We believe that the hypothesis of Hartley, Ferguson, and Moffett on the role of fetal DNA in the pathophysiology of preeclampsia (PE), although very interesting, “puts the cart before the horse.”

In Redman’s model of a 2-stage disorder of PE, the first stage is reduced placental perfusion and the second stage is the maternal syndrome (inflammatory/oxidative stress). The first stage is where the spiral arteries of the placental bed fail to undergo normal physiological change. We described the Doppler changes in the uteroplacental circulation in the midtrimester of normal nulliparous pregnancy, observing the development of a low-resistance circulation.

In the second stage of PE the spiral arteries undergo a disease process termed “acute atherosis” that results in further restriction of blood flow and even complete vascular occlusion. It was recently demonstrated that the oxidative stress injury to the DNA of the placenta in PE “is localized to the maternal and not the fetal side of the placenta.” This finding would indicate that the oxidative stress in PE is more injurious to maternal tissue than the fetoplacental unit and is most likely the cause of the acute atherosis.

In the second stage of PE there is excessive embolization of trophoblast that releases cell-free fetal DNA (cffDNA) into the maternal circulation. The cffDNA is then broken down in the maternal liver where the purines are catabolized to uric acid by xanthine oxidoreductase. We hypothesized that when the hepatocytes are presented with excessive amounts of purines for catabolism, in patients who subsequently develop PE, there is activation of xanthine oxidase, the more toxic isoenzyme of xanthine oxidoreductase, with the generation of reactive oxygen species (ROS) as byproducts. Excessive ROS production overwhelms the normal antioxidant ability of the tissues to produce oxidative stress. We are currently investigating hepatocyte pathophysiology in PE.

Oxidative stress is most likely the “horse” driving the development of the second stage of PE. CffDNA does play an important part in the pathogenesis of PE, being the early substrate for production of ROS but it is the “cart” not the “horse.” We do not see that the recent hypothesis present any convincing evidence that cffDNA plays a major direct role in the development of the signs and symptoms (stage 2) of PE. We propose that if cffDNA plays any direct part in the second phase of the pathophysiology of PE then it is only of minor relevance.