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National Collaborating Centre for Women's and Children's Health (UK). Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy. London: RCOG Press; 2010 Aug. (NICE Clinical Guidelines, No. 107.)

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  • In June 2019, NICE updated and replaced this guideline with NICE guideline NG133 on hypertension in pregnancy: diagnosis and management. Some of the 2010 recommendations have been retained in the new guideline. This 2010 full guideline includes the evidence supporting the 2010 recommendations. The sections that are no longer current are marked as Updated 2019 and grey shaded in the PDF.

In June 2019, NICE updated and replaced this guideline with NICE guideline NG133 on hypertension in pregnancy: diagnosis and management. Some of the 2010 recommendations have been retained in the new guideline. This 2010 full guideline includes the evidence supporting the 2010 recommendations. The sections that are no longer current are marked as Updated 2019 and grey shaded in the PDF.

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Hypertension in Pregnancy: The Management of Hypertensive Disorders During Pregnancy.

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4Management of pregnancy with chronic hypertension

4.1. Introduction

Women with chronic hypertension are at increased risk of pre-eclampsia but even in the absence of this there is increased perinatal mortality. The women frequently have co-morbidities and require care above that offered routinely.

This chapter provides guidance on advice for women with chronic hypertension planning pregnancy, care during pregnancy, use of antihypertensive drugs during pregnancy and the postnatal period, and fetal monitoring in women with chronic hypertension.

4.2. Pre-pregnancy advice

Women with medical disorders should receive advice before pregnancy to ensure their treatment is appropriate and to make them aware of any implications for pregnancy and childbirth. This will include general health issues that all women intending pregnancy should consider (see ‘Antenatal care’, NICE clinical guideline 62)1 and additional factors, which for hypertension include both lifestyle factors and safe medication.

4.2.1. Antihypertensive agents

Safety in pregnancy

Evidence was sought on the safety for the fetus of antihypertensive medications used currently for chronic hypertension in non-pregnant women and for those used during pregnancy in this group of women. The safety of antihypertensive drugs is particularly important in the periconceptional period and during the first trimester of pregnancy.

The literature search identified 136 articles, of which ten were retrieved. A further five studies were retrieved having been identified through reference lists in published papers. Of these, five studies were included in this review, four studies for ACE inhibitors and one for angiotensin II receptor blockers (ARBs).

Angiotensin-converting enzyme inhibitors

A retrospective cohort study conducted in the USA investigated the safety of ACE inhibitors in pregnancy.60 [EL = 2+] All infants enrolled in Tennessee Medicaid and born between 1985 and 2000 were eligible for inclusion. Exclusion criteria were maternal diabetes, exposure to ARBs, exposure to antihypertensive medication beyond the first trimester and exposure to other potential teratogens. The study included 29 096 infants with no exposure to antihypertensive drugs at any time during gestation and 209 infants who were exposed to ACE inhibitors in the first trimester. Eighteen infants had major congenital malformations not related to a chromosomal defect or a clinical genetic syndrome. Infants exposed to ACE inhibitors in the first trimester of pregnancy were more likely to develop congenital malformations compared with infants who were not exposed to any antihypertensive treatment (RR 2.71; 95% CI 1.72 to 4.27).

Another study conducted in the USA61 [EL = 3] included all adverse outcomes associated with enalapril use in pregnancy that were submitted to the US Food and Drug Administration (FDA) between 1986 and 2000 (108 reports). Adverse pregnancy outcomes were defined as any embryo-fetal adverse outcome, any congenital malformation, IUGR and preterm birth before 37 weeks. Of the 108 cases, 88.9% had embryo-fetal adverse outcomes defined as embryo-fetal death, miscarriage or stillbirth. In pregnancies that continued past 16 weeks (n = 95), 32.5% developed congenital malformations. In pregnancies continuing past 20 weeks (n = 91), 50% of the included cases suffered from IUGR and 64.3% were preterm (less than 37 weeks).

A case series of 19 newborns of women exposed to ACE inhibitors was compiled in the USA.62 [EL = 3] These originated from all women aged 15–44 years enrolled in Tennessee Medicaid who delivered a liveborn or stillborn infant between 1983 and 1988 and who were exposed to ACE inhibitors during pregnancy. Of the 19 infants, two were born preterm with serious life-threatening conditions. One preterm infant had kidney problems requiring dialysis and the other had microcephaly and occipital encephalocele. One infant was born at term but was hypoglycaemic. Sixteen infants were born at term and appeared normal.

A small case series conducted in the UK included 18 women (19 pregnancies) who were exposed to ACE inhibitors during pregnancy63 [EL = 3] and who were seen at an antenatal hypertension clinic between 1980 and 1997. Seventeen pregnancies ended in a live birth. One woman with type 1 diabetes and one with a mitral valve replacement had early miscarriages (7 and 8 weeks). There were no congenital malformations, kidney dysfunction or neonatal problems reported in infants of women who were exposed to ACE inhibitors at any stage of pregnancy.

Angiotensin II receptor blockers

One systematic review was identified in which ARBs were used in pregnancy.64 [EL = 3] Because no comparative studies could be identified, case reports, case series and post-marketing surveys were included in this review. In total, 64 published cases of women treated with ARBs during pregnancy were included.

