The relation of angiotensin-converting enzyme to the

pregnancy -induced hypertension-preeclampsia syndrome

John W. Goldkrand, M.D., and Armando M. Fuentes, M.D.

Albany, New York

Angiotensin-converting enzyme, the polypeptide that converts angiotensin I to angiotensin II, was

measured in the serum of 114 pregnant women who had normal blood pressure, pregnancy-induced hypertension-preeclampsia, and chronic hypertension with or without pregnancy-induced hypertension.

Angiotensin-converting enzyme levels were unrelated to weeks of gestation. The angiotensin-converting

enzyme levels were similar in normotensive women (21.1 ± 6.9 units/ml), women with chronic hypertension without pregnancy-induced hypertension (23.1 ± 2.7 units/ml), and patients with pregnancy­induced hypertension where magnesium sulfate (22.6 ± 8.7 units/ml) had been administered prior to

angiotensin-converting enzyme assay, but these values were significantly less than those in patients with pregnancy-induced hypertension with no magnesium sulfate (29.1 ± 6.5 units/ml) therapy and in women with chronic hypertension with superimposed pregnancy-induced hypertension (30.7 ± 4.4 units/ml)

(p < 0.005). Maternal venous and umbilical venous and arterial angiotensin-converting enzyme levels were as follows: The maternal venous level was less than the cord venous level and greater than the cord arterial value. Neither neonatal size nor twin gestation influenced the angiotensin-converting enzyme levels. Patients with diabetes mellitus had variable angiotensin-converting enzyme values regardless of the

status of the blood pressure. The physiologic theories of blood pressure control in pregnant women are discussed in relation to the renin-angiotensin, bradykinin, and prostaglandin systems. (AM J OBSTET

GVNECOL 1986;154:792-800.)

Key words: Angiotensin-converting enzyme, pregnancy-induced hypertension-preeclampsia, chronic hypertension with or without superimposed pregnancy-induced hypertension, vascular responsiveness to pressor substances

" ... It is the increased responsiveness of the arterial system to pressor substances which probably causes the generalized vasoconstriction and hypertension of pre­eclampsia."!

Hypertensive disease of pregnancy complicates ap­proximately 6% to 10% of all pregnancies and is re­sponsible for increased maternal and perinatal mor­tality and morbidity. Investigations to define the patho­physiology of the pregnancy-induced hypertension­preeclampsia syndrome have as common factors the renin-angiotensin system and the vascular responsive­ness to pressor substances. Angiotensin-converting en­zyme is a polypeptide with a molecular weight of 140,000 daltons, which is secreted by the vascular en­dothelium and converts the decapeptide angiotension I to the octapeptide angiotensin II, one of the most

potent vasoconstrictors. 2.3 Abdul-Karim and Assali1

demonstrated that normal pregnant women develop a

From the Division of Maternal-Fetal Medicine, Department of Ob­stetrics and Gynecology, Albany Medical College.

Presented at the Fourth Annual Meeting of the American Gyneco­logical and Obstetrical Society, Hot Springs, Virginia, September 4-7, 1985.

Reprint requests:john W. Goldkrand, M.D., Head, Division of Ma­ternal-Fetal Medicine, Department of Obstetrics and Gynecology, Albany Medical Center, 43 New Scotland Ave., Albany, New York 12208.

792

refractoriness to the pressor effects of infused angio­tensin 11.5 Angiotensinase, which inactivates angio­tensin II, has been found to increase throughout the course of pregnancy' and may contribute to this re­fractoriness. Cant et al.,3 Talledo et al.,6 and Chinn and Dusterdieck7 confirmed the increased sensitivity to infused angiotensin II in patients with or destined to develop the pregnancy-induced hypertension-pre­eclampsia syndrome. In normal pregnancy, no in­creased angiotensin-converting enzyme levels were noted by Parente et al.,' while Oats et aJ.2 showed a steady increase in the angiotensin-converting enzyme level from 30 weeks' gestation until term. In a prelim­inary study, we demonstrated significantly increased angiotensin-converting enzyme levels in patients with pregnancy-induced hypertension when compared with those in normal pregnant women.

Since angiotensin-converting enzyme appears to have a pivotal role in the renin-angiotensin system by converting angiotensin I to angiotensin II, it seemed appropriate to undertake the present investigation­to study clinically the relationships of angiotensin-con­verting enzyme concentrations in pregnant patients who are normotensive and those with the pregnancy­induced hypertension-preeclampsia syndrome and pa­tients with chronic hypertension with or without su­perimposed pregnancy-induced hypertension.

Volume 154 Number 4

Material and methods

Definitions Pregnancy-induced hypertension. Pregnancy-induced

hypertension was defined as an absolute blood pressure of 140/90 mm Hg or an increase in systolic blood pres­sure of 30 mm Hg and/or an increase in diastolic blood pressure of 15 mm Hg on two occasions, 6 hours apart, after 24 weeks' gestation.

Preeclampsia. Preeclampsia was defined as a triad of (1) the blood pressure changes noted in pregnancy­induced hypertension, (2) 24-hour urinary protein levels of :;;,300 mg, and (3) generalized edema. For the purposes of this study, pregnancy-induced hyperten­sion and preeclampsia were combined as components of a single abnormal physiologic and clinical syndrome.

