The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology

Benton, Samantha J.; Leavey, Katherine; Grynspan, David; Cox, Brian; Bainbridge, Shannon

doi:10.1016/j.ajog.2018.09.036

Cited by 87 publications

(86 citation statements)

References 62 publications

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“…(103,104) Such findings are frequently observed in women with preeclampsia. (101,(105)(106)(107)(108)(109)(110)(111)(112)(113)(114)(115)(116) Therefore, the underlying mechanisms responsible for the reduction in the rate of preterm delivery by preconception or early administration of aspirin might be similar to those proposed for preeclampsia. The results of the current meta-analysis have demonstrated that the administration of aspirin at <11 weeks' gestation is associated with a significant reduction in the risk of preterm birth.…”

Section: Resultsmentioning

confidence: 99%

Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia?

Chaemsaithong

Cuenca-Gomez

Plana

et al. 2020

American Journal of Obstetrics and Gynecology

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Condensation: Aspirin given at <11 weeks' gestation in high risk women does not reduce the risk of preeclampsia and gestational hypertension but may reduce the risk of preterm delivery. Short title: Early aspirin administration and preeclampsia PROSPERO registration number: CRD42019125006 AJOG at a Glance: Why was this study conducted? • To perform a systematic review and meta-analysis to evaluate the effect of lowdose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. Key findings • The administration of low-dose aspirin at <11 weeks' gestation in women with a history of recurrent pregnancy loss, women who had undergone in vitro fertilization or women with thrombophilia or antiphospholipid syndrome was associated with a non-significant decrease in the risk of preeclampsia, gestational hypertension, and any hypertensive disorder of pregnancy. • Early low-dose aspirin reduced the risk of preterm delivery but had no impact on the risk of fetal growth restriction. • Except for preterm delivery and any hypertensive disorder of pregnancy, sensitivity analysis demonstrated similar observations; confirming the robustness of our analysis. What does this add to what is known? • Administration of low-dose aspirin at <11 weeks' gestation to high risk women does not reduce the risk of preeclampsia, gestational hypertension, any hypertensive disorder of pregnancy and fetal growth restriction but might reduce the risk of preterm delivery at <37 weeks of gestation. ABSTRACT OBJECTIVE DATA: Pre-conception or early administration of low-dose aspirin might improve endometrial growth, placental vascularization and organogenesis. Most studies have evaluated the potential benefit of pre-conception or early administration of low-dose aspirin in women with a history of recurrent pregnancy loss, women who have undergone in vitro fertilization or women with thrombophilia or antiphospholipid syndrome. These women are at an increased risk of placenta-associated complications of pregnancy, including preeclampsia, preterm delivery and fetal growth restriction. STUDY: We performed a systematic review and meta-analysis to evaluate the effect of low-dose aspirin initiated at <11 weeks' gestation on the risk of preeclampsia, gestational hypertension, or any hypertensive disorder of pregnancy. Secondary outcomes included preterm delivery at <37 weeks' gestation and fetal growth restriction. STUDY APPRAISAL AND SYNTHESIS METHODS: We searched in MEDLINE via PubMed, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), ClinicalTrials.Gov and the World Health Organization International Clinical Trials Registry Platform (WHO-ICTRP) from 1985 to November 2018. Entry criteria were randomized controlled trials evaluating the effect of aspirin administered at <11 weeks' gestation in preventing preeclampsia and/or hypertensive disorders in pregnancy or improvi...

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Section: Resultsmentioning

confidence: 99%

Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia?

