Hypertensive disorders of pregnancy (ED)

The hypertensive disorders of pregnancy are the spectrum from the gestational hypertension through the pre-eclampsia and the eclampsia to the HELLP syndrome, and they are a leading cause of the maternal and the fetal morbidity and the mortality. The Fellowship candidate must recognise the spectrum and the severe features, give the magnesium sulphate for the seizure prophylaxis, control the severe-range blood pressure with the safe agent, and know that the delivery is the only cure.[1][3]

The spectrum (the classification)

The gestational hypertension is the new hypertension (the 140 over 90 or above) after the 20 weeks without the proteinuria or the end-organ dysfunction; it may progress to the pre-eclampsia. The pre-eclampsia is the new hypertension after the 20 weeks PLUS the proteinuria (the 300 mg per 24 hours, or the protein-creatinine ratio of 30 or above) or the end-organ dysfunction (the thrombocytopenia, the renal insufficiency, the impaired liver, the pulmonary oedema, the cerebral or the visual symptoms). It is subdivided into the without the severe features and the with the severe features (the blood pressure 160 over 110 or above, or the end-organ features). The eclampsia is the new-onset seizure in the woman with the pre-eclampsia. The HELLP syndrome is the haemolysis, the elevated liver enzymes, and the low platelets — the severe variant. The chronic hypertension is the pre-existing (before the 20 weeks), and the chronic hypertension with the superimposed pre-eclampsia.[1]

The pathophysiology

The pathophysiology is the incomplete trophoblastic invasion of the spiral arteries in the early pregnancy, the inadequate placental perfusion, and the release of the anti-angiogenic factors (the sFlt-1, the endoglin) with the reduction of the pro-angiogenic (the PlGF, the VEGF). This produces the widespread maternal endothelial dysfunction — the vasoconstriction, the end-organ ischaemia, the hypertension, the proteinuria, and the multi-organ involvement.[1]

The two-stage model and the angiogenic biomarkers (the sFlt-1 and the PlGF)

The pre-eclampsia is the two-stage disease of the placenta and the maternal endothelium, and the Fellowship candidate who can describe the two stages answers the viva on the mechanism. In the stage one (the early second trimester), the trophoblast fails to complete the normal second-wave invasion of the spiral arteries, so the spiral arteries remain the narrow, the high-resistance muscular vessels instead of transforming into the dilated, the low-resistance conduits. The placenta is rendered chronically ischaemic. In the stage two, the ischaemic placenta releases the anti-angiogenic factors — principally the soluble fms-like tyrosine kinase-1 (the sFlt-1) and the soluble endoglin — that bind and deplete the pro-angiogenic placental growth factor (the PlGF) and the vascular endothelial growth factor (the VEGF). The result is the generalised maternal endothelial dysfunction: the vasoconstriction, the enhanced sensitivity to the pressor agents, the capillary leak, the microthrombosis, and the activation of the coagulation cascade.[1]

The single mechanism of the endothelial dysfunction explains EVERY end-organ manifestation — the hypertension and the proteinuria from the renal endothelium, the transaminitis and the hepatic capsule pain from the hepatic endothelium, the pulmonary oedema from the pulmonary capillary leak, the thrombocytopenia from the consumption, and the cerebral vasospasm and the oedema that produce the headache, the visual disturbance, and the eclamptic seizures. This is the answer to "why does the pre-eclampsia affect every organ system?" — the unifying lesion is the endothelial dysfunction. [1]

The sFlt-1 to PlGF ratio is now the validated adjunct at the bedside. A ratio below 38 (the Elecsys assay) excludes the pre-eclampsia within the one week with the very high negative predictive value (above the 99 per cent), while a ratio above 85 (the early-onset, before the 34 weeks) or above 110 (the late-onset, at or after the 34 weeks) predicts the imminent disease. The ratio does NOT replace the clinical judgement, but it shortens the "is it the pre-eclampsia?" uncertainty in the woman with the borderline blood pressure and the atypical symptoms. [1]

The severe features

The severe features of the pre-eclampsia trigger the severe management and the consideration of the delivery: the blood pressure of 160 systolic or 110 diastolic or above on the two occasions, the thrombocytopenia (the platelets below 100), the progressive renal insufficiency (the creatinine above 1.1 or the doubled), the impaired liver function (the transaminases twice the normal) or the severe right-upper-quadrant or the epigastric pain, the pulmonary oedema, and the new-onset headache unresponsive to the analgesia or the visual symptoms (the scotomata, the blindness).[1]

