Inflammatory markers are elevated in early pregnancy, but not late pregnancy, in women with overweight and obesity that later develop preeclampsia.

PROBLEM: Obesity and preeclampsia both involve a pathological inflammatory response, which may be how obesity increases preeclampsia risk. Previous studies have failed to assess robust measurements of inflammatory markers across gestation, specifically in overweight/ obese women in the context of preeclampsia. METHOD OF STUDY: We measured 20 inflammatory markers in plasma via multiplex assay (ThermoFisher Inflammation 20 plex Human ProcartaPlex Panel) across the three trimesters of pregnancy in an existing cohort of overweight and obese women who developed preeclampsia (n = 37) and without preeclampsia (n = 74). Mann-Whitney U tests examined differences in inflammatory marker concentrations between cases and controls. Repeated measures ANOVA tests were used to explore differences in inflammatory marker concentrations over time within cases and controls. RESULTS: Pro-inflammatory markers (IL-1α, IL-1ß, IL-6, IFN-α, IFN-γ, GM-CSF, IL-12p70, IL-17α, TNF-α, IL-8) and anti-inflammatory markers (IL-4, IL-10, IL-13) were higher in the first and second trimester in participants who later developed preeclampsia compared to those who did not (p < .05). Only TNF-α and IL-8 remained elevated in the third trimester. Inflammatory markers did not change across pregnancy in preeclampsia cases but did increase across pregnancy in controls. CONCLUSION: Our findings diverge from prior studies, predominantly of non-obese women, that report lower circulating concentrations of anti-inflammatory cytokines in preeclampsia versus normotensive pregnancy, particularly by late pregnancy. We posit that women with overweight and obesity who develop preeclampsia entered pregnancy with a heightened pro-inflammatory state likely related to obesity, which increased risk for preeclampsia. Further studies are needed to investigate if inflammatory maker profiles differ between obese and non-obese women.

A longitudinal epigenome-wide association study of preeclamptic and normotensive pregnancy.

Background: While preeclampsia (PE) is a leading cause of pregnancy-related morbidity/mortality, its underlying mechanisms are not fully understood. DNA methylation (DNAm) is a dynamic regulator of gene expression that may offer insight into PE pathophysiology and/or serve as a biomarker (e.g., risk, subtype, a therapeutic response). This study's purpose was to evaluate for differences in blood-based DNAm across all trimesters between individuals eventually diagnosed with PE (cases) and individuals who remained normotensive throughout pregnancy, did not develop proteinuria, and birthed a normally grown infant (controls). Results: In the discovery phase, longitudinal, genome-wide DNAm data were generated across three trimesters of pregnancy in 56 participants (n=28 cases, n=28 controls) individually matched on self-identified race, pre-pregnancy body mass index, smoking, and gestational age at sample collection. An epigenome-wide association study (EWAS) was conducted, using surrogate variable analysis to account for unwanted sources of variation. No CpGs met the genome-wide significance p value threshold of 9×10-8, but 16 CpGs (trimester 1: 5; trimester 2: 1; trimester 3: 10) met the suggestive significance threshold of 1×10-5. DNAm data were also evaluated for differentially methylated regions (DMRs) by PE status. Three DMRs in each trimester were significant after Bonferonni-adjustment. Since only third-trimester samples were available from an independent replication sample (n=64 cases, n=50 controls), the top suggestive hits from trimester 3 (cg16155413 and cg21882990 associated with TRAF3IP2-AS1/TRAF3IP2 genes, which also made up the top DMR) were carried forward for replication. During replication, DNAm data were also generated for validation purposes from discovery phase third trimester samples. While significant associations between DNAm and PE status were observed at both sites in the validation sample, no associations between DNAm and PE status were observed in the independent replication sample. Conclusions: The discovery phase findings for cg16155413/cg21882990 (TRAF3IP2-AS1/TRAF3IP2) were validated with a new platform but were not replicated in an independent sample. Given the differences in participant characteristics between the discovery and replication samples, we cannot rule out important signals for these CpGs. Additional research is warranted for cg16155413/cg21882990, as well as top hits in trimesters 1-2 and significant DMRs that were not examined in the replication phase.

Breastfeeding and Later-Life Cardiometabolic Health in Women With and Without Hypertensive Disorders of Pregnancy.

