Many aspects of hypertension care outside pregnancy may be applied in pregnancy, but little information is available on which to base decision-making. It would seem reasonable to continue previous dietary salt restriction and physical activity in women with pre-existing (and controlled) hypertension, encourage a heart-healthy diet in all women with a hypertension disorder of pregnancy, and take patient preference into account when deciding on place of care. Although bed rest has become a key part of obstetric practice and for care of women with a hypertension disorder of pregnancy, in particular, the evidence is lacking to support this practice. This may also increase thromboembolic risk. Antihypertensive treatment is strongly advised for women with severe hypertension. The most common agents are parenteral labetalol, hydralazine, or oral nifedipine capsules. Clinicians should familiarise themselves with multiple agents. Until the role of antihypertensive treatment for non-severe hypertension in pregnancy is clarified by ongoing research, clinicians should explicitly state an individual patient’s blood pressure goal, which could reasonably be anywhere between 130/80 and 155/105 mmHg. Labetalol and methyldopa are used most commonly. Breastfeeding should be encouraged. Many risk factors for hypertension (e.g. obesity), as well as hospitalisation and pre-eclampsia, all increase the thromboembolic risk for pregnant women, and care providers should consider thromboprophylaxis in the appropriate setting. Finally, anaesthetists play a critical role in the management of women with a hypertension disorder of pregnancy, and should be involved earlier rather than later in the course of their care.
Introduction
The management of women with a hypertensive disorder of pregnancy (HDP) involves more than management of the hypertension. Women with pre-existing hypertension or gestational hypertension, particularly with onset at less than 34 weeks’ gestation, are at substantial risk of pre-eclampsia (i.e. up to 35%). Pre-eclampsia is a disorder of systemic endothelial cell dysfunction and, as such, care providers must provide comprehensive maternal and fetal surveillance.
In this chapter, we will review the effectiveness of practices traditionally applied to women with hypertension outside pregnancy, many of which are also used in pregnancy, namely dietary and lifestyle change, as well as antihypertensive treatment. Issues of particular relevance to women with pre-existing hypertension in pregnancy will also be considered as will thromboprophylaxis. Aspects of care related to anaesthesia and fluid management is applicable to all women with a HDP. Other chapters in this issue of Best Practice and Research Clinical Obstetrics and Gynaecology will cover areas of particular relevance to women with gestational hypertension or pre-eclampsia (see chapter on expectant versus temporising management of pre-eclampsia) and postpartum care and long-term maternal health (see chapter on postpartum evaluation, recurrence risk, and implications for long-term health).
Dietary and lifestyle changes
In the general population, non-pharmacological approaches to managing hypertension are encouraged and considered complementary to drug treatment. However, the short time frame for intervention in women with one of the HDP has meant that non-drug measures have been largely ignored in hypertension research. Greater understanding of the pathogenesis and physiology of HDP have led to renewed interest in dietary and lifestyle changes in the prevention and treatment of HDP, as well as the promotion of more restricted gestational weight gain within the 2009 Institute of Medicine recommendations.
Pre-eclampsia originates in the placenta. Various factors are released, which result in antagonism of angiogenesis, immune maladaptation, oxidative stress, and endothelial dysfunction. These, collectively, lead to the maternal syndrome that is most commonly manifest by new hypertension and proteinuria. Whether dietary change, supplementation with micronutrients, or both, may favourably influence the pathophysiological events that lead to the clinical diagnosis of pre-eclampsia and thereby prevent it, is discussed in the chapter on predicting and preventing the onset of pre-eclampsia. Here, we will discuss whether dietary changes, supplementation with micronutrients, or both, may favourably influence maternal and perinatal outcomes, once pre-eclampsia (or another HDP) has been diagnosed. Specifically, we need to consider women with pre-existing hypertension, gestational hypertension (that is isolated without evidence of pre-eclampsia), or pre-eclampsia (usually defined by proteinuria). For women with a HDP, of whatever variety, few data are available on the benefits or risks of dietary change on pregnancy outcome.
