hypertension in pregnancy: use of antihypertensive drugs

(,>/>>,,& c I < i O Oh%lt i ( , , I , < , , > / i , < , , i i l 199’

Acta Obstetricia et Gynecologica Scandinavica

ISS\ O / l ~ t / . t V Y

- REVIEW ARTICLE

Hypertension in pregnancy: use of antihypertensive drugs TORE HENRIKSEN

From the Department of Obstetrics and Gynecology, The National Hospital and Institute for Nutrition Research. University of Oslo, Oslo, Norway

The role of blood pressure measurement in antenatal care

There is d i d evidence that hypertension in pregnancy is associated with serious maternal and fetal complications ( 1 -4). In the mother these include eclampsia. HELLP syndrome with (multi) organ failure. cerebral hemorrhage and death. Fetuses of hypertensive mothers suffer an increasl-d risk of perinatal mortality and morbidity mainly due to prematurit4. intrauterine growth retardation and a b I- u p t i o p1 aceii t ae .

For all who take care of pregnant women it is essential 10 keep in mind that iizcwusc~ in blood pressure is often the first szp of a placental dysfunction disorder known traditionally as preec- lampsiia. To underscore this point it may be said that wlien frequent blood pressure measurements remain essential in the care of L I I I pregnant women, i t is due to the lack of better indicators of impending pi-eeclampsia.

The hypertensive pregnant woman

The finding of ‘high blood pressure’ in a pregnant \ ~ o i i x ~ n requires an approach that differs in several ma>s from that used in the general population. Firji. the main reason for treating high blood

pressure in the general population is to prevent the long term effects of chronic hypertension. This is not the primary objective in the care of hypertensive pregnant women. In pregnant women. there is no evidence that ‘normalization’ of the blood pressure should be a goal of the treatment (see below). Antihypertensive treatment in pregnancy is. in the majority of cases, more to compare with the acute treatment of hypertensive crisis in a non- pregnant individual. Secondly. an increase in diastolic blood pressure of 10 mmHg may require im- mediate action in a pregnant woman whereas it may be subjected to second evaluation months later in a non-pregnant individual. For this reason a reliable measurement of blood pressure in the pregnant woman is particularily important. Thirdly, the level of blood pressure or degree of increase in blood pressure does not always reflect the seriousness of one main cause of hypertension in pregnancy, namely preeclampsia. Fourthly. age is also important in obstetric practice as the risk of having chronic hypertension is higher in a 35 year old mother compared to one of 20. Fifthly. the practical consequences of findins high blood pressure in a pregnant woman depends very much on the gestational age. Sixthly. in the cases of preeclampsia pharmacological reduction in the maternal blood pressure m a y lead the obstetrician to believe the state of the patient has improved. This is most often a misinterpretation that ma]’ have fatal consequences. Finally. as already suggested.

Hypertension in pregnancy 97

be approximately 40% of the circumference at the midpoint of the upper arm. Cuffs of two different sizes should therefore be available: The standard one with a bladder size of 12-13x33-35 cm and one ‘obese’ size of 15-18x36-42 cin for those with arm circumference above 41 cm. If the cuff is too small ‘cuff hypertension’ may result. Automated blood pressure devices should be used with care in pregnancy in general and in hypertension in pregnancy in particular (9-10). Automated instru- ments, as well as the aneroid manometers should be calibrated at least twice a year.

2. In antenatal care blood pressure is one of the most important parameters used. The procedure should therefore be standardized and always per- formed by a skilled person. Recommendations for blood pressure measurements by sphygomanome- try are given by the American Heart Association (1 1). The essentials of these recommendations are shown in Table I.

3. Those who make clinical decisions on the basis of blood pressure measurements must keep in mind that, in each individual, blood pressure varies throughout the day and throughout pregnancy (12). In particular, in women in the early phases of pregnancy induced hypertension (preeclampsia) the blood pressure often varies even more than in normotensive individuals (13). The level of blood pressure should not be interpreted as a reliable expression of the severity of the preeclampsia syndrome (14-1 5). In particular intrauterine growth retardation may be marked at the time a moderate increase in blood pressure appears.

increuse in blood pressure during pregnancy is most often a symptom of an underlying process, usually preeclampsia. More attention should be paid to the underlying disorder than to the blood pressure as such.

Measuring blood pressure and using it as a variable in obstetric practice

Before using blood pressure as variable in clinical practice three requirements should be fulfilled (anybody who has been in clinical work will know that these rules are often violated).

1. The mercury manometer method remains the gold standard for measuring blood pressure in pregnancy. The equipment must be in good shape. Defects leading to leakage of air after inflation is commonly seen. The width of the bladder should

Table I. Essentials of measuring blood pressure in obstetric practice

Patient condition: Circumstances: Resting before measurement: at least 5 min. Comfortable temperature Patient position: upright sitting with sup- Silence in the room ported back. Arm position: Resting (relaxed) on the table with the upper arm at the level of the heart.