The ACOG and the NICE diagnostic criteria compared

The ACOG (the American College of Obstetricians and Gynecologists, the Practice Bulletin 222) and the NICE (the National Institute for Health and Care Excellence, the guideline NG133) differ in the small print of the diagnosis but agree on the spectrum and the severe-range threshold.[1][9]

The presentation

The hypertension is often asymptomatic and detected on the routine antenatal measurement. The symptoms of the severe disease are the headache, the visual disturbance (the scotomata, the flashing, the blindness), the epigastric or the right-upper-quadrant pain, the nausea and the vomiting, the facial and the hand oedema, and the reduced fetal movements. The eclampsia presents with the tonic-clonic seizure. The HELLP presents with the malaise, the nausea, and the right-upper-quadrant pain.[1][2]

The investigations

The blood pressure (the severe range 160 over 110 or above). The urine for the proteinuria (the dipstick 1 plus or above, quantitated by the protein-creatinine ratio or the 24-hour collection; the ratio of 30 or above or the 300 mg per 24 hours). The bloods — the full blood count (the platelets), the urea and electrolytes (the creatinine), the liver function (the transaminases), the LDH and the haemolysis for the HELLP, and the coagulation. The fetal — the cardiotocography, the ultrasound for the growth and the liquor and the Doppler.[1]

The fullPIERS model (the full Pre-eclampsia Integrated Estimate of RiSk) is the validated bedside tool that estimates the probability of the major adverse maternal outcome within the 48 hours from the gestation, the chest pain, the oxygen saturation, the platelets, the creatinine, and the AST. It supports the decision to escalate or to transfer.[6]

HELLP syndrome — the criteria and the classifications

HELLP — the haemolysis, the elevated liver enzymes, the low platelets — is the severe variant of the pre-eclampsia, and uniquely it may present with the only the modest hypertension and the minimal or the no proteinuria, which makes the bedside recognition harder. The Fellowship candidate must know the Tennessee (the Sibai) diagnostic criteria and the Mississippi classes, because they appear in the short-answer questions and they grade the severity. [1]

The Mississippi classification grades the severity by the platelet nadir: the class 1 (the platelets below 50) is the most severe with the highest risk of the morbidity; the class 2 (the platelets 50 to 100); the class 3 (the platelets 100 to 150) is the least severe. The class 1 carries the substantially higher risk of the disseminated intravascular coagulation, the transfusion, the wound infection, and the maternal death.[1]

Differential diagnosis — the hypertension in pregnancy

• Chronic hypertension — present before 20 weeks gestation; no proteinuria, no end-organ damage features.
• Gestational hypertension — new hypertension after 20 weeks without proteinuria or end-organ damage; may evolve into pre-eclampsia.
• Pre-eclampsia — new hypertension after 20 weeks with proteinuria or end-organ damage (the thrombocytopenia, the transaminitis, the renal impairment, the pulmonary oedema, the neurological features).
• Eclampsia — the generalised seizure in the pre-eclamptic patient; distinguish from the epilepsy, the hypoglycaemia, the intracranial haemorrhage, and the subarachnoid haemorrhage.
• HELLP syndrome — the haemolysis, the elevated liver enzymes, the low platelets; may present with a normal blood pressure; a subset of pre-eclampsia.
• Acute fatty liver of pregnancy (AFLP) — the HELLP mimic — the hypoglycaemia, the marked transaminitis, the coagulopathy, the encephalopathy, the renal failure; the Swansea criteria support the diagnosis. The delivery is also the cure; correct the hypoglycaemia and the coagulopathy first. [1]

For the eclamptic seizure the broader differential is the epilepsy, the subarachnoid or the intracerebral haemorrhage, the hypoglycaemia, the cerebral venous sinus thrombosis, the thrombotic thrombocytopenic purpura, and the amniotic fluid embolism — but in any woman over the 20 weeks (or the recently delivered), the eclampsia is the diagnosis until excluded, and the magnesium sulphate is given first. [1]

