Clinical Topic A-Z Clinical Speciality

Hypertension in pregnancy

Hypertension in pregnancy
D006973Hypertension
D011247Pregnancy
CardiovascularPregnancyWomen's health
2010-11-29Last revised in November 2010

Hypertension in pregnancy - Summary

Several different hypertensive disorders can complicate pregnancy. The National Institute for Health and Care Excellence (NICE) use the following working definitions.

Hypertension during pregnancy

A diastolic blood pressure of 90 mmHg or greater on two occasions more than 4 hours apart, and/or

A single diastolic blood pressure reading greater than 110 mmHg.

Mild, moderate, and severe hypertension

Mild hypertension: diastolic blood pressure of 90–99 mmHg and/or systolic blood pressure of 140–149 mmHg.

Moderate hypertension: diastolic blood pressure of 100–109 mmHg and/or systolic blood pressure of 150–159 mmHg.

Severe hypertension: diastolic blood pressure of 110 mmHg or greater and/or systolic blood pressure of 160 mmHg or greater.

Chronic hypertension

Hypertension that is present at the booking visit, or before 20 weeks' gestation, or in a woman already on antihypertensive medication (as the blood pressure tends to fall during the first and second trimesters, a woman with a high blood pressure before week 20 of pregnancy can be assumed to have pre-existing hypertension).

Gestational hypertension

New hypertension presenting after 20 weeks' gestation without significant proteinuria.

Pre-eclampsia:

New hypertension presenting after 20 weeks' gestation with significant proteinuria. Pre-eclampsia is a multi-system disorder which can affect the placenta, kidney, liver, brain, and other organs of the mother.

Pre-eclampsia superimposed on chronic hypertension: onset of new signs or symptoms of pre-eclampsia after 20 weeks' gestation in a woman with chronic hypertension.

HELLP syndrome (Haemolysis, Elevated Liver enzymes, and Low Platelets syndrome) is a severe form of pre-eclampsia. It is essentially a laboratory diagnosis.

Eclampsia is the occurrence of one or more seizures in a woman with pre-eclampsia.

Significant proteinuria is more than 300 mg protein in a 24-hour urine collection or more than 30 mg/mmol in a spot urinary protein/creatinine sample.

Women at high risk of pre-eclampsia should take aspirin 75 mg daily from 12 weeks of gestation until the birth of the baby.

Blood pressure should be taken and a dipstick urine test done for proteinuria at presentation and at each antenatal visit.

An explanation of the symptoms of pre-eclampsia should be given and the woman advised to seek immediate advice if she develops any of the following (including during the postpartum period):

Severe headaches (increasing frequency unrelieved by regular analgesics).

Vision problems, such as blurred vision, flashing lights, double vision, or floating spots.

Persistent new epigastric pain or pain in the right upper quadrant.

Vomiting.

Breathlessness.

Sudden swelling of the face, hands, or feet.

A urine dipstick test for protein should be done at initial presentation and each subsequent antenatal visit.

There are strict management criteria often requiring urgent admission or same day assessment depending on the gestational age, the level of blood pressure, the level of proteinuria, whether symptoms of pre-eclampsia are present, and whether the woman had pre-existing hypertension.

Post-partum monitoring and follow-up is essential.

Have I got the right topic?

156months3060monthsFemale

This CKS topic incorporates recommendations from the National Institute for Health and Care Excellence guidance Hypertension in pregnancy: the management of hypertensive disorders in pregnancy [National Collaborating Centre for Women's and Children's Health, 2010]. The guidance also covers the detection and management of proteinuria in pregnancy and is based on the Pre-eclampsia community guideline [PRECOG, 2004a].

This CKS topic does not cover the detailed management of hypertension in pregnancy in secondary care.

There are separate CKS topics on Diabetes - type 2 and Hypertension - not diabetic.

The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary health care.

How up-to-date is this topic?

How up-to-date is this topic?

Changes

Last revised in November 2010

November 2012 — minor update. The links to the electronic medicines website (www.medicines.org.uk) have been updated.

August to November 2010 — topic updated. The evidence-base has been reviewed in detail, and recommendations are more clearly justified and transparently linked to the supporting evidence.

There are no major changes to the recommendations.

Previous changes

January–March 2006 — rewritten. Validated in June 2006 and issued in July 2006.

October 2005 — minor technical update. Issued in November 2005.

March 2004 — reviewed. Validated in March 2003 and issued in April 2003.

November 1999 — written. Validated in March 2000 and issued in September 2000.

Update

New evidence

NICE Evidence published an evidence update on hypertension in pregnancy in May 2012. [Free Full-text (pdf)]

Evidence-based guidelines

Guidelines published since the last revision of this topic:

Mancia, G., Fagard, R., Narkiewicz, K., et al. (2013) 2013 ESH/ESC guidelines for the management of arterial hypertension. The Task Force for the management of arterial hypertension of the European Society of Hypertension (ESC) and of the European Society of Cardiology (ESC). European Heart Journal 34(28), 2159-2219. [Free Full-text]

HTAs (Health Technology Assessments)

No new HTAs since 1 October 2010.

Economic appraisals

No new economic appraisals relevant to England since 1 October 2010.

Systematic reviews and meta-analyses

Systematic reviews published since the last revision of this topic:

Gois, P.H.F. and Souza, E.R.D.M. (2013) Pharmacotherapy for hyperuricemia in hypertensive patients (Cochrane Review). The Cochrane Library. Issue 1. John Wiley & Sons, Ltd. www.thecochranelibrary.com [Free Full-text]

Hermes, W., Ket, J.C., van Pampus, M.G., et al. (2012) Biochemical cardiovascular risk factors after hypertensive pregnancy disorders: a systematic review and meta-analysis. Obstetrical and Gynecological Survey 67(12), 793-809. [Abstract]

TePoel, M.R., Saftlas, A.F. and Wallis, A.B. (2011) Association of seasonality with hypertension in pregnancy: a systematic review. Journal of Reproductive Immunology 89(2), 140-152. [Abstract]

Trivedi, N.A. (2011) A meta-analysis of low-dose aspirin for prevention of preeclampsia. Journal of Postgraduate Medicine 57(2), 91-95. [Abstract] [Free Full-text]

Primary evidence

No new randomized controlled trials published in the major journals since 1 October 2010.

Observational studies published since the last revision of this topic:

Orbach, H., Matok, I., Gorodischer, R., et al. (2013) Hypertension and antihypertensive drugs in pregnancy and perinatal outcomes. American Journal of Obstetrics and Gynecology 208(4), 301. [Abstract]

von Dadelszen, P., Payne, B., Li, J., et al. (2011) Prediction of adverse maternal outcomes in pre-eclampsia: development and validation of the fullPIERS model. Lancet 377(9761), 219-227. [Abstract]

New policies

No new national policies or guidelines since 1 October 2010.

New safety alerts

No new safety alerts since 1 October 2010.

Changes in product availability

No changes in product availability since 1 October 2010.

Goals and outcome measures

Goals

To support primary healthcare professionals:

To detect raised blood pressure early in pregnancy and postpartum

To control raised blood pressure during pregnancy and postpartum, when necessary

To detect pre-eclampsia early

To avoid maternal morbidity and mortality

To avoid fetal complications

Background information

Definition

What is it?

Several different hypertensive disorders can complicate pregnancy, and numerous different terms and definitions are used to describe them.

Working definitions used by the National Institute for Health and Care Excellence (NICE) are [National Collaborating Centre for Women's and Children's Health, 2010]:

Hypertension during pregnancy

A diastolic blood pressure of 90 mmHg or greater on two occasions more than 4 hours apart, and/or

A single diastolic blood pressure reading greater than 110 mmHg.

Mild, moderate, and severe hypertension

Mild hypertension: diastolic blood pressure of 90–99 mmHg and/or systolic blood pressure of 140–149 mmHg.

Moderate hypertension: diastolic blood pressure of 100–109 mmHg and/or systolic blood pressure of 150–159 mmHg.

Severe hypertension: diastolic blood pressure of 110 mmHg or greater and/or systolic blood pressure of 160 mmHg or greater.

Chronic hypertension

Hypertension that is present at the booking visit, or before 20 weeks' gestation, or in a woman already on antihypertensive medication (as the blood pressure tends to fall during the first and second trimesters, a woman with a high blood pressure before week 20 of pregnancy can be assumed to have pre-existing hypertension).

Gestational hypertension

New hypertension presenting after 20 weeks' gestation without significant proteinuria.

Pre-eclampsia

New hypertension presenting after 20 weeks' gestation with significant proteinuria. Pre-eclampsia is a multi system disorder which can affect the placenta, kidney, liver, brain, and other organs of the mother. It is thought to be due to widespread endothelial cell damage secondary to an ischaemic placenta, although the exact cause is unknown.

Pre-eclampsia superimposed on chronic hypertension: onset of new signs or symptoms of pre-eclampsia after 20 weeks' gestation in a woman with chronic hypertension [Duley et al, 2006].

HELLP syndrome (Haemolysis, Elevated Liver enzymes, and Low Platelets syndrome) is a severe form of pre-eclampsia. It is essentially a laboratory diagnosis.

Eclampsia is the occurrence of one or more seizures in a woman with pre-eclampsia.

Significant proteinuria is more than 300 mg protein in a 24-hour urine collection or more than 30 mg/mmol in a spot urinary protein/creatinine sample.

Measuring blood pressure

How should I measure blood pressure?

Use a properly calibrated, validated sphygmomanometer. For a list of blood pressure monitors that have met the British Hypertension Society criteria, see www.bhsoc.org.

Use an appropriately sized cuff:

Standard size (13 x 23 cm) for an arm circumference of up to 33 cm.

Large size (15 x 33 cm) for an arm circumference between 33 cm and 41 cm.

Thigh cuff (18 x 36 cm) for an arm circumference of 41 cm or more.

Less error is introduced by using a cuff which is too large, than a cuff which is too small.

Remove tight clothing. Ask the woman to sit or lie at 45°, with her arm at the level of her heart. Do not measure blood pressure with the woman lying on her side, as this will give a falsely low reading.

Inflate the cuff to 20–30 mmHg above palpated systolic blood pressure.

Lower the column slowly by 2 mmHg per second or per beat.

Record the blood pressure to the nearest 2 mmHg.

Use Korotkoff V (disappearance of heart sounds) for measurement of the diastolic pressure.

This is subject to less intra-observer and inter-observer variation than Korotkoff IV (muffling of heart sounds) and seems to correlate best with intra-arterial pressure in pregnancy.

In the 15% of pregnant women whose diastolic pressures fall to zero before the last sound is heard, record both phase IV and V readings (for example 148/84/0 mmHg).

[PRECOG, 2004a; NICE, 2008b]

Measuring proteinuria

How should I measure proteinuria?

Use an automated reagent-strip reading device, if available.

Otherwise, visually read dipsticks should be used.

Confirmation of proteinuria is usually done in secondary care, and the following methods are recommended:

Collection of urine over a 24-hour period.

Spot urinary protein:creatinine ratio.

[National Collaborating Centre for Women's and Children's Health, 2010]

Prevalence

How common is it?

Hypertensive disorders occur in up to 10% of all pregnancies; rates vary according to the population studied and the criteria used for confirming the diagnosis. Rates may be increasing [National Collaborating Centre for Women's and Children's Health, 2010].

Pre-existing (chronic) hypertension has been reported to occur in 0.6–2.7% of pregnant women [National Collaborating Centre for Women's and Children's Health, 2010]. A recent study of 1184 women who had given birth in Australia found that 1.3% of women had chronic hypertension [Roberts et al, 2008].

Gestational hypertension (new hypertension after 20 weeks' gestation without proteinuria) is probably under-reported, with recorded rates of 4.2–7.9% [National Collaborating Centre for Women's and Children's Health, 2010].

Pre-eclampsia rates are more accurately reported, although they range from 1.5–7.7%. The rate depends on parity: 4.1% for women in their first pregnancy and 1.7% for women in their second pregnancy [National Collaborating Centre for Women's and Children's Health, 2010].

HELLP syndrome (Haemolysis, Elevated Liver enzymes, and Low Platelets) occurs 0.5–0.9% of all pregnancies and in 10–20% of women with severe pre-eclampsia [Woudstra et al, 2010].

Eclampsia complicates 2.7 per 10,000 births [Knight and UKOSS, 2007].

A UK retrospective study of 1259 consecutive women classified, at the time (data from 1931–1990), as having an eclamptic convulsion found that the incidence fell by more than 90%, from 74 per 10,000 in the 1930s to 7.2 per 10,000 in the 1980s [Leitch et al, 1997]. Most of the reduction occurred over the first four decades, with little change in the last 20 years.

The same study found that the most notable decrease has been in antepartum and intrapartum cases of eclampsia. This occurred in association with the introduction of the National Health Service, with free comprehensive antenatal care for all. Therefore, there has been a relative increase in the proportion of postpartum cases from 19% in the decade 1931–1940 to 48% in 1981–1990.

Impact on pregnancy

What is the prognosis?

Pre-existing (chronic) hypertension

Most women with pre-existing hypertension will have mild to moderate hypertension, with a blood pressure less than 160/110 mmHg, and are at low risk of perinatal complications [National High Blood Pressure Education Program, 2000].

The likelihood of complications is increased in women with severe hypertension or with pre-existing cardiovascular or renal disease [Ferrer et al, 2000]. Such complications as pre-eclampsia, placental abruption, impaired fetal growth, and premature birth result in an increased risk of perinatal morbidity and mortality [Ferrer et al, 2000; Williams et al, 2004].

Gestational hypertension (new hypertension without proteinuria developing after 20 weeks' gestation)

Gestational hypertension occurring before 32 weeks is associated with small-for-gestational-age infants [PRECOG, 2004a].

The risk of progressing to pre-eclampsia depends on the stage of gestation at which hypertension occurs [PRECOG, 2004b]:

Before 32 weeks' gestation, 50% of pregnancies will progress to pre-eclampsia.

