In many centres, anaesthesia now incorporates perioperative medicine. Preeclampsia is a perioperative medical challenge requiring a multi-disciplinary team. New definitions stress the rapid progression of the disease and highlight the importance of early detection. Anaesthesiologists should understand the pathophysiology of the disease and develop the ultrasound skills required to assist in the assessment of disease severity. This facilitates the choice of anaesthesia method and perioperative management in complicated cases. Regional anaesthesia remains central, but there are important developments in the practice of general anaesthesia, if indicated. Appropriate haemodynamic monitoring should be established. Anaesthesiologists should also lead the resuscitation team in the management of cardiorespiratory failure and coagulopathy.
Preeclampsia and perioperative medicine in 2017
Hypertensive disorders of pregnancy are second only to acute obstetric haemorrhage as a direct cause of maternal death . Preeclampsia is the most prevalent high-risk condition. Pragmatic evidence-based best practices for perioperative care are essential. However, in this heterogeneous disease process, which often presents on an urgent basis, it is challenging to perform large randomised trials. Therefore, recommendations are frequently based on expert opinion and small studies. Despite extensive ongoing clinical and laboratory research, many concepts as basic as the disease pathophysiology remain unresolved. New research is elucidating the cellular origin and cardiovascular interactions; however, many implications for clinical practice remain unexplored.
Numerous authors describe the central role played by anaesthesiologists in integrating the rapidly developing field of perioperative medicine into current best practices for holistic patient care . Several departments of anaesthesiology have changed the name of the speciality to Anaesthesia and Perioperative Medicine . In particular, this applies to the management of preeclampsia, where obstetric anaesthesiologists are central to understanding the pathophysiology, assessing disease severity, and providing anaesthesia, cardiovascular monitoring, and critical care . The efforts of anaesthesiologists as part of a multi-disciplinary perioperative care team—including obstetricians, physicians, cardiologists, neonatologists, midwives and critical care specialists—can make considerable differences to short- and long-term clinical outcomes . Finally, it is important to empower patients to improve their own care journey through education and involvement in decision-making.
Prediction, screening and diagnosis of preeclampsia
Preeclampsia remains one of the leading causes of global maternal and perinatal morbidity and mortality , particularly in resource-restrained settings. Known major maternal risk factors for preeclampsia include previous preeclampsia, in particular early-onset disease, young maternal age, primiparity, pre-existing medical conditions such as anti-phospholipid syndrome, systemic lupus erythematosus (particularly with lupus nephritis), pre-existing hypertension or diabetes, and multiparity .
The International Society for the Study of Hypertension in Pregnancy have revised the diagnostic criteria for preeclampsia, with proteinuria no longer an essential requirement . After 20 weeks’ gestation, new-onset hypertension associated with proteinuria, evidence of end-organ involvement (thrombocytopaenia, renal insufficiency, impaired hepatic function, pulmonary oedema and cerebral or visual symptoms), or utero-placental dysfunction, is sufficient for diagnosis. Once diagnosed, it is recognised that preeclampsia can rapidly progress from ‘mild’ disease to severe end-organ involvement .
Early detection and referral are crucial, especially in environments with limited resources and lack of timely access to advanced health care . Even in high-resource settings, failure of early diagnosis of intrapartum hypertension was implicated in 60% of deaths . The potential benefit of early detection of preeclampsia is de-escalation of antenatal surveillance in a high-risk population where the disease has been excluded, and early commencement of prophylaxis for those at risk of recurrence . Although seemingly prudent, increased screening in high-risk populations has triggered a well-founded debate as to the clinical utility of early detection. Cost-efficacy of early detection tests as opposed to intensive antenatal surveillance [as is the current recommendation ] remains to be proven. In these patients, commencement of prophylactic agents such as aspirin and calcium is in any case recommended in early pregnancy . Unfortunately, genetic risk scores for essential hypertension have not been found to be associated with the risk of preeclampsia .