Technique:

0

0

0

Bare. arm without rolled up tight sleeves. Estimate the circumference of the arm (cuff size). Place the center of the bladder over the brachial artery. Avoid applying the cuff too loose. The lower end of the cuff should be around 2 cm above the antecubal fossa. Place the manometer so it can be seen easily (not too far away at eye level). Inflate the cuff to 70mmHg and then stepwise by 10 rnmHg until pulse no longer can be felt, note the pressure, before deflating. Place the bell of the stethoscope in the antecubal fossa. Inflate the cuff to a pressure 20-30 mmHg above the pressure noted above. Deflate at a speed of 2-3 mmHgisec, 1.e. 30-50 seconds is required for deflation. This is a crucial point Note the manometer pressure at the appearance of repetitive sound (Korot- koff phase I), when the sound muffles (Phase IV) and when it disappears (Phase V). Round off the readings (upward) to the nearest 2 mrnHg. If the blood pressure is increased (or increasing), repeat the reading as close to the end of the consultation as practical. If different from the first, repeat again. If the pressure is above 140190 mmHg at the first consultation, do the measurement also on the other arm. Record the pressure at phase I (systolic) and phase V (diastolic). If phase IV and V differs with 5 mmHg or more note phase IV in parenthesis. Measure the blood pressure on the same arm at later consultations.

Whether Korotkoffs phase IV or V should be used in antanatal care has been a subject of controversy for decades. In the present author’s opinion phase V is the primary choice in daily practice since it is most easily recognized and seems to correlate best with the intraarterial pressure (11) (16). In 5-10 percent of pregnant women phase V is absent and phase IV must be used. By rounding off the reading to nearest 2 mmHg rather than 5 mmHg raises the awareness of the observer resulting in a more precise measurement. Be aware that in a significant proportion of the patients a ‘white coat effect‘ is present, i.e. the blood pressure increases because of the mere presence of the physician. If this is suspected another health professional may repeat the measurement after the consultation or, if possible, at home.

What is ‘high blood pressure’ (chronic hypertension) and ‘significant increase in blood pressure’ (pregnancy induced hypertension or aggravation of chronic hypertension) in a pregnant woman? (A classification of hypertension in pregnancy is discussed below)

The US National Working group on high blood pressure in pregnancy defines chronic hypertension to be present if a pregnant woman is known to have hypertension before conception or if blood pressure is found to be above 140/90 mmHg before 20 weeks of gestation (16). The threshold of 1401 90 mmHg is to some extent arbitrary as no studies are available justifying the use of this value as compared to, for example, 130/85 or 160/95 mmHg. Pregnant women with a first trimester blood pressure above 140190 have a five times higher risk of developing preeclampsia compared to normoten- sives (17). The prevalence of blood pressure above 140/90 mmHg among pregnant women before 20 weeks gestation is 2-3% (17).

0 Actii Obstrt G),necol Scand 76 (1997)

' I ' reynancj rndaecd h?iyerfension: ( ' I I ' r w I<,rl,p"L' hi Trumieni

Iwper r e i l ' l o l i

b'iq I Classification of hypertensive pregnaiicy coiiiplications.

'Significant increase in blood pressure' (Preg- r i t n i c ~ j ~ iiiclircwl hj~perterzsion (PIH)) is defined by the Working group to be present if the diastolic blood pressure in a previously normotensive person is increased by 15 mmHg or more in the latter half of pregnancy compared to the average in the first half of that pregnancy ( I 6). Pregnancy induced hypertension is also present if the systolic blood pressure is increased likewise by 30 mmHg or more, indepen- dent of the diastolic pressure (16). These i~hresholds of pregnancy induced hypertension are a.lso some- what arbitrary (17-18). By using this definition one will be confronted with the question whether an increase in diastolic blood pressure from 70 to 85 has the same clinical significance as a change from 80 to 95 niinHg. (If proteinuria occurs in patients with PIH Imwlrinipsiu has developed, see below). By using irwwise in blood pressure when defining hypertension, rather than a fixed value, an individual- ized approach to the patient is underscored. In women with clzronic h!;rwrtcnsion there is no general agreement as to which change in blood pressure must be considered as an increase of clinical significance ( 17). The major point in the care of l.hese pregnancies is to detect superimposed preeclmipsiu where development of proteinuria and fetal growth retardation are the major parameters.

Classification of hypertension in pregnancy

A variety of classifications of hypertension in pregnancy have been proposed (1 6, 19-20). In addition, the terms used do not always have the satme mean- ing in the different classification. Most of the proposed classifications do not contribute to a better understanding of hypertensive pregnancy complications nor are they very helpful in the practical care of the hqpertensive pregnant woman. During the last 5- 10 years the terms and definitions of hypertensive pregnancy complications shown in the figure seems to have gained widespread acceptance.

. i ( ' / ( l ( ~ / l v l c ' I (;l'/l?c'o/ .%O/li/ 76 f 19971

Sipriniposed preeclunipsio has developed if proteinuria (see below) appears. This is usually, but not always, accompanied by increase in blood pressure (17). If the patient is proteinuric before 20 weeks of gestation preeclampsia can generally not be diagnosed. The patient should. however, be treated as if she had preeclampsia (i.e. having a placental disorder) because of the maternal and fetal risks associated with i t .

The term Pi.egnctnq. induced IiyIwtension i PIH i designates any significant increase in blood pressure after 20 weeks gestation in a previously normotensive woman.

If proteinuria (i.e.>300 mgi24 h) appears at any time after 20 weeks gestation or within the first 4- 6 days post partum in a woman with PIH she has developed preeclunipsiu. It is beyond the scope of the present theme to discuss the concept of preeclampsia as such (16, 21). 'The essence of this is that the clinical features of preeclampsia will, when they occur in second half of pregnancy. in most women be an expression of an underlying placental disorder. Therefore, better terms than preeclampsia would be the preeclampsia syndrome or the placenta dysfunction syindrome. Since hypertension is just one feature (and not necessarily the most serious one but nevertheless important!) of the syndrome, health professionals who have in their care pregnant women with hypertension should be able to recogni.ze and take into consider- ation all other features of the syndrome.

