Abstract
Key Practice Points
Key Facts
Severe preeclampsia and eclampsia represent the severe end of a spectrum of hypertensive disorders of pregnancy and are associated with a large proportion of the global burden of maternal and perinatal morbidity and mortality [1, 2]. Of these associated adverse events, more than 99% occur in less-developed countries [3]; more than half occur in three countries alone: India, Pakistan and Nigeria.
Definitions
Preeclampsia is broadly defined by the onset of hypertension (systolic blood pressure (BP) ≥140 mm Hg and/or diastolic BP ≥90 mm Hg) and features of end-organ involvement first diagnosed at ≥20+0 weeks of pregnancy [4, 5]. Features of target organ damage may be expanded to include placental damage, as inferred by abnormal angiogenic balance, either reduced pro-angiogenic factors (e.g., placental growth factor [PlGF]) or an abnormal ratio of anti- to pro-angiogenic factors (e.g., soluble fms-like tyrosine kinase-1 [sFlt-1]:PlGF ratio) [6–9].
Eclampsia is consistently defined as new onset and otherwise unexplained seizures in the setting of preeclampsia [10].
Key Practice Points
A broad definition of preeclampsia to include not only women with significant proteinuria offers increased safety to pregnant women. The broad definition usefully includes an anti-angiogenic factor imbalance.
Blood pressure devices should be validated for use in pregnancy and preeclampsia. If using unvalidated devices, they can be used for monitoring trends but should not guide decisions around therapeutics.
Pulse oximetry is a useful adjunct to care.
Collaboration and standardised management protocols optimise maternal and perinatal outcomes. Such women should be cared for in regional centres of excellence.
Key Actions: Accurate Measurement of Vital Signs
Measurement Errors in Aneroid and Automated BP Machines
BP measurement techniques are the same both during and outside pregnancy, including positioning and correct cuff size [11].
About half of aneroid devices give inaccurate BP readings >10 mm Hg as a result of institutional failures to maintain 6-monthly device calibration with resultant calibration drift; in contrast, the same error occurs in only 10% of mercury devices [12].
In addition, many automated devices, especially those used in critical care and high-dependency settings, are inaccurate in pregnancy [13] and most are inaccurate in preeclampsia, generally under-reading both systolic and diastolic values by 5 mm Hg, although there is considerable variation [13]. A list of validated devices is available and maintained online (www.dableducational.org/index.html); to date, few have been validated for use in pregnancy or preeclampsia specifically.
In the care of intensively monitored women, it may be reasonable to use commonly used automated devices (e.g., Dinamap) to track trends in BP, with validation of BP readings by hourly confirmation with either a validated automated or a calibrated manual device.
Pulse Oximetry
Pulse oximetry is widely available where care is provided to women with severe preeclampsia, especially in more developed countries.
In addition to heart rate and SpO2 readings, many pulse oximetry devices can provide an estimate of respiratory rate through detection of sinus arrhythmia; respiratory rate is often the most poorly observed vital sign but is critical in the early detection of pulmonary oedema.
Collaborative Approach
An important aspect of the care of women with severe preeclampsia is teamwork [14, 15]. Where women may be either severely or critically ill, an effective relationship and dialogue between obstetrics (including maternal-fetal medicine when available), obstetric internal medicine (again when available), obstetric anaesthesia, laboratory medicine, neonatology (when timing of delivery decisions need to be made around viability and transfer between institutions to ensure access to neonatal intensive care), midwifery/nursing and pharmacy are essential.
Depending upon local availability of specialist and subspecialist care, if the woman is too unstable to be transferred, or if transfer is precluded (e.g., by weather conditions), some members of the team may need to be recruited and consulted by teleconference. Ideally, virtual support systems will be planned in advance of emergency events.
In all settings, practicing the care of women with either severe preeclampsia or eclampsia through team drills will improve the quality of care received during actual events.
Place of Care
Optimally, all women with severe preeclampsia should be admitted to a tertiary centre with experience looking after such women. Therefore, women in smaller and lower-level facilities should be transferred to regional centres of excellence. However, there will be occasions when such a transfer of care is ill advised because of the status of the patient (e.g., massive subcapsular hepatic haematoma) or other factors (e.g., weather); in such circumstances, it is incumbent on the tertiary centre to provide support and advice by phone or weblink.
Time-of-Disease Assessment
Standardised Care
Standardised care and teamwork are essential to optimise maternal and fetal outcomes.