The ED acute management

The management has three pillars — the seizure prophylaxis, the blood-pressure control, and the delivery.[1][3]

1. The ABCDE, the intravenous access, the monitoring, the continuous cardiotocography for the fetus.
2. The magnesium sulphate — the cornerstone for the seizure prophylaxis and the treatment of the severe pre-eclampsia and the eclampsia. The loading 4 to 6 grams intravenously over 20 minutes, the infusion 1 to 2 grams per hour for the 24 hours or the 24 hours postpartum. The monitoring for the toxicity — the loss of the reflexes (the early sign), the respiratory rate (below 12 to 16), the urine output, and the level of the consciousness. The calcium gluconate (the 10 per cent, the 10 mL intravenously) is the antidote for the toxicity. The Cochrane evidence confirms the magnesium sulphate halves the risk of the eclampsia and is superior to the diazepam and the phenytoin for the eclamptic seizure.[3]
3. The blood-pressure control for the severe range (the 160 over 110 or above) to prevent the stroke — the intravenous labetalol (the 10 to 20 mg, titrated), the intravenous hydralazine (the 5 mg, titrated), or the oral nifedipine (the 10 mg). The target is the 140 to 150 over 90 to 100 (the avoidance of the precipitous drop that causes the fetal distress). The ACE inhibitors, the direct renin inhibitors, and the angiotensin receptor blockers are CONTRAINDICATED (the teratogenic and the fetotoxic), and the nitroprusside (the cyanide) and the diuretics (unless the pulmonary oedema) are avoided.
4. The delivery — the only cure. The obstetric team decides the timing and the mode by the gestational age and the maternal and the fetal status. The magnesium sulphate continues through the delivery and the 24 hours postpartum.
5. The fluids — the cautious, because the endothelial dysfunction and the capillary leak raise the risk of the pulmonary oedema.
6. The transfer to the maternity or the obstetric unit with the neonatal capability.

The magnesium sulphate regimens — the Pritchard, the Zuspan and the Belfort-Magee

The three named regimens all deliver the magnesium sulphate for the seizure prophylaxis and the treatment; the choice depends on the setting and the venous access. The Fellowship candidate must know the Zuspan (the IV) and the Pritchard (the IM) regimens by heart.[4][5]

The magnesium toxicity and the antidote

The magnesium toxicity is the dose-dependent, the life-threatening complication of the therapy itself, and the candidate who cannot describe it fails the station. The progressive sequence is the loss of the deep tendon reflexes (the earliest sign), then the somnolence and the slurred speech, then the respiratory depression (the respiratory rate under the 12 per minute), then the cardiac arrest. The therapeutic range is the plasma level of the 2 to 4 mmol per litre; the loss of the reflexes begins around the 5, the respiratory depression around the 6 to 7, and the cardiac arrest above the 12. [1]

The antidote is the calcium gluconate, the 10 mL of the 10 per cent (the 1 g) given intravenously over the 10 minutes. The toxicity is prevented by the bedside monitoring of the reflexes, the respiratory rate and the urine output at the least hourly, and by the dose reduction in the renal impairment. The myth that the nifedipine and the magnesium are the absolutely contraindicated together is just the myth — the synergy is mild and the combination is safe with the blood-pressure monitoring. [1]

The antihypertensive agents compared

The first-line agents for the severe range are the labetalol, the hydralazine and the nifedipine; the choice is informed by the comorbidity and the onset required. The CHIPS Trial (the Control of Hypertension in Pregnancy Study, 2015) established that the tight control of the diastolic to the 85 mm Hg did NOT increase the risk of the small-for-gestational-age infant and reduced the frequency of the severe maternal hypertension — the avoidance of the severe range matters more than the risk of the over-correction.[7]

The delivery — the only cure and the timing ladder

The definitive treatment of the pre-eclampsia is the delivery of the baby and the placenta, which removes the ischaemic placenta driving the disease. The timing balances the maternal risk of the continuing the pregnancy against the fetal risk of the prematurity.[1][9]

The eclampsia — the first ten minutes at the bedside

The eclamptic seizure is the generalised tonic-clonic convulsion in the woman with the pre-eclampsia. It is usually the self-limiting (the one to two minutes) but it carries the risk of the hypoxia, the aspiration, the trauma and the intracranial haemorrhage. The ED response is run in the parallel: protect the airway, give the magnesium, control the blood pressure, and prepare for the delivery AFTER the stabilisation.[4][3]

