The hypertensive disorders of pregnancy (HDP) remain one of the major causes of maternal mortality and morbidity worldwide. Many international guidelines exist for the classification and assessment of women with hypertension in pregnancy, but definitions and recommendations within these documents are variable. Many recommended investigations do not actually correlate with increased risk of adverse outcomes, making it difficult to determine true prognosis. Although standardised assessment and surveillance has been shown to improve outcomes, the application of these monitoring strategies in many areas of the world is not possible owing to the cost associated with them. Not all of the tests recommended for surveillance of women with pre-eclampsia are independently predictive of adverse outcomes, and many unnecessary tests could be avoided if those tests that are most informative where identified. The Pre-eclampsia Integrated Estimate of RiSk study has identified a group of tests that can be used to predict risk of outcomes accurately up to 7 days after admission to a tertiary hospital with pre-eclampsia. This model needs to be validated in new populations and in different clinical settings before it can be implemented into clinical practice. Until this happens, clinicians should consider the whole clinical picture when assessing women with pre-eclampsia and making decisions around expectant management compared with stabilisation and delivery. Future research in the area of prognosis should focus on women with variable definitions of pre-eclampsia and the other HDP. All studies reviewed were limited to cases of severe pre-eclampsia, and results may not be generalisable across the spectrum of the disorder.
Introduction
The hypertensive disorders of pregnancy (HDP), including chronic hypertension, gestational hypertension and pre-eclampsia, are of great concern to clinicians because of the associated adverse maternal and fetal outcomes. The HDP, specifically pre-eclampsia, remain one of the top four causes of maternal mortality and morbidity in high-, middle-, and low-income countries. Most deaths associated with these disorders occur in low- and middle-income countries.
In high-income countries, where maternal mortality is rare, severe morbidities resulting from HDP are of greater concern. Adverse maternal outcomes associated with HDP are a result of excessive inflammation and endothelial damage, and include eclampsia, stroke, retinal detatchment, acute renal failure, placental abruption, pulmonary oedema, liver haematoma, disseminated intravascular coagulation and cerebrovascular bleeding. Fetal complicationss include stillbirth, intracranial haemorrhage, oligohydramnios and fetal growth restriction. Both maternal and fetal outcomes tend to cluster around the diagnosis of pre-eclampsia (gestational hypertension and proteinuria), but gestational hypertension alone and other atypical forms of the disorder are not benign. Studies have found that 15–56% of women who initially present with gestational hypertension will progress to a diagnosis of pre-eclampsia. It is estimated that 15% of cases of severe pre-eclampsia, however defined, will result in significant maternal morbidity. This variability in presentation and progression presents a significant challenge for effective management of the HDP.
Despite recent advances in our understanding of the pathophysiology of pre-eclampsia delivery of the placenta remains the only cure. When presenting early in gestation, delivery is not always the best option for the fetus. Iatrogenic preterm delivery is associated with increased risks, whether it occurs in the early or late preterm period. Evidence from cohort studies and randomised-controlled trials show that, remote from term, prolongation of pregnancy by expectant management decreases serious perinatal morbidity without significant increases in maternal risk. Uncertainty, however, remains around the magnitude of maternal risk associated with expectant management, as randomised-controlled trials were limited to women with severe pre-eclampsia and underpowered to detect a difference in outcomes between groups. An accurate method of predicting maternal outcomes (prognosticating) is required so that perinatal benefits can be weighed against maternal risk.
Strategies for the assessment and surveillance of women with HDP should focus on predicting and avoiding associated adverse maternal and fetal outcomes. Several international guidelines for the management of women with hypertension in pregnancy exist. In this chapter we will review the classification systems provided in four of the more recently published guidelines, as well as their recommendations for assessment and surveillance. The evidence to support these recommendations, based on each suggested investigation’s ability to predict adverse maternal outcomes, will be reviewed, primarily focusing on the recommendations for maternal assessment. In addition, results from studies on multivariate prognostic models for the assessment of women with pre-eclampsia will be reviewed.
