Pre-eclampsia

Pre-eclampsia is the development of hypertension with proteinuria after 20 weeks of gestation. It is more commonly a disorder of women in their pregnancy. Pre-eclampsia is also known as pre eclampsia toxaemia (PET).

Epidemiology

Preeclampsia and eclampsia account for >50,000 maternal deaths yearly worldwide. It affects 1/30 and 1/60 women in their second or subsequent pregnancies. Like hypertensive disorders, the incidence of PET is correlated to ethnicity and race, most prevalent among black and Hispanic patients, resulting in approximately 26% of maternal deaths among this population in the US. Worldwide, preeclampsia effects 2% to 8% of pregnancies, but varies among race groups but also among those groups within different countries. Morbidity is higher in developing countries, particularly in Africa and Latin America.

There are several risk factors and predeterminants of preeclampsia:

• Prior hypertensive disease during a pregnancy

• Chronic hypertension

• Advanced maternal age (>40 years)

• Nulliparity

• Multifetal pregnancy

• BMI > 35kg/m2 at first visit

• Family history of preeclampsia (Incidence in daughters of mothers with PET is 1/4)

• Chronic kidney disease

• Autoimmune disease such as SLE and antiphospholipid antibody syndrome

• T1DM/T2DM

• Hydatidiform mole (molar pregnancy)

• Fetal macrosomia (A fetus larger than 4000 to 4500 grams)

• Assisted reproduction

Pathophysiology & Etiology

The exact nature of pre-eclampsia remains uncertain - nearly every major system in the body is affected by the advanced manifestations of the condition. The pathophysiology of PET is characterised by:

• Arteriolar vasoconstriction, particularly in the vascular bed of the uterus, placenta and kidneys

• Disseminated intravascular coagulation (D.I.C)

Blood pressure is determined by cardiac output and peripheral vascular resistance. As cardiac output is a function of stroke volume multiplied by heart rate, CO increases in all pregnant woman due to an increase of stroke volume. Nonetheless, CO increases but BP decreases in the mid-trimester. Thus, the most important regulatory factor of BP in pregnancy is the loss of peripheral resistance; otherwise all women would be hypertensive. There are two main pathophysiologies to PET; the first being the cause of pathological vasoconstriction and then the rise of pathologically lesions which precipitate a vicious cycle of PET.

Sympathetic tone remains unchanged, so thus PVR in pregnancy must be determined by the balance between humoral vasodilators and vasoconstrictors. In pregnancy, there is a specific loss of sensitivity to angiotensin II, which counters the effect of locally active prostaglandins, resulting in systemic vasodilation. However, any factors that increase RAAS or decrease tissue prostaglandins will result in a rise in BP, thus countering normal pregnancy changes. PET women tend to retain some sensitivity to infused AT2, and there is evidence that platelet AT2 receptors are increased, which increase the chances of vasoconstriction and platelet aggregation. There is also some current evidence that suggests PET is a disease of endothelial dysfunction - Nitric oxide (NO)/Endothelium derived relaxing factor (EDRF). In PET, NO synthesis is reduced, possibly due to inhibition of NO synthase activity. Another consideration is the damaging effects of lipid peroxides on the endothelium. Typically, production of antioxidants limit this effect, but in PET, antioxidant activity is reduced and endothelial damage occurs throughout the body, resulting in fluid loss from intravascular space. Although, these changes occur in 2nd trimester long before a rise in BP is measurable in mother.

Once vasoconstriction occurs in the placental blood, it results in placental damage and the consequent release of trophoblastic material into peripheral circulation. This material is rich in thromboplastins, which precipitate variable degrees of D.I.C. This process gives rise of pathological lesions most notably in the kidney, liver and placental bed. The renal lesions results in sodium and water retention, with most of this fluid moving into the extracellular space as plasma volume diminishes. At the same time, increased sodium retention results in increase vascular sensitivity to vasoconstriction, which promotes further vasoconstriction and tissue damage. This leads to a cycle of events that ultimately result in:

• Acute renal failure to tubular or cortical necrosis

• Hepatic failure with periportal necrosis

• Acute cardiac failure and pulmonary oedema

• Cerebral haemorrhage as BP becomes uncontrolled.