Chronic hypertension. Chronic hypertension included the elevation in blood pressure noted for pregnancy­induced hypertension occurring either before preg­nancy or before the twentieth week of gestation.

Superimposed pregnancy-induced hypertension. Super­imposed pregnancy-induced hypertension was defined as clinical findings of pregnancy-induced hypertension in patients previously diagnosed as having chronic hy­pertension.

Magnesium sulfate. Magnesium sulfate was adminis­tered by the intravenous route with an initial bolus of 2 to 4 gm, followed by 2 gm/hr to maintain a serum magnesium level of 4.5 to 6.5 mg/dl. Patients were treated at the physician's desire in mild preg­nancy-induced hypertension but routinely with severe pregnancy-induced hypertension-preeclampsia (blood pressure> 1601100 to 110 mm Hg). Notation was made of all patients receiving magnesium sulfate before angiotensin-converting enzyme levels were de­termined, and these were analyzed separately.

Mean arterial blood pressure. Mean arterial blood pres­sure was measured as:

Diastolic blood pressure + (systolic blood pressure - diastolic blood pressure)

2

This was measured before 20 weeks' and after 24 weeks' gestation in patients with normal blood pressure, pregnancy-induced hypertension-preeclampsia, and chronic hypertension.

Patients. Pregnant women were selected at random from the obstetric population delivered of their infants at the Albany Medical Center Hospital from January 1,1984, through July 1,1985. The patients were stud­ied in the third trimester of pregnancy on the basis of a clinical diagnosis of normal blood pressure, pregnancy-induced hypertension-preeclampsia, and chronic hypertension with or without pregnancy-in­duced hypertension (Table I). Samples of blood for measurement of serum angiotensin-converting enzyme levels were drawn either singly, about the time of de-

Angiotensin-converting enzyme and preeclampsia 793

Table I. Patient population: Distribution by diagnosis

Diagnosis

Normotensive Pregnancy-induced hypertension­

preeclampsia No magnesium sulfate With magnesium sulfate

Chronic hypertension No pregnancy-induced hyperten­sion-preeclampsia Superimposed pregnancy-induced hypertension-preeclampsia

Total Nonpregnant

36 21

5

3

n

49 57

8

114 9

There were five sets of twins in pregnancies with pregnancy­induced hypertension-preeclampsia and two in pregnancies without pregnancy-induced hypertension-preeclampsia.

livery, or during antepartum evaluation. In addition, serum uric acid and blood urea nitrogen were deter­mined. In 12 cases, nearly simultaneous samples for maternal venous and umbilical venous and arterial an­giotensin-converting enzyme levels were obtained. Nor­motensive control patients were chosen at random ei­ther at the time of labor and delivery or elective cesar­ean section or antepartum in the third trimester of pregnancy. The 114 patients were drawn from a pop­ulation of about 3325 women delivered of their infants during the study interval. The mean maternal ages were 25 ± 7 years in the normal population and 26 ± 7 years in the hypertensive population (p = NS). Racially, the groups were the same with 81 % Caucasian, 16% black, and 3% Indian or Oriental. At the Albany Medical Center, approximately 15% of the deliveries are in patients who are transported in from a 17-county regional perinatal network. In the study, 30% of the patients represented maternal transports, since hyper­tensive disease is a m<tior indication for transport. Both the normal and hypertensive patients had a mean gra­vidity of 2, and 48% were primigravid. Twenty-four percent of the patients smoked at least one half a pack of cigarettes a day,-29% hypertensive women and 71 % normal women. The mean weight gain in pregnancy was 33 pounds for both groups. The normotensive pa­tients were delivered at a mean of 38 weeks' gestation, and the hypertensive patients at a mean of 36 weeks' gestation (p < 0.025). The babies delivered of nor­motensive women were heavier (mean 3015 gm) than those of hypertensive women (2570 gm) (p < 0.02), while the placental weights were not significantly dif­ferent. There was no difference in the distribution of the sexes of the neonates. The hypertensive group tended to have a higher rate of cesarean delivery (55%) than the normotensive women (37%), but this was not statistically significant. Baseline control values of serum angiotensin-converting enzyme and uric acid were

794 Goldkrand and Fuentes

NORMOTI!NSIVI!

40

36

31 •

• • •• •

ACE 26

(units/mil 22

• • I • •• •

•• • •••• • • •• • ·1 .,. 17

12

36

33

28

ACE 23 (units/mil

18

13

8

.. I ... .. , . ••

WEEKS GESTATION

PIH·PRI!·ECLAMPSIA

• · .... 42

• · .... -.. ., , . , • I!. • • • ••• • I· I • • •

• 19 22 26

WEEKS GESTATION

Fig. 1. Angiotensin-converting enzyme (ACE) levels in the nor­motensive and pregnancy-induced hypertension-preeclamp­sia populations compared by the week of gestation when samples were drawn [normal: r2 = 0.003, Y = 25.5 + (- 0.106x); pregnancy-induced hypertension: r2 = 0.027, Y = 17.7 + 0.27x).

measured in nine normotensive, nonpregnant, non­hormone-using women, aged 24 to 34.

