Testing for proteinuria by dipstick estimation

• This is based on expert advice in the National Institute for Health and Clinical 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].

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 Clinical 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.

Referral to secondary care

• Expert opinion from the National Institute for Health and Clinical 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.

Management in secondary care

• The expert opinion of the National Institute for Health and Clinical 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].