Dietary and lifestyle changes
In the general population, non-pharmacological approaches to managing hypertension are encouraged and considered complementary to drug treatment. However, the short time frame for intervention in women with one of the HDP has meant that non-drug measures have been largely ignored in hypertension research. Greater understanding of the pathogenesis and physiology of HDP have led to renewed interest in dietary and lifestyle changes in the prevention and treatment of HDP, as well as the promotion of more restricted gestational weight gain within the 2009 Institute of Medicine recommendations.
Pre-eclampsia originates in the placenta. Various factors are released, which result in antagonism of angiogenesis, immune maladaptation, oxidative stress, and endothelial dysfunction. These, collectively, lead to the maternal syndrome that is most commonly manifest by new hypertension and proteinuria. Whether dietary change, supplementation with micronutrients, or both, may favourably influence the pathophysiological events that lead to the clinical diagnosis of pre-eclampsia and thereby prevent it, is discussed in the chapter on predicting and preventing the onset of pre-eclampsia. Here, we will discuss whether dietary changes, supplementation with micronutrients, or both, may favourably influence maternal and perinatal outcomes, once pre-eclampsia (or another HDP) has been diagnosed. Specifically, we need to consider women with pre-existing hypertension, gestational hypertension (that is isolated without evidence of pre-eclampsia), or pre-eclampsia (usually defined by proteinuria). For women with a HDP, of whatever variety, few data are available on the benefits or risks of dietary change on pregnancy outcome.
Dietary change
We were unable to identify trials examining the effect (on pre-eclampsia or other pregnancy outcomes) of ongoing salt restriction among women with pre-existing hypertension. Among women with ‘gestational hypertension’ (i.e. diastolic blood pressure>85 mmHg with either oedema or weight gain above 1 kg/wk), new salt restriction did not favourably influence outcomes (one trial, 361 women). We were also unable to identify trials of new salt restriction among women with pre-eclampsia; however, new salt restriction cannot be recommended on the basis of results of an observational study, which found that a low-salt diet did not decrease blood pressure but did accelerate volume depletion, a theoretical harm.
For any of the HDP, we were unable to identify trials that looked at the effect on pregnancy outcome of a heart-healthy diet or calorie restriction (among women who are overweight).
Physical activity
Exercise
Outside pregnancy, increased physical activity is recommended for blood-pressure reduction. Increasingly, physical activity is recommended in pregnancy. No trials were identified that examined the effect of exercise on outcomes among pregnant women with hypertension. The PARmed-X for Pregnancy guideline for assessment of physical activity readiness in pregnancy, lists pre-existing hypertension as a relative contraindication, and both gestational hypertension and pre-eclampsia as absolute contraindications to vigorous exercise.
Reduced physical activity
There has been great enthusiasm for making reduced physical activity part of the management strategy for women with a HDP, particularly pre-eclampsia. These recommendations, however, are based on tradition rather than solid evidence. The definition of bed rest, however, has varied widely, and compliance with recommendations questioned.
Workload reduction or cessation are commonly recommended for outpatients with pre-existing or non-severe gestational hypertension or pre-eclampsia. However, no trial data are available to support this practice.
The effectiveness of bed rest is discussed in the section on place of care below, as relevant trials have not examined bed rest distinct from participation in an antepartum home-care programme for outpatients, or hospitalisation.
Other lifestyle changes
Outside pregnancy, stress management may be useful if stress seems to be associated with hypertension.
Place of care
Out-of-hospital care
Out-of-hospital care for women with any of the HDP, but particularly pre-eclampsia, assumes that women do not have either severe disease or severe hypertension. It also assumes that, particularly for women with gestational hypertension or pre-eclampsia, full maternal and fetal assessment has been undertaken or is planned.
The options for outpatient care include obstetric day units and antepartum home-care programmes. Eligibility criteria for outpatient care of this type vary widely, but usually describe women who live reasonably close to hospital, have blood pressure that is not particularly labile and definitely not severe, have no significant co-morbid conditions that require intensive monitoring, are likely to comply with care protocols, and can be relied upon to report a change in maternal or fetal status.
Obstetric day unit
Eligibility for care in an obstetric day unit varies from 30–60% of women assessed. Women prefer this type of care, and costs are similar despite reductions in inpatient days of care. Trials have focused on gestational hypertension, and shown similar maternal and perinatal outcomes whether women are cared for in hospital obstetric day units or as inpatients (two trials, 449 women).