At 32–35 weeks, 40% will progress.

At 38 weeks, fewer than 10% will progress.

Pre-eclampsia (new hypertension in combination with proteinuria developing after 20 weeks' gestation)

Pre-eclampsia is associated with a risk of maternal and fetal complications. It is not possible to predict who is at risk of complications, and close monitoring is necessary. A systematic review found that the amount of proteinuria is a poor predictor of maternal and fetal outcomes [Thangaratinam et al, 2009].

Prognosis is particularly poor in pre-eclampsia occurring before 34 weeks' gestation, in eclampsia, and in HELLP syndrome (Haemolysis, Elevated Liver enzymes, and Low Platelets).

Eclampsia develops in fewer than 1% of women with pre-eclampsia [Sibai et al, 2005].

Proteinuria alone

Proteinuria is strongly associated with poor maternal and fetal outcome [PRECOG, 2004b].

It may be associated with previously undiagnosed underlying medical conditions and poor obstetric outcome.

It may also be the first clinical indication of pre-eclampsia. In one study, 10% of women with eclampsia had proteinuria (1+ or more) without hypertension at their last antenatal visit within 1 week of the onset of eclampsia.

Complications

What are the complications?

Complications that may occur with pre-eclampsia [Sibai et al, 2005; Duley et al, 2006]:

Central nervous system

Eclampsia (seizures).

Cerebral haemorrhage/infarction (stroke).

Cerebral oedema.

Cortical blindness.

Retinal oedema.

Retinal blindness.

Acute renal failure due to:

Renal cortical necrosis.

Renal tubular necrosis.

Respiratory system

Pulmonary oedema.

Laryngeal oedema.

Liver

Jaundice.

HELLP syndrome (Haemolysis, Elevated Liver enzymes, and Low Platelets).

Hepatic rupture.

Hepatic failure/necrosis.

Coagulation system

Disseminated intravascular coagulation.

Microangiopathic haemolysis.

Venous thromboembolism.

Placenta

Placental infarction.

Placental abruption.

Infant

Neonatal death.

Stillbirth. About 1 in 23 stillbirths in infants with or without a congenital abnormality occurred in women with pre-eclampsia [CEMACH, 2009].

Preterm birth.

Intrauterine growth restriction.

Maternal death is rare.

However, pre-eclampsia and eclampsia are the most common causes of maternal death after thromboembolism, with a rate of 8.5 per million pregnancies in the UK during 2003–2005 [CEMACH, 2007].

Causes of death due to pre-eclampsia and eclampsia include intracranial haemorrhage, cerebral infarction, cerebral oedema, acute respiratory distress syndrome and pulmonary oedema, hepatic rupture, and hepatic failure/necrosis [PRECOG, 2004b].

Long-term risks

What are the long-term risks of hypertensive disorders in pregnancy?

Risk to future pregnancies

In women with gestational hypertension, studies indicate that in a future pregnancy:

The risk of gestational hypertension ranges from 16–47%.

The risk of pre-eclampsia ranges from 2–7%.

In women with pre-eclampsia, studies indicate that in a future pregnancy:

The risk of gestational hypertension ranges from 13–53%.

The risk of pre-eclampsia ranges from 0–16%.

In women with severe pre-eclampsia, HELLP (Haemolysis, Elevated Liver enzymes, and Low Platelets) syndrome, or eclampsia:

Which led to birth before 34 weeks, the risk of pre-eclampsia in a future pregnancy is about 25%.

Which led to birth before before 28 weeks, the risk of pre-eclampsia in a future pregnancy is about 55%.

Long-term health risks

In women with gestational hypertension

There may be an increased risk of developing future hypertension and cardiovascular disease.

Compared with pre-eclampsia, there is much less evidence about the long-term consequences of gestational hypertension [Bellamy et al, 2007]. The National Institute for Health and Care Excellence states that there is less justification to advise this group of women about long-term risks [National Collaborating Centre for Women's and Children's Health, 2010].

In women with pre-eclampsia

There is good-quality evidence from two systematic reviews that women with a history of pre-eclampsia have a lifelong increased risk of hypertension and its consequences [Bellamy et al, 2007; McDonald et al, 2008].

The risk seems to be greatest in women who develop pre-eclampsia before 37 weeks' gestation.

There seems to be an increasing risk with the severity of hypertension.

It is not known whether pre-eclampsia is the cause of the subsequent increased risk or whether the pre-eclampsia is just part of the development of a hypertensive disorder.

There is good evidence from a large retrospective study that women who have had pre-eclampsia are at increased risk of developing end-stage renal disease, although the absolute risk is low [Vikse et al, 2008]. The risk is slightly higher than for the general population if they have no hypertension or proteinuria 6–8 weeks after the birth [National Collaborating Centre for Women's and Children's Health, 2010].

Management

Management

Scenario: High risk of pre-eclampsia : covers the identification and management of women who are at high risk of pre-eclampsia.

Scenario: Proteinuria and no hypertension : covers the management of new proteinuria in pregnant women who do not have hypertension.

Scenario: Pre-existing hypertension, or hypertension before 20 weeks : covers the assessment and management of women with chronic hypertension throughout pregnancy.

Scenario: New hypertension after 20 weeks : covers the assessment and management of women over 20 weeks' gestation who develop hypertension.

Scenario: Postpartum follow-up : covers the assessment and management of women in the postpartum period who have chronic hypertension, gestational hypertension, or pre-eclampsia. There are also sections on the identification and management of postpartum pre-eclampsia/eclampsia, and on breastfeeding and antihypertensive drugs.

Scenario: High risk of pre-eclampsia

Scenario: Identification and management of women at high risk of pre-eclampsia

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Women at high risk

Who is at high risk of developing pre-eclampsia?

Women are at high risk of pre-eclampsia if they have:

One of the following high risk factors:

A history of hypertensive disease during a previous pregnancy.

Chronic kidney disease.

Autoimmune disease, such as systemic lupus erythematosus or antiphospholipid syndrome.

Type 1 or type 2 diabetes.

Chronic hypertension.

Thrombophilia.

Two or more of the following moderate risk factors:

First pregnancy.

Aged 40 years or older.

Pregnancy interval of more than 10 years.

Body mass index (BMI) of 35 kg/m2 or greater at the first visit.

Family history of pre-eclampsia.

Multiple pregnancy.

Basis for recommendation

Basis for recommendation

Having reviewed the available evidence, the National Institute for Health and Care Excellence (NICE) defined high-risk and moderate-risk groups [National Collaborating Centre for Women's and Children's Health, 2008; National Collaborating Centre for Women's and Children's Health, 2010].

Management

How do I manage a woman at high risk of developing pre-eclampsia?

For women at high risk of pre-eclampsia:

Give advice about a healthy lifestyle.

Advice should be the same as for healthy pregnant women and should include advice regarding rest, work, exercise, and weight. Beginning or continuing a moderate course of exercise during pregnancy is not associated with adverse outcomes.

Prescribe aspirin 75 mg daily from 12 weeks of gestation until the birth of the baby:

If the woman has either:

One or more high risk factors for developing pre-eclampsia.

Two or more moderate risk factors for developing pre-eclampsia.

Seek specialist advice before prescribing aspirin:

For girls younger than 16 years of age.

If blood pressure is uncontrolled or if the woman has thrombophilia.

Dipstick the urine for protein at initial presentation and each subsequent antenatal visit.

Warn about symptoms of pre-eclampsia and advise the woman to seek immediate advice if she develops any of the following (including during the postpartum period):

Severe headaches (increasing frequency unrelieved by regular analgesics).

Vision problems, such as blurred vision, flashing lights, double vision, or floating spots.

Persistent new epigastric pain or pain in the right upper quadrant.

Vomiting.

Breathlessness.

Sudden swelling of the face, hands, or feet.

Basis for recommendation

Basis for recommendation

Advice about a healthy lifestyle

The National Institute for Health and Care Excellence (NICE) looked at the evidence on lifestyle in women at risk of hypertensive disorders during pregnancy [National Collaborating Centre for Women's and Children's Health, 2010].

Rest

NICE reviewed the available evidence and concluded that there is insufficient evidence for the use of rest in any form to prevent hypertensive disease in pregnancy.

Exercise

NICE concluded that there is evidence from a Cochrane systematic review that exercise has no significant effect on reducing the incidence of pre-eclampsia.

Work

NICE found six studies on working hours and physical activity, including lifting heavy weights, and concluded that generally poor-quality evidence showed no effect.

Weight

NICE identified no evidence on maintaining a healthy weight during pregnancy.

NICE concluded that advice on rest, exercise, and work for women at risk of hypertensive disorders of pregnancy should be the same as the advice given to healthy pregnant women in their guideline Antenatal care, routine care for the healthy pregnant woman [National Collaborating Centre for Women's and Children's Health, 2008].

Advice about moderate exercise

This recommendation is based on expert advice from NICE [National Collaborating Centre for Women's and Children's Health, 2008].

Use of aspirin for women at high risk of pre-eclampsia

The recommendations to use aspirin is based on expert advice from NICE [National Collaborating Centre for Women's and Children's Health, 2010]. NICE reviewed evidence from a Cochrane systematic review and a large meta-analysis of individual patient data and concluded that:

The use of low-dose aspirin was consistent with a small risk reduction for pre-eclampsia, and there is a clear benefit in their defined high-risk groups.

Moderate risk has been poorly defined in studies. However, the presence of two moderate risk factors would confer a greater risk that any risk factor considered individually.

Data on the safety of aspirin in the doses used for the prevention of pre-eclampsia are sufficient.

The recommendation to start aspirin at 12 weeks' gestation is based on expert advice from NICE, as this is the earliest gestational age for which there is available evidence concerning the use of aspirin for the prevention of pre-eclampsia [National Collaborating Centre for Women's and Children's Health, 2010].

Most of the CKS expert reviewers recommended that aspirin should be given to girls younger than 16 years of age on specialist advice only.

Some of our expert reviewers warned against prescribing aspirin to women with uncontrolled blood pressure. CKS recommends that in such women, it is best to seek specialist advice about whether or not to prescribe aspirin.

Women with thrombophilia

NICE has stated that evidence on the association between thrombophilia and hypertensive disorders remains unclear. Only women with certain types of thrombophilia are at an increased risk of pre-eclampsia. These thrombophilias include women with hyperhomocysteinaemia, prothrombin heterozygosity, anticardiolipin antibodies, and Factor V Leiden heterozygosity. CKS therefore recommends that specialist advice is sought before prescribing aspirin.

Testing for proteinuria

Expert opinion in the NICE guideline Antenatal care, routine care for the healthy pregnant woman states that when blood pressure is measured at each antenatal check, a urine sample should be tested at the same time for proteinuria [National Collaborating Centre for Women's and Children's Health, 2008]. NICE based this recommendation on evidence from a retrospective study of 53 women that found that those with proteinuria greater 500 mg per day had a high risk of pre-eclampsia [Stettler and Cunningham, 1992].

Proteinuria is an important sign of pre-eclampsia after a gestation of 20 weeks. However, throughout pregnancy proteinuria may also be caused by an underlying medical condition [National Collaborating Centre for Women's and Children's Health, 2008].

Symptoms of pre-eclampsia

These recommendations are based on expert advice from NICE [National Collaborating Centre for Women's and Children's Health, 2010] and three narrative reviews [Sadovsky, 2002; Duley et al, 2006; Young et al, 2010].

A key recommendation from the 1998 Confidential Enquiry into Maternal Deaths that is accepted good clinical practice is that all women should receive antenatal education so that they are aware of the symptoms associated with pre-eclampsia (such as headache or epigastric pain), its importance, and the need to obtain medical advice [DH, 1998].

Measures not recommended for the prevention of hypertensive disorders of pregnancy

A review of the literature for all of the following was undertaken by NICE [National Collaborating Centre for Women's and Children's Health, 2010].

Nitric oxide

NICE concluded that there is limited high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of nitric oxide donors, such as glyceryl trinitrate.

Progesterone

NICE concluded that there is limited high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of progesterone.

Diuretics

NICE concluded that there is limited high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of diuretics.

Low-molecular-weight heparin

NICE reviewed the evidence from an open-label randomized controlled trial involving 80 women with the angiotensin converting enzyme DD genotype who had a history of pre-eclampsia [Mello et al, 2005]. This genotype is associated with thrombophilia and fetal loss. Although this study showed a clinically significant reduction in pre-eclampsia and its sequelae, NICE concluded that the study was of poor quality, and therefore the evidence is limited. NICE therefore have not recommended the use of low molecular weight heparin because of the risks associated with its use.

Calcium

NICE concluded that there is high quality evidence from a Cochrane systematic review that calcium supplementation reduces the risk of pre-eclampsia in women who have a low dietary intake of calcium (which does not generally apply to women in the UK). The benefits of calcium supplementation are greatest in women who are at high risk of pre-eclampsia. If calcium intake is known to be adequate then there is no statistically significant benefit. Therefore, NICE decided that routine calcium supplementation in the UK could not be justified.

Magnesium

NICE identified no evidence on the use of magnesium.

Antioxidants

NICE concluded that there is high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of antioxidants. There is evidence from two randomized trials done since this review that there is no benefit from the use of antioxidants [Roberts et al, 2010; Xu et al, 2010]. One of the trials has suggested that there might be an increased risk of fetal loss and perinatal death associated with their use [Xu et al, 2010].

Folic acid

NICE found only poor-quality evidence from a large prospective cohort study involving 2951 women that investigated whether folic acid started early in the second trimester of pregnancy reduced the risk of pre-eclampsia. Although the results did suggest a possible benefit, NICE concluded that the results were likely to be confounded by other factors, including the use of other vitamins. There was no statistically significant evidence that folic acid alone reduced the risk of pre-eclampsia. Although folic acid is recommended in pregnancy for other reasons, it is not recommended for use to prevent hypertensive disorders of pregnancy.

Fish oils

NICE concluded that there is high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of fish or algal oils.

