Summary

Hypertensive disorder in pregnancy is a major health problem. It also represents an important cause of maternal mortality. The term "hypertension in pregnancy", nevertheless, refers to a myriad of conditions in which management strategies differ. Few controlled studies are currently available to support the treatment guidelines for these conditions although hypertensive disorders are thought to be the most common medical conditions of pregnancy. The purpose of this review is to discuss the current evidence and management issues from the perspective of general practitioners.

摘要

懷孕期間血壓高是一個重要的健康問題。它亦是妊娠期重要的致命原因。事實上，妊娠期血壓高關係到多類情況，而各有不同治療策略。雖然妊娠期血壓高被認為是懷孕期間最常見的問題，但現時能夠支持其治療指引的實證研究卻很少。本文是從一個全科醫生的角度去討論現有的驗證和治療方法。

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Introduction

An intriguing aspect of managing hypertension in pregnancy is the uncertain benefits of treating the condition. Proper management of hypertension in pregnancy requires an understanding of several issues. The issues to consider include: what is hypertension in pregnancy; what are the objectives of treating hypertension in pregnancy; how is hypertension among pregnant women managed according to evidence-based medicine; and are there guidelines for family doctors to follow? In this review, the subject of hypertension in pregnancy will be covered from the perspective of family physicians or practitioners. The detailed role of obstetrician specialist care in foetal evaluation or managing eclampsia close to term and intrapartum, on the other hand, will not be discussed.

How to diagnose and classify hypertension in pregnancy

Hypertension in pregnancy refers to a broad spectrum of conditions in which blood pressure varies and dictates different targets of treatment.^1,2 As a family practitioner, diagnosis of a hypertensive disorder in a pregnant woman does not end with reading the (Korotkoff V) value or automated oscillometric device; precise diagnosis depends upon the gestational age at presentation. Although it is uncommon for family physicians to provide the primary obstetric care, the schema of classifying hypertension in pregnancy should be made clear to every doctor to facilitate communication.

The current National High Blood Pressure Education Program (NHBPEP) 2000 Working Group Report endorses the updated classification system of hypertension in pregnancy originally proposed by the American College of Obstetricians and Gynecologists (ACOG) Committee on Terminology in 1972.³ In principle, it defines hypertension as blood pressure > 140 mmHg systolic or > 90 mmHg diastolic, confirmed by two separate measurements, and classifies hypertension in pregnancy as: chronic hypertension; gestational hypertension; pre-eclampsia-eclampsia; and pre-eclampsia superimposed on chronic hypertension (Figure 1). In many ways, these definitions are more for epidemiological and research purposes than practical use. The stringent characterization of patient to guide clinical management is not easy to achieve. The major limitations are the need to know the blood pressure in the first half of pregnancy; an especially vexing problem is the lack of precise clinical details. For instance, when a pregnant woman from mainland China attends her prenatal care at 20 weeks' gestation for the first time and cannot provide details about her blood pressure reading in her first half of pregnancy, one cannot distinguish chronic hypertension from gestational hypertension. To further complicate the picture, many women with chronic hypertension have normal blood pressure during the second trimester because of the physiologic decrease in blood pressure at that time.^4,5 This effect is often exaggerated in women with chronic hypertension, thus masking its recognition and leading to misdiagnosis of gestational hypertension or pre-eclampsia later in pregnancy. Although chronic hypertension has been thought to complicate 3-5% of pregnancy,^1,5 this figure is expected to rise given the current trend for women to delay their childbearing years till the third or fourth decade. Occasionally, the diagnosis of chronic hypertension is only made several months postpartum, when the blood pressure fails to normalize as would be expected with gestational hypertension.

The complexity of defining and classifying hypertension in pregnancy is further caused by the limitations of conventional blood pressure measurement.⁶ Whilst the nomenclature of hypertension in pregnancy represents a mysterious "black box" to most of us, the apparently straightforward blood pressure measurement has turned out to be a daunting task on second thought. To the surprise of most doctors, the measurement of blood pressure is not as simple as it looks. In clinical practice, many practitioners in antenatal care fail to have their sphygmomanometer calibrated, as reported to be the case with 78% of obstetricians and midwives. The same survey in Australia reported that only 45% of obstetricians used a large cuff when required (appropriate cuff size 1.5 times the upper arm circumference or cuff bladder covering 80% of the arm).⁷ Diversity in blood pressure measurement in pregnancy was further highlighted by the observation that only 10% of practitioners measured blood pressure to the nearest 2 mmHg, whereas almost one-quarter chose to round blood pressure readings to the nearest 10 mmHg.⁸ As a general rule, blood pressure should be measured when the woman is seated, with her feet supported or on the ground, and her arm at the level of the heart. Measurement should be made with a cuff of appropriate size and recorded to the nearest 2 mmHg.⁹ The conventional practice of using a mercury sphygmomanometer has now tended to be replaced by the automated electronic device. This has however, yet to be specifically validated for use in pregnancy.