As vasoconstriction increases, the placenta becomes grossly infarcted, resulting in IUGR, increased risk of placental abruption and sometimes fetal death.

Placental pathology

Placental infarcts occur in normal pregnancy, but are more extensive in PET. THe characteristic features found are:

• Increased syncytial knots or sprouts

• Increased loss of syncytium

• Proliferation of cytotrophoblast

• Thickening of the trophoblastic basement membrane

• Villous necrosis

In the uteroplacental bed, the normal invasion of extravillous cytotrophoblast along the luminal surface of the maternal spiral arterioles does not occur beyond the deciduomyometerial junction, and there is apparent constriction, and there is apparent constriction of the vessels between the radial artery and the decidual portion - resulting in reduced uteroplacental blood flow and placental hypoxia.

Renal pathology

The characteristic appearance of renal lesion in PET is one of increased capillary cellularity and reduced vascularity. The renal lesion is histologically the most specific feature of preeclampsia:

• Swelling and proliferation of endothelial cells to such a point that capillary vessels become obstructed

• Hypertrophy and hyperplasia of the intercapillary or mesangial cells

• Profibrin deposition on the basement membrane and between and within the endothelial cells

The lesion is found in 71% of primigravid women who develop PET but only 29% of multiparous; there is a much higher incidence of women with chronic renal disease in multiparous pregnancies. The glomerular lesion is always associated with proteinuria and reduced glomerular filtration resulting in raised serum creatinine (>90). Decreased renal blood flow and proximal tubular changes result in impaired uric acid secretion, which can lead to hyperuricemia.

The placental factor theory of preeclampsia - sFlt1

Soluble fms-like tyrosine kinase 1 (sFlt-1) is a tyrosine kinase with antiangiogenic properties; it is a non-membrane associated splice variant of VEGF receptor 1 (Flt-1). sFlt-1 binds the angiogenic factoes VEGF and PLGF, reducing blood vessel growth through reduction of free VEGF and PLGF concentrations. High levels of sFlt-1 is implicated in the pathogenesis of preeclampsia.

Normally, during early formation of the placenta, extravillous cytotrophoblasts, a type of specialised fetal cell, enter the spiral arteries of the uterus. The invasion spurs remodelling of the epithelial layer of the uterine arteries, increasing their conductance and decreasing their resistance to meet the increase blood flow demands of pregnancy. Specifically, invading cytotrophoblasts achieve this by up-regulating the expression of adhesion molecules characteristic of endothelial cells in a process known as pseudovasculogenesis.

In pre-eclamptic patients, this arterial transformation is incomplete as cytotrophoblasts fail to completely switch to their adhesion molecule expression pattern to an endothelial form. The balance of pro- and anti-angiogenic factors and their receptors (VEGF-A, PLGF, Flt-1 and sFlt-1) is thought to mediate this process. In women who develop preeclampsia, the sFlt-1 to PLGF ratio is higher than normal pregnancy. sFlt-1 is produced in the placenta is thought to act in the maternal bloodstream to act on distant tissues, explaining the multi-system endothelial dysfunction observed in PET women. Adenoviral transfer of the sFlt-1 gene to pregnant rats has been shown to produce a syndrome similar to preeclampsia.

sFlt-1 is produced in small amounts by endothelial cells and monocytes, the placenta is theorised to be the major source of sFlt-1 during pregnancy. sFlt-1 mRNA shows strong expression in the placenta, and serum sFlt-1 falls significantly in patients after delivery of the placenta. Expression of sFlt-1 is stimulated by hypoxic conditions. In healthy pregnancies, the placenta develops in a hypoxic environment, leading to a 20-fold increase in sFlt-1 expression. In early-onset PET, the increase is 43 times more pronounced, and may be spurred by conditions of poor uterine profusion leading to more severe local hypoxia. Inhibition of NO signalling has also been associated with elevation of serum sFlt-1 in a rat model of PET.

