0021-972X/92/7405-1095$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright 0 1992by The Endocrine Societ?
Vol. 74, No. 5 Printed
in U.S.A.
Increases in Plasma Atria1 Natriuretic Peptide Concentration Antedate Clinical Evidence of Preeclampsia” MAUREEN P. MALEE, ROBERT N. TAYLOR,
KATHLEEN AND JAMES
M. MALEE, M. ROBERTS
SCOTT
D. AZUMA,
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143; Northwestern University (K.M.M.), Chicago, Illinois 60611; and Loyola University of Chicago (S.D.A.), Chicago, Illinois 6061 I
ABSTRACT. Atria1 natriuretic peptide (ANP) concentrations are typically elevated in hypervolemic states. However, ANP levels have been reported to be increased in the peripartum period in women with preeclampsia, a disorder characterized by central hypovolemia. We postulated that ANP levels are elevated in preeclamptic patients before clinically evident disease. ANP concentrations were determined in three groups: uncomplicated pregnancies, pregnancies complicated by preeclampsia, and nonpregnant reproductive-aged women. The former groups were matched for gestational age at plasma sampling and delivery. The plasma samples, obtained prospectively from each patient during the first, second, and third trimesters and within 72 h postpartum, were frozen before RIA. A significant gestational
increase in ANP was noted in both groups of pregnant women, with third trimester levels exceeding first trimester levels (P < 0.05). Consistent with previous reports, ANP levels were elevated in overtly preeclamptic patients us. matched controls in the third trimester. The ANP concentration was also significantly increased during the second trimester in women destined to develop preeclampsia. Postpartum ANP values decreased in the preeclamptic group to approach the level in normal patients postpartum. Thus, it appears that the stimuli of ANP secretion differ in uncomplicated and preeclamptic patients. Moreover, an elevation of plasma ANP is detectable before the onset of clinical evidence of preeclampsia. (J Clin Endocrinol Metab 74: 1095 1100, 1992)
A
ANP concentrations are typically markedly elevated (6, 7) when determined in women with clinically evident disease. It, thus, appears that the mechanism(s) responsible for ANP secretion differs in uncomplicated and preeclamptic pregnancies. Since there is evidence that the pathophysiological changes in preeclampsia antedate clinical recognition of the disorder, we examined ANP concentrations longitudinally in women destined to develop preeclampsia and in matched controls. We report that ANP is increased in the second trimester of pregnancy in women who will become preeclamptic, months before clinical diagnosis of the disorder.
TRIAL natriuretic peptide (ANP) is a volume regulatory hormone with potent natriuretic, diuretic, and vasorelaxant activities. In the adult, ANP secretion is stimulated by increased atria1 pressure and alterations in sodium balance (1,2). Elevated plasma concentrations of ANP accompany several pathological disorders characterized by fluid overload, including cirrhosis, congestive heart failure, and chronic renal failure (3, 4). ANP levels comparable to those in nonpregnant reproductiveaged women have been reported in some women with uncomplicated pregnancies (5). Elevated concentrations also have been reported in this group, with the increases being attributed to plasma volume expansion (6). In pregnancies complicated by preeclampsia, a disorder exclusive to pregnancy and characterized by hypertension, proteinuria, edema with central hypovolemia, and laboratory evidence of multiple organ system involvement,
Subjects Experimental
subjects
All pregnant University
and Methods
women of California,
registering for prenatal care at the San Francisco, and at San Francisco
General Hospital since July 1988 were invited to participate in a prospective study of preeclampsia. Participating patients gave written informed consent, using a form approved by the University’s Committee on Human Research.
Received February 14, 1991. Address all correspondence and requests for reprints to: M P. Malee, M.D., Ph.D., Department of Obstetrics and Gynecology, IJniversity of Iowa, Iowa City, Iowa 52242. * This work was supported by NIH Grant HD-24180. This is publication 13 from the University of California San Francisco Preeclampsia Program Project.
Sample collection In pregnant women participating in the study, first, second, and third trimester venous blood samples were obtained during 1095
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
MALEE
1096
routine out-patient visits. Blood was drawn from the left antecubital vein after approximately 30 min of stabilization in a seatedposition. During these visits, blood pressure(first and fifth heart sounds) and weight were recorded. Due to the prospective longitudinal design of this study, no systematic differencesexisted betweenthe samplingtechniquesof uncomplicated us. preeclamptic women. Peripartum and postpartum phlebotomy techniqueswere similarly standardized (recumbent position) for uncomplicated and preeclamptic patients. Peripartum blood sampleswereobtained before the administration of analgesics,anesthetics,antihypertensive agents, or magnesiumsulfate, and postpartum sampleswere drawn after discontinuation of magnesiumsulfate seizure prophylaxis. Thus, no obvious confounding systematic variation between the two pregnant groupsexisted. Blood samplesfrom pregnant [uncomplicated (n = 10) and preeclamptic (n = lo)] and nonpregnant (n = 10) subjectswere handled similarly. Plasmawasprepared by centrifugation at 6000 x g for 30 min. aliquoted, and frozen (-70 C) within 8 h of venipuncture. The mean time to plasma processingwas identical in both groups; moreover, regression analysisrevealed no apparent effect of time before processing on ANP concentration for all samples.Sampleswere stored frozen until RIA. Subject selection
The womenstudied in this cohort were followed throughout pregnancy, during labor and delivery, and for more than 12 weekspostpartum with serial clinical observations, including measurementsof blood pressureand proteinuria. At the completion of the final postpartum evaluation (~12 weeks after delivery), the clinical and laboratory data were reviewed by a jury of clinical investigators who were blinded to the resultsof the plasma ANP determinations. Preeclamptic patients fulfilled criteria recommendedby Chesley(8), namely nulliparity, absenceof a history of hypertension before pregnancy, increase in diastolic pressureof 15 mm Hg or systolic pressureof 30 mm Hg comparedto blood pressuresobtained before 20 gestational weeks,proteinuria greater than 0.5 g/24 h or greater than 30 mg/dL in a catheterized specimen,hyperuricemia greater than 5.5 mg/dL [or 1 SD greater than the normal mean value for gestationslessthan 36 weeks (9)], and return to normal blood pressureand resolution of proteinuria by 12 weekspostpartum. Normal controls were selectedfrom the samecohort of parturients, in whom neither hypertension, proteinuria, nor hyperuricemia was observedthroughout the study period. None of the patients was sodiumrestricted. They had normal diets and took no medications except prenatal vitamins. Criteria that resulted in the exclusion of patients from this study were the identification of any chronic metabolic disease,evidence of illicit drug use by urine toxicology screens,or the failure of elevated blood pressure, hyperuricemia, or proteinuria to resolve within 12 weeks of delivery. Patients from the normal group were matched as closely as possibleby age, gestational age at delivery and at times of blood sampling, weight, and parity to the preeclampticpatients. Nonpregnant normotensive reproductive-agedwomenserved as controls.