Garlic

NICE concluded that there is limited good quality evidence from a Cochrane systematic review for the use of garlic to prevent pre-eclampsia, but increasing the intake of garlic is not recommended, as no significant effect was found.

Dietary salt restriction

NICE reviewed evidence from a randomized controlled trial involving 361 women and concluded that there is limited good-quality evidence that a low sodium diet does not prevent subsequent development of pre-eclampsia in women with weight gain and mild hypertension. However, although NICE does not recommend salt restriction to prevent pre-eclampsia, it stresses the importance of a healthy lifestyle and the importance of salt reduction in chronic hypertension.

Scenario: Proteinuria and no hypertension

Scenario: Proteinuria and no hypertension in pregnancy

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Less than 20 weeks' gestation

How do I manage women with new proteinuria without hypertension at less than 20 weeks' gestation?

If the woman is 20 weeks' gestation or less and is found to have proteinuria but is not hypertensive:

Consider possible urinary tract infection (UTI):

If a woman has symptoms of a UTI, or urinary dipstick test is positive for nitrite, or is positive for both leukocyte esterase and blood, make a working diagnosis of UTI and manage appropriately. Urine should be sent for culture and sensitivity.

For detailed information on the diagnosis and management of UTI in pregnancy, see the CKS topic on Urinary tract infection (lower) - women.

If there is no evidence of a UTI and the woman has 1+ protein or more on repeat dipstick testing, consider underlying medical conditions and assess for chronic kidney disease. For more information, see the CKS topic on Chronic kidney disease - not diabetic.

Basis for recommendation

Basis for recommendation

Considering possible urinary tract infection (UTI)

It is good clinical practice to consider possible UTI in a woman who is pregnant and has a positive dipstick for protein. However, it should be noted that although protein may occur in the urine of women with a UTI, the presence of protein does not independently predict a UTI [Little et al, 2009]. For detailed information on the diagnosis of UTI, see the CKS topic on Urinary tract infection (lower) - women.

Assessing for chronic kidney disease

National guidelines on early identification and management of chronic kidney disease recommend that all people with an incidental finding of proteinuria or haematuria (not due to UTI) should be tested for possible chronic kidney disease, and underlying medical conditions should be considered [NICE, 2008a]. For further information, see the CKS topic on Chronic kidney disease - not diabetic.

After 20 weeks' gestation

How do I manage women with new proteinuria without hypertension after 20 weeks' gestation?

If the woman is over 20 weeks' gestation and has new proteinuria but no hypertension:

If she has symptoms of pre-eclampsia, arrange same-day hospital assessment.

If there are no symptoms of pre-eclampsia:

Consider possible urinary tract infection (UTI).

If there is 1+ protein: if the woman has symptoms of a UTI, or the dipstick test is positive for nitrite or is positive for both leukocyte esterase and blood, make a working diagnosis of UTI and manage appropriately. Urine should be sent for culture and sensitivity. Ensure follow up within 1 week and reassess. For detailed information on the diagnosis and management of UTI, see the CKS topic on Urinary tract infection (lower) - women.

If there is 2+ protein or more on dipstick testing: even if the woman has symptoms of a UTI or the dipstick test is positive for nitrite, or is positive for both leukocyte esterase and blood, seek same day specialist advice.

If there is no evidence of a UTI:

If there is 1+ protein on dipstick testing of urine, review 1 week later. If proteinuria is persistent, seek specialist advice.

If there is 2+ protein or more on dipstick testing, seek same day specialist advice.

Symptoms of pre-eclampsia

Symptoms of pre-eclampsia

Symptoms of pre-eclampsia

Severe headaches (increasing frequency unrelieved by regular analgesics).

Vision problems, such as blurred vision, flashing lights, double vision, or floating spots.

Persistent new epigastric pain or pain in the right upper quadrant.

Vomiting.

Breathlessness.

Sudden swelling of the face, hands, or feet.

Basis for recommendation

Basis for recommendation

Admitting to hospital if there is proteinuria and symptoms of pre-eclampsia, even if the woman is not hypertensive

The Pre-eclampsia Community Guideline (PRECOG) development group reviewed the available evidence and concluded that proteinuria may be the first clinical indication of pre-eclampsia [PRECOG, 2004b]. Therefore, if the woman has symptoms suggestive of pre-eclampsia and proteinuria, then she should be assumed to have pre-eclampsia until proven otherwise.

Considering possible urinary tract infection (UTI)

It is good clinical practice to consider possible UTI in a woman who is pregnant and has a positive dipstick test for protein. However, although protein may occur in the urine of women with a UTI, the presence of protein does not independently predict a UTI [Little et al, 2009]. For detailed information on the diagnosis of UTI, see the CKS topic on Urinary tract infection (lower) - women.

Reassessment of normotensive women with 1+ protein who are well within 1 week, and seeking specialist advice if there is persistent proteinuria

The recommendation to re-assess in 1 week is based on expert advice from PRECOG [PRECOG, 2004a].

PRECOG does not give specific advice on what action to take if a woman has persistent 1+ protein and is otherwise well [PRECOG, 2004a]. However, there is evidence that significant proteinuria is predictive of developing pre-eclampsia and poor pregnancy outcomes, and national guidelines advise that the presence of proteinuria should alert the healthcare professional to the need for increased surveillance [National Collaborating Centre for Women's and Children's Health, 2008]. In the absence of guidance to inform management, CKS recommends seeking specialist advice if proteinuria persists, as specialist assessment and increased monitoring may be necessary.

Seeking same day specialist advice if there is 2+ proteinuria

PRECOG recommends that all women with 2+ protein or more on dipstick testing who are over 20 weeks' gestation should have early assessment in secondary care, as this may indicate impending pre-eclampsia or an underlying medical problem [PRECOG, 2004a]. Many of the CKS expert reviewers advised that all women with 2+ protein or more on dipstick testing should have hospital assessment within 48 hours regardless of whether or not a urinary tract infection may be the cause. Therefore CKS recommends that same-day specialist advice should be obtained.

Quantification of proteinuria by a 24-hour urine collection or spot albumin:creatinine ratio

CKS has not recommended that GPs initiate a 24-hour collection of urine or spot albumin:creatinine ratio for quantification of protein, as this will usually be initiated in secondary care. GPs should note that:

The National Institute for Health and Care Excellence (NICE) recommends that a 24-hour urine collection or a spot urinary protein:creatinine ratio are the only reliable methods for quantification of proteinuria in women at risk of pre-eclampsia [National Collaborating Centre for Women's and Children's Health, 2010].

Scenario: Pre-existing hypertension, or hypertension before 20 weeks

Scenario: Chronic (pre-existing) hypertension, or new hypertension before 20 weeks' pregnancy

156months3060monthsFemale

Assessment

How do I assess a woman with chronic hypertension?

Take a history.

Length of time that the woman has had known hypertension and her level of control.

Past and current medication.

Problems in previous pregnancies, their management, and the outcome of these pregnancies.

Consider whether investigation is required for possible secondary causes of hypertension. For more information, see the section on Secondary hypertension in the CKS topic on Hypertension - not diabetic.

Perform a dipstick urine for proteinuria at presentation and at each antenatal visit. Use an automated dipstick if available.

Ask about symptoms of pre-eclampsia at each review after 20 weeks' gestation.

Severe headaches (increasing frequency unrelieved by regular analgesics).

Vision problems, such as blurred vision, flashing lights, double vision, or floating spots.

Persistent new epigastric pain or pain in the right upper quadrant.

Vomiting.

Breathlessness.

Sudden swelling of the face, hands, or feet.

Basis for recommendation

Basis for recommendation

Take a history and assess if investigation for secondary causes is required

CKS has based these recommendations on accepted clinical practice.

Dipstick urine for proteinuria

Proteinuria in women with chronic hypertension may be:

Due to underlying renal disease.

Due to the development of pre-eclampsia if it is new and occurs after 20 weeks' gestation.

The National Institute for Health and Care Excellence (NICE) recommends the use of automated dipstick testing in secondary care. Evidence from a meta analysis of six trials and a prospective study showed that visual dipstick analysis of urine with a 1+ threshold is not accurate at detecting clinically significant proteinuria. Its use in clinical decision making is therefore limited. Accuracy is improved by using an automated dipstick device. Primary care clinicians should use automated dipsticks if they have access to them.

Assessing for symptoms of pre-eclampsia

This recommendation is based on expert advice [National Collaborating Centre for Women's and Children's Health, 2010] and three narrative reviews [Sadovsky, 2002; Duley et al, 2006; Young et al, 2010]. Women with chronic hypertension are at increased risk of pre-eclampsia [National Collaborating Centre for Women's and Children's Health, 2010].

Management

How should I manage a woman with chronic hypertension?

Advise the woman that:

She should restrict her dietary intake of salt (sodium). For more information, see the section on Lifestyle advice in the CKS topic on Hypertension - not diabetic.

Bed rest is not recommended.

She will require regular monitoring of her blood pressure throughout her pregnancy, and is likely to require more frequent antenatal checkups than usual.

The aim of treatment is to adequately control her blood pressure throughout her pregnancy.

For uncomplicated hypertension, keep the blood pressure less than 150/100 mmHg (but diastolic pressure no less than 80 mmHg).

If there is evidence of target-organ damage (for example kidney disease), keep the blood pressure less than 140/90 mmHg.

Warn about symptoms of pre-eclampsia and that she should seek immediate advice if she develops any symptoms after 20 weeks' gestation (including during the postpartum period).

Prescribe aspirin 75 mg daily from 12 weeks' gestation. Explain that this is believed to help prevent the development of pre-eclampsia.

Seek specialist advice before prescribing aspirin if blood pressure is uncontrolled.

If she is taking an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-II receptor antagonist (AIIRA), stop this immediately and prescribe an alternative treatment if necessary.

Explain that there is an increased risk of congenital abnormalities if these drugs are taken during pregnancy.

Refer the woman to a specialist in hypertensive disorders if the woman has secondary hypertension, or a renal physician, an endocrinologist, or a specialist in connective tissue disease as appropriate.

Otherwise, refer the woman to an obstetric physician.

While the woman is waiting to see a specialist, continue her usual antihypertensive treatment (unless she is taking an ACE inhibitor or AIIRA).

If the woman is not currently taking antihypertensive treatment:

If her blood pressure is high, discuss management with a specialist.

If her blood pressure is normal (which may be because of the physiological drop in blood pressure that occurs in early pregnancy), monitor her blood pressure regularly.

If the woman develops proteinuria after 20 weeks' gestation then her care becomes that of a woman with pre-eclampsia.

Basis for recommendation

Basis for recommendation

Low salt diet

On the basis of expert opinion, the National Institute for Health and Care Excellence (NICE) recommends that pregnant women with chronic hypertension should follow the same general advice in relation to dietary salt intake as women with hypertension who are not pregnant [National Collaborating Centre for Women's and Children's Health, 2010]. This is because the pathogenesis is the same and reducing the intake of salt can lower blood pressure.

Bed rest

NICE reviewed the literature on the benefits of bed rest during pregnancy in women with chronic hypertension [National Collaborating Centre for Women's and Children's Health, 2010]. NICE reviewed a randomized controlled trial (RCT) done in 218 women in Zimbabwe. This study examined the effectiveness of hospital bed rest compared with normal activities at home on the risk of developing severe hypertension in women with chronic hypertension or gestational hypertension [National Collaborating Centre for Women's and Children's Health, 2010]. Thirty-three women in the chronic hypertension group were randomized to normal activities at home (18 women) or hospital bed rest (15 women). There was no statistically significant difference between the two groups with regard to the development of severe hypertension, proteinuria, or severe proteinuria. NICE concluded that there is no evidence that bed rest is beneficial. There is also concern that prolonged bed rest may increase the risk of venous thromboembolism.

Frequency of monitoring of blood pressure

There is no evidence on which to base recommendations regarding frequency of antenatal contacts for women with chronic hypertension. The view of NICE, however, is that the routine schedule for antenatal care monitoring of blood pressure is inadequate for pregnant women with chronic hypertension [National Collaborating Centre for Women's and Children's Health, 2010].

Target blood pressure

NICE reviewed the literature and found that [National Collaborating Centre for Women's and Children's Health, 2010]:

There is evidence from two good-quality studies that there is less risk of severe hypertension with 'tight' blood pressure control but no other differences in maternal or perinatal outcomes, including fetal growth.

A meta-regression of RCTs found that the more blood pressure is reduced in pregnant women with hypertension, the more the birthweight of their infants is reduced. This meta-regression included women taking methyldopa, acebutolol, atenolol, labetalol, metoprolol, oxprenolol, pindolol, propranolol, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, ketanserin, hydralazine, isradipine, nicardipine, nifedipine, verapamil, and clonidine.

On the basis of these studies, NICE recommends that:

Treatment should aim to lower blood pressure from the moderate or severe range, but excessive reduction of blood pressure should be avoided as this may affect fetal growth.

Women with target-organ damage would need a lower blood pressure target than women without target-organ damage.

Advising about symptoms of pre-eclampsia

This recommendation is based on expert advice from NICE and three narrative reviews [Sadovsky, 2002; Duley et al, 2006; Young et al, 2010]. Women with chronic hypertension are at increased risk of pre-eclampsia [National Collaborating Centre for Women's and Children's Health, 2010].

A key recommendation from the 1998 Confidential Enquiry into Maternal Deaths that is accepted good clinical practice is that all women should receive antenatal education so that they are aware of the symptoms associated with pre-eclampsia (such as headache or epigastric pain), its importance, and the need to obtain medical advice [DH, 1998].

Aspirin to prevent pre-eclampsia

NICE concluded that there is evidence from a meta-analysis that aspirin is effective in reducing the risk of pre-eclampsia, including in women who have chronic hypertension [National Collaborating Centre for Women's and Children's Health, 2010].

