Abnormal 1,25-dihydroxyvitamin D metabolism in preeclampsia Phyllis August, MD, Beth Marcaccio, MD,Joseph M. Gertner, MD, Maurice L. Druzin, MD, Lawrence M. Resnick, MD, and John H. Laragh, MD New York, New York We previously reported that preeclampsia is associated with hypocalciuria (N Engl J Med 1987;316:715). The purpose of this study was to determine whether alterations in calcium regulatory hormones are present in preeclampsia and, if so, whether they are responsible for hypocalciuria. Thirty-two pregnant women were studied in the second and third trimesters of pregnancy (11 women with preeclampsia, nine with chronic hypertension, and 12 normotensive women). 1,25-Dihydroxyvitamin D, C-terminal parathyroid hormone, ionized calcium, and urinary calcium excretion were measured. 1,25-Dihydroxyvitamin D was significantly lower in the women with preeclampsia in the third trimester when the disease developed (37.8 ± 15 pg/ml) than in women with chronic hypertension (75 ± 15 pg/ml, p < 0.05) and normal women (65 ± 10 pg/ml, p < 0.05). Parathyroid hormone was higher, but not significantly, in those with preeclampsia. Ionized calcium was not significantly different among the three groups. Urinary calcium excretion was abnormally low for pregnancy «50 mg/24 hr) in all but one women with preeclampSia. We conclude that 1,25-dihydroxyvitamin 0 is reduced in preeclampsia and may lead to hypocalciuria by causing decreased intestinal absorption of calcium, stimulation of parathyroid hormone, and increased distal renal tubular resorption of calcium. The cause of reduced 1,25-dihydroxyvitamin D in preeclampsia is unknown and may be due to either diminished renal or placental production of the hormone. (AM J QBSlET GVNECOL 1992;166:1295-9.)
Key words: Preeclampsia, calcium metabolism, 1,25-dihydroxyvitamin D, hypocalciuria
Alterations in calcium metabolism have been reported in human essential hypertension and experimental animal models of hypertension and have been implicated in the pathogenesis of elevated blood pressure. I .' It has also been suggested recently that calcium regulation may be abnormal in preeclampsia, a hypertensive disorder unique to pregnancy. We previously reported that preeclampsia is associated with hypocalciuria: an observation subsequently confirmed by other investigators. 5 . ' Moreover, we suggested that measurement of urinary excretion of calcium may be useful in distinguishing preeclampsia from other forms of gestational hypertension. We hypothesized that hypocalciuria is due to increased renal tubular resorption of calcium rather than decreased filtered load, because fractional excretion of calcium was significantly lower in women with preeclampsia. From the Cardiovascular Center, the Department of Obstetrics and Gynecology, and the Department of Pediatrics, The New York Hospital-Cornell Medical Center. Supported fry GrantHL-18323-SCRfrom the National Heart, Lung, and Blood Institute of the National Institutes of Health. ReceivedforpublicationJune 13, 1991; revised September 10,1991; accepted September 13, 1991. Reprint requests: Phyllis August, MD, Cardiovascular Center, The New York Hospital-Cornell Medical Center, 525 E. 68th St., Starr4, New York, NY 10021. 6/1 133788
We report here an investigation of the hormonal basis for hypocalciuria. We determined the concentrations of 1,25-dihydroxyvitamin D, parathyroid hormone, and serum and urinary calcium in women with preeclampsia and compared them with those of normotensive pregnant women and women with chronic hypertension. It was considered important to study 1,25dihydroxyvitamin D levels because either a low level (e.g., primary deficiency leading to decreased serum calcium, increased parathyroid hormone, and increased renal tubular resorption of calcium) or a high level (e.g., primary calcium deficiency leading to increased parathyroid hormone, increased tubular resorption of calcium, and increased renal la-hydroxylase activity) might be associated with hypocalciuria, and possible therapeutic options might be different. We report here that 1,25-dihydroxyvitamin D levels are significantly lower in preeclampsia and parathyroid hormone is higher, compared with levels in normal and chronically hypertensive pregnant women.