Pathophysiology and the search for biomarkers
The search for understanding of the pathophysiology of preeclampsia has unravelled likely molecular pathways related to its pathogenesis. For a successful pregnancy, extravillous and interstitial trophoblast (EVT/IVT) have to be self-sufficient, invade the maternal decidua and ultimately transform the maternal spiral arteries as endovascular trophoblast. Simultaneously, along with decidual immune cells, they must evade maternal immune surveillance . Failure of deep myometrial EVT invasion of spiral arteries results in placental hypoperfusion, hypoxia and release of factors (largely by the syncytiotrophoblast) into the maternal circulation, with consequent systemic endothelial dysfunction . Factors involved in the invasion of EVT [e.g. a disintegrin, metalloprotease-12 and pregnancy-associated plasma protein-A (PAPP-A)], maternal immune modulation (pentraxin 3), the transformation and remodelling of maternal vessels [placental protein 13 (PP13) and P-selectin], and placental hormones (hCG, activin, and inhibin) and placental factors [e.g. angiogenic factors such as soluble fms-like kinase-1, placental growth factor (PlGF) and soluble endoglin] are some of the biomarkers investigated for the early detection of preeclampsia .
Overall, despite extensive research in the field, these biomarkers have low predictive values in isolation but are better at the prediction of early- than late-onset preeclampsia. This possibly reflects pathophysiological differences. Because of the low prevalence of preeclampsia (2–8%), any good predictive test requires a high positive likelihood ratio . A recent meta-analysis examining serum screening in the first trimester to predict preeclampsia, small-for-gestational-age infants and pre-term delivery showed that no biomarker in isolation met the WHO-suggested criteria for a predictive test (positive likelihood ratio of >10 and negative likelihood ratio of <0.1; see Table 1 ). Although B-type natriuretic peptide (BNP) may be of future use in assessing severity, several studies have shown that it is an inadequate predictor of risk of developing preeclampsia .
| Biomarker | Positive likelihood ratio | Negative likelihood ratio | Sensitivity | Specificity |
|---|---|---|---|---|
| PAPP-A | 2.98 (2.55–3.41) | 0.70 (0.65–0.74) | 39% (33–47%) | 87% (82–90%) |
| PP13 | 4.20 (3.69–4.71) | 0.60 (0.53–0.66) | 47% (39–54%) | 89% (85–91%) |
| PIGF | 6.05 (5.55–6.55) | 0.48 (0.43–0.52) | 56% (52–61%) | 91% (89–92%) |
The future of prediction
Uterine artery Doppler velocimetry is a surrogate marker of the transformation status of the maternal vasculature. Although measuring flow velocity rather than true flow volumes in the placental bed vessels , it is the only single test that exceeds 60% sensitivity for the prediction of early-onset preeclampsia in a high-risk population . It has thus been useful for the prediction and prevention of placental-based adverse outcomes such as intra-uterine growth restriction or placental abruption.
Taken individually, major maternal historical risk factors (particularly a history of previous preeclampsia) have a higher predictive value than individual serum markers or uterine artery Doppler assessment. However, combination screening using clinical risk factors, multiple serum biomarkers and uterine artery velocimetry has the highest sensitivity and specificity for the prediction of preeclampsia, and is likely the future of early detection .
Prediction, screening and diagnosis of preeclampsia
Preeclampsia remains one of the leading causes of global maternal and perinatal morbidity and mortality , particularly in resource-restrained settings. Known major maternal risk factors for preeclampsia include previous preeclampsia, in particular early-onset disease, young maternal age, primiparity, pre-existing medical conditions such as anti-phospholipid syndrome, systemic lupus erythematosus (particularly with lupus nephritis), pre-existing hypertension or diabetes, and multiparity .
The International Society for the Study of Hypertension in Pregnancy have revised the diagnostic criteria for preeclampsia, with proteinuria no longer an essential requirement . After 20 weeks’ gestation, new-onset hypertension associated with proteinuria, evidence of end-organ involvement (thrombocytopaenia, renal insufficiency, impaired hepatic function, pulmonary oedema and cerebral or visual symptoms), or utero-placental dysfunction, is sufficient for diagnosis. Once diagnosed, it is recognised that preeclampsia can rapidly progress from ‘mild’ disease to severe end-organ involvement .