In addition, recent work has suggested that a subset of women who appeared to have chronic hypertension early in their pregnancy will in fact have white-coat hypertension (persistently raised clinic blood pressure with normal blood pressure at other times). Approximately the figure is one in three women presenting in this way.^10,11 This is denoted by high office blood pressure readings with normal average 24 hour ambulatory blood pressure. Such figures are close to the prevalence rate as described in non-pregnant women with apparent stage I hypertension.¹² Although the role of ambulatory blood pressure measurement in pregnancy remains as an area of debate, pregnant women with white-coat hypertension can be reassured that they will have better pregnancy outcomes than women with true hypertension. Having said this, continued maternal monitoring throughout pregnancy remains important in order to detect the small group of white-coat hypertensives (< 10%) who may develop pre-eclampsia.¹¹ Interestingly, fairly similar obstetric and perinatal outcomes to normotensive women have been observed among women with white-coat hypertension subjects apart from an apparent increased caesarean section rate among the latter.^10,11 It looks as if the high caesarean rate simply reflects doctors' reaction to blood pressure measured in the office or clinic near term pregnancy - there still exists a considerable uncertainty (and possibly fear of litigation) among obstetricians as to how best to manage these women.

Do we need to treat hypertension, when and why

To understand the management of hypertension in pregnancy, one should realize that our objectives are threefold: to protect the woman from dangerously high blood pressure; to permit continuation of the pregnancy, foetal growth and maturation; and lastly, to maximize the likelihood of delivering a healthy infant at term by preventing excessive increases in blood pressure that would lead to early delivery. In simple term, we need to consider the well-being of two subjects whenever we talk about pregnancy - that of the mother and the baby.¹

From the perspective of the hypertensive mother, the main concerns are to prevent or reduce the risk of cerebral complications such as encephalopathy or arterial haemorrhage; there is ample evidence that the likelihood of these complications is particularly high in women with severe hypertension. Exact treatment thresholds, as stated in most treatment guidelines, vary and largely reflect consensus of experts rather than solid scientific evidence (Table 1).^3,13-15 Interestingly, a Canadian survey demonstrated that family doctors and obstetricians tend to agree for non-pharmacologic treatment regarding diastolic blood pressure between 80-89 mmHg, although there is little agreement about diastolic blood pressure treatment goal when treatment is initiated for diastolic blood pressure greater than 90-99 mmHg.¹⁶ As a general rule, the current recommendations to treat range from thresholds of 150 to 160 mmHg (systolic) and 100 to 110 mmHg (diastolic), with lower thresholds in cases of pre-existing hypertension and target-organ damage. Indeed, the benefits of treating severe hypertension are not exclusively confined to the mother. For instance, a worsening foetal morbidity and mortality have been well recognized in pregnant women who have a diastolic blood pressure of 110 mmHg or higher during the first trimester.^17,18

Conversely, it is much less clear whether pharmacological treatment of women with mild, uncomplicated hypertension during pregnancy will improve the perinatal outcome. At the very least, there is thus far no concrete data to support that antihypertensive therapy in the setting of mild uncomplicated hypertension will reduce the incidence of abruptio placentae or perinatal death. A further Cochrane review showed that drug therapy for mild to moderate hypertension during pregnancy halves the risk of severe hypertension, but reductions in pre-eclampsia, perinatal death, preterm birth, or small for gestational age babies were unproven.¹⁹ One of the reasons for the uncertainty pertains to the low event rate of these obstetric complications; it has been estimated that, in order to detect a 50 percent reduction in the frequency of either abruptio placentae or perinatal death, recruitment of at least 4000 women would be needed in any antihypertensive intervention trial.²

There is also controversy over whether maternal hypertension, particularly pregnancy-induced hypertension, may serve some adaptive role of the foetus in the face of uteroplacental dysfunction. Should that be the case, reduction of maternal blood pressure could have lowered placental perfusion, in the setting of failure to autoregulate flow at the intervillous level. Of note, a meta-analysis of trials involving 2 640 women showed that a 10 mmHg reduction in mean arterial pressure induced by antihypertensive drugs was associated with a 176 G decrease in birth weight.²⁰ Another national database analysis involving 3 244 singleton small for gestational age infants recently demonstrated that maternal hypertension (primarily pre-eclampsia) was independently associated with a better acute neonatal physiological condition and survival.²¹ Such findings raise the possibility of evolutionary selection pressure for pregnancy hypertension. Stated alternatively, overzealous blood pressure control may lead to placental hypoperfusion and hence would compromise the foetus as placental blood flow cannot undergo autoregulation.

