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Attila Molvarec, MD, PhD
1st Department of Obstetrics and Gynecology, Semmelweis
University, Budapest, Hungary
Hypertensive Disorders of Pregnancy
Hypertensive disorders of pregnancy
Affect 10-20% of pregnancies
Increasing incidence (increase in maternal age,
obesity, multiple pregnancies, chronic diseases)
Major causes of maternal and perinatal morbidity and
mortality
15% of preterm deliveries (In Hungary: 1200 preterm
births/year)
30% of maternal deaths
• Preeclampsia
• Superimposed preeclampsia
• Chronic hypertension
• Gestational hypertension
Classification (NHBPEP-2000)
HYPERTENSION IN PREGNANCY
hypertension after
midpregnancy with or w/o
proteinuria
=
gestational hypertension
preeclampsia
hypertension
already present before
pregnancy or diagnosed in
the first half of pregnancy
=
chronic hypertension
Causes of
Chronic Hypertension in Pregnancy
• Chronic essential hypertension (90%)
• Renal
– Acute and chronic glomerulonephritis
– Interstitial nephritis
– Diabetic glomerulosclerosis
– Renal artery stenosis
– Polycystic kidney disease
– Renal transplant
• Endocrine
– Cushing’s disease and syndrome
– Hyperaldosteronism
– Pheochromocytoma
• Other
– Coarctation of the aorta
– Collagen vascular disease
Etiology of Preeclampsia
Disease of theories
• „X” factor
• abnormal lipid metabolism
• reduced antioxidant status
• reduced production of nitric oxide
• abnormal immune response to pregnancy
• dietary calcium, magnesium, selenium content
Etiology of Preeclampsia
Disturbed interaction between NK cells and extravillous
cytotrophoblast
• HLA-E: inhibit cytolytic activity through CD94/NKG2A
• HLA-G: stimulate angiogenic cytokine (VEGF, PlGF,
angiopoietin-2) production through KIR2DL4
• HLA-C: regulate cytokine production
KIRA: inhibitory KIRB: stimulatory
HLA-C2 + KIRAA
HELLP syndrome, DIC
Eclampsia
Abruptio placentae
Pulmonary oedema
Acute renal failure
Liver failure or haemorrhage
Hypertensive encephalopathy, stroke
Death
Long-term cardiovascular morbidity
Maternal complications
Causes of Maternal Mortality in
Preeclampsia
Cerebral haemorrhage 30–40%
Pulmonary oedema 30–38%
Cerebral oedema 19%
Renal failure 10%
Coagulopathy 9%
Airway obstruction 6%
Preterm delivery
Fetal growth restriction (IUGR)
Hypoxia-neurologic injury
Perinatal death
Long-term cardiovascular morbidity
associated with low birtweight (fetal origin
of adult diseases)
Perinatal complications
Organ-specific Changes
Associated with Preeclampsia
• Cardiovascular: generalized vasospasm, increased peripheral
resistance
• Central nervous: cerebral oedema and haemorrhages
• Hepatic: periportal necrosis, subcapsular haematoma
• Renal: proteinuria, decreased GFR rate and urate excretion
• Haematological:
– platelet activation and depletion, coagulopathy
– decreased plasma volume
Symptoms of Preeclampsia
• may be asymptomatic
• headache
• visual disturbance
• epigastric and right upper abdominal pain
• oedema
• Systolic blood pressure 140–159 mmHg
• Diastolic blood pressure 90–109 mmHg
• Proteinuria >300 mg/day but <5 g/day
Criteria for Mild Preeclampsia
• Blood pressure readings with the patients at rest, of at least
160 mmHg systolic or 110 mmHg diastolic on two occasions
at least 6 h apart,
• Proteinuria levels of at least 5 g in a 24 h urine collection,
• Impaired liver function,
• Thrombocytopenia (PLT <100 000/L),
• Oliguria 24 urine output <400 ml,
• Visual disturbances, headache, epigastric pain
• Pulmonary oedema or cyanosis
Criteria for Severe Preeclampsia
Investigations for Preeclampsia
(prenatal care)
• BP and pulse rate controll
• 24 h urine collection (total protein)
• Full blood count (Hb, Htk, PLT)
• Liver and renal function
• Obs. subjective signs of preeclampsia
• Haemodynamic controll
• Ultrasound assessment
• NST
Antihypertensive Medicaments
in Preeclampsia (1)
Methyldopa:
• it has been extensively studied,
• its safe use is well established,
• it reduces systemic vascular resistance,
• peak plasma concentration reached 2 hours,
• maximum fall in arterial pressure occurs 4–8 hours
after an oral dose,
• doses: 500–3000 mg in two to four divided doses.
Antihypertensive Medicaments in
Preeclampsia (2)
Calcium channel blockers:
• nifedipine for acute and chronic treatment,
• it may be given as second-line treatment or in
combination with methyldopa or a -blocker,
• with magnesium-sulphate may result profound
hypotension,
• it does not affect on uteroplacental blood flow
Antihypertensive Medicaments in
Preeclampsia (3)
Hydralazine:
• for the acute management of hypertensive
emergencies,
• it reduces blood pressure by lowering systemic
vascular resistence,
• it has variable effect on uteroplacental blood flow,
• after volume expansion fetal distress does not occur.