The mean duration of treatment during a pregnancy with an adverse fetal outcome was 26.3 ± 10.5 weeks, compared with 17.3 ± 11.6 weeks for those with a favourable outcome (P = 0.04). Of the included cases, 37 women (58%) had favourable and 27 women (42%) had unfavourable outcomes (mainly congenital malformations such as limb, skull, face, kidney and pulmonary defects). Of the women with unfavourable outcomes, ten had been exposed to valsartan, nine to losartan, six to candesartan and two to irbesartan. Of the women with favourable outcomes, six had been exposed to valsartan, one to telmisartan and one to losartan. One study reported 29 cases exposed to candesartan, irbesartan, losartan or valsartan where women gave birth to healthy babies without providing details about how many women were exposed to each drug, its dose, or details about the newborns. More cases of co-morbidities and cigarette smoking were reported among women who had adverse fetal outcomes.

Safety of other antihypertensive medications in pregnancy

Other antihypertensives commonly used in pregnancy are summarised in Table 4.1 (further details are provided in Appendices M and N).

Table 4.1. Safety data for antihypertensive drugs in pregnancy.

Table 4.1

Safety data for antihypertensive drugs in pregnancy.

Evidence statement

There are limited good-quality studies on drug safety for ACE inhibitors. One retrospective cohort study of [EL = 2+] and three small case series [EL = 3] were included. The cohort study found congenital malformations to be nearly three times more likely in infants whose mothers took ACE inhibitors compared with those whose mothers did not. Similarly, two small case series found a high prevalence of congenital malformations and IUGR while another small case series found no adverse outcomes.

A systematic review of case reports/series [EL = 3] that investigated the drug safety of ARBs showed that treatment was on average 9 weeks longer in women not taking ARBs compared with those who did. Overall, 42% of pregnancies exposed to ARBs had unfavourable outcomes (defined as any congenital malformation).

GDG interpretation of the evidence

Studies in which ACE inhibitors were used throughout pregnancy suggested increased rates of congenital malformations, IUGR, hypoglycaemia, kidney disease and preterm birth.

Studies of the use of ARBs in pregnancy also showed unfavourable outcomes (mainly congenital malformations).

Despite the relatively poor quality of these studies and the fact that maternal disease severity and other therapeutic drug use could not be excluded as potential causes for the adverse fetal effects reported, there is sufficient concern to avoid the use of ACE inhibitors and ARBs both in women planning pregnancy and for the treatment of hypertension in pregnancy.

For antihypertensive drugs currently in use, other than ACE inhibitors and ARBs, there is no evidence for teratogenicity, although the quality of the data is generally poor. Chlorothiazide may carry the risk of congenital abnormality, neonatal thrombocytopenia, hypoglycaemia and hypovolaemia.

Recommendations

Women with chronic hypertension should be given advice and treatment in line with ‘Hypertension: the management of hypertension in adults in primary care’ (NICE clinical guideline 34), unless it specifically differs from recommendations in this guideline.

Tell women who take angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs):

  • that there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy
  • to discuss other antihypertensive treatment with the healthcare professional responsible for managing their hypertension, if they are planning pregnancy.

Stop antihypertensive treatment in women taking ACE inhibitors or ARBs if they become pregnant (preferably within 2 working days of notification of pregnancy) and offer alternatives.

Tell women who take chlorothiazide:

  • that there may be an increased risk of congenital abnormality and neonatal complications if these drugs are taken during pregnancy
  • to discuss other antihypertensive treatment with the healthcare professional responsible for managing their hypertension, if they are planning pregnancy.

Tell women who take antihypertensive treatments other than ACE inhibitors, ARBs or chlorothiazide that the limited evidence available has not shown an increased risk of congenital malformation with such treatments.

4.2.2. Diet

Clinical effectiveness

The evidence for general advice for people with hypertension is contained in ‘Hypertension: management of hypertension in adults in primary care’ (NICE clinical guideline 34).3

GDG interpretation of the evidence

The GDG’s view is that pregnant women with chronic hypertension should follow the general advice contained in ‘Hypertension: management of hypertension in adults in primary care’ (NICE clinical guideline 34)3 in relation to dietary salt intake.4 The rationale for this is that chronic hypertension in pregnancy has the same pathogenesis as chronic hypertension in non-pregnant people.

Recommendation

Encourage women with chronic hypertension to keep their dietary sodium intake low, either by reducing or substituting sodium salt, because this can reduce blood pressure. [This recommendation is adapted from ‘Hypertension: management of hypertension in adults in primary care’ (NICE clinical guideline 34).]

4.3. Prevention of pre-eclampsia

Clinical effectiveness

Aspirin

Section 3.2 presents overall evidence on aspirin for prevention of pre-eclampsia, including a meta-analysis of individual-patient data assessing the effectiveness of antiplatelet agents, mainly aspirin, in preventing pre-eclampsia.42 [EL = 1++] The study involved a meta-analysis of individual-patient data for women at risk of developing pre-eclampsia, gestational hypertension or IUGR based on their previous pregnancy history, a pre-existing medical condition (for example, kidney disease, diabetes, an immune disorder or chronic hypertension) or obstetric risk factors early in their current pregnancy (for example, being a primigravida or having a multiple pregnancy). Trials that included women who started treatment postpartum or had a diagnosis of pre-eclampsia at trial entry were excluded, as were studies with quasi-random designs. No language restrictions were applied as selection criteria.