Antepartum home-care programme
Of women considered for care by a formal home-care programme, about 25% are eligible. Although programmes vary in their details, all involve some component of daily contact and (usually) a weekly hospital or office outpatient visit. Some component of bed rest is also the norm.
Women can accurately measure blood pressure at home using an automated device. Although those blood-pressure values are not consistently different from those measured in hospital, they vary widely, with differences ranging from 8.5 mmHg below to 15.4 mmHg above values during hospitalisation compared with non-hospitalised days, particularly among women receiving antihypertensive treatment. No trials were identified that compared a formal antepartum home-care programme with either hospital day care or inpatient care. In observational studies of antepartum home care (compared with inpatient care), hospital admission (25%) and re-admission rates (44%) were quite high. Home care, however, was less costly while resulting in similar maternal and perinatal outcomes among women with gestational hypertension (592 women) or mild pre-eclampsia (321 women).
Inpatient care with or without bed rest
For women with gestational hypertension, some bed rest in hospital (compared with routine activity at home) decreased the occurrence of severe hypertension (RR 0.58, 95% CI 0.38 to 0.89) and preterm birth (RR 0.53, 95% CI 0.29 to 0.99) (two trials, 304 women). Whether the effects were a result of bed rest or hospitalisation was not known. One of the trials enrolled 33 women with pre-existing hypertension, but results for these women were not reported separately. The same trial was conducted in a health-care setting that is not applicable to that in most well-resourced settings. Women preferred unrestricted activity at home, with 49% of hospitalised women reporting that they would choose different management for a future pregnancy, compared with 16% of women allocated to routine activity at home.
For women with pre-eclampsia, two small trials have compared strict bed rest, with some bed rest, for hospitalised women. Among women with non-proteinuric hypertension, strict bed rest reduced the risk of severe hypertension (RR 0.58, 95% CI 0.38 to 0.89) and a borderline reduction in the rate of preterm birth (two trials, 145 women).
As risks are associated with bed rest, including thromboembolism and social and economic disruption for outpatients bed rest must be shown to be beneficial before it can be recommended as part of routine inpatient (or outpatient) care (National Institute for Health and Clinical Excellence guidelines ). Recommendations for thromboprophylaxis associated with bed rest are available (Royal College of Obstetricians and Gynaecologists Green-top guideline 37).
Antihypertensive treatment
The goals of antihypertensive treatment in pregnancy are to both optimise pregnancy outcome and avoid the complications of acute severe hypertension. The goals are not to prevent cardiovascular disease in later life. Most trials have enrolled a ‘mixed’ population of women with various HDPs. The blood-pressure treatment thresholds and goals are not different depending on the HDP. However, the goals are lower in the presence of pre-existing maternal co-morbidities, such as pre-gestational diabetes or renal disease, as these women are treated to lower blood-pressure goals outside pregnancy. It is generally agreed that that severe hypertension (i.e. ≥160–170/110 mmHg; (see Chapter on assessment, surveillance and prognosis) should be treated in pregnancy to decrease maternal morbidity and mortality. Treatment of non-severe hypertension (i.e. 140–159/90–109 mmHg) is far more controversial.
Severe hypertension
Most women with severe hypertension in pregnancy will have pre-eclampsia, and the rise in their blood pressure may be acute. Given theoretical concerns about loss of cerebrovascular autoregulation in association with such potentially large and acute increases in blood pressure, the severe hypertension of pre-eclampsia is considered to be a hypertensive ‘urgency’, even in the absence of maternal symptoms, such as headache. Severe elevations of blood pressure (i.e. ≥160/110 mmHg) should be confirmed, after 15 min, before antihypertensive treatment is given.
Antihypertensive drugs
As the need for treatment of severe hypertension is accepted, all relevant trials have compared one antihypertensive agent with another. Most agents have been given parenterally, with the exception of nifedipine. A few trials have also given labetalol or hydralazine orally.