Some CKS expert reviewers warned against prescribing aspirin to women with uncontrolled blood pressure. CKS recommends that in such women, it is best to seek specialist advice about whether or not to prescribe aspirin.

Stopping angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists (AIIRA)

There is limited evidence regarding the use of ACE inhibitors or AIIRAs during pregnancy. Studies suggest that ACE inhibitors are associated with congenital malformations, intrauterine growth retardation, and premature delivery, and that AIIRAs are associated with congenital malformations.

NICE states that there is sufficient concern, despite the relatively poor quality of the studies, to recommend avoiding ACE inhibitors and AIIRAs during pregnancy [National Collaborating Centre for Women's and Children's Health, 2010].

Chlorothiazide is also possibly teratogenic but is not prescribable in the UK

NICE noted a possible association with congenital abnormalities, neonatal thrombocytopenia, neonatal hypoglycaemia and hypovolaemia, and possible maternal electrolyte imbalance [National Collaborating Centre for Women's and Children's Health, 2010].

Other antihypertensive drugs during pregnancy

NICE reviewed studies of other antihypertensive drugs and found:

No obvious association with congenital abnormalities for the following drugs: methyldopa, labetalol, atenolol, metoprolol, oxprenolol, pindolol, prazosin, nifedipine, verapamil, bendroflumethiazide, furosemide, and hydralazine. No or very little information about other antihypertensive drugs is available.

Antihypertensives reduce the risk of severe hypertension but not of proteinuria.

From the limited available evidence, it is not possible to determine the best antihypertensive treatment for pregnant women with chronic hypertension.

Referral to a specialist

NICE states that the evidence from trials on the treatment of blood pressure does not make it possible to determine the best antihypertensive treatment for a pregnant woman [National Collaborating Centre for Women's and Children's Health, 2010]. CKS recommends seeking specialist advice before starting treatment. If the woman's blood pressure is normal, then it should be checked regularly.

Scenario: New hypertension after 20 weeks

Scenario: New hypertension after 20 weeks' pregnancy

156months3060monthsFemale

Assessment

How should I assess a woman with new hypertension after 20 weeks' gestation?

Check urine for protein (subsequent frequency of monitoring will be determined by secondary care). If available, use automated dipstick testing.

Ask about symptoms of pre-eclampsia at presentation and each subsequent antenatal check.

Severe headaches (increasing frequency unrelieved by regular analgesics).

Vision problems, such as blurred vision, flashing lights, double vision, or floating spots.

Persistent new epigastric pain or pain in the right upper quadrant.

Vomiting.

Breathlessness.

Sudden swelling of the face, hands, or feet.

Basis for recommendation

Basis for recommendation

Testing for proteinuria by dipstick estimation

This is based on expert advice in the National Institute for Health and Care Excellence (NICE) guideline Antenatal care: routine care for the healthy pregnant woman [NICE, 2008b] which recommends testing for protein at each antenatal visit. This is particularly important in women with new hypertension who are at an increased risk of pre-eclampsia [National Collaborating Centre for Women's and Children's Health, 2010]. Rarely, pre-eclampsia may present atypically without proteinuria [Sibai et al, 1993].

There is good evidence from a systematic review and a subsequent prospective study that automated dipstick testing is more accurate than visually read dipstick testing [National Collaborating Centre for Women's and Children's Health, 2010].

Assessing for symptoms of pre-eclampsia

This recommendation is based on expert advice from NICE [National Collaborating Centre for Women's and Children's Health, 2010] and three narrative reviews [Sadovsky, 2002; Duley et al, 2006; Young et al, 2010]. Women with new hypertension are at increased risk of pre-eclampsia [National Collaborating Centre for Women's and Children's Health, 2010].

Initial primary care management

How should I manage a woman with new hypertension after 20 weeks' gestation?

If urine is negative for protein:

Admit immediately if the woman has severe hypertension (blood pressure 160/110 mmHg or higher) or if she has symptoms of pre-eclampsia.

Otherwise, discuss with the local maternity unit to arrange urgent assessment.

If urine is positive for protein (1+ protein or more on automated dipstick testing, or a trace or more on visual dipstick testing):

Discuss immediately with the local maternity unit, to arrange urgent assessment or admission.

Basis for recommendation

Basis for recommendation

Management of gestational hypertension (new hypertension presenting at 20 weeks' gestation or more without proteinuria)

These recommendations are based on expert opinion from the National Institute for Health and Care Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2010], which recommends:

That all women with gestational hypertension should be offered an integrated package of care that may include hospital admission, regular measurement of blood pressure, testing for proteinuria, and relevant blood tests.

Admission to hospital if blood pressure is 160/110 mmHg or greater.

Expert assessment is also recommended as pre-eclampsia may present atypically; 20% of women with atypical eclampsia have minimal or absent proteinuria [Young et al, 2010].

Management of pre-eclampsia

These recommendations are based on expert opinion from NICE [National Collaborating Centre for Women's and Children's Health, 2010], which recommends:

That all women with pre-eclampsia should be offered immediate admission and an integrated package of care, regular measurements of blood pressure, testing for proteinuria, and relevant blood tests.

Dipstick analysis of proteinuria and decision to refer

NICE reviewed the evidence and recommended that an automated dipstick is used for diagnosing pre-eclampsia in secondary care and that a 1+ protein result or more on an automated dipstick should be quantified by using a 24-hour urine collection or a spot urinary protein:creatinine sample [National Collaborating Centre for Women's and Children's Health, 2010]. There are no recommendations for primary care clinicians who may only have access to visual dipstick testing. NICE based its decision on a review of the available evidence and concluded that:

Visual dipstick testing is a poor test for the diagnosis of pre-eclampsia.

A negative dipstick result does not exclude significant proteinuria.

NICE based its recommendation mainly on evidence from a meta analysis of six trials and a subsequent prospective study that showed visual dipstick analysis of urine with a 1+ threshold is unreliable for detecting clinically significant proteinuria [Waugh et al, 2004]. Its use in clinical decision making is therefore of limited usefulness. Although accuracy may be improved by using a higher cut-off point (such as 2+), there are only limited data of poor methodological quality for this threshold. Accuracy was improved by using an automated dipstick device.

Most primary care physicians will only have access to visual dipstick analysis of urine and will need to make a clinical decision taking into account the result. In addition, accurate quantification of proteinuria by collection of a 24-hour urine sample or by urinary protein:creatinine ratio would take an unacceptable length of time. Therefore, CKS recommends that primary care clinicians seek immediate specialist advice for pregnant women who are more than 20 weeks' gestation who present with new hypertension and a trace or more of protein in their urine on visual dipstick urinalysis. If access to the more accurate automated dipstick testing is available, then a threshold of 1+ protein is recommended, in keeping with NICE guidelines.

Secondary care - gestational hypertension

How will gestational hypertension be managed in secondary care?

The following is a summary of secondary care management recommended by the National Institute for Health and Care Excellence (NICE).

Women with severe hypertension will be admitted.

Blood pressure will be measured four times a day. The woman will be kept in hospital until her blood pressure is 159/109 mmHg or lower.

Blood will be taken to test for kidney function, electrolytes, full blood count, transaminases and bilirubin on presentation.

Urine will be tested for protein using automated dipsticks or urinary protein:creatinine ratio.

Antihypertensive medication will be prescribed:

Labetalol is the first choice.

Methyldopa and nifedipine are alternatives after consideration of the adverse effect profile for the mother and the fetus.

Follow up

Once blood pressure has fallen to 159/109 mmHg or lower, women will be followed up in outpatients/an early pregnancy assessment centre with twice-weekly blood pressure monitoring; twice-weekly automated dipstick testing for protein: and once-weekly blood tests for urea and electrolytes, full blood count, transaminases, and bilirubin.

Birth before 37 weeks will only be offered to women with refractory severe hypertension after a course of antenatal steroids (if required) has been completed.

Women with moderate hypertension will be managed and followed up in an outpatient setting or at a pregnancy assessment centre.

Blood will be taken for urea and electrolytes, full blood count, transaminases, and bilirubin, if not already done by the GP on presentation.

Antihypertensive medication will be prescribed:

Labetalol is the first choice.

Methyldopa and nifedipine are alternatives after consideration of the adverse effect profile for the mother and the fetus.

Follow up

Will be in outpatients/a pregnancy assessment unit with twice-weekly blood pressure monitoring, and twice-weekly testing of urine for protein using automated dipsticks or urinary protein:creatinine ratio.

Further blood tests will not be performed unless the woman develops proteinuria.

Women with mild hypertension will be managed and followed up in an outpatient setting or at a pregnancy assessment centre.

Blood tests other than those done for routine antenatal care will not be needed.

Monitoring will be as follows:

If presenting before 32 weeks, or if at high risk of pre-eclampsia, the woman will have blood pressure monitoring and testing of urine for protein using automated dipsticks or urinary protein:creatinine ratio twice a week.

If presenting after 32 weeks and not at high risk of pre-eclampsia, the woman will have blood pressure and urine checked for protein using automated dipsticks or urinary protein:creatinine ratio not more often than once per week.

Bed rest in hospital is not recommended as a treatment for gestational hypertension.

Aspirin 75 mg daily will be prescribed until the birth of the baby only if the woman has either:

One or more high risk factors for pre-eclampsia.

Two or more for moderate risk factors for pre-eclampsia.

Basis for recommendation

Basis for recommendation

Referral to secondary care

Expert opinion from the National Institute for Health and Care Excellence (NICE) is that all pregnant women with any degree of new-onset hypertension require a full assessment in secondary care by a healthcare professional who is trained in the management of hypertensive disorders [National Collaborating Centre for Women's and Children's Health, 2010].

Monitoring and review

NICE found [National Collaborating Centre for Women's and Children's Health, 2010]:

No studies that provided evidence on the frequency of blood pressure measurements. It recommends that the frequency of monitoring will be determined by the degree of hypertension and may be influenced by medical history and the presence of risk factors.

The evidence regarding the gestational age at diagnosis and the subsequent development of severe pre-eclampsia or fetal growth restriction difficult to interpret. NICE agreed that the development of gestational hypertension before 35 weeks deserves special consideration and monitoring.

Only poor-quality evidence about the role of haematological and biochemical blood tests. NICE suggests the limited use of the recommended blood tests to help to rule out disease progression.

Drug treatment of gestational hypertension

NICE studied the Cochrane systematic review [Abalos et al, 2007] on the use of antihypertensive therapy for mild to moderate hypertension in pregnancy [National Collaborating Centre for Women's and Children's Health, 2010]. Realizing that this review did not specifically address the treatment of women with gestational hypertension, NICE looked at all of the individual studies. In many of the studies either the population investigated was not clearly defined or it included a mixed population. NICE concluded that:

There is limited good-quality evidence about treatment for gestational hypertension. This evidence does not support blood pressure-lowering treatment for mild or moderate gestational hypertension with the aim of improving pregnancy outcomes, but it does support starting treatment once severe hypertension has developed.

There is not enough evidence to know whether antihypertensive treatment prevents rare serious events, such as a stroke or placental abruption.

There is insufficient evidence about the target blood pressure; it must be low enough to prevent secondary damage, such as stroke, without being excessively low and thereby potentially affecting fetal growth.

There is good evidence to show that beta-blockers and labetalol reduce the risk of severe hypertension. One small, poor-quality, quasi-randomized trial found a statistically significant reduction in the risk of pre-eclampsia/proteinuria with labetalol compared with methyldopa. However, proteinuria was not defined.

There was little evidence regarding calcium-channel blockers.

NICE reached a consensus that the association between beta-blockers and reduced fetal growth was likely to be the result of excessive lowering of blood pressure and related to the dose.

Taking the above into account, NICE recommends that:

Labetalol should be used first line as it seems to be as effective and safe as other antihypertensive drugs and it is licensed for use in pregnancy.

Alternative treatment including methyldopa and nifedipine should be offered after considering adverse effect profiles for the woman, fetus, and newborn baby. NICE recommends using these treatments in women of Afro–Caribbean origin as it is not known if this group of women responds well to beta-blockers in pregnancy (a poor response to beta-blockers has been recognized in people of Afro–Caribbean origin who are not pregnant).

Timing of the birth

NICE reviewed the evidence from a large, open-label, randomized controlled trial (RCT) done in the Netherlands [National Collaborating Centre for Women's and Children's Health, 2010]. Although NICE concluded that because of different clinical practice the results are not directly applicable to the UK, their expert view was that if gestational hypertension becomes severe (160/110 mmHg or greater) even though the women is being treated with antihypertensive drugs, then the woman should be offered immediate birth after a course of antenatal steroids.

Bed rest

NICE recommends that bed rest in hospital should not be offered as a treatment for gestational hypertension. NICE reviewed the evidence in relation to bed rest in an RCT carried out on 218 women in Zimbabwe. This study examined the effectiveness of hospital bed rest compared with normal activities at home on the risk of severe hypertension in women with chronic hypertension or gestational hypertension [National Collaborating Centre for Women's and Children's Health, 2010].

There were 185 women in the gestational hypertension group who were randomized to normal activities at home (90 women) or hospital bed rest (95 women).

Although the study found that hospital bed rest was more effective than continuing normal activities at home (OR 0.52, 95% CI 0.27 to 0.99), NICE pointed out that that the study was small and also conducted in a healthcare setting which was not applicable to the UK. NICE were also concerned that prolonged bed rest may increase the risk of venous thromboembolism.

Use of aspirin in women with gestational hypertension

NICE reviewed the evidence from [National Collaborating Centre for Women's and Children's Health, 2010]:

A Cochrane systematic review that reported a 40% reduction in the relative risk of progressing to pre-eclampsia in women with gestational hypertension taking aspirin compared with placebo or no treatment.

A small RCT that found no statistically significant difference for progression to moderate or severe pre-eclampsia between 23 women who were randomized to take 100 mg of aspirin a day and 24 women who received a placebo.

Considering the above, NICE did not consider the evidence sufficient to support the use of aspirin in women with gestational hypertension unless they have additional risk factors for pre-eclampsia.