International guidelines for classifying and monitoring hypertensive disorders of pregnancy
The international guidelines reviewed here were intended to provide useful criteria for diagnosis and risk stratification, and effective management strategies in order to guide care and ultimately reduce adverse outcomes. Unfortunately, consensus amongst these documents relating to definitions and management strategies is lacking, and is confusing for clinicians. In addition, many of the criteria for severity stipulated in these guidelines have not been properly evaluated on the basis of their prognostic value. An overview of the classification systems is presented in Table 1 . Severity criteria and definitions for HDP are presented from the UK’s National Institute for Health and Clinical Excellence (NICE), the Society of Obstetricians and Gynaecologists of Canada (SOGC), the American Society of Hypertension (ASH) and the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ).
| NICE (2010) | SOMANZ (2008) | SOGC (2008) | ASH (2008) | |
|---|---|---|---|---|
| Pre-existing or chronic hypertension (blood pressure ≥140/90 before 20 +0 week’s gestation) | Chronic hypertension: before 20 weeks’ gestation or being treated at time of referral primary or secondary aetiology | Chronic hypertension: essential secondary white coat with or without superimposed pre-eclampsia | Pre-existing hypertension: with or without co-morbid conditions with or without superimposed pre-eclampsia | Chronic hypertension: with or without superimposed pre–eclampsia |
| Gestational hypertension (blood pressure ≥140/90 after 19 +6 weeks’ gestation) | Gestational hypertension: without significant proteinuria | Gestational hypertension: without significant proteinuria returning to normal within 12 weeks postpartum | Gestational hypertension: with or without co-morbid conditions with or without superimposed pre-eclampsia | Gestational hypertension or transient hypertension: blood pressure returning to normal within 6 weeks’ postpartum; Late postpartum hypertension: blood pressure rise developing up to 6 months postpartum and normalised by 1 year postpartum. |
| Pre-eclampsia (clinical definition) | New hypertension (blood pressure ≥140/90) presenting after 20 weeks’ gestation with clinically relevant proteinuria (see significant proteinuria, below) | Gestational hypertension plus one or more of the following: dipstick proteinuria confirmed by either random protein–creatinine ratio >30 mg/mmol or 0.3 g every 24 h serum or plasma creatinine >90 μM oliguria thrombocytopoaenia haemolysis disseminated intravascular coagulation raised serum transaminases severe epigastric or right upper quadrant pain eclampsia Hypereflexia with sustained clonus severe headache persistent visual disturbances stroke pulmonary oedema fetal growth restriction placental abruption | Pre-existing hypertension and resistant hypertension, new proteinuria, or adverse condition (see severity criteria, below) Gestational hypertension plus proteinuria (spot protein–creatinine ratio >30 mg/mmol or 0.3 g every 24 h), or adverse condition | Gestational hypertension or Chronic hypertension with proteinuria (dipstick ≥ +1, spot protein–creatinine ratio ≥30 mg/mmol or ≥0.3 g every 24 h). |
| Pre-eclampsia (research definition) | Not defined | De–novo hypertension >20 +0 weeks’, returning to normal postpartum with properly documented proteinuria | Not defined | Not defined |
| Severe hypertension | 160/110 mmHg | 170/110 mmHg | 160/110 mmHg | 160/110 mmHg |
| Significant proteinuria | >300 mg/d or >30 mg/mmol on spot protein–creatinine ratio | Not defined | >300 mg/d or >30 mg/mmol on spot protein–creatinine ratio | >300 mg/d or >30 mg/mmol on spot protein–creatinine |
| Severity criteria | Severe hypertension Maternal symptoms (vision problems, severe headache, epigastric pain, vomiting, papiloedema) Biochemical abnormalities or haematological impairment (platelet count <100 x 10 9 /l or AST/ALT >70 U/L, elevated serum creatinine) | Not defined | Gestational age at onset <34 +0 weeks’ heavy proteinuria Maternal symptoms (persistent, new or unusual headache, visual disturbances, persistent abdominal or right upper quadrant pain, severe nausea or vomiting, chest pain or dyspnoea) Maternal signs of end-organ dysfunction (eclampsia, severe hypertension, pulmonary oedema, or suspected placental abruption) Abnormal maternal laboratory testing (elevated serum creatinine; elevated AST, ALT or LDH with symptoms; platelet count <100 × 10 9 /L; or serum albumin <20 g/L) Fetal morbidity (oligohydramnios, intrauterine growth restriction, absent or reversed end-diastolic flow in the umbilical artery by Doppler velocimetry). Intrauterine fetal death | <35 weeks’ gestation Maternal symptoms (headache, visual disturbances, abdominal pain) Severe diastolic hypertension (>110 mmHg) Significant proteinuria or oliguria Increased serum creatinine Decreased glomerular filtration rate Increased AST or LDH Fetal morbidity (non-reassuring cardiotogograph) |
