- Email: [email protected]
creatinine ratio and microalbuminuria in the prediction of preeclampsia
Calcium/ creatinine ratio and microalbuminuria in the prediction of preeclampsia M. Hellen Rodriguez, MD, Damon I. Masaki, MD, Jorge Mestman, MD, Dinesh Kumar, MD, and Robert Rude, MD Los Angeles, California Eighty-eight normotensive gravid women between 24 and 34 weeks of gestation underwent urine evaluation for the presence of microalbuminuria and urinary calcium excretion (calcium/creatinine ratio). Preeclampsia subsequently developed in 83% of patients with a high level of microalbuminuria (""11 µg/ml) and a low calcium/creatinine ratio (,,;Q.04). Conversely, 94% of women who did not demonstrate high microalbuminuria and a low calcium/creatinine ratio remained normotensive at the time of delivery. These results suggest that changes in renal function are present in gravid women who are otherwise free of symptoms in whom preeclampsia will eventually develop. Testing for microalbuminuria and a calcium/creatinine ratio may be a useful screening tool in predicting the subsequent development of preeclampsia. (AM J 0BSTET GYNECOL 1988;159:1452-5.)
Key words: Microalbuminuria, calcium/creatinine ratio, preeclampsia
Several methods of identifying pregnant women who are at risk for preeclampsia have been proposed. These include the use of an angiotensin II pressor response, 1 the rollover test, 2 the isometric handgrip exercise test," and the mean arterial pressure test.' These tests, however, have had limitations as screening tools in the clinical setting because of either their complexity, the high incidence of false-positive results, or the subjective nature of result interpretation. Renal function changes in preeclampsia have been documented and several prospective studies indicate that at least some of these changes are present before the clinical diagnosis of preeclampsia. Proteinuria has classically been an important sign in the diagnosis of preeclampsia. However, customary dipstick methods for detecting proteinuria fail to detect minimal elevations in urinary excretion of albumin that may be present before other clinical signs and symptoms of preeclampsia. With the recent development of the radioimmunoassay for detection of microalbuminuria, it is now possible to detect minimal elevations in albumin excretion that would have gone unnoticed in the past.
From the Departments of Obstetrics and Gynecology and Medicine, Universit)" of Southern California School of Medicine, and Los Angeles County-University of Southern California Medical Centfl". Supported by a grant (GCRC RR-43) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Pre.1ented at the Thirty-fifth Annual Meeting of the Society for Gynecologic Investigation, Baltimore, Maryland, March 17-20, 1988. Reprint requests: M. Hellen Rodriguez. MD, San Gabriel Valley Perinatal Medical Group, 1135 S. Sunset Ave., Suite 402, West Cm•ina, CA 91793.
1452
In addition, Taufield et al. 5 have recently demonstrated that preeclampsia is associated with hypocalciuria. The purpose of this study was to determine whether the presence of microalbuminuria or hypocalciuria, or both, in the pregnant woman who is free of symptoms can predict the subsequent development of preeclampsia. Patients and methods
Normal pregnant women between 24 and 34 weeks of gestation being seen at the Los Angeles County/University of Southern California Women's Hospital for prenatal care were invited to participate in the study. Women were excluded from the study if they had a history of chronic hypertension, diabetes, renal disease, if at the time of entry into the study they had a blood pressure that was :;,, 140/90 mm Hg, or if they had any evidence of proteinuria by the dipstick method. Once the patients were entered into the study, a first-morning fasting urine specimen was analyzed for microalbuminuria, and calcium and creatinine levels. No dietary alterations were recommended. After urine collection, the patients received routine prenatal care, and at the time of delivery the charts were reviewed for the presence of preeclampsia. The presence of preeclampsia was defined as the presence of a blood pressure of 140/90 mm Hg or a rise of 30 mm Hg in systolic pressure or of 15 mm Hg in diastolic pressure (measured twice, 6 hours apart at bed rest) associated with proteinuria or edema, or both. The concentration of urine albumin was established by a double-antibody iodine 125 radioimmunoassay (Diagnostic Products Corporation, Los Angeles, Calif.) designed for the detection of concentrations of al-
Calcium/creatinine and microalbuminuria in preeclampsia
Volume 159 1\umber 6
1453
Ca/Cr• .04 80%.