If proteinuria does not develop in a woman with PIH she has trmzsient 1qper.tension. By definiton transient hypertension disappears within a few weeks post partum. It is therefore a retrospective diagnosis. Transient hypertension is often named gestational hypertension. The term gestational hypertension is again used interchangeably with PIH. it is even used for any h:ypertension in pregnancy. The term therefore confixes more than it clarifies but is still frequently in use.

The rationale of treating hypertension in pregnancy

The objective of treating hypertension in pregnancy is defined by the endpoints chosen.

In the present author's opinion the following endpoints should be included:

1. Serious maternal complications. particularly HELLP-syndrome, (multi-) organ failure. cerebral hemorrhage and eclampsia.

2. The progression of preeclampsia (measured as prolongation of pregnancy particularly in the group with early onset preeclampsia).

3. Risk of superimposed preeclampsia.


fects on common perinatal parameters. The power of the individual studies are, however, low for de- tection of smaller differences, for example in birthweight or neurological development of the child. In one study of women with chronic hypertension lower mid-pregnancy loss was found in the treatment group (36). It has, however, been questioned whether this reduction was due to changes in preeclampsia-related pathology (1 7). Concerns arose following reports that babies born by mothers treated with beta-adrenergic antagonists (atenolol or propranolol) had reduced birthweight if treated over prolonged time (22, 32, 37). In studies with oxprenolol this was not found (24, 25, 38, 39). In a recent review on use of nifedipine as an antihypertensive agent in pregnancy no adverse effects on perinatal outcome parameters were found (40). Several authors have reported cases where maternal hypotension caused by antihypertensive drugs has affected the fetus adversely (17, 41, 42).

Perinatal outcome (perinatal mortality, fetal distress, neonatal complications). Birth weight (prematurity and gestational age corrected birth weight). Long term prognosis of the children of hypertensive mothers. Long term cardiovascular risk of the mother.

Does pharmacological treatment of hypertension in pregnancy affect these endpoints? Ad I , 2 and 3. Prevention of serious maternal conqdications, progression of preeclampsia and risk of superimposed preeclarnpsia

Blake & MacDonald showed in a randomized survey that intensive antihypertensive treatment reduced the risk of developing proteinuria (22). Rub- in et al. reported similar findings (23). This effect of antihypertensive treatment has not been confirmed by others (24, 25). Rubin et al. and Leather et al. reported one week prolongation of pregnancy after antihypertensive treatment (23, 26). However, in both studies delivery took place in the last four weeks of pregnancy, so the clinical significance of the prolongation is small. In two later studies by Sibai et al. no effect was found of two different antihypertensive agents on the progression of the preeclamptic state or length of pregnancy (27, 28). Superimposed preeclampsia has not been shown to be prevented by antihypertensive treatment (1 5, 29, 30). The effect of antihypertensive treatment (of either chronic hypertension or preeclampsia) on the risk of developing the HELLP syndrome or organ failure associated with it, eclampsia or maternal overall death has not been subjected to specific randomized studies. However, the data from the studies cited above do not indicate that antihypertensive treatment prevents development of HELLP syndrome or its complications (27-30). (Cerebral hemorrhage or other cerebrovascular endpoints have never be subjected to randomized studies in the context of hypertension in pregnancy). Antihypertensive treatment is indicated on the basis of the knowledge of the association between hypertension and cerebrovascular disease in the general population (31). In addition, in the rare cases of mothers with renal diseases or heart failure antihypertensive treatment will usually be indicated to minimize end organ damage (31).

Ad 4 and 5. Perinutal outcome and birthweight

In a number of studies perinatal outcome has been included in the endpoints of trials of antihypertensive treatment (23-25, 27, 28, 30, 32-35). Alto- gether these studies do not indicate beneficial ef-

Ad 6. Long term effect on children

Long term effects on children born by mothers who received antihypertensive treatment in pregnancy has been subjected to very few studies. One exception is children born to mothers treated in pregnancy with methyldopa (43). These children have been followed up to school age and no signs of adverse effects were found (17, 43).

Ad 7 Eifect on the long term maternal risk of cardiovascular diseases

Recent studies indicate that women with pregnancy induced hypertension have increased risk of cardiovascular and renal diseases later in life (44, 45). However, it is not known whether treatment with antihypertensive drugs in pregnancy would reduce this risk.

Principles of antihypertensive treatment in pregnancy Chronic hypertension

A large proportion of women with chronic hypertension will in an obstetric context have mild to moderate hypertension (i .e blood pressure below 17011 10 mmHg) (1 7). Women planning pregnancy should have their antihypertensive regimen reviewed with respect to whether the antihypertensive treatment may be temporarily stopped or whether their medication should be changed to agents com- patible with pregnancy. (The latter would be the case if she is using ACE-inhibitors (and possibly A11 receptor antagonists), see below).

0 Arta Ohstet G j w r o l Srrrrid 76 (1997)

100 T. Ht.nrik.ren

M,,’oniori using tintil.l?.llertensi,.c drugs ut tlie.fjrst irnteiiritirl visit

A small proportion (10-20%) of the women having chronic hypertension in pregnancy are using antihypertensive agents at the first antanatal visit (46).