‘Bundles’ of complex care have been introduced in some centres and include the management of severe hypertension [16]. The bundle goes beyond the ‘response’ of antihypertensive therapy and both escalation measures for those unresponsive to standard treatment and postpartum follow-up to reporting and systems learning, readiness and recognition and prevention.
Formal Time-of-Disease Risk Stratification/Outcome Prediction Models
The miniPIERS (Preeclampsia Integrated Estimate of Risk) is used when laboratory tests are not readily available.
The demographics-, symptom- and sign-based miniPIERS model was developed and validated in referral centres located in Brazil, Fiji, Pakistan, South Africa and Uganda [17].The final miniPIERS model included parity (nulliparous versus multiparous), gestational age on admission, headache/visual disturbances, chest pain/dyspnoea, vaginal bleeding with abdominal pain, systolic blood pressure and dipstick proteinuria. A predicted probability ≥25% to define a ‘positive’ test classified women with 85.5% accuracy. The open-access online miniPIERS calculator is available at https://pre-empt.bcchr.ca/monitoring/minipiers.
fullPIERS for When Laboratory Tests Are Readily Available
The fullPIERS model includes demographics, symptoms, signs, and laboratory tests [18]. The fullPIERS was developed and internally validated in Australia, Canada, New Zealand and the United Kingdom [19, 20]. Following the same model development procedures as miniPIERS, independently informative predictors of adverse maternal outcomes include gestational age, chest pain or dyspnoea, oxygen saturation, platelet count and creatinine and aspartate transaminase (AST) concentrations (in the United Kingdom, alanine transaminase [ALT] can be substituted for AST). The fullPIERS model predicts adverse maternal outcomes within 48 hours of admission with preeclampsia (AUROC 0.88 [95% confidence interval [CI] 0.84–0.92], and performed well (AUROC >0.7) up to 7 days after admission [19, 20]. The fullPIERS model has been externally and temporally validated in both less and more developed country settings, is superior to the PREP (Prediction models for Risks of complications in Early-onset Pre-eclampsia) model for predicting adverse outcomes in women with early-onset preeclampsia [21] and is recommended by the 2019 update of the UK National Institute for Health and Care Excellence guidelines for pregnancy hypertension. The open-access online fullPIERS calculator is available at: https://pre-empt.bcchr.ca/monitoring/fullpiers.
CIPHER for Women Receiving Critical Care
The aim of the CIPHER (Collaborative Integrated Pregnancy High-dependency Estimate of Risk) model is to provide an internally validated multivariable prognostic model calibrated specifically for pregnant or recently delivered women admitted for critical care [22]. Predictors included in the final CIPHER model are maternal age, surgery in the preceding 24 hours, systolic blood pressure, Glasgow Coma Scale score, serum sodium, serum potassium, activated partial thromboplastin time, arterial blood gas (ABG) pH, serum creatinine and serum bilirubin. The CIPHER model is a pragmatic risk prediction tool, as it identifies critically ill pregnant women at highest risk for adverse outcomes, informs counselling of patients and their families about risk and facilitates benchmarking of outcomes between centres by adjusting for baseline risk. The open-access online CIPHER calculator is available at https://pre-empt.bcchr.ca/monitoring/cipher.
Fetal Assessment
Severe preeclampsia is often associated with significant fetal growth restriction (FGR). The computerised cardiotocograph/non-stress test (cCTG) reflects changes in fetal autonomic and chemoreceptor activity, as placental oxygenation deteriorates in women with FGR [23, 24]. Progression of the ductus venosus (DV) waveform to absent and reverse a-wave (atrial contraction) patterns is generally limited to severe and early-onset FGR [25, 26]. At ≥32 weeks, late decelerations and reduced variability noted on CTG almost invariably precede DV abnormalities [27], while fetal hypoxaemia and acidaemia result in autonomic system–mediated decreased fetal heart rate variation (i.e., lower cCTG short-term variability [cCTG-STV]). Shallow late decelerations are indicative of both fetal acidaemia and its effect on myocardial tissue [28].
Key Management
Timing and Route of Delivery
Timing of Delivery
Delivery is the only intervention that initiates resolution of preeclampsia; however, it should be remembered that it initiates and does not cure the condition. In women with severe preeclampsia, the woman’s clinical and laboratory state may well deteriorate for 24–72 hours before resolution of the condition begins. Using our definition of severe preeclampsia, all women with severe preeclampsia should be delivered immediately (either vaginally or by caesarean section), regardless of gestational age.
