Hematocrit and plasma albumin levels difference may be a potential biomarker to discriminate preeclampsia and eclampsia in patients with hypertensive disorders of pregnancy
Dong-Mei Dai
a, Jing Cao
a, Hong-Mei Yang
b, Hai-Mei Sun
a, Yu Su
a, Yuan-Yuan Chen
a, Xiao Fang
a, Wang-Bin Xu
a,⁎
aDepartment of Intensive Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China
bDepartment of Gynecology, The Geriatrics Hospital of Yunnan Province, Kunming, Yunnan 650041, China
a b s t r a c t a r t i c l e i n f o
Article history:
Received 19 October 2016
Received in revised form 21 November 2016 Accepted 1 December 2016
Available online 3 December 2016
Background:We evaluated whether alterations of hemoglobin (HB), hematocrit (HCT), serum albumin level (ALB), and the difference of HCT and ALB can be used in the diagnosis of preeclampsia and eclampsia in patients with hypertensive disorders of pregnancy (HDP).
Methods:A total of 509 individuals were recruited and divided into 4 groups: Group 1, 170 healthy non–pregnant women; Group 2, 125 normal pregnant women; Group 3, 105 pregnant women diagnosed with gestational and chronic hypertension; Group 4, 109 pregnant women diagnosed as having preeclampsia and eclampsia. Data of HB, HCT, ALB, globulin (GLB) were collected at the time of a prenatal examination during the third trimester.
Results:Alterations in the HCT and the ALB levels in these groups were significantly different. Group 4 had a higher mean HCT-ALB value (Pb0.01), but lower ALB and GLB values compared with the other three groups.
We used Groups 2 and 3 as the respective reference to draw the receiver operating characteristic (ROC) curves of HCT-ALB in Group 4, and found that the threshold values of maximum index corresponding were 12.95 and 12.65 (sensitivityN57.0%, specificityN98.9%), respectively.
Conclusions:The value of HCT-ALBN12.65 might be used as a potential biomarker for the auxiliary diagnosis of preeclampsia and eclampsia in HDP.
© 2016 Elsevier B.V. All rights reserved.
Keywords:
Hypertensive disorders of pregnancy (HDP) Eclampsia
Preeclampsia Hematocrit (HCT) Albumin (ALB)
1. Introduction
The hypertensive disorders of pregnancy (HDP) remain a major cause of maternal and fetal morbidity and mortality. Preeclampsia, by it- self, is a complication in 5% to 10% of pregnancies worldwide[1–3]. The clinical characteristics of HDP are high blood pressure affecting the func- tion and causing physical damage to multiple organs, such as heart, lung, kidney, blood and nervous system. The American College of Obste- tricians and Gynecologists has classified hypertension during pregnancy into 4 categories: 1) Gestational hypertension, 2) Preeclampsia and eclampsia, 3) Chronic hypertension, and 4) Preeclampsia superimposed on chronic hypertension[4]. At the present time, the clinical diagnosis of preeclampsia is defined byfinding an elevated blood pressure and/or the severity of 24-h urine protein[5]. However, proteinuria is a poor predictor of either maternal or fetal complications in women with pre- eclampsia[6].
The pathophysiological basis of preeclampsia and eclampsia is the in- jury to systemic small arteries and capillary endothelial cells, which leads
to increased vascular permeability and in turn to hemoconcentration, hypoalbuminemia and edema[7,8]. Therefore, there may be an increase of hematocrit (HCT), a reduction of serum albumin (ALB), and an in- crease in the HCT and ALB difference in patients with preeclampsia and eclampsia. The physiological increase of plasma volume would cause changes of maternal blood components during pregnancy[9], such as a decreased hemoglobin (HB) and ALB, and an increased HCT[10]. The ef- fects of the pregnancy-related changes in maternal HB, ALB and HCT levels on the outcome of pregnancies have been widely studied [11–14]. It was proposed that the increased HCT, HB and red cell mass in early pregnancy can be considered as a risk factor for preeclampsia [15], and the changes in HCT levels between thefirst half and the second half of pregnancy might suggest preeclampsia[12].