E7’ AL.
.I(‘E&M.lSM
f?xtmction
nnti R/t\ o/plasm0
At room temperature and using a vacuum manifold, 1 ml, plasma was extracted on Amprep minicolumns (C18; Amersham International, Aylesbury, Buckinghamshire, United Kingdom) using 60% CH,,CN and 0.1% trifluoroacetic acid (Sigma Chemical Co., St. Louis, MO). The desiredeluate was collected, concentrated under nitrogen, centrifuged under vacuum, and reconstituted with assay buffer for RIA. Recovery was 87%. ANP levels were determined by an ANP RIA kit, using an antibody specific for (u-humanANP (aa98-126,Peninsula Laboratories, Inc., Belmont, CA) according to the manufacturer’s specifications. The sensitivity was 1 pg/tube. All data reported in this paper were from samplesanalyzed simultaneously in duplicate, with the results averaged; intraassay variation was 3.19 + 0.25%. However, typical ANP interassay variation in this laboratory is 7.26 k 0.39%. Statistics
Nonparametric statistics were useddue to the small sample size. The Spearman p statistic was used to determine the relationship between ANP and weight gain and betweenANP and meanarterial pressure(MAP). The Mann-Whitney U test for small sampleswas calculated to determine group differences.Student’s t test was used for the multiple comparisons in Table 3. Significance was taken at P c 0.05 for two-sided tests. Results Descriptive data for the women participating in the study are reported in Table 1. Table 2 depicts peripartum clinical findings for both uncomplicated and preeclamptic gestations. As anticipated from the diagnostic criteria, the mean MAP in the preeclamptic group (96.4 rtr 1.8 mm Hg) significantly exceeded that in the uncomplicated pregnancy group (82.7 + 2.1 mm Hg) in the third trimester (P < 0.05). Total weight gain in the preeclamptic group (19.8 + 1.8 kg) exceeded that in the uncomplicated group (13.7 + 1.8 kg; P < 0.05). The plasma levels of ANP and MAPS in matched uncomplicated and pree‘I‘~t31.E
1.
Uescriptivedata UncomplicatedPreeclamptic
Gestationalageat delivery(weeks) Gravidity Parity Modeof delivery (sl,) Ceearean section Vaginaldelivery Newborn
wt (g)
Race(%) Caucasian Black Hispanic Other No. ” Mean
40.4 + 0.5” 2.8 f 0.7 0.9 f 0.3
37.6 It 0.6 1.6 f 0.3 0.0
20 80
50 50
3353.0
f 197.1 2887.5f 143.2 80
10 10
40 20 30
10 10
t SIN.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
10
INCREASES
IN ANP
ANTEDATE
TABLE 2. Antepartum clinical findings
MAP (mm Hg) Proteinuria (negative to 4+) Wt gain (kg) Uric acid (mmol/L) Creatinine (mmol/L) Hemoglobin (g/L) Hematocrit (vol fraction)
Discussion
Uncomplicated 82.7 * 2.1” Negative 13.7 + 1.8 0.22 + 0.01 57 f 2 126 f 3 0.36 f 0.01
Preeclamptic 96.5 + l.Sb 2+ 19.8 f l.Sb 0.36 + 0.01 63 f 12 123 + 4 0.36 + 0.01
’ Mean f SEM. b P < 0.05.
clamptic pregnant women followed longitudinally and in nonpregnant reproductive-aged women are listed in Table 3. The MAP values in the first and second trimesters were not different in the uncomplicated (82.6 + 2.2 and 83.3 + 2.3 mm Hg) and preeclamptic (86.7 + 3.4 and 82.1 + 2.4 mm Hg) groups. The postpartum ANP level in the uncomplicated pregnancy group (17.0 + 1.3 pg/mL) exceeded concentrations attained throughout gestation (P C 0.05). However, in the preeclamptic group, the greatest ANP level achieved was that in the third trimester (31.0 + 4.3 pg/mL). Moreover, the second trimester ANP concentration was elevated in preeclamptic women (18.5 f 3.4 pg/mL). Both of these second and third trimester ANP values in the preeclamptic group significantly exceeded levels in the uncomplicated group (P < 0.05). These data are also presented in scattergram form in Fig. 1. Finally, there was a significant positive correlation between ANP levels and MAP in the third trimester of preeclamptic gestations (r = 0.662; P < 0.05). However, no correlations were noted between ANP levels and mean arterial pressure in the first and second trimesters, weight gain, blood urea nitrogen, uric acid, or creatinine in either the uncomplicated or preeclamptic group. TABLE 3. Plasma ANP levels and MAP in uncomplicated reproductive-aged women
ANP is the 2%amino acid carboxy-terminal end of the 126-amino acid ANP prohormone (10) that is synthesized in cardiac myocytes. ANP has potent vasorelaxant, natriuretic, and diuretic activities, and plasma concentrations are reportedly unchanged or increased in uncomplicated pregnancy (5, 6). The wide variation in previously reported circulating levels of ANP in pregnancy may be a function of differing extraction methods and/ or antibody specificity. Previous studies, however, have also been limited, in that they did not follow the same population longitudinally. In the present study ANP concentrations during uncomplicated pregnancy were significantly increased in the third trimester, but were greatest when determined within the first 72 h postpartum. These changes were not surprising given the gradual but marked increase in plasma volume during normal pregnancy, the progressive sodium accumulation, and the acute physiological increase in right and left atria1 pressures after placental separation (11-13). Moreover, the further increase in ANP observed in the early puerperium coincides with the shift in body fluid from extravascular to intravascular space and subsequent diuresis (14). Merkouris et al. (15) reported similar findings in a cross-sectional study of uncomplicated pregnancy and its puerperal period, and Robson et al. (16) noted significant increases in atria1 dimensions by echocardiogram when examined 48 h after delivery. Several investigators (6, 7) have noted a significant elevation in ANP coincident with clinically evident preeclampsia, with the degree of elevation reflecting the severity of disease. Significantly increased ANP levels similarly were found with clinical evidence of disease in the current study. An elevation of ANP in preeclampsia
and preeclamptic
pregnant women followed longitudinally
1st trimester 9 rt 1 weeks” (5.9-11.6)b
2nd trimester 23 + 1 weeks (14.7-27.7)
Uncomplicated ANP (pg/mL) MAP (mm Hg) Preaclamptic
10.9 + 1.1’ 82.6 f 2.2
ANP WmL) MAP (mm Hg)
12.9 f 0.9 86.7 + 3.4
Nonpregnant ANP @g/mL)
1097
PREECLAMPSIA
14.2 + 1.5
and in nonpregnant
3rd trimester 37 f 1 weeks (34.1-41.7)
Postpartum 27.6 f 2.6 h (24-72)
12.1 f 0.9 83.2 3~ 2.3
14.2 jl 0.5” 82.7 k 2.1
17.0 f 1.3d*’ 86.4 It 2.5
18.5 f 3.4”j 82.1 t 2.4
31.1 + 4.3d’ 96.5 + l.Sd,‘l
21.8 f 2.8“ 88.9 f 2.1
--
’ Mean + SEM weeks gestation or hours postpartum. b Range in weeks gestation or hours postpartum is in parentheses. ’ Mean rf: SEM. d P < 0.05 us. first trimester value in the same group. ‘P < 0.05 us. all antepartum values in the same group. ‘P < 0.05 us. comparable values in the uncomplicated group.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
MALEE
1098 80 ,
I
*
I
0 ’ 2nd trimester
3rd trimester
postpartum
FIG. 1. Longitudinal plasma ANP concentrations in women with normal and preeclamptic pregnancies. Plasma ANP concentrations (picograms per mL) in 10 uncomplicated pregnancies (0) and 10 matched pregnancies in whom preeclampsia developed (0) are plotted in a scattergram. Longitudinal samples obtained during the second and third trimesters of pregnancy and within 72 h postpartum are indicated. (First trimester values are reported in Table 3.) Conservative nonparametric statistical analyses revealed significant differences between the 2 groups in the second and third trimesters (P c 0.05, by MannWhitney tests). Horizontal bars indicate the mean ANP concentrations for each patient group.
