Postpartum Serum Digoxin-like Immunoreactive Substance Concentration in Preeclamptic pregnancies


Seok-Won Kang, M.D., Eun-Hwan Jeong, M.D., Do-Hoon Lee, M.D.*, Ill-Woon Ji, M.D., Bo-Ra Son, M.D.*

Department of Obstetrics and Gynecology, and Clinical Pathology*, Chungbuk National University College of Medicine

Cheongju, Korea


Purpose: To determine clinical usefulness of serum digoxin-like immunoreactive substance levels as a predictor of preeclampsia, we evaluated the relationship between serum digoxin-like immunoreactive substance levels and gestational age, and compared pre and postpartum digoxin-like immunoreactive substance levels in normal and preeclamptic patients.
Material and Methods: We measured serum digoxin-like immunoreactive substance levels with Fluorescence Polarization Immunoassay (Abbott, IL) in 73 patients during either the first (n=11), second (n=31), or third (n=31) trimesterof pregnancy. We also measured serial serum digoxin-like immunoreactive substance levels in 21 normotensive and 23 preeclamptic patients at immediate prepartum, postpartum 24 hours, postpartum 36 hours, and postpartum 1 week. Statistical evaluation was performed with the linear regression, repeated measures analysis of variancee and t-test.
Results: Serum digoxin-like immunoreactive substance levels increased throughout gestation (y=0.575x + 15.144; r2=0.3237; p<0.0001), and decreased rapidly after delivery in normal pregnancies (prepartum, 0.38 ± 0.12; postpartum 24 hours, 0.24 ± 0.09; postpartum 36 hours, 0.25 ± 0.1; postpartum 1 week, 0.19 ± 0.07 ng/ml, p<0.0001). There was no significant postpartum decrease in preeclamptic pregnancies (0.35 ± 0.19; 0.29 ± 0.19; 0.34 ± 0.17; 0.25 ± 0.12, respectively, p=0.2249). There was no difference in digoxin-like immunoreactive substance levels between normal and preeclamptic pregnancies of third trimester (0.354 ± 0.19 ng/ml vs. 0.381 ± 0.12 ng/ml, p=0.533).
Conclusion: Serum digoxin-like immunoreactive substance levels increase with gestational age, and decrease rapidly after delivery. However, measuring digoxin-like immunoreactive substance levels is not useful as a predictor of preeclampsia.

Key words: Digoxin-like immunoreactive substance, preeclampsia, predictor, postpartum
Chungbuk J Med 1998;8(2):



Introduction

Endogenous digoxin-like immunoreactive substances have been found in various condition associated with volume expansion, including pregnancy. Because physiologic activities of digoxin-like immunoreactive substance includes natriuresis,1) Na+/K+ adenosine triphosphatase inhibition,2) and peripheral vasoconstriction,3) it has been speculated as a causative agent in the development of preeclampsia.4) The levels of digoxin-like immunoreactive substance increase with gestational age.5-7) Several investigators have suggested that digoxin-like immunoreactive substance level is higher in pregnancy-induced hypertension than in normotensive pregnancy,4,7,8) but others have found no difference.6,9)
To date, all studies of digoxin-like immunoreactive substance in pregnancy have measured levels before delivery, and none has followed a population of pregnant women after delivery. It is therefore not known whether the rate of reduction of digoxin-like immunoreactive substance is different between normotensive and preeclamptic women.
The aims of this study were (i) to compare postpartum change of digoxin-like immunoreactive substance levels between normotensive and preeclamptic patients, and (ii) to determine the potential role of digoxin-like immunoreactive substance in the prediction of preeclampsia.