~
60%
40%
20% 0%'--~~~_L_~~~_L_~~~L_~~~L_~~~L_~~__J
0
0.1
0.3
0.2
0.4
0.5
0.6
1-SPECIFICITY Fig. I. Receiver operator curve for calcium/creatinine (Ca/Cr) ratio. Threshold value set at 0.04.
Table I. Maternal characteristics of study groups Group 1: Patients in whom preeclampsia did not develop (n = 78)
Mean maternal age (yr) ( :t: 1 SD) Primigravida women Mean gestational age (wk) at entrance into study (:t: 1 SD) Mean arterial blood pressure in mm Hg (:t: I SD) at entrance into study Mean urine calcium/ creatinine ratio at entrance into study (:t: 1 SD) Mean albumin concentration (µg/ml) at entrance into study ( :t: I SD) Mean gestational age (wk) at delivery ( :t: I SD) Mean arterial blood pressure (mm Hg) ( :t: 1 SD) at delivery
Group 2: Patients in whom preeclrunpsia developed (n = 10)
Total: All /wtients entered into .1111dv
27.3 :t: 6.1
30.6 :t: S.8
28.l :t: S.3
9 28 :t: 2.9
4 30 :t: 3.1
13 28 :t: 2.7
(n =
8BJ
70.7 :t: 8.8
72.3 :t: 12.9
71.S :t: 8.4
0.13 :t: 0.11
0.07 :t: 0.12
0.12 :t: 0.11
5.68 :t: 6.7
8.84 :t: 7.6
5. 76 :t: 6.:)
40 :t: 1.9
38 :t: 2.5
40 :t: 2.1
78.3 :t: 8.5
101.5 :t: 8.6
80.1 :t: 8.7
bumin not detectable by conventional dipstick methods. Urine calcium concentration was determined by atomic absorption spectrophotometry. Urine creatinine concentration was determined with a colorimetric AutoAnalyzer. The calcium concentration (in milligrams per deciliter) was divided by the creatinine concentation (in milligrams per deciliter) to derive the calcium/ creatinine ratio. With use of the receiver operator curve, threshold values of albumin concentrations and calcium/creatinine ratio for the subsequent development of preeclampsia were established. 6 The sensitivity, specificity,
and positive and negative predictive values of a low calcium/creatinine ratio and a high albumin concentration, and the combination were then calculated. This investigation was approved by the U niversitv of Southern California School of Medicine Human Research Committee. Results Table I presents information on the maternal characteristics of all patients entered into the study, patients who remained normotensive (group I), and patients in whom preeclampsia developed (group 2). Preeclampsia
1454
Rodriguez et al.
December l 988 Am J Obstet Gynecol
SENSITIVITY 100%.--~~~~~~~~~~~~~~~~~~~~~~~~--,
80%
[Alb] • 11 Ug/MI
t 60%
40%
20%
0%"'-~~~~~__J~~~~~~--'-~~~~~~--'-~~~~~~~
0
0.3
0.2
0.1
0.4
1-SPECIFICITY Fig. 2. Receiver operator curve for albumin concentration (Alb). Threshold value set at 11 µg/ml.