History and Presentation

PET typically has a hallmark history and physical signs, although several atypical presentations may exist. The most common symptoms in patients with PET:

• New-onset frontal headache

  • Not accountable by any other alternative diagnosis (history of migraines etc)

  • Unresponsive to medication

• Blurring of vision

• Sudden onset vomiting and right epigastric pain

• Oedema

The most important symptom is the development of epigastric pain; either during pregnancy or in the immediate postpartum. It is commonly misdiagnosed or overlooked as a feature of severe pre-eclampsia and impending eclampsia.

Hyperreflexia and ankle clonus could be signs of neurological involvement and thus impending pre-eclampsia. Although, hyperreflexia may be normal in pregnancy so the presence of clonus is much more worrying.

Hypertension in pregnancy is defined as a systolic pressure above 140 mmHg or a diastolic pressure above 90 mmHg on two or more occasions at least 4 hours apart. Diastolic pressure is taken at the fifth Korotkoff sound; at times in pregnancy, there is no sound - in these circumstances, use the fourth sound. Some definitions of hypertension also include reference to a rise in systolic of at least 30mmHg and a rise in diastolic pressure of at least 15mmHg. There is no evidence that women have an adverse outcome if BP is less than 140/90. Oedema is defined as the development of pitting oedema or a weight gain in excess of 2.3kg in a week.

Patients with a SBP > 140 mmHg or a DBP > 90mmHg should raise suspicion for preeclampsia. In patients at or further than 20 weeks gestation, blood pressure reading on 2 measurements at least 4 hours apart should be evaluated with further diagnostic workup.

Diagnosis and Evaluation

Criteria for admission

• Sustained systolic >160

• Any maternal biochemical concern:

  • Rise in creatinine (>90)

  • Rise in ALT (>70, or twice upper limit of normal range)

  • Fall in platelet count (<150,000/microlitre)

• Signs of impending eclampsia, pulmonary oedema, or other signs of severe pre-eclampsia

• Suspected fetal comrpomise

• Any other clinical sign that cause concern

Maternal investigations

• 4 hourly blood pressure

• Regular urine checks

  • Screen with urine dipstick. If urine dipstick +ve, do PCR (Protein-Creatinine ratio)

    • If PCR > 0.3g/L in a 24-hour collection or 1g/L random, confirmed PET

• PCR (Protein-Creatinine ratio)

• Maternal screening screening for PET (Accuracy is unknown for twins)

  • Serum sFlt-1/PLGF (Roche)

    • <38 : Low risk

    • 38-110 : High risk

    • >110 : Confirmed PET

  • Serum PLGF (Quidel)

    • < 12pg/mL : Highly abnormal - positive (highly abnormal and suggestive of patients with severe placental dysfunction and at increased risk of pre-term birth

    • 12 pg/mL and 99 pg/mL : Abnormal - positive (suggestive of patients with placental dysfunction and at increased risk of preterm birth)

    • 100 pg/mL or more : Normal - negative (No placental dysfunction and unlikely to progress to birth within 14 days of the test)

Maternal labs

• FBC to check for thrombocytopenia and haemolysis

• U+Es for renal function

• LFT : Check liver function for hepatic involvement

• Clotting studies if severe pre-eclampsia and/or thrombocytopenia

  • Synthetic liver function & ?DIC/HELLP

• Catecholamine measurements in the presence of severe hypertension if -ve proteinuria to rule out pheochromocytoma.

Fetoplacental investigations

PET is an important cause of fetal growth restriction and perinatal death, so the fetus must be monitored closely:

• Serial ultrasounds

  • Measurements of fetal growth every 2 weeks

  • Measurements of liquor volume and fetal doppler up to twice weekly

  • Bloods twice weekly

  • Daily CTG

• Only repeat urine dip if clinically indicated/new signs symptoms

• Doppler

  • Resistance to flow in UA is a measure of placental blood vessels integrity, with raised resistance being a measure of small-vessel disease. The fetal middel cerebral artery normal has high resistance, and a fall in resistance relates to vasodilation and fetal hypoxia.