When advising this group of women on anti- hyperlensive treatment two questions usually arise. She wants to know if the drug she is using may affect her fetus. None of the antihypertensive drugs commonly used in pregnancy seem to be teratogenic although methyldopa is the only one for which re- assuring data are available (17). The second question that has to be considered is whether the andiypertensive should be discontinued. There is no general agreement on this subject. In some women the physiological vasodilation will reduce or abolish the need for continued antihypertensive treatment. At present most authors agree that the medication can safely be stopped in these cases provided the! are closely followed up (15--17). It is, however. of great importance that the patient’s medical history is thoroughly reviewed. Particularly in cases of secondary hypertension, nephrologist or other relevant specialist should be consulted.

We discuss below which blood pressure level would indicate (continuation of) antihypertensive treatment and what level would be considered thera- peutically optimal.

CVoiurrr 11ho w e not iisirig rmtiltypcv-tensiw agents ut the firne of’tlir,first visit

I f her blood pressure is above 140190 she lias chronic hypertension. as defined above. Most authors do not consider the diagnosis by itself to be an indi- cation for antihypertensive treatment (15, 16, 17, 47). As discussed above. antihypertensive treatment of mild to moderate hypertension in pregnancy does not generally improve the outcome of the mother or her fetus. However, there is also agrel-ment that when the blood pressure reaches certain levels antihypertensive treatment should be initiated due to the knowledge of the relation between cerebrovascular diseases and hypertension in the general population (31). Less agreement exists at which blood pressure level antihypertensive treatment should be started. Most authors recommend introduction of ant ill! pertensive medication when the diastolic blood pressure is between 100 and 110 rnmHg (15- 17.18).

To 11 lirth l r i ~ l 5houltl the blood pressure be reduced

If a didstolic blood pressure below 105 rnmHg does not indicate treatment it is reasonable to consider d dl,i~tolic blood pressure between 100-105 as the

J O i / Oh\l< I ~ r 1 1 7 1 , 1 0 / Scr//ld 76 / I9971

aim of the treatment. For patients with kidney diseases many clinicians will endeavor to normalize the blood pressure (i.e. down to around 140190) in order to keep the hypertensive end organ complications at a minimum. Since the blood flow in the uteroplacental circulation is assumed to be very much dependent on the perfusion pressure it must be a major aim not to reduce the blood pressure too much, in addition to keeping it stable (41). This is particularily important for those with preeclamptic hypertension where placental insuf- ficiency is often present.

There are also indications that if the placen- tation has taken place under conditions of elevated maternal blood pressure the placental function may be particular sensitive to reduction in perfusion pressure (49).

Regardless of whether distolic pressure of 95 or 105 mmHg should be the goal of the antihypertensive treatment, it is more important to bear in mind that women with chronic hypertension have several times increased risk of developing preeclampsia (1 7). Many develop early onset preeclampsia with the result that perinatal morbidity and mortality is particularly high (4, 6. 41). Reduced work load and regular rest is considered an important part of the antihypertensive regime by most clinicians. Whether these measures can prevent or postpone superimposed preeclampsia is, however, not known.

Antih,vpertensive treatment of’ womeii nvith p e e r lumpsiu

The main rationale for antihypertensive treatment is the same as for chronic hypertension: the fear of maternal cerebrovascular catastrophies or rapid exacerbations of preexisting cardiovascular or renal diseases.

Again there is no general agreement at which blood pressure level antihypertensive medication should be started. The recommendations vary from 160-1701100 mmHg to 160-18011 10 (16,17,48,50). The present author doe:; not generally treat preeclamptic blood pressures below 170/110 mmHg. The objective of antihypertensive treatment should be to stabilize the blood pressure around 160-1 701 105 more than to reduce it further for the reasons discussed above. It may be argued that preeclamptic patients with low platelet count should receive antihypertensive treatment on more liberal indications. There are no data supporting this.

Transient 11) perrcmion

This is a retrospective diagnosis and is obstetrically a benign condition (retrospectively). Transient hy-


pertension seems to respond more easily to antihypertensive treatment than preeclampsia (35). Whether blood pressure reduction in women with transient hypertension is of any benfit is not known. There is no reason to use other criteria for antihypertensive treatment of this group than for the other types of hypertension in pregnancy.

Choice of antihypertensive agents for treating hypertension in pregnancy General remarks

The estimated or expected duration of antihypertensive treatment in pregnancy may be important with respect to the choice of drug. This is illustrated by the effect of short and long term use of atenolol on birthweight (23, 32). Short term treatment with atenolol (i.e. <4-6 weeks) does not seem to affect birthweight whereas long term use may. Except for methyldopa, the documentation of the safety of long term antihypertensive treatment for the fetus is, for most preparations, limited (16, 17,48).

Some antihypertensive drugs have side effects mimicking symptoms of serious progression of preeclampsia (hydralazine, Ca+ + -channel blockers).

Finally, particularily PI-selective P-receptor antagonist may change the fetal heart rate patterns (reduced basal rate and lower amplitudes of the accelerations).

Diuretics

Diuretics are currently rarely used as antihypertensive agents in pregnancy. Collins et al. have reviewed the use of diuretics in pregnancy (51). In several studies diuretics have been claimed to prevent ‘preeclampsia’. However, in most of these cases the cri- terion of preventing preeclampsia was reduction in blood pressure which is not a sufficient endpoint (51). No studies of sufficient size or quality have demonstrated a positive effect on perinatal mortality or morbidity.

