Selecting emergency therapy for patients with pre-eclampsia

KEYWORDS:

• Pregnancy
• hypertension
• preeclampsia
• antihypertensive drugs
• therapy

1. Introduction

Preeclampsia (PE) is a life-threatening hypertensive disorder affecting 2–8% of pregnancies and a leading cause of adverse maternal, fetal and neonatal outcomes [1]. Although the definition of PE varies between guidelines, PE with severe features is a complex multisystem disorder characterized by severe hypertension [systolic/diastolic blood pressure (SBP/DBP) ≥160/110 mmHg on two occasions at least 4 h apart] in a previously normotensive woman or superimposed on preexisting hypertension at or after 20 weeks gestation; proteinuria (≥300 mg per 24 h; protein/creatinine ratio ≥0.3 mg/dL; dipstick reading of 2+) and/or evidence of maternal organ dysfunction: liver impairment (elevated transaminases: ALT or AST>40 IU/L ± right upper quadrant or epigastric abdominal pain), acute kidney injury (serum creatinine >1.1 mg/dL or a doubling of the serum creatinine concentration in the absence of other renal disease), hematological complications (thrombocytopenia: platelet count <150,000/μL, disseminated intravascular coagulation, hemolysis), pulmonary edema, new-onset headache unresponsive to medication or visual disturbances; and utero-placental dysfunction (e.g., fetal growth restriction, abnormal umbilical artery Doppler wave form analysis, or stillbirth) [2–7].

All women when first diagnosed of severe PE should all be assessed in hospital by a multidisciplinary team of experts in the management of hypertensive disorders of pregnancy. They should perform a fetal and maternal assessment to determine the affected organs, and planning delivery as it remains the only cure of PE. Optimal timing of delivery is based on gestational age, disease severity, and the balance between the benefits of delivery and the risks of conservative management [1]. International Guidelines discuss the time of delivery and recommend a single course of antenatal corticosteroids to accelerate fetal lung maturation in women with severe PE receiving expectant management [2–7].

Once PE is diagnosed, control of blood pressure (BP) and seizures are the priority in the emergency setting. Acute-onset severe hypertension (SBP/DBP ≥160/110 mmHg) measured and confirmed within 15 min during pregnancy or postpartum represents an obstetrical hypertensive emergency for both mother and fetus and requires in-hospital care and immediate BP reduction (within 30–60 min) to reduce maternal morbidity and mortality and to prolong the pregnancy for fetal benefit as much as possible [2–9]. Severe systolic, rather than diastolic, hypertension is the most important predictor of maternal acute cerebrovascular complications (stroke, intracranial hemorrhage, hypertensive encephalopathy), end organ damage and death, while DBP >110 mm Hg is associated with an increased risk of placental abruption and intrauterine growth restriction [2,5,6,10]. The goal is to reduce SBP to <160/105 mmHg over minutes to hours and then to achieve a sustained BP of 140–150/90–100 mm Hg to prevent prolonged exposure to severe systolic hypertension and the subsequent loss of cerebral vasculature autoregulation, and protect the pregnant woman from stroke and other end-organ damages, while maintaining utero-placental blood flow to avoid fetal distress [5,6,9]. Lowering BP to ‘normal’ ranges (<140/90 mmHg) does not confer additional benefit but might lead to maternal end-organ hypoperfusion or affect placental perfusion and fetal growth [8–10]. Thus, close maternal and fetal monitoring is recommended to avoid hypotension following antihypertensive therapy. Blood pressure measurements should be performed every 15–30 min until BP is <160/110 mmHg; then, at least 4 times daily while the woman is an inpatient, depending on clinical circumstances [7].