Table 1: Recommendations related to the threshold of pharmacologic treatment of hypertension in pregnancy issued by authoritative and international bodies
Reference	Threshold for treatment	Remarks
Canadian Hypertension Society Consensus Conference13	SBP > 169 mmHg or DBP > 109 mmHg with symptoms	SBP > 139 mmHg or DBP > 89 mmHg with • gestational hypertension with   symptoms or proteinuria • pre-existing hypertension with   underlying conditions or target   organ damage • pre-existing hypertension with   superimposedgestational   hypertension
National High Blood Pressure Education Program Working Group3	SBP 150 - 160 mmHg or DBP 100 - 110 mmHg or the presence of target organ damage
Australasian Society of the Study of Hypertension in Pregnancy14	DBP > 90 mmHg	suggestion to maintain SBP 110-140 mmHg and DBP 80-90 mmHg
Royal College of Obstetricians and Gynaecologists15	DBP > 105 mmHg	lower threshold if disease onset at < 28 weeks gestation
Abbreviation: SBP = systolic blood pressure; DBP = diastolic blood pressure.

Choices of drug treatment of hypertension in pregnancy

All classes of antihypertensive drugs have either been shown, or are assumed, to cross the placenta and reach the foetal circulation. Their potential adverse effects are either poorly established or unclearly quantified, because evidence is largely limited to only case reports. Decisions regarding which drugs to use are largely driven by balancing the unknown risks (owing to limited studies in pregnant women) against the unknown benefits of blood pressure control (again owing to limited studies).²²

Pre-pregnancy counselling should theoretically be offered to all women who are on antihypertensive medication. Due to the high prevalence of unplanned pregnancies this might not be possible. At the first prenatal visit during early pregnancy, it is not unreasonable to discontinue antihypertensive drugs in women with uncomplicated mild chronic hypertension^5,22,23 as long as close monitoring is possible (after the initial but temporary physiologic fall in blood pressure, and in particular, for early signs of pre-eclampsia). Drug therapy can be reinstituted when blood pressure rises to a concern level depending on the guidelines used (Table 1). The drug of choice include methyldopa, labetalol, hydralazine and long-acting calcium channel blockers (nifedipine sustained release tablets, but not nifedipine capsules). Among them, methyldopa probably has the longest track record of safety even though available data are inadequate to provide head-to-head comparison. Thus far, no direct adverse effect of this drug on the foetus (by lowering uteroplacental blood flow or influence on the umbilical circulation) has been demonstrated. Previously, short-term treatment with methyldopa during the third trimester has been shown to have no adverse effects on uteroplacental and foetal haemodynamics.²⁴ In a recent experiment measuring in vitro drug effect on human umbilical artery resistance, it has been shown that most drugs, except methyldopa, have significant direct effects on the feto-placental circulation.²⁵ Most important of all, methyldopa remains the only antihypertensive drug with a 7.5-year follow-up evaluation of children born to treated mothers. This careful prospective, albeit underpowered, study noted similar birth weight, neonatal complications, intelligence and neurocognitive development in children of treated and untreated women, despite a somewhat smaller head circumference in male offsprings exposed to methyldopa at 16 to 20 weeks of gestation.²⁶ As a cautionary note in methyldopa use, this drug should theoretically be avoided in women with a prior history of depression owing to the increased risk of postnatal depression.²⁷

Women of childbearing age treated with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) should be informed of the need for drug discontinuation within the first trimester should they become pregnant. Although there are no data to suggest teratogenicity of these drugs, adverse foetal (developmental) effects are noted due to their action on the foetal renin-angiotensin system (during the second and third trimesters), and ischaemia from maternal hypotension and compromised foetal-placental blood flow. Blockade of the conversion of angiotensin I to angiotensin II is supposed to have adverse effects on the developing foetal kidneys. Reported foetotoxicity of ACE inhibitors and ARB include oligohydramnios or foetal anuria, intrauterine growth retardation, pulmonary hypoplasia, renal tubular dysplasia, hypocalvaria or incomplete ossification of foetal cranium.²⁸ This has led to the general guidelines to avoid ACE inhibitors and ARB during the second and third trimester of pregnancy, and that women who become pregnant whilst taking these drugs change to another antihypertensive drug of different class as soon as the pregnancy is recognized.^22,27-29 Whilst the greatest risk to the foetus appears to be associated with drug exposure in the third trimester, proper patient education is warranted to ensure timely discontinuation. As indications for ACE inhibitors have expanded, their use among women of reproductive age (and hence first-trimester foetal exposure) has increased. It should be noted that a recently published exploratory epidemiologic study raises the concern of major congenital anomalies among 209 children whose mothers were prescribed ACE inhibitors during the first trimester (but not later in pregnancy) in the United States.³⁰ Pending further study to determine the precise risk and relationship of individual ACE inhibitors, it would now appear reasonable to have a detailed discussion with all women of childbearing age who are prescribed ACE inhibitors.