Neonates. All babies were evaluated by the Neona­tology Staff irrespective of the study. The neonatal complications were sepsis (two in normotensive moth­ers and two in hypertensive mothers) and respiratory distress syndrome (one in the normotensive group and nine in hypertensive women). One infant of a mother with pregnancy-induced hypertension died of congen­ital heart disease. The overall perinatal mortality was 8.7 per 1000 live births.

To correct for possible birth weight differences among babies born at differing gestational ages, all ba­bies were classified as appropriate for gestational age, small for gestational age, and large for gestational age according to the University of Colorado data, which were used by the Albany Medical Center Neonatology Group. Mothers with pregnancy-induced hypertension were delivered of more small for gestational age babies than were those who were normotensive (p < 0.025) (normotensive: appropriate for gestational age, 44; small for gestational age, three; large for gestational age, four; hypertensive-pregnancy-induced hyperten-

April, 1986 Am J Obstet Gynecol

sion: appropriate for gestational age, 35; small for ges­tational age, 14; large for gestational age, seven) .

Laboratory. The angiotensin-converting enzyme lev­els were measured according to the method of Lie­berman8 in the Chemistry Laboratory of the Albany Medical Center Hospital. This method utilizes a spec­trophotometric analysis of the free hippuric acid cleaved from hippuryl-L-histidyl-L-Ieucine by angio­tensin-converting enzyme. The blood was drawn in a 10 ml clot tube, spun, and then kept either refrigerated or frozen at -4° C before analysis. The interassay vari­ability is ± 5 units/ml. The blood urea nitrogen and uric acid determinations were performed in the same laboratory.

Statistics. Data were analyzed by standard statistical procedures on the VAX computer with the use of mean, standard deviations, X2, and Student's t test.

Results

Angiotensin-converting enzyme levels (Figs. 1 and 2). The determinations of serum angiotensin-con­verting enzyme levels obtained from the twenty-fifth to the forty-third week of gestation from all patients with normal blood pressure and those with the pregnancy­induced hypertension-preeclampsia syndrome were examined graphically (Fig. I) against the week of gestation during which the samples were obtained. The angiotensin-converting enzyme levels appeared to be independent of gestational age. Nonpregnant women had an angiotensin-converting enzyme level of 29.3 ± 6.4 units/ml, which was significantly greater than that of pregnant women with normal blood pres­sure (21.1 ± 6.9 units/ml, p < 0.005) (Fig. 2.). Among those women with the pregnancy-induced hyperten­sion-preeclampsia syndrome, those receiving magne­sium sulfate before the measurement of angiotensin­converting enzyme had levels of 22.6 ± 8.7 units/ml, which was lower than that of those with no magnesium sulfate therapy (29.1 ± 6.5 units/ml, p < 0.005). The angiotensin-converting enzyme level in women with chronic hypertension without pregnancy-induced hy­pertension (23.1 ± 2.7 units/ml) was less than that of those with superimposed pregnancy-induced hyper­tension (30.7 ± 4.4 units/m!, p < 0.005) and bore the same relationship as the patient with pregnancy-in­duced hypertension with or without magnesium sulfate therapy. Normotensive women had angiotensin-con­verting enzyme levels similar to those of patients with chronic hypertension and no pregnancy-induced hy­pertension and those with pregnancy-induced hyper­tension and magnesium sulfate therapy.

There were seven sets of twins; five had mothers with pregnancy-induced hypertension and two mothers were normotensive. When the angiotensin-converting enzyme levels were compared to those of the women

Volume 154 Number 4

Angiotensin-converting enzyme and preeclampsia 795

35

30

ACE (unilslml) 25

20

29.l±U :l1.t±U 9.1:t1.22.6::t:8.7 30.7:4.04 23.1:2.7 M "'I N ==49 M :::36 N :21 N:3 N= 5

NOHPRESNANT PRESNANT NO IIgS0, IIgSO, "'" NO "'" NORMAL BP PlH·PRE-ECLAMPSIA CHRONIC HYPERTENSION

1IOIII'IIt811AIIT nllOllMOTEMSI'IE ,<0.01$

WI CItIOIItIl'I'EIITlfISIDIIIIOPII ,<0.05 "CItIIOCHt?ElnoSlllfl·"" ,lIS , ..

WI "'.wmI",SO. n~I"'1'IH

ntHlQlltt.,.1I01'1H

nCIIICIIC'IP-1I01'1H

PIlI' NO PIlI' TWINS

,,, IIOIIMCIlUIIWE ,,"',110..,50. ",1.'01 VI TWIII·IID'" .<O.OS

" .''''.WITH ..... nMOIIt,IP·1I01'11 ntlllOllC' .. ·wmtPII

,lIS 1WII$·.,....Al .. nSlllilETOllIlOllfllAllP ,lIS ,lIS _U:TGII·", nTWIIS·'" p<UI ,<us

CllllOIC ."lIDl'INwltlllllllC ,,,·,..,<0.005 (""'="'·I'II(·ECUlIII'SIAj

Fig, 2, Angiotensin-converting enzyme (ACE) levels in the various patient groups divided by the blood pressure status. MgS04 = Treated with magnesium sulfate before angiotensin-converting enzyme determination. No MgS04 = No magnesium sulfate given before angiotensin-converting enzyme determination.