Early detection and referral are crucial, especially in environments with limited resources and lack of timely access to advanced health care . Even in high-resource settings, failure of early diagnosis of intrapartum hypertension was implicated in 60% of deaths . The potential benefit of early detection of preeclampsia is de-escalation of antenatal surveillance in a high-risk population where the disease has been excluded, and early commencement of prophylaxis for those at risk of recurrence . Although seemingly prudent, increased screening in high-risk populations has triggered a well-founded debate as to the clinical utility of early detection. Cost-efficacy of early detection tests as opposed to intensive antenatal surveillance [as is the current recommendation ] remains to be proven. In these patients, commencement of prophylactic agents such as aspirin and calcium is in any case recommended in early pregnancy . Unfortunately, genetic risk scores for essential hypertension have not been found to be associated with the risk of preeclampsia .
Pathophysiology and the search for biomarkers
The search for understanding of the pathophysiology of preeclampsia has unravelled likely molecular pathways related to its pathogenesis. For a successful pregnancy, extravillous and interstitial trophoblast (EVT/IVT) have to be self-sufficient, invade the maternal decidua and ultimately transform the maternal spiral arteries as endovascular trophoblast. Simultaneously, along with decidual immune cells, they must evade maternal immune surveillance . Failure of deep myometrial EVT invasion of spiral arteries results in placental hypoperfusion, hypoxia and release of factors (largely by the syncytiotrophoblast) into the maternal circulation, with consequent systemic endothelial dysfunction . Factors involved in the invasion of EVT [e.g. a disintegrin, metalloprotease-12 and pregnancy-associated plasma protein-A (PAPP-A)], maternal immune modulation (pentraxin 3), the transformation and remodelling of maternal vessels [placental protein 13 (PP13) and P-selectin], and placental hormones (hCG, activin, and inhibin) and placental factors [e.g. angiogenic factors such as soluble fms-like kinase-1, placental growth factor (PlGF) and soluble endoglin] are some of the biomarkers investigated for the early detection of preeclampsia .
Overall, despite extensive research in the field, these biomarkers have low predictive values in isolation but are better at the prediction of early- than late-onset preeclampsia. This possibly reflects pathophysiological differences. Because of the low prevalence of preeclampsia (2–8%), any good predictive test requires a high positive likelihood ratio . A recent meta-analysis examining serum screening in the first trimester to predict preeclampsia, small-for-gestational-age infants and pre-term delivery showed that no biomarker in isolation met the WHO-suggested criteria for a predictive test (positive likelihood ratio of >10 and negative likelihood ratio of <0.1; see Table 1 ). Although B-type natriuretic peptide (BNP) may be of future use in assessing severity, several studies have shown that it is an inadequate predictor of risk of developing preeclampsia .
| Biomarker | Positive likelihood ratio | Negative likelihood ratio | Sensitivity | Specificity |
|---|---|---|---|---|
| PAPP-A | 2.98 (2.55–3.41) | 0.70 (0.65–0.74) | 39% (33–47%) | 87% (82–90%) |
| PP13 | 4.20 (3.69–4.71) | 0.60 (0.53–0.66) | 47% (39–54%) | 89% (85–91%) |
| PIGF | 6.05 (5.55–6.55) | 0.48 (0.43–0.52) | 56% (52–61%) | 91% (89–92%) |
The future of prediction
Uterine artery Doppler velocimetry is a surrogate marker of the transformation status of the maternal vasculature. Although measuring flow velocity rather than true flow volumes in the placental bed vessels , it is the only single test that exceeds 60% sensitivity for the prediction of early-onset preeclampsia in a high-risk population . It has thus been useful for the prediction and prevention of placental-based adverse outcomes such as intra-uterine growth restriction or placental abruption.
Taken individually, major maternal historical risk factors (particularly a history of previous preeclampsia) have a higher predictive value than individual serum markers or uterine artery Doppler assessment. However, combination screening using clinical risk factors, multiple serum biomarkers and uterine artery velocimetry has the highest sensitivity and specificity for the prediction of preeclampsia, and is likely the future of early detection .
