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(Hypertension. 2005;46:1250.)
© 2005 American Heart Association, Inc.

Editorial Commentaries

Hypertension During Pregnancy

A Disorder Begging for Pathophysiological Support

Ravi I. Thadhani; Richard J. Johnson; S. Ananth Karumanchi

From the Departments of Medicine and Obstetrics and Gynecology (R.T.), Massachusetts General Hospital, Harvard Medical School, Boston, Mass; Departments of Medicine and Obstetrics and Gynecology (S.A.K.), Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Mass; and Division of Nephrology (R.J.J.), Hypertension and Transplantation, University of Florida, Gainesville.

Correspondence to Ravi I. Thadhani, MD, MPH, Bullfinch 127, 55 Fruit St, Massachusetts General Hospital, Boston, MA 02114. E-mail thadhani.r{at}mgh.harvard.edu

Hypertension during pregnancy remains a common and potentially devastating complication.^1,2 Hypertension can be isolated (gestational hypertension) or associated with proteinuria (preeclampsia) and, rarely, can manifest as a consequence of either preexisting or new onset renal (usually glomerular) disease. Preeclampsia is a particularly worrisome diagnosis, because it carries increased risk for morbidity to the mother and child and may accelerate to the condition of eclampsia in which seizures develop in association with a high risk for fetal and maternal mortality.

Although, ideally, the diagnosis of these conditions should involve the use of biomarkers that reflect the underlying pathophysiology of the disease process, the lack of clinically available assays has forced the clinician to diagnose the condition based solely on the clinical presentation. Unfortunately, although establishing cut points for elevated blood pressure and urine protein excretion appears to be straightforward, these continuous variables lend themselves to arbitrary definitions, and this likely explains why the precise definition of preeclampsia has changed several times and why different organizations continue to classify preeclampsia differently.³ A recent report from the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy³ nicely summarized the current status of diagnosing preeclampsia: "Although our current understanding of this syndrome has increased, the criteria used to identify the disorder remain subject to confusion and controversy. The confusion doubtless reflects the fact that preeclampsia is a syndrome, which means that attempts at definition use arbitrarily selected markers rather than changes of pathophysiologic importance." Adding to this confusion is the fact that a woman may be delivered well before specific research criteria are met, especially if she is at or near term. Although certainly appropriate for clinical medicine, such practice leads to significant misclassification, because accurate assessment of phenotypes is critical for research purposes.

Indeed, we have known for some time that preeclampsia extends well beyond isolated elevated blood pressure and a rise in urine albumin excretion,^4,5 and several attempts have been made to incorporate a variety of biomarkers into the clinical definition in hopes of better refining the diagnosis.³ Ideally, the following biomarkers of "pathophysiologic importance" would assist greatly in the diagnosis and management of preeclampsia and potentially provide the underpinnings for targeted therapies. For example, recent findings have implicated altered circulating angiogenic factors in the pathophysiology of preeclampsia,^6,7 and detecting an imbalance of specific angiogenic proteins in maternal circulation and urine appears to predict the development and confirm the diagnosis of preeclampsia.^8–12 Nonetheless, until assays for these bioavailable markers become clinically available, certain traditional and readily available laboratory tests, such as serum uric acid, deserve to be revisited, especially as improved study designs more accurately assess their utility.

An association of uric acid with eclampsia has been known since the late 1800s.¹³ Whereas serum uric acid usually falls to levels well below 4 mg/dl during early-to-middle pregnancy, in patients with preeclampsia, levels often rise >4.5 mg/dl.^14,15 Several studies have correlated the rise in uric acid with the severity of the preeclamptic syndrome and with the degree of glomerular injury.^14,15 Although hyperuricemia does correlate with maternal morbidity, there is an even stronger association of uric acid with the risk for small birth weight infants and with overall fetal mortality.^14,15 Nevertheless, whereas once viewed as a helpful marker to distinguish preeclampsia from the more benign forms of gestational hypertension, several recent studies have challenged the use of serum uric acid in predicting either preeclampsia or its myriad of complications.^16–18

