Assoc. Prof. RNDr. Ilona Hromadnikova, PhD.Assoc. Prof. RNDr. Ilona Hromadnikova, PhD.

Department of Molecular Biology and Cell Department of Molecular Biology and Cell Pathology, Third Faculty of Medicine, UKPathology, Third Faculty of Medicine, UK

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Pregnancy induced hypertension with proteinuria and oedema after the 20th week of gestation

Increases maternal and perinatal mortality, morbidity, prematurity and IUGR

Incidence 4-8%, perinatal mortality 4-28%, prematurity 15-40%

First pregnancy – two times higher incidence

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2/3 PEP - first pregnancy, defect of immunological adaption

Genetic predisposition – role of HLA system

Chronic diseases (diabetes mellitus, chronic hypertension, renal disorders)

Very young pregnant women, women older than 35 years (vascular lesions in uterus)

Conditions with increased oxygen requirements (mola hydatiformis, hydrops fetalis)

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1. Defect in expression of adhesive cytotrophoblast molecules → inadequate remodelation of spiral arteries → less blood flow → decreased uteroplacental perfusion

1. Ischemic placenta harms the foetus, released toxic substances and regulation factor injures also the mother

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Defect in pregnancy adaption

Trophoblast hypoperfusion (leads to release of toxic substances)

Local consequences: ischaemia of trophoblast leads to• Thrombocyte aggregation with thrombotization of spiral arteries• Hypoperfusion of intervillous space• Placental infarcts

Growth retardationPlacenta prematurity

Systemic consequences• Generalized damage of endothelial cells

↓ prostacyclin, ↓ EDRF (endothelium-derived relaxing factor)↑ vascular reactivityVasoconstriction

Glomerular endotheliosis

↑ capillary permeability↓ antithrombin IIIAggregation of thrombocytesMicroangiopathy

Multiple organ damage

Hypertension

Proteinuria

Oedema

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CNS: oedema, microbleeding → hyperreflexia, headache, nausea (↑ intracranial pressure)can lead to eclamptic attack (generalized tonic-clonic seizure, unconsciousness, coma)

Proteinuria, oligouria, anuria Liver: swelling, subcapsular bleeding → epigastrium

pain Heart: in serious cases heart failure Microthrombuses in blood vessels Uteroplacental unit: chronic placental insufficiency →

severe IUGR, placental abruption, death

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↓ ↓ PP-13 (placental protein 13) – most promising PP-13 (placental protein 13) – most promising marker for preeclamsia predictionmarker for preeclamsia prediction

↓ ↓ ADAM 12ADAM 12 ↓↓PAPP-A PAPP-A

PP-13 serum concentration in the PP-13 serum concentration in the 1st trimester (Chafetz (Chafetz et al., et al., 2007)2007)

Inhibition of angiogenesis, hypoxiaInhibition of angiogenesis, hypoxia

Key molecule: VEGF-A (vascular endothelial growth factor A)Key molecule: VEGF-A (vascular endothelial growth factor A)

VEGFR1 = sFlt-1 – VEGFR1 = sFlt-1 – ↑ ↑ production, antagonist of production, antagonist of angiogenic factors VEGF (endothelial factor), PIGF angiogenic factors VEGF (endothelial factor), PIGF (placental growth factor)(placental growth factor)

VEGFR2 = oncologicalVEGFR2 = oncological

In PET – In PET – ↑↑sFlt-1, sFlt-1, ↓↓PIGF – up to several weeks before PIGF – up to several weeks before onset, including I. trimesteronset, including I. trimester

Diagnostic criteria Blood pressure, proteinuria (phys. up to 300

mg/24h), oedema

Laboratory criteria Hyperuricemia (more than 320 μmol/l) Increased serum creatinine Hypoalbuminemia Increased levels of aminotransferases -

alaninaminotransferases a aspartataminotransferases

Hemoconcentration

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Preeclampsia classification according to Vedra and American National High Blood Pressure Education Programme (1990)

I. Preeclampsia Hypertension with proteinuria, event. oedema after the 20th week of gestation

a) Mild Milder symptoms

b) Severe BP > 160/110 mmHgProteinuria > 5g/24hOliguria < 400 ml/24hPain in epigastriumCNS: blurring of vision, hyperreflexia, headacheRetinal bleeding, Pulmonary oedema, cyanosis

II. Eclampsia Convulsive stage

III. Chronic hypertension prior to pregnancy Hypertension before the 20th week of gestation, permanent

IV. Superimposed preeclampsia Chronic HTN plus new onset proteinuria or other signs or symptoms of preeclampsia

V. Transitory hypertension After the 20th week of gestation, disappear before or up to 10 days after delivery

VI. Non-classified hypertension Hypertension diagnosed only during one examination

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Low dosage of acetylsalicylic acid – inhibition of cyclooxygenase → ↓ thromboxane A2

change of ratio from vasoconstrictive thromboxane to vasodilating prostacyclin + antioxidant effect