The phrase ‘planned delivery on the best day in the best way’ reflects the myriad of considerations regarding timing (and mode) of delivery [26]. Timing of delivery will reflect evolving complications (Table 4.1). Consensus-derived indications for delivery are (1) term gestation, (2) development of severe maternal complication(s) (Table 4.1) (3) stillbirth or (4) fetal monitoring results that indicate delivery (see the section ‘Fetal Assessment’).
| Organ system affected | Adverse conditions (that increase the risk of severe preeclampsia) | Severe preeclampsia(complications that warrant delivery irrespective of gestational age) |
|---|---|---|
| CNS | Headache/visual symptoms | Eclampsia PRES Cortical blindness or retinal detachment Glasgow Coma Scale <13 Stroke, TIA or RIND |
| Cardiorespiratory | Chest pain/dyspnoea Oxygen saturation <97% | Uncontrolled severe hypertension (over a period of 12 hours despite use of three antihypertensive agents) Oxygen saturation <90%, need for ≥50% oxygen for >1 hour, intubation (other than for caesarean section), pulmonary oedema Positive inotropic support Myocardial ischemia or infarction |
| Haematological | Elevated WBC count Elevated INR or aPTT Low platelet count | Platelet count <50 × 109/L Transfusion of any blood product |
| Renal | Elevated serum creatinine Elevated serum uric acid | Acute kidney injury (creatinine >150 µM with no prior renal disease) New indication for dialysis |
| Hepatic | Nausea or vomiting RUQ or epigastric pain Elevated serum AST, ALT, LDH or bilirubin Low plasma albumin | Hepatic dysfunction (INR >2 in absence of DIC or warfarin) Hepatic haematoma or rupture |
| Feto-placental | Non-reassuring FHR FGR Oligohydramnios Absent or reversed end-diastolic flow by Doppler velocimetry | Abruption with evidence of maternal or fetal compromise Reverse ductus venosus A wave Stillbirth |
Modified from Magee et al. [5].
ALT, alanine transaminase; aPTT, activated partial thromboplastin time; AST, aspartate transaminase; DIC, disseminated intravascular coagulation; FGR, fetal growth restriction; FHR, fetal heart rate; INR, international normalised ratio; LDH, lactate dehydrogenase; PRES, posterior reversible encephalopathy syndrome; RIND, reversible ischaemic neurological deficit; RUQ, right upper quadrant; TIA, transient ischaemic attack; WBC, white blood cell.
Currently, no tool exists to guide balancing risks, benefits and the preferences of the woman and her family.
The best treatment for the mother is always delivery, limiting her exposure to preeclampsia; therefore, expectant management is best considered when potential perinatal benefits are substantial, usually at early gestational ages. For women with non-severe preeclampsia complicated by HELLP (haemolysis, elevated liver enzymes, low platelet count) syndrome at 24+0–34+6 weeks gestation, it may be reasonable to delay delivery long enough to administer antenatal corticosteroids for acceleration of fetal pulmonary maturity, especially as there is often temporary improvement in maternal laboratory testing.
Expectant management of preeclampsia refers to attempted pregnancy prolongation following a period of maternal and fetal observation and assessment and maternal stabilisation. Expectant management should occur only in an experienced unit where neonates can be cared for at the woman’s current gestational age (as delivery cannot be accurately anticipated).
Expectant management at <24+0 weeks is associated with perinatal mortality >80% and maternal complications of 27%–71% (including one maternal death). Consequently, termination of pregnancy should be discussed.
Expectant management at 24+0–33+6 weeks may decrease neonatal respiratory distress syndrome, necrotising enterocolitis and neonatal intensive care, despite poor fetal growth velocity during the time gained [29, 30]. Rates of serious maternal complications appear very low (median < 5%) [31]; however, these low levels of maternal risk are predicated on obsessive maternal and fetal surveillance. Timing of delivery should be individualised, recognising that, on average, pregnancy prolongation is 2 weeks. If preeclampsia is complicated by HELLP syndrome, fewer days will be gained (median: 5 days) and serious maternal morbidity will be higher (median: 15%); >50% have temporary improvement of HELLP which may enable regional anaesthesia or vaginal delivery.
For late preterm preeclampsia (34+0–36+6 weeks), delaying delivery facilitates cervical ripening and vaginal delivery and reduces the risks of neonatal respiratory morbidity, but at a modest risk to mothers [32].