The severe pre-eclampsia — the first hour at the bedside

The complications

The maternal complications are the eclampsia (the seizures), the intracranial haemorrhage and the stroke, the placental abruption, the disseminated intravascular coagulation, the pulmonary oedema, the hepatic rupture and the infarction, the HELLP, the renal failure, and the death. The fetal complications are the intrauterine growth restriction, the placental abruption, the prematurity (the iatrogenic), the intrauterine death, and the neonatal complications.[1]

The postpartum course

The pre-eclampsia may develop or worsen in the postpartum period (up to the six weeks), with the highest risk in the first 48 hours to the two weeks. The magnesium sulphate continues for the 24 hours postpartum, the blood-pressure medication continues, and the postpartum review is essential.[2]

The prevention — the aspirin prophylaxis

The woman identified as the moderate- or the high-risk for the pre-eclampsia in the first trimester is offered the low-dose aspirin 150 mg nocte from the 12 weeks until the 36 weeks. The ASPIRIN Trial (the Rolnik 2017) and the meta-analysis of the individual-patient data established that the aspirin reduces the preterm (under the 37 weeks) pre-eclampsia by about the 60 per cent in the high-risk woman, with the greatest benefit when it is started before the 16 weeks.[8] The calcium 1 to 1.5 g daily is recommended where the dietary intake is low.

The long-term maternal cardiovascular sequelae

The woman who has had the pre-eclampsia carries roughly the doubled lifetime risk of the cardiovascular disease — the ischaemic heart disease, the stroke, the hypertension, the venous thromboembolism and the chronic kidney disease. The risk is higher and earlier after the preterm pre-eclampsia, the recurrent pre-eclampsia and the HELLP. The discharge is the opportunity for the primary prevention: advise on the future risk, optimise the weight, the blood pressure and the lipids, and arrange the primary-care follow-up. The shared aetiology (the endothelial dysfunction and the metabolic syndrome) is the explanation, not the vindication.[2]

The landmark trials — the evidence base

The common pitfalls

The recurring errors are: the under-recognition of the severe features (the 160 over 110, the thrombocytopenia, the transaminitis); the omission of the magnesium sulphate for the severe pre-eclampsia; the ACE inhibitor or the direct renin inhibitor for the blood pressure (the teratogenic and the fetotoxic); the precipitous blood-pressure drop (the fetal distress); the over-resuscitation with the fluid (the pulmonary oedema); the failure to involve the obstetric team early; and the under-appreciation of the postpartum risk. [1]

The exam pearls

• The new hypertension after the 20 weeks plus the proteinuria or the end-organ dysfunction = the pre-eclampsia; the seizure = the eclampsia. Do not wait for the textbook blood pressure.
• The severe-range blood pressure is the 160 systolic or the 110 diastolic — this is the threshold for the urgent treatment to prevent the stroke.
• The magnesium sulphate is the prophylaxis AND the treatment — the loading 4 g IV over the 20 minutes, then the 1 g per hour for the 24 hours; the 2 g bolus for the recurrent seizure.
• The calcium gluconate 10 mL of the 10 per cent IV is the antidote for the magnesium toxicity. The earliest sign is the loss of the patellar reflex.
• The target blood pressure is the 140 to 150 over 90 to 100 — never the normal. The ACE inhibitors, the ARBs and the renin inhibitors are the absolutely contraindicated.
• The delivery is the only cure. The magnesium continues for the 24 hours postpartum.
• The HELLP may present with the normal blood pressure — the haemolysis, the elevated liver enzymes, the low platelets. The dexamethasone does NOT treat the established HELLP.
• The postpartum pre-eclampsia arises de novo — up to the six weeks, peaking at the 48 hours to the two weeks. The normal antenatal course does not exclude it.
• The aspirin 150 mg nocte from the 12 weeks reduces the preterm pre-eclampsia by about the 60 per cent in the high-risk woman. [1]

SAQs — exam practice

Red flags

The following features identify the severe disease or the dangerous situation, in which the magnesium sulphate and the blood-pressure control and the obstetric involvement are the priority: [1]