2. Materials and methods
2.1. Study subjects and ethics statement
All the subjects were enrolled in the First Affiliated Hospital of Kun- ming Medical University (KMU) from January 2013 to October 2015.
We collected the related data of HB, HCT, ALB, GLB, height, weight and gestational situation of each participant. The diagnostic criteria of HDP
⁎ Corresponding author at: Department of Intensive Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan 650032, China.
E-mail address:[email protected](W.-B. Xu).
http://dx.doi.org/10.1016/j.cca.2016.12.001 0009-8981/© 2016 Elsevier B.V. All rights reserved.
Contents lists available atScienceDirect
Clinica Chimica Acta
j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / c l i n c h i m
were based on the clinical characteristics as previously reported[16]
and were listed inTable 1. The subjects were divided into 4 groups:
Group 1 has 170 healthy non–pregnant women who attended for a physical examination in the First Affiliated Hospital of KMU, with an age ranging from 20 to 40 y. Group 2 has 125 normal pregnant women who delivered a baby in the same hospital, with an age from 21 to 37 y. Group 3 has 105 patients who were diagnosed as having HDP, but without preeclampsia/eclampsia. These patients aged from 26 to 36 y, including 70 patients with gestational hypertension and 35 patients with chronic hypertension. Group 4 has 109 patients who were diagnosed as already having preeclampsia and eclampsia
(including 6 preeclampsia, 86 severe preeclampsia and 17 eclampsia patients), with an age from 17 to 43 y (Table 2). The value of the HCT- ALB difference was calculated for each group. Pregnant women who had received blood or protein products by infusion, developed gesta- tional moderate to severe anemia, gestational severe bacterial infection disease, intrauterine fetal death or severe liver and kidney diseases were excluded from this study.
The Ethics Committee of the First Affiliated Hospital of KMU ap- proved the study protocol for the collection of blood samples. Written informed consent was obtained from each subject. The procedures were carried out in accordance with the approved guidelines.
2.2. Statistical analysis
The values of HB, HCT, ALB, GLB and HCT-ALB were presented as the mean ± SEM. The difference between two groups was compared by using the Student'st-test, whereas differences between three or more groups were evaluated by one-way analysis of variance (ANOVA). The ROC curves of HCT-ALB of Group 4 were prepared by using Groups 2 and 3 as the reference standard, respectively. We calculated AUC and the right index, and took the largest right index corresponding indica- tors to calculate the diagnostic threshold. All statistical analyses were performed by using SPSS (ver 21.0). APb0.05 was regarded as statisti- cally significant.
3. Results and discussion
The subjects in the 4 groups under study had a similar age (PN0.05;
Table 2) and were from the same geographical region. There was also no statistically significant difference in the gestational age at enrolment in the subjects of Groups 2, 3 and 4 (PN0.05 data not shown). Therefore, potential differences of HB, HCT and ALB among the groups might re- flect the different nature of their diseases, leaving aside any genetic ef- fect. All tested variables (HB, HCT, ALB, GLB and HCT-ALB) were normally distributed according to the Kolmogorov-Smirnov test (PN0.05), except for HB level in Group 1 (P= 0.005). Compared with Group 1, the levels of HB, HCT and ALB were decreased and the levels of HCT-ALB were increased in Groups 2 and 3 (Pb0.01;Table 3). The level of HCT-ALB was also increased (Pb0.01;Table 3) in Group 4, which had a decreased levels of ALB. Group 4 had an increase of HB, HCT and HCT-ALB levels and a decreased ALB and GLB levels in compar- ison with those of Group 2 and Group 3 (Pb0.01;Table 3). Note that most of eclampsia patients (13/17) had a high HCT-ALB level (N12) in Group 4. When we took Group 2 and Group 3 as the respective reference to draw the ROC curves of HCT-ALB of Group 4 (SeeFig. 1), we found that the AUC were 0.786 and 0.804, respectively. The cut-point of HCT-ALB values were 12.95 (with sensitivity of 57% and specificity of 99.2%) and 12.65 (with sensitivity of 58.1% and specificity of 98.9%) base on Youden index (Table 4), respectively. These results suggested that HCT-ALB levels difference might be of reasonably good sensitivity and high specificity for the diagnosis of preeclampsia and eclampsia.