is perplexing, since most studies characterize preeclamptic women as hypovolemic compared to normal pregnant women (17), and known stimuli for ANP secretion in adults include hypervolemia and tachycardia (1, 2). As reviewed by Clark and Cotton (18), common central hemodynamic findings in preeclampsia include normal heart rate; low to normal central venous pressure, a measure of the preload of the right heart; and a low, normal, or rarely elevated pulmonary capillary wedge pressure, reflecting the preload of the left heart. The afterload of the right heart, indicated by pulmonary vascular resistance, is not elevated in preeclampsia. However, the afterload of the left heart, the systemic vascular resistance, is variably elevated in preeclampsia (19). No studies in which afterload is singly affected and accompanied by alterations in ANP concentrations are available. It should be noted, however, that a recent report by Easterling et al. (20) suggests that cardiac output is actually increased in preeclampsia throughout pregnancy and that the hemodynamic abnormality persists postpartum. Thus, in preeclampsia, a stimulus to the secretion of ANP that is to date unknown and/or alterations in the metabolic clearance of ANP could be evoked. This conclusion is supported by the finding in the present investigation that an elevation of the ANP concentration antedates clinical evidence of disease. These data reiterate the systemic nature of the disease and the concept that effects on multiple organ systems and the fetoplacental unit antedate clinical evidence of disease. Other mechanisms for increased ANP concentrations
El’
.4L.
JCE&M.1932
in preeclampsia also have been proposed. Niesert and Kaulhausen (21) suggested that ANP levels were elevated in preeclampsia secondary to decreased clearance, which, in turn, was a function of decreased glomerular filtration rate or increased blood pressure. Although the glomerular filtration rate in preeclampsia may be less than that in normal pregnancy, it is unlikely to be the cause of increased ANP, since it is rarely less than that in nonpregnant controls (22). Moreover, Yamamoto et al. (23) found that in nonpregnant adults, impaired renal function (creatinine, 2.0-8.3 mg/dL) unaccompanied by cardiomegaly or hypertension was not associated with increased ANP levels. Finally, creatinine levels in our preeclamptic group were not different from control values, and there was no correlation of ANP levels with creatinine concentrations. The ANP concentrations in preeclampsia also do not appear to be a function of the absolute elevation in blood pressure, since ANP levels were significantly different in pregnant women with chronic hypertension vs. those with preeclampsia with comparable blood pressures (22); it should be noted, however, that the stimulus for secretion could differ in the acute us. chronic hypertensive state. Dermal microcirculation is reportedly disturbed by generalized vasoconstriction in preeclampsia (22), but systemic vascular resistance (afterload) is variably affected in preeclampsia (18). Hatjis and Grogan (24) reported a decreased affinity of placental ANP receptors in preeclamptic pregnancies. If placental receptor-mediated clearance plays a major role in ANP metabolism, then decreased receptor affinity could be reflected in increased plasma ANP levels. The possible relationship between ANP and other vasoactive peptides has not been studied in cases of preeclampsia. It has been reported that endothelin-1 (ET-l) can induce the release of ANP both in vivo and in vitro (25, 26). We have previously shown that immunoreactive ET-l levels are elevated in the plasma of women with symptomatic preeclampsia relative to levels in matched normal pregnant controls (27). In the previous longitudinal study we did not detect elevated circulating systemic ET-l concentrations during the midtrimester in asymptomatic women destined to develop preeclampsia. However, since the endothelins are believed to act as paracrine effecters, it is possible that focal ET-l activity is elevated early in the disorder and that increased plasma ANP levels are a sensitive marker of the phenomenon. The pathophysiology of preeclampsia remains poorly understood. Although the disease involves endothelial damage, vasospasm, hypertension, and multiorgan dysfunction, the mediator(s) of this process is unclear (28). The finding that increased plasma ANP antedates the diagnosis of preeclampsia by weeks to months adds to
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
INCREASES
IN ANP
ANTEDATE
several lines of evidence that pathophysiological changes antedate the clinical recognition of the disorder. These include increased sensitivity to vasopressors (29, 30), reduced plasma volume (31), activation of the coagulation cascade (32, 33), hyperuricemia (34), elevated plasma growth factor activity (35), and increased plasma fibronectin (36, 37). As physiological derangements can be detected in asymptomatic women destined to develop preeclampsia, reliable clinical or laboratory predictors of this syndrome have been actively sought. It is obvious that the early recognition of preeclampsia is paramount in reducing maternal and fetal neonatal mortality. Angiotensin sensitivity does appear to aid in the prediction of preeclampsia, but practical disadvantages limit its usefulness as a screening test. The other changes described have not been adequately evaluated as predictors, but, based on large variations between individual women, are unlikely to prove useful. Unfortunately, the overlap of second trimester values in our preliminary study also make it unlikely that ANP will be clinically useful as a cross-sectional predictor of preeclampsia. In conclusion, the results of this longitudinal study indicate that the ANP concentration is increased in women with preeclampsia and that this increase antedates clinically evident disease. The mechanism(s) responsible for the elevation requires further investigation. References 1. Rodeheffer RJ, Tanaka I, Imada T, Hollister AS, Robertson D, Inagami T. Atria1 pressure and secretion of atria1 natriuretic factor into the human central circulation. J Am Co11 Cardiol. 