Pre-eclampsia and Eclampsia

This hypertensive disorder of pregnancy is defined as a new onset of hypertension and proteinuria after 20 weeks of gestation. In Australia, we don't need proteinuria; we are happy to make the diagnosis with any sort of organ dysfunction. The definition of eclampsia is the presence of otherwise unexplainable seizures in a patient with preeclampsia.

This comes up fairly frequently in the SAQs. In broader terms, the pregnancy-related SAQs which are not about the jaundiced comatose woman are usually about the hypertensive seizure lady. These two variants between them seem to cover about 75% of the total spectrum of past paper questions. So, knowing these topics well sets you up to pass the majority of O&G material in the Part II exam. Here is a list of previous preeclampsia related questions:

  • Question 19 from the second paper of 2014 (diagnostic approach) 
  • Question 20 from the first paper of 2012  (diagnostic approach and causes of seizures) 
  • Question 23  from the first paper of 2011 (management of severe preeclampsia)
  • Question 1 from the second paper of 2008 (identical to Question 23)

Of these, several are not specifically about preeclampsia. Rather, it is the most sensible differential from a list of differentials which the candidates are expected to generate. For instance, Question 19 from the second paper of 2014 offers a scenario where a medically complex pregnant patient presents in such a manner as to bring up serotonin syndrome and PRES as sensible differentials, and preeclampsia is merely one of the possibilities.

Risk factors for preeclampsia:

There are certain features, identifiable at antenatal booking, which are associated with an increased risk of preeclampsia:

Risk factors for pre-eclampsia and eclampsia

  • First pregnancy
  • Multiple gestation
  • Obesity
  • African-American descent
  • Molar pregnancy
  • Pre-existing hypertension
  • Family history
  • Previous pre-eclampsia

Others have held forth extensively on the pathogenesis of this condition; suffice to say it is thought to be a systemic response to placental hypoperfusion, with increased activation of the potent vasoconstrictor endothelin-1, as well as an increased sensitivity to vasoconstrictors in general, and a down-regulation of vasodilatory mechanisms such as nitric oxide synthase.

Diagnostic features

In order to be labelled as a pregnant woman with preeclampsia, one must have a certain set f features:

Diagnostic criteria for preeclampsia:

  • Hypertension: 140/90 mmHg
  • Proteinuria: Over 0.3g of protein in a 24 hr collection;
    • a random urine protein./creatinine ratio over 30mg/mmol

Furthermore, there are several features which suggest that the condition is severe, and worth worrying about:

Features of severe preeclampsia:

  • Severe Hypertension: 160/110 mmHg
    • Intracranial haemorrhage or stroke can occur
  • Cardiovascular collapse:
    • Normal contractility but massively increased afterload
    • This progresses to pulmonary oedema
  • Massive Proteinuria: Over 2g of protein in a 24 hr collection;
  • Renal failure with oliguria
    • Uric acid levels may rise
  • Deranged LFTs
    • There may be hepatic oedema and rupture
  • Visual disturbance, clonus, headaches
    • this progresses to seizures, cerebral oedema and stroke
    • There may be a posterior reversible encephalopathy
  • Thrombocytopenia, DIC, haemolysis

Investigations

A standard panel of tests should be requested:

  • FBC
  • EUC
  • LFT
  • Coags
  • Uric acid levels
  • Urinalysis

Continuous ECG monitoring of the mother, and continuous foetal heart monitoring should commence.

Workup of the non-specific preeclampsia-like presentation in the pregnant patient

Question 19 from the second paper of 2014 presented a scenario with numerous possible causes for fever and decreased level of consciousness; the question from the college was mainly about generating differentials and doing a diagnostic workup. The list of differentials was enormous, made more so by the following features of the presenting history:

  • Low-grade fever
  • Hypertension, on labetalol
  • Confusion
  • Recent delivery of a stillborn foetus at 32 weeks
  • DIC as a complication of vaginal delivery
  • On paraetamol, tramadol and an SSRI
  • Background history of Hep C

With this, you could do just about any sort of differential diagnosis list. Here is a sample, adopted from the chapter on approaching the unconscious ICU patient.

