Attila Molvarec, MD, PhD 1st Department of Obstetrics and Gynecology, Semmelweis University, Budapest, Hungary Hypertensive Disorders of Pregnancy
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