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Hypertensive Disorders of Pregnancy: PreeclampsiaFrom eMedWiki

Hypertensive disorders of pregnancy are a leading cause of maternal and fetal morbidity and mortalityworldwide. The most life-threatening of these conditions is preeclampsia, a multisystem disorder characterisedby the development of hypertension and proteinuria after 20 weeks gestation [1]. Preeclampsia is associated withincreased risks of placental failure, cerebrovascular and cardiovascular complications, disseminatedintravascular coagulation, and maternal death [1]. Early diagnosis is imperative therefore, as close observationand prompt management could prevent potentially fatal sequelae for both mother and baby.

Contents1 Background Information

1.1 Blood Pressure in Pregnancy1.2 Hypertensive Disorders of Pregnancy

2 Diagnosis3 Epidemiology4 Risk Factors5 Pathophysiology

5.1 Molecular Mechanisms5.1.1 Abnormal Placentation5.1.2 Endothelial Activation and Dysfunction

5.2 Haemodynamic Changes6 Management7 References

Background Information

Blood Pressure in Pregnancy

Normal pregnancy is characterised by a fall in both blood pressure (BP) and peripheral vascular resistance(PVR) soon after conception [2]. An increased synthesis of vasodilating prostaglandins causes peripheralvasodilation so marked that, despite increases in cardiac output and plasma volume in the range of 40%, meanarterial pressure decreases approximately 10mmHg [2]. This decrease in BP is detectable in the first trimester,reaching a nadir in the second trimester, before rising to pre-conception levels towards the end of the thirdtrimester [3].

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Figure 1. HypertensiveDisorders of Pregnancy

Hypertensive Disorders of Pregnancy

Preeclampsia is part of a spectrum of conditions known as the hypertensive disorders of pregnancy (Figure 1).In these disorders, there is an increase in BP to:

Systolic BP ≥ 140 mmHg, and/or:Diastolic BP (Korotkoff V)≥ 90 mmHg [3]

A systolic BP of ≥160 mmHg and/or a diastolic BP of ≥ 110 mmHg indicates severe hypertension [3].

Diagnosis Criteria

ChronicHypertension

Hypertension present before pregnancy, diagnosedbefore 20 weeks' gestation, or failing to resolve within12 weeks postpartum.

Can be primary or secondary.

Preeclampsia-eclampsia

Hypertension that developed after 20 weeks' gestation(can rarely occur earlier with trophoblastic diseasessuch as hydatidiform mole), proteinuria is present.

Preeclampsiasuperimposed on

chronichypertension

New onset proteinuria after 20 weeks in a womanwithout proteinuria at start of pregnancy.

An increase in proteinuria, BP levels,thrombocytopenia or abnormal liver enzymes in thosewho already had proteinuria at the start of pregnancy.

Gestationalhypertension

Hypertension diagnosed after 20 weeks' gestation withno proteinuria.

Reclassified 3 months postpartum as 'transienthypertension' if blood pressure returns to normal.

DiagnosisThe current lack of a robust diagnostic test makes preeclampsia a challenging condition to diagnose. Thecardinal features of preeclampsia are new-onset hypertension (as described above) and proteinuria; the presenceof protein in urine, which is diagnosed by the excretion of ≥ 300mg over a 24 hour period, or protein tocreatinine ratio ≥ 30mg/mmol [5]. With this classical presentation, women typically develop the disorder after20 weeks gestation and prior to 48 hours postpartum [6].

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Figure 2. Diagnostic Criteriafor Preeclampsia [4]

Figure 3. Risk Factors forPreeclampsia [8]

However, a percentage of women present atypically with minimal or no proteinuria. Thus, preeclampsia is alsosuspected if proteinuria is absent but hypertension is accompanied by one or more of the following (Figure 2):[7]

Renal insufficiency: creatinine concentration in plasma (or serum) of more than 0.09 mmol/l or oliguria.Liver disease: raised serum transaminases, severe epigastric or right upper quadrant pain.Neurological problems: convulsions, severe headaches, persistent visualdisturbances.Haematological disturbances: thrombocytopenia, disseminatedintravascular coagulation, haemolysis.Fetal growth restriction.

Epidemiology

More than 4 million women develop preeclampsia every year [8]. The disorderis a major cause of maternal and neonatal death and morbidity worldwide,affecting approximately 5-7% of first pregnancies and recurring in 13-18% ofsubsequent pregnancies [5]. Although mortality is highest in developingcountries, preeclampsia accounts for as much as 15-20% of maternal mortalityin developed countries [9], and is responsible for a high proportion of antenatalhospital admissions, fetal growth restriction, labour inductions and the development of seizures (eclampsia) [10].Preeclampsia is expected to increase as conditions such as diabetes and obesity that place women at riskcontinue to become more prevalent.

Risk FactorsSeveral risk factors have been identified with the development of preeclampsia (Figure 3).