Table II, Paired samples of maternal and cord blood angiotensin-converting enzyme levels, with samples obtained nearly simultaneously from each compartment

Angiotensin-converting enzyme

Maternal Umbilical cord Umbilical cord venous venous . arterial

Diagnosis (unitslml) (unitslml) (unitslml)

Pregnancy-induced hypertension-preeclampsia, no magnesium sulfate 37.8 37.4 34.5

Normotensive

Pregnancy-induced hypertension-preeclampsia with magnesium sulfate

Diabetes (Classes D to R), pregnancy-induced hypertension­preeclampsia

34.0 37.8 37.8 23.7 22.0 11.6 21.0 19.0 18.6 19.7

35.7

27.2 37.8 47.7 21.0 13.7 37.0 22.0 23.0 24.4 10.2 22.2 18.8 20.4 21.7 15.7

43.7

With magnesium sulfate = Treated with magnesium sulfate before angiotensin-converting enzyme determination; no mag­nesium sulfate = no magnesium sulfate given before angiotensin-converting enzyme determinations. Results show: Maternal venous value was less than the cord venous value and greater than the cord arterial value.

with singleton pregnancies with or without pregnancy­induced hypertension, there were no differences.

The mothers whose babies were classified as small for gestational age (n = 17) had angiotensin-convert­ing enzyme levels that were comparable to those of mothers of normal-weight babies from both the nor­motensive and hypertensive groups.

The study population had 10 patients with diabetes mellitus complicating pregnancy: (1) normotensive, Class A (n = 4) and Class D (n = 1); (2) pregnancy­induced hypertension, Class B (n = 2), Class C (n = 1), and Classes D to R (n = 1); (3) chronic hypertension,

Class R (n = I). There was a wide range of angiotensin­converting enzyme values in those patients, from 14.6 to 45.3 units/ml, which did not appear to correlate with either the diabetic classification or the normotensive­hypertensive category.

Paired samples, obtained nearly simultaneously, were drawn from the maternal venous and umbilical venous blood of 12 patients and umbilical arterial blood in six maternal/neonatal sets (Table II). The values, regard­less of the status of blood pres~;ure, showed a rather uniform relationship: The maternal venous value was less than the cord venous value and greater than the

796 Goldkrand and Fuentes

110

100

!lAP 90

'""'"' 80

11.4%11.1 1"'%1.1 M-ac 111-35

IU:t11.1 '7.1:t12.1

"-37 ,.-3& H.5±U 1".7±7.'

N-1D 1i1_11

April,1986 Am J Obstet Gynecol

70L-__ _L ____ L-__ _L ____ L_ __ ~ ____ L_ __ _L ____ L_ __ ~

<20 ...... >24 ..... NClllIIOTt1ISI1IE

PREGNANT

IIAP <20_.

- .. PIt nCIIUIIIC .IP

PIt nCIIIDMIC t.

, .. (II <1.011 11<1.001

<20..... >24 ..... PIt"

NO lllsa,

<20..... >24 .....

CHIIOIIC H'_ NO PIt"

MAP >24_S

IIIIIIIOTBIIIYEnPit nCIIIDMIC tIP

"CtIIGIE .IP PIt

11<"'.' ,<1.101 ,<D.'l

NCIIIIIOTt1ISI1E <20 _I .. >24 _S p <0.05

Fig. 3. Mean arterial blood pressure (MAP) in normotensive women, women with pregnancy-induced hypertension (PIH) in whom magnesium sulfate was not given, and patients with chronic hyper­tension before 20 weeks and after 24 weeks of gestation.

8

6 URIC ACII

mg/dl

5

U:tl.l tI~2:2

PIt NO 1IgSD,

7.1:t1.' N.,

IIII'IEIIAIIT nALlIllllEll ..... ,<1.11 II)III01'8IIIVE .. ........ ,< 1.001 .. YI......... '(0 .... PIt·IIDIIIIIO. YI ... • .. IO. ,<uz

Fig. 4. Uric acid levels in patients according to the status of the blood pressure. MgS04 = Treated with magnesium sulfate before angiotensin-converting enzyme determination. No MgS04 = No mag­nesium sulfate given before angiotensin-converting enzyme determination.

cord arterial value. In four pregnancies, amniotic fluid was obtained for angiotensin-converting enzyme de­termination and was consistently <5 units/m!.

Mean arterial blood pressure (Fig. 3). The mean arterial blood pressure was calculated in normotensive women, women with pregnancy-induced hyperten­sion-preeclampsia, and women with chronic hyper­tension before the twentieth week and after the twenty-fourth week of gestation. In each group, the mean arterial blood pressure at >24 weeks was sig­nificantly higher than that at <20 weeks (normal blood pressure, p < 0.05; pregnancy-induced hyper­tension, p < 0.001; chronic hypertension, p < 0.001). The mean arterial blood pressure at <20 weeks was the same in the normotensive group and the group with pregnancy-induced hypertension, and both were

less than that from patients with chronic hypertension (p < 0.01).