During pregnancy, the maternal vascular tone is decreased and both cardiac output and blood volume are increased to supply enough oxy- gen and nutrients to the fetus and placenta[17]. Long before the forma- tion of the placenta, the reactivity of blood vessels against angiotensin II and catecholamine is reduced. Meanwhile, the increase in endothelial prostacyclin and nitric oxide production causes a decrease in systemic vascular tone, vasodilation, a decrease of cardiac afterload and barore- ceptor activation, thereby resulting in an increase in the heart rate, car- diac output, cardiac contractility and increased systemic vein transfer to artery. At the same time, changes in the renin-angiotensin-aldosterone system and the increase in secretion of cortisol and antidiuretic hor- mone cause an increase of blood volume to restore cardiac preload.
The decreased vascular reactivity also inhibits the release of atrial natri- uretic peptide[18]. As the pregnancy progresses, increased estrogen levels promote sodium retention by increasing the hepatic synthesis Table 1
Diagnostic criteria of with the hypertensive disorders of pregnancy.
Hypertensive disorders of pregnancy
Clinical characteristicsa
Gestational hypertension Onset of hypertension after gestational week 20, blood pressure≥140 mmHg systolic or≥90 mmHg diastolic, and 12 weeks postpartum returns to normal, and the urinary protein test negative; patient with blood pressure≥160 mmHg systolic or≥110 mmHg diastolic was diagnosed as having severe gestational hypertension.
Chronic hypertension Presence or history of hypertension preconception or in thefirst half period of pregnancy, blood pressure≥140 mmHg systolic or≥90 mmHg diastolic, and no aggravation during the gestation period; Or patient diagnosed as hypertension from 20 weeks of pregnancy and continuing past 12 weeks postpartum. Urine protein test negative.
Preeclampsia/eclampsia Preeclampsia.De novohypertension (blood pressure≥140/90 mmHg) after gestational week 20, and new onset of one or more of the following: proteinuria≥0.3 g/24 h or urinary protein/creatinine ratio≥0.3 or random urinary protein≥(+) when it unable to carry out urinary protein quantitation; Urine protein test negative, but with any of the organs (heart, lung, liver, kidneyetc.) or systems (blood system, digestive system, nervous system) involved. Blood pressure and/or urinary protein levels continue to rise.
Severe preeclampsia. Patient with preeclampsia appear with any of the following: (1) blood pressure≥160 mmHg systolic or≥110 mmHg diastolic; (2) persistent headache, visual disturbances or other central nervous system abnormalities; (3) persistent pain of epigastrium and liver subcapsular hematoma or rupture of the liver; (4) elevated blood alanine
aminotransferase (ALT) or aspartate aminotransferase (AST) levels; (5) impaired renal function: proteinuria≥0.3 g/24 h; oliguria (24 h urine outputb400 ml, or hourly urine outputb17 ml) or serum creatinineN106μmol/l;
(6) hypoalbuminemia with ascites, pleural or pericardial effusion; (7) hematological disorders, like platelet count was persistent decline andb 100 × 109/l. and microvascular hemolysis (anemia, jaundice or elevated blood lactate dehydrogenase (LDH) levels); (8) heart failure;
(9) pulmonary edema; (10) fetal growth restriction or oligohydramnios, fetal death and placental abruption.