Cardiac pathophysiology
The current dogma is that preeclampsia features impaired invasion by EVT and abnormal vascular re-modelling of the spiral arteries. This leads to placental hypoxia, the release of inflammatory cytokines and anti-angiogenic proteins, endothelial dysfunction, and systemic hypertension with reduced organ perfusion . However, a recent review challenges the concept of a unified theory for preeclampsia . The authors theorise that the development of the disease depends upon a mismatch between maternal supply and fetal oxygen demand. Pre-placental, placental and post-placental conditions may result in relative hypoxaemia. Both vasoconstrictors and vasodilators are produced, with subsequent increased perfusion of vascular beds, which results in endothelial damage and hypertension. These theories encourage individualised therapy to match the dominant abnormality in each patient.
Transthoracic echocardiography (TTE) is useful for the assessment of critically ill pregnant women . It has been of great value in the elucidation of cardiac pathophysiology in preeclampsia. Together with prior clinical research, TTE has allowed for the confident practice of regional anaesthesia (RA) in uncomplicated severe disease. Typical echocardiographic features include increased left ventricular (LV) mass, diastolic dysfunction, and increased pericardial fluid . Cardiac output in uncomplicated severe disease is usually well preserved, as is ejection fraction – the so-called “inovasoconstrictor” state . Concomitant anaemia may further increase LV stroke work index . Early-onset disease may be associated with lower cardiac output and higher systemic vascular resistance . In addition, preterm preeclampsia has a higher prevalence of severe LV hypertrophy, and diastolic and systolic dysfunction . Echocardiographic speckle-tracking is an emerging method of measuring myocardial strain, which is more sensitive than LV ejection fraction in the detection of systolic dysfunction in preeclampsia . Recent cardiac magnetic resonance imaging studies show that the myocardial wall composition may differ from normal parturients, consisting of oedema in addition to hypertrophied muscle .
Although cardiac dysfunction is typically different from that encountered in peripartum cardiomyopathy (PPCM) , heart failure with reduced ejection fraction may occur in preeclampsia . The possibility of shared pathways of abnormal angiogenesis with PPCM remains controversial . Rarely, preeclampsia may complicate prior heart failure because of conditions such as LV non-compaction . Moderate to severe abnormalities in LV function persist a year postpartum in approximately 37% and 55% of late- and early-onset diseases, respectively . A comparison of outcome between hypertensive heart failure and PPCM showed that chronic heart failure, intracardiac thrombus, pulmonary hypertension and death were more common in PPCM . However, this does not take into account death in the immediate peripartum period due to acute cardiac failure, which does occur in preeclampsia.
Prediction of preeclampsia severity and complications
Early-onset preeclamptics more commonly have maternal complications such as HELLP syndrome and eclampsia and a higher fetal mortality . The practice of an interventionist or expectant approach in preeclampsia varies between units and individual practitioners, and depends on a balance between the risks of fetal immaturity and those of maternal deterioration or placental calamity.
Recent advances in the prediction of individualised severity and complications include the use of clinical scores, strong ion analysis of maternal acid-base status, echocardiography (possibly in combination with biomarkers such as BNP) and lung ultrasound. Ultrasonographic measurement of optic nerve sheath diameter is a new modality. Cerebral oximetry using near infrared spectroscopy has been experimentally used with promising results .
Maternal risk determination includes clinical assessment, haematological and biochemical investigations. Scoring systems such as the recent fullPIERS model may predict patients who are at high risk of adverse outcomes, and for whom expectant management is less favourable . This is a composite assessment of age, chest pain/dyspnoea, peripheral oxygen saturation, platelet count, serum creatinine and aspartate transaminase level.
Recent investigation into venous acid-base status showed that although the overall base excess in severe preeclampsia is similar to that in healthy pregnancy, preeclampsia is associated with a greater imbalance, offsetting hypoalbuminaemic alkalosis against hyperchloraemic acidosis . Rather than the absolute value of base excess, the magnitude of these opposing contributors may be a better indicator of the severity of disease. In the future, hypoalbuminaemic alkalosis may predict fetal compromise and requirement for early delivery.