Antihypertensive Medicaments in
Preeclampsia (4)
Other antihypertensive medicaments:
• cardioselective -blockers,
• - and -adrenoreceptor blocker (labetalol),
• urapidil,
• ketanserin,
• prazosin.
Future: NO donors (?), prostacyclin (?)
ACE inhibitors (Angiotensin II receptor blockers)
• 1st trimester
• Cardiovascular malformations
(RR: 3,72 95% CI: 1,89 -7,30)
• Central nervous system malformations (RR: 4,39 95% CI: 1,37-14,02)
• 2nd-3rd trimester
• Fetal hypotension, renal tubular dysplasia, anuria-
oligohydramnios, pulmonary hypoplasia, IUGR
• Hypocalvaria
• Intrauterine death
Drugs contraindicated in pregnancy
Indications for Delivery in
Patients with Preeclampsia
Maternal indications: (One or more of following)
• Uncontrolled severe hypertension (RR>160/110 mmHg despite
max. recommended doses of two antihypertensive medications)
• Eclampsia
• GOT or GPT > 2x upper limit of normal with epigastric pain
• Platelet count < 100 000/L
• Persistent severe headache or visual changes
• Pulmonary oedema
• Compromised renal function
• Abruptio placentae
Indications for Delivery in
Patients with Preeclampsia
Fetal indications:
• Severe growth retardation (fetal weight < 5th percentile)
• Pathologic NST
• Pathologic fetal or umbilical blood flow
• Biophysical profile < 6
• Severe oligohydramnios (AF index < 2)
• Gestational age > 37 weeks in mild preeclampsia
> 34 weeks in severe preeclampsia
• Decreased plasma colloid oncotic pressure
1. Used of large amount of crystalloids
2. Loss of albumin in urine and interstitium
3. Blood loss during and after delivery
• Increased capillary wedge pressure
1. Iatrogenic fluid overload
2. Postpartum mobilization of extravascular fluid
3. Impaired renal function or renal failure
• Capillary endothelial damage
1. Increased permeability
2. Increased interstitial oncotic pressure
• Left ventricular dysfunction
Mechanisms Associated with
Pulmonary Oedema in Preeclampsia
H = hemolysis
• abnormal peripheral smear
• lactate dehydrogenase (LDH) > 600 U/L
EL = elevated liver enzymes
• serum aminotransferases (AST, ALT) > 70 U/L
• lactate dehydrogenase (LDH) > 600 U/L
LP = low platelets
• platelet count < 150 000/L (Mississippi I:<50, II: 51-100,
III: 101-150)
EPIGASTRIC PAIN in 90%
HELLP syndrome (Weinstein 1982)
Histopathology
• Fibrin thrombi in portal vessels
and periportal sinusoids
• Parenchymal haemorrhage
• Hepatocellular necrosis
MAHA
Frequency: 10–15 % in severe preeclampsia
Clinical symptoms:
Malaise 100%
Nausea (with or without vomiting) 100%
Epigastric pain 90%
Right upper–quadrant tenderness on palpitation 100%
Oedema 69%
Weinstein – HELLP syndroma (n=29)
cholelythiasis peptic ulcer
cholecystitis pancreatitis
viral infection kidney stones
appendicitis pyelonephritis etc.
Imitators of HELLP syndrome: TTP, HUS, AFLP
Differential Diagnosis of HELLP syndrome
Thrombotic microangiopathies
• Frequency: 1/25000 (as in non-pregnant women)
• Pregnancy does not predispose, in the 3rd trimester or postpartum
• Thrombotic thrombocytopenic purpure (TTP): MAHA, thrombocytopenia,
neurological disturbances, renal dysfunction and fever
ADAMTS13 activity<10% (ADAMTS13 gene mutations, autoantibodies,
drugs)
• Hemolytic uremic syndrome: renal failure is dominant, neurological
symptoms are rare
Shiga- and verocytotoxin producing bacteria, pneumococcus sepsis,
complement regulatory defects (hereditary or acquired)
• Therapy: corticosteroids, plasmapheresis, IVIG, transfusion, dialysis
DIC 21%
Abruptio placentae 16%
Acute renal failure 8%
Severe ascites 8%
Pulmonary oedema 6%
Below 5%:
Subcapsular liver hematoma, ARDS,
cerebral oedema
Maternal letality: 1–24%
Maternal Complications
in 442 Patients with HELLP syndromes (Sibai BM: Am J Obstet Gynecol 1993; 169: 1000–1006)
Termination of pregnancy (SC)
Corticosteroids
Abrasion
Plasmapheresis
Hysterectomy
Management of HELLP syndrome
There is no reliable early biochemical marker (sFlt-1,
PlGF?)
Uterine artery doppler: in high-risk population
Low dose aspirin: in high-risk women
LMWH: in thrombophilias
Calcium supplementation: at high risk with low dietary
calcium intake
Not recommended: antioxidant vitamins (C, E), fish oil
Prediction and prevention of preeclampsia