Update on hypertensive disorders in pregnancy

Key points.

• •The target blood pressure during pregnancy is <135/85 mmHg.
• •New risk prediction models for pre-eclampsia can help guide decision making.
• •Labetalol, hydralazine and immediate-release oral nifedipine are suitable treatment options for hypertensive emergencies.
• •Hypertensive disorders during pregnancy are associated with a long-term increased risk of cardiovascular diseases so women should be offered lifelong follow-up.

Learning objectives.

By reading this article you should be able to:

• •Describe the diagnostic criteria for hypertension and pre-eclampsia.
• •Identify risk factors for developing pre-eclampsia.
• •Apply risk prediction models for pre-eclampsia in clinical practice.
• •Formulate management plans for women presenting with hypertensive emergencies during pregnancy.

Introduction

Hypertensive disorders during the peripartum period are common and are accompanied by increased maternal and fetal morbidity and mortality. They encompass chronic pre-existing hypertension, gestational hypertension and pre-eclampsia. The confidential enquiries into maternal deaths revealed that 2% were attributable to pre-eclampsia and eclampsia.¹ Untreated hypertension can lead to adverse events for both mother and baby, including maternal cardiovascular morbidity and stroke, increased risk of preterm birth and small for gestational age babies. Cardiovascular diseases in later life are also more common in these women.

This article provides an update on the assessment and management of hypertensive disorders in pregnancy of particular relevance to the anaesthetist.

Hypertension

According to the American College of Obstetricians and Gynecologists (ACOG), hypertension in pregnancy is diagnosed if the systolic blood pressure (SBP) is ≥140 mmHg, diastolic BP (DBP) is ≥90 mmHg, or both, ideally confirmed on two occasions or at least 4 h apart.²

Chronic hypertension is hypertension that presents before 20 weeks' gestation. The majority of cases are attributable to essential hypertension, which may be associated with obesity or a family history of hypertension. Secondary causes are much less common. This category also includes white coat hypertension, which refers to a BP ≥140/90 mmHg within a hospital setting but not at home. Ambulatory BP monitoring over 24 h can confirm chronic hypertension. Up to half of women with white coat hypertension develop gestational hypertension or pre-eclampsia.

Gestational hypertension is new onset hypertension that develops after 20 weeks' gestation without any features of pre-eclampsia. Transient gestational hypertension, particularly if noted before 33 weeks' gestation, is associated with up to 40% risk of developing true gestational hypertension or pre-eclampsia.³ Twenty-five percent of women with true gestational hypertension or chronic hypertension will develop pre-eclampsia. Therefore, these women require additional monitoring throughout their pregnancy.

Pre-eclampsia

Definition and diagnosis

The International Society for the Study of Hypertension in Pregnancy (ISSHP) defines pre-eclampsia as new onset hypertension (SBP ≥140 mmHg, DBP ≥90 mmHg, or both) accompanied by one or more of the following features at or after 20 weeks' gestation.⁴

• •Proteinuria

Proteinuria is considered positive if 1+ or more. The National Institute for Health and Care Excellence (NICE) guidelines define significant proteinuria as a urine protein:creatinine ratio (PCR) ≥30 mg mmol⁻¹, albumin:creatinine ratio (ACR) ≥8 mg mmol⁻¹, or both.⁵ Pre-eclampsia can present without proteinuria.

• •
  Other maternal organ dysfunction, including:

  • ○
    Acute kidney injury (increase in serum creatinine of ≥90 μmol L⁻¹)
  • ○
    Liver involvement (elevated transaminases, increase in alanine transaminase ≥70 IU L⁻¹, or twice upper limit of normal range)
  • ○
    Neurological complications (including eclamptic seizures, severe headaches, persistent visual scotomata, clonus, blindness, altered mental status or stroke)
  • ○
    Haematological complications (thrombocytopaenia – platelet count <150,000 μl⁻¹, disseminated intravascular coagulation [DIC], haemolysis)
• •Uteroplacental dysfunction (e.g. abnormal umbilical artery Doppler waveform analysis, restricted fetal growth or stillbirth)

Pre-eclampsia represents a potentially progressive clinical condition; therefore, the sub-categories ‘mild’ and ‘severe’ should no longer be used.⁴ The ACOG describe pre-eclampsia as being with or without severe features (Table 1).⁶ The ISSHP diagnostic criteria includes clonus but not hyperreflexia as this is highly subjective and often present in otherwise healthy women.

Table 1.