Background Breastfeeding is associated with improved cardiometabolic profiles decades after pregnancy. Whether this association exists for women who experience hypertensive disorders of pregnancy (HDP) is unknown. The authors examined whether breastfeeding duration or exclusivity are associated with long-term cardiometabolic health, and whether this relationship differs by HDP status. Methods and Results Participants (N=3598) were from the UK ALSPAC (Avon Longitudinal Study of Parents and Children) cohort. HDP status was assessed by medical record review. Breastfeeding behaviors were assessed by contemporaneous questionnaires. Breastfeeding duration was categorized as never, <1, 1 to <3, 3 to <6, 6 to <9, and 9+ months. Breastfeeding exclusivity was categorized as never, <1, 1 to <3, and 3 to 6 months. Measures of cardiometabolic health (body mass index, waist circumference, C-reactive protein, insulin, proinsulin, glucose, lipids, blood pressure, mean arterial pressure, carotid intima-media thickness, and arterial distensibility) were measured 18 years after pregnancy. Analyses were conducted using linear regression adjusting for relevant covariates. Breastfeeding was associated with improved cardiometabolic health (lower body mass index, waist circumference, C-reactive protein, triglycerides, insulin, and proinsulin) in all women, but not for every breastfeeding duration. Interaction tests revealed additional benefits in women with a history of HDP, with the strongest benefit observed in the 6- to 9-month breastfeeding category (diastolic blood pressure, -4.87 mm Hg [95% CI, -7.86 to -1.88], mean arterial pressure -4.61 [95% CI, -7.45 to -1.77], and low-density lipoprotein cholesterol, -0.40 mmol/L [95% CI, -0.62 to -0.17 mmol/L]). Differences in C-reactive protein and low-density lipoprotein "survived" Bonferroni correction (P<0.001). Similar results were observed in the exclusive breastfeeding analyses. Conclusions Breastfeeding may be a mechanism to reduce the cardiovascular disease sequela associated with HDP; however, there is a need to establish whether associations reflect a causal effect.

An exploratory study of white blood cell proportions across preeclamptic and normotensive pregnancy by self-identified race in individuals with overweight or obesity.

Objective: Examine white blood cell (WBC) proportions across preeclamptic (n = 28 cases) and normotensive (n = 28 controls) pregnancy in individuals with overweight/obesity.Methods: WBC proportions were inferred from genome-wide DNA methylation data and compared by case/control status and self-identified race.Results: In Trimester 1, ean B cell proportions were suggestively lower in cases in the overall sample and significantly lower in White participants but not in Black participants. More significant WBC proportion changes were observed across normotensive than preeclamptic pregnancy.Conclusions: These findings in a small sample demonstrate need for additional studies investigating the relationship between self-identified race and WBCs in pregnancy.

An Exploratory Study of Epigenetic Age in Preeclamptic and Normotensive Pregnancy Reveals Differences by Self-Reported Race but Not Pregnancy Outcome.

Preeclampsia is a leading cause of maternal and neonatal morbidity and mortality. Chronological age and race are associated with preeclampsia, but the role of these factors is not entirely understood. We hypothesized that DNA methylation age, a measure of biological age, would be higher in individuals with preeclampsia than in individuals with normotensive pregnancy and that DNA methylation age would differ by race across pregnancy. This was a longitudinal, exploratory study of 56 pregnant individuals (n = 28 preeclampsia cases and n = 28 normotensive controls). Genome-wide DNA methylation data were generated from trimester-specific peripheral blood samples. DNA methylation age was estimated using the "Improved Precision" clock, and ∆age, the difference between DNA methylation age and chronological age, was computed. DNA methylation age was compared with chronological age using Pearson correlations. The relationships between ∆age and preeclampsia status, self-reported race, and covariates were tested using multiple linear regression and performed both with and without consideration of cell-type heterogeneity. We observed strong correlation between chronological age and DNA methylation age across pregnancy, with significantly stronger correlation observed in White participants than in Black participants. We observed no association between ∆age and preeclampsia status. However, ∆age was higher in participants with higher pre-pregnancy body mass index in trimester 1 and lower in Black participants than in White participants in trimesters 2 and 3. Observations were largely consistent when controlling for cell-type heterogeneity. Our findings in a small sample support the need for additional studies to investigate the relationship between race and biological age, which could provide further insight into racial disparities across pregnancy. However, this study does not support an association between ∆age and preeclampsia status.

DNA Methylation of Endoglin Pathway Genes in Pregnant Women With and Without Preeclampsia.

