Maternal and Umbilical Cord Plasma Renin Activity in Pregnancy Induced Hypertension

Abstract

Plasma renin activity (PRA) was determined by radioimmunoassay in maternal and cord blood of 20 women with pregnancy-induced hypertension (PIH) and in 20 normal pregnant controls. The mean maternal PRA among the group of PIH was significantly lower than that of normal pregnancy (P < 0.01). There were significant negative relationship between maternal PRA and each of the systolic blood pressure (r = - 0.59, P < 0.05) diastolic blood pressure (r = - 0.5, P < 0.05) oedema of lower limbs (r = 0.46. P < 0.05) and proteinuria (r = - 0.61, P < 0.01). The mean fetal PRA among PIH group was also lower than that of normal pregnancy but with no statistically significant difference (P > 0.05). There was no significant relationship (r = 0.47, P < 0.05) between maternal and fetal PRA. No significant correlation was found between fetal PRA and any of the other parameters. PRA level is significantly depressed in PIH. Apparently this is the result of PIH and PRA is not involved in the pathogenesis of PIH. The trigger of PIH seems to be fetal rather than maternal in origin.

Introduction

Although eclampsia had been described since more than two hundred years, the etiology and pathogenesis of pregnancy induced hypertension (PIH) is still a matter of controversy and research. A systemic vasoconstriction is a key component in the pathogenesis of PIH (Wallenburg, 1988) and the renin-angiotensin system is incriminated in this process (Creer, 1992).

Renin is a proteolytic enzyme produced in the kidnev, uterus and chorion and acts on the renin substrate alpha 2-globulin to produce the decapeptide angiotensin I which produces the octapeptide angiotensin II (A II) which is a potent vasoconstrictor. It plays an important role in maintenance of blood pressure and the release of aldosterone which in turn affects sodium and water balance. It closely resembles the phenomenon of pregnancy induced hypertension (Symonds, 1988).

Montoneri et al. (1985) reported no important differences between normal and toxaemic pregnancies concerning either plasma renin activity or aldosterone.

In 1987, Brar and co-workers reported no differences in active and prorenin in maternal blood of normal or PIH patients. In spite of that Furuhashi and his colleagues (1991) reported that plasma renin activity (PRA) was significantly higher and AII was slightly higher in preeclampsia than in normal pregnancy.

In contrast, a large group of authors reported that PRA and AII were lower in women with pregnancy induced hypertension than in normal pregnancy (Carr and Gent 1983, Broughton Pipkin 1988, and Hanssens et al. 1991).

High concentrations of renin and relatively low levels of renin substrate are present in the fetus early in pregnancy as detected in blood samples obtained by fetoscopy in middle trimester of pregnancy and the values are similar to those demonstrated in the full term foetus (Symonds and Craven, 1985). It is believed that the fetal renin angiotensin system is contributing in the pathogenesis of pregnancy induced hypertension.

Symonds and co-workers in 1984 reported a lower level of plasma renin concentration (PRC) and PRA in the cord blood of infants born to hypertensive women although this difference did not achieve statistical significance.

In contrast, Brar et al. (1987) reported significantly higher levels of active renin in fetal artery and vein in pregnancy-induced hypertension compared with normal subjects. Understanding the pathogenesis of PIH is the first step for treatment of that mysterious disease.

The aim of this work was to detect the role of maternal and fetal plasma renin activitv in PIH. 

Materials and Methods

The study included 20 normal pregnant women and 20 women with pregnancy induced hypertension with comparable age range. The gestational ages of all the cases were ranging between 28-40 weeks. The cases were taken from Departments of Obstetrics in Benha and Mansoura university hospitals in the period from August 1994 to June 1995.

For each patient a full obstetric history was taken including anv past history of essential hypertension, chronic nephritis, thyrotoxicosis, pheochromocytoma, renal artery stenosis or coarctation of the aorta. Such cases had been excluded from the studv. A thorough general examination including blood pressure, oedema and albuminuria, in addition to routine obstetric examination were done. The patients were not on antihypertensive therapy, particularly those drugs acting on the renin angiotensin system.

The diagnosis of hypertension was made on the basis of a blood pressure equal to or greater than 140/90 mm Hg on two or more occasions 6 hours apart, after 20 min rest in the left lateral supine position.

A venous blood sample was collected from an antecubital vein after 20 min rest in the left lateral supine position. The fetal blood samples were collected from the umbilical cord immediately after clamping the cord and before placental separation. The samples were collected into EDTA as an anticoagulant, kept in ice and centrifuged at 2000 rpm to separate the plasma. The haemolyzed samples were discarded. The sera were stored in - 20^oC till time of assay. The plasma renin activitv was determined by radioimmunoassay using gama counter and kits from Sorin Biomedica-ltaly.

Results

The normal and PIH groups were comparable to each other as shown in table 1, except for blood pressure. The incidence of significant proteinuria (> +) was significantly higher in PIH (100%) compared to none in normal group. Also edema has a higher percentage (100%) in PIH compared to normal group (20%). The mean maternal plasma renin activity was lower in PIH group than normal droup (1.56 + 1.19 vs 10.01 7 ng/ml/h). The difference was statistically highly significant (P <0.01) as shown in table 2.

Fetal plasma renin activity was lower in PIH group than normal group (9.04 + 7.88 vs 12.5 + 8.97 ng/ml/h). The difference was not statistically significant (P > 0.05) as shown in table 3.

A significant negative correlation was found between maternal plasma renin activity and systolic blood pressure, diastolic blood pressure, edema and proteinuria as shown in table 4.

Also maternal plasma renin activity showed a significant positive relationship with fetal plasma renin activity and gravidity (table 4). Fetal plasma renin activitv failed to show any significant association with blood pressure, edema or proteinuria.