Definitions of HDP are subdivided into chronic hypertension, gestational hypertension, and pre-eclampsia. Pre-eclampsia is then further defined as severe or non-severe, based on the presence or absence of a variety of additional signs, symptoms and laboratory findings. For all classification systems, hypertension is defined as systolic blood pressure greater than or equal to 140 mmHg, diastolic blood pressure greater than or equal to 90 mmHg, or both. In both the NICE and SOGC guidelines, definitions are based on real-time diagnosis and do not require retrospective knowledge. This is an improvement on past guidelines, in which diagnosis could not be confirmed until several weeks’ postpartum, making decisions around care based on that diagnosis difficult.
For both the NICE and SOMANZ guidelines, recommendations for maternal assessment and surveillance differ on the basis of the diagnosis, as outlined in Table 2 . In the NICE guidelines, these monitoring strategies also depend on severity of hypertension, where more intense and regular surveillance is recommended for women with severe hypertension greater than 160/110 mmHg. In contrast, the SOGC recommends that the same monitoring strategy is used for all cases, regardless of diagnosis. Increased monitoring for women with severe pre-eclampsia, and consequently less monitoring for with what is felt to be milder disorder, reflects an attempt to reduce unnecessary interventions and testing in women felt to have less severe disease (better prognosis), therefore reducing costs. This is carried out with a goal of reducing unnecessary iatrogenic preterm birth.
| NICE (2010) | SOMANZ (2008) | SOGC (2008) | |
|---|---|---|---|
| Investigations at initial presentation | For gestational hypertension and mild hypertension: routine antenatal surveillance For gestational hypertension and moderate or severe hypertension or pre-eclampsia: blood pressure, kidney function, electrolytes, full blood count, transaminases, and bilirubin | Assessment of symptoms, blood pressure, urine dipstick and proteinuria by spot or 24 h if dipstick ≥ 1+, full blood count, urea, creatinine, electrolytes and liver function | Blood pressure, haemoglobin, WBC and differential, platelet count, blood film, INR and aPTT, fibrinogen, serum creatinine, serum uric acid, glucose, AST, ALT, LDH, albumin, billirubin, urinalysis (routine and microscopy), proteinuria (assessed by urinary protein dipstick, spot protein–creatinine ratio, or 24 h urinalysis) |
| Investigations for ongoing monitoring | For gestational hypertension and mild hypertension: routine antenatal surveillance For gestational hypertension and moderate or severe hypertension or pre-eclampsia: blood pressure, kidney function, electrolytes, full blood count, transaminases, and bilirubin | Assessment of symptoms, blood pressure, urine dipstick and proteinuria by spot or 24 h if dipstick ≥ 1+, full blood count, urea, creatinine, electrolytes and liver function | Blood pressure, haemoglobin, WBC and differential, platelet count, INR and aPTT, a fibrinogen, a serum creatinine, serum uric acid, AST, ALT, LDH, albumin, billirubin, proteinuria (assessed by urinary protein dipstick, spot protein–creatinine ratio, or 24 h urinalysis) |
| Timing of investigations | Blood pressure four times a day unless ≥160/110 mmHg then blood pressure more than four times per day depending on clinical circumstances | Urinalysis assessed at each visit until diagnosis of pre-eclampsia made, then daily Laboratory blood investigations twice weekly or more if unstable | Serial surveillance of blood pressure and proteinuria: laboratory investigations carried out at least once per week antenatally and at least once in the first 3 days postpartum |
| Proteinuria at each visit until pre-eclampsia diagnosis made then repeat measurement not recommended. | |||
| Blood tests two to three times a week depending on severity of hypertension and presence of proteinuria |
a Tests of coagulation are recommended if there is thrombocytopoenia or placental abruption. INR, international normalised ratio; aPTT, activated partial thromboplastin time; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; NICE, National Institute for Health and Clinical Excellence; SOGC, Society of Obstericians and Gynaecologists of Canada; SOMANZ, Society of Obstetric Medicine of Australia and New Zealand; WBC, white blood cells.