Table II. Screening value of hypocalciuria and microalbuminuria Calcium/ creatinine ratio ~0.04
Patients with preeclampsia Patients with norma! outcome Sensitivity (%) Specificity (%) Positive predictive value(%) Negative predictive value (%)
Albumin ""11 µ,glml
7
5
4
14
Calcium I creatinine ratio ~0.04 and albumin ""I I µ,glml
5
70
50
50
95 64
82 26
99 83
96
93
94
developed in IO (11.3%) patients. The mean maternal age, gestational age at entrance into the study, and mean arterial blood pressure at entrance into the study of these patients did not significantly differ from those of patients who remained normotensive. Forty percent of the patients in whom preeclampsia developed were primigravid compared with 11.5% of those who remained normotensive. With use of the receiver operator curve (Fig. l) a urine calcium/creatinine ratio threshold value of 0.04 was chosen as predictive for the development of preeclampsia. Seven of 10 patients in whom preeclampsia developed had a calcium/creatinine ratio of ~0.04. Four patients in whom preeclampsia did not develop had a calcium/creatinine ratio of ~0.04. This gives the calcium/ creatinine ratio a sensitivity of 70%, a specificity of 95%, a positive predictive value of 64%, and a negative predictive value of 96%. Again, with use of the receiver operator curve (Fig. 2) a urine albumin concentration of 11 µg/ml was
chosen as predictive for the development of preeclampsia. Five of 10 patients in whom preeclampsia developed had an albumin concentration ~ 11 µg I ml. Fourteen patients who remained normotensive had an albumin level ~ 11 µg I ml. This gives the test a sensitivity of 50% and a specificity of 82%, a positive predictive value of 26%, and a negative predictive value of 93%. When both tests are combined and required to predict the subsequent development of preeclampsia, five of 10 patients in whom preeclampsia developed and one who remained normotensive met both criteria. This resulted in a sensitivity of 50%, specificity of 99%, positive predictive value of 83%, and a negative predictive value of 94%. A summary of the above results is given in Table II. Comment
Preeclampsia can cause changes in virtually all organ systems, most notably the cardiovascular, renal, hematologic, and immunologic systems. Some of these
Volume 159 Number 6
changes are present before the clinical diagnosis of preeclam psia, as has been clearly demonstrated by several investigators. 1• 7 Proteinuria and alterations in calcium excretion are common features of various forms of hypertension and renal disorders. Minimally increased excretion of albumin is not generally measurable by the dipstick method, which is the test ordinarily used to screen for proteinuria. Such slightly increased excretion of albumin has been shown to be predictive of the subsequent development of clinical nephropathy in insulin-dependent diabetic patients. 8 Because proteinuria is one of the classic signs of preeclampsia, it was hypothesized that the presence of microalbuminuria or hypocalciuria might be useful in predicting which patients will develop preeclampsia. Our study confirms that changes in renal function are present in some otherwise symptom-free patients in whom preeclampsia will eventually develop. Classically, preeclampsia is a disease of the primigravid patient, with at least two thirds of the cases occuring in this group. 9 Only 40% of our patients in whom preeclampsia developed were primigravid. This may indicate that our population, which consists mostly of a lower socioeconomic group of Hispanic women, may constitute a subgroup of patients in whom preeclampsia will develop that may differ from the general population. Before this data can be generalized, it needs to be duplicated in other population groups. We conclude that in our population the presence of microalbuminuria in combination with a low calcium/ creatinine ratio may be a useful screening tool between 24 to 34 weeks of gestation for predicting the
Calcium I creatinine and microalbuminuria in preeclampsia 1455
development of preeclampsia in patients who are free of symptoms. When used as a single test, the urinary calcium/ creatinine ratio is a better predictor of preeclampsia than the urinary microalbumin concentration, and it is easily and inexpensively available.
'REFERENCES I. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest l 973;52:2682-9. 2. Gant NF, Chand S, Worley RJ, Whalley PJ, Crosby UD, MacDonald PC. A clinical test useful for predicting the development of acute hypertension in pregnancy. AYI .J 0BSTET GYNECOL 1974;120:1-7. 3. Degani S, Abinader E, Eibschitz I, Oettinger M, Shapiro I, Sharf M. Isometric exercise test for predicting gestational hypertension. Obstet Gynecol I 985;65:652-4. 4. Oney T, Kaulhausen H. The value of mean arterial blood pressure in the second trimester (MAP-2 value) as a predictor of pregnancy-induced hypertension and preeclampsia: a preliminary report. Clin Exp Hypertens (B) 1983; B2:2 I 1-6. 5. Taufield PA, Ales KL, Resnik LM, Druzin ML, Gertner JM, Laragh JH. Hypocalciuria in preeclampsia. N Engl .J Med 1987;316:715-8. 6. Fink DJ, Galen RF. Probabilistic approach to clinical decision support. In: Williams BT, ed. Computer aids to clinical decisions. vol. 2. Boca Raton, Florida: CRC, 1982: 165. 7. Gallery EDM, Gyory AZ. Glomerular and proximal renal tubular function in pregnancy-associated hypertension: a prospective study. Eur J Obstet Gynecol Reprod Biol l 979;9:3-12. 8. Viberti GC, Hill RD,Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982;1:1430-2. 9. MacGillivray I. Some observations in the incidence of preeclampsia. J Obstet Gynaecol Br Emp l 958;65:536-9.