Uric acid and blood urea nitrogen. The uric acid level (Fig. 4) in nonpregnant women (4.1 ± 1.2 mg/dl) was less than the third-trimester level in normotensive women (5.4 ± 1.2 mg/dl, p < 0.01). Patients with preg­nancy-induced hypertension and not receiving mag­nesium sulfate had higher levels of uric acid (6.4 ± 1.0 mg/dl) than the normotensive women (p < 0.005), while those with pregnancy-induced hypertension and receiving magnesium sulfate had the highest values (7.8 ± 1.6 mg/dl, p < 0.001).

The blood urea nitrogen of normotensive women (9.2 ± 2.4 mg/dl) was less than that of patients with pregnancy-induced hypertension without (12.2 ± 3.9 mg/dl) or with (14.7 ± 6.8 mg/dl) magnesium sulfate

Volume 154 Number 4

NORMAL

Angiotensin-converting enzyme and preeclampsia 797

INACTIVE THROMBOXANE A2

RENIN PROQUCTS t ANGIOTENSINOGEN_AI \!)ACE ® t PG CYClO-OXYGENASE

0BPF0 1"-An BRADYKININ + ENDOPEROXIDASE + PGE

ARACHIDONIC ACID

PROSTACYCLIN

PIH·PRB·aCLAMNIA THROMBOXANE Ao..

RENIN· INACTIVE t ANGIOTENSINOGEN-AI* PRODUCTS CYCLO·OXYGENASE ARACHIDONIC

ACID I EllACE (j) t PG , t (3 OPF 0 l,,",PGE

An • 8RADYKININ + ENDOPEROXIDASE PAOsrACYCLlN

Fig. 5. Theoretical interrelationship of the renin-angiotensin system, bradykinin, and the prostaglan­dins in pregnant patients with normal blood pressure and those with the pregnancy-induced hyper­tension (PIH)-preeclampsia syndrome. * = Increased (?). ACE = Angiotensin-converting enzyme. BPF = Bradykinin-potentiating factor. + = Stimulates reaction. - = Slows or blocks reaction.

(p < 0.001). However, in the two groups of patients with pregnancy-induced hypertension, there were no differences.

Comment This study demonstrates that serum angiotensin-con­

verting enzyme levels show significant changes in preg­nancies that are complicated by hypertensive diseases when compared with pregnancies in normotensive women. We have shown that there is no correlation (r = 0.05) when the angiotensin-converting enzyme levels are compared to week of gestation (Fig. I). This agrees with Parente et al.,5 but other authors.' 9 have described a steady increase in angiotensin-converting enzyme after 30 weeks of gestation. That our non­pregnant angiotensin-converting enzyme levels are considerably higher than those from normal pregnancy confirms the literature"' 9; these levels are comparable to those in patients with pregnancy-induced hyperten­sion not requiring magnesium sulfate and those with chronic hypertension and with superimposed preg­nancy-induced hypertension (Fig. 2). Abdul-Karim and Assali4 found that the nonpregnant woman was more responsive than the normotensive pregnant woman to an infusion of angiotensin II. They stated that the ben­eficial effect of pregnancy on hypertension was related to elevated angiotensinase activity and an increased de­struction of angiotensin II. The literature seems to fa­vor decreased angiotensin II levels in patients with pregnancy-induced hypertension,' but Symonds et al.lO reported increased angiotensin II levels in preeclamp­sia. They claim that the concentration of angiotensin­converting enzyme in pregnancy-induced hypertension is too high to be the rate-limiting step in angiotensin II production. Thus there is a dilemma as to whether there is increased angiotensin II production or in­creased angiotensin II inactivation. In either case, an elevated angiotensin-converting enzyme level could be expected to occur. Of importance is the loss of refrac­toriness of arterioles in pregnant patients who have or

will have pregnancy-induced hypertension. Gant et al. II demonstrated that increased sensitivity to angiotensin II infusion was present by 18 weeks and was the earliest indicator of subsequent pregnancy-induced hyperten­sion. Even changes in plasma volume did not signifi­cantly affect vascular sensitivity to angiotensin II. Gant et al. l

• correlated the positive pressor response in pa­tients with pregnancy-induced hypertension in the su­pine position in the third trimester (rollover test) with the sensitivity to infused angiotensin II. This had a high predictive value for the future occurrence or absence of pregnancy-induced hypertension. Lee and Todd l3

showed increased angiotensin-converting enzyme and catecholamine levels in mothers with a positive rollover test.

The rise in angiotensin-converting enzyme levels from patients with pregnancy-induced hypertension appears at about the same time that the clinical disease becomes evident. Therefore, the angiotensin-convert­ing enzyme levels did not seem to be able to predict which patients are at risk for pregnancy-induced hy­pertension. However, when a patient has elevated blood pressure in pregnancy, the angiotensin-convert­ing enzyme value is able to identify those patients with a diagnosis of pregnancy-induced hypertension. To confirm that angiotensin-converting enzyme appears to be a late or acutely occurring phenomenon, one must look at pregnant patients with chronic hypertension. In this study, these women have angiotensin-converting enzyme levels comparable to those in normotensive women, until they develop superimposed pregnancy­induced hypertension. Then the angiotensin-convert­ing enzyme levels become elevated as are those in nor­mal patients who develop pregnancy-induced hyper­tension. This correlates with the findings of Gant et al.,14 who showed the angiotensin II refractoriness to be similar in women with chronic hypertension and normotensive women until the superimposition of pregnancy-induced hypertension. Then angiotensin II refractoriness was lost. There was no difference in an-

