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Biomarker for hypertension-preeclampsia: are we close yet?Baha M. Sibai, MD

H ypertensive disorders are the most frequent medical

complication during pregnancy. These disorders are

usually categorized into those that preexist pregnancy (under-lying microvascular disease) andthose that develop forthefirst

time after 20 weeks of gestation (gestational hypertension or

preeclampsia).1-3  In addition, preeclampsia can superimpose

on any of the aforementioned preexisting conditions, or it can

develop in women who are thought initially to have gestational

hypertension.4 Hypertension and preeclampsia are also classi-

fied as either mild or severe on the basis of a certain threshold

of systolic or blood pressure values or certain amounts of pro-

teinuria or the presence of multisystem dysfunction.1-6

Preeclampsia is also a syndrome that is characterized by het-

erogenous clinical findings for which the pathogenesis can dif-

fer in women with various preexisting risk factors. The patho-genesis of preeclampsia may be different than that in women

with preexisting vascular or renal disease or autoimmune dis-

ease (such as chronic hypertension, pregestational diabetes

mellitus, connective tissue disease, or thrombophilias).1  The

clinical findings of preeclampsia can also manifest as either a

maternal syndrome alone, a fetal syndrome (reduced fetal

growth and fluid), or both. In addition, these manifestations

can develop for the firsttimeatϽ37 weeks ofgestation,at term,

in labor, or in the postpartum period.2  Therefore, maternal

and perinatal outcomes in these various disorders will depend

on gestational age at the time of the onset of the disease, the

severity of the condition, and the presence or absence of pre-existing medical conditions. For example, women with mild

gestational hypertension or mild preeclampsia that is develop-

ing at term have pregnancy outcomes that are similar to that in

women with normotensive pregancies.2,6 In contrast, women

who experience mild gestational hypertension remote from

term and those with severe gestational hypertension have

higher maternal and perinatal morbidities than do those with

mild preeclampsia at term.2,4,6

In healthy, pregnant women, preeclampsia usually is diag-

nosed in the presence of new onset of hypertension plus pro-

teinuria after 20 weeks of gestation.3 However, several studies

have found that either hypertension or proteinuria can be ab-sent in 10%-15% of pregnant women who experience the syn-

drome of hemolysis, elevated liver enzymes, and low platelet

count (HELLP)7  and in approximately 20%-25% of women

who experience eclampsia.8  The diagnostic criteria for pre-

eclampsiain healthy women arenotuseful in women whohave

preexisting hypertension only or proteinuria only or both. Inthese women, the diagnosis of  superimposed preeclampsia is

defined as either new onset proteinuria or elevated uric acid

levels(womenwith hypertensiononly) or newonset hyperten-

sion (proteinuria only) or a sudden increase in blood pressure

or a suddenincreasein theamountofproteinuria with or with-

out onset of symptoms or abnormal blood tests.3,5 However,

these definitions are arbitrary and lack reliable data to support

their validity.

Consequently, the current diagnostic criteria for gestational

hypertension and preeclampsia and their subtypes are not as

clear as onethinks, and there is difficulty identifying those who

are at risk for adverse pregnancy outcome. Thus, there is anurgent need for biochemical markers that can identify women

who are at risk, confirm the diagnosis in suspected cases, and

identify those women who are at risk for adverse pregnancy 

outcome (Table I).

Recently, several studies have documented that 2 antiangio-

genic peptides that are produced by the placenta (soluble film-

like tyrosine kinase 1 [sFlt-1] and soluble endoglin) are ele-

vated in women with established preeclampsia.9,10  Some of 

these studies have also shown that the serum levels of these

peptides are significantly higher in those women who have se-

vere preeclampsia than in those women with mild disease. In

addition, these levels are elevated particularly in women with

early onset preeclampsia.9,10

In this issue, Salahuddin et al report on the diagnostic use-

fulness of soluble sFlt-1 and soluble endoglin in hypertensive

diseases of pregnancy. In this pilot study, theauthors evaluated

the clinical usefulness of serum levels of SFlt-1, endoglin, and

uric acid in women with gestational hypertension (n ϭ 17

women), chronic hypertension (nϭ 19 women), preeclampsia

(nϭ19 women), and normal third-trimesterpregnancies (nϭ

20 women). Theauthors found that serum sFlt-1 and endoglin

levels had high sensitivity and specificity in differentiating

women with preeclampsia from those with various hyperten-

sive diseases ofpregnancy. A major strengthof their study is the

findings of good positive and negative likelihood ratios for

these peptides in differentiating preeclampsia from the other

hypertensivedisorders. In contrast, serum uric acid levels were

not found to be adequate markers for this purpose.

The findings of Salahuddin et al provide important clinical

information for practicing physicians. In addition, they add to

our knowledge regarding the pathogenesis of the various hy-

pertensive disorders of pregnancy. However, this study war-

rants several comments. First, thenumberof women who were

studied in each group is limited to draw valid conclusions.

Second, 24-hour urine protein values were not obtained in allwomen with presumed gestational hypertension and in those

From the University of Cincinnati College of Medicine, Cincinnati,

OH.