Material and Methods

Study design. We measured serum digoxin-like immunoreactive substance levels in 73 patients during either the first (n=11), second (n=31), or third (n=31) trimester of pregnancy. We excluded the patients who were chronically hypertensive, or receiving digitalis glycosides. We also measured serial serum digoxin-like immunoreactive substance levels in 31 normotensive and 23 preeclamptic patients at immediate prepartum, postpartum 24 hours, postpartum 36 hours, and postpartum 1 week.
Twentythree women in the third trimester of pregnancy were transferred to our hospital with the diagnosis of preeclampsia as defined a blood pressure of ≥140/90 mm Hg persistently, and proteinuria and/or edema.
Blood samples were obtained by venipuncture, transferred into plain tube, and stored in 4℃ refrigerator until centrifugation at 2000 g for 10 minutes. Serum was aspirated and stored at -70℃ until assayed. The time from venipuncture to serum freezing was less than 2 hours.
Digoxin-like immunoreactive substance. Digoxin-like immunoreactive substance levels were measured by a commercially available Fluorescence Polarization Immunoassay kit (Abott, IL). All samples were assayed in duplicate. The limit of detection of this assay was 0.1 ng/ml.
Statistical analysis. The relationship between digoxin-like immunoreactive substance levels and gestational age was analysed with linear regression model. One-way analysis of variance was used to detect differences in age and digoxin-like immunoreactive substance levels among the three trimesters. Data of each group in the third trimester were compared with unpaired t-test and chi-square test. Postpartum data of each group were compared with repeated measures analysis of variance. Significance was established at p<0.05.

Results

There were no significant differences in age or parity among the patients in three trimesters as determined by analysis of variance (Table I). Digoxin-like immunoreactive substance levels increased significantly with increasing gestational age (Table I and Figure 1).

Table I. Demographic data for normotensive women in the three trimester.
First trimester
(n=11)		Second Trimester
(n=31)		Third trimester
(n=31)		P value
Age (yr)
mean ± SEM
median (range)
30.0 ± 3.73
28 (26-37)		29.0 ± 4.24
28 (18-40)		29.4 ± 5.00
29 (20-42)		NS
Parity
nullipara
multipara
4
7		12
19		14
17		NS
Gestational age (wk)
mean ± SEM
median (range)
9.3 ± 1.86
9.0 (6.9-12.1)		20.4 ± 4.38
18.9 (14.9-28.1)		38.8 ± 2.42
38.9 (35.0-43.5)		-
Digoxin-like immunoreactive substance (ng/ml)
mean ± SEM
median (range)
0.232 ± 0.051
0.25 (0.14-0.29)		0.254 ± 0.0851
0.24 (0.1-0.48)		0.381 ± 0.1211
0.38 (0.21-0.66)		0.0001



Demographic data comparing normotenstive (n=31) and preeclamptic women (n=23) who were admitted for delivery are shown in Table II. Preeclamptic patients weighed more at delivery, whereas gestational age and birth weight of infants born to preeclamptic mother were lower. There was no significant difference in digoxin-like immunoreactive substance levels between normotensive and preeclamptic patients at third trimester (Table II).

Table II. Demographic data for normotensive and preeclamptic women in third trimester.
Normotensive
(n=31)		Preeclamptic
(n=23)		P value
Age (yr)
mean ± SEM
median (range)
29.4 ± 5.00
29 (20-42)		27.7 ± 4.54
27 (21-38)		NS
Parity
nullipara
multipara
14
17		15
8		NS
Weight (kg)
mean ± SEM
median (range)
61.4 ± 9.06
60 (44-81)		71.3 ± 11.82
69 (52-95)		0.0035
Gestational age (wk)
mean ± SEM
median (range)
38.8 ± 2.42
39.3 (35.9-42.9)		36.4 ± 3.92
35.0 (27.1-43.7)		0.0031
Infant weight (gm)
mean ± SEM
median (range)
3392.8 ± 450.82
3312 (2098-4378)		2327.7 ± 1038.47
2116 (680-5104)		0.0002
Digoxin-like immunoreactive substance (ng/ml)
mean ± SEM
median (range)
0.381 ± 0.1211
0.38 (0.21-0.66)		0.336 ± 0.181
0.35 (0.08-0.75)		NS
Digoxin-like immunoreactive substance (ng/ml);
patients matched for gestational age
mean ± SEM
median (range)
0.415 ± 0.1635†
0.41 (0.21-0.66)		0.325 ± 0.1635‡
0.35 (0.08-0.53)		NS
†: n=18
‡: n=13


Because paients with preeclampsia had significantly lower gestational age, 13 patients with preeclampsia and 18 without preeclampsia who were in third trimester were matched for gestational age. Serum levels of digoxin-like immunoreactive substance were not different between the matched groups (Table II).
The digoxin-like immunoreactive substance level decreased rapidly after birth in normotensive women, but not in the preeclamptic women (Table III and Figure 2).