798 Goldkrand and Fuentes

giotensin-converting enzyme levels according to weeks of gestation in the third trimester. This would allow diagnostic impressions to be made irrespective of ges­tational age. An interesting and important observation is the effect of magnesium sulfate on angiotensin-con­verting enzyme levels in patients with pregnancy-in­duced hypertension. In patients receiving magnesium sulfate, the angiotensin-converting enzyme levels were decreased to those of normotensive women and those with chronic hypertension without pregnancy-induced hypertension. This phenomenon is probably not due to plasma volume expansion as the uric acid levels and blood urea nitrogen did not demonstrate a similar de­crease. In fact, patients who receive magnesium sulfate and who have more severe pregnancy-induced hyper­tension have uric acid levels greater than those of women not receiving magnesium sulfate (p < 0.02) (Fig. 4). Is this then due to an effect of magnesium sulfate on the arteriolar endothelium where angio­tensin-converting enzyme is produced, or is it due to interference with the angiotensin-converting enzyme assay? The answer to this is still unknown. Elevation of uric acid has come to be an indicator of the severity of pregnancy-induced hypertension, and this progressive elevation may be indicative of poor fetal outcome.

Twin pregnancies in patients with pregnancy-in­duced hypertension were associated with angiotensin­converting enzyme levels that were higher (34.2 ± 6.5 units/ml) than those of singleton pregnancies with pregnancy-induced hypertension (29.1 ± 6.5 units/m!, p < 0.05). However, with no pregnancy-induced hy­pertension, the angiotensin-converting enzyme (20.5 units/ml) was similar to that in normotensive women with singleton pregnancies (21.1 ± 6.9 units/ml, p NS).

The explanation does not lie with the placental size, as the total placental weights were comparable in the twin gestations with or without pregnancy-induced hyper­tension.

From the literature, paired samples of maternal ve­nous and umbilical venous and arterial angiotensin­converting enzyme levels have shown that the angio­tensin-converting enzyme is the same in all three spaces, that the cord venous levels are greater than cord arterial or maternal venous levels, or that the umbilical venous angiotensin-converting enzyme concentration is less than that in maternal venous blood.2 In our study (Table II), the values suggest that the maternal venous value is less than the cord venous value and greater than the cord arterial value. The question remains if these differences are real. An additional source of an­giotensin-converting enzyme in pregnancy may well be the placenta,15 with distribution to both maternal and fetal circulations. The amniotic fluid levels are signifi­cantly less than in the other compartments «5 units/ ml) and, therefore, are probably of little significance.

April, 1986 Am J Obstet Gynecol

An increased angiotensin-converting enzyme concen­tration is not exclusive to pregnancy-induced hyper­tension. Angiotensin-converting enzyme is shown to be elevated in sarcoid, thyroid disease, and in neonates with respiratory distress syndrome, and we now have one patient with systemic lupus erythematosus at 8 weeks' gestation, with normal blood pressure, whose angiotensin-converting enzyme level is 34.8 units/ml. Lieberman and Sastrel6 reported elevated angiotensin­converting enzyme levels in diabetic patients, but our experience shows variable values that do not seem to be predictive of whether the patient has pregnancy­induced hypertension. Observation of mean arterial blood pressure (Fig. 3) before 20 and after 24 weeks in normotensive gestations demonstrated a rise in the third trimester of pregnancy. This may well correspond with the mild decrease and plateau in angiotensin II refractoriness shown by Gant et al.3 The mean arterial blood pressure in patients with pregnancy-induced hy­pertension and chronic hypertension with or without superimposed pregnancy-induced hypertension fol­lowed expected patterns.

The theoretical interrelationships of the components that control blood pressure in normal pregnancy and those complicated by pregnancy-induced hyperten­sion-preeclampsia are seen in Fig. 5. The renin-angio­tensin system seems to be well established. Estrogen may drive the system by increasing angiotensinogen substrate, as pregnancy is associated with increased ma­ternal-placental estrogen levels. Although angiotensin­converting enzyme is predominantly found in the lung" and is the usual site of conversion for angiotensin I to angiotensin II, in pregnancy, the placenta" may play an important and additional role in this system. Normally the increased substrate may lead to in­creased angiotensin II but progressive increases in angiotensinase' protect the mother from the angio­tensin II. Bradykinin, a potent vasodilator, sits in bal­ance with angiotensin II. It is a competitive inhibitor of angiotensin I conversion, and bradykinin-potentiat­ing factors inhibit the destruction of bradykinin and block the conversion of angiotensin I to angiotensin II. However, bradykinin is inactivated in the lungs, which suggests that angiotensin-converting enzyme may well promote this inactivation of bradykinin or blocking of bradykinin-potentiating factors. An imbalance in this

system may then explain the increased sensitivity of the arterioles to angiotensin II and the clinical presentation of pregnancy-induced hypertension. The linkage of this system to the prostaglandins was provided by the facts that indomethacin, a prostaglandin synthetase in­hibitor, decreased the refractoriness to angiotensin II in normal pregnant women, that infusions of prosta­glandin E2 lower angiotensin II sensitivity, and that prostaglandin 12 (prostacyclin) was responsible for va-