Severe hypertension in-hospital is treated with short-acting drugs, including intravenous labetalol and hydralazine or immediate release-IR oral nifedipine (particularly when intravenous access is not available), so that doses that can be repeated in 15–30 min if SBP/DBP persists ≥160/100 mmHg [2–9]. In some guidelines, hydralazine is no longer a first-choice drug because it produces more perinatal adverse effects than other drugs [3,7], but it can be used when nifedipine or labetalol failed to achieve BP control. Oral methyldopa is widely recommended because of its safety profile, but presents a slow onset of action and a mild antihypertensive effect, so that more women will not achieve BP goals in monotherapy [8,9]. In a retrospective cohort study in 239,454 patients with PE, the rate of patients receiving these antihypertensives increased from 37.8% in 2006 to 49.4% in 2015; during this time period, the risk for stroke for severe PE significantly decreased from 13.5 per 10,000 deliveries in 2006–2008 to 6.0 in 2012–2014 [11].

Two meta-analysis suggested that labetalol, hydralazine, and nifedipine can achieve BP control in more than 70% of women, although some differences may exist in their safety profile [12,13]. A recent open-label, randomized controlled trial compared oral labetalol, methyldopa, and nifedipine retard for treating severe hypertension in pregnancy in low-resource settings [14]. Nifedipine and labetalol, as single drugs, were significantly more effective for lowering SBP/DBP to 120–150/70–100 mmHg within 6 h than methyldopa, without differences between nifedipine and labetalol. However, more neonates born to women assigned to the nifedipine group were admitted to the intensive care unit, primarily because more low or very low birth weight babies were born to mothers in the nifedipine group. Based on these results, it was proposed to include these oral antihypertensives for the treatment of severe hypertension in pregnancy.

However, until better evidence is available, the choice between these antihypertensive drugs should be guided by the physician’s experience with a particular drug, its safety profile and patient´s characteristics (i.e. calcium-channel blockers should be selected in women of African or Caribbean family origin) and preferences [7,9]. Table 1 summarizes the first-/second-choice antihypertensive drugs recommended in several international guidelines [2–6,15].

Table 1. Antihypertensives recommended in different guidelines for the treatment of acute-severe hypertension in pregnancy. Taken from Tamargo et al. [8].

Guideline [reference]	Severe hypertension
ISSHP [2]	1. Definition: ≥160/110 mm Hg 2. Treatment: First line: labetalol (IV, oral), hydralazine (IV), nifedipine-IR (oral) Second line: oral methyldopa, nifedipine-XL, oxprenolol, prazosin
ESC [3]	1. Definition: ≥170/110 mmHg is an emergency 2. Treatment: First line: labetalol (IV), methyldopa (oral), nifedipine (IR, oral) Second choice: hydralazine (IV), urapidil (IV) Hypertensive crisis: sodium nitroprusside (IV) Preeclampsia associated with pulmonary edema: nitroglycerin (IV)
CANADIAN [4]	1. Definition: ≥160/110 mmHg 2. Treatment: First line: Labetalol (IV), hydralazine (IV), nifedipine-IR (oral) Second line: clonidine (oral), labetalol (oral), nitroglycerin (IV infusion), methyldopa (oral); captopril (oral) only post-partum
ACOG [56,]	1. Definition: ≥160/110 mm Hg 2. Treatment: First line: labetalol (IV, oral), hydralazine (IV), nifedipine-IR* (oral) Second line: nicardipine or esmolol by infusion pump
NICE [7]	1. Definition: ≥160/110 mmHg 2. Treatment: First line: labetalol (IV, oral), hydralazine (IV), nifedipine-IR (oral) Second line: oral labetalol, nifedipine-XL and methyldopa
SOMANZ [15]	1. Definition: ≥170/110 mmHg 2. Treatment: First line: diazoxide (IV), hydralazine (IV), labetalol (IV), nifedipine-IR* (oral) Second line: oral clonidine, hydralazine, labetalol, methyldopa, nifedipine-XL, oxprenolol, and prazosin

* It should be considered as first-line therapy, particularly when IV access is not yet available; labetalol can be administered orally if immediate release oral nifedipine is not available.