Calcium (lower risk of hypertension, generally therapeutic effect on preeclampsia is low)

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Mature foetus – termination of pregnancy (risk of change to severe preeclampsia)

Early pregnancy – conservative treatment with frequent monitoring Bed rest, on the left side Control of blood pressure, weight, proteinuria Laboratory tests (min. 2x a week)

Monitoring of the foetus

When symptoms of severe preeclampsia – termination of pregnancy (with no regards to fetal maturity)

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Ultrasound (biometry, amniotic fluid volume, fetal movement)

Biophysical profile Doppler ultrasound

noninvasive examination of umbilical and uteroplacental circulation – diagnosis of fetal hypoxia

Pathological circulation – first changes in uterine artheries, then in fetal ones

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Change in the frequency of a wave reflected by red blood cells moving in blood flow

RI index – resistance index , RI = 1 when no diastolic flow PI index – pulsatility index, higher pulsatility – higher PI

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S – max., systolic velocityD – min., diastolic flowV – mean velocity

Arteria uterina – characterizes uteroplacental circulation Notch – physiologically present in the 1st and in the beginning of

the 2nd trimester, if later – risk of placenta-associated disorders Lower diastolic flow - higher risk of PETBetter indicator for art. uterina – RI (improbable reverse of no flow)

Phys., 24th week of gestation Pregnancy with placenta-associated disorder15

Normal impedance to flow the uterine arteries in 1st trimester

Normal impedance to flow the uterine arteries in early 2ndtrimester

Normal impedance to flow the uterine arteries in late 2nd and 3rd trimester

Normal impedance to flow the uterine arteries (with the characteristic waveform of early diastolic notching)

Increased impedance to flow in the uterine arteries (with the characteristic waveform of early diastolic notching)

Very high resitance flow in the uterine arteries (with reverese diastolic flow)

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Screening – Notch present after 20th week of gestation and RI higher than 0,6 – necessary repetition during 24. – 26th weeks of gestation – predictors of PEP/IUGR

Arteria umbilicalis – indicator of fetoplacental circulation

Diastolic flow present from the 13th week PI decreases from 1,3 (middle gestational age)

to 0,8 (time of delivery) Information about fetal condition, monitoring

of IUGR Information up to several weeks before CTG

changes (much severe fetal hypoxia)

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Normal impedance to flow the umbilical arteries and normal pattern of pulsatility at the umbilical vein in 1st trimester

Normal impedance to flow the umbilical arteries and umbilical vein in early 2ndtrimester

Normal impedance to flow the umbilical arteries and umbilcal vein in late 2nd and 3rd trimester

Umbilical arteries- high pulsatility index

Umbilical arteries- very high pulsatility index.- end diastolic velocity- pulsation in the umbilical vein

Umbilical arteriesSevere cases absence of reversal of end diastolic frequencies

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PI decreases from 1,3 (middle gestational age) to 0,8 (time of delivery)

During pathological changes, fetal hypoxia – increase of blood flow resistance, ↑ PI, lower diastolic flow or reverse flow

Anticonvulsives

Magnesium sulfate, benzodiazepines, liquid balance

Antihypertension therapy – to prevent maternal complications: intracranial bleeding, heart failure, placenta abruption

Mild preeclampsia – metyldopa (Dopegyt), cardioselective beta-blocking agents (Vasocardin)

Accute need to decrease blood pressure - calcium channel blocker (Cordipin)

Sever preeclampsia – dihydralazine (Nepresol)

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Appearance of tonic-clonic seizures, usually after severe preeclampsia

Eclampsia sine eclampsia„silent eclampsia without seizures“ – after splitting headache

40% of eclamptic attacks after delivery

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Etiology: non-adequately treated or untreated PETPathogenesis: generalised vasospasm, hypoxia and

oedema, hypoxia and brain oedema

4 phases: 1. Prodromal – anxiety, facial spasm, headache,

epigastrium pain, nausea, sickness2. Tonic spasms3. Clonic spasms4. Coma

Generally – spasms in the second half of gestation - considered as eclampsia with subsequent therapy

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Immediate treatment of symptoms Stabilisation of mother Delivery – with no regard to fetal maturity, the

only therapy

Waiting for fetal maturity increases maternal and infantile mortality

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Foetus is smaller than expected for the corresponding gestational age

Fetal weight is below the 10th percentile for gestational age as determined through an ultrasound.