Volume 154 Number 4

sodilation, decreased platelet adhesiveness, and pre­vention of fibrin deposition. Prostaglandin 12 was found to be decreased in pregnancies associated with preg­nancy-induced hypertension, leaving a relative imbal­ance with increased thromboxane A2. Thromboxane A2 is released from the platelets and is responsible for vasoconstriction, platelet adhesiveness, and fibrin de­position. Thus Page's "inner vicious circle'" of de­creased uterine placental perfusion associated with va­soconstriction, damage to the placenta, thromboplastin release, intravascular coagulopathy, fibrin deposition in the kidney, decreased glomerular filtration rate, so­dium and water retention, and intracellular shift of sodium to increase vascular sensitivity to pressors ex­plains the clinical situation of pregnancy-induced hy­pertension. However, the critical piece in this puzzle is the finding that bradykinin has control over the pro­duction of prostaglandin E and prostaglandin 12 and bridges the gap between the renin-angiotensin system and the prostaglandins in the physiologic control mech­anisms of pregnancy-induced hypertension. Angio­tensin-converting enzyme, by its role in conversion of angiotensin I to angiotensin II and the inactivation of bradykinin, may be partially responsible for the de­crease in prostaglandin E and prostaglandin 12 in preg­nancy-induced hypertension-preeclampsia.

The current study has shown significant relationships of angiotensin-converting enzyme to the clinical pic­tures of pregnancy-induced hypertension that occur in previously normotensive and chronically hypertensive pregnant women. Simultaneous measurements of sev­eral of the components of the systems controlling vas­cular reactivity are required and may confirm the now theoretical mechanisms responsible for the mainte­nance of normal blood pressure in normal pregnancy or the occurrence of elevated blood pressure in preg­nancy-induced hypertension-preeclampsia.

REFERENCES 1. Page EW. On the pathogenesis of pre-eclampsia and

eclampsia. j Obstet Gynaecol Br Commonw 1972;79:883. 2. Oats jN, Broughton Pipkin F, Symonds EM, Craven DJ.

A prospective study of plasma angiotensin-converting en­zyme in normotensive primigravidae and their infants. Br j Obstet Gynaecol 1981;88:1204.

3. Gant NF, Daley GL, Chand S, Whalley Pj, MacDonald PC. A study of angiotensin pressor response throughout primigravid pregnancy. j Clin Invest 1973;52:2682.

4. Abdul-Karim R, Assali N. Pressor response to angiotonin in pregnant and nonpregnant women. AM j OBSTET Gy­NECOL 1961;82:246.

5. Parente jV, Franco jG, Greene Lj, et al. Angiotensin­converting enzyme: serum levels during normal preg­nancy. AMj OBSTET GYNECOL 1979;135:586.

6. Talledo OE, Chesley LC, Zuspan FP. Renin-angiotensin system in normal and toxemic pregnancies. AM j OBSTET GYNECOL 1968; 100:218.

7. Chinn RH, Dusterdieck G. The response of blood pres­sure to infusion of angiotensin II: relation to plasma

Angiotensin-converting enzyme and preeclampsia 799

concentrations of renm and angiotensin II. Clin Sci 1972;42:489.

8. Lieberman]. Elevation of serum angiotensin convert­ing enzyme (ACE) level in sarcoidosis. Am j Med 1975;59:365.

9. Rasmussen AB, Pedersen EB, Romer FK, et al. The in­fluence of normotensive pregnancy and preeclampsia on angiotensin converting enzyme. Acta Obstet Gynecol Scand 1983;62:341.

10. Symonds EM, Broughton Pipkin F, Craven]. Changes in the renin-angiotensin system in primigravidae with hy­pertensive disease of pregnancy. Br j Obstet Gynaecol 1975;82:643.

11. Gant NF, Chand S, Whalley Pj, MacDonald PC. The na­ture of pressor responsiveness to angiotensin II in human pregnancy. Obstet Gynecol 1974;43:854.

12. Gant NF, Chand S, Worley Rj, et al. A clinical test useful for predicting the development of acute hypertension in pregnancy. AMj OBSTET GYNECOL 1974;120:1.

13. Lee MI, Todd HM. Plasma catecholamines and angio­tensin-converting enzyme activity in hypertensive subjects with positive roll over tests. Obstet Gynecol 1984;63:511.

14. Gant NF,jimenezjM, Whalley Pj, Chand S, MacDonald PC. A prospective study of angiotensin II pressor re­sponsiveness in pregnancies complicated by chronic es­sential hypertension. AM j OBSTET GYNECOL 1977; 127:369.

15. Latorowicz A, Malofiejen M. Kinases and converting en­zyme in human placenta. Biochem Pharmacol 1978; 27:2829.

16. Lieberman j, Sastre A. Serum angiotensin-converting en­zyme: elevations in diabetes mellitus. Ann Intern Med 1980;93:825.

We will furnish a complete list of references upon request.

Discussion DR. NORMAN GANT, Dallas, Texas. I thoroughly

enjoyed reading the paper by Goldkrand and Fuentes. The authors observed that the angiotensin-converting enzyme was elevated in patients with pregnancy­induced hypertension when compared with normo­tensive pregnant women or pregnant women with un­complicated chronic hypertension. In fact, the serum levels of angiotensin-converting enzyme were elevated in patients with pregnancy-induced hypertension to values essentially the same as observed in nonpregnant subjects.