An analysis of all the women at risk of pre-eclampsia showed that antiplatelet agents were effective in reducing the risk (RR 0.90; 95% CI 0.84 to 0.97). While there was no separate analysis for women with chronic hypertension, a subgroup analysis for women with chronic hypertension showed no evidence that effectiveness of antiplatelets differed in women with chronic hypertension and in those with other risk factors but no chronic hypertension (P = 0.28).

Dipyridamole

No evidence was identified in relation to the effectiveness of dipyridamole.

Cost effectiveness

Health economic modelling established the cost effectiveness of low-dose aspirin (75 mg/day) for women at risk of pre-eclampsia (see Section 3.2 and Appendix H).

Evidence statement

A meta-analysis of individual-patient data [EL = 1++] that included women with chronic hypertension showed antiplatelet agents to be effective in reducing the risk of developing pre-eclampsia (RR 0.90; 95% CI 0.84 to 0.97). An original health economic analysis also showed aspirin prophylaxis in women at risk of pre-eclampsia to be cost saving.

GDG interpretation of the evidence

The clinical effectiveness evidence relating to antiplatelet agents is best for low-dose aspirin and suggests that treatment modifies the risk of pre-eclampsia in women with chronic hypertension. The time at which treatment should start is unclear but the GDG’s view is that it is important to start using aspirin from 12 weeks (this being the earliest gestational age for which evidence concerning the use of aspirin in the prevention of pre-eclampsia was identified). The recommendation to offer aspirin to women with chronic hypertension who are pregnant is covered by the recommendation for all women at high risk of pre-eclampsia that is presented in Section 3.2.

4.4. Treatment of hypertension

This section examines the use of therapies for controlling blood pressure during pregnancy in women with chronic hypertension. This evidence should be considered along with the evidence presented on the treatment of gestational hypertension (see Section 6.4) as some trials of treatment included women with chronic hypertension or gestational hypertension.

4.4.1. Antihypertensives

Clinical effectiveness

Methyldopa

An RCT involving 300 women was conducted in the USA to compare the effect of methyldopa and labetalol with no treatment in chronic hypertension.65 [EL = 1−] Women with mild or moderate chronic hypertension at 6–13 weeks were randomised to receive methyldopa (n = 87), labetalol (n = 86) or no treatment (n = 90). All included women were seen in the first trimester and were hospitalised at the time of the initial antenatal visit. Women with associated medical complications other than chronic hypertension were excluded. All women were followed up throughout pregnancy. Ninety-one percent of the women had received various antihypertensive treatments before pregnancy, including diuretics, methyldopa and various beta-blocker and other antihypertensive drugs. Methyldopa was started at 750 mg/day and increased as needed to a maximum of 4 g/day to achieve a target systolic blood pressure of less than 140 mmHg and diastolic blood pressure of less than 90 mmHg. Treatment with labetalol started at 300 mg/day and increased to a maximum of 2400 mg/day. If the maximum doses did not achieve the target blood pressure, hydralazine was added to a maximum oral dose of 300 mg/day. Women in the no-treatment group who had severe hypertension (systolic pressure above 160 mmHg or diastolic blood pressure above 110 mmHg) received methyldopa but remained in the no-treatment group for the analysis. Women receiving methyldopa were as likely as women in the no-treatment group to develop pre-eclampsia (OR 1.21; 95% CI 0.55 to 2.65). Similarly, there were no differences between the treatment group receiving methyldopa and the no-treatment group for the following outcomes: need for additional drugs, incidence of placental abruption, preterm birth (before 37 weeks), SGA and perinatal deaths.

A small RCT (n = 25) conducted in the USA investigated the efficacy of methyldopa in chronic hypertension.66 [EL = 1−] Inclusion criteria were blood pressure of 140/90 mmHg on two separate occasions separated by at least 6 hours, no evidence of proteinuria (24-hour urine protein below 100 mg), presumed chronic hypertension, gestational age below 34 weeks and singleton pregnancy. Thirteen women received one tablet of methyldopa (250 mg) three times a day and 12 women received a placebo tablet three times a day. These doses were increased every 48 hours as needed to a maximum of two tablets four times a day (2 g) to maintain blood pressure at or below 140/90 mmHg. Pre-eclampsia was defined as a sudden rise in systolic blood pressure by 30 mmHg or in diastolic blood pressure by 15 mmHg, and increased weight gain (more than 2 lbs/week) or proteinuria (2+ or greater on urinary dipstick). The incidence of pre-eclampsia was similar in the two groups (38.4% versus 33.3%) and no statistically significant differences were found for birthweight or ponderal index (both corrected for gestational age).

Labetalol

An RCT investigated the effectiveness of labetalol and methyldopa in chronic hypertension.65 [EL = 1−] Women who received labetalol were as likely as women in the no-treatment group to develop superimposed pre-eclampsia (OR 1.06; 95% CI 0.47 to 2.37). There were no differences between the treatment and the no-treatment groups regarding need for additional drugs, the incidence of placental abruption, preterm birth (before 37 weeks), SGA or perinatal deaths.

