%CI: 1.05, 1.27) for 1SD increase in log-homocysteine, and 1.10 (95%CI: 0.99, 1.22) for 1SD increase in log-vitamin B12. No interactions among the biomarkers were identified. Women who self-reported consumption of folic acid (1 mg/day) throughout their pregnancy had an adjusted OR for pre-eclampsia of 0.86 (95%CI: 0.67, 1.09) compared to women that reported no consumption of folic acid at any point during pregnancy. Overall, this study demonstrated that maternal serum concentrations of folate were associated with a protective effect for pre-eclampsia while concentrations of homocysteine were associated as a risk factor. No association between maternal vitamin B12 concentrations and pre-eclampsia was found.

In a follow up to the ASPRE (Aspirin for Evidence-Based Pre-eclampsia Prevention trial) study, Wright et al examined the effects of aspirin on length of stay in the neonatal intensive care unit.3 This was driven by the fact that despite the reduction in pre-eclampsia observed in the ASPRE study the incidence of admission to the neonatal intensive care unit, which was one of the secondary outcomes, was not significantly affected (odds ratio, 0.93; 95% confidence interval, 0.62-1.40).

Within the original study, there were 1620 participants and 1571 neonates who were liveborn. The total length of stay in neonatal intensive care was substantially longer in the placebo than aspirin group (1696 vs 531 days). This is a reflection of significantly shorter mean lengths of stay in babies admitted to the neonatal intensive care unit from the aspirin than the placebo group (11.1 vs 31.4 days), a reduction of 20.3 days (95% confidence interval, 7.0-38.6; P = 0.008).

Neonatal intensive care of babies born at <32 weeks' gestation contributed 1856 (83.3%) of the total of 2227 days in intensive care across both treatment arms. These occurred in 9 (1.2%) of the 777 livebirths in the aspirin group and in 23 (2.9%) of 794 in the placebo group (odds ratio, 0.42; 95% confidence interval, 0.19-0.93; P = 0.033). Overall, in the whole population, including 0 lengths of stay for those not admitted to the neonatal intensive care unit, the mean length of stay was longer in the placebo than aspirin group (2.06 vs 0.66 days; reduction of 1.4 days; 95% confidence interval, 0.45-2.81; P = 0.014). This corresponds to a reduction in length of stay of 68% (95% confidence interval, 20-86%). Overall, in pregnancies at high risk of pre-eclampsia administration of aspirin reduces the length of stay in the neonatal intensive care unit by about 70%. This reduction could essentially be attributed to a decrease in the rate of births at <32 weeks' gestation, mainly because of prevention of early pre-eclampsia. The body of evidence linking pre-eclampsia with long term with long term maternal morbidity continues to grow. Using a Nationwide register based cohort study in Denmark, Kristensen et al investigated associations between pre-eclampsia and later risk of kidney disease.4 Data from women with at least one pregnancy lasting at least 20 weeks between 1978 and 2015 was examined. The cohort consisted of 1,072,330 women followed for nearly 20 million person years (average 18.6 years/woman). Compared with women with no previous pre-eclampsia, those with a history of pre-eclampsia were more likely to develop chronic renal conditions: hazard ratio 3.93 (95% confidence interval 2.90 to 5.33, for early preterm pre-eclampsia (delivery <34 weeks); 2.81 (2.13 to 3.71) for late preterm pre-eclampsia (delivery 34-36 weeks); 2.27 (2.02 to 2.55) for term pre-eclampsia (delivery ≥37 weeks). In particular, strong associations were observed for chronic kidney disease, hypertensive kidney disease, and glomerular/proteinuric disease. Adjustment for cardiovascular disease and hypertension only partially attenuated the observed associations. Stratifying the analyses on time since pregnancy showed that associations between pre-eclampsia and chronic kidney disease and glomerular/proteinuric disease were much stronger within five years of the latest pregnancy (hazard ratio 6.11 (3.84 to 9.72) and 4.77 (3.88 to 5.86), respectively) than five years or longer after the latest pregnancy (2.06 (1.69 to 2.50) and 1.50 (1.19 to 1.88). By contrast, associations between pre-eclampsia and acute renal conditions were modest. In conclusion the authors demonstrated that pre-eclampsia, particularly early preterm pre-eclampsia, was strongly associated with several chronic renal disorders later in life.  

References

1. Duhig KE, Myers J, Seed PT, et al. Placental growth factor testing to assess women with suspected pre-eclampsia: a multicentre, pragmatic, stepped-wedge cluster-randomised controlled trial. Lancet. 2019;393(10183):1807-18.
2. Serrano NC, Quintero-Lesmes DC, Becerra-Bayona S, et al. Association of pre-eclampsia risk with maternal levels of folate, homocysteine and vitamin B12 in Colombia: A case-control study. PloS one. 2018;13(12):e0208137.
3. Wright D, Rolnik DL, Syngelaki A, et al. Aspirin for Evidence-Based Preeclampsia Prevention trial: effect of aspirin on length of stay in the neonatal intensive care unit. Am J Obstet Gynecol. 2018;218(6):612 e1- e6.
4. Kristensen JH, Basit S, Wohlfahrt J, Damholt MB, Boyd HA. Pre-eclampsia and risk of later kidney disease: nationwide cohort study. BMJ. 2019;365:l1516.