Initiation of diuretic antihypertensive treatment during pregnancy is exceptional in current obstetric practice. A main argument has been that diuretics reduce the maternal plasmavolume which again has been reported to be associated with poor perinatal outcome (52, 53).

In those cases where a woman is being treated with diuretics at the time she becomes pregnant and her hypertension is well regulated, there is little evidence that continuation would have any adverse effects on the mother or her fetus (16, 48, 51). It should, however, be discontinued if signs of fetal growth retardation or preeclampsia appear (compare effects of diuretics on the

maternal plasma volume). In exceptional cases, with documented salt sensitivity, use of diuretic agents may be attempted in pregnancy.

Sympa tholy t ic agents

Methyldopa Methyldopa is the drug most frequently used as

antihypertensive agent in pregnancy in UK and USA (17, 54, 55, 56). This is due to the long clinical experience with the drug and because niethyl- dopa is the only agent which has been subjected to long term follow up among children born by mothers who used the drug during pregnancy. The result of these studies did not find any indications of adverse effect on children up to 7 years of age (57). It was noted that children born to mothers who had been treated with methyldopa had a slightly smaller head circumference. The latter ob- servation has been judged not to be of clinical significance (17, 57).

In several countries methyldopa is considered the first drug of choice in long term treatment of chronic hypertension in pregnancy and also to control preeclamptic hypertension after the acute management (16, 17, 40, 48).

/3-receptor anatagonists

Non-selec t ive Several reports show that use of propranolol is

associated with low birthweight, fetal distress and increased perinatal mortality (37, 58, 59). Propran- 0101 is therefore not recommended as an antihypertensive agent in pregnancy.

Oxprenolol has ISA effect. The significance of this in pregnancy is not known. In 1979 Gallery et al. reported higher birthweights of babies born to mothers treated with oxprenolol compared to methyldopa (38). The average treatment was 7 weeks, with a wide range. In a later study by Gal- lery et al. they confirmed their results (39). How- ever, the different effect of oxprenolol and methyldopa on fetal weight diminished with the length of the treatment. In a placebo controlled study Plouin et al. found oxprenolol safe to the fetus but no enhancing effect on birthweight was oberved compared to placebo (mean treatment time 10 weeks) (25). Fidler et al. did not find any difference in fetal outcome when oxprenolol was compared to methyldopa (2-10 weeks treatment) (24).

Cardioselective (PI) /I-receptor unatagorzists

A tenolol-metoprolol In a placebo-controlled trial Rubin et al. found

beneficial effect on fetal morbidity and respiratory

0 Acta Obstet Gqnecol Scutid 76 (1997)

I03 T. Heririksen

distress following antihypertensive treatment with atenolol (23 1. This large and well controlled study has been an important basis for discussing the use of P-receptor antagonists (47, 60, 61). In the work by Rubin et al. the length of treatment was a few weeks. In ii later study Butters et al. treated hypertension in pregnancy through the second and last trimester with atenolol and found reduced birthwight in the atenolol-group compared to placebo (12). Montan et al. observed potentially nega- tive effects of atenolol (compared to pindolol) on fetal henlodynamic parameters (62). Ateriolol does not seem 10 be recommendable in pregnancy, es- peciallq. if needed more than a few weeks.

Metoprolo1 has not been subjected to randomized placebo-controlled studies. It seems to be comparable t o nicardipine (mean treatment time 8 [veeks) and hJsdralazine in terms of antihypertensive effects and on selected perinatal outcome parameters (63. 64).

In short term treatment (<4-6 weeks) P-receptor antagonists seem safe and useful provided that signs of intrauterine growth retardation are not present. The fetal effects of long term treatment (>&lo weeks) with P-receptor antagonists in pregnancy have not been subjected to studies of sufficient power. In particular, the cardioselective (PI) P-receptor antagonists and propranolol have been reported to give reduced birthweight in long term treatment.

a- d i w i tv;:. ic ii I Tugmi ists

Prazosin has. in a small non-controlled study, been used in combination with oxprenolol in cases of severe hypertension in pregnancy (65). No serious adverse effects were reported that coul'd be attri- buted ro the treatment. Diazoxide has been proposed to be combined with hydralazine in cases whet-e the latter is ineffective (48).

The experience with these drugs is limited and general recommendations cannot be given.

.Mi loti a- i i i d /i- retepfor untugoni~ts

Labetolol has, by many. been considered a safe and effective drug to treat particularly preeclamptic hypertension (66). However, Sibai found in a placebo controlled trial of 200 patients with preeclampsia remote from term reduced birthweight in the treatment group (27). In a study of non-proteinuric pregnant? induced hypertension Pickles et al. did not find any adverse effects on the fetal outcome compared to placebo during a few weeks' treatment ( 3 3 ) There is one study of the perinatal effects of long term treatment (from late first tri- mestcr) M ith labetolol in women with mild chronic

l i r l ~ ( l l ) \ t ( r ( r l t w ~ ( o l Sc~iriil 76 i l 9 9 7 )

hypertension (30). No difference in outcome was observed when compared to methyldopa or no drug. The uteroplacental circulation does not seem to be adversely affected by labetolol (1 7).