Table 1 : Means and standard deviation of age, duration of pregnancy, systolic blood pressure and diastolic blood pressure.

Pregnancy induced hypertension
X ± S. D. (Range)

Normal Pregnancy
X ± S. D. (Range)

t

p

27.5 ±4.9 (21 - 37)

27.1 ± 5.1 (20±38)

> 0.05

37.2 ± 2.6 (32.0 - 40.0)

38.2 ± 1.7 (36.0 ± 40.0)

> 0.05

175.5± 18.5 (150 - 210)

120.2 ± 7.7 (100 + 130)

< 0.01

114.0 ± 9.9 (100 - 130)

78.0 ±3.8 (70 - 80)

< 0.01

Table 2 : Means and standard deviation and range of maternal plasma renin activity among the studied group.

Maternal (PRA)
ng /ml / h

Pregnancy induced hypertension
(n = 20)

Normal Pregnancy
(n = 20)

X

1.56

10.01

± S. D.

± 1.19

±7.00

Range

0.29 - 4.7

8.81 - 23.06

t

5.322

p

< 0.01

Table 3: Means, standard deviation and range of fetal plasma renin activity among the studied group.

Fetal (PRA) ng/ml/h

Pregnancy induced hypertension
(n = 20)

Normal Pregnancy
(n = 20)

X

9.04

12.50

± S. D.

± 7.88

8.97

Range

0.82 - 28.34

1.50 - 39.21

t

1.29

p

> 0.05

Table 4 : Correlation between maternal plasma renin activity (PRA) and other variables.

Variables

Maternal plasma renin activity (PRA)

r

p

+ 0.473

< 0.05

+ 0.350

< 0.05

0.591

< 0.05

0.583

< 0.05

0.456

< 0.05

0.614

< 0.01

Discussion

The causative role of the renin angiotensin system in hypertensive diseases has been a subject of controversy for many years. An association between certain forms of hypertension and elevated blood levels of AII has been established. In benign and uncomplicated essential hypertension, the levels are usually normal. However, in severe essential hypertension, renal and malignant hypertension, a significant correlation has been shown between diastolic blood pressure and blood AII concentrations (Catt et al., 1971).

During normal pregnancy, there is a significant increase in PRA, plasma renin concentration (PRC), renin substrate (RS) (Hsuch et al., 1982) and plasma AII (Hanssens et al., 1991). The main increase in PRA occurs in the first 12 weeks of pregnancy, declining gradually until term, and falling quickly after delivery (Hsuch et al., 1982).

Beilin et al. (1983) reported significantly lower levels of PRA, AII and catecholamines in pregnancy, as well as loss of diurnal fall of AII which was noticed in normotensive pregnancies. Sipes et al. (1989) reported significant lower level of PRA but a significant higher level of angiotensin-converting enzyme in preeclamptic group. Audust et al. (1990) reported that renin-angiotensin-aldosterone system is stimulated throughout pregnancy, but in the early third trimester, when precelampsia was diagnosed, plasma renin activity (PRA) and urine aldosterone were decreased. Furuhashi, et al. (1991) reported that PRA and 6-keto-PGFI alpha levels in preeclampsia were significantly lower than those of normal pregnancy. Tsai et al. (1994), reported that PRA decreased to non-pregnant level after hypertension was established. This study also showed a highly significant decrease in PRA levels in PIH than normal pregnancy. This goes also with the observation that AII concentrations in women with pregnancy induced hypertension are about 25% lower than in normal pregnancy and resembled those in non-pregnant women and the lowest AII levels were found in women with more severe forms of pregnancy induced hypertension (Hassens et al., 1991). These results disagree with Montoneri et al. (1985) and Brar et al. (1987) who reported no differences between normotensive and pregnaney-induced hypertension groups. Again they are completely contradictory to that of Furuhashi et al. (1990) who reported higher levels of PRA, 6-keto-PGFI alpha and AII in preeclamptic women compared to normal pregnancies.

It is surprising that the main bulk of studies including ours, show either a significant decrease in maternal PRA in PIH or no change.

Apparently, the renin angiotensin system, contrary to the old belief, is not involved in the pathogenesis of PIH. Actually this system is suppressed, rather than triggered, in PIH. This suppression is a part of the defence mechanism of the body against the elevated blood pressure. We can speculate that the pathogenesis of precelampsia is fetoplacental in origin, rather than maternal and other systems of the maternal side are actually involved in fighting hypertension to correct the disturbances caused by the external (fetal ?!) invader. Though Gant and co-workers (1973) demonstrated that increased vascular sensitivity to AII clearly proceeded the onset of PIH, other investigators suggested a role for prostaglandins (E₂ and I₂) in the protective mechanisms against PIH (Friedman, 1988) and the vasoactive refractoriness which occurs during normal pregnancy.

As regard the fetal plasma renin activity our results and those of Symonds et al. (1984) showed that the mean fetal PRA among the group of PIH was slightly lower than that of normal pregnancy group. These were contradictory to that of Brar et al. (1987) who reported that umbilical artery and vein contained significantly higher active renin in PIH compared with normal subjects.

We speculate that the renin angiotensin system is stimulated by normal pregnancy leading to a high level of maternal PRA. This level is decreased when PIH develops probably due to decreased renin production by the kidney due to sodium and water retention as a negative feed-back mechanism. The key may lie in the increased sensitivity to angiotensin II in PIH than in normal pregnancy and not its concentration which is actually decreased in PIH as a part of the protective mechanisms. Fetal renin levels are largely dependent on the production of renin from the fetal kidney. Thus, the factors which suppress plasma renin levels in the maternal circulation in PIH appears to produce similar effects in the foetus. A feto-placental initiator of the process of PIH is strongly suggested while the maternal side is only responding.

References:

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