Cardiologists have recently endorsed the use of focused cardiac ultrasound (foCUS) performed by non-cardiologists, typically in the perioperative setting as a point-of-care (POC) tool . Consequently, TTE has contributed to the elucidation of the cardiac pathophysiology in severe preeclampsia, and POC use enables decision-making, which influences anaesthesia and obstetric management. Key clinical questions can be rapidly answered at the bedside using simple protocols such as the Rapid Obstetric Screening Echocardiography (ROSE) scan . Valuable information may be gleaned in critically ill patients with preeclampsia concerning volume status, chamber size, and ventricular function . TTE also allows for the assessment of patient-specific abnormalities such as chronic hypertension with superimposed preeclampsia, morbid obesity, or valvular heart disease. With the expansion of interest and training, more non-cardiologists will become accredited in this field.
BNP is a promising biomarker. It is now available as a POC test and could indicate cardiac dysfunction in preeclampsia. A systematic review concluded that patients with preeclampsia had higher serum BNP levels in the third trimester than healthy parturients. Several studies in the analysis found an association between elevated BNP levels and echocardiographically demonstrated cardiac dysfunction, including raised systemic vascular resistance, decreased cardiac output, and LV diastolic dysfunction . Subsequently, early-onset preeclamptics have been found to have higher BNP levels than patients with late-onset disease, and both had higher levels than healthy parturients. Proteinuria and total protein levels correlated with the elevation of BNP levels. A cut-off of <24.5 pg·ml −1 excluded preeclampsia, with a negative predictive value of 85% . However, a study examining early prediction in the second trimester found similar plasma NT-proBNP values between women who developed preeclampsia after 34 weeks and controls . Presently, there are no studies that determined BNP cut-off levels with a high sensitivity and specificity for heart failure, either with preserved or low ejection fraction.
In addition to foCUS, lung ultrasound has become a valuable adjunct for the diagnosis of lung and/or cardiac pathology, and in 2012 the first international evidence-based guidelines were published . In a recent study, lung and cardiac ultrasound were performed in 20 women with severe preeclampsia and healthy controls. Interstitial oedema (a precursor of alveolar oedema) was found in 25% of the cases, as assessed by sonographic B-line artefacts. These are visible when interlobular oedema is present at the pleural interface, creating bright echo-dense rays which initiate at the pleura and extend to the end of the sonographic field (also known as ‘comet tails’ or ‘lung comets’, hence the name ‘echo comet score’) . High lung comet scores correlated with raised LV end-diastolic pressure, as assessed by tissue Doppler indices . A subsequent investigation found that the echo comet score was higher before than after delivery, and that tissue Doppler indices did not change after delivery. Increased extravascular lung water in preeclampsia pre-delivery could thus be associated with increased pulmonary capillary permeability rather than cardiac dysfunction .
Neurological markers of disease severity are currently being investigated. Optic nerve sheath diameter (ONSD) has been compared between preeclamptic women and healthy controls . The authors found that 19% of the patients had ONSD of >5.8 mm, which was associated with a 95% risk of raised intra-cranial pressure in other clinical settings. There was no correlation between the severity of disease and ONSD increase. Several studies in preeclampsia using cerebral imaging have shown evidence for cerebral oedema, mostly in eclamptic women. Larger series should show whether an increase in ONSD translates into an index of severity of preeclampsia, raised intracranial pressure or higher risk of eclampsia. Regional cerebral oxygen saturation (rcSO 2 ) of haemoglobin has been measured using near-infrared spectroscopy in severe preeclampsia. rcSO 2 was significantly lower in preeclamptic women but increased to control values after the administration of magnesium sulphate, while percentage change correlated negatively with blood pressure .
Anaesthesia and perioperative management
Obstetric practices in preeclampsia are well established. Prompt control of hypertension, fluid restriction, seizure prophylaxis in high-risk groups, and expedited delivery in the presence of severe maternal disease features or fetal compromise are the core principles .