Prognosis in medicine, and in the context of this review, refers to the probability of developing an adverse health outcome during the course of that persons care. Having the ability to predict the likelihood of an individual developing a poor outcome based on that individual’s clinical picture is critical for decision making by both the healthcare provider and patient. Any classification system and monitoring strategy is only useful if it discriminates groups accurately on the basis of prognosis, and can identify those women for whom interventions or treatments are most appropriate.
In the following section, results from studies on the prognostic value of several clinical and laboratory investigations in women with pre-eclampsia are reviewed. Guidelines used for reviewing prognostic studies are presented in Table 3 . Studies were included if they reported on the associated risk, or prognostic value of the predictor, with adverse maternal, fetal outcomes, or both. It is important to distinguish the identification of a risk factor and a prognostic factor. These concepts are often used interchangeably in the published studies, but are actually very different. Risk factors have a causal association with the adverse outcome, with the strength of this association generally expressed as an odds ratio or relative risk. Prognostic factors, on the other hand, give information on the absolute probability of an outcome, independent of causation. Prognostic value is generally expressed in terms of likelihood ratios, sensitivity, specificity, positive predictive value or negative predictive value or the area under the curve of the receiver operating characteristic (AUC ROC).
| Test | Definition | Criteria for use in prognosis |
|---|---|---|
| Likelihood ratio (LR) | Likelihood ratios give a measure of the effect of a positive test (LR+) or negative test (LR–) on the post-test probability of outcome. The further from 1, in both cases, the greater the effect of the test. | LR+ >5.0 and LR– <0.2 |
| Area under the curve of the receiver operating characteristic (AUC ROC) | The receiver operating curve is a plot of sensitivity versus 1-specificity for a test. The AUC ROC is a measure of a tests ability to discriminate between those patients with or without an outcome. An AUC ROC of 1.0 gives perfect discrimination and 0.5 would be similar to random chance | ≥0.70 |
International guidelines for classifying and monitoring hypertensive disorders of pregnancy
The international guidelines reviewed here were intended to provide useful criteria for diagnosis and risk stratification, and effective management strategies in order to guide care and ultimately reduce adverse outcomes. Unfortunately, consensus amongst these documents relating to definitions and management strategies is lacking, and is confusing for clinicians. In addition, many of the criteria for severity stipulated in these guidelines have not been properly evaluated on the basis of their prognostic value. An overview of the classification systems is presented in Table 1 . Severity criteria and definitions for HDP are presented from the UK’s National Institute for Health and Clinical Excellence (NICE), the Society of Obstetricians and Gynaecologists of Canada (SOGC), the American Society of Hypertension (ASH) and the Society of Obstetric Medicine of Australia and New Zealand (SOMANZ).