Eclampsia. Other signs that cannot be explained on the basis of preeclampsia, convulsions Preeclampsia superimposed
on chronic hypertension
Patients with proteinuria≥0.3 g/24 h or random urinary protein≥(+) after gestational week 20;
proteinuria before 20 weeks of pregnancy and significantly increased urinary protein excretion after gestational week 20; further increase in blood pressure and with any other feature of severe preeclampsia.
aMainly based on the previously reported criteria[16].
of angiotensinogen[19]. In addition, the uterine placental circulation (a low resistance physiological arteriovenous shunt) also stimulates the increase in blood volume[20]. These effects contribute to an increase of blood volume by 40%–47%[21], cardiac output by 30–40%[22], and uterine bloodflow by about 8 fold[23]in the late stages of a normal pregnancy. Any disease that changes these normal physiological mech- anisms can be expected to adversely affect a pregnancy.
Maternal blood volume begins to increase in thefirst trimester of pregnancy, and 12 weeks after menelipsis, the expansion of the blood volume is about 15% as compared to a non-pregnant woman[24]. The rate of increase of blood volume is fastest in gestational week 12, signif- icantly slows after gestational week 12, and then maintains a constant level until the last weeks of pregnancy. The increase of plasma and red blood cells leads to an increase in blood volume. Normally, plasma
increases more than red blood cells, and the body is therefore in a rela- tively anemic state in pregnancy, so that hemoglobin and hematocrit levels are reduced in pregnant women. The average hematocrit is about 37.5% at delivery[25]. Due to the increase of blood volume, albu- min is diluted and becomes relatively lower. In this study, we confirmed the decreased levels of hemoglobin, hematocrit, and albumin in healthy pregnant women as compared to the levels found in healthy non- pregnant women.
Previous studies of pregnant women who had gestational hyperten- sion without proteinuria showed an inconsistent result of blood volume changes when compared to non-pregnant women. For instance, Gallery et al.[26]reported that the plasma volume was reduced, while Brown et al.[27]found that there was no change of plasma volume in gesta- tional hypertension. The difference of baseline and the measurement Table 2
Clinical characteristics of the subjects enrolled in this study.
Characteristics Group 1 Group 2 Group 3 Group 4
Number, n 171 125 105 109
Maternal age, year 32.89 ± 8.83 26.78 ± 4.54 31.77 ± 4.95 31.40 ± 5.59
BMI, kg/m2 21.38 ± 3.38 27.20 ± 6.11a 28.75 ± 5.29a 28.56 ± 4.40a
Gestational week at delivery, week – 38.3 ± 1.78 36.94 ± 5.20 33.27 ± 4.12
Group 1: healthy non–pregnant women; Group 2: women with normal pregnancies; Group 3: women with gestational hypertension and chronic hypertension; Group 4: women with preeclampsia and eclampsia.
aCompared with Group 1,Pb0.01.
Table 3
Comparison of the values of HB, HCT, ALB, GLB and HCT-ALB in the 4 groups of subjects.
Characteristics Group 1 (n= 170) Group 2 (n= 125) Group 3 (n= 105) Group 4 (n= 109)
HB, g/l 138.81 ± 7.80 130.08 ± 11.7a 129.46 ± 11.9a 137.90 ± 20.90b,c
HCT, % 41.97 ± 2.21 39.50 ± 3.06a 39.04 ± 3.32a 41.45 ± 6.15b,c
ALB, g/l 42.48 ± 2.16 31.48 ± 2.41a 31.32 ± 3.18a 26.79 ± 4.68a,b,c
GLB, g/l 31.38 ± 2.81 32.95 ± 3.15a 32.97 ± 4.13a 30.50 ± 6.33b,c
HCT-ALB –0.51 ± 2.56 8.02 ± 3.08a 7.53 ± 3.10a 14.65 ± 6.97a,b,c
HB - Hemoglobin concentration; HCT - Hematocrit; ALB - Serum albumin; GLB - Globulin.
aCompared with Group 1,Pb0.01.
b Compared with Group 2,Pb0.01.
c Compared with Group 3,Pb0.01.