Key words: Microalbuminuria, calcium/creatinine ratio, preeclampsia
Several methods of identifying pregnant women who are at risk for preeclampsia have been proposed. These include the use of an angiotensin II pressor response, 1 the rollover test, 2 the isometric handgrip exercise test," and the mean arterial pressure test.' These tests, however, have had limitations as screening tools in the clinical setting because of either their complexity, the high incidence of false-positive results, or the subjective nature of result interpretation. Renal function changes in preeclampsia have been documented and several prospective studies indicate that at least some of these changes are present before the clinical diagnosis of preeclampsia. Proteinuria has classically been an important sign in the diagnosis of preeclampsia. However, customary dipstick methods for detecting proteinuria fail to detect minimal elevations in urinary excretion of albumin that may be present before other clinical signs and symptoms of preeclampsia. With the recent development of the radioimmunoassay for detection of microalbuminuria, it is now possible to detect minimal elevations in albumin excretion that would have gone unnoticed in the past.
From the Departments of Obstetrics and Gynecology and Medicine, Universit)" of Southern California School of Medicine, and Los Angeles County-University of Southern California Medical Centfl". Supported by a grant (GCRC RR-43) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Pre.1ented at the Thirty-fifth Annual Meeting of the Society for Gynecologic Investigation, Baltimore, Maryland, March 17-20, 1988. Reprint requests: M. Hellen Rodriguez. MD, San Gabriel Valley Perinatal Medical Group, 1135 S. Sunset Ave., Suite 402, West Cm•ina, CA 91793.
1452
In addition, Taufield et al. 5 have recently demonstrated that preeclampsia is associated with hypocalciuria. The purpose of this study was to determine whether the presence of microalbuminuria or hypocalciuria, or both, in the pregnant woman who is free of symptoms can predict the subsequent development of preeclampsia. Patients and methods
Normal pregnant women between 24 and 34 weeks of gestation being seen at the Los Angeles County/University of Southern California Women's Hospital for prenatal care were invited to participate in the study. Women were excluded from the study if they had a history of chronic hypertension, diabetes, renal disease, if at the time of entry into the study they had a blood pressure that was :;,, 140/90 mm Hg, or if they had any evidence of proteinuria by the dipstick method. Once the patients were entered into the study, a first-morning fasting urine specimen was analyzed for microalbuminuria, and calcium and creatinine levels. No dietary alterations were recommended. After urine collection, the patients received routine prenatal care, and at the time of delivery the charts were reviewed for the presence of preeclampsia. The presence of preeclampsia was defined as the presence of a blood pressure of 140/90 mm Hg or a rise of 30 mm Hg in systolic pressure or of 15 mm Hg in diastolic pressure (measured twice, 6 hours apart at bed rest) associated with proteinuria or edema, or both. The concentration of urine albumin was established by a double-antibody iodine 125 radioimmunoassay (Diagnostic Products Corporation, Los Angeles, Calif.) designed for the detection of concentrations of al-
Calcium/creatinine and microalbuminuria in preeclampsia
Volume 159 1\umber 6
1453
Ca/Cr• .04 80%.
~
60%
40%
20% 0%'--~~~_L_~~~_L_~~~L_~~~L_~~~L_~~__J
0
0.1
0.3
0.2
0.4
0.5
0.6
1-SPECIFICITY Fig. I. Receiver operator curve for calcium/creatinine (Ca/Cr) ratio. Threshold value set at 0.04.