  • When resistance umbilical vessels > middle cerebral vessels, known as cerebral/placental ratio, is greater than 1, the fetus is at significant risk of morbidity associated with hypoxia

    • Consideration must be given to very close observation or delivery of these pregnancies irrespective of fetal growth parameters, albeit it that fetus' that are growth restricted from maternal PET are more likely to have abnormal CPR. At any time, absent or reverse flow in diastole in the UA indicates severe vessel disease with probable fetal compromise, and delivery of the fetus must be considered if CTG is abnormal.

  • As a single investigation, doppler US of maternal vessel after 14 weeks has not been shown to add the ability to effectively treat maternal PET.

  • Antenatal CTG measured daily in admitted cases of PET. CTG recordings are used in conjunction with Doppler assessment.

PLGF testing

There are many different types of PLGF tests that N.I.C.E recommends. We can either look at a pure PLGF ratio (Quidel, PerkinElmer PLGF 1-2-3) or sFlt-1/PLGF ratio (Roche, ThermoFisher). Cut off ratios change based on the test and whether sFlt-1/PLGF ratio or pure PLGF.

Treatment & Management

The development of more than 1+ proteinuria or a spot urinary protein/creatinine ratio of more than 0.3g/L is an absolute indication for close surveillance of the pregnancy, as this constitutes the dividing line between minimal risk and significant risk to both mother and baby.

If hypertension persists or worsens and the mother is at or close to term, the fetus should be delivered. If it considered that the fetus would benefit from further time in-utero and there is no maternal contraindication, treatment with antihypertensive drug should be considered. It must be remembered that prolonging pregnancy in PET is solely for the benefit of the fetus.

Drug therapy

In the presence of an acute hypertensive crisis, controlling the BP with medication is essential, but in the cases of mild gestational hypertension and moderate PET, their role is more contentious. There is convincing evidence that the treatment of mild or moderate chronic hypertension in pregnancy reduces the risk of developing severe hypertension and the need for hospital admission.

In women with gestational hypertension, treatment should be confined to those who fail to respond to conservative management. Stopping work should be considered for women with gestational hypertension. Early antihypertensive treatment reduces risk of progression to severe proteinuric hypertension.

BP > 170 systolic or 110 diastolic must be treated as a matter of urgency. Data from the UK maternal death enquiry in 2011 show that treatment is warranted at levels above 150/100mHg.

Drugs used for management of hypertension in pregnancy

• Methyldopa (oral)

• Hydralazine (oral and IV)

• Combined alpha and beta-blockers such as labeatol (oral or IV)

• Alpha blockers such as prazosin (oral)

• CCB such as nifedipine

ACE-I is contraindicated in pregnancy - oligohydramnios, foetal and neonatal renal failure, bony malformations, limb contractures, pulmonary hypoplasia, prolonged hypotension and neonatal death.

If acute control is required, IV bolus of hydralazine 5mg or labetalol 20mg should be administered. Where a women is <34 weeks gestation and hypertensive disease is severe enough to require delivery, betamethasone 11.4mg IM, two doses 12-24 hours apart, should be given. Steroids minimise neonatal consequences of prematurity like RDS, intraventricular hemorrhage and necrotising enterocolitis

Induction of labour

In a pregnancy complicated by hypertensive disease, delivery of the fetus should be considered for the following maternal and/or fetal/placental reasons:

Maternal

• Gestation > 37 weeks

• Uncontrollable BP, despite using 3 or more classes of antihypertensive

• HELLP

• Rising hepatic involvement

• Falling platelets

• Falling HB due to haemolysis

• Deteriorating renal function

• Eclampsia

• Acute pulmonary oedema

Fetal/placental

• Fetal compromise on CTG tracing

• Absent or reversal of end-diastolic flow in the UA

• Abnormal CPR on doppler

• No fetal growth over more than 2 weeks

• Placental abruption with fetal compromise

If the fetus is due to be delivered <30 weeks, a loading dose and an infusion of magnesium sulphate should be considered in the hour before delivery by lower uterine segment CS or during an induced labour, as it provides neuroprotection for the neonatal brain. If magnesium sulphate is used as prophylaxis of maternal seizures, no further doing is required.