Fig. 1.The ROC curves of HCT-ALB difference in Group 4 with Group 2 (A) or Group 3 (B) as the reference standard.
methods may account for the differences between these two studies.
Silver et al.[28]measured blood volumes of 15 pregnant women with hypertension at late pregnancy and found that there was no statistically significant difference of plasma and red blood cell volume between nor- motensive pregnant women and women with gestational hypertension in late pregnancy. The pregnancy-induced hypertension in pregnant women is also in a relatively anemic state and the levels of hemoglobin and hematocrit are reduced, which is consistent with that of normoten- sive pregnant women. We confirmed this observation in this study and found that the levels of hemoglobin, hematocrit and albumin are de- creased in women affected by gestational hypertension and chronic hy- pertension in pregnancy.
The expected increase in blood volume has been found to be signif- icantly limited in preeclampsia and eclampsia patients. Pritchard et al.
[29]reported that on average the blood volume increases by 47% during normal pregnancy, however, the change in blood volume of women with eclampsia in late pregnancy was limited, and increased by only 16%. Similarly, Zeeman et al.[30]reported that 44 pregnant women in the third trimester had an increase of about 47% of blood volume as compared to their non-pregnant level. However, in 29 cases of pre- eclampsia, the blood volume was only increased by about 9%. Salas et al.[21]monitored the plasma volume of 17 patients with preeclamp- sia and 95 normotensive pregnant women, and demonstrated that the plasma volume of women who developed preeclampsia (about 2290 ml) was different from normal pregnant women (about 2460 ml) by gestational week 12. This difference reached a peak at the gestational weeks 14–17 (2325 ml for patients with preeclampsia and 2609 ml for normal pregnant women) and continued into the third tri- mester. Therefore, the difference in plasma volume between women who develop preeclampsia and normotensive pregnant women occurs in early pregnancy. Dysfunction of the renin-angiotensin-aldosterone system and vasodilator system, resulted in an increase of peripheral vas- cular resistance, decline of cardiac output, limitation of blood volume expansion, and elevation of blood pressure in preeclampsia patients [25]. The dysfunction of vasomotor and endothelial damage in pre- eclampsia patients caused an increased vascular permeability which accounted for the limited blood volume amplification, and this was ag- gravated when the patients had hypoalbuminemia. In preeclampsia pa- tients, capillary endothelial cell damage and albumin leakage into the interstitial space caused hemoconcentration, hypoalbuminemia and edema[16,31], resulting in HCT elevation and ALB reduction,finally lead to a higher HCT-ALB difference. We confirmed this speculation in our study. We showed that the levels of HB and ALB, except for HCT, were significantly decreased in our preeclampsia patients as compared to women with normal pregnancies, gestational hypertension, or chron- ic hypertension in pregnancy. The HCT-ALB value increased in normal pregnancy (mean ± SEM, 8.02 ± 3.08), gestational hypertension and chronic hypertension with pregnancy (mean ± SEM, 7.53 ± 3.10) com- pared with healthy non–pregnant women (mean ± SEM,−0.51 ± 2.56). In particular, the HCT-ALB value of patients with preeclampsia and eclampsia (mean ± SEM, 14.65 ± 6.97) was much higher than any of the other groups under study, suggesting that the HCT-ALB differ- ence could be used as a potential biomarker, albeit arbitrary, in the diag- nosis of preeclampsia and eclampsia patients in HDP. It is to be noted that we collected the data of HB, HCT, ALB, GLB from all the pregnant women at the time of a prenatal examination during the third trimester, but a patient with preeclampsia can be defined as having the condition
after 20 weeks of gestation by measuring the blood pressure and detect- ing proteinuria. Future study with a large sample size is needed to show whether the value of HCT-ALB is raised from 20 weeks of gestation. In addition, we did not analyze patients with preeclampsia and patients with eclampsia separately in this study, as the sample size of eclampsia patients was relatively small and probably had no sufficient statistical power, albeit that most of eclampsia patients (13/17) had a high HCT- ALB value (N12).