Table I. Maternal characteristics of study groups Group 1: Patients in whom preeclampsia did not develop (n = 78)
Mean maternal age (yr) ( :t: 1 SD) Primigravida women Mean gestational age (wk) at entrance into study (:t: 1 SD) Mean arterial blood pressure in mm Hg (:t: I SD) at entrance into study Mean urine calcium/ creatinine ratio at entrance into study (:t: 1 SD) Mean albumin concentration (µg/ml) at entrance into study ( :t: I SD) Mean gestational age (wk) at delivery ( :t: I SD) Mean arterial blood pressure (mm Hg) ( :t: 1 SD) at delivery
Group 2: Patients in whom preeclrunpsia developed (n = 10)
Total: All /wtients entered into .1111dv
27.3 :t: 6.1
30.6 :t: S.8
28.l :t: S.3
9 28 :t: 2.9
4 30 :t: 3.1
13 28 :t: 2.7
(n =
8BJ
70.7 :t: 8.8
72.3 :t: 12.9
71.S :t: 8.4
0.13 :t: 0.11
0.07 :t: 0.12
0.12 :t: 0.11
5.68 :t: 6.7
8.84 :t: 7.6
5. 76 :t: 6.:)
40 :t: 1.9
38 :t: 2.5
40 :t: 2.1
78.3 :t: 8.5
101.5 :t: 8.6
80.1 :t: 8.7
bumin not detectable by conventional dipstick methods. Urine calcium concentration was determined by atomic absorption spectrophotometry. Urine creatinine concentration was determined with a colorimetric AutoAnalyzer. The calcium concentration (in milligrams per deciliter) was divided by the creatinine concentation (in milligrams per deciliter) to derive the calcium/ creatinine ratio. With use of the receiver operator curve, threshold values of albumin concentrations and calcium/creatinine ratio for the subsequent development of preeclampsia were established. 6 The sensitivity, specificity,
and positive and negative predictive values of a low calcium/creatinine ratio and a high albumin concentration, and the combination were then calculated. This investigation was approved by the U niversitv of Southern California School of Medicine Human Research Committee. Results Table I presents information on the maternal characteristics of all patients entered into the study, patients who remained normotensive (group I), and patients in whom preeclampsia developed (group 2). Preeclampsia
1454
Rodriguez et al.
December l 988 Am J Obstet Gynecol
SENSITIVITY 100%.--~~~~~~~~~~~~~~~~~~~~~~~~--,
80%
[Alb] • 11 Ug/MI
t 60%
40%
20%
0%"'-~~~~~__J~~~~~~--'-~~~~~~--'-~~~~~~~
0
0.3
0.2
0.1
0.4
1-SPECIFICITY Fig. 2. Receiver operator curve for albumin concentration (Alb). Threshold value set at 11 µg/ml.
Table II. Screening value of hypocalciuria and microalbuminuria Calcium/ creatinine ratio ~0.04
Patients with preeclampsia Patients with norma! outcome Sensitivity (%) Specificity (%) Positive predictive value(%) Negative predictive value (%)
Albumin ""11 µ,glml
7
5
4
14
Calcium I creatinine ratio ~0.04 and albumin ""I I µ,glml
5
70
50
50
95 64
82 26
99 83
96
93
94
developed in IO (11.3%) patients. The mean maternal age, gestational age at entrance into the study, and mean arterial blood pressure at entrance into the study of these patients did not significantly differ from those of patients who remained normotensive. Forty percent of the patients in whom preeclampsia developed were primigravid compared with 11.5% of those who remained normotensive. With use of the receiver operator curve (Fig. l) a urine calcium/creatinine ratio threshold value of 0.04 was chosen as predictive for the development of preeclampsia. Seven of 10 patients in whom preeclampsia developed had a calcium/creatinine ratio of ~0.04. Four patients in whom preeclampsia did not develop had a calcium/creatinine ratio of ~0.04. This gives the calcium/ creatinine ratio a sensitivity of 70%, a specificity of 95%, a positive predictive value of 64%, and a negative predictive value of 96%. Again, with use of the receiver operator curve (Fig. 2) a urine albumin concentration of 11 µg/ml was