Table III. Postpartum change of digoxin-like immunoreactive substance levels.
Immediate prepartum
(ng/ml)		Postpartum 24 hours
(ng/ml)		Postpartum 36 hours
(ng/ml)		Postpartum 1 week
(ng/ml)		P value
Normotensive
(n=13)
0.382 ± 0.1245
0.37 (0.21-0.66)		0.241 ± 0.1087
0.25 (0.02-0.44)		0.247 ± 0.1128
0.23 (0.06-0.47)		0.182 ± 0.06
0.19 (0.07-0.26)		0.0001
Preeclamptic
(n=16)
0.336 ± 0.181
0.35 (0.08-0.69)		0.27 ± 0.1578
0.235 (0.05-0.64)		0.341 ± 0.1579
0.37 (0.05-0.55)		0.251 ± 0.1255
0.205 (0.13-0.54)		NS
Values are mean ± SEM, median (range).



Discussion

Our study confirms previous reports5,6) that digoxin-like immunoreactive substance in the serum of normotensive women rises with gestational age. The digoxin-like immunoreactive substance level did not differ significantly between the normotensive women and preeclamptic women in the third trimester. This finding is also in agreement with some work,3) but contrast with other reports.7,8) In addition, we found that digoxin-like immunoreactive substance levels decreased rapidly after delivery in normotensive women, but not in preeclamptic patients (Figure 2).
Because digoxin-like immunoreactive substance has several physiologic activities including, natriuresis,1) Na+/K+ adenosine triphosphatase inhibition,2) and peripheral vasoconstriction,3) it has been speculated as a causative agent in the development of preeclampsia.4) Several investigators reported higher concentrations of digoxin-like immunoreactive substance in patients with preeclampsia than in those without preeclampsia.4,10) However, we found no difference in digoxin-like immunoreactive substance levels between normotensive and preeclamptic patients.
Expansion of plasma volume during pregnancy is well established phenomenon. Plasma volume begins to expand from early first trimester, increases rapidly during second trimester, and then slowly but progressively increases during third trimester.11) Digoxin-like immunoreactive substance levels increase along with this plasma volume expansion throughout gestation.
Reduction of plasma volume in pregnancies complicated by preeclampsia is also a well-established association.12) However, peripheral vascular resistence is concurrently increased in preeclamptic pregnancies. These two combined phenomenon may explain the absence of difference of digoxin-like immunoreactive substance levels between normotensive and preeclamptic patients.
It has been speculated that the fetus is the source of digoxin-like immunoreactive substance, rather than the mother.2,9) If it is true, digoxin-like imunoreactive substance level should decrease rapidly after delivery in both group. However, it did not decrease significantly in preeclamptic patients, but did in normotensive women. Therefore, we speculate that this phenomenon was due to intravascular mobilization of extravascular fluid after delivery in preeclamptic patients. The evidence of intravascular fluid flux includes falling hematocrit values, stable weight, and pathologic elevation of pulmonary capillary wedge pressure with concurrent hyperdynamic ventricular function.13) Furthermore, there is a significantly increased diuresis in preeclamptic patient after delivery than in normotensive women.
This fluid influx may trigger production and secretion of digoxin-like immunoreactive substance, and may result in natriuresis. Thus, digoxin-like immunoreactive substance may be maternal origin rather than fetal and/or placental origin.
Because almost all of the preeclamptic patients were transferred from other hospital, we could not measure the digoxin-like immunoreactive substance in the serum of preeclamptic women longitudinally remote from term. However, digoxin-like immunoreactive substance concentrations in serum of preeclamptic patients showed a wide range of distribution, the same increasing tendency along gestational age, and no significant difference compare to those of normotensive women. Thus, we conclude that serum digoxin-like immunoreactive substance level cannot be used as a predictor of preeclampsia.

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