Atenolol

A UK RCT evaluated the effectiveness of atenolol in women with chronic hypertension.67 [EL = 1−] Women were recruited at between 12 and 24 weeks if they had a systolic blood pressure between 140 and 170 mmHg or diastolic blood pressure between 90 and 110 mmHg on two occasions separated by at least 24 hours. Women who had any contraindications to the use of a beta-blocker were excluded. Of a total of 33 women, 15 were randomised to receive atenolol, 14 to receive placebo and four were withdrawn from the study. Women in the treatment group received 50 mg/day atenolol, increasing until blood pressure was below 140/90 mmHg or a dose of 200 mg/day was reached.

There was a statistically significant difference between the treatment and placebo groups in mean diastolic blood pressure (difference 7.0 mmHg; 95% CI 2.9 to 10.0; P = 0.001) and in mean birthweight (difference 901 g; 95% CI 440 to 1380; P < 0.001). However, there was no statistically significant difference between the treatment and placebo groups in mean systolic blood pressure after entry to the study (that is, after treatment; P = 0.08)). Babies born to mothers who received atenolol were on average 901 g lighter (mean birthweight 2629 g) than babies born to women receiving placebo (mean birthweight 3530 g).

Calcium-channel blockers

No evidence was identified in relation to nifedipine, amlodipine or nicardipine.

Diuretics

An RCT conducted in the USA investigated the effectiveness of continuing diuretics or stopping diuretics during pregnancy.68 [EL = 1−] The study population consisted of 20 women who had a documented history of long-term hypertension and were receiving diuretics at entry to the study. Women were randomly assigned to continue their diuretic throughout pregnancy (n = 10) or to discontinue immediately (n = 10). All women included had mild or moderate hypertension (diastolic blood pressure between 90 and 110 mmHg) and were in the first trimester of pregnancy. To keep systolic blood pressure below 160 mmHg and/or diastolic blood pressure below 110 mmHg, methyldopa was added when necessary. All women were prescribed a daily diet containing approximately 2 g of sodium and they were instructed to avoid the addition of salt during food preparation. There was no statistically significant difference between the groups in the incidence of pre-eclampsia (treatment group: 1/10; stopping treatment: 1/10; P > 0.05), nor for any of the other outcomes investigated (birthweight, SGA, 5-minute Apgar score).

Antihypertensives with diuretics

An RCT from the USA evaluated the effectiveness of antihypertensive treatment on pregnancy outcome in women with mild chronic hypertension.69 [EL = 1−] Inclusion criteria were a documented history of hypertension (blood pressure at or above 140/90 mmHg) before pregnancy or the finding of hypertension on at least two consecutive measurements more than 24 hours apart before 20 weeks, as well as classification of the hypertension as mild by severity criteria, including a diastolic blood pressure below 100 mmHg and the absence of target-organ damage. Nulliparous women, women whose pregnancies were complicated by other major medical problems such as diabetes or multiple pregnancy, and women whose antenatal care began after 20 weeks were excluded. Study participants were randomly allocated to treatment (n = 29) or no-treatment groups (n = 29). Eleven women in the treatment group received methyldopa and thiazide, ten continued to use hydralazine and thiazide, and eight continued with methyldopa, hydralazine and thiazide. No placebo was used for the no-treatment group. Women in the no-treatment group whose hypertension became aggravated received antihypertensive treatment before giving birth but remained in the no-treatment group in the analysis. The intervention was continued antihypertensive treatment. Four women (of 29) in the treatment group had pregnancy-aggravated hypertension (defined as increase in diastolic blood pressure to a level above 100 mmHg on two consecutive measurements 6 hours or more apart) compared with 13 women (of 29) in the no-treatment group (P < 0.05). None of the other outcomes investigated (preterm birth before 37 weeks, birthweight below 2501 g, fetal distress or SGA) showed statistically significant differences between the two groups.

Evidence statement

There were limited good-quality trials to evaluate the effectiveness of alpha- and beta-blockers and methyldopa for treatment of chronic hypertension during pregnancy. Results from two trials showed no difference between women receiving methyldopa or labetalol and those receiving placebo in the incidence of pre-eclampsia. A third trial found atenolol to be useful in lowering diastolic blood pressure but not systolic blood pressure.

Only one trial of small sample size [EL = 1−] was found using diuretics alone. The results showed no statistically significant differences between the two study groups for any outcomes of interest.

One RCT [EL = 1−] compared continued treatment with discontinued treatment with antihypertensive agents and diuretics in women with mild chronic hypertension. It was found that women on antihypertensive treatment had a lower incidence of pregnancy-aggravated hypertension than women on no treatment. The groups were similar regarding all other outcomes.