1986;8:18~26. 2. Tikkanen T, Tikkanen I, Fyhrquist F. Plasma atria1 natriuretic peptide in DOCA-NaCl-treated rats. Acta Physiol &and. 1987;129:151-5. 3. Nishiuchi T, Saito H, Yamasaki Y, Saito S. Radioimmunoassay for atria1 natriuretic peptide: method and results in normal subjects and patients with various diseases. Clin Chim Acta. 1986;159:45-, 57. 4. Yamaji T, Ishibashi M, Sekihara H, Takaku F, Nakaoka H, Fujii J. Plasma levels of atria1 natriuretic peptide in primary aldosteronism and essential hvnertension. J Clin Endocrinol Metab. -_ 1986;63:815-8. 5. Hirai N, Yanaihara T, Nakayama T, Ishibashi M, Yamaji ‘I’. Plasma levels of atria1 natriuretic peptide during normal pregnancy and in pregnancy complicated by hypertension. Am J Obstet Gynecol. 198&159:27-31. 6. Miyamoto S, Shimokawa H, Sumioki H, Touno A, Nakano H. Circadian rhythm of plasma atria1 natriuretic peptide, aldosterone, and blood pressure during the third trimester in normal and preeclamptic pregnancies. Am J Obstet Gynecol. 1988;158:393-9. 7. Thomsen JK, Storm TL, Thamsborg G, deNully M, Bodker B. Skouby S. Atria1 natriuretic peptide concentrations in preeclampsia. Br Med J. 1987:294:1508-10. 8. Chesley LC. Diagnosis of preeclampsia. Obstet Gynecol. 1985;65:423-5. 9. Lind T, Godfrey KA, Otun H. Changes in serum uric acid concentrations during normal pregnancy. Br .J Obstet Gynaecol. 1984;91:128-32. 10. DeBold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid, potent natriuretic response to the intravenous injection of atrial
PREECLAMPSIA
1099
myocardial extract in rats. Life Sci. 1981;28:89-94. 11. Lindheimer MD. Katz A. Renal nhvsioloav in nretmancv. In: Seldin DW, Giebisch D, eds. The kidney, physic&y andpathophysiology. New York: Raven Press; 1985;2017-41. 12. Pritchard ,JA. Changes in blood volume during labor and delivery. Anesthesiology. 1965;26:393-9. 13. Metzler CH, Lee M, Thrasher TN. Ramsay DJ. Increased right or left atria1 pressure stimulates release of atria1 natriuretic peptides in conscious dogs. Endocrinology. 1986;119:2396-8. 14. Davidson JM, Dunlop W. Changes in renal hemodynamics and tubular function induced by normal human pregnancy. Semin Nephrol. 1984;4:198-207. 15. Merkouris RW, Miller FC, Catanzarite V, Quirk JG, Rigg LA, Veselv DL. Increase in the nlasma levels of the N-terminal and Cterminal portions of the prohormone of atria1 natriuretic factor during normal pregnancy.Am J Obstet Gynecol. 1990;162:859-64. 16. Robson SC. Hunter S. Dunlon W. Left atria1 dimension during early puerperium. Landet. 1987;2:111-22. 17. Hays PM, Cruikenhank DP, Dunn LJ. Plasma volume determination in normal and preeclamptic pregnancy. Am J Obatet Gynecol. 1985;151:958-66. 18. Clark SL, Cotton DB. Clinical indications for pulmonary artery catheterization in the patient with severe preeclampsia. Am d Obstet Gynecol. 1988;158:453-8. 19. Phelan JP, Yurth DA. Severe preeclampsia. I. Peripartum hemodynamic observations. Am J Obstet Gvnecol. 1982;144:17-22. 20. Easterling TR, Benedetti TK, Schmucker BC, Millard SP. Maternal hemodynamics in normal, preeclamptic pregnancies: a longitudinal study. Obstet Gvnecol. 1990;76:1061-9. 21. Niesert S, Kaulhausen H. Atria1 natriuretic peptide (ANPl during pregnancy. Clin Exp Hypertension Preg. 19887:99-105. 22. Sumioki H. Shimokawa H. Mivamoto S. Uezonr K. Utsunomiva T. Nakand H. Circadian variations of plasma atria1 natriuretic peptide in four types of hypertensive disorder during pregnancy. Br J Obstet Gynaecol. 1989;96:922-7. L ‘3 Yamamoto Y, Higa T, Kitamura K, Tanaka K, Kangawa K, Matsua H. Plasma concentration of human atria1 natriuretic polypeptide in patients with impaired renal function. Clin Nephrol. 1987;27:846. ‘4. Hatjis CG, Grogan DM. Changes in placental atria1 natriuretic pept,ide receptors associated wit,h severe toxemia of pregnancy. Placenta. 1989;10:153-9. 2,5 Garcia R, Lachance D, Thibault G. Positive inotropic action, natriuresis and atria1 natriuretic factor release induced by endothelin in the conscious rat. d Hypertension. 1990;8:725-31. 26. Sei CA, Glembotski CC. Calcium dependence of phenylalanine-, endothelin-, and potassium chloride-stimulated atria1 natriuretic factor secretion from long term primary neonatal rat atria1 cardiocytes. J Biol Chem. 1990;265:7166-72. 27. Taylor RN, Varma M, Teng NNH, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab. 1990;71:16757. 28. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200-4. 29. Gant NF, Chand S, Worley RJ, Whalley PJ, Crosby UD, MacDonald PC. A clinical test useful for predicting the development of acute h,ypertension of pregnancy. Am J Obstet Gynecol. 1974;120:1-7. 30. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout nrimigravid pregnancy. J Clin Invest: 1973;52:2682-9. 31. Gallerv EDM. Hunvor SN. Gvorv AZ. Plasma volume contraction: a significant factor in both pregnancy-associated hypertension (pre-eclampsia) and chronic hypertension in pregnancy. Q J Med. 1979;48:593-60’. 32. Weiner CP, Brandt .J. Plasma antithrombin III activity: an aid to the diagnosis ofpreeclampsia. Am .I Obstet Gynecol. 1982;142:27581. 38. Redman CWG, Denson KWE, Benin LJ, Bolton FG, Stirrat GM. Factor VIII consumption in preeclampsia. Lancet. 1977;2:1249--52. C,
,
G
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
1100
MALEE
34. Hill LM. Metabolism of uric acid in normal and toxemic pregnancy. Mayo Clin Proc. 1978;53:743-51. 35. Taylor RN, Heilbron DC, Roberts JM. Growth factor activity in the blood of women in whom preeclampsia develops is elevated from early pregnancy. Am J Obstet Gynecol. 1990;163:1675-7. 36. Laxarchick J, Stubbs TM, Romein L, Van Dorsten JP, Loadholt
E7’ A,!,.
JCS&M*1992 Vo114.No5
CB. Predictive value of fibronectin levels in normotensive gravid women destined to become preeclamptic. Am J Gbstet Gynecoi. 1986;154:1050-2. 37. Lockwood CJ, Peters JH. Increased plasma levels of EDl+ cellular fibronectin precede the clinical signs of preeclampsia. Am d Obstet. Gynecol. 1990;162:358-62.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
Vol. 74, No. 5 Printed
in U.S.A.
