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

Saleh et al report their investigations examining the association between low Soluble Fms-Like Tyrosine Kinase-1 (sFlt-1), Endoglin, and Endothelin-1 levels in women with confirmed or suspected pre-eclampsia and Proton Pump Inhibitors (PPIs).¹ 

PPIs decrease trophoblast sFlt-1 and endoglin secretion in vitro but are also commonly used during pregnancy to combat reflux disease. Using a prospective cohort of 430 women with confirmed or suspected pre-eclampsia, 40 of whom were taking PPIs the authors examined angiogenic concentrations. Of the 40 women using PPIs, 6 were taking esomeprazole, 32 omeprazole, and 2 pantoprazole for 8 to 45 (median 29) days before sFlt-1 measurement. Measurements were made once at study entry between weeks 20 and 41 (median 33 weeks).

PPI use was associated with lower sFlt-1 levels, with no change in placental growth factor levels, both when compared with all non-PPI users and with 80 gestational age-matched controls selected from the non-PPI users. No sFlt-1/placental growth factor alterations were observed in women using ferrous fumarate or macrogol. Women using antihypertensive medication displayed higher sFlt-1 levels and lower placental growth factor levels. The PPI use-associated decrease in sFlt-1 was independent of the application of antihypertensive drugs and also occurred when restricting our analysis to patients with hypertensive disease of pregnancy at study entry. PPI users displayed more cases with pre-existing proteinuria, less gestational hypertension, and a lower number of neonatal sepsis cases. Finally, the plasma endoglin and endothelin-1 levels were lower while sFlt-1 levels correlated positively with both.

These interesting results warrant further investigation including possibly prospective trials to investigate the therapeutic potential of PPIs in pre-eclampsia.

Increasingly, the divide between gestational hypertension and pre-eclampsia is blurring with gestational hypertension increasingly being associated with maternal and fetal morbidity.²

Shen et al performed a comparison of risk factors and outcomes of women with gestational hypertension or pre-eclampsia. A total of 7633 pregnant women recruited between 12 and 20 weeks’ gestation in the Ottawa and Kingston Birth Cohort from 2002 to 2009 were included in the analysis. Cox proportional hazards model was used to identify and compare the risk factors for gestational hypertension and pre-eclampsia by treating gestational age at delivery as the survival time. Subgroup analysis was performed for early and late onset pre-eclampsia.

Gestational hypertension and pre-eclampsia shared most risk factors including overweight and obesity, nulliparity, pre-eclampsia history, type 1 and 2 diabetes, and twin birth. Effect size of pre-eclampsia history (RR = 14.1 for gestational hypertension vs. RR = 6.4 for pre-eclampsia) and twin birth (RR = 4.8 for gestational hypertension vs. RR = 10.3 for pre-eclampsia) showed substantial difference. Subgroup analysis showed that early and late onset pre-eclampsia shared some risk factors with different effect sizes, whereas folic acid supplementation showed protective effect for early onset pre-eclampsia only. Pre-eclampsia was strongly associated with several adverse outcomes including Caesarean section, placental abruption, small for gestational age, preterm birth, and 5 min Apgar score < 7, whereas gestational hypertension was associated with increased risk of preterm birth only.

Villa et al performed a cluster analysis to estimate the risk of pre-eclampsia in the high-risk prediction and prevention of pre-eclampsia and intrauterine growth restriction (PREDO) study.³ This was with the aim of examining different subtypes which may rise from different pathophysiological backgrounds. Early onset disease is associated with placental dysfunction. Late-onset disease develops predominantly due to metabolic disturbances, obesity, diabetes, lipid dysfunction, and inflammation, which affect endothelial function.

903 pregnant women with risk factors for pre-eclampsia at gestational weeks 12+0-13+6 were recruited. Each individual outcome diagnosis was independently verified from medical records. The authors applied a Bayesian clustering algorithm to classify the study participants to clusters based on their particular risk factor combination. For each cluster, the risk ratio of each disease outcome was calculated, relative to the risk in the general population.

The risk of pre-eclampsia increased exponentially with respect to the number of risk factors. 25 clusters were identified. Pre-eclampsia in a previous pregnancy (n = 138) increased the risk of pre-eclampsia 8.1 fold (95% confidence interval (CI) 5.7-11.2) compared to a general population of pregnant women. Having a small for gestational age infant (n = 57) in a previous pregnancy increased the risk of early-onset pre-eclampsia 17.5 fold (95%CI 2.1-60.5). Cluster of those two risk factors together (n = 21) increased the risk of severe pre-eclampsia to 23.8-fold (95%CI 5.1-60.6), intermediate onset (delivery between 34+0-36+6 weeks of gestation) to 25.1-fold (95%CI 3.1-79.9) and preterm pre-eclampsia (delivery before 37+0 weeks of gestation) to 16.4-fold (95%CI 2.0-52.4).

Body mass index over 30 kg/m2 (n = 228) as a sole risk factor increased the risk of pre-eclampsia to 2.1-fold (95%CI 1.1-3.6). Together with pre-eclampsia in an earlier pregnancy the risk increased to 11.4 (95%CI 4.5-20.9). Chronic hypertension (n = 60) increased the risk of pre-eclampsia 5.3-fold (95%CI 2.4-9.8), of severe pre-eclampsia 22.2-fold (95%CI 9.9-41.0), and risk of early-onset pre-eclampsia 16.7-fold (95%CI 2.0-57.6). If a woman had chronic hypertension combined with obesity, gestational diabetes and earlier pre-eclampsia, the risk of term pre-eclampsia increased 4.8-fold (95%CI 0.1-21.7). Women with type 1 diabetes mellitus had a high risk of all subgroups of pre-eclampsia.

In conclusion this study demonstrates that the risk of pre-eclampsia increases exponentially with respect to the number of risk factors. It provides excellent very useful clinical information regarding the implications of having more than one risk factor and their additive effects.

References

1. Saleh L, Samantar R, Garrelds IM, van den Meiracker AH, Visser W, Danser AHJ. Low Soluble Fms-Like Tyrosine Kinase-1, Endoglin, and Endothelin-1 Levels in Women With Confirmed or Suspected Preeclampsia Using Proton Pump Inhibitors. Hypertension. Sep 2017;70(3):594-600.
2. Shen M, Smith GN, Rodger M, White RR, Walker MC, Wen SW. Comparison of risk factors and outcomes of gestational hypertension and pre-eclampsia. PloS one. 2017;12(4):e0175914.
3. Villa PM, Marttinen P, Gillberg J, et al. Cluster analysis to estimate the risk of preeclampsia in the high-risk Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) study. PloS one. 2017;12(3):e0174399.