Review
If we know so much about preeclampsia, why haven’t we cured the disease?

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Abstract

Preeclampsia has been recognized for at least 100 years. In the last 20 years, the consideration of the disorder as more than simply hypertension in pregnancy has led to an explosion in knowledge about preeclampsia pathophysiology. It is now evident that for most cases of preeclampsia, the root cause is the placenta. Relatively reduced placental perfusion leads to inflammation, oxidative stress, and endoplasmic reticulum stress, which converge to modify maternal physiology, with endothelium an important target. Although preeclampsia is characteristically diagnosed in the last third of pregnancy, it is evident that many of these pathophysiological changes can be detected long before clinically evident disease. Furthermore, it is evident that the “maternal constitution,” including genetic, behavioral, and metabolic factors, influences the maternal response to the abnormal placentation of preeclampsia. These insights would seem to provide a guide for the prediction of the disorder in early pregnancy, along with targets for intervention. However, this has not been the case. Predictive tests guided by this knowledge do not predict well and several interventions guided by the expanded understanding of pathophysiology do not prevent the disease. We propose that these failures are secondary to the fact that preeclampsia is more than one disorder. Further, we suggest that future progress toward prediction and prevention will require research guided by this concept.

Introduction

The adverse pregnancy condition, preeclampsia, has been recognized as a significant contributor to maternal and fetal mortality and morbidity for over 100 years. In the late 19th century it was recognized that eclampsia, which had been considered a convulsive disorder of pregnancy for almost a thousand years, was preceded by increased maternal blood pressure and proteinuria, hence preeclampsia. Not long after these observations, it was evident that even without seizures, preeclampsia indicated a potentially fatal disease for mothers and babies (Chesley, 1978).

Early research in preeclampsia was heavily influenced by the original, serendipitous observations of increased blood pressure and proteinuria. Most research was directed at attempts to understand solely the high blood pressure and renal dysfunction. Not surprisingly, little progress was made in understanding the syndrome. In the last 20 years, the recognition that preeclampsia is a multisystemic syndrome that is associated with increased inflammatory activation (Redman et al., 1999), endothelial dysfunction (Roberts et al., 1989), an abnormal balance of angiogenic and antiangiogenic factors (Maynard and Karumanchi, 2011), and profound metabolic changes (Hubel, 2006), has redirected preeclampsia research. As a result, our understanding of the pathophysiology of this disorder has increased strikingly. Furthermore, there has been a substantial increase in the understanding of the process of trophoblast invasion, long recognized as a key feature of preeclampsia (Kaufmann et al., 2003).

Ordinarily, as understanding of the pathophysiology of a disease increases, the ability to predict, prevent, and treat the disease will increase accordingly. This has not been the case with preeclampsia. The inability to treat preeclampsia is not too puzzling since the pathological changes present in women with overt preeclampsia strongly indicate that once clinically evident, the process is not reversible. However, despite an apparently in-depth understanding of the pathophysiology of preeclampsia, we have not been able to reliably predict or prevent the disease. This stimulates the title of this manuscript, a statement made by noted preeclampsia investigator, Joey Granger. “If we know so much about preeclampsia, why haven’t we cured the disease?”

In this manuscript we will review the current concepts of the pathophysiology of preeclampsia, explore what is “wrong” with these concepts, and attempt to assess how we should move forward in our study of this enigmatic condition.

Section snippets

Current concepts of the pathophysiology of preeclampsia

A useful model for understanding the pathophysiology of preeclampsia has been to consider the disorder with a two-stage model (Gammill and Roberts, 2007, Sargent et al., 2006). In the two-stage model (Fig. 1) Stage 1 is inadequate placental perfusion and Stage 2 is the maternal syndrome resulting from inadequate placental perfusion. A crucial question in preeclampsia research is, what links the two stages?

The translation of these current concepts to clinical care

With the wealth of information that has been accumulated in women prior to clinically evident preeclampsia, and the use of these data to support hypotheses relevant to the pathophysiology, it would seem that we are poised for great advances in the management of the disorder. As stated previously, it does not seem likely that treatment at the time of the disease would be more than palliative because of what appear to be irreversible pathological changes. Thus, most efforts have been directed at

Why does prevention not prevent and prediction not predict?

When large studies do not demonstrate efficacy for a therapy, while small studies do, the most obvious explanation is publication bias. That is, small studies that are effective are published, while small studies in which intervention was not successful are not, and may not even be submitted for publication. It is also possible that the failure to identify predictors or preventive agents is because we have not chosen the right link between Stage 1 and Stage 2 or that treatment was too early, or

Subtypes of preeclampsia?

We have alluded to some obvious potential subtypes that warrant studies searching for different pathophysiological bases. Are early and late preeclampsia or preeclampsia with or without fetal growth restriction all one disease? Preeclampsia also seems to primarily affect different target organs in different women. This may be due to varying maternal sensitivity, but it is nonetheless worth exploring similarities and differences in women with preeclampsia primarily affecting the liver, the

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