Increases in Plasma Atria1 Natriuretic Peptide Concentration Antedate Clinical Evidence of Preeclampsia” MAUREEN P. MALEE, ROBERT N. TAYLOR,
KATHLEEN AND JAMES
M. MALEE, M. ROBERTS
SCOTT
D. AZUMA,
Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California 94143; Northwestern University (K.M.M.), Chicago, Illinois 60611; and Loyola University of Chicago (S.D.A.), Chicago, Illinois 6061 I
ABSTRACT. Atria1 natriuretic peptide (ANP) concentrations are typically elevated in hypervolemic states. However, ANP levels have been reported to be increased in the peripartum period in women with preeclampsia, a disorder characterized by central hypovolemia. We postulated that ANP levels are elevated in preeclamptic patients before clinically evident disease. ANP concentrations were determined in three groups: uncomplicated pregnancies, pregnancies complicated by preeclampsia, and nonpregnant reproductive-aged women. The former groups were matched for gestational age at plasma sampling and delivery. The plasma samples, obtained prospectively from each patient during the first, second, and third trimesters and within 72 h postpartum, were frozen before RIA. A significant gestational
increase in ANP was noted in both groups of pregnant women, with third trimester levels exceeding first trimester levels (P < 0.05). Consistent with previous reports, ANP levels were elevated in overtly preeclamptic patients us. matched controls in the third trimester. The ANP concentration was also significantly increased during the second trimester in women destined to develop preeclampsia. Postpartum ANP values decreased in the preeclamptic group to approach the level in normal patients postpartum. Thus, it appears that the stimuli of ANP secretion differ in uncomplicated and preeclamptic patients. Moreover, an elevation of plasma ANP is detectable before the onset of clinical evidence of preeclampsia. (J Clin Endocrinol Metab 74: 1095 1100, 1992)
A
ANP concentrations are typically markedly elevated (6, 7) when determined in women with clinically evident disease. It, thus, appears that the mechanism(s) responsible for ANP secretion differs in uncomplicated and preeclamptic pregnancies. Since there is evidence that the pathophysiological changes in preeclampsia antedate clinical recognition of the disorder, we examined ANP concentrations longitudinally in women destined to develop preeclampsia and in matched controls. We report that ANP is increased in the second trimester of pregnancy in women who will become preeclamptic, months before clinical diagnosis of the disorder.
TRIAL natriuretic peptide (ANP) is a volume regulatory hormone with potent natriuretic, diuretic, and vasorelaxant activities. In the adult, ANP secretion is stimulated by increased atria1 pressure and alterations in sodium balance (1,2). Elevated plasma concentrations of ANP accompany several pathological disorders characterized by fluid overload, including cirrhosis, congestive heart failure, and chronic renal failure (3, 4). ANP levels comparable to those in nonpregnant reproductiveaged women have been reported in some women with uncomplicated pregnancies (5). Elevated concentrations also have been reported in this group, with the increases being attributed to plasma volume expansion (6). In pregnancies complicated by preeclampsia, a disorder exclusive to pregnancy and characterized by hypertension, proteinuria, edema with central hypovolemia, and laboratory evidence of multiple organ system involvement,
Subjects Experimental
subjects
All pregnant University
and Methods
women of California,
registering for prenatal care at the San Francisco, and at San Francisco
General Hospital since July 1988 were invited to participate in a prospective study of preeclampsia. Participating patients gave written informed consent, using a form approved by the University’s Committee on Human Research.
Received February 14, 1991. Address all correspondence and requests for reprints to: M P. Malee, M.D., Ph.D., Department of Obstetrics and Gynecology, IJniversity of Iowa, Iowa City, Iowa 52242. * This work was supported by NIH Grant HD-24180. This is publication 13 from the University of California San Francisco Preeclampsia Program Project.
Sample collection In pregnant women participating in the study, first, second, and third trimester venous blood samples were obtained during 1095
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
MALEE
1096
routine out-patient visits. Blood was drawn from the left antecubital vein after approximately 30 min of stabilization in a seatedposition. During these visits, blood pressure(first and fifth heart sounds) and weight were recorded. Due to the prospective longitudinal design of this study, no systematic differencesexisted betweenthe samplingtechniquesof uncomplicated us. preeclamptic women. Peripartum and postpartum phlebotomy techniqueswere similarly standardized (recumbent position) for uncomplicated and preeclamptic patients. Peripartum blood sampleswereobtained before the administration of analgesics,anesthetics,antihypertensive agents, or magnesiumsulfate, and postpartum sampleswere drawn after discontinuation of magnesiumsulfate seizure prophylaxis. Thus, no obvious confounding systematic variation between the two pregnant groupsexisted. Blood samplesfrom pregnant [uncomplicated (n = 10) and preeclamptic (n = lo)] and nonpregnant (n = 10) subjectswere handled similarly. Plasmawasprepared by centrifugation at 6000 x g for 30 min. aliquoted, and frozen (-70 C) within 8 h of venipuncture. The mean time to plasma processingwas identical in both groups; moreover, regression analysisrevealed no apparent effect of time before processing on ANP concentration for all samples.Sampleswere stored frozen until RIA. Subject selection
The womenstudied in this cohort were followed throughout pregnancy, during labor and delivery, and for more than 12 weekspostpartum with serial clinical observations, including measurementsof blood pressureand proteinuria. At the completion of the final postpartum evaluation (~12 weeks after delivery), the clinical and laboratory data were reviewed by a jury of clinical investigators who were blinded to the resultsof the plasma ANP determinations. Preeclamptic patients fulfilled criteria recommendedby Chesley(8), namely nulliparity, absenceof a history of hypertension before pregnancy, increase in diastolic pressureof 15 mm Hg or systolic pressureof 30 mm Hg comparedto blood pressuresobtained before 20 gestational weeks,proteinuria greater than 0.5 g/24 h or greater than 30 mg/dL in a catheterized specimen,hyperuricemia greater than 5.5 mg/dL [or 1 SD greater than the normal mean value for gestationslessthan 36 weeks (9)], and return to normal blood pressureand resolution of proteinuria by 12 weekspostpartum. Normal controls were selectedfrom the samecohort of parturients, in whom neither hypertension, proteinuria, nor hyperuricemia was observedthroughout the study period. None of the patients was sodiumrestricted. They had normal diets and took no medications except prenatal vitamins. Criteria that resulted in the exclusion of patients from this study were the identification of any chronic metabolic disease,evidence of illicit drug use by urine toxicology screens,or the failure of elevated blood pressure, hyperuricemia, or proteinuria to resolve within 12 weeks of delivery. Patients from the normal group were matched as closely as possibleby age, gestational age at delivery and at times of blood sampling, weight, and parity to the preeclampticpatients. Nonpregnant normotensive reproductive-agedwomenserved as controls.
E7’ AL.
