Pre-eclampsia - The "uterine reinnervation" view.

Difficult vaginal deliveries, gynaecological surgery, and, persistent straining during defaecation injure uterine nerves. Cytokines released from injured, uterine nerves cause regeneration of new nerves with altered structures and functions. In structural terms, these new nerves proliferate in chaotic and dysfunctional patterns with abnormal, cross-sectional profiles. In functional terms they are particularly sensitive to "stretch" or mechanosensory transduction. Release of neural cytokines also causes hyperplasia of the walls of adjacent, denervated uterine arterioles that may reduce uteroplacental blood flow during pregnancy. In the "uterine reinnervation" view, "stretch" applied to injured uterine nerves triggers uterorenal nerves to cause vasoconstriction in the renal cortex, hypertension and proteinuria i.e. the key features of preeclampsia. There are two intrauterine mechanisms that stretch injured, uterine nerves (a) in the placental bed, (b) in the extraplacental myometrium, respectively. In "early-onset" preeclampsia (<34weeks), continuing increases in maternal plasma volume, increase blood flow through denervated, and, narrowed uterine arterioles in the placental bed, stretching injured perivascular nerves resulting in preeclampsia with a small-for-gestational-age fetus. In "late-onset" preeclampsia (>34weeks), nulliparity, multiple pregnancy, concealed abruption and polyhydramnios increase myometrial tension and results in preeclampsia with an appropriate-for-gestational-age fetus. Widespread activation of autonomic nerves results in multi-system features of these syndromes. Changes in placental site and circulatory compliance may contribute to different phenotypes of the preeclamptic syndromes in subsequent pregnancies. The "uterine reinnervation" view offers an explanation of the common clinical features of the preeclamptic syndromes through a single pathophysiological mechanism, namely, prepregnancy injury to uterine nerves. Importantly, it offers an explanation for resolution of the symptoms and signs of preeclampsia with delivery of the fetus, the "early" and "late-onset" preeclamptic syndromes, and, the established clinical associations of the condition including nulliparity, hydramnios, multiple pregnancy, molar pregnancy, concealed abruption, etc. Establishing the presence of injured nerves expressing mechanoreceptors in the uterus, and, neural cytokines in thickened, uterine arterioles, will assist in developing this view. However, myometrial hyperplasia during the second half of pregnancy separates injured uterine nerves from injured uterine arterioles ensuring that the key pathoanatomical relationship in preeclampsia will be difficult to demonstrate.