Obstetricians most frequently prescribe parenteral hydralazine or labetalol for treatment of severe hypertension. A meta-analysis of the relevant trials (21 trials, 1085 women) found that, compared with other short-acting antihypertensives (including nifedipine capsules), parenteral hydralazine was associated with more adverse effects, including maternal hypotension, caesarean section, and adverse fetal-heart rate effects. It must be emphasised, however, that hypotension may result with any short-acting antihypertensive agent given to women with severe hypertension, even without evidence of pre-eclampsia; these women are commonly intravascularly volume depleted. Therefore, it may be prudent to continuously monitor fetal heart rate until blood pressure has stabilised. In the same meta-analysis, labetalol was found to be associated with more neonatal bradycardia (which required intervention in one out of six affected babies) ; however, this does not seem to be a problem in clinical practice.
Oral labetalol has been used successfully for hypertensive urgencies as part of a general management protocol for pre-eclampsia. In the 2010 NICE guidelines, oral labetalol is included in the list of first-line agents for treatment of severe hypertension.
The nifedipine preparations that are appropriate for treatment of severe hypertension are the capsule and the intermediate-acting tablet, although the availability of the latter is becoming restricted. Most investigators of randomised trials did not specify whether nifedipine capsules were bitten (before swallowing), which may have a greater effect on blood pressure. Use of the 5 mg (compared with 10 mg) capsule may reduce the risk of a precipitous fall in blood pressure, but no studies have compared the 5 mg and 10 mg doses.
MgSO 4 should not be used as an antihypertensive per se . When MgSO 4 is used for other indications (such as eclampsia prophylaxis or treatment, or for fetal neuroprotection), a loading intravenous (iv) dose of 2–5 g may be associated with a transient fall in blood pressure 30 min later, but this has not been consistently shown. The concomitant use of MgSO 4 and nifedipine has no contraindication, as the risk of neuromuscular blockade is less than 1%, and blockade is reversed with 10 g of intravenous calcium gluconate.
Nitroglycerine is primarily venodilatory. Theoretically, it may not be a good choice of antihypertensive drug in women with pre-eclampsia. However, no adverse clinical effects have been shown in small studies. Diazoxide was previously associated with excessive maternal hypotension, but more recently, low-dose diazoxide (15 mg iv) resulted in similar outcomes compared with hydralazine (5 mg iv) in one small trial. For refractory hypertension, in an intensive-care setting, use of sodium nitroprusside can be considered. In a case series of 22 women (24 fetuses), the stillbirth rate was 27.8%, but the investigators attributed these deaths to the underlying disease process, rather than to the nitroprusside.
For non-severe hypertension
How to manage non-severe blood pressure (140–159/90–109 mmHg) is controversial. Any antihypertensive treatment will, compared with placebo or no treatment, decrease the risk of transient, severe hypertension (RR 0.50, 95% CI 0.41 to 0.61; 19 trials, 2409 women; NNT 9 to 17), without a clear difference in other maternal or perinatal outcomes, such as stroke, pre-eclampsia, perinatal death, or preterm delivery (28 trials, 3200 women). Antihypertensive treatment, however, may actually be harmful, on the basis ofresults of a small pilot randomised-controlled trial and a meta-regression of randomised-controlled trials, which found a significant relationship between the antihypertensive-induced fall in mean arterial pressure and the risk of small gestational age infants or infants with lower birthweight.
Otherwise healthy women
For women without co-morbid conditions, a wide range of acceptable blood-pressure thresholds is available that is consistent with the published evidence: 140–159/90–105 mmHg. Choosing an upper-limit treatment blood pressure threshold of 159/105 mmHg acknowledges intra-patient variability in blood pressure, the inaccuracies of blood-pressure measurement, the desire to avoid severe hypertension (severe blood pressure ≥160–170 mmHg or diastolic blood pressure ≥110 mmHg), and the recognition that outside of pregnancy, non-severe hypertension is not an indication for immediate treatment. Therefore, a reasonable target blood pressure of antihypertensive treatment is 130–155 mmHg systolic, and 80–105 mmHg diastolic.
Women with co-morbid conditions
For women with co-morbid conditions, blood pressure should be normalised, with a reasonable goal being 130–139/80–90 mmHg. Choosing a higher blood-pressure goal than the non-pregnancy recommendation of blood pressure less than 130/80 mmHg represents a compromise between maternal protection and maintenance of placental perfusion.