Differential Diagnosis
of Unconsciousness and Fever
in the Pregnant Patient
Causes Investigations

Vascular causes:

  • Cerebral venous sinus thrombosis
  • PRES, hypertensive encephalopathy
  • Subarachnoid haemorrhage
  • CT brain +/- CT angiogram (venogram)
  • MRI brain

Infectious causes:

  • Meningitis 
  • Encephalitis without meningism
  • Neurological sequelae of systemic infection, eg. septic encephalopathy
  • Inflammatory markers
  • Blood cultures
  • Antenatal history, (i.e. thinking about Group A  streptococci)
  • LP, CSF microscopy and culture
  • CT brain to rule out brain abscess

Drug-related causes:

  • Paracetamol overdose with hepatic encephalopathy
  • Serotonin syndrome
  • Tramadol overdose
  • Overdose (or, just real party-style dosing) of recreational drugs
  • History  of drug abuse
  • Examination findings consistent with IVDU
  • Clinical features of  a recognisable toxidrome, eg. opiate, or classicl features of serotonin syndrome
  • Paracetamol level
  • CK, urinary myoglobin

Intrinsic neurological cause

  • Worsening of seizure disorder, associated with pregnancy (i.e. non-convulsive status epilepticus)
  • History of epilepsy
  • History or typical seizure control measures and compliance with them

Autoimmune causes

  • SLE-related Cerebral vasculitis
  • "Vasculitic screen" -ANA, ENA, ANCA, etc
  • CTA or MRA with contrast
  • ESR

Traumatic or environmental causes

  • Traumatic brain injury due to accident or non-accidental trauma 
  • Hypothermia or hyperthermia
  • History of domestic violence
  • History of exposure to the elements (eg. known to be homeless)
  • Clinical features consistent with non-accidental injury, eg. brusing at varying stages of evolution 

Endocrine and metabolic causes:

  • Hypoadrenalism
  • Hypothyroidism
  • Hepatic encephalopathy
  • Uremic encephalopathy
  • Wernicke's encephalopathy
  • Hyper or hyponatremia
  • Hyper or hypoglycamia
  • Numerous others!
  • Random cortisol
  • Short syncathen test
  • TFTs, free T3 and T4
  • EUC and CMP - for renal function and sodium
  • BSl, ketones, serum osmolality (HONK, hypoglycaemia)
  • Red cell transketolase (thiamine deficiency)
  • LFTs (acute hepatitis)
  • Coags (chornic hepatitis - synthetic function)
  • Ammonia level (hepatic encephalopathy, valproate overdose)
  • ABG (hypoxia, hypercapnea, acidosis of other causes)

Differentials specific to pregnancy:

  • Eclampsia or preeclampsia
  • HELLP
  • Historic details of antenatal care, eg. has anybody tested for proteinuria

Causes of worsening seizure control in pregnancy

So, perhaps it is not eclampsia but the consequences of normally well controlled epilepsy going haywire. Reasons an epileptic might have more seziures during pregnancy:

  • Poor compliance
  • Anxiety regarding teratogenicity, and cessation of drugs on those grounds
  • Increased clearance of the drug
  • Increased volume of distribution
  • Stress and sleep deprivation
  • Malabsorption of oral agents due to poor stomach emptying

Weirdly, progensterone has an antiepileptic effect, and its levels are wildly elevated in pregnancy. In fact Vajda et al (2007) did a review of this issue and found that "the epileptic process seemed to become “better” no less often than it became “worse” during pregnancy". 

Consequences of seizures in terms of perinatal morbidity and mortality

Consequences to the foetus:

Management of preeclampsia

The key step is to get the baby out. Everything returns to normal after delivery. Except pulmonary oedema: this may actually be exacerbated.

While you are organising the delivery, there are various supportive measures which should be taken:

Blood pressure control

On one hand, one must prevent maternal stroke, intracranial haemorrhage and cerebral oedema. On the other hand, one must perfuse the placenta. The key is to keep the systolic under 160, and the diastolic under 110.

Labetalol, hydralazine and nifedipine are used as first line agents. There is no difference between them in terms of outcomes.

Methyldopa and sodium nitroprusside are second-line agents, if the hypertension is refractory.

Anticonvulsants

Magnesium sulfate is the primary agent. Both Oh's manual and the RCOG statement quote the MAGPIE study, which convincingly demonstrated a reduction in maternal morbidity with magnesium. How it works, nobody knows. It has a half-life of 4 hours and is rapidly excreted (its pharmacokentics are dealt with elsewhere). One aims for a serum level of 2.0-3.5mmol/L.