Chaemsaithong

Cuenca-Gomez

Plana

et al. 2020

American Journal of Obstetrics and Gynecology

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“…38,51 Specifically, within a large cohort of 330 placentas that represented a wide range of preeclampsia clinical presentations and co-occurring complications (SGA, chronic hypertension [CH], and preterm labor), clustering revealed 5 patient groups based solely on placental gene expression, which included 4 subtypes of preeclampsia samples within clusters 1, 2, 3, and 5 (cluster 4 was composed almost exclusively of preterm control placentas with chorioamnionitis). 38 Using a combined transcriptional, 38 clinical, 38 epigenetic, 52 and histopathologic 53 approach, we have further described each of these distinct preeclampsia placental subtypes: cluster 1 preeclampsia samples demonstrated molecular similarity to healthy term control placentas and very little placental disease, which suggests that this may be a predominately "maternal" preeclampsia subtype that is driven by preexisting, subclinical, maternal cardiovascular disease; cluster 2 preeclampsia was termed "canonical", with overwhelming evidence of maternal vascular malperfusion and placental hypoxia; cluster 3 contained a less prevalent "immunologic" subtype of preeclampsia that was marked by signs of heightened immune response at the maternal-fetal interface, similar to an allograft rejection; 30,31 and, finally, a subtype of preeclamptic placentas with chromosomal abnormalities, but no other strong clinical, epigenetic, or histologic association, was discovered in cluster 5. Notably, patients with both maternal hypertension (preeclampsia or CH) and SGA split across all 4 of these clusters.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate relationships between normotensive and hypertensive SGA pregnancies with suspected FGR, relevant samples from our previous preeclampsia cohort with available matched microarray, histologic, and clinical information 38,53 were also included in the current analysis (n¼77). These consisted of samples classified as preeclampsia and SGA (preeclampsia-SGA; n¼37), CH and SGA (CH-SGA; n¼14), or normotensive term AGA control samples (N-AGA; n¼26).…”

Section: Dataset Aggregation Unsupervised Clustering and Principal mentioning

confidence: 99%

“…55 CH was defined as systolic pressure 140 mm Hg and/or sustained diastolic pressure 90 mm Hg before the 20th week of gestation, and SGA was defined as earlier. Given our previous identification of very similar placental gene expression and histologic profiles between cases of preeclampsia and CH, 38,53 these 2 groups were analyzed together frequently as a single hypertensive group (H-SGA; n¼51). Microarray data for these original 77 samples are available under the Gene Expression Omnibus accession number GSE75010.…”

Section: Dataset Aggregation Unsupervised Clustering and Principal mentioning

confidence: 99%

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Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia

Gibbs

Leavey

Benton

et al. 2019

American Journal of Obstetrics and Gynecology

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“…Distinct molecular subtypes of PE that go beyond the distinction of early vs. late-onset disease are emerging [99][100][101] . While much work remains to define these subtypes, our analysis suggests clustering of different trait associations within the broad categories of early vs. late-onset.…”

Section: Discussionmentioning

confidence: 99%

Risk of preeclampsia in patients with genetic predisposition to common medical conditions: a case-control study

Gray

Kovacheva

Mirzakhani

et al. 2020

Preprint

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RUNNING TITLE: Preeclampsia genetic predispositionWord count: 3500; Abstract: 246 ABSTRACT Objective: To assess whether women with a genetic predisposition to medical conditions known to increase preeclampsia risk have an increased risk of preeclampsia in pregnancy.Design: Case-control study.Setting and population: Preeclampsia cases (n=498) and controls (n=1864) of European ancestry from 5 US sites genotyped on a cardiovascular gene-centric array.Methods: Significant single nucleotide polymorphisms (SNPs) from 21 traits in 7 disease categories (cardiovascular, inflammatory/autoimmune, insulin resistance, liver, obesity, renal, thrombophilia) with published genome-wide association studies (GWAS) were used to create a genetic instrument for each trait. Multivariable logistic regression was used to test the association of each continuous, scaled genetic instrument with preeclampsia. Odds of preeclampsia were compared across quartiles of the genetic instrument and evaluated for significance using a test for trend. Main Outcome Measures: preeclampsia.Results: An increasing burden of risk alleles for elevated diastolic blood pressure (DBP) and increased body mass index (BMI) were associated with an increased risk of preeclampsia (DBP: overall OR 1.11 (1.01-1.21), p=0.025; BMI: OR 1.10 (1.00-1.20), p=0.042), while risk alleles associated with elevated alkaline phosphatase (ALP) were protective (OR 0.89 (0.82-0.97), p=0.008), driven primarily by pleiotropic effects of variants in the FADS gene region. The effect of DBP genetic loci was even greater in early-onset (<34 weeks) preeclampsia cases (OR 1.30 (1.08-1.56), p=0.005). For all other traits, the genetic instrument was not robustly associated with preeclampsia risk. Conclusions:These results suggest that the underlying genetic architecture of preeclampsia is shared with other disorders, specifically hypertension and obesity. ABSTRACT Genetic predisposition to increased diastolic blood pressure and obesity increases the risk of preeclampsia.

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The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology

Cited by 87 publications

References 62 publications

Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia?

Does low-dose aspirin initiated before 11 weeks’ gestation reduce the rate of preeclampsia?

Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia

Risk of preeclampsia in patients with genetic predisposition to common medical conditions: a case-control study

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