.I(‘E&M.lSM
f?xtmction
nnti R/t\ o/plasm0
At room temperature and using a vacuum manifold, 1 ml, plasma was extracted on Amprep minicolumns (C18; Amersham International, Aylesbury, Buckinghamshire, United Kingdom) using 60% CH,,CN and 0.1% trifluoroacetic acid (Sigma Chemical Co., St. Louis, MO). The desiredeluate was collected, concentrated under nitrogen, centrifuged under vacuum, and reconstituted with assay buffer for RIA. Recovery was 87%. ANP levels were determined by an ANP RIA kit, using an antibody specific for (u-humanANP (aa98-126,Peninsula Laboratories, Inc., Belmont, CA) according to the manufacturer’s specifications. The sensitivity was 1 pg/tube. All data reported in this paper were from samplesanalyzed simultaneously in duplicate, with the results averaged; intraassay variation was 3.19 + 0.25%. However, typical ANP interassay variation in this laboratory is 7.26 k 0.39%. Statistics
Nonparametric statistics were useddue to the small sample size. The Spearman p statistic was used to determine the relationship between ANP and weight gain and betweenANP and meanarterial pressure(MAP). The Mann-Whitney U test for small sampleswas calculated to determine group differences.Student’s t test was used for the multiple comparisons in Table 3. Significance was taken at P c 0.05 for two-sided tests. Results Descriptive data for the women participating in the study are reported in Table 1. Table 2 depicts peripartum clinical findings for both uncomplicated and preeclamptic gestations. As anticipated from the diagnostic criteria, the mean MAP in the preeclamptic group (96.4 rtr 1.8 mm Hg) significantly exceeded that in the uncomplicated pregnancy group (82.7 + 2.1 mm Hg) in the third trimester (P < 0.05). Total weight gain in the preeclamptic group (19.8 + 1.8 kg) exceeded that in the uncomplicated group (13.7 + 1.8 kg; P < 0.05). The plasma levels of ANP and MAPS in matched uncomplicated and pree‘I‘~t31.E
1.
Uescriptivedata UncomplicatedPreeclamptic
Gestationalageat delivery(weeks) Gravidity Parity Modeof delivery (sl,) Ceearean section Vaginaldelivery Newborn
wt (g)
Race(%) Caucasian Black Hispanic Other No. ” Mean
40.4 + 0.5” 2.8 f 0.7 0.9 f 0.3
37.6 It 0.6 1.6 f 0.3 0.0
20 80
50 50
3353.0
f 197.1 2887.5f 143.2 80
10 10
40 20 30
10 10
t SIN.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
10
INCREASES
IN ANP
ANTEDATE
TABLE 2. Antepartum clinical findings
MAP (mm Hg) Proteinuria (negative to 4+) Wt gain (kg) Uric acid (mmol/L) Creatinine (mmol/L) Hemoglobin (g/L) Hematocrit (vol fraction)
Discussion
Uncomplicated 82.7 * 2.1” Negative 13.7 + 1.8 0.22 + 0.01 57 f 2 126 f 3 0.36 f 0.01
Preeclamptic 96.5 + l.Sb 2+ 19.8 f l.Sb 0.36 + 0.01 63 f 12 123 + 4 0.36 + 0.01
’ Mean f SEM. b P < 0.05.
clamptic pregnant women followed longitudinally and in nonpregnant reproductive-aged women are listed in Table 3. The MAP values in the first and second trimesters were not different in the uncomplicated (82.6 + 2.2 and 83.3 + 2.3 mm Hg) and preeclamptic (86.7 + 3.4 and 82.1 + 2.4 mm Hg) groups. The postpartum ANP level in the uncomplicated pregnancy group (17.0 + 1.3 pg/mL) exceeded concentrations attained throughout gestation (P C 0.05). However, in the preeclamptic group, the greatest ANP level achieved was that in the third trimester (31.0 + 4.3 pg/mL). Moreover, the second trimester ANP concentration was elevated in preeclamptic women (18.5 f 3.4 pg/mL). Both of these second and third trimester ANP values in the preeclamptic group significantly exceeded levels in the uncomplicated group (P < 0.05). These data are also presented in scattergram form in Fig. 1. Finally, there was a significant positive correlation between ANP levels and MAP in the third trimester of preeclamptic gestations (r = 0.662; P < 0.05). However, no correlations were noted between ANP levels and mean arterial pressure in the first and second trimesters, weight gain, blood urea nitrogen, uric acid, or creatinine in either the uncomplicated or preeclamptic group. TABLE 3. Plasma ANP levels and MAP in uncomplicated reproductive-aged women
ANP is the 2%amino acid carboxy-terminal end of the 126-amino acid ANP prohormone (10) that is synthesized in cardiac myocytes. ANP has potent vasorelaxant, natriuretic, and diuretic activities, and plasma concentrations are reportedly unchanged or increased in uncomplicated pregnancy (5, 6). The wide variation in previously reported circulating levels of ANP in pregnancy may be a function of differing extraction methods and/ or antibody specificity. Previous studies, however, have also been limited, in that they did not follow the same population longitudinally. In the present study ANP concentrations during uncomplicated pregnancy were significantly increased in the third trimester, but were greatest when determined within the first 72 h postpartum. These changes were not surprising given the gradual but marked increase in plasma volume during normal pregnancy, the progressive sodium accumulation, and the acute physiological increase in right and left atria1 pressures after placental separation (11-13). Moreover, the further increase in ANP observed in the early puerperium coincides with the shift in body fluid from extravascular to intravascular space and subsequent diuresis (14). Merkouris et al. (15) reported similar findings in a cross-sectional study of uncomplicated pregnancy and its puerperal period, and Robson et al. (16) noted significant increases in atria1 dimensions by echocardiogram when examined 48 h after delivery. Several investigators (6, 7) have noted a significant elevation in ANP coincident with clinically evident preeclampsia, with the degree of elevation reflecting the severity of disease. Significantly increased ANP levels similarly were found with clinical evidence of disease in the current study. An elevation of ANP in preeclampsia
and preeclamptic
pregnant women followed longitudinally
1st trimester 9 rt 1 weeks” (5.9-11.6)b
2nd trimester 23 + 1 weeks (14.7-27.7)
Uncomplicated ANP (pg/mL) MAP (mm Hg) Preaclamptic
10.9 + 1.1’ 82.6 f 2.2
ANP WmL) MAP (mm Hg)
12.9 f 0.9 86.7 + 3.4
Nonpregnant ANP @g/mL)
1097
PREECLAMPSIA
14.2 + 1.5
and in nonpregnant
3rd trimester 37 f 1 weeks (34.1-41.7)
Postpartum 27.6 f 2.6 h (24-72)
12.1 f 0.9 83.2 3~ 2.3
14.2 jl 0.5” 82.7 k 2.1
17.0 f 1.3d*’ 86.4 It 2.5
18.5 f 3.4”j 82.1 t 2.4
31.1 + 4.3d’ 96.5 + l.Sd,‘l
21.8 f 2.8“ 88.9 f 2.1
--
’ Mean + SEM weeks gestation or hours postpartum. b Range in weeks gestation or hours postpartum is in parentheses. ’ Mean rf: SEM. d P < 0.05 us. first trimester value in the same group. ‘P < 0.05 us. all antepartum values in the same group. ‘P < 0.05 us. comparable values in the uncomplicated group.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
MALEE
1098 80 ,
I
*
I
0 ’ 2nd trimester
3rd trimester
postpartum
FIG. 1. Longitudinal plasma ANP concentrations in women with normal and preeclamptic pregnancies. Plasma ANP concentrations (picograms per mL) in 10 uncomplicated pregnancies (0) and 10 matched pregnancies in whom preeclampsia developed (0) are plotted in a scattergram. Longitudinal samples obtained during the second and third trimesters of pregnancy and within 72 h postpartum are indicated. (First trimester values are reported in Table 3.) Conservative nonparametric statistical analyses revealed significant differences between the 2 groups in the second and third trimesters (P c 0.05, by MannWhitney tests). Horizontal bars indicate the mean ANP concentrations for each patient group.