Labetolol is widely employed to treat hypertension in pregnancy. Short term usage seems safe although reduced birthweight has been reported in preeclamptic women (27). It may be questioned whether it has any advantage over CA++ channel blockers or a stepwise combination of hydralazine and p-receptor antagonist in treatment of preeclamptic hypertension. Although one study indicates no adverse fetal effects, the safety of labetolol in long term treatment cannot be considered sufficiently settled. However, in cases of severe chronic hypertension where methyldopa is contraindicated (e.g. drug induced liver damage), not tolerated or ineffective, labetolol may be used.

Vmodilutors

(Di)hydralazine is extensively used as an agent to treat acute development of hypertension in pregnancy, particularly in preleclamptic patients (1 7.48, 61). Placebo-controlled :studies on the use of hydralazine in acute treatment of hypertension in pregnancy have not been reported. Hydralazine and labetolol have been compared in acute management of hypertension in pregnancy and were similarly effective (67). Hydralazine does not seem to have any adverse effect on fetal circulation (68).

The long experience with (di)hydralazine, its ef- fectiveness either given as bolus injection (IV or IM) or as continuous infusion, and the fact that it can be combined with it loading dose of methyldopa, are the main reasons why most authors recommend the drug as the first drug of choice in acute management of obstetric hypertension ( 1 5 , 16, 17, 40, 48).

The main use of hydralazine is in the acute treatment of hypertension i.e. before the effect of a more permanent drug has begun to work. If needed (di)hydralazine can also be combined with P-receptor antagonists (15, 16, 48). The side effects of (di)hydralazine (headache, tremulousness and vomiting ) may mimic the symptoms of impending eclampsia or HELLP syndrome.

Cci +-channel blockers

Animal studies have shown limb and digital defects in fetuses exposed in utero to Ca-+-channel blockers (69). These teratogenic effects may be due to drug induced decrease in uteroplacental blood- flow in the animals studied (70). In a recent prospective cohort study no major increase in terato-


genic risk was observed (71). Sibai et al. compared nifedipine with bedrest treatment alone in patients at 26-36 weeks of gestation, in management of preeclampsia remote from term. Nifedipine was effective in reducing the maternal blood pressure but had no effect on maternal hospitalization or perinatal outcome (28). Nifedipine has been compared to hydralazine in treating severe preeclamptic hypertension (72). The newborns of the nifedipine group spent fewer days in the neonatal intensive care unit. The perinatal outcome was similar. No randomized studies of sufficient size on long term nifedipine treatment of women with chronic hypertension in pregnancy have been reported. Several studies on the effect of nifedipine on the uteroplacental or fetal circulation have not shown any adverse effects (73, 74).

Isradipine does not seem to affect birthweight pregnancy when used late in pregnancy up to 2-4 weeks (35). Isradipine effectively reduces the blood pressure in non-proteinuric hypertensive women but not in preeclamptic patients (35). Isradipine does not seem to affect adversely the uteroplacental or fetal hemodynamics (75).

Nimodipine has been used orally as an agent in acute management of preeclampsia during the last 24 hours before delivery (76). Good effects on maternal blood pressure and beneficial effects on fetal and maternal hemodyamic parameters were observed. If Ca++-channel blockers are used in combination with magnesium sulfate the hypotensive effect may be potentiated (48).

Most Ca++-channel blockers seem effective in reducing maternal blood pressure. No adverse effect on the fetus have been observed in short term treatment. The safety of using Ca++- channel blockers in long term treatment in pregnancy (i.e. from first trimester) needs to be confirmed by more studies. In cases where methyldopa cannot be given nifedipine (as an alternative to labetolol) may be used based on the epidemiological data cited above.

Angiotensin converting enzyme inhibitors

ACE-inhibitors are now widely used in non-pregnant individuals. It is considered contraindicated in pregnancy due to several reports on neotatal death or renal failure (77).

Women who become pregnant when being treated with ACE-inhibitors should have their antihypertensive regimen changed. Women who are planning pregnancy should use other antihypertensive drugs than ACE-inhibitors (78). The experience with ACE inhibitors makes angiotensin I1 receptor antagonists presently contraindicated in pregnancy.

Concluding remarks

The objective of the present article was to discuss the principles of pharmacological treatment of hypertension in pregnancy. However, as already suggested, increasing blood pressure is only a sign of an underlying disease, usually preeclampsia or superimposed preeclampsia. Repetitive measurements of blood pressure is by most of us used in monitoring the preeclamptic patient although it is well known that the degree of hypertension is not closely correlated to the severity of the disease (14, 17 ). The central parameters in the surveillance of preeclamptic pregnancies are clinical and labora- tory signs of impending maternal multiorgan af- fection (cerebral symptoms, pain and rightward tenderness in the epigastrium, nausea, rapidly increasing edema, hyperreflexia, increasing proteinuria, increasing transaminases, hemolysis, de- creasing platelet counts, progressively falling serum albumin and disseminated intravascular co- agulation). In addition, close monitoring of the fetal wellbeing is mandatory irrespective of the severity of the maternal symptoms. Although hospitalization and bed rest never has been proven to be beneficial to the preeclamptic mother or her fetus, decades of clinical experience supports its useful- ness in the practical management of the patients.