4.4.2. Level of blood pressure control

Clinical effectiveness

One RCT70 [EL = 1+] conducted in Egypt compared effectiveness of applying ‘tight’ versus ‘less tight’ control of mild chronic or gestational hypertension in pregnancy. Women with blood pressure of 140–159/90–99 mmHg with live fetus(es) and gestational age 20–33+6 weeks were included. Women with blood pressure equal to or higher than 160/100 mmHg, proteinuria, diabetes, chronic kidney disease or fetal anomalies were excluded. Women were randomly assigned to tight blood pressure target (n = 63; target blood pressure less than 130/80 mmHg) or less tight blood pressure target (n = 62; target blood pressure 130–139/80–89 mmHg). There were no statistically significant differences in baseline characteristics between the two groups.

Women in the tight control group were less likely to develop severe hypertension (RR 0.32; 95% CI 0.14 to 0.74) and to be admitted to hospital (RR 0.39; 95% CI 0.18 to 0.86). Babies born to women in the tight group had higher gestational ages at delivery (36.6 ± 2.2 weeks versus 35.8 ± 2.2 weeks; P < 0.05) and were less likely to born preterm (RR 0.52; 95% CI 0.28 to 0.99). There were no statistically significant differences between groups in terms of intrauterine fetal death, admission to NICU or IUGR.

One multicentre RCT71 [EL = 1+] (a pilot trial for the Control of Hypertension in Pregnancy Study; CHIPS) was conducted in Canada, New Zealand, Australia and the UK to compare the effects of tight and very tight control of blood pressure in women with chronic or gestational hypertension (diastolic blood pressure 90–109 mmHg, live fetus(es) and 20–33+6 weeks). The study excluded women with diastolic blood pressure consistently lower than 85 mmHg, severe systolic hypertension (170 mmHg or higher), proteinuria, contraindication to less tight or tight control, contraindication to pregnancy prolongation, or delivery anticipated within a week, or known lethal or major fetal anomaly. Women were randomly assigned to either ‘less tight’ (n = 66; target diastolic blood pressure 100 mmHg) or ‘tight’ (n = 66; target diastolic blood pressure 85 mmHg) control of blood pressure. There were no significant differences in baseline characteristics between the two groups.

No statistically significant differences were found between the two groups in terms of gestational age at delivery (36.9 ± 3.0 weeks versus 36.3 ± 3.3 weeks; P = 0.278), serious perinatal complications (14% versus 22%; RR 0.63; 95% CI 0.29 to 1.36), care in NICU (23% versus 34%; RR 0.67; 95% CI 0.38 to 1.18), serious maternal complications (4.6% versus 3.1%; RR 1.48; 95% CI 0.26 to 8.55) or the number of women who received magnesium sulphate for pre-eclampsia (15% versus 19%; RR 0.82; 95% CI 0.38 to 1.77). No differences were found in the proportions of infants less than 10th centile for gestation (30% versus 29%; RR 1.04; 95% CI 0.61 to 1.76) or in infants with birthweight less than 2500 g (35% versus 49%; RR 0.71; 95% CI 0.47 to 1.07). Pre-eclampsia was reported in 62% of the ‘less tight’ group and in 52% of the ‘tight’ group (RR 1.34; 95% CI 0.94 to 1.89), and severe hypertension in 58% versus 40% (RR 1.42; 95% CI 1.00 to 2.01).

One meta-regression conducted in Canada included 45 RCTs with a total of 3773 women taking antihypertensives (including methyldopa, acebutolol, atenolol, labetalol, metoprolol, oxprenolol, pindolol, propranolol, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, ketanserin, hydralazine, isradipine, nicardipine, nifedipine, verapamil and clonidine).72 [EL = 1+] The aim of the study was to estimate the association of treatment-induced mean arterial pressure with SGA babies and birthweight. A greater difference in MAP between control and treatment groups was associated with a higher proportion of SGA babies (15 RCTs, 1587 women; P < 0.05). In relation to birthweight, when one RCT was excluded owing to outlying results, a 10 mmHg fall in mean arterial pressure was associated with a 145 g decrease in birthweight (26 RCTs, number of women not reported; P < 0.05). However, three RCTs reported statistically significant differences in gestational age at delivery between the two groups. There was no statistically significant association between mean arterial pressure and birthweight when the RCT with outlier results was included (27 RCTs, 2305 women; P value not reported).

Evidence statement

One RCT [EL = 1+] investigated ‘tight’ versus ‘less tight’ control of hypertension in women with chronic or gestational hypertension. Women in the tight control group were less likely to develop severe hypertension or to be admitted to hospital and their babies were less likely to be born preterm. There were no differences in intrauterine fetal death, admission to NICU or IUGR.

Another RCT [EL = 1+] looked at ‘tight’ versus ‘less tight’ control of hypertension in women with existing or gestational hypertension. There were no significant differences between the groups in terms of gestational age at delivery, serious perinatal complications, care in NICU, serious maternal complications or the number of women who received magnesium sulphate for pre-eclampsia. However, the risk of severe hypertension was lower in women in the tight control group.

A meta-regression [EL = 1+] showed that every 10 mmHg fall in mean arterial pressure in women taking antihypertensives (including methyldopa, acebutolol, atenolol, labetalol, metoprolol, oxprenolol, pindolol, propranolol, bendrofluazide, chlorothiazide, hydrochlorothiazide, ketanserin, hydralazine, isradipine, nicardipine, nifedipine, verapamil and clonidine) was associated with a 145 g decrease in birthweight.

