麻豆传媒

With new genetic variants identified for preeclampsia and gestational hypertension, researchers created polygenic risk scores (PRS) that may better identify candidates for prophylactic low-dose aspirin among pregnant mothers.

There were 18 independent genetic loci significantly associated with hypertensive disorders of pregnancy (HDPs) -- 12 of them new (i.e., MTHFR-CLCN6, WNT3A, NPR3, PGR, and RGL3) -- based on an expanded multi-ancestry genome-wide association study (GWAS) meta-analysis for preeclampsia/eclampsia and a separate GWAS for gestational hypertension alone.

From this, PRS for each outcome were derived, fine-tuned on the U.K. Biobank dataset, and externally validated on the and , according to Pradeep Natarajan, MD, MMSc, of Massachusetts General Hospital and Harvard Medical School in Boston, and colleagues.

The PRS predicted HDP risk among nulliparous female individuals independent of first-trimester risk factors, with the top 10% highest scorers confirmed to be at significantly higher risk of preeclampsia and gestational hypertension. What's more, high PRS scores could widen the pool of individuals eligible for preventive low-dose aspirin by up to 8.3%, the study authors estimated in their report, published in .

This may have implications for improving upon the "modest" predictive ability of clinical risk factors for HDPs, the investigators suggested, citing existing first-trimester screening algorithms such as the based on maternal history and biomarkers.

"Among established risk factors for preeclampsia, nulliparity carries the largest population-attributable risk (approximately one-third), and most affected individuals lack any overt prepregnancy risk factors other than nulliparity," according to Natarajan's group.

"Improving pregnancy risk prediction, therefore, remains a pressing clinical need to optimize HDP prevention," the authors stressed. "In contrast with markers measured during pregnancy, PRS can be calculated anytime from birth, including preconception, and may therefore also inform preconception counseling and health optimization."

HDPs carry a known association with maternal strokes and need for preterm delivery and low birth weight in babies. Pregnant women who develop these high blood pressure (BP) conditions are also shown to be at excess long-term risk of cardiovascular disease and chronic hypertension. Additionally, they are at greater risk of cognitive decline later in life and early death.

Worryingly, these BP conditions are becoming more common over time, with CDC estimates suggesting that the prevalence of HDP among delivery hospitalizations increased .

The U.S. Preventive Services Task Force recently proposed expanding routine screening for preeclampsia to include all HDPs. In a B grade recommendation, the Task Force said that all pregnant people should have their BP measured at each prenatal visit to help identify and prevent serious health issues related to hypertensive disorders of pregnancy.

Management of HDPs include close fetal and maternal monitoring, antihypertension medications, and magnesium sulfate for seizure prophylaxis when indicated. A finding of preeclampsia can only be treated by delivery, timed according to gestational age and whether severe features of preeclampsia are present.

Meanwhile, no HDP prediction tools are currently endorsed by U.K. or U.S. guidelines.

Natarajan and colleagues created their PRS after running GWAS studies on discovery and follow-up cohorts using multi-ancestry meta-analysis.

HDP cases were identified using ICD codes and defined as:

• Preeclampsia: new-onset hypertension or worsening hypertension after 20-week gestation plus proteinuria or other evidence of end-organ dysfunction

• Gestational hypertension: new-onset hypertension without accompanying features of preeclampsia

• Eclampsia: progression of preeclampsia to maternal seizures

Included in the study were 20,064 preeclampsia/eclampsia cases with 703,117 control individuals, and 11,027 gestational hypertension cases accompanied by 412,788 control individuals.

The authors acknowledged that they lacked granular information such as HDP subtype, preterm vs term vs postpartum onset, and presence of fetal growth restriction.

Another limitation of the study was that over 80% of participants in the GWAS were of European ancestry, so the PRS generally performed better in this group. This is "consistent with many prior published PRS and a well-recognized challenge in contemporary genetics," Natarajan and co-authors wrote.

"Future studies are required to ascertain whether PRS may augment existing risk algorithms," the team added.

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