In short, we used the ROC analysis to estimate the predictive ability of HCT-ALB levels difference for discriminating preeclampsia and eclampsia in patients with HDP. We found that HCT-ALB difference (es- peciallyN12.65) might be a potential biomarker in pregnant women who are developing preeclampsia or eclampsia.
Acknowledgments
We thank Ian Logan for language editing. This study was supported by the Science Research Project of Yunnan Province Education Depart- ment (2014C050Y).
References
[1] C.W. Redman, Current topic: pre-eclampsia and the placenta, Placenta 12 (1991) 301–308.
[2] J.J. Walker, Pre-eclampsia, Lancet 356 (2000) 1260–1265.
[3] R. Luo, X. Shao, P. Xu, et al., MicroRNA-210 contributes to preeclampsia by downreg- ulating potassium channel modulatory factor 1, Hypertension 64 (2014) 839–845.
[4] American College of Obstetricians and Gynecologists, Task force on hypertension in pregnancy. Hypertension in pregnancy. Report of the American College of Obstetri- cians and Gynecologists' Task Force on hypertension in pregnancy, Obstet. Gynecol.
122 (2013) 1122–1131.
[5] A.L. Tranquilli, G. Dekker, L. Magee, et al., The classification, diagnosis and manage- ment of the hypertensive disorders of pregnancy: a revised statement from the ISSHP, Pregnancy Hypertension 4 (2014) 97–104.
[6] S. Thangaratinam, A. Coomarasamy, F. O'Mahony, et al., Estimation of proteinuria as a predictor of complications of pre-eclampsia: a systematic review, BMC Med. 7 (2009) 10.
[7] M.D. Lindheimer, A.I. Katz, Preeclampsia: pathophysiology, diagnosis, and manage- ment, Annu. Rev. Med. 40 (1989) 233–250.
[8] V.L. Bills, A.H. Salmon, S.J. Harper, et al., Impaired vascular permeability regulation caused by the VEGF(1)(6)(5)b splice variant in pre-eclampsia, BJOG 118 (2011) 1253–1261.
[9] F. Hytten, Blood volume changes in normal pregnancy, Clin. Haematol. 14 (1985) 601–612.
[10] J.C. Forest, J. Masse, J.M. Moutquin, Maternal hematocrit and albumin as predictors of intrauterine growth retardation and preterm delivery, Clin. Biochem. 29 (1996) 563–566.
[11] M.M. Murphy, J.M. Scott, J.M. McPartlin, J.D. Fernandez-Ballart, The pregnancy- related decrease in fasting plasma homocysteine is not explained by folic acid sup- plementation, hemodilution, or a decrease in albumin in a longitudinal study, Am. J.
Clin. Nutr. 76 (2002) 614–619.
[12] M.G. Khoigani, S. Goli, A. Hasanzadeh, The relationship of hemoglobin and hemato- crit in thefirst and second half of pregnancy with pregnancy outcome, Iran J. Nurs.
Midwifery Res. 17 (2012) S165–S170.
[13] S.C. Chang, K.O. O'Brien, M.S. Nathanson, J. Mancini, F.R. Witter, Hemoglobin concen- trations influence birth outcomes in pregnant African-American adolescents, J. Nutr.
133 (2003) 2348–2355.
[14]O. Stephansson, P.W. Dickman, A. Johansson, S. Cnattingius, Maternal hemoglobin concentration during pregnancy and risk of stillbirth, JAMA 284 (2000) 2611–2617.
[15] S. Stoev, I. Dikov, S. Iovchev, S. Ivanov, Hemorheological parameters in the prognosis of the risk of fetal retardation in pregnancy with arterial hypertension, Akush Ginekol (Sofiia) 35 (1996) 23–24.
