Pre-eclampsia is a complication of pregnancy that is associated with substantial maternal and fetal morbidity and mortality. The disease presents with new-onset hypertension and often proteinuria in the mother, which can progress to multi-organ dysfunction, including hepatic, renal and cerebral disease, if the fetus and placenta are not delivered. Maternal endothelial dysfunction due to circulating factors of fetal origin from the placenta is a hallmark of pre-eclampsia. Risk factors for the disease include maternal comorbidities, such as chronic kidney disease, hypertension and obesity; a family history of pre-eclampsia, nulliparity or multiple pregnancies; and previous pre-eclampsia or intrauterine fetal growth restriction. In the past decade, the discovery and characterization of novel antiangiogenic pathways have been particularly impactful both in increasing understanding of the disease pathophysiology and in directing predictive and therapeutic efforts. In this Review, we discuss the pathogenic role of antiangiogenic proteins released by the placenta in the development of pre-eclampsia and review novel therapeutic strategies directed at restoring the angiogenic imbalance observed during pre-eclampsia. We also highlight other notable advances in the field, including the identification of long-term maternal and fetal risks conferred by pre-eclampsia.
Pre-eclampsia is defined as new-onset hypertension and proteinuria or other end-organ damage such as to the liver or brain occurring after 20 weeks of pregnancy.
Pre-eclampsia is characterized by defective placentation, placental ischaemia, abnormal spiral artery remodelling, oxidative stress at the maternal–fetal interface and angiogenic imbalance in the maternal circulation with ensuing endothelial and end-organ damage.
High levels of antiangiogenic factors and low levels of proangiogenic factors are useful biomarkers for the early detection and prognosis of pre-eclampsia; these markers also serve as theranostics in clinical trials.
Delivery is currently the only definitive treatment for pre-eclampsia; aspirin is recommended for prevention of pre-eclampsia in women at high risk.
Potential therapeutic strategies for pre-eclampsia include targeted apheresis, antibody therapies, RNA interference and small-molecule inhibitors of factors that have a role in placental dysfunction.
Evidence is emerging of long-term increased risk of cardiovascular and kidney disease in women who have experienced pre-eclampsia; pre-eclampsia is also an important risk factor for neonatal respiratory distress syndrome and bronchopulmonary dysplasia.
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The authors thank I. Stillman at the Department of Pathology, Beth Israel Deaconess Medical Center, USA, for providing the histology image used in figure 3.
Nature Reviews Nephrology thanks A. Hennessy and the other anonymous reviewers for their contribution to the peer review of this work.
S.A.K. is co-inventor on multiple patents (US Patent and Trademark Office (USPTO) #7,740,849, #7,407,658, #7,335,362, #7,344,892 and #8969322B2) related to the use of angiogenic markers for the diagnosis, prediction and therapy of pre-eclampsia. R.T. is a co-inventor on a patent (USPTO #7,344,892) related to the use of angiogenic proteins for the prediction of pre-eclampsia. These patents are held at Harvard Hospitals (Beth Israel Deaconess Medical Center and Massachusetts General Hospital). S.A.K and R.T. have financial interests in Aggamin Therapeutics LLC and have previously served as consultants for Roche Diagnostics and ThermoFisher. S.A.K. has received a research grant from Siemens. R.T. and T.B. have received a research grant from Kaneka Pharmaceuticals. The other authors report no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- Hydatidiform mole
A gestational, trophoblastic disease that occurs after aberrant fertilization, originates in the placenta and has potential to invade the uterus and metastasize.
- Trisomy 13
A severe chromosomal disorder caused by an extra copy of chromosome 13 that is characterized by multiple congenital abnormalities with a classic triad of abnormally small or missing eyes, cleft lip and/or palate and extra digits.
- Genome-wide association study
An analysis of markers (usually single-nucleotide polymorphisms) across the entire genome to identify those that are statistically more or less common in one population (often patients with a specific disease) than in another population (typically people who are unaffected by the specific disease).
- Spiral arteries
Small arteries derived from uterine arteries that supply blood to the endometrium of the uterus during the luteal phase of the menstrual cycle. These arteries are remodelled into highly dilated vessels by the action of invading trophoblasts during normal pregnancy to support the growing demands of the fetus.
- Foam cells
Cells that contain vacuoles or fat-laden macrophages seen in atherosclerosis.
- HELLP syndrome
A complication of pregnancy that is characterized by a syndrome of haemolysis, elevated liver enzymes and low platelet count.
An insoluble form of tissue storage iron.
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Phipps, E.A., Thadhani, R., Benzing, T. et al. Pre-eclampsia: pathogenesis, novel diagnostics and therapies. Nat Rev Nephrol 15, 275–289 (2019). https://doi.org/10.1038/s41581-019-0119-6
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