0002-9378/free

© 2007 Mosby, Inc. All rights reserved.

doi: 10.1016/j.ajog.2007.04.021

See related article, page 28

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JULY 2007 American Journal of Obstetrics &  Gynecology 1

7/28/2019 Biomarker for Hypertension-preeclampsia

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with chronic hypertension, which casts doubt about these di-

agnoses. It is well-established that both urine dipstick protein

(negative to trace values) and protein to creatinine rates corre-

late poorly with quantitative proteinuria. Third, the authors

provided no information about the number of women who

experienced superimposed preeclampsia, and they do not de-

scribe the criteria for such a diagnosis. Finally, the study does

not provide answers regarding the potential value of these

markers in predicting adverse pregnancy outcome in these

women.In a related study, Masuyama et al11  measured circulating

angiogenic factors in 15 women with severe preeclampsia, 10

women with gestational proteinuria (no hypertension), 15

women with chronic glomerulonephritis(5 women hadsuper-

imposed preeclampsia; 5 women had exacerbated proteinuria,

and 5 women had normal outcome), and in 30 women with

normotensive pregnancies. The authors found that serum lev-

els of placental growth factor were lower and that serum levels

of sFlt-1were higherin womenwith severepreeclampsia andinthose women with gestational proteinuria, compared with

normotensive pregnancies. In addition, among women with

chronic glomerulonephritis, serum sFlt-1 values were signifi-cantly higher among those women who experienced superim-

posed preeclampsia, compared with those women who had

either severe proteinuria (absent hypertension) or a normal

clinical course. Again, this study had its limitations regarding

thesamplesize andthe diagnostic criteria forpreeclampsiaand

severe proteinuria. For example, preeclampsia was defined as

gestational hypertension with or without proteinuria, and se-

vere proteinuria was defined as protein excretion of Ͼ

2 g/24hour.11

In summary, several questions remain unanswered by this

study and previous studies withregard to thepotential value of 

serum angiogenic factors in the prediction of the future devel-

opment of preeclampsia in low-risk or high-risk women (Ta-

ble) and in identifying those women whose condition will

progress to severe disease or result in adverse pregnancy out-

come. Therefore, there is an urgent need for large prospective

studies to evaluate the value of these markers in both normal

and high-risk women. f

REFERENCES

1. Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet

2005;365:785-99.

2. Sibai BM. Diagnosis and management of gestational hypertension and

preeclampsia. Obstet Gynecol 2003;102:181-92.

3. Reportof theNationalHigh Blood Pressure EducationProgram.Work-

ing group report on high blood pressure in pregnancy. Am J Obstet

Gynecol 2000;183:S1-22.

4. Barton JR, O’Brien JM, Bergaver NK, Jacques DL, Sibai BM. Mild

gestational hypertension remote from term: prognosis and outcome.

 Am J Obstet Gynecol 2001;184:979-83.

5. Brown MA, Hague WM, Higgins J, Lowe S, McCowan L, Oats J, et al.

 The detection, investigation and management of hypertension in preg-

nancy: executive summary. Aust NZJ Obstet Gynaecol 2000;40:139-55.

6. Hauth JC, Ewell MG, Levine RL, Esterlitz JR, Sibai BM, Curet LB.Pregnancy outcome in healthy nulliparous women who subsequently de-

veloped hypertension. Obstet Gynecol 2000;95:24-8.

7. Sibai BM. Diagnosis, controversies, and management of HELLP syn-

drome. Obstet Gynecol 2004;103:981-91.

8. Sibai BM. Diagnosis, prevention, and management of eclampsia. Ob-

stet Gynecol 2005;105:402-10.

9. Levine RJ, Maynard SE, Qian C, et al. Circulating angiogenic factors

and the risk of preeclampsia. N Engl J Med 2004;350:672-83.

10. Levine RJ, Lam C, Qian C, et al. Soluble endoglin, a novel circulating

anti-angiogenic factor in preeclampsia. N Engl J Med 2006;

355:992-1005.

11. Masuyama H, Suwaki N, Nakatsukasa H, Masumoto H, Tateishi Y,

Hiramatrsu Y. Circulating angiogenic factors in preeclampsia, gestational

proteinuria, and preeclampsia superimposed on chronic glomerulo-ne-phritis. Am J Obstet Gynecol 2006;194:551-6.

TABLE

Potential benefit of a biochemical marker inhypertension-preeclampsia

Predict women at risk for subsequent preeclampsia.................................................................................................................................................................................

Rule out the disease in suspected cases........................................................................................................................................................................

Women with proteinuria Ϯ symptoms........................................................................................................................................................................

Women with hypertension only.................................................................................................................................................................................

Identify women with mild disease whose condition will progress tosevere disease

.................................................................................................................................................................................

Identify women with preeclampsia that is associated with adversepregnancy outcome

.................................................................................................................................................................................

Confirm the diagnosis in women with preexisting medical conditions........................................................................................................................................................................

Chronic hypertension, renal disease........................................................................................................................................................................

 Autoimmune disease........................................................................................................................................................................

Pregestational diabetes mellitus........................................................................................................................................................................

Thrombophilia

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2 American Journal of Obstetrics &  Gynecology JULY 2007