Secondary care - pre-eclampsia

How will pre-eclampsia be managed in secondary care?

The following is a summary of secondary care management recommended by the National Institute for Health and Care Excellence (NICE).

Women with pre-eclampsia will be admitted.

Blood pressure will be measured at least four times a day.

The amount of protein in the urine will be quantified but once a diagnosis of significant proteinuria has been made the quantification will not be repeated.

Women with severe or moderate pre-eclampsia will be prescribed labetalol as first-choice treatment to keep diastolic blood pressure less than 80–100 mmHg and systolic blood pressure less than 150 mmHg. Methyldopa and nifedipine are alternatives after consideration of the adverse effect profile for the mother and the fetus.

Blood tests

Blood tests for urea and electrolytes, full blood count, transaminases, and bilirubin will be done three times a week for women with moderate or severe pre-eclampsia, and twice a week for women with mild pre-eclampsia.

Timing of birth

Birth will be offered to women presenting with pre-eclampsia before 34 weeks, after discussion with neonatal and anaesthetic teams and a course of antenatal steroids has been given, if severe hypertension develops which is refractory to treatment, or if maternal or fetal indications for urgent intervention develop.

Birth will be offered to women who develop severe pre-eclampsia after 34 weeks when their blood pressure has been controlled and a course of antenatal steroids has been completed (if appropriate).

Birth will be offered to women with mild or moderate pre-eclampsia at 34+0 to 36+6 weeks depending on their maternal and fetal condition, risk factors, and availability of neonatal intensive care.

Birth within 24–48 hours will be offered to women with mild or moderate pre-eclampsia after 37+0 weeks.

Basis for recommendation

Basis for recommendation

Management in secondary care

The expert opinion of the National Institute for Health and Care Excellence (NICE) is that assessment of women with pre-eclampsia should always be done by a healthcare professional trained in the management of hypertensive disorders of pregnancy [National Collaborating Centre for Women's and Children's Health, 2010].

NICE recommends that all women with pre-eclampsia with a blood pressure of 140/90 mmHg or greater be admitted.

Monitoring and review

NICE reviewed the available evidence and concluded that [National Collaborating Centre for Women's and Children's Health, 2010]:

There are no data to inform the frequency of blood pressure monitoring, and this should depend on the severity of hypertension and the presence of risk factors. There is no evidence to support a change from the routine practice of measuring blood pressure at least four times a day in women with mild or moderate new hypertension and proteinuria while an inpatient. Blood pressure should be recorded more frequently in women with severe pre-eclampsia to detect rises in blood pressure and to monitor response to therapy. The risk of stroke is increased if hypertension is severe.

Once the diagnosis of significant proteinuria has been made, there is little benefit from repeating the analysis. There is only a weak association between more than 5 g of protein in the urine per 24 hours and stillbirth, admission to neonatal intensive care unit, and small-for-gestational-age infants. The degree of protein in the urine does not seem to be related to outcome for the mother. Therefore, NICE considers that the evidence does not support repeated measurement of urinary protein once significant proteinuria is established.

There is sufficient evidence that in women with pre-eclampsia, measuring platelet count, serum creatinine, and transaminases is useful in monitoring progression to more severe disease. Although rising serum uric acid is associated with severe pre-eclampsia this test has not been shown to be of additional value. Available evidence shows that a coagulation screen is not helpful if the platelet count is above 100 x 109/L.

Drug treatment of pre-eclampsia

NICE reviewed the available evidence and concluded that [National Collaborating Centre for Women's and Children's Health, 2010]:

There is limited good-quality evidence about treatment of pre-eclampsia. There is no evidence that lowering blood pressure in women with mild or moderate pre-eclampsia improves pregnancy outcomes compared with starting treatment once the woman has developed severe hypertension. However, there is insufficient evidence to know whether antihypertensive treatment prevents rarer outcomes such as a stroke or placental abruption.

There is some evidence about appropriate target blood pressure. There seems to be an increased risk of severe hypertension with less tight control (diastolic values above 90 mmHg or 100 mmHg).

There is some evidence from a randomized controlled trial that labetalol reduces the risk of progression to severe hypertension.

There is little evidence on the use of calcium-channel blockers.

NICE considered that the association of beta-blockers with reduced fetal growth was a result of excessive lowering of blood pressure.

Expert opinion from NICE is that:

Labetalol seems to be as effective and safe as other drugs used for hypertension for managing pre-eclampsia and it is licensed for use in pregnancy.

Labetalol should be used as first-line treatment.

Alternative treatment includes methyldopa and nifedipine, and these should be offered after considering adverse effect profiles for the woman, fetus, and newborn baby. NICE recommends using these treatments in women of Afro–Caribbean origin, as it is not known whether they respond well to beta-blockers in pregnancy (a poor response to beta-blockers has been recognized in people of Afro–Caribbean origin who are not pregnant).

Timing of the birth

These recommendations are based on expert advice from NICE after their review of the available evidence [National Collaborating Centre for Women's and Children's Health, 2010].

Scenario: Postpartum follow-up

Scenario: Postpartum follow-up for hypertensive disorders in pregnancy

156months3060monthsFemale

Follow-up for chronic hypertension

How should I follow up a woman with chronic hypertension postpartum?

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 the woman's antihypertensive treatment is changed after birth.

Aim to keep blood pressure lower than 140/90 mmHg.

For the first 2 weeks after the birth:

Continue the antihypertensive treatment used during pregnancy, unless the woman is taking methyldopa.

If she is taking methyldopa, this should be stopped 2 days after the birth, as it may increase the risk of depression. Antihypertensive treatment that the woman took before planning a pregnancy should be restarted unless there are contraindications to a particular drug because the woman is breastfeeding or is planning further pregnancies.

Review antihypertensive treatment.

Review long-term antihypertensive treatment 2 weeks after the birth.

Consider restarting the woman's pre-pregnancy hypertensive treatment unless there are contraindications to a particular drug because she is breastfeeding or planning further pregnancies.

Target blood pressures will be those used in the long-term treatment of hypertension. For more information, see the CKS topic on Hypertension - not diabetic, or for women with diabetes, see the CKS topic on Diabetes - type 2.

Ensure that future antihypertensive treatment and monitoring is discussed in primary care 6–8 weeks after the birth at her postnatal review.

Basis for recommendation

Basis for recommendation

Monitoring and control of blood pressure after the birth

These recommendations are based on the expert opinion of the National Institute for Health and Care Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2010].

NICE identified no evidence about the frequency of postnatal observations or investigations.

Its recommendations are, therefore, based on the knowledge that blood pressure peaks between 3–5 days after birth, and that it is sensible to monitor blood pressure if changes are made to treatment.

Choice of antihypertensive drug

NICE identified no evidence about the choice of antihypertensive treatment postpartum. As there is no evidence for any particular antihypertensive, NICE considered that antenatal antihypertensive treatment should continue in the post-natal period unless methyldopa has been used (because of the risk of depression with methyldopa) [National Collaborating Centre for Women's and Children's Health, 2010].

Stopping methyldopa

NICE is aware of a Medicines and Healthcare products Regulatory Agency (MHRA) report that considers methyldopa to be the drug of choice during pregnancy and breastfeeding [MHRA, 2009]. The MHRA states that methyldopa may not be suitable for some women. However, NICE considers that this drug should not be used during the post-natal period, as women are already at risk of depression, and if possible, it should be stopped and the antihypertensive treatment that the woman was taking before her pregnancy be restarted.

Review of antihypertensive treatment

NICE recommends that long-term antihypertensive treatment is reviewed 2 weeks after the birth [National Collaborating Centre for Women's and Children's Health, 2010]. CKS recommends that former antihypertensive treatment be restarted, unless there are contraindications such as the woman is breastfeeding or planning another pregnancy.

It is the opinion of NICE that women with chronic hypertension should be offered a formal medical review of their hypertension at their routine post-natal review [National Collaborating Centre for Women's and Children's Health, 2010].

Follow-up for gestational hypertension

How should I follow up a woman with gestational hypertension postpartum?

The following is a summary of secondary care management recommended by the National Institute for Health and Care Excellence (NICE).

Most women will be followed up by the maternity unit until their blood pressure has returned to normal or until the woman has been referred to a specialist for a medical review should her blood pressure remain elevated. The woman should be given a care plan by the hospital detailing:

Who will provide follow-up care, including medical review if needed.

Frequency of blood pressure monitoring.

Thresholds for reducing or stopping treatment.

Indications for referral to primary care for blood pressure review.

Self-monitoring for symptoms of pre-eclampsia.

The woman should have her blood pressure measured:

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.

If the woman has not taken any antihypertensive treatment during pregnancy:

Aim to keep her blood pressure lower than 140/90 mmHg.

Antihypertensive treatment will be started if blood pressure rises above 149/99 mmHg.

If antihypertensive treatment has been used during the antenatal period:

The same treatment will be continued, unless the woman has been taking methyldopa which should be stopped 2 days postpartum because of the risk of depression.

If blood pressure falls below 140/90 mmHg, reducing antihypertensive treatment will be considered.

Antihypertensive treatment will be reduced or stopped if the woman's blood pressure falls below 130/80 mmHg.

If the woman has gestational hypertension she should be offered a medical review either in the community or at the hospital:

If she remains on antihypertensive treatment 2 weeks after transfer to community care.

At her post-natal review 6–8 weeks after the birth.

Women who still need antihypertensive medication at the time of this review should be offered a specialist assessment of their hypertension.

Basis for recommendation

Basis for recommendation

Monitoring and review by a specialist

The National Institute for Health and Care Excellence (NICE) is aware that a few women with presumed gestational hypertension will have undiagnosed chronic hypertension [National Collaborating Centre for Women's and Children's Health, 2010]. NICE has therefore recommended an individualized care plan before transfer to community care.

Monitoring and control of blood pressure postpartum

These recommendations are expert opinion from NICE [National Collaborating Centre for Women's and Children's Health, 2010].

NICE identified no evidence about the frequency of postnatal observations or investigations.

Its recommendations are therefore based on the knowledge that blood pressure peaks between 3–5 days after birth and that it is sensible to monitor blood pressure if changes are made to treatment.

Choice of antihypertensive drug

NICE identified only one small randomized controlled trial that compared timolol with methyldopa, and therefore concluded that there is no evidence for any particular antihypertensive. NICE recommends that antenatal antihypertensive treatment should continue in the postnatal period unless methyldopa has been used.

Stopping methyldopa

NICE is aware of a Medicines and Healthcare products Regulatory Agency (MHRA) report that considers methyldopa to be the drug of choice during pregnancy and breastfeeding [MHRA, 2009]. The MHRA states that methyldopa may not be suitable for some women. However NICE considers that this drug should not be used during the post-natal period, as women are already at risk of depression, and if possible, it should be stopped.

Advice on review and referral

These recommendations are expert opinion from NICE [National Collaborating Centre for Women's and Children's Health, 2010]. NICE also considers that all women with gestational hypertension should have a review of their blood pressure at the post-natal review 6–8 weeks after the birth. Who carries out this review will depend on local circumstances and expertise, and NICE were not prescriptive about this. However NICE recommend that if the woman still requires antihypertensive treatment 6–8 weeks after the birth, then she should be offered a specialist assessment.

Follow-up for pre-eclampsia

How should I follow up a woman with pre-eclampsia postpartum?

The following is a summary of secondary care management recommended by the National Institute for Health and Care Excellence (NICE).

The woman should not be discharged home until she has no symptoms of pre-eclampsia, her blood pressure is 149/99 mmHg or lower, and her blood tests are improving.

All women should be given a care plan that includes information about:

Who will provide follow-up care, including medical review if needed.

Frequency of blood pressure monitoring.

Thresholds for reducing or stopping treatment.

Indications for referral to primary care for blood pressure review.

Self-monitoring for symptoms of pre-eclampsia.

Women with pre-eclampsia who did not take antihypertensive treatment and have given birth and who have been discharged home will have:

Their blood pressure measured:

At least once between day 3 and day 5 after birth.

On alternate days until their blood pressure normalizes, if their blood pressure was abnormal between day 3 and day 5.

If blood tests are stable or improving but not in the normal range they will be repeated as clinically indicated.

The aim is to keep blood pressure lower than 140/90 mmHg.

Antihypertensive treatment will be started if blood pressure is 150/100 mmHg or higher.

Symptoms of pre-eclampsia, such as severe headache and epigastric pain, will be asked about each time blood pressure is measured.

Women with pre-eclampsia who took antihypertensive treatment and have given birth will have:

Their blood pressure measured every 1–2 days for up to 2 weeks after transfer to primary care until the woman is off treatment and has no hypertension.

If blood tests are stable or improving but not in the normal range, they will be repeated as clinically indicated.

The antihypertensive treatment used during the pregnancy will be continued, unless the woman has been taking methyldopa, which should be stopped 2 days postpartum because of the risk of depression. Antihypertensive treatment that the woman took before planning a pregnancy will be restarted unless there are contraindications to a particular drug because the woman is breastfeeding or is planning further pregnancies.

A reduction in antihypertensive treatment will be considered if their blood pressure falls below 140/90 mmHg.

Antihypertensive treatment will be reduced if their blood pressure falls below 130/80 mmHg.

Symptoms of pre-eclampsia, such as severe headache and epigastric pain, will be asked about each time blood pressure is measured.

Women with pre-eclampsia will be offered a medical review either in the community or at the hospital:

If they remain on antihypertensive treatment 2 weeks after transfer to community care.

At their post-natal review 6–8 weeks after the birth.

Women who still need antihypertensive medication at the time of this review should be offered a specialist assessment of their hypertension.

Perform dipstick testing of the urine. Women with 1+ proteinuria or more but normal blood pressure should be reviewed 3 months postpartum to assess kidney function and to consider referral to a renal specialist.

Basis for recommendation

Basis for recommendation

Monitoring and review by a specialist

The National Institute for Health and Care Excellence (NICE) recommends that an individualized care plan should be established before transfer to community care [National Collaborating Centre for Women's and Children's Health, 2010].