Drugs are presented in alphabetic order. ACOG: American College of Obstetricians and Gynecologists. CANADIAN: Canadian Hypertensive Disorders of Pregnancy Working Group. ESC: 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. IR: immediate release. ISSHP: International Society for the Study of Hypertension in Pregnancy. IV: intravenous. NICE: National Institute for Health and Care Excellence in the United Kingdom. SOMANZ: Society of Obstetric Medicine of Australia and New Zealand. XL: extended release.

Intravenous nitroglycerin is the drug of choice when PE is associated with pulmonary edema and/or coronary artery disease, and hydralazine and nitrates in the presence of hypertension, severe left ventricular dysfunction and/or evidence of congestion in decompensated heart failure [3]. Sodium nitroprusside is recommended in hypertensive crises when other treatments have failed to control the BP and delivery is imminent. However, it should be used for the shortest time possible because of the risk of maternal/fetal cyanide and thiocyanate toxicity, transient fetal bradycardia, and intracranial pressure with potential worsening of cerebral edema in the mother. Because plasma volume is reduced in PE, diuretics should be best avoided and plasma volume expansion minimized, limiting total fluids to 80–85 mL/h (1 mL/kg/h) unless there are other ongoing fluid losses (hemorrhages).

Women with a hypertensive ‘urgency’ (SBP/DBP ≥160/110 mmHg) without signs/symptoms of acute end-organ damage may be treated with oral agents to produce an initial BP reduction of less than 25% in the first hours of treatment, and a more gradual decrease over hours thereafter. A faster BP reduction may produce a fetal underperfusion, because the feto-placental unit does not autoregulate blood flow [2–6,9]. Renin-angiotensin-aldosterone system inhibitors (i.e. angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aliskiren, sacubitril/valsartan, mineralocorticoid receptor antagonists) are fetotoxic and contraindicated, while prazosin and atenolol are not recommended during pregnancy [3,7,9].

Severe postpartum hypertension can be treated as already described, but other antihypertensives (amlodipine, atenolol, amlodipine, atenolol, captopril, enalapril, nifedipine retard, quinapril) can be used [8,9]. Diuretics, methyldopa, or angiotensin receptor blockers should be avoided in breastfeeding women [8,9]. Guidelines provide contradictory recommendations on the use of nonsteroidal anti–inflammatory drugs (NSAIDs) for postpartum analgesia in women with PE. They should be avoided when BP is difficult to control or there is evidence of acute kidney injury. Postpartum thromboprophylaxis should be considered in women with PE, particularly in the presence of other risk factors.

Antihypertensive therapy for mild-moderate hypertension during pregnancy reduced the risk of severe hypertension, but had little or no effect on the risk of PE, β-adrenergic blockers, and calcium channel blockers being more effective than other antihypertensives [16]. In pregnant women with hypertension during pregnancy, the CHIPS trial showed that the tight control of maternal BP (target DBP 85 mmHg) reduced the risk of severe maternal hypertension compared with less-tight control (target DBP 100 mmHg), without differences in the risk of adverse perinatal outcomes and serious maternal complications [17]. In a post hoc analysis of this trial, severe hypertension was a risk marker for adverse maternal and perinatal outcomes, independent of BP control or PE development [18]. These findings strongly suggest that women at high risk of the complications of severe hypertension may benefit of a tight BP control.

Magnesium sulfate halves the risk of eclampsia and is the drug of choice for the prophylaxis of seizures in women with PE with severe features or severe hypertension in the intrapartum/postpartum periods, but it is not routinely recommended in PE without severe features [19]. Given prior to preterm birth magnesium sulfate prevents cerebral palsy and reduces the combined risk of fetal/infant death or cerebral palsy [20]. However, guidelines provide contradictory recommendations on the safety coadministration of magnesium sulfate and nifedipine [2–7].