is perplexing, since most studies characterize preeclamptic women as hypovolemic compared to normal pregnant women (17), and known stimuli for ANP secretion in adults include hypervolemia and tachycardia (1, 2). As reviewed by Clark and Cotton (18), common central hemodynamic findings in preeclampsia include normal heart rate; low to normal central venous pressure, a measure of the preload of the right heart; and a low, normal, or rarely elevated pulmonary capillary wedge pressure, reflecting the preload of the left heart. The afterload of the right heart, indicated by pulmonary vascular resistance, is not elevated in preeclampsia. However, the afterload of the left heart, the systemic vascular resistance, is variably elevated in preeclampsia (19). No studies in which afterload is singly affected and accompanied by alterations in ANP concentrations are available. It should be noted, however, that a recent report by Easterling et al. (20) suggests that cardiac output is actually increased in preeclampsia throughout pregnancy and that the hemodynamic abnormality persists postpartum. Thus, in preeclampsia, a stimulus to the secretion of ANP that is to date unknown and/or alterations in the metabolic clearance of ANP could be evoked. This conclusion is supported by the finding in the present investigation that an elevation of the ANP concentration antedates clinical evidence of disease. These data reiterate the systemic nature of the disease and the concept that effects on multiple organ systems and the fetoplacental unit antedate clinical evidence of disease. Other mechanisms for increased ANP concentrations
El’
.4L.
JCE&M.1932
in preeclampsia also have been proposed. Niesert and Kaulhausen (21) suggested that ANP levels were elevated in preeclampsia secondary to decreased clearance, which, in turn, was a function of decreased glomerular filtration rate or increased blood pressure. Although the glomerular filtration rate in preeclampsia may be less than that in normal pregnancy, it is unlikely to be the cause of increased ANP, since it is rarely less than that in nonpregnant controls (22). Moreover, Yamamoto et al. (23) found that in nonpregnant adults, impaired renal function (creatinine, 2.0-8.3 mg/dL) unaccompanied by cardiomegaly or hypertension was not associated with increased ANP levels. Finally, creatinine levels in our preeclamptic group were not different from control values, and there was no correlation of ANP levels with creatinine concentrations. The ANP concentrations in preeclampsia also do not appear to be a function of the absolute elevation in blood pressure, since ANP levels were significantly different in pregnant women with chronic hypertension vs. those with preeclampsia with comparable blood pressures (22); it should be noted, however, that the stimulus for secretion could differ in the acute us. chronic hypertensive state. Dermal microcirculation is reportedly disturbed by generalized vasoconstriction in preeclampsia (22), but systemic vascular resistance (afterload) is variably affected in preeclampsia (18). Hatjis and Grogan (24) reported a decreased affinity of placental ANP receptors in preeclamptic pregnancies. If placental receptor-mediated clearance plays a major role in ANP metabolism, then decreased receptor affinity could be reflected in increased plasma ANP levels. The possible relationship between ANP and other vasoactive peptides has not been studied in cases of preeclampsia. It has been reported that endothelin-1 (ET-l) can induce the release of ANP both in vivo and in vitro (25, 26). We have previously shown that immunoreactive ET-l levels are elevated in the plasma of women with symptomatic preeclampsia relative to levels in matched normal pregnant controls (27). In the previous longitudinal study we did not detect elevated circulating systemic ET-l concentrations during the midtrimester in asymptomatic women destined to develop preeclampsia. However, since the endothelins are believed to act as paracrine effecters, it is possible that focal ET-l activity is elevated early in the disorder and that increased plasma ANP levels are a sensitive marker of the phenomenon. The pathophysiology of preeclampsia remains poorly understood. Although the disease involves endothelial damage, vasospasm, hypertension, and multiorgan dysfunction, the mediator(s) of this process is unclear (28). The finding that increased plasma ANP antedates the diagnosis of preeclampsia by weeks to months adds to
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
INCREASES
IN ANP
ANTEDATE
several lines of evidence that pathophysiological changes antedate the clinical recognition of the disorder. These include increased sensitivity to vasopressors (29, 30), reduced plasma volume (31), activation of the coagulation cascade (32, 33), hyperuricemia (34), elevated plasma growth factor activity (35), and increased plasma fibronectin (36, 37). As physiological derangements can be detected in asymptomatic women destined to develop preeclampsia, reliable clinical or laboratory predictors of this syndrome have been actively sought. It is obvious that the early recognition of preeclampsia is paramount in reducing maternal and fetal neonatal mortality. Angiotensin sensitivity does appear to aid in the prediction of preeclampsia, but practical disadvantages limit its usefulness as a screening test. The other changes described have not been adequately evaluated as predictors, but, based on large variations between individual women, are unlikely to prove useful. Unfortunately, the overlap of second trimester values in our preliminary study also make it unlikely that ANP will be clinically useful as a cross-sectional predictor of preeclampsia. In conclusion, the results of this longitudinal study indicate that the ANP concentration is increased in women with preeclampsia and that this increase antedates clinically evident disease. The mechanism(s) responsible for the elevation requires further investigation. References 1. Rodeheffer RJ, Tanaka I, Imada T, Hollister AS, Robertson D, Inagami T. Atria1 pressure and secretion of atria1 natriuretic factor into the human central circulation. J Am Co11 Cardiol. 1986;8:18~26. 