[16]J.M. Roberts, F.G. Cunningham, M.D. Lindheimer, Chesley's Hypertensive Disorders in Pregnancy, Academic Press, 2009.
[17] L. Carbillon, M. Uzan, S. Uzan, Pregnancy, vascular tone, and maternal hemodynam- ics: a crucial adaptation, Obstet. Gynecol. Surv. 55 (2000) 574–581.
[18]W. Ganzevoort, A. Rep, G.J. Bonsel, J.I. de Vries, H. Wolf, Plasma volume and blood pressure regulation in hypertensive pregnancy, J. Hypertens. 22 (2004) 1235–1242.
[19]A.B. Chapman, W.T. Abraham, S. Zamudio, et al., Temporal relationships between hormonal and hemodynamic changes in early human pregnancy, Kidney Int. 54 (1998) 2056–2063.
[20] P. Rosso, E. Donoso, S. Braun, R. Espinoza, C. Fernández, S.P. Salas, Maternal hemody- namic adjustments in idiopathic fetal growth retardation, Gynecol. Obstet. Investig.
35 (1993) 162–165.
[21] S.P. Salas, G. Marshall, B.L. Gutiérrez, P. Rosso, Time course of maternal plasma vol- ume and hormonal changes in women with preeclampsia or fetal growth restric- tion, Hypertension 47 (2006) 203–208.
[22] M.M. Lees, S.H. Taylor, D.B. Scott, M.G. Kerr, A study of cardiac output at rest throughout pregnancy, J. Obstet. Gynaecol. Br. Commonw. 74 (1967) 319–328.
Table 4
The characteristics of the ROC curves of the HCT-ALB differences in Group 4.
Item Reference standard
AUCa Threshold Sensitivity Specificity Youden index
HCT-ALB Group 2 0.786 12.95 57.0% 99.2% 0.562
Group 3 0.804 12.65 58.1% 98.9% 0.570
aAUC: the area under curve.
[23] S.K. Palmer, S. Zamudio, C. Coffin, S. Parker, E. Stamm, L.G. Moore, Quantitative esti- mation of human uterine artery bloodflow and pelvic bloodflow redistribution in pregnancy, Obstet. Gynecol. 80 (1992) 1000–1006.
[24] I.M. Bernstein, W. Ziegler, G.J. Badger, Plasma volume expansion in early pregnancy, Obstet. Gynecol. 97 (2001) 669–672.
[25]M.M. Corton, L. Kenneth, B. Steven, H. Barbara, Williams Obstetrics 24/E (EBOOK), McGraw Hill Professional, 2014.
[26] E.D. Gallery, M.D. Mitchell, C.W. Redman, Fall in blood pressure in response to vol- ume expansion in pregnancy-associated hypertension (pre-eclampsia): why does it occur? J. Hypertens. 2 (1984) 177–182.
[27] Brown MA, Zammit VC, M. MD. Extracellularfluid volumes in pregnancy-induced hypertension. J. Hypertens. 1992; 10:61–68.
[28]H.M. Silver, M. Seebeck, R. Carlson, Comparison of total blood volume in normal, preeclamptic, and nonproteinuric gestational hypertensive pregnancy by simulta- neous measurement of red blood cell and plasma volumes, Am. J. Obstet. Gynecol.
179 (1998) 87–93.
[29] J.A. Pritchard, F.G. Cunningham, S.A. Pritchard, The Parkland Memorial Hospital pro- tocol for treatment of eclampsia: evaluation of 245 cases, Am. J. Obstet. Gynecol. 148 (1984) 951–963.
[30] G.G. Zeeman, F.G. Cunningham, J.A. Pritchard, The magnitude of hemoconcentration with eclampsia, Hypertens. Pregnancy 28 (2009) 127–137.
[31] R. Chihara, H. Nakamoto, H. Arima, et al., Systemic capillary leak syndrome, Intern.
Med. 41 (2002) 953–956.