4.4.3. Bed rest

Clinical effectiveness

An RCT was conducted in Zimbabwe on the effectiveness of hospital admission for bed rest compared with continued normal activities at home.73 [EL = 1+] Two hundred and eighteen women with singleton pregnancies and blood pressure of 140/90 mmHg or higher, without proteinuria and at between 28 and 38 weeks of gestation were included in the study; of these, 33 had chronic hypertension. Women who were symptomatic, had a diastolic blood pressure of 100 mmHg or higher, a caesarean section scar or an antepartum haemorrhage during the pregnancy were excluded. Women were randomly allocated to hospital bed rest (n = 15 with chronic hypertension) or encouraged to continue normal activities at home (n = 18 with chronic hypertension). No statistically significant differences were found for development of severe hypertension, proteinuria or severe proteinuria.

Evidence statement

One small RCT from Zimbabwe showed no difference in the incidence of pre-eclampsia between women with chronic hypertension who had bed rest in hospital and those did not.

GDG interpretation of the evidence

Antihypertensives

The evidence from trials on treatment of blood pressure does not make it possible to determine the preferred antihypertensive agent for pregnant women with chronic hypertension. The available evidence suggests that antihypertensive treatment reduces the risk of severe hypertension but not the development of proteinuria. The GDG’s view is that further research is needed in relation to the efficacy and safety of antihypertensive agents when used during pregnancy by women with chronic hypertension. Such research should include placebo-controlled trials as well as head-to-head comparisons between various antihypertensive agents.

Level of blood pressure control

The GDG considered that the effect on fetal growth with some agents (mainly beta-blockers) is related to their greater effectiveness in reducing blood pressure. Two good-quality studies looking at the effect of ‘tight’ blood pressure control (defined differently in each trial) showed an increased risk of severe hypertension with less tight control of blood pressure, but no other differences in maternal or perinatal outcomes, including fetal growth. A meta-regression of RCTs demonstrated that the more blood pressure was reduced in women taking antihypertensives (including (including methyldopa, acebutolol, atenolol, labetalol, metoprolol, oxprenolol, pindolol, propranolol, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, ketanserin, hydralazine, isradipine, nicardipine, nifedipine, verapamil and clonidine), the more the birthweight of their babies was reduced.

The GDG’s view is that treatment should aim to lower blood pressure from the moderate or severe range while avoiding excessive reductions that may affect fetal growth, whatever antihypertensive agent is used. Women with evidence of target-organ damage from hypertension will need a lower target blood pressure than women without these changes, in line with ‘Hypertension’, NICE clinical guideline 34,3 which includes the following recommendations:

Drug therapy reduces the risk of cardiovascular disease and death. Offer drug therapy to:

  • patients with persistent high blood pressure of 160/100 mmHg or more
  • patients at raised cardiovascular risk (10-year risk of cardiovascular disease ≥ 20% or existing cardiovascular disease or target-organ damage) with persistent blood pressure of more than 140/90 mmHg).
Bed rest

The evidence in relation to bed rest comes from a small RCT that examined the effectiveness of hospital bed rest and showing no beneficial effect of such rest in women with chronic hypertension. Prolonged bed rest can increase the risk of venous thromboembolism and the GDG advises against such rest.

Secondary chronic hypertension

The GDG’s view is that pregnant women with secondary chronic hypertension should be offered referral to a specialist in hypertensive disorders, such as an obstetric physician, a renal physician, an endocrinologist or a specialist in connective tissue disease.

Recommendations

In pregnant women with uncomplicated chronic hypertension aim to keep blood pressure less than 150/100 mmHg.

Do not offer pregnant women with uncomplicated chronic hypertension treatment to lower diastolic blood pressure below 80 mmHg.

Offer pregnant women with target-organ damage secondary to chronic hypertension (for example, kidney disease) treatment with the aim of keeping blood pressure lower than 140/90 mmHg.

Offer pregnant women with secondary chronic hypertension referral to a specialist in hypertensive disorders.

Offer women with chronic hypertension antihypertensive treatment dependent on pre-existing treatment, side-effect profiles and teratogenicity.

Research recommendation

Which antihypertensive agent is best for use in women with chronic hypertension during pregnancy?

Why this is important

The literature on anti-hypertensive medication in women with chronic hypertension is inadequate to determine if any particular agent would offer advantages over placebo control or other antihypertensive agents. All drugs in common use have potential side effects and potential fetal and neonatal effects. As chronic hypertension is becoming more common it seems sensible to revisit therapy to ensure both efficacy and safety. Randomised controlled trials should be carried out in women with chronic hypertension during pregnancy to assess the commonly used antihypertensive agents relative to placebo control, and to compare different antihypertensives using head-to-head trials. Outcomes of interest are: level of blood pressure control for each type of drug, incidence of pre-eclampsia and complications of severe hypertension, efficacy, side effects, and perinatal morbidity and mortality.