Methods Thirty-two pregnant women were studied during the second and third trimesters of pregnancy. Preeclamptic women were recruited from consecutively hospitalized patients with the disease. An attempt was made to minimize the uncertainty in the diagnosis of preeclampsia; 1295
1296 August et al.
April 1992 Am J Obstet Gynecol
Table I. Clinical characteristics of study patients (third trimester)
Maternal age (yr) Gestational age (wk) Parity Nulliparous Multiparous Race Black White Other
Normal (n = 9)
Chronic hypertension
Preeclampsia
(n = 9)
(n = 9)
29 ± 4.2 33.9 ± 2.7
32 ± 2.8 35 ± 0.8
26 ± 6* 31.2 ± 3.7
8 I
4
7 2
2
4 4
5
o 7 2
7
o
I
*p < 0.02, compared with chronic hypertension. Table II. Blood pressure and laboratory data on study patients (third trimester) Normal (n = 9)
Maximal mean arterial pressure (mm Hg) Urine protein (mg/24 hr) Serum uric acid (mg/dl) Serum creatinine (mg/dl) Platelet count ( x 10')
83 93 5.3 0.8 250
± ± ± ± ±
5 47 1.07 0.06 80
Chronic hypertension
Preeclampsia
(n = 9)
(n = 9)
102 ± 10*
181 4.03 0.7 244
± 56 ± 1.06
± O.ll ± 64
131 ± 17t 3631 ± 4114t 8.4 ± 1.5§ 1.1 ± 0.39t 144 ± 115
Mean arterial pressure calculated as: (Systolic pressure plus 2 x Diastolic pressure) divided by 3.
*p < 0.02, compared with normal pregnancy. tp < 0.001, compared with normal pregnancy and chronic hypertension. tp < 0.05, compared with chronic hypertension. §p < 0.01, compared with normal pregnancy and chronic hypertension.
therefore patients with mild disease were excluded. Women with chronic hypertension were recruited from the office practices of the investigators. Normotensive women were healthy pregnant volunteers recruited from the employees of The New York Hospital. Patients with preexisting intrinsic renal disease were excluded. None of the subjects was receiving diuretics during the study. All patients were taking prenatal vitamins that contained 200 to 600 mg of calcium carbonate per tablet. All patients were eating an unrestricted diet either at home or, in the case of the preeclamptic women, in the hospital. Hypertension in pregnancy 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 IS mm Hg in diastolic pressure. Preeclampsia was defined as hypertension associated with excretion of >300 mg of urinary protein per 24 hours (or >2 + in a single voided specimen) or abnormal liver function tests and decreased platelet count. 8 Chronic hypertension was defined as the presence of a documented blood pressure of >140/90 mm Hg before pregnancy. None of the patients with chronic hypertension had superimposed preeclam psia. Venous blood was collected from pregnant women in the second and third trimesters. Twenty-four-hour urine collections were obtained at the same times, except when a woman with severe preeclampsia was de-
livered
Key words: Preeclampsia, calcium metabolism, 1,25-dihydroxyvitamin D, hypocalciuria
Alterations in calcium metabolism have been reported in human essential hypertension and experimental animal models of hypertension and have been implicated in the pathogenesis of elevated blood pressure. I .' It has also been suggested recently that calcium regulation may be abnormal in preeclampsia, a hypertensive disorder unique to pregnancy. We previously reported that preeclampsia is associated with hypocalciuria: an observation subsequently confirmed by other investigators. 5 . ' Moreover, we suggested that measurement of urinary excretion of calcium may be useful in distinguishing preeclampsia from other forms of gestational hypertension. We hypothesized that hypocalciuria is due to increased renal tubular resorption of calcium rather than decreased filtered load, because fractional excretion of calcium was significantly lower in women with preeclampsia. From the Cardiovascular Center, the Department of Obstetrics and Gynecology, and the Department of Pediatrics, The New York Hospital-Cornell Medical Center. Supported fry GrantHL-18323-SCRfrom the National Heart, Lung, and Blood Institute of the National Institutes of Health. ReceivedforpublicationJune 13, 1991; revised September 10,1991; accepted September 13, 1991. Reprint requests: Phyllis August, MD, Cardiovascular Center, The New York Hospital-Cornell Medical Center, 525 E. 68th St., Starr4, New York, NY 10021. 6/1 133788
We report here an investigation of the hormonal basis for hypocalciuria. We determined the concentrations of 1,25-dihydroxyvitamin D, parathyroid hormone, and serum and urinary calcium in women with preeclampsia and compared them with those of normotensive pregnant women and women with chronic hypertension. It was considered important to study 1,25dihydroxyvitamin D levels because either a low level (e.g., primary deficiency leading to decreased serum calcium, increased parathyroid hormone, and increased renal tubular resorption of calcium) or a high level (e.g., primary calcium deficiency leading to increased parathyroid hormone, increased tubular resorption of calcium, and increased renal la-hydroxylase activity) might be associated with hypocalciuria, and possible therapeutic options might be different. We report here that 1,25-dihydroxyvitamin D levels are significantly lower in preeclampsia and parathyroid hormone is higher, compared with levels in normal and chronically hypertensive pregnant women.
