Preeclampsia was once called “the disease of theories,” but research efforts this past decade have produced exciting breakthroughs that may bring us closer to causality, improve diagnosis and even prediction, and lead to prevention and/or specific treatments. Some speculation remains over different theories including: changes in biology of the placenta, the systemic inflammatory response, a variety of hormones and other proteins that are in the mother’s circulation, changes in immune factors, improper cardiovascular adaptations to the pregnant state, underlying maternal risks for cardiovascular disease, associations with insulin resistance and diabetes, and deficiencies in essential nutrients, minerals, and vitamins.
The most plausible theories focus on the placenta and describe the disorder in two stages. In the first, the initiating cause results in the placenta producing factors (e.g., specific proteins, placental “debris”) that enter the maternal circulation and are believed responsible for producing the next stage. This is the second stage, which results in the overt maternal “disease” (high blood pressure, kidney, liver and coagulation abnormalities). The overt disease depends not only on the action of the circulating factors from the placenta, but also the health of the mother, including diseases that may affect the vasculature (such as preexisting cardiovascular, renal, metabolic, and genetic factors; and obesity).
A promising area of recent research involves the role of proteins produced by the placenta that inhibit angiogenesis (the production of new blood vessels). Two of these “antiangiogenic factors” (soluble Fms-like tyrosine kinase-1, and soluble endoglin) have been shown to produce a preeclampsia like disease in rodents. Their concentrations rise in the mother’s circulation weeks to months before the disease manifests. Placentas of women destined to develop preeclampsia overproduce these proteins that then enter the mother’s circulation. Neutralizing their actions is now being investigated in animal models, and in some studies has reversed the disease in rodents. . Excitement regarding these interventions is tempered by a limited understanding of the functional role of antiangiogenic substances in normal pregnancy.
If the ability of these antiangiogenic proteins to cause preeclampsia is confirmed by research in humans, why the placenta overproduces them remains unknown. Hence, many of the other areas of investigation mentioned above may be important. Preeclampsia may have multiple causes, and other leads are being investigated, including prostaglandins, digoxin-like molecules, immunological mechanisms, autoantibodies that trigger receptors that lead to vessel constriction (agonistic autoantibodies to the angiotensin 1 receptor), oxidative stress, mitochondrial pathology, the impact of hypertension and prehypertension on endovascular health, and genes sensitive to low oxygen environments.
Basic research into causes of preeclampsia, lacking for decades, is being revitalized, albeit more slowly than needed. While we are moving closer to historically elusive answers, the true cause of preeclampsia remains unknown. Successful ongoing research needs far more support and funding.