Severe features associated with pre-eclampsia.⁶ DBP, diastolic BP; SBP, systolic BP

Severe features
SBP ≥160 mmHg or DBP ≥110 mmHg
Thrombocytopaenia (platelet count ≤100,000 μl−1)
Impaired liver function (aspartate transaminase or alanine transaminase levels elevated to twice the upper limit of normal and severe persistent right upper quadrant or epigastric pain not accounted for by alternative diagnoses)
Renal insufficiency (doubling of the serum creatinine concentration in the absence of other renal disease)
Pulmonary oedema
New onset headache, unresponsive to medication and not accounted for by alternative diagnoses
Visual disturbance

HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome is potentially life-threatening to both mother and baby, and represents a severe form of pre-eclampsia. Women may be critically unwell at presentation with placental abruption or DIC.

Risk factors

Numerous strong and moderate risk factors have been identified for development of pre-eclampsia (Table 2).⁷ Risk prediction tools that incorporate multiple features including placental biomarkers, uterine artery Doppler measurements and maternal risk factors, might aid earlier diagnosis and improved outcomes. Placental growth factor (PlGF) is a placental biomarker, with levels that peak between 26 and 30 weeks' gestation and reduce towards term.⁸ PlGF is decreased in pre-eclampsia, particularly in severe disease. A multicentre study found that in women with possible pre-eclampsia presenting before 35 weeks' gestation, those with low PlGF (<12 pg ml⁻¹) are likely to develop pre-eclampsia requiring delivery within 14 days of testing.⁹ The PlGF test has a sensitivity of 96% and a negative predictive value (NPV) of 98%.

Table 2.

Strong and moderate risk factors for development of pre-eclampsia⁷

Strong risk factors	Moderate risk factors
Prior pre-eclampsia	Primiparity
Chronic hypertension	Primipaternity – changed paternity and inter-pregnancy interval >5 yrs
Maternal BMI >30	Advanced maternal age ≥40 yrs
Pregestational diabetes mellitus	Family history of pre-eclampsia
Antiphospholipid syndrome/systemic lupus erythematosus (SLE)	Multiple gestation
Assisted reproductive therapies	Chronic kidney disease

Another placental biomarker, soluble fms-like tyrosine kinase 1 (sFlt-1), is an antagonist of PlGF that causes vasoconstriction and endothelial damage, and is increased in pre-eclampsia. There is an increased risk of pre-eclampsia in women with a high sFlt-1 to PlGF ratio.¹⁰ A short-term absence of pre-eclampsia can be predicted by a sFlt-1/PlGF ratio of ≤38.¹¹ The sFlt-1/PlGF ratio has a sensitivity of 80% and NPV of 99.3%. Overall, angiogenic biomarkers can help to rule out pre-eclampsia and expedite diagnosis in women with pre-eclampsia. NICE recommends the use of PlGF test and the Elecsys immunoassay sFlt-1:PlGF ratio, in combination with standard clinical assessment, to help exclude women with pre-eclampsia between 20 weeks and before 35 weeks of gestation.¹²

There is some evidence to support the use of new risk prediction models for identifying risks of maternal adverse outcomes from pre-eclampsia.

Both the PREP-S (Prediction model for Risks of complications in Early-onset Pre-eclampsia [survival analysis model ]) and fullPIERS (Pre-eclampsia Integrated Estimate of Risk) are validated risk prediction models based on gestational age, vital signs and biochemical observations.^13,14 PREP-S can be used up to 34 weeks' gestation whereas fullPIERS can be used at any time during pregnancy. Notably, neither of the models can predict fetal outcomes. These risk prediction models are recommended by NICE and can be used to help guide decision making, particularly regarding the decision to admit a woman to hospital.⁵

Prevention

General lifestyle advice about maintaining a healthy diet and exercise should be given to all pregnant women. There is a lower rate of hypertensive disorders and gestational diabetes in women who take regular aerobic exercise during pregnancy.¹⁵

Aspirin

The ASPRE (Aspirin for Evidence-Based Preeclampsia Prevention) trial concluded there was a lower rate of preterm pre-eclampsia in women taking aspirin 150 mg at night from 11–14 weeks' to 36 weeks' gestation compared with placebo (1.6% vs 4.3%).¹⁶ NICE recommends that women at high risk of developing pre-eclampsia be given aspirin 75–150 mg daily from 12 weeks until the birth of the baby.⁵ Women with two or more moderate risk factors should also be offered aspirin.