Methods Thirty-two pregnant women were studied during the second and third trimesters of pregnancy. Preeclamptic women were recruited from consecutively hospitalized patients with the disease. An attempt was made to minimize the uncertainty in the diagnosis of preeclampsia; 1295
1296 August et al.
April 1992 Am J Obstet Gynecol
Table I. Clinical characteristics of study patients (third trimester)
Maternal age (yr) Gestational age (wk) Parity Nulliparous Multiparous Race Black White Other
Normal (n = 9)
Chronic hypertension
Preeclampsia
(n = 9)
(n = 9)
29 ± 4.2 33.9 ± 2.7
32 ± 2.8 35 ± 0.8
26 ± 6* 31.2 ± 3.7
8 I
4
7 2
2
4 4
5
o 7 2
7
o
I
*p < 0.02, compared with chronic hypertension. Table II. Blood pressure and laboratory data on study patients (third trimester) Normal (n = 9)
Maximal mean arterial pressure (mm Hg) Urine protein (mg/24 hr) Serum uric acid (mg/dl) Serum creatinine (mg/dl) Platelet count ( x 10')
83 93 5.3 0.8 250
± ± ± ± ±
5 47 1.07 0.06 80
Chronic hypertension
Preeclampsia
(n = 9)
(n = 9)
102 ± 10*
181 4.03 0.7 244
± 56 ± 1.06
± O.ll ± 64
131 ± 17t 3631 ± 4114t 8.4 ± 1.5§ 1.1 ± 0.39t 144 ± 115
Mean arterial pressure calculated as: (Systolic pressure plus 2 x Diastolic pressure) divided by 3.
*p < 0.02, compared with normal pregnancy. tp < 0.001, compared with normal pregnancy and chronic hypertension. tp < 0.05, compared with chronic hypertension. §p < 0.01, compared with normal pregnancy and chronic hypertension.
therefore patients with mild disease were excluded. Women with chronic hypertension were recruited from the office practices of the investigators. Normotensive women were healthy pregnant volunteers recruited from the employees of The New York Hospital. Patients with preexisting intrinsic renal disease were excluded. None of the subjects was receiving diuretics during the study. All patients were taking prenatal vitamins that contained 200 to 600 mg of calcium carbonate per tablet. All patients were eating an unrestricted diet either at home or, in the case of the preeclamptic women, in the hospital. Hypertension in pregnancy 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 IS mm Hg in diastolic pressure. Preeclampsia was defined as hypertension associated with excretion of >300 mg of urinary protein per 24 hours (or >2 + in a single voided specimen) or abnormal liver function tests and decreased platelet count. 8 Chronic hypertension was defined as the presence of a documented blood pressure of >140/90 mm Hg before pregnancy. None of the patients with chronic hypertension had superimposed preeclam psia. Venous blood was collected from pregnant women in the second and third trimesters. Twenty-four-hour urine collections were obtained at the same times, except when a woman with severe preeclampsia was de-
livered