The establishment of safe RA for labour and caesarean delivery in preeclampsia is one of the most important developments in the past 25 years in obstetric anaesthesia. Neuraxial anaesthesia offers advantages in preeclampsia in terms of control of hypertension and simplicity of airway management . The indications for general anaesthesia (GA) for caesarean section in preeclamptic women with preserved ejection fraction are eclampsia with altered mentation, coagulopathy, and thrombocytopaenia. Although new evidence is sparse, in HELLP syndrome most anaesthesiologists adhere to an early report , which showed that thromboelastographic maximum amplitude decreased once platelet numbers decreased to below 75 × 10 9 ·L −1 Abruptio placentae without maternal haemodynamic compromise or cardiotocograph abnormality is not a contraindication to RA. GA introduces problems of difficult tracheal intubation and hypertensive response. Therefore, ideal modern management for preeclamptics is early establishment of epidural analgesia in labour, and spinal anaesthesia for caesarean delivery in cases in whom an epidural catheter has not been sited. However, many units around the world still provide routine GA .
Only one randomised study examined fetal acid-base status in spinal versus GA . The umbilical arterial base deficit was significantly higher in the former group. More of the study vasopressor (ephedrine) was used in the spinal anaesthesia group, but the median pre-delivery dose was zero . Modern practice employing phenylephrine for closer control of blood pressure would possibly eliminate these differences.
Several published observational case series describe anaesthesia in eclampsia . Unless the usual contraindications to RA apply, spinal anaesthesia for caesarean delivery is the method of choice in patients in whom the Glasgow Coma Scale (GCS) score is ≥ 14, anti-hypertensive and magnesium sulphate therapy has been administered, and cardiac failure is absent. This includes those in whom a difficult tracheal intubation is anticipated. Patients with persistent decreased level of consciousness who require emergency delivery should receive a general anaesthetic. The occurrence of a seizure during caesarean section in a patient with preeclampsia or eclampsia is very rare, but practitioners should be prepared .
Regional anaesthesia strategies
Concerns about hypotension due to RA in uncomplicated preeclampsia with severe features were based on the perceived contracted intravascular volume. These have been unfounded and are the subject of an insightful editorial . Ideally, epidural or combined spinal-epidural anaesthesia (CSE) should be initiated early in labour, allowing extension for operative delivery in urgent cases. CSE has no clear benefits in preeclampsia. If an epidural catheter has not been placed, intrathecal anaesthesia with a small-bore atraumatic needle is appropriate. The ED50 for the spinal component of CSE was found to be similar in normotensive women and those with severe preeclampsia . In early-onset severe preeclampsia where the fetus is small for gestational age, it may be advisable to increase the spinal dose of bupivacaine, particularly in view of the low risk of hypotension.
Control of spinal hypotension
It is well established that spinal hypotension is less severe in preeclampsia , probably as a consequence of the inovasoconstrictor state . Spinal anaesthesia induces modest afterload reduction . In preeclampsia, the well-preserved or increased inotropy will usually result in effective compensation for vasodilatation. If significant hypotension occurs, this may point to the absence of severe features of preeclampsia, the presence of undiagnosed haemorrhage, cardiac failure, or concomitant valvular stenosis . Spinal hypotension is unlikely to be clinically significantly worse than hypotension associated with epidural anaesthesia . Oxytocin causes acute hypotension and should be administered slowly and in small doses . Myocardial infarction has been reported with ergometrine, which should be avoided .
In healthy parturients, there is disruption of the endothelial glycocalyx by fluid loading prior to spinal anaesthesia, which may reduce its effectiveness . Recent work demonstrates reduced mRNA transcription resulting in an altered glycocalyx structure in preeclampsia. This correlated with maternal hypertension and neonatal birth weight . If these changes are also reflected in the pulmonary endothelial glycocalyx, this would give further credence to restrictive fluid management strategies and preferential use of vasopressors in managing spinal hypotension in preeclampsia.
Preeclamptic patients require less vasopressors for the control of spinal hypotension . A randomised trial has shown that phenylephrine 50 μg is more effective than ephedrine 15 mg in restoring systemic vascular resistance after spinal hypotension. Phenylephrine reverses the reduction in systemic vascular resistance induced by spinal anaesthesia and may be superior to ephedrine for the management of acute spinal hypotension in the absence of systolic heart failure. A further randomised trial showed that the choice of vasopressor does not influence fetal acid-base status in caesarean delivery for a non-reassuring fetal heart tracing .
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