Top Things to Know: Appraising the Preclinical Evidence of the Role of the Renin-Angiotensin-Aldosterone System in Antenatal Programming of Maternal and Offspring CV Health across the Life Course

Published: March 23, 2023

  1. The antenatal period, spanning conception to birth, is critical for maternal and fetal health, as exposure to adverse health conditions and environmental stressors during this time can alter structural, physiological, and metabolic fetal development and maternal health to improve short-term survival, but at the expense of programmed adverse cardiovascular health in the long term, leading to consequences for the mother and her offspring.
  2. Despite decades of research, recommendations for pre-eclampsia treatment have not changed, and the prevalence of hypertension in pregnancy continues to increase. Treatment strategies vary around the world, with significant disparities in the screening and follow-up for the development of hypertension and cardiovascular disease in affected women during the postpartum period and beyond, including in women from marginalized populations in the United States.
  3. This scientific statement is a comprehensive synthesis of preclinical and translational scientific evidence of the mechanistic role of the renin-angiotensin-aldosterone system (RAAS) in antenatal programming of hypertension and cardiovascular disease. Its goal is to 1) ensure future research utilizes best research practices with appropriate scientific rigor; 2) identify pressing needs; and 3) guide future investigations to maximize potential outcomes for women after pregnancy and their offspring.
  4. The understanding of mechanisms underlying RAAS programming in offspring has advanced significantly in recent years. As an example, models of maternal nutrient deprivation or excess demonstrate major epigenetic alterations to several RAAS gene promoters. These alterations occur in various tissues that directly affect adaptive kidney and cardiovascular structure and function across the life course, with adverse effects that are likely perpetuated over multiple generations.
  5. Placental insufficiency is a hallmark of many adverse pregnancy events that program later disease in the offspring. Adequate fetal perfusion requires sufficient maternal cardiovascular and placental health; hence, interruptions in the maternal, placental, or fetal renin-angiotensin-aldosterone system can potentially adversely affect fetal and maternal cardiovascular health in the short and long term.
  6. SARS-CoV-2-related RAAS dysregulation during pregnancy could theoretically contribute to adverse perinatal outcomes, including preeclampsia, preterm birth, and growth restriction, and program adverse cardiovascular changes that may increase the risk of developing hypertension and cardiovascular disease, but more preclinical and clinical data are necessary to support these hypotheses.
  7. The existing knowledge on the mechanisms responsible for antenatal programming of hypertension and cardiovascular disease remains limited, despite decades of high-quality research in this area. While RAAS dysregulation is established as an important driver of antenatal programming, there remain crucial gaps in the field due in part to methodological limitations and a lack of consensus that have significantly hindered translation to clinical practice.
  8. Manipulating the RAAS during specific phases of gestation is difficult for many biological and technical reasons. Genetic manipulations to specifically target the antenatal period can be complicated due to the potential expression of targeted genes in maternal tissues before pregnancy and during lactation versus in the offspring. Experimental RAAS manipulations during the antenatal period are possible but require consideration of many additional variables to achieve sufficient scientific rigor.
  9. In summary, a wide array of antenatal manipulations are used in animal models to investigate -angiotensin-aldosterone system programming and later offspring cardiovascular health. Collectively, these studies highlight the diverse array of mechanisms that alter the RAAS system and prompt questions about the utility of measuring and manipulating the RAAS in the antenatal period to develop novel diagnostic and therapeutic tools.
  10. RAAS programming has enormous potential to inform the development of diagnostic and prognostic biomarkers and novel therapeutics to improve perinatal outcomes in the short-term and long-term cardiovascular health in women and their offspring. Consensus concerning RAAS methods is imperative to foster more rapid translation into clinical research and practice.


Alexander BT, South AM, August P, Bertagnolli M, Ferranti EP, Grobe JL, Jones EJ, Loria AS, Safdar B, Sequeira-Lopez MLS; on behalf of the American Heart Association Council on the Kidney in Cardiovascular Disease; Council on Cardiovascular and Stroke Nursing; Council on Cardiovascular Radiology and Intervention; Council on Hypertension; and Council on Lifestyle and Cardiometabolic Health. Appraising the preclinical evidence of the role of the renin-angiotensin-aldosterone system in antenatal programming of maternal and offspring cardiovascular health across the life course: moving the field forward: a scientific statement from the American Heart Association [published online ahead of print March 23, 2023]. Hypertension. doi: 10.1161/HYP.0000000000000227