Antenatal Programming of Hypertension: Paradigms, Paradoxes, and How We Move Forward

Abstract

Purpose of review: Synthesize the clinical, epidemiological, and preclinical evidence for antenatal programming of hypertension and critically appraise paradigms and paradoxes to improve translation.

Recent findings: Clinical and epidemiological studies persistently demonstrate that antenatal factors contribute to programmed hypertension under the developmental origins of health and disease framework, including lower birth weight, preterm birth, and fetal growth restriction. Preclinical mechanisms include preeclampsia, maternal diabetes, maternal undernutrition, and antenatal corticosteroid exposure. However, clinical and epidemiological studies to date have largely failed to adequately identify, discuss, and mitigate many sources and types of bias in part due to heterogeneous study designs and incomplete adherence to scientific rigor. These limitations have led to incomplete and biased paradigms as well as persistent paradoxes that have significantly limited translation into clinical and population health interventions. Improved understanding of these paradigms and paradoxes will allow us to substantially move the field forward.

Keywords: Cardiovascular disease; Causal inference; Developmental origins of health and disease; Growth restriction; Life course; Low birth weight; Nephron number; Preterm birth.

Figure 1

Graphical causal model (directed acyclic graph) representing the concept that traditionally defined exposures such as lower birth weight, preterm birth, and fetal growth restriction may actually be intermediate factors on the causal pathway. Research question-defined exposures are denoted by green nodes with black arrowheads; the outcome is denoted as a blue node with a black bar. Green nodes denote ancestors of the exposures while the blue node denotes an ancestor of the outcome. Causal pathways are denoted with green arrows, while undefined pathways are denoted with black arrows. Arrows represent true causal relationships. Additional arrows are omitted for clarity, such as that preeclampsia and preterm birth likely would cause antenatal corticosteroid exposure.

Figure 2

Directed acyclic graph of the association of gestational age with youth-onset hypertension with childhood adiposity as a mediator. Gestational age has a direct effect of hypertension and an indirect effect mediated through adiposity. The exposure gestational age is denoted with a green node with black arrowhead; the outcome hypertension is denoted as a blue node with a black bar. Blue nodes denote ancestors of the outcome, while the red node denotes a confounding factor and red arrows denote non-causal, biasing pathways. Causal pathways are denoted with green arrows.