Failure to induce labour when needed can lead to IUGR, fetal hypoxia and eventually death. It can also lead to placental infarction and eventual abruption.

• 34 weeks - continue surveillance unless indication for delivery

  • MgSO4

Prevention

There is no doubt that careful management and anticipation can largely prevent the occurence of eclampsia, but preventing PET should be the gold standard. The first opportunity to prevent PET is at the 12-week scan. In the mother, the finding of increased resistance in the uterine arteries at 12 weeks, along with a finding of maternal hypertension and low pregnancy associated plasma protein A/PLGF levels, has been associated with poor pregnancy outcome, in particular early-onset PET (significant PET before 32 weeks).

Advise pregnant women at high risk of pre-eclampsia to take 75mg to 150mg of apsirin daily from 12 weeks until the birth of the baby. Women at high risk include:

• Hypertensive disease during previous pregnancy

• CKD

• Autoimmune disease (SLE, anti-phospholipid syndrome)

• T1DM/T2DM

• Chronic hypertension

Advise pregnant women with more than 1 moderate risk factor for PET to take 75mg to 150mg of aspirin daily from 12 weeks until the birth of the baby:

• Nulliparity

• Age 40 years or older

• Pregnancy interval of more than 10 years

• BMI > 35kg/m2 or more at first visit

• Family history of PET

• Multifetal pregnancy

HELLP

A severe manifestation of PET is HELLP. This manifestation is an extension of DIC causing hemolysis and low platelets. There is endothelial dysfunction and hypoxia in the liver resulting in the release of liver transaminases, especially ALT. Thrombocytopenia is often rapidly progressive and if left to become severe may result in haemorrhage into the brain and the liver. It demands intervention and immediate consideration of termination of the pregnancy after any treatable manifestations such as hypertension are controlled.

Development of seizures - eclampsia

The onset of convulsions in pregnancy complicated by PET denotes the onset of eclampsia. It is more common in primigravid women. It carries serious risk of intrauterine death and maternal death from cerebral haemorrhage and/or renal and hepatic failure. All cases must be managed in a hospital with ICU. Any women admitted to hospital with seizures during pregnancy or is admitted in a coma associated with hypertension should be considered to suffer from eclampsia until proved otherwise.

Control of fits should be done with magnesium sulphate. Nonetheless, they are typically self-limiting and management is to ensure patient safety. MS also reduces platelet aggregation and minimise effects of DIC. Treatment is started with 4g given over 20 minutes. Blood levels are maintained with 1g/hour. Blood level of magnesium should only be measured if there is significant renal failure ot seizures recur (therapeutic index is 2-4 mmol/L). Greater than 5 mmol/L causes loss of patellar reflexes, and a value >6 causes respiratory depression. Magnesium can be given IM but is painful and may lead to abscess formation - preferred route is therefore by IV administration.

If platelets are >80, we can give clexane post delivery. If not, increased risk of haemorrhage. Avoid NSAIDs due to renal function and avoid ergotamines for delivery of the placenta.

Prognosis

Early diagnosis timed with intervention and appropriate maternal and fetal monitoring significantly improve maternal and fetal outcomes. As PET continues to responsible for up to a quarter of maternal deaths in certain ethnic backgrounds (Afro-caribbean and latin americans), prompt care and routine monitoring heavily decrease morbidity and mortality.

There are maternal complications associated with PET:

• Stroke

• Liver oedema, hepatic failure, HELLP

• Glomerular endothelial swelling, proteinuria, AKI

• Endothelial damage, capillary leakage, clotting disorder

• Cerebral oedema, haemorrhage and retinal detachment

• Pulmonary oedema

Differential diagnosis

• Chronic hypertension/Essential hypertension

• Secondary hypertension (Pheochromacytomas etc)

• Antiphospholipid syndrome

• Thrombotic microangiopathies

• SLE

• Epilepsy or seizure disorder

• Chronic renal disease

• Chronic liver disease

• Serotonin syndrome