Burton G.J.1, Hempstock J.1 and Jauniaux E.2 1University of Cambridge, Anatomy, Cambridge and 2Royal Free and University College, Obstetrics and Gynaecology, London, UK
Introduction: Onset of the maternal arterial circulation to the human placenta is not fully established until 10-12 weeks of pregnancy. Consequently early development takes place in a low oxygen environment, and placental tissues display low concentrations and activities of antioxidant enzymes. In spontaneous miscarriage onset of the circulation is premature. We hypothesize that this results in oxidative stress to the placental tissues, which in turn contributes to failure of the pregnancy.
Materials and methods: The study was approved by the University College London Hospitals Committee on the Ethics of Human Research. Doppler ultrasonography was performed on 65 women with missed miscarriages prior to evacuation, and on 65 women undergoing termination of normal pregnancies at 8-13 weeks gestational age. The presence of continuous venous-like flow in the central or peripheral regions of the placenta was recorded. Placental samples were obtained by a chorionic villous sampling procedure, and processed for immunohistochemistry and electron microscopy.
Results: In normal pregnancies onset of the maternal circulation is a progressive phenomenon, starting in the periphery at 8-10 weeks and gradually extending to the centre. The associated rise in oxygen tension causes oxidative stress manifested by higher levels of peroxynitrite formation and morphological damage to the syncytiotrophoblast. In missed miscarriage onset of the circulation is premature and generalized throughout the placenta (X2=l3.2l, P<0.001). Villi from the central region display higher levels of oxidative stress than those from normal placentas, particularly in early gestation and in cases of recent fetal demise. Morphological damage was more extensive, in many cases leading to sloughing of the syncytiotrophoblast. The regeneration of a new functional syncytium from underlying cytotrophoblast cells restores hormonal function to the placenta.
Conclusions: Our results are consistent with the hypothesis that high levels of trophoblastic oxidative stress, secondary to premature and generalized onset of the maternal intraplacental circulation, contribute to pregnancy failure in missed miscarriage. The effect is independent of karyotype, and deficient trophoblast invasion is the root cause. There appear to be parallels between villous regression in missed miscarriage and the formation of the chorion laeve in normal pregnancies.