Monitoring and investigations postpartum

These recommendations are expert opinion from NICE [National Collaborating Centre for Women's and Children's Health, 2010].

NICE identified no evidence about investigations and treatment and, therefore, recommends that the investigations and observations relevant to the antenatal period also applied to the post-natal period, taking into account that blood pressure peaks between 3–5 days after birth.

Women may develop pre-eclampsia after birth and NICE recommends that symptoms of pre-eclampsia be enquired about at each assessment.

Choice of antihypertensive drug

NICE found a lack of good-quality evidence about choice of drug and whether antihypertensive treatment should be given routinely to women with pre-eclampsia. It therefore recommends that antihypertensive treatment used during the pregnancy should be continued, unless this was methyldopa.

Stopping methyldopa

NICE is aware of a Medicines and Healthcare products Regulatory Agency (MHRA) report that considers methyldopa to be the drug of choice during pregnancy and breastfeeding [MHRA, 2009]. The MHRA states that methyldopa may not be suitable for some women. However NICE considers that this drug should not be used during the postnatal period, as women are already at risk of depression, and if possible, it should be stopped.

Advice on review and referral

These recommendations are based on expert opinion from NICE [National Collaborating Centre for Women's and Children's Health, 2010]. NICE also considers that all women with pre-eclampsia should have a review of their blood pressure at the postnatal review 6–8 weeks after the birth. Who carries out this review will depend on local circumstances and expertise, and NICE were not prescriptive about this. However, NICE recommends specialist referral for women with persistent hypertension or proteinuria or both.

Postpartum (pre)eclampsia

How do I manage a woman with postpartum pre-eclampsia or eclampsia?

Consider the possibility of imminent pre-eclampsia/eclampsia in a woman up to 4 weeks postpartum (even if she has not had previous hypertension or pre-eclampsia) if she develops any of the following:

Severe headaches (increasing frequency unrelieved by regular analgesics).

Vision problems, such as blurred vision, flashing lights, double vision, or floating spots.

Persistent new epigastric pain or pain in the right upper quadrant.

Vomiting.

Hypertension.

Proteinuria.

Breathlessness due to pulmonary oedema.

Sudden swelling of the face, hands, or feet.

Consider the possibility of eclampsia in any woman who has a seizure within 4 weeks of delivery.

All women with suspected postpartum pre-eclampsia or eclampsia should be admitted to hospital for immediate assessment.

Basis for recommendation

Basis for recommendation

Importance of considering the possibility of pre-eclampsia/eclampsia even if the woman has not had antepartum or intrapartum pre-eclampsia

Pre-eclampsia and eclampsia may both present for the first time after delivery [Mathew et al, 2003; Duley et al, 2006].

In a study of 23 women with late postpartum eclampsia, only five had been previously diagnosed with pre-eclampsia [Chames et al, 2002].

A prospective descriptive study of every case of eclampsia in the UK in 1992 found that 44% of cases occurred postpartum [Douglas and Redman, 1994].

Possibility of presenting up to 4 weeks after delivery

A multicentre, retrospective analysis of data involving 89 women with eclampsia found that 29 women had postpartum eclampsia and 23 (79%) of these women had late-onset eclampsia (developing more than 48 hours after delivery) [Chames et al, 2002].

In a multicentre, retrospective analysis of 3988 women diagnosed with pre-eclampsia, 229 (5.7%) were diagnosed during the postpartum period [Matthys et al, 2004]. Of these, 151 women were studied and 29 (16%) developed eclampsia. The average time from delivery to readmission was 7 days and ranged from 1 day to 24 days.

Importance of considering the possibility of eclampsia in any woman who has a seizure within 4 weeks of delivery

Symptoms and signs of pre-eclampsia usually precede eclampsia, but not always, which can make diagnosis difficult.

Case studies of three women report eclampsia developing without preceding hypertension or proteinuria [Dziewas et al, 2002].

Importance of considering pre-eclampsia if the woman develops a headache, vision symptoms, abdominal pain, or typical symptoms

In a multicentre, retrospective analysis of data involving 89 women with eclampsia, 29 women had postpartum eclampsia, and 21 of these had at least one prodromal symptom that heralded the onset of eclampsia: 20 women had headache, 10 women had vision changes, 5 women had nausea or vomiting, and 2 women had epigastric pain [Chames et al, 2002].

Case studies have shown that acute severe headache, vision disturbances, and gastrointestinal symptoms may herald impending eclampsia [Veltkamp et al, 2000; Dziewas et al, 2002; Mathew et al, 2003; Graeber et al, 2005; Munjuluri et al, 2005].

A case-control study of 53 women admitted in the postpartum period found that headache, a blind spot, cortical blindness, malaise, nausea, and vomiting were more likely to occur in women with postpartum severe pre-eclampsia or eclampsia than in women with intrapartum pre-eclampsia [Atterbury et al, 1998].

Immediate referral to hospital

This is accepted good clinical practice.

Antihypertensive drugs in breastfeeding

Which antihypertensive drugs can be used during breastfeeding?

The following are considered to be safe during breastfeeding:

Labetalol

Nifedipine

Enalapril

Captopril

Atenolol

Metoprolol

Methyldopa

Do not prescribe the following:

Angiotensin-converting enzyme inhibitors, other than captopril and enalapril.

Angiotensin-II receptor antagonists.

Amlodipine.

Basis for recommendation

Basis for recommendation

The National Institute for Health and Care Excellence (NICE) reviewed the available evidence on use of antihypertensive drugs in breastfeeding women [National Collaborating Centre for Women's and Children's Health, 2010]. The studies identified measured non-clinical endpoints, such as secretion of the drug in the mother's milk or detection of the drug in the infant's plasma. No studies were found on whether antihypertensive drugs taken while breastfeeding had adverse effects on the infants.

Use of labetalol, nifedipine, and methyldopa

NICE concluded that:

The drugs mostly likely to be used by breastfeeding women seem to be suitable: labetalol, nifedipine, and methyldopa.

However, NICE does not recommend the use of methyldopa in the postnatal period due to the risk of depression. This view conflicts with advice from the Medicines and Healthcare products Regulatory Agency (MHRA), which recommends methyldopa as the drug of choice during breastfeeding [MHRA, 2009].

Use of atenolol and metoprolol

NICE commented that there are no known adverse effects.

Use of angiotensin-converting enzyme (ACE) inhibitors

There is conflicting advice about the use of ACE inhibitors:

NICE recommends that if ACE inhibitors are needed, then captopril or enalapril should be used because of the quality and quantity of associated safety data.

However, the MHRA recommends that ACE inhibitors should not be used by breastfeeding mothers in the first few weeks after delivery. This is because, although amounts of the drug transferred to the infant by breastfeeding are unlikely to be clinically relevant, data are insufficient to exclude the possibility of profound hypotension in the infant. The MHRA considers that pre-term infants may be at particular risk. The MHRA suggests that the use of captopril, enalapril, or quinapril may be considered in older infants who are being breastfed.

Use of angiotensin-II receptor antagonists (AIIRAs)

Both NICE and the MHRA agree that AIIRAs should not be used as there are no data on their use and their effects on breastfeeding infants.

Use of amlodipine

NICE found insufficient evidence of safety and, therefore, does not recommend the use of amlodipine.

Use of diuretics

NICE make no statement regarding the use of diuretics for treating hypertension in a woman who is breastfeeding.

Although the amount of bendroflumethiazide excreted in breast milk is too small to be harmful, care is needed that the diuresis does not cause dehydration, leading to inhibition of breastfeeding. However, this is less likely if a low dose of 2.5 mg daily is used [LactMed, 2007].

Important aspects of prescribing information relevant to primary healthcare are covered in this section specifically for the drugs recommended in this CKS topic. For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (eMC) (http://medicines.org.uk/emc), or the British National Formulary (BNF) (www.bnf.org).

Aspirin

Aspirin

The use of aspirin for pre-eclampsia is an unlicensed indication.

The effects of low-dose aspirin during pregnancy have been studied extensively.

There is no good evidence to suggest that low-dose aspirin is associated with an increased risk of fetal toxicity or congenital abnormalities.

No increase in bleeding complications, decrease in fetal urine excretion, or significant effects on the ductus arteriosus have been associated with low-dose aspirin.

Dyspepsia is a common adverse effect, and gastroprotection with omeprazole may be needed for women who are at high risk of gastrointestinal ulceration or bleeding.

Basis for recommendation

The information on the safety of low-dose aspirin in pregnancy is based on advice from NICE [National Collaborating Centre for Women's and Children's Health, 2010], and from the UK Teratology Information Service, formerly the National Teratology Information Service (NTIS) [NTIS, 2008a].

CKS recommends the use of omeprazole if gastroprotection is needed in a pregnant woman taking aspirin because:

Omeprazole is licensed for use in pregnancy [ABPI Medicines Compendium, 2008].

Proton-pump inhibitors (such as omeprazole) are known to be more effective than H2-receptor antagonists (such as ranitidine) in preventing and treating gastrointestinal adverse effects associated with nonsteroidal anti-inflammatory drugs. For further information, see the CKS topic on Dyspepsia - proven peptic ulcer.

Although there are no controlled trials addressing the safety of omeprazole in pregnancy, the available data from observational studies do not suggest an increased risk of adverse fetal effects with in utero exposure to omeprazole [UKMi, 2007; NTIS, 2008b]. For further information, see the section on Supporting evidence in the CKS topic on Dyspepsia - pregnancy-associated.

Labetalol

Labetalol

Labetalol is licensed for the treatment of hypertension in pregnancy.

Start with a dose of labetalol 100 mg twice a day.

Increase the dose at weekly intervals if needed by 100–200 mg per day until an adequate reduction in blood pressure is achieved, or adverse effects prevent further dose increases.

A dose of 100–400 mg twice a day is usually effective. The maximum recommended dose is 2400 mg daily.

Tiredness and headache are the most commonly reported adverse effects.

Postural hypotension and dizziness can also occur, most commonly at high doses.

Rarely, liver damage has occurred after treatment with labetalol. Stop treatment and check liver function test if liver damage is suspected.

Basis for recommendation

This information is based on the manufacturer's Summary of Product Characteristics [UCB Pharma Ltd, 2010].

Methyldopa

Methyldopa

Methyldopa is not specifically licensed for the treatment of hypertension in pregnancy. However, the manufacturer states that methyldopa can be used during pregnancy if there is no safer alternative available.

It should be avoided in women with a history of depression or with active liver disease.

Check full blood count and liver function tests before treatment and every few weeks during the first 6–12 weeks of treatment, or if unexplained fever occurs.

Methyldopa has been reported to very rarely cause hepatitis, jaundice, and bone-marrow depression.

Start with methyldopa 250 mg twice a day. Increase the dose every few days as needed until an adequate reduction in blood pressure is achieved, or adverse effects prevent further dose increases. The maximum recommended dose is 3 g daily.

Gastrointestinal disturbances (such as nausea, vomiting, constipation, or diarrhoea), dry mouth, or a sore tongue may occur. These usually resolve with continued treatment.

Postural hypotension, dizziness, and bradycardia may also occur. Consider dose reduction if they are troublesome.

Drowsiness is common at the start of treatment or after a dose increase, but usually resolves after a few days. Advise the woman not to drive or operate machinery if affected.

If depression occurs, stop methyldopa and seek specialist advice regarding alternative antihypertensive treatment. If an antidepressant is indicated, see the CKS topic on Depression - antenatal and postnatal.

Basis for recommendation

This information is based on the manufacturer's Summary of Product Characteristics [Activas, 2007].

Nifedipine

Nifedipine

Modified-release nifedipine should be used. The manufacturer states that:

Nifedipine is contraindicated in pregnancy before 20 weeks' gestation.

Nifedipine should only be used after 20 weeks' gestation if other treatment options are not indicated or have failed.

A dose of 20–30 mg once a day is usually sufficient. Increase the dose at weekly intervals if needed by 30 mg per day until an adequate reduction in blood pressure is achieved, or adverse effects prevent further dose increases. The maximum recommended dose is 90 mg once a day.

Vasodilatory adverse effects (flushing, headaches, ankle swelling) are common but often improve with continued use. Diuretics should not be prescribed to relieve ankle swelling.

Gingival hyperplasia sometimes occurs. Drug withdrawal usually results in disappearance of the symptoms.

Advise women to avoid drinking grapefruit juice whilst taking nifedipine.

Basis for recommendation

This information is based on the manufacturer's Summary of Product Characteristics [ABPI Medicines Compendium, 2010].

There are only limited data on the safety of nifedipine in the first trimester of pregnancy, and animal studies suggest possible fetal toxicity.

Immediate-release nifedipine preparations are not recommended because their use may be associated with large variations in blood pressure and reflex tachycardia [BNF 59, 2010].

Safety of antihypertensives

Can a woman with pre-existing hypertension who is pregnant continue her current antihypertensive?