To differentiate:Foetuses constitutively small but healthy (50-80%)x small foetuses because of pathological conditions

Classification of fetal growth (Hájek a kol., 2004)

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8x times higher perinatal mortality and 10x times higher incidence of long-lasting healthy problems

Classification:1. Symmetric or primary growth

all internal organs being reduced in size 20% to 25% of all cases of growth restriction.

2. Asymmetric or secondary growth restriction head and brain being normal in size, but the

abdomen is smaller typically this is not evident until the third

trimester.

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Maternal risk factors: IUGR in previous pregnancy Chronic hypertension, preeclampsia Chronic renal disorders Maternal weight of less than 50 kg Severe anaemia Alcohol, cigarettes, drugs Poor nutrition during pregnancy Diabetes mellitus

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Fetal predispositions: Fetal infections Birth defects or chromosomal abnormalities Multiple pregnancy Female foetus (generally smaller) Low levels of amniotic fluid or oligohydramnion

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Physical constitution 40% - in some families smaller children, no increase of perinatal morbidity and mortality

Uteroplacental perfusion 40% (most often PET) Genetic factors10% Influence of environment10%

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Fundal height (between 20th – 34th week of gestation)

Ultrasound biometry Doppler ultrasound Amniotic fluid volume Fetal karyotyping, suspect to birth defects Biochemical screening Cardiotocography

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PI art. umbilicalis PI over 2SD – monitoring PI over 3SD, absence of diastolic flow, reverse flow→ termination of pregnancy

Decreased PI in a. cerebri media

Combination of ↑ PI in a. umbilicalis, ↓ PI in a. cerebri media and abnormal pulsation in v. umbilicalis – risk of cardial failure and antenatal fetal death

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Rest, diet Change of position Increase of plasma volume β-sympatomimetics – relaxation of uterus,

↑ uteroplacental perfusion Heparin and anticoagulants Aspirin Oxygen therapy Amnioinfusion (150-250 ml of phys. solution)

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Extrauterine environment more advantageous

Usually after 32nd week of gestation, no growth during last 2-3 weeks, diagnosis of hypoxia CTG: no reaction, silence Doppler ultrasound Biophysical profile: lack of breathing movements,

no movement of limbs and trunk

Induction or SC

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Effective screening programme for prediction would be very useful

Still no simple and reliable diagnostic tests Doppler ultrasound monitoring and prophylaxis

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Bell E, Nat Rev Im. 200434

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Fetal DNA (~1% of total DNA)

Maternal DNA(~99% of total DNA)

Fetal DNA (no change)

Maternal DNA (digested)

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Preeclampsia+/- IUGR:Sensitivity: 82 % (9/11)

IUGR:Sensitivity: 100% (4/4)

with 92% specificity

90% in the I. trim.(18/20)92% in the II. trim. (22/24)95% in the III. trim. (19/20)

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Preeclampsia Preeclampsia +/- IUGR:+/- IUGR:Sensitivity: 76 % Sensitivity: 76 % (16/21)(16/21)

IUGR:IUGR:Sensitivity: 60 % Sensitivity: 60 % (6/10)(6/10)

with 94 % specificitywith 94 % specificity88 % in the I. trim. (7/8)88 % in the I. trim. (7/8)100% in the II. trim. 100% in the II. trim. (10/10)(10/10)93% in the III. trim. 93% in the III. trim. (13/14)(13/14)

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Spearman´s rank correlation Spearman´s rank correlation coefficient: 0,89coefficient: 0,89(p < 0,001)(p < 0,001)

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Preeclampsia+/- IUGR :Sensitivity: 85 % (22/26)

IUGR:Sensitivity: 80%(8/10)

with 95% specificity

100% in the I. trim. (20/20)87,5% in the II. trim. (21/24)*100% in the III. trim. (20/20)

*three boundary results

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Preeclampsia - ↑ of blood pressure from the 32th week of gestation

Proteinuria, no IUGR SC 36+6, ♂ eutrophic, 3130 g Dopegyt

RASSF1A

SRY

GLO

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TK 160/100, oligohydramnion Pathological Doppler ultrasound No breathing observed PET + IUGR SC 30+5, ♀ 980 g

RASFF1A

GLO

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Fetal birth defect suspicion IUGR – 3 weeks Abnormal placenta – oedema? Pericardial exudate Susp. agenesis corpus callosum Induced abort in the 23rd w. , ♀

RASSF1A

GLO

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POSSIBLE POSSIBLE PREDICTION??PREDICTION??

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SRY gen RASSF1A gen

GLO gen

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SRY gen RASSF1A gen

GLO gen

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