| NICE (2010) | SOMANZ (2008) | SOGC (2008) | ASH (2008) | |
|---|---|---|---|---|
| Pre-existing or chronic hypertension (blood pressure ≥140/90 before 20 +0 week’s gestation) | Chronic hypertension: before 20 weeks’ gestation or being treated at time of referral primary or secondary aetiology | Chronic hypertension: essential secondary white coat with or without superimposed pre-eclampsia | Pre-existing hypertension: with or without co-morbid conditions with or without superimposed pre-eclampsia | Chronic hypertension: with or without superimposed pre–eclampsia |
| Gestational hypertension (blood pressure ≥140/90 after 19 +6 weeks’ gestation) | Gestational hypertension: without significant proteinuria | Gestational hypertension: without significant proteinuria returning to normal within 12 weeks postpartum | Gestational hypertension: with or without co-morbid conditions with or without superimposed pre-eclampsia | Gestational hypertension or transient hypertension: blood pressure returning to normal within 6 weeks’ postpartum; Late postpartum hypertension: blood pressure rise developing up to 6 months postpartum and normalised by 1 year postpartum. |
| Pre-eclampsia (clinical definition) | New hypertension (blood pressure ≥140/90) presenting after 20 weeks’ gestation with clinically relevant proteinuria (see significant proteinuria, below) | Gestational hypertension plus one or more of the following: dipstick proteinuria confirmed by either random protein–creatinine ratio >30 mg/mmol or 0.3 g every 24 h serum or plasma creatinine >90 μM oliguria thrombocytopoaenia haemolysis disseminated intravascular coagulation raised serum transaminases severe epigastric or right upper quadrant pain eclampsia Hypereflexia with sustained clonus severe headache persistent visual disturbances stroke pulmonary oedema fetal growth restriction placental abruption | Pre-existing hypertension and resistant hypertension, new proteinuria, or adverse condition (see severity criteria, below) Gestational hypertension plus proteinuria (spot protein–creatinine ratio >30 mg/mmol or 0.3 g every 24 h), or adverse condition | Gestational hypertension or Chronic hypertension with proteinuria (dipstick ≥ +1, spot protein–creatinine ratio ≥30 mg/mmol or ≥0.3 g every 24 h). |
| Pre-eclampsia (research definition) | Not defined | De–novo hypertension >20 +0 weeks’, returning to normal postpartum with properly documented proteinuria | Not defined | Not defined |
| Severe hypertension | 160/110 mmHg | 170/110 mmHg | 160/110 mmHg | 160/110 mmHg |
| Significant proteinuria | >300 mg/d or >30 mg/mmol on spot protein–creatinine ratio | Not defined | >300 mg/d or >30 mg/mmol on spot protein–creatinine ratio | >300 mg/d or >30 mg/mmol on spot protein–creatinine |
| Severity criteria | Severe hypertension Maternal symptoms (vision problems, severe headache, epigastric pain, vomiting, papiloedema) Biochemical abnormalities or haematological impairment (platelet count <100 x 10 9 /l or AST/ALT >70 U/L, elevated serum creatinine) | Not defined | Gestational age at onset <34 +0 weeks’ heavy proteinuria Maternal symptoms (persistent, new or unusual headache, visual disturbances, persistent abdominal or right upper quadrant pain, severe nausea or vomiting, chest pain or dyspnoea) Maternal signs of end-organ dysfunction (eclampsia, severe hypertension, pulmonary oedema, or suspected placental abruption) Abnormal maternal laboratory testing (elevated serum creatinine; elevated AST, ALT or LDH with symptoms; platelet count <100 × 10 9 /L; or serum albumin <20 g/L) Fetal morbidity (oligohydramnios, intrauterine growth restriction, absent or reversed end-diastolic flow in the umbilical artery by Doppler velocimetry). Intrauterine fetal death | <35 weeks’ gestation Maternal symptoms (headache, visual disturbances, abdominal pain) Severe diastolic hypertension (>110 mmHg) Significant proteinuria or oliguria Increased serum creatinine Decreased glomerular filtration rate Increased AST or LDH Fetal morbidity (non-reassuring cardiotogograph) |
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