Table 1 . Antihypertensives and possible risks to the fetus.
Antihypertensive Risk to the fetus Comments
Methyldopa Low No obvious association with congenital abnormalities. Possible reduced systolic blood pressure of 4-5 mmHg in the neonate for the first 2 days after delivery.
Labetalol Low No obvious association with congenital abnormalities, but limited data in the first trimester. Possible mild hypotension in the neonate within the first 24 hours after delivery.
Atenolol Risk in the second and third trimesters No obvious association with congenital abnormalities, but limited data in the first trimester. Decreased fetal heart rate described. Low birthweight/placental weight reported.
Metoprolol Risk in the second and third trimesters No obvious association with congenital abnormalities, but limited data in the first trimester. Conflicting studies regarding effect on birthweight.
Nifedipine Low No obvious association with congenital abnormalities, but limited data in the first trimester. Use in the second and third trimesters has shown no effect on fetal or neonatal heart rates.
Amlodipine Unknown No data on use of amlodipine during pregnancy. Amlodipine is likely to cross the placenta.
Felodipine Limited data suggest possible risk Only four cases of felodipine exposure during pregnancy have been reported, with no adverse outcomes. Felodipine is likely to cross the placenta. Felodipine produced limb defects in animal studies.
Diltiazem Limited data suggest possible risk There are only limited data on the use of diltiazem during pregnacy. One very small study (27 infants) found an increased risk of cardiovascular malformations, but causality has not been established.
Verapamil Low No obvious association with congenital abnormalities, but limited data in the first trimester. The manufacturer also reports use in the first trimester without adverse effects to the fetus.
Bendroflumethiazide Unknown risk in first trimester Low risk after 30 weeks Monitor maternal hypovolaemia There are only limited data on the use of bendroflumethiazide during the first trimester of pregnancy. Chlorothiazide, a closely related thiazide diuretic, has no obvious association with congenital abnormalities. No adverse effects to the fetus reported in a large study of use after 30 weeks of pregnancy (1011 women).
Prazosin Limited data suggest low risk Only 18 cases of prazosin exposure have been reported, with no adverse outcomes. Prazosin is likely to cross the placenta. Animal studies do not suggest an increased risk of congenital malformations.
Other alpha-blockers Unknown No data on use of doxazosin, indoramin, or terazosin during pregnancy.
Data from: [Micromedex, 2010; National Collaborating Centre for Women's and Children's Health, 2010]

Evidence

Evidence

Supporting evidence

Aspirin for prevention

Evidence on the use of aspirin to prevent pre-eclampsia

There is good evidence from a Cochrane systematic review and a large meta-analysis that the use of low-dose aspirin results in a small reduction in the risk of developing pre-eclampsia in high risk women.

A Cochrane systematic review (search date: July 2006) assessed the effectiveness and safety of antiplatelet drugs in women at risk of pre-eclampsia [Duley et al, 2007]. Pre-eclampsia is associated with a reduction in the production of prostacyclin, which is a vasodilator, and excessive production of thromboxane, which is a vasoconstrictor and stimulant of platelet aggregation. It is hypothesised that low-dose aspirin in particular, might prevent or delay development of pre-eclampsia. Fifty-nine trials were included in the review (37,560 women).

Antiplatelet use was associated with:

A 17% reduction in the risk of pre-eclampsia (46 trials; 32,891 women; relative risk [RR] 0.83, 95% CI 0.77 to 0.89; NNT = 72).

A significantly better absolute risk reduction in women at high risk of pre-eclampsia (risk difference [RD] –5.2%, 95% CI –7.5 to –2.9; NNT = 19) compared with women at moderate risk (RD –0.84, 95% CI –1.37 to –0.3; NNT = 119).

An 8% reduction in the relative risk of pre-term birth (29 trials, 31,151 women; RR 0.92, 95% CI 0.88 to 0.97; NNT = 72).

A 14% reduction in fetal or neonatal deaths (40 trials, 33,098 women; RR 0.86, 95% CI 0.76 to 0.98; NNT = 243).

A 10% reduction in small-for-gestational-age babies (36 trials, 23,638 women; RR 0.90, 95% CI 0.83 to 0.98; NNT = 114).

A 40% reduction in the relative risk of pre-eclampsia in women with gestational hypertension (five trials, 1643 women; RR 0.60, 95% CI 0.45 to 0.78).

The authors concluded that antiplatelet drugs (low-dose aspirin in particular) have moderate benefits when used for prevention of pre-eclampsia and its consequences.

A meta-analysis of individual patient data from 31 randomized controlled trials, involving 32,217 women and their 32,819 infants, studied the primary prevention of pre-eclampsia using antiplatelet drugs [Askie et al, 2007]:

Women receiving antiplatelet drugs had a reduced risk of pre-eclampsia (RR 0.90, 95% CI 0.84 to 0.97).

There was no evidence that the effect of antiplatelet drugs was any different in a subgroup of women with chronic hypertension compared with women with other risk factors but no chronic hypertension.

The authors concluded that the use of antiplatelet agents during pregnancy results in moderate but consistent reductions in the relative risk of pre-eclampsia.

Drug treatments for prevention

Evidence on drug treatments (other than aspirin) to prevent hypertensive disorders of pregnancy

Nitric oxide

Evidence on nitric oxide for the prevention of hypertensive disorders of pregnancy

There is limited high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders following the use of nitric oxide donors.

A Cochrane systematic review (search date: November 2006) assessed the effectiveness and safety of nitric oxide donors and precursors for preventing pre-eclampsia and its complications [Meher and Duley, 2007]. Pre-eclampsia is associated with endothelial dysfunction, and nitric oxide is involved in many functions of the endothelium, including vasodilatation and inhibition of platelet aggregation. It has been hypothesized that pre-eclampsia may be associated with nitric oxide deficiency and that treatments which increase nitric oxide may prevent pre-eclampsia.

Six randomized trials involving 310 women were included. Four trials were assessed as being of good quality. The other two trials were of uncertain quality.

The four trials of good quality (170 women) compared nitric oxide donors (glyceryl trinitrate) or precursors (L-arginine) with either placebo or no intervention. It was not possible to draw reliable conclusions about whether pre-eclampsia and its complications are prevented by nitric oxide donors or its precursors (RR 0.83, 95% CI 0.49 to 1.41) because data were insufficient.

The authors concluded that there is insufficient evidence to draw reliable conclusions about whether nitric oxide donors and precursors prevent pre-eclampsia or its complications.

Progesterone

Evidence on progesterone for the prevention of hypertensive disorders of pregnancy

There is limited high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of progesterone.

A Cochrane systematic review (search date: April 2006) assessed the effects of progesterone during pregnancy on the risk of pre-eclampsia and its complications [Meher and Duley, 2006a]. Progesterone has been advocated for prevention of pre-eclampsia and its complications, but is no longer used. Two trials of uncertain quality were included in the reviews and involved 296 women. Both trials compared progesterone injections with no progesterone.

One trial that included 168 women found no statistically significant difference in the incidence of pregnancy induced hypertension (RR 1.10, 95% CI 0.33 to 3.66).

One trial that included 128 women found no statistically significant difference in the incidence of pre-eclampsia (RR 0.21, 95% CI 0.03 to 1.77).

The authors concluded that there was insufficient evidence to reach reliable conclusions about the effect of progesterone in preventing pre-eclampsia and its complications. Therefore, progesterone is not recommended for this use in clinical practice.

Diuretics

Evidence on diuretics for the prevention of hypertensive disorders of pregnancy

There is limited high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of diuretics.

A Cochrane systematic review (search date: April 2005) assessed the effects of diuretics on prevention of pre-eclampsia and its complications [Churchill et al, 2007]. Diuretics were formerly used in pregnancy to prevent or delay the development of pre-eclampsia. However, there are concerns that diuretics may further reduce plasma volume in women with pre-eclampsia, thereby increasing the risk of adverse effects to the mother and baby, particularly fetal growth.

Five studies involving 1836 women were included, all of uncertain quality.

Four studies involving 1391 women compared a diuretic with placebo or no treatment. The incidence of pre-eclampsia was lower in the women on placebo or no treatment, but the result was not statistically significant (RR 0.68, 95% CI 0.45 to 1.03).

There was an increased risk of nausea and vomiting with thiazide diuretics (two trials, 1217 women; RR 5.81, 95% CI 1.04 to 32.46).

The authors concluded that it was not possible to draw reliable conclusions about the effects of diuretics on the prevention of pre-eclampsia and its complications because data were insufficient. However, no clear benefits were found and there was an increased risk of adverse effects. Therefore, the use of diuretics for the prevention of pre-eclampsia and its complications is not recommended.

Dietary supplements for prevention

Evidence on dietary supplements to prevent hypertensive disorders of pregnancy

Calcium

Evidence on calcium to prevent hypertensive disorders of pregnancy

There is high-quality evidence from a Cochrane systematic review that calcium supplementation reduces the risk of pre-eclampsia in women who have a low dietary intake of calcium. The benefits of calcium supplementation are greatest in women who are at high risk of pre-eclampsia.

A Cochrane systematic review (search date: October 2009) assessed the effects of taking calcium supplements during pregnancy on the risk of hypertensive disorders of pregnancy and their related outcomes [Hofmeyr et al, 2010].

Twelve studies of good quality were included in the review. Compared with placebo, calcium supplementation:

Reduced the risk of high blood pressure (11 trials, 14,946 women; RR 0.70, 95% CI 0.57 to 0.86).

Reduced the risk of pre-eclampsia (12 trials, 15,206 women; RR 0.48, 95% CI 0.33 to 0.69).

Reduced the risk of maternal death or serious morbidity (four trials, 9732 women; RR 0.80, 95% CI 0.65 to 0.97).

The reduction was greatest for:

Women at high risk of pre-eclampsia (five trials, 587 women; RR 0.22, 95% CI 0.12 to 0.42).

Women with a low baseline calcium intake (seven trials, 10,154 women; RR 0.36, 95% CI 0.18 to 0.70).

There was no overall effect on the risk of pre-term birth, stillbirth, or death before hospital discharge.

The authors concluded that calcium supplementation seems to almost halve the risk of pre-eclampsia, and to reduce the incidence of maternal death or serious morbidity.

Antioxidants

Evidence on antioxidants to prevent hypertensive disorders of pregnancy

There is high-quality evidence from a Cochrane systematic review and two randomized controlled studies that there is no reduction in hypertensive disorders during pregnancy following the use of antioxidants. One of the randomized controlled trials suggested that an increased risk of fetal loss and perinatal death may be associated with their use.

A Cochrane systematic review (search date: May 2007) assessed the safety and effectiveness of antioxidants during pregnancy on preventing or delaying the onset of pre-eclampsia [Rumbold et al, 2008]:

Oxidative stress may be a factor involved in the development or pre-eclampsia. Therefore, taking antioxidants, such as vitamins C and E and selenium, may reduce the risk of pre-eclampsia.

Ten trials including 6533 women were included in the review.

There was no benefit in terms of prevention of pre-eclampsia (nine trials, 5446 women; RR 0.73, 95% CI 0.51 to 1.06).

A subsequent multicentre, randomized, double-blind trial allocated 10,154 low-risk, nulliparous women to take either 1000 mg vitamin C plus 400 IU vitamin D daily, or a placebo starting between the ninth and sixteenth weeks of pregnancy [Roberts et al, 2010]. Primary outcomes were pregnancy-associated hypertension, or biochemical features suggesting the development of pre-eclampsia or serious adverse outcomes in the mother or the fetus, such as eclamptic seizure or perinatal death. Outcome data were available for 9969 women.

There was no significant difference between the antioxidant and placebo groups in the rates of:

Primary outcomes (6.1% and 5.7%, respectively; RR 1.07, 95% CI 0.91 to 1.25).

Pre-eclampsia (7.2% and 6.7%, respectively; RR 1.07, 95% CI 0.93 to 1.24).

The authors concluded that vitamin C and E supplementation started between the ninth and sixteenth weeks of pregnancy in low-risk, nulliparous women did not reduce the risk of pregnancy-associated hypertension.

Another multicentre, randomized, controlled trial carried out in Canada and Mexico allocated 2647 women to take either 1000 mg vitamin C plus 400 IU vitamin D daily or a placebo starting between 12 and 18 weeks of gestation [Xu et al, 2010]. Primary outcomes were gestational hypertension and adverse effects due to this.

There was no significant difference between the antioxidant and placebo groups for the risk of gestational hypertension (RR 0.99, 95% CI 0.78 to 1.26).

The trial had to be stopped because the relative risk of perinatal death and fetal loss was much higher in the group receiving the antioxidants (1.69% compared with 0.78%; RR 2.2, 95% CI 1.02 to 4.73).

The authors concluded that antioxidants did not reduce the risk of gestational hypertension but did seem to increase fetal loss and perinatal death.

Fish and algal oils

Evidence on fish and algal oils to prevent hypertensive disorders of pregnancy

There is high-quality evidence from a Cochrane systematic review that there is no reduction in hypertensive disorders during pregnancy following the use of fish or algal oils.

A Cochrane systematic review (search date: December 2005) studied the effect of fish and algal oils on the risk of pre-eclampsia (and also preterm birth, low birthweight, and small-for-gestational age) [Makrides et al, 2006].

Six studies involving 2783 women were included. Three trials including the largest (1477 women) were of high quality. Marine oils given orally were compared with no treatment or placebo.

There was no statistically significant difference between the groups in the relative risk of high blood pressure (five trials, 1831 women; RR 1.09, 95% CI 0.9 to 1.33).

There was no statistically significant difference in women with singleton pregnancies between the groups in the relative risk of pre-eclampsia (four trials, 1186 women; 95% CI 0.43 to 1.04).

There was also no clear difference between the groups in relation to preterm birth, low birthweight, and small-for-gestational age.

The authors concluded that evidence wa insufficient to recommend the use of marine oils during pregnancy to reduce the risk of pre-eclampsia or of having a preterm birth, a low-birthweight infant, or a small-for-gestational-age infant.

Garlic

Evidence on garlic to prevent hypertensive disorders of pregnancy

Evidence is insufficient to recommend the use of garlic to prevent pre-eclampsia and its complications.

A Cochrane systematic review assessed the effects of garlic on prevention of pre-eclampsia and its complications [Meher and Duley, 2006c]. A further literature search for this Cochrane systematic review in January 2010 did not find any new evidence to necessitate an update to the text. There is a hypothesis that garlic may prevent pre-eclampsia and its complications by lowering blood pressure, inhibiting platelet aggregation, and reducing oxidative stress.

One trial that was of uncertain quality and included 100 women compared garlic with placebo.

There was no statistically significant difference between the garlic and control groups in the risk of:

Pre-eclampsia (RR 0.78, 95% CI 0.31 to 1.93).

Gestational hypertension (RR 0.50, 95% CI 0.25 to 1.00).

The authors concluded that evidence is insufficient to recommend increased garlic intake for preventing pre-eclampsia and its complications.