chosen as predictive for the development of preeclampsia. Five of 10 patients in whom preeclampsia developed had an albumin concentration ~ 11 µg I ml. Fourteen patients who remained normotensive had an albumin level ~ 11 µg I ml. This gives the test a sensitivity of 50% and a specificity of 82%, a positive predictive value of 26%, and a negative predictive value of 93%. When both tests are combined and required to predict the subsequent development of preeclampsia, five of 10 patients in whom preeclampsia developed and one who remained normotensive met both criteria. This resulted in a sensitivity of 50%, specificity of 99%, positive predictive value of 83%, and a negative predictive value of 94%. A summary of the above results is given in Table II. Comment
Preeclampsia can cause changes in virtually all organ systems, most notably the cardiovascular, renal, hematologic, and immunologic systems. Some of these
Volume 159 Number 6
changes are present before the clinical diagnosis of preeclam psia, as has been clearly demonstrated by several investigators. 1• 7 Proteinuria and alterations in calcium excretion are common features of various forms of hypertension and renal disorders. Minimally increased excretion of albumin is not generally measurable by the dipstick method, which is the test ordinarily used to screen for proteinuria. Such slightly increased excretion of albumin has been shown to be predictive of the subsequent development of clinical nephropathy in insulin-dependent diabetic patients. 8 Because proteinuria is one of the classic signs of preeclampsia, it was hypothesized that the presence of microalbuminuria or hypocalciuria might be useful in predicting which patients will develop preeclampsia. Our study confirms that changes in renal function are present in some otherwise symptom-free patients in whom preeclampsia will eventually develop. Classically, preeclampsia is a disease of the primigravid patient, with at least two thirds of the cases occuring in this group. 9 Only 40% of our patients in whom preeclampsia developed were primigravid. This may indicate that our population, which consists mostly of a lower socioeconomic group of Hispanic women, may constitute a subgroup of patients in whom preeclampsia will develop that may differ from the general population. Before this data can be generalized, it needs to be duplicated in other population groups. We conclude that in our population the presence of microalbuminuria in combination with a low calcium/ creatinine ratio may be a useful screening tool between 24 to 34 weeks of gestation for predicting the
Calcium I creatinine and microalbuminuria in preeclampsia 1455
development of preeclampsia in patients who are free of symptoms. When used as a single test, the urinary calcium/ creatinine ratio is a better predictor of preeclampsia than the urinary microalbumin concentration, and it is easily and inexpensively available.
'REFERENCES I. Gant NF, Daley GL, Chand S, Whalley PJ, MacDonald PC. A study of angiotensin II pressor response throughout primigravid pregnancy. J Clin Invest l 973;52:2682-9. 2. Gant NF, Chand S, Worley RJ, Whalley PJ, Crosby UD, MacDonald PC. A clinical test useful for predicting the development of acute hypertension in pregnancy. AYI .J 0BSTET GYNECOL 1974;120:1-7. 3. Degani S, Abinader E, Eibschitz I, Oettinger M, Shapiro I, Sharf M. Isometric exercise test for predicting gestational hypertension. Obstet Gynecol I 985;65:652-4. 4. Oney T, Kaulhausen H. The value of mean arterial blood pressure in the second trimester (MAP-2 value) as a predictor of pregnancy-induced hypertension and preeclampsia: a preliminary report. Clin Exp Hypertens (B) 1983; B2:2 I 1-6. 5. Taufield PA, Ales KL, Resnik LM, Druzin ML, Gertner JM, Laragh JH. Hypocalciuria in preeclampsia. N Engl .J Med 1987;316:715-8. 6. Fink DJ, Galen RF. Probabilistic approach to clinical decision support. In: Williams BT, ed. Computer aids to clinical decisions. vol. 2. Boca Raton, Florida: CRC, 1982: 165. 7. Gallery EDM, Gyory AZ. Glomerular and proximal renal tubular function in pregnancy-associated hypertension: a prospective study. Eur J Obstet Gynecol Reprod Biol l 979;9:3-12. 8. Viberti GC, Hill RD,Jarrett RJ, Argyropoulos A, Mahmud U, Keen H. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982;1:1430-2. 9. MacGillivray I. Some observations in the incidence of preeclampsia. J Obstet Gynaecol Br Emp l 958;65:536-9.