Calcium

Where calcium dietary intake is low, supplementation (>1 g day⁻¹) may lower the chances of developing pre-eclampsia.⁴

Folic acid

The recently published folic acid supplementation in pregnancy on pre-eclampsia (FACT) trial found that in high-risk women, high-dose folic acid supplementation (4 mg day⁻¹) beyond the first trimester does not prevent pre-eclampsia.¹⁷

Management

Blood pressure

The threshold for initiating antihypertensive treatment for all hypertensive disorders in pregnancy has been lowered. A sustained BP ≥140/90 mmHg warrants treatment, targeting a BP ≤135/85 mmHg.⁵ The main aim of controlling the maternal BP is the prevention of intracerebral haemorrhage and stroke. The rate of stroke during the peripartum period in women with pre-eclampsia is 133 per 100,000, with haemorrhagic stroke being more common than ischaemic stroke.¹⁸ NICE recommends offering oral labetalol as initial therapy, followed by nifedipine and then methyldopa as alternatives.⁵ Second- and third-line agents include hydralazine and prazosin.⁴ Women with severe hypertension (SBP ≥160 mmHg, DBP ≥110 mmHg, or both) should be admitted to hospital for assessment and treatment in a monitored setting.

Labetalol is a non-selective beta blocker and the most commonly used beta blocker in pregnancy. Other β₁-selective drugs such as bisoprolol and metoprolol can also be used but atenolol should be avoided. Care should be taken in women with asthma when using beta blockers.

Dihydropyridine calcium channel blockers, such as nifedipine, are also used during pregnancy. Immediate-release oral nifedipine can cause profound hypotension so its use should be avoided concomitantly with magnesium sulphate, as the potential synergistic action can result in fetal compromise. Modified release nifedipine might be more suitable. Women taking thiazide diuretics, angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) should have their medication reviewed, and a safer alternative offered when they become pregnant, owing to the risk of congenital abnormalities.⁵

Timing of birth

Women should have BP monitoring, urinalysis and blood tests performed with the frequency adjusted according to the clinical picture.⁵ Foetal assessment with ultrasound should be performed every 2–4 weeks as clinically indicated.⁵ A planned birth before 37 weeks should be considered for women with pre-eclampsia with severe features (Table 3). After 37 weeks' gestation, birth should be initiated for women with pre-eclampsia within 24–48 h.

Table 3.

Severe features associated with pre-eclampsia that warrant consideration of planned early birth before 37 weeks' gestation^4,5

Severe features
Inability to control maternal BP despite using 3 or more classes of antihypertensives in appropriate doses
Progressive deterioration in liver function, renal function, haemolysis, or platelet count
Maternal pulse oximetry less than 90% on air
Ongoing neurological features, such as severe intractable headache, repeated visual scotomata or eclampsia
Placental abruption
Reversed end-diastolic flow in the umbilical artery Doppler velocimetry, a non-reassuring cardiotocograph or stillbirth

Hypertensive emergencies

An ACOG committee defined severe hypertension as an acute onset BP ≥160/110 mmHg persisting for ≥15 min.² A hypertensive emergency may present with end organ damage such as myocardial infarction, pulmonary oedema, respiratory failure or stroke. Risk factors for hypertensive emergencies in pregnancy are listed in Table 4.¹⁹

Table 4.

Risk factors for hypertensive emergencies in pregnancy¹⁹

Risk factors
Pre-eclampsia
Chronic renal disease
Cardiac disease
Non-compliance with antihypertensive medication
Use of uterotonic drugs for prevention and treatment of postpartum haemorrhage (e.g. ergometrine)
Concomitant use of recreational drugs (e.g. cocaine, methamphetamine)
Low socioeconomic status
Non-Hispanic black population

Initial investigations for suspected hypertensive emergencies in pregnancy include blood tests (full blood count [FBC], creatinine, electrolytes, lactate dehydrogenase [LDH], fibrinogen, haptoglobin); urine (PCR, ACR, microscopy); ECG and fundoscopy. Additional specific tests can be considered depending on the clinical picture, and these include echocardiography (ischaemia or heart failure); brain or chest imaging (stroke or aortic dissection); renal ultrasound (renal parenchymal disease); urinary drug screen (suspected cocaine or methamphetamine use); and serum cardiac troponin (acute myocardial ischaemia) or B-type natriuretic peptide (heart failure). An assessment of fetal well-being should be performed and may include ultrasound examination for fetal growth, Doppler flow studies and cardiotochography (CTG).