The future in clinical research on hypertensive pregnancy complications

Since the only effective treatment of preeclampsia is delivery, the major clinical challenge are those women who develop the syndrome before 33-35 weeks of gestation. These pregnancies have some features that are not seen to the same degree among those who develop late onset preeclampsia. First, the risk of recurrence of the disease in the next pregnancy is high in this group (79). Secondly, they seem to be at increased risk of developing chronic hypertension (80). Thirdly, growth retardation is more frequent in the early onset preeclampsia (41). Fourthly, early onset preeclampsia is accompanied by higher risk for maternal and fetal complications (6, 79). Fifthly, women at risk of early onset preeclampsia are the only group where aspirin prophylaxis seems to have some beneficial effect (81). From a clinical point of view future preeclampsia research should pay more attention to pregnancies with early onset disease. Any treatment or intervention that may allow prolongation of these pregnancies, even by only 1-2 weeks, compared to current management, would represent a clinically significant improvement (82).

Tremendous effort has been made to find factors that may be of pathogenic importance in the devel-

0 Acta Obstet Gynecol Scnnd 76 (19971


pregnancy: effects on fetal hemodynamics. BMJ 1992; 304: 946-9.

63. Jannet D, Carbonne B, Sebban E, Milliez J. Nicardipine versus metoprolol in the treatment of hypertension during in pregnancy: A randomized comparative trial. Obstet Gynecol 1994; 84: 354-9.

64. Sandstr~m B. Antihypertensive treatment with the adrenergic beta receptor blocker metoprolol during pregnancy. Gynecol Obstet Invest 1978; 9: 195-204.

65. Lubbe WF, Hodge JV Combined alpha- and beta-adreno- receptor antagonism with prazosin and oxprenolol in control of severe hypertension in pregnancy. NZ Med J 1981: 94: 169-72.

66. Michael CA. The evaluation of labetolol in the treatment of hypertension complicating pregnancy. Br J Clin Pharmacol

67. Mabie WC, Gonzalez AR, Sibai BM, Amon E. A comparative trial of labetolol and hydralazine in the acute management of severe hypertension complicating pregnancy. Ob- stet Gynecol 1987; 70: 328-33.

68. Gudmundsson S, Gennser G, Maral K. Effects of hydralazine on placental and renal circulation in preeclampsia. Acta Obstet Gynecol Scand 1995; 74: 415-8.

69. Yoshida T, Tadegawa Y, Miyago M, Hasegawa Y. Hyperphalangism induced by Ca-blockers in rat feuses. Teratology 1989; 40: 668-9.

70. Danielsson BR, Danielson M, Reiland S, Rundquist E, Dencker L, Regard CG. Histological and in \+fro studies supporting decreased uteroplacental blood flow as expla- nation for digital defects after administration of vaso- dilators. Teratology 1990; 41: 181-93.

71. Magee LA, Schick B, Donnenfeld AE, Sage SR, Conover B, Cook L et al. The safety of calcium channel blockers in human pregnancy: A prospective, multicenter cohort study. Am J Obstet Gynecol 1996; 174: 823-8.

72. Fenakel K, Fenakel G, Appelman Z, Lurie S, Katz Z. Sho- ham (Schwartz) Z. Nifedipine in treatment of severe preeclampsia. Obstet Gynecol 1991; 77: 331-7.

73. Moretti MM, Fairlie FM, Akl S. Khoury AD. Sibai BM. The effect of nifedipine therapy on fetal and placental Doppler waveforms in preeclampsia remote from term. Am J Obstet Gynecol 1990; 163: 18468.

74. Hanretty KP, Whittle JM, Howie, Rubin PC. Effect of nifedipine on Doppler flow velocity waveforms in severe preeclampsia. BMJ 1989; 299: 1205-6.

75. Wide-Svennson DH, Ingemarsson I, Andersson K-E, An- andakumar C, Arulkumaran S, Ratman S. Isradipine reduces the blood pressure, but not placental flow in pregnancy induced hypertension. Clin Exp Hypertens Preg- nancy 1991; B10: 49-60.

76. Belfort MA, Saade GR, Moise KJ. Cruz A, Adam K, Kramer W et al. Nixnodipine in the management of preeclampsia: maternal and fetal effects. Am J Obstet Gynecol

77. Rosa FW, Bosco LA, Graham CF, Milstien JB, Dreis M, Creamer J. Neonatal anuria with maternal angiotensin converting enzyme inhibition. Obstet Gynecol 1989; 74: 37 1 4 .

78. Editorial. Are ACE inhibitors safe in pregnancy? Lancet 1989; ii: 482-3.

79. Sibai BM, Mercer B, Sarinoglu C. Severe preeclampsia in the second trimester: Recurrence risk and long term prognosis. Am J Obstet Gynecol 1991; 165: 1408-12.

80. Arngrimsson R, Purandare S, Connor M, Walker JJ. Bjarnsson S, Soubrier F et al. Angiotensinogen: a candi- date gene involved in preeclampsia? Nature Genetics 1993;

81. Ylikorkala 0. Aspirin for the prevention of pre-eclampsia: where do we stand? Acta Obstet Gynecol Scand 1995, 74: 407-9.

1982; 3 (SUPPI): 127-36.

1994; 171: 417-24.

4: 114-15.

40. Levin AC, Doering PL, Hatton RC. Use of nifedipine in the hypertensive diseases of pregnancy. Ann Pharmacother

41. Derham RJ, Hawkins DF, de Vries LS, Aber VW, Elder MG. Outcome of pregnancies complicated by severe hypertension and delivered before 34 weeks; stepwise logistic re- gression analysis of prognostic factors. Br J Obstet Gynaec-

42. Vink GJ, Moodley J, Philpott RH. Effect of dihydralazine on the fetus in the treatment of maternal hypertension. Ob- stet Gynecol 1980; 55: 519-21.