Nulliparity: Although having a history of severe or early preeclampsiaincreases risk in a subsequent pregnancy, preeclampsia is generallyregarded as a disease of first pregnancy [9].Genetic factors: Family studies show that the incidence is 3-4 timesgreater if a first degree relative suffered from the disorder [10].New paternity: It is more common in multigravidas who have a newpartner, suggesting that prior exposure to paternal antigens may beprotective for future pregnancies [7].Pregnancy assisted by reproductive technology: Advances intechnology have introduced several challenges for the maternal immunesystem. Women at an increased risk include those: [7]:

Older than 40Infertile during their first gestationObese with polycystic ovaries syndromePregnant by donated gametes

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Figure 4. Abnormalplacentation in preeclampsia.(Upper panel: normalpsuedovasculogenesis, lowerpanel: placental ischaemia) [11]

Medical conditions: Risk increases with chronic hypertension, diabetes mellitus, obesity, renal disease,metabolic syndrome and hypercoagulable states [6].Environment: Incidence is higher in women who live at high altitudes and in the third world, suggestingthat hypoxia and unknown environmental factors may also contribute [11].

Pathophysiology

Molecular Mechanisms

Although our understanding of the pathophysiology of preeclampsia has increased over the past 50 years, itremains quite incomplete. Current understanding of the disorder is as a two-stage process:

1. A variable first stage in which disordered vascular development of the placenta predisposes the placentato hypoxia, followed by:

2. The release of soluble factors which leads to widespread maternal vascular endothelial effects and amulti-systemic disorder. This accounts for the hypertension, proteinuria and other systemicmanifestations of preeclampsia.

Abnormal Placentation

As shown in the upper panel of Figure 4, normal placentation involves theinvasion and remodelling of uterine spiral arteries by cytotrophoblast cells ofthe placenta. These cells migrate in a retrograde manner from the decidual tothe myometrial segments, differentiating from an epithelial to an endothelialphenotype and replacing the musculoelastic walls of the spiral arteries with afibrinous material that permits them to dilate into wide, vascular sinusoids [12].This process, referred to as ‘pseudovasculogenesis’, results in a widening ofthe arteries to approximately 4-6 fold their width in non-pregnant women,thereby increasing blood flow to the developing fetoplacental unit [9].Remodelling is normally complete by 18 weeks' gestation [13].

For unknown reasons in preeclampsia, trophoblastic invasion and subsequentremodelling of the spiral arteries is deficient. Failure of the cytotrophoblasts toadopt an invasive endothelial phenotype results in shallow and incompleteendovascular invasion; it may occur in the decidual but not the myometrialsegments of the artery, and in some vessels the process does not occur at all [2].The musculoelastic walls are retained and the channels remain narrow,

resulting in spiral artery diameters that are only 40% as wide as those in a normal pregnancy [12]. This failure toconvert the spiral arteries to low-resistance vascular channels (as shown in the lower panel of Figure 4), resultsin placental ischaemia and poor placental perfusion [10].

Endothelial Activation and Dysfunction

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Figure 5. Mechanism ofendothelial dysfunction causedby sFlt-1 antagonism of VEGFand PlGF [11]

Figure 6. Enlarged swollenglomerulus (arrow) andswollen capillary endothelialcells (arrowheads) [5]

Uteroplacental hypoperfusion in turn causes the placenta to release varioussubstances that enter the mother’s circulation, including circulating solublefactor fms-like tyrosine kinase 1 (sFlt-1). sFlt-1 causes widespread dysfunctionof the maternal vascular endothelium by antagonising vascular endothelialgrowth factor (VEFG) and placental growth factor (PlGF), proteins which arerequired to maintain endothelial health in several tissues (Figure 5) [11]. Innormal pregnancy, modest concentrations of VEGF, PlGF, and sFlt-1 areproduced for healthy endothelial cells to maintain vascular integrity, preventplatelet adhesion and influence the tone of underlying vascular smooth muscle[13]. In preeclampsia however, excess soluble Flt-1 binds circulating VEGFand PlGF and prevents their interaction with endothelial cell-surface receptors[11]. This results in:

Decreased production of the vasodilators prostacyclin, prostaglandin E2, and nitric oxide by endothelialcells. In normal pregnancies, these oppose the effects of angiotensin II, which increases blood pressure bysignalling arterial vasoconstriction after binding to its receptor [6]. In preeclampsia therefore, there is anenhanced vascular sensitivity to angiotensin II and norepinephrine with subsequent vasoconstriction,causing the hypertension of preeclampsia. [11].

Inadequate production of antiagreggatory prostacyclin and nitric oxide, which leads to surface-mediatedplatelet activation. Here, platelets adhere to and release thromboplastic substances such as tissue factorand vasoconstrictor thromboxane A2. These constituents contribute to platelet aggregation and inducefibrin formation [7], accounting for the development of disseminated intravascular coagulation [12].

Activation of this coagulation cascade and loss of vascular integrity affects most maternal organ systems due tocompromised blood flow, but predominantly the kidneys, liver and brain.