Treatment should be initiated urgently in a high dependency setting, aiming for a stepped controlled reduction of blood pressure. Hypertensive emergencies can be treated with intravenous labetalol, hydralazine and immediate-release oral nifedipine without the need for invasive cardiac monitoring.² Labetalol 20 mg i.v. can be given over 2 min, and increased incrementally up to 80 mg i.v. If the BP remains high, another antihypertensive agent such as hydralazine can be added. Hydralazine is a direct vasodilator and may cause adverse effects when used in large bolus doses without titration. These include maternal hypotension, increased risk of emergency Caesarean section, placental abruption and fetal tachycardia. Judicious fluid administration is recommended for women with acute-onset severe hypertension but up to 500 ml crystalloid fluid i.v. may need to be administered with i.v. hydralazine.⁵ An initial dose of hydralazine 5–10 mg i.v. over 2 min can be followed by a further 10 mg i.v. after 20 min if the BP remains high.

A suggested initial dose of immediate-release oral nifedipine is 10 mg, followed by a further 20 mg if the BP remains high after 20 min.

An i.v. infusion of glycerol trinitrate (GTN), 5–100 μg min⁻¹ titrated to effect, can be used for acute pulmonary oedema associated with severe hypertension and pre-eclampsia. Diuretics such as furosemide (20–60 mg i.v.) are also considered safe. The majority of cases of acute pulmonary oedema occur after delivery and may be associated with excessive volumes of i.v. fluids and autotransfusion after uterotonic administration. Therefore, in women with pre-eclampsia with severe features, maintenance fluids should be restricted to 80 ml h⁻¹, unless there are other ongoing fluid losses, and careful fluid balance monitoring is required.⁵ The third stage should be managed with oxytocin and ergometrine should be avoided.

Eclampsia

Eclamptic seizures are usually self-limiting but may cause maternal hypoxia and a risk of pulmonary aspiration requiring airway protection. The risk of stroke in women with eclampsia is approximately 10 times higher than women with pre-eclampsia.¹⁸ When a woman with pre-eclampsia presents with persistent neurological symptoms or signs (severe intractable headache, signs of cerebral irritability, clonus or visual disturbance) magnesium sulphate is the first-line treatment for prevention of eclamptic seizures. It is usually given as an initial loading dose of 4–6 g i.v. over 20–30 min followed by a continuous infusion of 1–2 g h⁻¹ until delivery for 24 h.⁶ Further 2–4 g boluses can be given for recurrent seizures. Magnesium sulphate can also be given i.m. into the gluteal muscle with a loading dose of 10 g given as 5 g i.m. into each buttock followed by further doses of 5 g every 4 h. Deep tendon reflexes should be monitored throughout treatment as they are diminished with magnesium toxicity. Risk of magnesium toxicity is increased in compromised renal function and can lead to reduced ventilatory frequency, low oxygen saturations and progressive muscle paralysis. The targeted serum magnesium therapeutic range is 2–4 mmol L⁻¹. Magnesium toxicity is treated with calcium gluconate (10 ml of 10% concentration given over 10 min i.v.). NICE does not recommend the use of benzodiazepines or other standard anticonvulsants as an alternative to magnesium sulphate in women with eclamptic seizures.⁵

Considerations for anaesthesia

Analgesia

Women with pre-eclampsia with severe features would benefit from neuraxial analgesia during labour as this can help reduce the sympathetic response to pain and facilitate cardiovascular stability, and offers the facility to top up the epidural for operative delivery. Neuraxial techniques are contraindicated in the presence of coagulopathy or thrombocytopaenia because of the increased risk of epidural haematoma. A recent platelet count and coagulation studies should be obtained before performing a neuraxial block in women with pre-eclampsia with severe features because of the risk of thrombocytopaenia, and more rarely DIC, either of which may present precipitously. The platelet count should be obtained within 6 h of performing regional analgesia or more recently in those with HELLP syndrome or DIC. The Association of Anaesthetists provides guidance on the relative risks related to neuraxial blockade in patients with pre-eclampsia, depending on the platelet count and coagulation status.²⁰ The risk of epidural haematoma is extremely low (<0.2%) in the presence of a platelet count >70 × 10⁹ L⁻¹.²¹ When regional analgesia is contraindicated, inhalation and parenteral analgesia may be used. Remifentanil patient-controlled analgesia (PCA) is a good alternative to regional analgesia.²²

Anaesthesia

When operative delivery is required, central neuraxial anaesthesia is preferred over general anaesthesia for most women with pre-eclampsia. Spinal, epidural or a combined spinal/epidural anaesthesia can all be used with good effect. General anaesthesia is associated with risks of airway problems and increased systemic and cerebral blood pressures during laryngoscopy leading to cerebrovascular haemorrhage. The hypertensive response to laryngoscopy must be actively managed with i.v. opioids such as alfentanil 25 μg kg⁻¹ or remifentanil 1 μg kg⁻¹, or other antihypertensive drugs such as labetalol 0.25 mg kg⁻¹ or esmolol 500 μg kg⁻¹ bolus.²³ Aim to maintain BP at pre-induction values and prevent the increase of mean arterial pressures above 110 mmHg. Any anaesthesia-related hypotension can be treated with i.v. boluses or infusions of an alpha agonist such as phenylephrine or metaraminol, titrated to effect.