Although some treatment guidelines have chosen lower blood-pressure treatment goals for women with pre-eclampsia, antihypertensive treatment does not decrease maternal morbidity in pre-eclampsia or eclampsia. However, in some circumstances (e.g. severe headache) it seems prudent to normalise blood pressure, and others in which it may not (e.g. absent end-diastolic flow in the fetal umbilical artery).
Antihypertensive drugs
When a decision is made to use antihypertensive treatment, no definitive data are available to guide the choice of agent. Treatment is most commonly required in the third trimester of pregnancy when blood pressure is on the rise, such that an increase in antihypertensive dose should be anticipated. Guidance for use of specific antihypertensive medications does not differ by the type of HDP.
The relevant antihypertensive agent compared wit placebo (or no therapy) trials have been designed to determine the relative benefits and risks of treatment, as discussed above. The following agents have been compared with placebo or no treatment (with treatment when blood pressure has reached a diastolic of 100–110 mmHg): methyldopa, labetalol (a combined alpha and non-selective beta-blocker), beta-blockers (acebutolol, mepindolol, metoprolol, pindolol, and propranolol), calcium channel blockers (isradipine, nicardipine, nifedipine, and verapamil), hydralazine, prazosin, and ketanserin (28 trials, 3200 women).
In comparative trials of one antihypertensive drug compared with another for non-severe hypertension, most commonly, beta-blockers have been compared with methyldopa. Beta-blockers (i.e. labetalol, pindolol, metoprolol or oxprenolol) may be more effective antihypertensive drugs than methyldopa (RR 0.75, 95% 0.58 to 0.94) (10 trials, 539 women), but no other differences in maternal or perinatal outcomes have been shown (19 trials, 1282 women).
In international clinical practice, labetaolol and methyldopa are the most commonly used agents for non-severe hypertension in pregnancy. No reliable data are available on long-term developmental outcomes to guide one’s choice of antihypertensive agent. Limited data from placebo-controlled trials have not revealed adverse effects of (any) antihypertensive agent on health or neurodevelopment assessed at 1 year (nifedipine, 110 children), 18 months (atenolol, 190 children), or 7.5 years (methyldopa, 242 children) in placebo-controlled trials. Emerging observational data on the neuro-developmental effect of methylopa and labetalol have raised concerns about each. Methyldopa treatment and duration (25 children) was associated with a negative effect on children’s performance IQ at 4–5 years of age, compared with labetalol (32 children). On the other hand, labetalol, compared with methyldopa, was associated with a heightened risk of attention deficit hyperactivity disorder in children of primary school age (202 children). This highlights the need to first determine whether antihypertensive treatment for non-severe hypertension in pregnancy is necessary.
Mention should be made of a few specific agents that should not be used in pregnancy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) are fetotoxic, especially to the fetal kidney. The bulk of the evidence also suggests that these agents are teratogenic (see section on aspects of care specific to women with pre-existing hypertension, below). As with other drugs used commonly to treat the HDP, a number of ACE inhibitors are, however, acceptable for use during breastfeeding.
Thiazide diuretics can be considered for use. Concerns that they may inhibit the normal plasma volume expansion of pregnancy did not translate into a heightened risk of pre-eclampsia, or any difference in adverse maternal or perinatal outcomes (five trials, 1836 women). It is not clear why atenolol (compared with other cardioselective beta-blockers) may be associated with adverse effects on fetal growth ; however, until new data are available, it may be prudent to use other agents. More stillbirths were reported in the prazosin arm of one trial. Oral hydralazine is associated with more maternal side effects if used as monotherapy.
Oral antihypertensive drugs do not seem to change fetal heart rate or pattern, but the data are not robust ; a cautious approach would be to not attribute changes in fetal heart rate or pattern to an antihypertensive distinct from its haemadynamic effects.
Aspects of care specific to women with pre-existing hypertension
Many women of child-bearing age are hypertensive, and the increasing rate of obesity and advanced maternal age are associated with increased rates of pre-existing hypertension in pregnant women. The issues to consider are presented in Table 1 .