2. Expert opinion

The present treatment of PE is based in controlling BP and preventing eclamptic seizures without taking into consideration the underlying pathophysiology of this complex syndrome where many organ systems are involved. However, antihypertensive therapy does not modify the pathophysiology of PE, is empirically recommended if BP is above a certain threshold (without consensus on what this should be) and few studies reported hard cardiovascular maternal and fetal outcomes beyond BP control [9]. In the next future, an improvement in early diagnosis of women at high risk of PE with severe features and the better understanding of the pathophysiology should be translated into a more rational treatment to target directly the maternal placental dysfunction leading to endothelial dysfunction and multiorgan failure. Clinical trials using maternal hemodynamics to guide the antihypertensive treatment should help us to identify which drugs provide the safer and more effective BP control and improve maternal and perinatal outcomes [21]. Finally, because women with PE are at an increased risk of cardiovascular, renal, and cerebrovascular diseases and diabetes later in life [1,22], they should receive postnatal counseling regarding the management of future pregnancies and lifestyle modification should be strongly encouraged to decrease their cardiovascular risk [1,22]. Therefore, an improvement in early detection, prevention, and physiopathology-guided management of PE with severe features hold the promise of improving the diagnosis and treatment of this multisystem disorder in the coming years. Table 2 summarizes the gaps in evidence and main challenges in the diagnosis and treatment of PE with severe features.

Table 2. Gaps in evidence and main challenges in the diagnosis and treatment of pre-eclampsia with severe features.

PE is a complex syndrome with different risk factors, clinical presentations, pathophysiology, prognosis, and response to therapy Address pathophysiological mechanisms, rather than controlling BP and preventing seizures, is the best way to improve maternal and fetal outcomes A better understanding of the pathophysiology should be translated into a more rational design of new safer and more effective of PE

(2) Prediction of pre-eclampsia is challenging, because its clinical presentation is highly variable. Current standard criteria for PE diagnosis are suboptimal because they have low predictive value to detect adverse maternal and fetal outcomes There is a need of sensitive and specific predictive algorithms that can identify in early pregnancy women at risk of developing PE Models combining biomarkers, clinical, ultrasonographic, and laboratory parameters have been developed, but they remain investigational

(3) Antihypertensive therapy does not modify the pathophysiology and is empirically recommended when BP is above a certain threshold Current recommendations for antihypertensive therapy are not based on an assessment of maternal hemodynamics It is uncertain whether a hemodynamic-guided antihypertensive therapy can favorably modify maternal and fetal outcomes Large, long-term, head-to-head comparative RCTs between the first choice drugs are needed to confirm their efficacy and safety in women with acute-onset severe hypertension Most trials are small and short term; with wide variations on how PE was defined, basal characteristics and comorbidities of the recruited population; and few studies reported hard CV maternal and fetal outcomes (i.e. cardiovascular events or mortality) beyond BP control It is necessary to know the short-/long-term outcomes for women and babies after PE

(4) There is a need for standardized, evidence-based, clinical guidelines for the prophylaxis and treatment of women with PE There are discrepancies between guidelines in the accepted standard of care for the management of acute-severe hypertension There is no consensus on the BP threshold at which antihypertensive therapy should be to started and to which levels BP should be maintained

(5) Women with a history of PE are at an increased risk of cardiovascular, renal, and diabetic complications later in life What interventions are more effective in preventing or reducing the risk of subsequent cardiovascular, renal, and diabetic burden remains unknown

BP: blood pressure. CV: cardiovascular. PE: pre-eclampsia with severe features. RCTs: randomized clinical trials.

Declaration of interest

The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

We thank P Vaquero for her invaluable technical assistance.

Additional information

Funding

This work was supported by grants from the Ministerio de Ciencia e Innovación (SAF2017-88116-P), the Instituto de Salud Carlos III [PI16/00398, CIBER-Cardiovascular (CB16/11/00303)] and the Comunidad de Madrid (B2017/BMD-3738).