Rest for prevention

Evidence on rest to prevent hypertensive disorders of pregnancy

Evidence is insufficient on the use of rest in any form to prevent hypertensive disease in pregnancy.

A Cochrane systematic review (search date: January 2010) assessed the effects of rest or advice to reduce physical activity during pregnancy on preventing pre-eclampsia and its complications in women with normal blood pressure [Meher and Duley, 2006b]. A further literature search for this Cochrane systematic review in January 2010 did not find any new evidence to necessitate an update to the text.

Two small trials of uncertain quality involving 106 women were included. Both trials recruited women with a singleton pregnancy who were at moderate risk of pre-eclampsia. The women were at 28–32 weeks' gestation.

In one trial, 4–6 hours rest in the left lateral position was compared with unrestricted activity. There was a statistically significant reduction in the relative risk (RR) of pre-eclampsia (RR 0.05, 95% CI 0.00 to 0.83), but not in the risk of gestational hypertension (RR 0.25, 95% CI 0.03 to 2.00).

The other trial also involved the use of nutritional supplementation, which may have been a confounding factor.

The authors concluded that evidence is insufficient to recommend rest or reduced activity in women to prevent pre-eclampsia and its complications.

Exercise for prevention

Evidence on exercise to prevent hypertensive disorders of pregnancy

There is evidence from a Cochrane systematic review that exercise has no significant effect on the incidence of pre-eclampsia.

A Cochrane systematic review (search date: December 2005) assessed the effects of exercise, or increased physical activity, on prevention of pre-eclampsia and its complications [Meher and Duley, 2006d]. Regular physical activity is known to reduce the risk of hypertension in non-pregnant people. It has been suggested that exercise may help prevent pre-eclampsia and its complications.

Two small, good quality trials involving 45 women were included. Both trials compared moderate-intensity regular aerobic exercise with normal physical activity during pregnancy.

There was no statistically significant difference between the two groups for the prevention of pre-eclampsia (RR 0.31, 95% CI 0.01 to 7.09). The confidence intervals were wide.

The authors concluded that evidence is insufficient to make reliable conclusions about the effects of exercise on prevention of pre-eclampsia and its complications.

Dipsticks to estimate proteinuria

Evidence on the use of dipsticks to estimate proteinuria

Evidence from a meta-analysis of six trials and a prospective study showed that visual dipstick analysis of urine with a 1+ threshold is not accurate at detecting clinically significant proteinuria. Its use in clinical decision making is therefore limited. Accuracy is improved by using an automated dipstick device.

A meta-analysis investigated the accuracy of point of care urine dipstick to predict significant proteinuria in pregnancy [Waugh et al, 2004].

Pooled results from six heterogeneous studies included in this review were as follows:

Sensitivity 55%.

Specificity 84%.

Positive predictive value 72%.

Negative predictive value 30%.

Positive likelihood ratio 3.48 (95% CI 1.66 to 7.27).

Negative likelihood ratio 0.6 (95% CI 0.45 to 0.8).

Accuracy was improved by using an automated dipstick device:

Sensitivity 82%.

Specificity 81%.

Positive predictive value 77.7%.

Negative predictive value 15.6%.

Positive likelihood ratio 4.27 (95% CI 1.2.78 to 6.56).

Negative likelihood ratio 0.22 (95% CI 0.14 to 0.36).

The authors concluded that the accuracy of dipstick testing with a 1+ threshold is poor for detecting clinically significant proteinuria. Its use in clinical decision making is therefore of limited usefulness. Although accuracy may be improved by using a higher cut-off point (such as 2+), there are only limited data of poor methodological quality for this threshold.

A subsequent prospective diagnostic study [Waugh et al, 2005] compared visual and automated readings of protein dipsticks with a 24 hour urinary-protein measurement:

The visually read protein dipstick results for significant proteinuria (1+) were:

Sensitivity of 51% (95% CI 39% to 62%).

Specificity of 78% (95% CI 68% to 86%).

Likelihood ratio for positive result 2.27 (95% CI 1.47 to 3.51).

Likelihood ratio for a negative result 0.635 (95% CI 0.49 to 0.82).

The automated reading device results for protein were:

Sensitivity of 82% (95% CI 71% to 90%).

Specificity of 81% (95% CI 71% to 88%).

Likelihood ratio for positive result 0.225 (95% CI 2.78 to 6.56).

Likelihood ratio for a negative result 0.635 (95% CI 0.14 to 0.37).

Stopping ACE inhibitors or AIIRAs

Evidence for stopping angiotensin-converting enzyme (ACE) inhibitors or angiotensin-II receptor antagonists (AIIRAs)

There is limited good quality evidence that the use of angiotensin-converting enzyme (ACE) inhibitors leads to increased rates of congenital malformations, intrauterine growth retardation, and premature delivery, and that the use of angiotensin-II receptor antagonists (AIIRAs) leads to an increased rate of congenital malformations.

A review of the literature was undertaken by the National Institute for Health and Care Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2010] on:

ACE inhibitors

One retrospective cohort study was carried out in Tennessee, USA [Cooper et al, 2006]. Two hundred and nine infants exposed to ACE inhibitors in the first trimester of pregnancy were compared with 29,096 infants who were not exposed to antihypertensive medication throughout pregnancy. Eighteen of the infants exposed to ACE inhibitors had major congenital malformations (relative risk 2.71, 95% CI 1.72 to 4.27).

A study included 108 reports of adverse outcomes associated with the use of enalapril during pregnancy; of the 95 pregnancies that continued beyond 16 weeks, 32.5% had congenital malformations.

A small case series of 19 newborn infants: two had life-threatening abnormalities and were born preterm. A third infant was born at term but was hypoglycaemic.

One small case study of 19 pregnancies (2 early miscarriages, 17 live births) in which the women had been exposed ACE inhibitors at some stage of the pregnancy found that none of the 17 infants had congenital abnormalities, kidney dysfunction, or neonatal problems.

AIIRAs

One systematic review included case reports, case series, and post-marketing surveys [Velazquez-Armenta et al, 2007]. This included 64 published reports of women exposed to AIIRAs during pregnancy: 27 women (42%) had infants with unfavourable outcomes (mainly congenital abnormalities).

Level of blood pressure control

Evidence on the level of blood pressure control in pregnant women with chronic hypertension

There is evidence from two good-quality studies that there is less risk of severe hypertension developing in pregnant women with chronic hypertension if they have 'tight' control of blood pressure. A meta-regression of randomized controlled trials (RCTs) has shown that the more that blood pressure is reduced in pregnant women with chronic hypertension, the more the birthweight of their infants is reduced.

An RCT in Egypt compared the effectiveness of applying 'tight' versus 'less tight' blood pressure control in women with mild chronic or gestational hypertension in pregnancy [El Guindy and Nabhan, 2008]. The study included women with blood pressures of 140–159/90–99 mmHg and a gestational age of 20–33+6 weeks. The RCT excluded women with a blood pressure of 160/100 mmHg or above, or who had proteinuria, diabetes, chronic kidney disease, or fetal anomalies. Sixty-three women were randomized to a tight blood pressure target (< 130/80 mmHg) and 62 women to a less tight blood pressure target (130–139/80–89 mmHg).

Women in the tight control group:

Were less likely to develop severe hypertension (RR 0.32, 95% CI 0.14 to 0.74).

Delivered babies with older gestational ages (36.6 +/– 2.2 weeks compared with 35.8 +/– 2.2 weeks: p < 0.05).

Had fewer pre-term deliveries (RR 0.52, 95% CI 0.28 to 0.99).

There were no significant differences between groups regarding stillbirth or intrauterine growth retardation.

A multicentre RCT which was a pilot trial for the Control of Hypertension in Pregnancy Study (CHIPS) was carried out in Canada, New Zealand, Australia, and the UK [Magee et al, 2007] in women with chronic or gestational hypertension (diastolic blood pressure 90–109 mmHg, with an onset between 20 weeks and 33 weeks and 6 days).

Women were randomized to tight (66 women) and very tight (66 women) control of blood pressure.

Women with diastolic blood pressure consistently lower than 85 mmHg, severe systolic hypertension (170 mmHg or greater), proteinuria, or contraindications to less tight or tight control, or contraindications to prolonging pregnancy were excluded from the trial. Women expected to deliver within 1 week were also excluded.

The risk of severe hypertension was lower in women in the tight control group.

There were no significant differences between the groups for:

Gestational age at delivery.

Serious maternal or perinatal complications.

Need for neonatal care.

A meta-regression analysis of published data investigated the association of treatment-induced mean arterial pressure with small-for-gestational-age infants and birthweight. Forty-five RCTs included 3773 women taking antihypertensive drugs, including methyldopa, acebutolol, atenolol, labetalol, metoprolol, oxprenolol, pindolol, propranolol, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, ketanserin, hydralazine, isradipine, nicardipine, nifedipine, verapamil, and clonidine [Von Dadelszen et al, 2000]. The meta-regression found that:

A greater difference in mean arterial pressure between control and treatment groups was associated with a higher proportion of small-for-gestational-age infants (15 RCTs, 1587 women). After exclusion of a small trial with methodological problems this result was found to be significant.

A 10 mmHg fall in mean arterial pressure was associated with a decrease in birthweight of 145 g (26 RCTs, total number of women not reported, one study with outlying results excluded; p < 0.05).

There was no statistically significant association between mean arterial pressure and birthweight when an RCT with outlying results was included (27 RCTs, 2305 women).

The authors concluded that anti-hypertensive therapy may affect fetal growth.

Effectiveness of antihypertensive drugs

Evidence on the effectiveness of antihypertensive drugs in pregnant women with chronic hypertension

From the limited available evidence, it is not possible to determine the best antihypertensive treatment for pregnant women with chronic hypertension.

The following is a summary of trials reviewed by the National Institute for Health and Care Excellence (NICE) [National Collaborating Centre for Women's and Children's Health, 2010].

Methyldopa

A randomized controlled trial (RCT) involving 300 women found that women taking methyldopa were as likely to develop pre-eclampsia as women on no treatment (odds ratio [OR] 1.21, 95% CI 0.55 to 2.65). There was no difference between the group receiving methyldopa and the no treatment group regarding the following outcomes: need for additional drugs, incidence of placental abruption, pre-term birth at less than 37 weeks, small-for-gestational age, and perinatal death.

A small RCT randomized 25 women who had chronic hypertension of pregnancy to receive either methyldopa (13 women) or placebo (12 women). The incidence of pre-eclampsia was similar in both groups and after correction for gestational age, there was no statistically significant difference between the groups for birthweight and fat content of the infant (ponderal index).

Labetalol

An RCT involving 300 women found that women taking labetalol were as likely to develop pre-eclampsia as women on no treatment (OR 1.06, 95% CI 0.47 to 2.37). There was no difference between the group receiving labetalol and the no treatment group regarding the following outcomes: need for additional drugs, incidence of placental abruption, pre-term birth at less than 37 weeks, small-for-gestational age, and perinatal death.

Atenolol

A small trial included 29 women with chronic hypertension who were between 12 and 24 weeks gestation. The women were randomized to receive either atenolol (15 women) or placebo (14 women). Atenolol was effective in lowering diastolic but not systolic blood pressure. Infants born to the women who received atenolol were on average 901 g lighter than infants born to the women who received placebo.

Calcium-channel blockers

NICE identified no evidence on nifedipine, amlodipine, or nicardipine.

Diuretics

A small trial randomized women to continue their diuretic through pregnancy (10 women) or to stop their diuretic immediately (10 women). There was no statistically significant difference in outcomes between the two groups.

Antihypertensives with diuretics

A small trial of 58 women randomized the participants to receive either treatment (29 women) or no treatment (29 women). The treatment group included 11 women who received methyldopa and thiazide; 10 women who received hydralazine and thiazide; and eight women who received thiazide, methyldopa, and hydralazine. Fewer women in the treatment group than in the no treatment group had pregnancy-aggravated hypertension (p = 0.05).

Search strategy

Scope of search

A full literature search was not requested/required as this topic review is primarily based on the National Institute for Health and Care Excellence (NICE) guideline, Hypertension in pregnancy: the management of hypertensive disorders in pregnancy [National Collaborating Centre for Women's and Children's Health, 2010] and the Pre-eclampsia community guideline [PRECOG, 2004a].

Topic specific literature search sources

Action on Pre-eclampsia

Centre for Maternal and Child Enquiries

Sources of guidelines

National Institute for Health and Care Excellence (NICE)

Scottish Intercollegiate Guidelines Network (SIGN)

National Guidelines Clearinghouse

New Zealand Guidelines Group

British Columbia Medical Association

Canadian Medical Association

Institute for Clinical Systems Improvement

Guidelines International Network

National Library of Guidelines

National Health and Medical Research Council (Australia)

Alberta Medical Association

University of Michigan Medical School

Michigan Quality Improvement Consortium

Royal College of Nursing

Singapore Ministry of Health

Health Protection Agency

National Resource for Infection Control

CREST

World Health Organization

NHS Scotland National Patient Pathways

Agency for Healthcare Research and Quality

TRIP database

Patient UK Guideline links

UK Ambulance Service Clinical Practice Guidelines

RefHELP NHS Lothian Referral Guidelines

Medline (with guideline filter)

Sources of systematic reviews and meta-analyses

The Cochrane Library :

Systematic reviews

Protocols

Database of Abstracts of Reviews of Effects

Medline (with systematic review filter)

EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

NIHR Health Technology Assessment programme

The Cochrane Library :

NHS Economic Evaluations

Health Technology Assessments

Canadian Agency for Drugs and Technologies in Health

International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

The Cochrane Library :

Central Register of Controlled Trials

Medline (with randomized controlled trial filter)

EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

Bandolier

Drug & Therapeutics Bulletin

MeReC

NPCi

DynaMed (access via the CKS website)

TRIP database

Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

Department of Health

Health Management Information Consortium (HMIC)

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