The authors also observed that the angiotensin-con­verting enzyme levels were reduced to normal levels in the third trimester of pregnancy in women with preg­nancy-induced hypertension who were treated with magnesium sulfate. The authors then compared these serum angiotensin-converting enzyme values to mean arterial blood pressures as well as blood urea nitrogen and uric acid values obtained in the same patients. As one might expect, uric acid and blood urea nitrogen levels were elevated in patients with pregnancy-induced hypertension whether or not they were treated with magnesium sulfate.

The authors also simultaneously measured serum an­giotensin-converting enzyme values in women and in the cord blood of their infants. Unfortunately, there were not enough values to draw any firm conclusions from this portion of the study nor were there enough

800 Goldkrand and Fuentes

values obtained in patients with diabetes to draw any firm conclusions.

The authors discussed their observations and pro­posed an interesting hypothesis that angiotensin-con­verting enzyme might be involved in the suppression of bradykinin. This in turn might result in a decreased production of prostacyclin and prostaglandin E2 in vas­cular endothelium resulting in the increased sensitivity to angiotensin II that precedes the onset of pregnancy­induced hypertension. I found this hypothesis fasci­nating and an idea that needs to be investigated. I have several questions, however, concerning the present study before I am willing to accept the role of angio­tensin-converting enzyme in the proposed hypothesis.

The results reported for angiotensin-converting en­zyme in the present study were reported as units per milliliter. Because these values were not reported as specific activities, it is entirely possible that what the authors are observing in this study is a constriction in plasma volume resulting in an artificial elevation of angiotensin-converting enzyme levels in women with pregnancy-induced hypertension. They mention this but do not elaborate on this possibility. I believe it is imperative that this issue be resolved.

The observation that magnesium sulfate lowers an­giotensin-converting enzyme values to normal levels in patients with pregnancy-induced hypertension is inter­esting and may well be, as suggested by the authors, the result of magnesium sulfate acting directly on en­dothelium to increase the production of angiotensin­converting enzyme. Certainly there is a recent report that magnesium sulfate stimulates vasodilation and an increase in prostacyclin in the human umbilical cord (Altura et ai., Science 1983;221 :376). It also may be that magnesium sulfate has a similar affect by increas­ing the angiotensin-converting enzyme production as well as prostacyclin production in vascular endothe­lium. If so, this would be a valuable piece of information that would be yet another reason for using magnesium sulfate to arrest and prevent seizures in patients with pregnancy-induced hypertension as well as to increase tissue perfusion in the mother as well as the fetus.

The authors also acknowledge that magnesium sul­fate might interfere with the assay of angiotensin-con­verting enzyme. It is a very simple matter to ascertain if this is a possibility by simply adding magnesium sul­fate to serum obtained from untreated preeclamptic women and then running the assay. In this way one would have eliminated the endothelium as a possible source of angiotensin-converting enzyme and could in a very short period of time ascertain whether the mag­nesium sulfate is merely interfering with the assay.

In closing, let me say that the authors should be con-

April, 1986 Am J Obstet Gynecol

gratulated for a carefully conducted clinical study. Their review of the literature and their hypothesis for a mechanism to explain their observations were well done. I urge them to resolve, as soon as possible, the questions that I have raised concerning what may very well be an extremely important observation in our con­tinuing search for a cause of pregnancy-induced hy­pertension.

DR. GoLDKRAND (Closing). First I would like to thank Dr. Gant for his kind remarks and for preparing for us the next stage in our investigation.

I would also like to take this opportunity to thank my coinvestigator, Dr. Fuentes, who was really one of the prime movers in this project and I think deserves credit for his work.

In relation to the comments that Dr. Gant made, I think they are very important as to whether we are seeing an effect that is due to constriction of blood volume. However, we have not yet looked at other fac­tors. The suggestion of using Evans blue dye to evaluate the supposition that this may be a blood volume phe­nomenon raises a real question. The fact is that the change in angiotensin-converting enzyme does not oc­cur early. It is a late-occurring phenomenon.

If the sample for measurement of angiotensin-con­verting enzyme is drawn early, it does not really have predictive value. Differential diagnosis is possible in the patient who presents with hypertension, but there may be an abnormality of the elevated enzyme. Dr. Gant's comments may be true and have yet to be elucidated.

The effect of magnesium sulfate is certainly one that needs to be evaluated very soon. We have also won­dered about this effect. With our use of Swan-Ganz catheters in some of our extremely ill patients, we have not really seen a major change in some of the factors that might accompany the production of prostacyclin and block the potential action of angiotensin-convert­ing enzyme.

Part of the problem is that the true half-life of this enzyme is not known because it has not been well worked out, and the effects that may be taking place from a therapeutic modality may not immediately dem­onstrate any change. At other times, when using other treatment modalities for a longer time, we do see changes both in blood volume and in stabilization of patients, so there may be a time factor here that needs to be evaluated.

However, the effect of magnesium sulfate on the assay is certainly a question that is begged very strongly and is about to be answered in the laboratory by the addition of magnesium sulfate to the blood sample to see if it has a direct effect on the assay method.