In this issue of Hypertension, Roberts et al¹⁹ revisit the clinical use of serum uric acid as an aid in assessing the risk for adverse outcomes among women with hypertensive disorders of pregnancy. Using a nested case-control design, serum uric acid was available or was subsequently measured in >900 women at admission for labor and delivery. Importantly, women were categorized in 8 different groups using various combinations of hypertension, proteinuria, and hyperuricemia. It is always a sacrifice of power when outcome data are divided into multiple strata; however, a compelling case is made for the clinical utility of such stratification, and Roberts et al.¹⁹ acknowledge that additional verification of their results is needed. Importantly, Roberts et al¹⁹ move beyond the traditional clinical criteria of hypertension and proteinuria by focusing on clinically relevant adverse outcomes, such as small-for-gestational-age infant and preterm delivery. Results of this study suggest that the subset of women with elevated serum uric acid levels represents a unique group at significantly increased risk for adverse outcomes. Interestingly, the risk imparted to the group with elevated serum uric acid levels appears to be independent of concomitant proteinuria, and the risk follows a linear trend according to serum levels of uric acid. In short, Roberts et al¹⁹ take uric acid out of the realm of "aiding" in the diagnosis of preeclampsia, which is how serum uric acid has been traditionally viewed,³ to one in which serum uric acid appears to have an independent link with adverse outcomes.

Recent studies provide a potential mechanism to explain why uric acid may be an independent risk factor for small-for-birth-weight infants. Uric acid has recently been shown to reduce endothelial nitric oxide bioavailability and to inhibit endothelial cell proliferation.^20–22 Because maternal uric acid passes freely into the placenta,²³ a rise in uric acid could lead to an inhibition of fetal angiogenesis in the third trimester, which might lead not only to a small infant, but also to the inhibition of kidney growth with a reduction in nephron number.^20,23 A similar association of small-birth-weight infants has been associated with circulating levels of asymmetrical dimethylarginine, which is another inhibitor of endothelial function.²⁴ Indeed, there is also accumulating evidence that uric acid may have a potential contributory role in the maternal phenotype,²⁵ although other factors, including oxidative stress and circulating inhibitors of vascular endothelial growth factor, likely have a more dominant role.²⁶

In conclusion, the results of this article and those of recent studies illuminating the biological basis of preeclampsia suggest that we should once again revisit the clinical criteria for hypertension in pregnancy with a focus on biomarkers linked with the pathophysiology of the disorder. More specifically, if the results of the Roberts et al¹⁹ study are verified prospectively and found to be generalizable (eg, across different ages, races, and ethnicities), it would be reasonable to incorporate the measurement of serum uric acid in the standard assessment of women with hypertension in pregnancy. Some would argue that this test is already performed on a regular basis among women with hypertension in pregnancy. Although this may be true, our approach should shift from one in which we view uric acid as a simple supportive measure used to confirm the diagnosis of preeclampsia to one in which we appreciate its independent link with adverse outcomes. Preeclampsia remains a condition begging for supportive biological measures linked to the underlying pathophysiology of the disease, and this and other recent studies move us in the right direction toward this goal.

	Acknowledgments

 
Supported by grants HD39223 and DK067397 (R.I.T.), HL079594 (S.A.K.), and HL068607 (R.J.J.).

	Footnotes

 
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.

S.A.K. is a co-inventor on multiple provisional patents filed by the Beth Israel Deaconess Medical Center on the role of angiogenic proteins for the diagnosis and treatment of preeclampsia. R.T. is a co-inventor on a patent filed by the Massachusetts General Hospital on the role of SHBG/PLGF for the prediction of preeclampsia. R.J is an inventor on several pending and published patents with the Universities of Florida and Washington on uric acid and VEGF in renal and cardiovascular diseases.

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