Month in Review: June

Women with preexisting or gestational diabetes mellitus have an increased risk for developing preeclampsia. Diabetes and pregnancy are both characterized by very high prorenin levels and renin-angiotensin system activation. Prorenin bound to the (pro)renin receptor has enzymatic activity. Sugulle et al¹ examined the role of the Soluble (pro)renin receptor in preeclampsia and diabetic pregnancies. They hypothesized that soluble (pro)renin receptor levels are elevated in high-risk pregnancies. To examine this hypothesis, third trimester maternal blood samples from complicated pregnancies (n = 165), (preeclampsia [n = 76], diabetes mellitus [type I diabetes, n = 35; type II diabetes, n = 11; gestational diabetes mellitus, n = 43]), and healthy pregnancies (n = 49) were analyzed for prorenin, renin, and soluble (pro)renin receptor.

There were no significant differences in prorenin or renin levels between the study groups in a multivariate model. In the group of women with gestational diabetes, soluble (pro)renin receptor concentrations were significantly higher compared with healthy pregnancies or preeclampsia. Soluble (pro)renin receptor did not correlate with renin or prorenin levels for any of the study groups. Overall, the results demonstrated that soluble (pro)renin receptor is dysregulated in pregnancies affected by diabetes mellitus, but not preeclampsia. Alterations in circulating soluble (pro)renin receptor are unrelated to renin/prorenin in pregnancy but may be of pathophysiological relevance in diabetic pregnancies in a renin-angiotensin system-independent manner.

The long-term implications of a pregnancy affected by preeclampsia are becoming increasingly clearer.  Preeclampsia carries increased risks of cardiovascular- and metabolic diseases in mothers and offspring during the life course. While the severe early-onset PE (EOPE) phenotype originates from impaired placentation in early pregnancy, late-onset PE (LOPE) is in particular associated with pre-existing maternal cardiovascular- and metabolic risk factors. Herzog et al² examined early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn. They hypothesized that preeclampsia is associated with altered epigenetic programming of placental and fetal tissues and that these epigenetic changes might elucidate the increased cardiovascular- and metabolic disease susceptibility in preeclampsia offspring. They conducted a nested case-control study within The Rotterdam Periconceptional Cohort comprising 13 EOPE, 16 LOPE, and three control groups of 36 uncomplicated pregnancies, 27 normotensive fetal growth restricted and 20 normotensive preterm birth (PTB) complicated pregnancies. Placental tissue, newborn umbilical cord white blood cells (UC-WBC) and umbilical vein endothelial cells were collected and DNA methylation of cytosine-guanine dinucleotides was measured by the Illumina HumanMethylation450K BeadChip. An epigenome-wide analysis was performed by using multiple linear regression models. Epigenome-wide tissue-specific analysis between EOPE and PTB controls revealed 5001 mostly hypermethylated differentially methylated positions (DMPs) in UC-WBC and 869 mostly hypomethylated DMPs in placental tissue, situated in or close to genes associated with cardiovascular-metabolic developmental pathways. This study demonstrated differential methylation in UC-WBC and placental tissue in EOPE as compared to PTB, identifying DMPs that are associated with cardiovascular system pathways. Future studies should examine these loci and pathways in more detail to elucidate the associations between prenatal PE exposure and the cardiovascular disease risk in offspring.

Increasingly we see papers suggesting predictive ability of biomarkers for the prediction of preeclampsia. However, many are isolated and not validated. Allen et al³ conducted an external validation of preexisting first-trimester preeclampsia prediction models. The authors conducted a systematic review of literature that assessed biomarkers, uterine artery Doppler and maternal characteristics in the first trimester for the prediction of preeclampsia was performed and models selected based on predefined criteria. Validation was performed by applying the regression coefficients that were published in the different derivation studies to our cohort. We assessed the models’ discrimination ability and calibration. Twenty models were identified for validation. The discrimination ability observed in derivation studies (Area Under the Curves) ranged from 0.70 to 0.96 when these models were validated against the validation cohort, these AUC varied importantly, ranging from 0.504 to 0.833. Comparing Area Under the Curves obtained in the derivation study to those in the validation cohort we found statistically significant differences in several studies.

The authors concluded that there currently isn’t a definitive prediction model with adequate ability to discriminate for preeclampsia, which performs as well when applied to a different population and can differentiate well between the highest and lowest risk groups within the tested population. The pre-existing large number of models limits the value of further model development and future research should be focussed on further attempts to validate existing models and assessing whether implementation of these improves patient care.

Vishnyakova et al⁴ conducted a study examining the mitochondrial role in adaptive response to stress conditions in preeclampsia. The study involved 38 patients: 14 with uncomplicated pregnancy; 13 with early-onset PE (eoPE); and 11 with late-onset PE (loPE). The immunophenotype of cells isolated from the placenta and all biopsy samples were stained positive for Cytokeratin 7, SOX2, Nestin, Vimentin, and CD44 and then characterized. The authors demonstrated a significant increase in OPA1 mRNA and protein expression in the eoPE placentas. Moreover, TFAM expression was down-regulated in comparison to the control (p < 0.01). Mitochondrial DNA copy number in eoPE placentas was significantly higher than in samples from normal pregnancies. An increase of maximum coupled state 3 respiration rate in mitochondria isolated from the placenta in the presence of complex I substrates in the eoPE group and an increase of P/O ratio, citrate synthase activity and decrease of Ca(2+)-induced depolarization rate in both PE groups was demonstrated. The results suggest an essential role of mitochondrial activity changes in an adaptive response to the development of preeclampsia.

References

1. Sugulle M, Heidecke H, Maschke U, et al. Soluble (pro)renin receptor in preeclampsia and diabetic pregnancies. J Am Soc Hypertens. 2017;11(10):644-652.
2. Herzog EM, Eggink AJ, Willemsen SP, et al. Early- and late-onset preeclampsia and the tissue-specific epigenome of the placenta and newborn. Placenta. 2017;58:122-132.
3. Allen RE, Zamora J, Arroyo-Manzano D, et al. External validation of preexisting first trimester preeclampsia prediction models. Eur J Obstet Gynecol Reprod Biol. 2017;217:119-125.
4. Vishnyakova PA, Volodina MA, Tarasova NV, et al. Mitochondrial role in adaptive response to stress conditions in preeclampsia. Sci Rep. 2016;6:32410.