Respiratory paralysis is difficult to accomplish; you need a level over 7.5mmol/L. As long as the deep tendon reflexes are present, you are unlikely to develop that sort of toxicity.

Seizure control in eclampsia

  • Give an extra dose of magnesium
  • Administer IV diazepam
  • Consider phenytoin
  • If all else fails, its time for thiopentone and intubation.

In general, there might be many possible aetiologies for the seizures, and one must consider a CT head to exclude major structural pathology.

A template approach

  • Attention to the ABCS, with management of life-threatening problems simultanous with a rapid focused examination and a brief history.
  • Airway:
    • Assess the need for airway support in context of post-ictal unconscious state
    • Weigh benefits of intubation against risks in context of the known airway access problems associated with pregnancy
  • Breathing/ventilation
    • Assess oxygenation and briefly examine for aspiration
    • High flow oxygen via NRBM if patient is not in need of immediate intubation
  • Circulatory support
    • Assess cardiovascular stability
      • left lateral 30° tilt if hypotensive
    • Access with widebore cannula
  • Immediate investigations:
    • FBC - looking for thrombocytopenia
    • LFTs - looking for HELLP, hepatic encephalopathy
    • EUC - looking for hyponatremia
    • CMP
    • Coags
    • Antiepileptic drug levels, if relevant
    • CT brain, if the patient fails to awaken
  • Specific management
    • Antihypertensives:
      • labetalol, nifedipine or hydralazine are of equivalent benefit
      • methyldopa and sodium nitroprusside are second line agents
    • Antiepileptic therapy:
      • Loading dose of magnesium sulfate, followed by an infusion, aiming at a serum level of 2.0-3.5mmol/L
      • Diazepam and phenytoin can be considered if seziures are refractory
    • Arrange for a consultation with the obstetrician regarding the safety and practicality of immediate delivery.

 

References

Oh's Intensive Care manual: Chapter 63   (pp. 677) Preeclampsia  and  eclampsia by Wai  Ka  Ming  and  Tony  Gin

RCOG Guidelines for the management of severe pre-eclampsia/eclampsia (2006)

Duckitt, Kirsten, and Deborah Harrington. "Risk factors for pre-eclampsia at antenatal booking: systematic review of controlled studies." Bmj 330.7491 (2005): 565.

Lorquet, Sophie, et al. "Aetiology and physiopathology of preeclampsia and related forms." Acta Clinica Belgica 65.4 (2010): 237-241.

Young, Brett C., Richard J. Levine, and S. Ananth Karumanchi. "Pathogenesis of preeclampsia." Annual Review of Pathological Mechanical Disease 5 (2010): 173-192.

Altman, D., et al. "Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial."Lancet 359.9321 (2002): 1877-1890.

Beach, Robert L., and Peter W. Kaplan. "Seizures in pregnancy: diagnosis and management." International review of neurobiology 83 (2008): 259-271.

Walker, S. P., M. Permezel, and S. F. Berkovic. "The management of epilepsy in pregnancy." BJOG: An International Journal of Obstetrics & Gynaecology116.6 (2009): 758-767.

Chen, Yi-Hua, et al. "Affect of seizures during gestation on pregnancy outcomes in women with epilepsy." Archives of neurology 66.8 (2009): 979-984.

Otani, Koichi. "Risk factors for the increased seizure frequency during pregnancy and puerperium." Psychiatry and Clinical Neurosciences 39.1 (1985): 33-42.

Teramo, K., et al. "Fetal heart rate during a maternal grand mal epileptic seizure." Journal of Perinatal Medicine-Official Journal of the WAPM 7.1 (1979): 3-6.

LaJoie, Josiane, and Solomon L. Moshé. "Effects of seizures and their treatment on fetal brain." Epilepsia 45.s8 (2004): 48-52.

Klein, Pave, and Andrew G. Herzog. "Hormonal effects on epilepsy in women."Epilepsia 39.s8 (1998): S9-S16.

Vajda, Frank JE, et al. "Seizure control in antiepileptic drug‐treated pregnancy." Epilepsia 49.1 (2008): 172-176.