4.5. Fetal monitoring

Clinical effectiveness

The fetus in a pregnancy complicated by hypertension may be at risk of increased perinatal mortality and morbidity. There were no specific studies dealing with fetal monitoring in pregnancies complicated by chronic hypertension. However, guidance on monitoring can be extrapolated from the overall data presented in Chapter 8. This is reasonable because the central problem for all pregnancies complicated by any form of hypertension is placental insufficiency with a common path of effect, which is IUGR, fetal hypoxia and ultimately fetal death.

Uterine artery Doppler velocimetry

Uterine artery Doppler velocimetry has been proposed as a method of pregnancy assessment that may, if abnormal, indicate an increased risk of pre-eclampsia. A search was carried out for studies that, as far as possible, included chronic hypertension, and five studies were identified

One diagnostic study74 [EL = II] studied women with chronic hypertension (n = 42). Thirty-seven women had mild hypertension (blood pressure 140–159/90–109 mmHg) and five had severe hypertension (blood pressure above 160/110 mmHg). Women with autoimmune disorders treated with corticosteroids and those with fetal chromosomal abnormalities or rhesus isoimmunisation were excluded. All women underwent uterine Doppler velocimetry at 23–24 weeks.

Using resistance index to interpret Doppler velocimetry results (abnormal being above the 90th percentile of the reference group) showed a sensitivity of 78% and specificity of 45% for pre-eclampsia superimposed on chronic hypertension. When the endpoint was IUGR, the test showed a sensitivity of 50% and a specificity of 39%.

Another diagnostic study75 [EL = II] examined a group of 78 pregnant women with chronic hypertension (diastolic blood pressure above 90 mmHg). Uterine artery Doppler velocimetry was conducted at 24–25 weeks and the endpoint outcomes were pregnancy-aggravated hypertension (diastolic blood pressure increase of more than 15 mmHg), superimposed pre-eclampsia, IUGR or placental abruption. When used for any complication, the resistance index (abnormal being 2 SD above normal for gestational age) had a sensitivity of 76% and specificity of 84%. Using bilateral notch and abnormal resistance index had a sensitivity of 62% and specificity of 100%.

Three diagnostic studies76–78 [EL = II] investigated the use of uterine artery Doppler velocimetry at 22–24 weeks of gestation in women with high-risk pregnancy (previous pre-eclampsia, previous stillbirth, previous placental abruption, previous IUGR, chronic hypertension, diabetes, autoimmune disease, kidney disease or habitual abortion).

Using resistance index gave a sensitivity of 78–97% and a specificity of 42–71% for prediction of pre-eclampsia. One study78 (n = 116) reported data on the use of resistance index in predicting IUGR, with a sensitivity of 84% and specificity of 39% for SGA babies.

The evidence is summarised in Tables 4.2 and 4.3.

Table 4.2. Use of uterine artery Doppler velocimetry to predict pre-eclampsia or IUGR in women with chronic hypertension or mixed high-risk factors.

Table 4.2

Use of uterine artery Doppler velocimetry to predict pre-eclampsia or IUGR in women with chronic hypertension or mixed high-risk factors.

Table 4.3. Use of uterine artery Doppler velocimetry to predict pregnancy-aggravated hypertension, superimposed pre-eclampsia, IUGR and placental abruption in women with chronic hypertension.

Table 4.3

Use of uterine artery Doppler velocimetry to predict pregnancy-aggravated hypertension, superimposed pre-eclampsia, IUGR and placental abruption in women with chronic hypertension.

Evidence statement

One diagnostic study [EL = II] showed that uterine artery Doppler velocimetry at 24 weeks has a sensitivity of 78% and specificity of 45% when using resistance index to identify risk of pre-eclampsia.

Studies where women with chronic hypertension were included as part of a larger group of high-risk women showed sensitivities of 80% and over but poor specificity (generally less than 70%).

GDG interpretation of the evidence

No studies have evaluated fetal monitoring specifically in women with chronic hypertension and therefore inference on monitoring must be made from general studies of high-risk pregnancies that included women with chronic hypertension.

Fetal monitoring

In spite of the lack of relevant evidence for the use of biometry in hypertensive disorders, the GDG felt that the recognised risk of IUGR in this group results in a need for fetal biometry and fetal monitoring within its recommendations.

Uterine artery Doppler velocimetry

The information on the predictive value of uterine artery Doppler velocimetry in women at high risk of pre-eclampsia, including those with chronic hypertension, is of poor quality and uses a variety of Doppler measurements and outcomes.

Overall, the GDG’s view is that the negative predictive ability and the sensitivity are not sufficiently discriminatory to allow clinicians to alter management for individual women. Given that women with chronic hypertension are already advised to take aspirin during pregnancy, the GDG has not found any evidence that discrimination by Doppler velocimetry would drive clinical intervention or alter outcomes.

Recommendations relating to fetal monitoring for women with chronic hypertension are presented in Chapter 8.

4.6. Antenatal consultations

The frequency of antenatal contacts for women with chronic hypertension cannot be specified as the care of each pregnancy needs to be individualised. The only evidence on antenatal schedules is found in ‘Antenatal care’, NICE clinical guideline 621 and the GDG is clear that the routine schedule alone would be inadequate for pregnant women with chronic hypertension. If proteinuria develops then the care would become that of a woman with pre-eclampsia (see Chapter 7).