OBJECTIVE: We compared blood-based DNA methylation levels of endoglin (ENG) and transforming growth factor beta receptor 2 (TGFßR2) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies. METHODS: We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of ENG (CpG Island 114642) and TGFßR2 (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [(ENG subset: n = 20 (9 cases, 11 controls); TGFßR2 subset: n = 28 (15 cases, 13 controls)]. RESULTS: The majority of the preeclampsia cases delivered at ⩾34 weeks' gestation (83%). Average methylation levels for ENG ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; P = .102) and TGFßR2 (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; P = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the ENG analytic subset revealed a trend between levels of ENG methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; P = .062). CONCLUSION: Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that ENG and TGFßR2 DNA methylation plays in preeclampsia pathophysiology.

Plasma concentrations of soluble endoglin in the maternal circulation are associated with maternal vascular malperfusion lesions in the placenta of women with preeclampsia.

We evaluated the association between plasma soluble endoglin (sENG) and maternal vascular malperfusion (MVM) lesions of the placenta in women with preeclampsia. We measured sENG (sCD105) by ELISA in N = 70 women diagnosed with preeclampsia (median [IQR] GA at sampling = 36.4 [6.0] weeks) and available placental pathology. Placental pathology reports were reviewed for evidence of MVM based on the presence of ≥1 of the following: villous infarct, decidual vasculopathy, accelerated villous maturation, intervillous fibrin deposition, and/or low placental weight (<10th percentile for GA). We categorized plasma sENG concentrations into tertiles and used a modified Poisson regression approach to estimate the prevalence of MVM associated with sENG. We separately estimated the association between sENG and accelerated villous maturation, villous infarct, and low placental weight, the three most frequent lesions in the sample. We adjusted all models for age, parity, pre-pregnancy obesity, smoking, and infant sex. The prevalence of MVM in our sample of women with preeclampsia was 74%. Women in the highest sENG tertile had a higher prevalence of MVM (aPR[adjusted prevalence ratio] 1.70, 95% CI 1.15-2.52), low placental weight (aPR 3.26, 95% CI 1.25-8.50), and villous infarcts (aPR 2.93, 95% CI 1.27-6.73) compared with women in the lowest sENG tertile, after adjusting for covariates. Medium (aPR 2.57, 95% CI 1.17-5.66) and high (aPR 3.14, 95% CI 1.47-6.70) tertile concentrations of sENG were associated with higher accelerated villous maturation. Our results suggest that sENG may mark a more severe placental phenotype of preeclampsia, although findings should be replicated in larger cohorts.

Endoglin pathway genetic variation in preeclampsia: A validation study in Norwegian and Latina cohorts.

OBJECTIVE: The purpose of this study was to validate our previous genetic association findings related to the endoglin (ENG) pathway from an American Caucasian preeclampsia cohort in independent preeclampsia cohorts. We also sought to explore the ENG pathway for new genetic associations in these independent cohorts. STUDY DESIGN: We used a tagging single nucleotide (tSNP) approach to assess genetic variability across five ENG pathway genes (ENG, TGFß1, TGFßR1, ALK1, and TGFßR2) in a Caucasian cohort from Norway (n = 77 preeclampsia cases & n = 63 normotensive controls) and a White Hispanic cohort from Southern California (n = 69 preeclampsia cases & n = 106 normotensive controls). MAIN OUTCOME MEASURES: Univariate analyses (Chi Square, Fisher's Exact) and multivariate logistic regression were conducted to evaluate the association between tSNP genotype distributions and pregnancy outcome in each cohort. Logistic regression models were adjusted for maternal age at delivery, infant sex, parity, smoking during pregnancy, and pre-pregnancy BMI. RESULTS: Although we were unable to replicate our previous SNP-specific findings (ENG rs11792480, rs10121110; TGFßR2 rs6550005; p's > 0.05), we found that genetic variation in TGFßR1[ALK5] (rs6478974) and TGFßR2 (rs11129420, rs6802220, rs1155708, rs3773640, rs3773663) was significantly associated with preeclampsia in the Norwegian cohort and genetic variation in ALK1 (rs706819) and TGFßR2 (rs9843942) was significantly associated with preeclampsia in the Latina cohort. CONCLUSION: Overall, our results provide further support for the involvement and investigation of the endoglin pathway in preeclampsia.

CE: Preeclampsia: Current Approaches to Nursing Management.