Furthermore, the safety of beta blockers (particularly atenolol) and thiazide diuretics still remains unresolved if used during pregnancy. Despite the lack of evidence for any substantial teratogenic risk, these drugs still causes concern of a different nature. It is our preference not to use thiazide diuretics which might lead to hyperuricaemia, as this would invalidate serum uric acid as a laboratory marker in the diagnosis of superimposed pre-eclampsia.

Child delivery - end of the story or start of the problem

A discussion of management of labour and delivery is beyond the scope of this review, but postpartum care needs to be addressed given the role of family doctors after the mothers are discharged home.

While the definitive treatment of pre-eclampsia is delivery, women still require close monitoring in the postpartum state (regardless of the type of antenatal hypertensive disorder). As a matter of fact, blood pressure classically rises progressively over the first five postnatal days, and peaks on days three to six after delivery.^1,31,32 Mechanism of such pattern of blood pressure has not been fully elucidated; possible pathogenesis owing to mobilization of body water and sodium (accumulated during pregnancy) from extravascular to intravascular space has been proposed. As such, women with pregnancy induced hypertension usually will need antihypertensives temporarily for days to weeks. Their blood pressure should be monitored closely, ideally with evaluation in their home, to avoid hypotension as the women's blood pressure returns to normal baseline level. Since most of these women have been discharged home, the advantage of care provided by family practitioners is obvious. With the enthusiasm and attention towards the newborn within the family, the care deserved by the mother might easily be forgotten after childbirth.

Limited information about how to prevent and treat postpartum hypertension, is highlighted by a recent Cochrane review including six trials.³³ Notably, there are no reliable data to guide or suggest the best drug of choice for women who are hypertensive postpartum. Therefore, practitioners are advised to use the agent which they are most familiar with.^1,33

In addition, there is an emerging body of evidence which demonstrates the long-term sequelae of hypertension in pregnancy. Despite the inherent limitations of epidemiological studies, most of them support a link between a history of hypertensive pregnancy and future risk of hypertension, stroke and, to a lesser extent, ischaemic heart disease in later life.^34-36 Putatively, the physiologic changes of pregnancy can reveal risk of chronic diseases and herald future cardiovascular and metabolic disease. Therefore, consideration should be given to primary prevention after pregnancy, having established their increased risk. From the perspective of family physicians and public health, how best to intervene is uncertain. Weight reduction where appropriate is clearly of value, along with regular monitoring of blood pressure, dietary advice and increased exercise.³⁷

Conclusion

Practising in accord with evidence-based medicine precepts might not be straightforward to the practitioners when the "best" evidence for a particular subject is lacking. Without doubt, considerably more commitment is needed for health-care providers and the research community to improve the knowledge of hypertension in pregnancy and to better care for those affected or at risk. Regardless of the therapeutic controversy in managing hypertension during pregnancy, it would seem to be a golden opportunity for family practitioners to look at the cardiovascular health of women after a diagnosis of "blood pressure problem" during pregnancy. Pregnancy, by itself, offers a window into the women's health.^37,38 Although data is lacking to guide the frequency of screening for cardiovascular disease in later life after an episode of hypertensive disorder in pregnancy, it would be appropriate to promote a greater awareness of this association, with a view for earlier diagnosis and intervention. Pregnancy induced hypertension should prompt a family practitioner referral, at least, to have an annual blood pressure measurement and advice on primary prevention.

Declaration of interest: none

Key messages

1. Hypertension in pregnancy is not a single disease entity.
2. . White-coat hypertension is not uncommon in pregnancy.
3. The doctrine of treating hypertension in pregnancy dictates that we are taking care of two subjects - the mother and the foetus.
4. Antihypertensive treatment for mild chronic hypertension benefits the mother, but its impact on perinatal outcomes is less clear.
5. Use of angiotensin-converting-enzyme inhibitors during the second and third trimesters of pregnancy is definitely contraindicated, and exposure during the first trimester should also be avoided.
6. Retrospective studies (based on patient recall) and prospective recording of blood pressure suggested that women with hypertension in pregnancy run a greater risk of developing cardiovascular disease in later life.

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References