Recommendation

In women with chronic hypertension, schedule additional antenatal consultations based on the individual needs of the woman and her baby.

4.7. Timing of birth

Clinical effectiveness

Maternal indications

No specific evidence was identified in relation to timing of birth for women with chronic hypertension. The GDG considered that the advice on timing of birth for women with chronic hypertension should be the same as for women with gestational hypertension (see Section 6.7). If proteinuria develops then the management becomes that described for women with pre-eclampsia (see Section 7.7).

Fetal indications/

No specific evidence was identified for fetal monitoring in pregnancies complicated by chronic hypertension. Because women with chronic hypertension are more likely to have underlying vascular disease than women with gestational hypertension, and possibly those with pre-eclampsia, the risk of IUGR is probably greater. Decisions about the timing of birth in women with chronic hypertension is, therefore, more likely to involve consideration of fetal indications, such as poor growth or impending fetal death.

GDG interpretation of the evidence

The GDG’s view is that timing of birth in women with chronic hypertension should be the same as for women with gestational hypertension. However, fetal indications for IUGR and impending fetal death may occur more commonly in women with chronic hypertension.

Recommendations

Do not offer birth to women with chronic hypertension whose blood pressure is lower than 160/110 mmHg, with or without antihypertensive treatment, before 37 weeks.

For women with chronic hypertension whose blood pressure is lower than 160/110 mmHg after 37 weeks, with or without antihypertensive treatment, timing of birth, and maternal and fetal indications for birth should be agreed between the woman and the senior obstetrician.

Offer birth to women with refractory severe chronic hypertension, after a course of corticosteroids (if required) has been completed.

4.8. Postnatal investigation, monitoring and treatment

This section relates to women with chronic hypertension who have not developed pre-eclampsia.

Frequency of postnatal observations or investigations

No evidence was identified in relation to frequency of observations or investigations.

Choice of antihypertensive treatment

No evidence was identified in relation to choice of antihypertensive treatment in the postnatal period for women with chronic hypertension. The use of antihypertensive drugs during breastfeeding is discussed in Chapter 11.

GDG interpretation of the evidence

There is little evidence to support the use of basic observations in the postnatal period and these should be largely clinically driven in type and frequency. Peak blood pressure in the postnatal period occurs 3–5 days after the birth and blood pressure should be assessed at this time, whatever the birth or postnatal setting. Similarly, blood pressure monitoring would be sensible if treatment were altered, in this case by restarting previous antihypertensive therapy. The GDG’s view is that women with chronic hypertension should be offered a formal medical review at the postnatal review (6–8 weeks after the birth) and that their pre-pregnancy care team should conduct the review. The review should include measurement of blood pressure, urine testing and review of antihypertensive drugs.

Target blood pressures will be those used in long-term treatment of hypertension.

There is no evidence in relation to the effectiveness of antihypertensive drugs in the postnatal period for women with chronic hypertension. The GDG’s view is, therefore, that antenatal antihypertensive treatment should continue in the postnatal period.

The GDG is aware of a Medicines and Healthcare products Regulatory Agency (MHRA) newsletter (May 2009 issue of the MHRA Drug Safety Update, available at www.mhra.gov.uk/Publications/Safetyguidance/DrugSafetyUpdate/CON046451) that identifies methyldopa as the antihypertensive of choice during pregnancy and breastfeeding. However, the MHRA Drug Safety Update does not reflect the well-recognised association between methyldopa and clinical depression. Although maternal depression was reported in only one of the 21 studies considered by the GDG in relation to methyldopa,79 the GDG’s view is that this drug should not be used in the postnatal period because women are already at risk of depression at this time; use of methyldopa should be stopped within 2 days of the birth where feasible.

Recommendations

In women with chronic hypertension who have given birth, measure blood pressure:

  • daily for the first 2 days after birth
  • at least once between day 3 and day 5 after birth
  • as clinically indicated if antihypertensive treatment is changed after birth.

In women with chronic hypertension who have given birth, aim to keep blood pressure lower than 140/90 mmHg.

In women with chronic hypertension who have given birth:

  • continue antenatal antihypertensive treatment
  • review long-term antihypertensive treatment 2 weeks after the birth.

If a woman has taken methyldopa† to treat chronic hypertension during pregnancy, stop within 2 days of birth and restart the antihypertensive treatment the woman was taking before she planned the pregnancy.

Offer women with chronic hypertension a medical review at the postnatal review (6 8 weeks after the birth) with the pre-pregnancy care team.

†

This guideline assumes that prescribers will use a drug’s summary of product characteristics (SPC) to inform decisions made with individual patients. Drugs for which particular attention should be paid to the contraindications and special warnings during pregnancy and lactation are marked with † and detailed in Section 1.6.

Copyright © 2011, Royal College of Obstetricians and Gynaecologists.

No part of this publication may be reproduced, stored or transmitted in any form or by any means, without the prior written permission of the publisher or, in the case of reprographic reproduction, in accordance with the terms of licences issued by the Copyright Licensing Agency in the UK [www.cla.co.uk]. Enquiries concerning reproduction outside the terms stated here should be sent to the publisher at the UK address printed on this page.

The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore for general use.

Bookshelf ID: NBK62651
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