: Preeclampsia, one of four hypertensive disorders of pregnancy, has traditionally been characterized as new-onset hypertension and proteinuria developing after 20 weeks' gestation. It is, however, now understood to be a complex, progressive, multisystem disorder with a highly variable presentation and a number of potentially life-threatening complications. The American College of Obstetricians and Gynecologists Task Force on Hypertension in Pregnancy has refined preeclampsia diagnostic criteria accordingly, and as the disorder's pathogenesis has been more clearly defined, new targets for screening, diagnosis, prevention, and treatment have emerged. This clinical update provides a review of current practice related to preeclampsia risk assessment, prediction, and management. It discusses preeclampsia pathophysiology and points readers to valuable health care resources on the topic.

Primer in Genetics and Genomics, Article 1: DNA, Genes, and Chromosomes.

Precision medicine refers to the practice of determining a patient's unique genetic, biomarker, and other characteristics for the purpose of improving his or her clinical outcomes. Not all patients with the same clinical diagnosis respond equally to identical treatment regimens. By examining patients at the molecular level, health-care providers will be better able to apply the most effective therapies that each individual requires. To understand precision medicine, nurses must have a solid understanding of genomics and proteomics. The purpose of this article is to (1) provide a historical review of what and how we have learned about the genome, particularly in the past century, (2) explain the processes whereby genetic information in cellular DNA is transcribed to messenger RNA and translated to protein, and (3) introduce genetic and epigenetic mechanisms that regulate gene expression.

Uric Acid Determination in Gestational Hypertension: Is it as Effective a Delineator of Risk as Proteinuria in High-Risk Women?

We asked, is uric acid as effective as proteinuria at identifying perinatal risk in high-risk women with gestational hypertension? Uric acid was measured in samples obtained ≈4.6 weeks predelivery in 259 women with prior preeclampsia from the National Institute of Child Health and Human Development network study of low-dose aspirin to prevent preeclampsia. Participants were grouped according to the presence/absence of gestational hypertension (H), proteinuria (P), and hyperuricemia (U). Adverse perinatal outcomes were not different between H or U and women with normal values (normal blood pressure, urinary protein, and uric acid [NNN]). Preterm birth was greater in hypertension and proteinuria (HP) and hypertension and hyperuricemia (HU) compared to NNN (relative risk [RR] = 2.4, P = .03 and 3.8, P < .01), respectively. In addition, in HU women, delivery was earlier (36.6 ± 3.4 vs 38.4 ± 2.3 weeks, P < .001) and small for gestational age infants

The -93T/G LPL Promoter Polymorphism Is Associated With Lower Third-Trimester Triglycerides in Pregnant African American Women.

BACKGROUND: Hypertriglyceridemia is a risk factor for cardiovascular disease and several pregnancy complications. Lipoprotein lipase (LPL) genetic variation modulates nonpregnancy plasma triglycerides, but its effects during pregnancy are unknown. The G allele of the LPL -93T/G promoter polymorphism is 16-23 times more prevalent in Blacks than in Whites, contributing to lower triglycerides in nonpregnant African Americans by increasing LPL expression. PURPOSE: This study investigated whether the triglyceride-lowering effect of -93G is observed in African Americans during pregnancy. METHODS: Genotyping was performed on 124 African American women with uncomplicated pregnancies for common functional LPL polymorphisms/mutations (-93T/G, D9N, N291S, and S447X). Third-trimester plasma triglyceride, high- and low-density lipoprotein cholesterol, apolipoprotein B, and free fatty acid concentrations were measured with colorimetric assays. Clinical characteristics and lipid values were compared across the -93T/G genotypes. RESULTS: Triglycerides were significantly lower in women with the -93GG compared to the -93TT genotype, both with (n = 124, p = .02) and without (n = 108, p = .03) inclusion of participants with other LPL variant alleles. Triglyceride differences persisted after adjustment for prepregnancy body mass index, gestational age at delivery, and smoking. There were no significant differences in the other lipids or apolipoprotein B by -93T/G genotype. CONCLUSIONS: Despite the considerable metabolic changes accompanying pregnancy, the triglyceride-lowering effect associated with the -93GG LPL genotype in African Americans persists during late pregnancy. The -93GG genotype might protect against pregnancy complications stemming from hypertriglyceridemia, but the overall increased risk of pregnancy complications in African American women points to complex, multifactorial relationships among risk factors, race, and adverse pregnancy outcomes.