43. Cockburn J, Mar VA, Ounsted M, Redman CWG. Final report of study on hypertension during pregnancy; the effects of specific treatment on the growth of children. Lancet 1982: i: 647-9.

44. Jonsdottir L. Arngrimsson R, Geirsson R, Sigvaldason H, Sigfusson N. Death rates from ischemic disease in women with a history of hypertension in pregnancy. Acta Obstet Gynecol Scand 1995; 74: 772-6.

45. Nissel H, Lintu H, Lunell NO, Merllerstrom G, Pettersson E. Blood pressure and renal function seven years after pregnancy complicated by hypertension. Br J Obstet Gynaecol

1994;28: 1871-8.

01 1989; 96: 1173-81.

1995; 102: 876-81. 46. Henriksen T. Unpublished data. 47. Wide-Swensson DH, Montal F, Ingemarsson I. How Swed-

ish obstetricians manage hypertensive disorders in pregnancy. Acta Obstet Gynecol Scand 1994; 73: 619-24.

48. Lindheimer MD. Hypertension in pregnancy. Hypertension

49. Marsal K. Personal communication. 50. Anderson GD, Sibai BH. Hypertensive in pregnancy. in:

Gabbe SG, Niebyl JR, Simpson JL. Obstetrics. Normal and problem pregnancies. New York. Churchill Livingstone

51. Collins R, Yusuf S, Peto R. Overview of randomized trials of diuretics in pregnancy. Br Med J 1985: 290: 17-23.

52. Sibai BM, Addella TN, Anderson GD. Plasma volume de- terminations in pregnancies complicated with chronic hypertension and intrauterine fetal demise. Obstet Gynecol

53. Sibai BM, Grossman RA, Grossman HG. Effects of diuretics on plasma volume in pregnancies with long term hypertension. Am J Obstet Gynecol 1984; 150: 831-5.

54. Trudinger BJ, Rarik 1. Attitudes to management of hypertension in pregnancy. A survey of Australian fellows. Aust NZ J Obstet Gynecol 1982; 22: 191-7.

55. Lewis PJ. Bulpitt CJ, Zuspan FP. A comparison of current British and American practice in management of hypertension in pregnancy. J Obstet Gynecol 1980; 1: 78-83.

56. Treatment of hypertension in pregnancy. Swedish Medical Agency Products Publications 1997. In press.

57. Redman CWG, Ounsted MK. Safety for the child of drug treatment for hypertension in pregnancy. Lancet 1992: i: 1237.

58. Lieberman BA, Stirrat GM, Dohen SL, Beard RW, Pinker GD. Belsey E. The possible adverse effect of propranolol on the fetus in pregnancy complicated by severe hypertension. Br J Obstet Gynaecol 1978; 85: 678-83.

59. Habib A. McArthy JS. Effects on the neonate of proprano- lo1 administered during pregnancy. J Pediatr 177; 91: 808- 11.

60. de Swiet M. Antihypertensive drugs in pregnancy. BMJ 1985; 291: 365-6.

61. Barron VM, Murphy MD, Lindheimer MD. Management of hypertension during pregnancy. In: Laragh JH, Brenner BM, eds. Hypertension. Diagnosis and management. New York: Raven Press 1990; 1809-27.

62. Montan S, Ingemarsson I, Marsal K, Sjerberg N-0. Ran- domized controlled trial of atenolol and pindolol in human

1993; 127: 127-37.

1986. pp. 819-63.

1982: 60: 174-8.

0 Acrrr Ohstet Gynrcol Scand 76 119971

106 T. Hn.zl-iksen

82. Odendaiil HJ. Pattison RC. Bani R, Grove D, v.W. Kotze T. ,Aggressive or expectant management for patients with severe preeclampsia between 78-34 weeks gestation: a randomized controlled trial. Obstet Gynecol 1990; 76: 1070-5.

8-3. Erskine KJ. ILeren SA. Davies R. An altered ration of 182 (9. 1 I ) to 1 8 2 (9.12) linoleic acid in plasma phospholopids as a possible predictor of preeclampsia. Lancet 1985: i: 554-5.

84. Lararchick J. Stubbs THM, Romein L, Van Dorsten JP. Loadholt CB. Predictive value of fibronectin levels in nor- nioteiisive gravid women destined to become preeclamptic. Am J Obstet Gynecol 1986: 154: 1050-2.

X 5 . Fitzgerald DJ. Entma SS. Mulloy K. FitzGerald GA. De- creased prostacyclin biosynthesis preceding the clinical manifestation of pregnancy induced hypertensi'on. Circula- tion 1987: 75: 956-63.

56. Sihai BH. Gordon T. Thom E. Caritis SN. Klebanoff M. McNellis D et al. Risk factors for preeclampsia in healthy

nulliparous women: A prospective multicenter study. A m J Obstet Gynecol 1995: 172: 642-8.

87. Lorentzen B, Drevon CA, Endresen MJR. Henriksen T. Fatty acid pattern of free and esterified fatty acids in sera of women with normal and preeclamptic pregnancy. Br J Obstet Gynaecol 1995: 102: 530--7.

Address for correspondence: Professor Tore Henriksen Department of Obstetrics and Gynecology The National Hospital Pilest redet 0027 Oslo Norway

C .4ctii Oh.ytet G>.necol Scand 76 i 1997)

hypertension in pregnancy: use of antihypertensive drugs

Documents