Haemodynamic Changes

The endothelial abnormalities cause many of the normal physiological changesoccurring in pregnancy to be reversed.

Change Normal Pregnancy Preeclampsia

Cardiac output ↑↑ No change or↓↓

Peripheral vascular resistance(PVR) ↓↓ ↑↑

Blood pressure ↓↓ ↑↑

Glomerular filtration rate(GFR)

↑↑ 30-40% normalpregnancy ↓↓

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In the kidney, endothelial damage produces the characteristic pathologic lesion glomerular endotheliosus [14].Glomerular endotheliosus is characterised by ultrastructural changes in renal glomeruli, including:

Generalised endothelial and mesangial cell swelling which leads to a 'bloodless' glomerular capillary(Figure 6) [11].Subendothelial deposits of fibrin within the glomerular capillaries that increases the filtration surface area[6]. This causes the proteinuria in preeclampsia.

When numerous glomeruli are affected, blood flow to the cortex is reduced, possibly resulting in renal corticalnecrosis that may be bilateral and fatal [12].

ManagementAs progression from preeclampsia to eclampsia can be fatal for both mother and fetus, prevention of eclampsiais one of the primary goals in preeclampsia management. Directed by the results of initial maternal and fetalassessment, including fetal gestational age, fetal status and severity of maternal condition [7], management mayinvolve close in-hospital or out-patient monitoring, antihypertensive therapy and prophylactic intravenousmagnesium sulphate.

However, as the primary cause of preeclampsia is the placenta, only delivery of the placenta will stop thecascade of events that eventually lead to maternal and fetal death.

References

1. ↑ 1.0 1.1 "Wagner, L.K. (2004). Diagnosis and Management of Preeclampsia. American Family Physician,70(12):2317-24."

2. ↑ 2.0 2.1 2.2 "Burrow, G.N. & Ferris, T.F. (1995). Medical Complications During Pregnancy (4th ed).USA: Saunders Company."

3. ↑ 3.0 3.1 3.2 "ASSHP (2010). Concensus Statment: Hypertension in Pregnancy. Retrieved 16th May 2010,from http://www.health.nsw.gov.au/policies/PD/2005/pdf/PD2005_346.pdf"

4. ↑ "ANZCA (2008). Management of Preeclampsia & Eclampsia. Retrieved 25th May 2010, fromhttp://www.anzca.edu.au/fellows/sig/obstetric-anaesthesia-sig/"

5. ↑ 5.0 5.1 5.2 "Park, M. & Brewster, U.C. (2007). Management of Preeclampsia. Hospital Physician, pp 25-32. Retrieved 28th May 2010, from http://www.turner-white.com/memberfile.php?PubCode=hp_nov07_eclamp.pdf"

6. ↑ 6.0 6.1 6.2 6.3 "Young, B.C., Levine, R.J. & Karumanchi, S.A. (2010). Pathogenesis of Preeclampsia.Annual Review of Pathology: Mechanisms of Disease, 5: 173-92. "

7. ↑ 7.0 7.1 7.2 7.3 7.4 "Baha, S., Dekker, G. & Kupferminc, M. (2005). Preeclampsia. Lancet, 365: 785-99."8. ↑ 8.0 8.1 "Magee LA, Helewa M, Moutquin J-M, et al. (2008). Diagnosis, Evaluation, and Management of

the Hypertensive Disorders of Pregnancy. Journal of Obstetrics and Gynaecology Canada, 30:S1-S48."9. ↑ 9.0 9.1 9.2 "Wilson, M.L., Goodwin, T.M, Pan, V.L., & Ingles, S.A. (2003). Molecular Epidemiology of

Preeclampsia. Obstretical & Gynecological Survey, 58(1): 39-66."

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10. ↑ 10.0 10.1 10.2 "Beischer, N.A., Mackay, E.V. & Colditz, P.B. (1997). Obstretrics and the Newborn: AllIllustrated Textbook (3rd ed). London: Saunders Company Limited."

11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 "Karumanchi, S.A., Maynard, S.E., Stillman, I.E., Epstein, F.H. &Sukhatme, V.P. (2005). Preeclampsia: A renal perspective. Kidney International, 67: 2101-2113."

12. ↑ 12.0 12.1 12.2 12.3 "Kumar, V., Abbas, A.K., Fausto, N. & Mitchell, R. (2007). Robbins Basic Pathology(8th ed). USA: Saunders Elsevier."

13. ↑ 13.0 13.1 "Williams, D.J. & Swiet, M. (1997). The pathophysiology of preeclampsia. Intensive CareMed, 23: 620-629."

14. ↑ "Maynard, S.E., Venkatesha, S., Thadhani, R. & Karumanchi, S.A. (2005). Soluble Fms-like TyrosineKinase 1 and Endothelial Dysfunction in the Pathogenesis of Preeclampsia. Pediatric Research, 57(5 Pt2): 1R-7R."

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