It is important to continue magnesium sulphate infusions to reduce the risk of seizures, and the rate may be increased temporarily to reduce the hypertensive response to laryngoscopy. Magnesium sulphate potentiates the action of all non-depolarising neuromuscular blocking agents, so smaller doses are required. Alternatively, an intubating dose of rocuronium 1.2 mg kg⁻¹ may be used and residual block reversed using sugammadex. Magnesium does not affect the action of suxamethonium or sugammadex.

Other risks associated with general anaesthesia are failed intubation secondary to generalised airway and subglottic oedema, mucosal bleeding and pulmonary aspiration. Mallampati scores can deteriorate in labour and increase risks of failed intubation, and the use of a videolarygoscope is recommended.²⁴ A smaller-than-expected tracheal tube diameter (e.g. 5.5–6.5 mm I.D.) may also be required if there is subglottic oedema.

Monitoring

Women with pre-eclampsia should have regular monitoring of oxygen saturations, ventilatory frequency, heart rate, and noninvasive arterial pressure. Invasive arterial and central venous pressure monitoring is not required routinely but should be considered in high risk patients with resistant hypertension and heart failure. As part of accurate fluid balance assessment and to reduce the risk of pulmonary oedema, urine output should be continuously monitored as acute deterioration in renal function can occur. Women with pre-eclampsia may be managed on a labour or postnatal ward, high dependency unit, or ICU depending on the severity of symptoms, and decisions should be made by a multidisciplinary team. Transfer to the ICU should be considered under the following circumstances¹⁹:

• •Need for respiratory support, including possible intubation
• •Tachypnoea >35 breaths min⁻¹
• •Heart rate <40 or >150 beats min⁻¹
• •Need for additional vasopressor or other cardiovascular support
• •Need for more invasive monitoring
• •Abnormal ECG requiring further intervention (e.g. cardioversion)
• •Need for additional i.v. antihypertensive medication
• •Acid–base or severe electrolyte abnormalities

Follow-up

Postpartum hypertension can persist for up to 6–8 weeks, so all women should be offered follow-up 6–8 weeks after the birth. Regardless of the type of hypertensive disorder during pregnancy, all women postnatally have an increased risk of cardiovascular disease, stroke, diabetes, chronic kidney disease and venous thromboembolism, compared with women who have had normotensive pregnancies.⁴ Therefore, all of these women should have lifelong follow-up with their general practitioner arranged.

Summary

Hypertensive disorders during pregnancy continue to be a considerable cause of morbidity and mortality to both mother and fetus. Guidelines have been updated in recent years, and there are new risk prediction tools that can be used to guide decision making in women with pre-eclampsia. Anaesthetists play an important role in the care of these women, providing analgesia, anaesthesia and critical care during hypertensive emergencies. Understanding these disorders and management of their complications is vital for improving outcomes for mothers and babies.

Declaration of interests

The authors declare that they have no conflicts of interest.

MCQs

The associated MCQs (to support CME/CPD activity) are accessible at www.bjaed.org/cme/home by subscribers to BJA Education.

Biographies

Jennifer GoddardMBiol FRCA PgDip Edu is a specialty registrar in Poole who has undertaken higher training in obstetric anaesthesia.

Michael Y. K. WeeBSc (Hons) FRCA is a consultant and visiting professor at Bournemouth University. He is past Hon. Secretary of the OAA; vice-president of the Association of Anaesthetists; examiner of the Royal College of Anaesthetists and a contributor to Standards in Obstetric Anaesthesia Services. Professor Wee had published more than 40 peer-reviewed articles on obstetric anaesthesia.

Latha VinayakaraoMRCOG MRCPI is a consultant obstetrician with special interests in maternal and fetal medicine. She is the clinical lead for obstetrics at her trust, quality improvement lead for adoption of PlGF-based testing for the diagnosis of pre-eclampsia and co-lead for the Wessex Intrapartum Care Network.

Matrix codes: 1A02, 2B06, 3B00