With term preeclampsia (37+0–42+0 weeks), labour induction is indicated to reduce poor maternal outcome (relative risk [RR] 0.61; 95% CI 0.45–0.82) [33].
Route of Delivery
All women with preeclampsia should be considered for labour induction. Choosing the mode of delivery should take into consideration both gestational age and fetal status. In severe early-onset preeclampsia with clinical evidence of fetal compromise, caesarean delivery may be preferable.
For labour induction, cervical ripening (even with an unfavourable cervix), increases the chance of vaginal delivery. With severe preeclampsia, this will take more time and be less successful compared with normotensive pregnancy. Neither FGR nor oligohydramnios are contraindications to induction.
Rates of vaginal delivery after induction are 6.7%–10% at 24–28 weeks (suggesting advisability of caesarean delivery with viable fetuses), 47.5% at 28–32 weeks, 68.8% at 32–34 weeks and 30% with birthweights <1500 g [34]. Vaginal delivery likelihood is reduced (but still exceeds 50%) when there is increased umbilical artery resistance [35].
Postnatal Course and Care
Women at greatest risk of postpartum hypertension are those who delivered preterm, and, for multiparous women, those with higher urate levels [36]. Postpartum deterioration of maternal end-organ function occurs in up to 25%, usually in the early puerperium, especially with severe disease.
De novo postpartum hypertension is most common on days 3–6 and may be either isolated or associated with preeclampsia-related end-organ dysfunction.
Non-steroidal anti-inflammatory drugs (NSAIDs), often self-administered analgesics, may exacerbate hypertension or cause acute kidney injury and may best be avoided with resistant hypertension, azotaemia or thrombocytopoenia. Initiating thromboprophylaxis should be based on number of thromboembolic risk markers, especially preeclampsia associated with adverse perinatal outcome, advanced maternal age, obesity, prolonged antenatal bed rest, postpartum haemorrhage and emergency caesarean delivery [37]. The duration of thromboprophylaxis may vary from until full mobilisation to 4–6 weeks postpartum.
Blood Pressure Control
The guidance for BP control is similar between all women during pregnancy, intrapartum or postnatally (irrespective of breastfeeding).
The implications of hypertension for the mother and baby depend both on the absolute level of BP and the rate at which it has risen. An abrupt increase in intraluminal pressure may result in mechanical distension of the cerebral vessel wall and structural damage.
Severe Hypertension
National and international guidance consistently recommends that severe pregnancy hypertension (systolic BP ≥160 mm Hg or diastolic BP ≥110 mm Hg) requires antihypertensive therapy to avoid acute cerebrovascular complications, particularly stroke. As in non-pregnancy, severe hypertension not associated with end-organ complications is usually a medical ‘urgency’ and BP can be lowered over hours. In contrast, women with end-organ complications (e.g., pulmonary oedema or acute kidney injury) should have their BP lowered over a shorter time frame; to be conservative, women with headache and visual symptoms should be regarded as having end-organ complications.
As for nonpregnancy, the goal should be to lower BP to non-severe levels (i.e., <160/110 mm Hg) over hours without reducing it by more than 25% initially, with gradual lowering over hours thereafter.
The intravascular volume depletion of preeclampsia can precipitate hypotension after the administration of antihypertensive drugs.
Hydralazine may be a less effective antihypertensive and associated with more maternal adverse effects as compared with calcium channel blockers. Hydralazine may be a more effective antihypertensive but associated with more maternal hypotension and adverse effects as compared with parenteral labetalol.
Oral nifedipine and parenteral nicardipine appear to be similarly effective for BP control as parenteral labetalol. The 10 mg nifedipine tablet may be associated with less maternal hypotension compared with the 10 mg capsule when it is bitten/punctured [38]. The 5 mg capsule may reduce the risk of a precipitous fall in BP.
In women with severe hypertension in pregnancy, single agents, nifedipine (10 mg, repeated hourly up to 30 mg) and labetalol (200 mg, repeated hourly up to 600 mg) were found to be superior to methyldopa (1000 mg as a single dose). However, while superior for maternal BP control, nifedipine use was associated with more frequent adverse neonatal events.
In summary, oral nifedipine, parenteral hydralazine and parenteral labetalol are the most commonly studied antihypertensive agents for severe hypertension. As none is clearly superior, each is a reasonable choice, in doses listed in Table 4.2.
Table 4.2 Commonly used antihypertensives for severe and non-severe pregnancy hypertension
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