2. Tikkanen T, Tikkanen I, Fyhrquist F. Plasma atria1 natriuretic peptide in DOCA-NaCl-treated rats. Acta Physiol &and. 1987;129:151-5. 3. Nishiuchi T, Saito H, Yamasaki Y, Saito S. Radioimmunoassay for atria1 natriuretic peptide: method and results in normal subjects and patients with various diseases. Clin Chim Acta. 1986;159:45-, 57. 4. Yamaji T, Ishibashi M, Sekihara H, Takaku F, Nakaoka H, Fujii J. Plasma levels of atria1 natriuretic peptide in primary aldosteronism and essential hvnertension. J Clin Endocrinol Metab. -_ 1986;63:815-8. 5. Hirai N, Yanaihara T, Nakayama T, Ishibashi M, Yamaji ‘I’. Plasma levels of atria1 natriuretic peptide during normal pregnancy and in pregnancy complicated by hypertension. Am J Obstet Gynecol. 198&159:27-31. 6. Miyamoto S, Shimokawa H, Sumioki H, Touno A, Nakano H. Circadian rhythm of plasma atria1 natriuretic peptide, aldosterone, and blood pressure during the third trimester in normal and preeclamptic pregnancies. Am J Obstet Gynecol. 1988;158:393-9. 7. Thomsen JK, Storm TL, Thamsborg G, deNully M, Bodker B. Skouby S. Atria1 natriuretic peptide concentrations in preeclampsia. Br Med J. 1987:294:1508-10. 8. Chesley LC. Diagnosis of preeclampsia. Obstet Gynecol. 1985;65:423-5. 9. Lind T, Godfrey KA, Otun H. Changes in serum uric acid concentrations during normal pregnancy. Br .J Obstet Gynaecol. 1984;91:128-32. 10. DeBold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid, potent natriuretic response to the intravenous injection of atrial
PREECLAMPSIA
1099
myocardial extract in rats. Life Sci. 1981;28:89-94. 11. Lindheimer MD. Katz A. Renal nhvsioloav in nretmancv. In: Seldin DW, Giebisch D, eds. The kidney, physic&y andpathophysiology. New York: Raven Press; 1985;2017-41. 12. Pritchard ,JA. Changes in blood volume during labor and delivery. Anesthesiology. 1965;26:393-9. 13. Metzler CH, Lee M, Thrasher TN. Ramsay DJ. Increased right or left atria1 pressure stimulates release of atria1 natriuretic peptides in conscious dogs. Endocrinology. 1986;119:2396-8. 14. Davidson JM, Dunlop W. Changes in renal hemodynamics and tubular function induced by normal human pregnancy. Semin Nephrol. 1984;4:198-207. 15. Merkouris RW, Miller FC, Catanzarite V, Quirk JG, Rigg LA, Veselv DL. Increase in the nlasma levels of the N-terminal and Cterminal portions of the prohormone of atria1 natriuretic factor during normal pregnancy.Am J Obstet Gynecol. 1990;162:859-64. 16. Robson SC. Hunter S. Dunlon W. Left atria1 dimension during early puerperium. Landet. 1987;2:111-22. 17. Hays PM, Cruikenhank DP, Dunn LJ. Plasma volume determination in normal and preeclamptic pregnancy. Am J Obatet Gynecol. 1985;151:958-66. 18. Clark SL, Cotton DB. Clinical indications for pulmonary artery catheterization in the patient with severe preeclampsia. Am d Obstet Gynecol. 1988;158:453-8. 19. Phelan JP, Yurth DA. Severe preeclampsia. I. Peripartum hemodynamic observations. Am J Obstet Gvnecol. 1982;144:17-22. 20. Easterling TR, Benedetti TK, Schmucker BC, Millard SP. Maternal hemodynamics in normal, preeclamptic pregnancies: a longitudinal study. Obstet Gvnecol. 1990;76:1061-9. 21. Niesert S, Kaulhausen H. Atria1 natriuretic peptide (ANPl during pregnancy. Clin Exp Hypertension Preg. 19887:99-105. 22. Sumioki H. Shimokawa H. Mivamoto S. Uezonr K. Utsunomiva T. Nakand H. Circadian variations of plasma atria1 natriuretic peptide in four types of hypertensive disorder during pregnancy. Br J Obstet Gynaecol. 1989;96:922-7. L ‘3 Yamamoto Y, Higa T, Kitamura K, Tanaka K, Kangawa K, Matsua H. Plasma concentration of human atria1 natriuretic polypeptide in patients with impaired renal function. Clin Nephrol. 1987;27:846. ‘4. Hatjis CG, Grogan DM. Changes in placental atria1 natriuretic pept,ide receptors associated wit,h severe toxemia of pregnancy. Placenta. 1989;10:153-9. 2,5 Garcia R, Lachance D, Thibault G. Positive inotropic action, natriuresis and atria1 natriuretic factor release induced by endothelin in the conscious rat. d Hypertension. 1990;8:725-31. 26. Sei CA, Glembotski CC. Calcium dependence of phenylalanine-, endothelin-, and potassium chloride-stimulated atria1 natriuretic factor secretion from long term primary neonatal rat atria1 cardiocytes. J Biol Chem. 1990;265:7166-72. 27. Taylor RN, Varma M, Teng NNH, Roberts JM. Women with preeclampsia have higher plasma endothelin levels than women with normal pregnancies. J Clin Endocrinol Metab. 1990;71:16757. 28. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200-4. 29. Gant NF, Chand S, Worley RJ, Whalley PJ, Crosby UD, MacDonald PC. A clinical test useful for predicting the development of acute h,ypertension of pregnancy. Am J Obstet Gynecol. 1974;120:1-7. 30. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout nrimigravid pregnancy. J Clin Invest: 1973;52:2682-9. 31. Gallerv EDM. Hunvor SN. Gvorv AZ. Plasma volume contraction: a significant factor in both pregnancy-associated hypertension (pre-eclampsia) and chronic hypertension in pregnancy. Q J Med. 1979;48:593-60’. 32. Weiner CP, Brandt .J. Plasma antithrombin III activity: an aid to the diagnosis ofpreeclampsia. Am .I Obstet Gynecol. 1982;142:27581. 38. Redman CWG, Denson KWE, Benin LJ, Bolton FG, Stirrat GM. Factor VIII consumption in preeclampsia. Lancet. 1977;2:1249--52. C,
,
G
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
1100
MALEE
34. Hill LM. Metabolism of uric acid in normal and toxemic pregnancy. Mayo Clin Proc. 1978;53:743-51. 35. Taylor RN, Heilbron DC, Roberts JM. Growth factor activity in the blood of women in whom preeclampsia develops is elevated from early pregnancy. Am J Obstet Gynecol. 1990;163:1675-7. 36. Laxarchick J, Stubbs TM, Romein L, Van Dorsten JP, Loadholt
E7’ A,!,.
JCS&M*1992 Vo114.No5
CB. Predictive value of fibronectin levels in normotensive gravid women destined to become preeclamptic. Am J Gbstet Gynecoi. 1986;154:1050-2. 37. Lockwood CJ, Peters JH. Increased plasma levels of EDl+ cellular fibronectin precede the clinical signs of preeclampsia. Am d Obstet. Gynecol. 1990;162:358-62.
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 23 November 2015. at 08:43 For personal use only. No other uses without permission. . All rights reserved.
