Marwan Alhalabi MD PhDProfessor in Reproductive Medicine Faculty of Medicine Damascus University

And

Medical Director Orient Hospital Assisted Reproduction Center Damascus – Syria

Hypertensivedisordersarethemostcommonandyetseriousconditionsseeninobstetrics

• Incidenceis5-10%.

• Themostfrequentcauseofiatrogenicprematurity.

• Pretermdelivery

• Intrauterinegrowthrestriction (IUGR)

• Perinataldeath

• Maternalcerebrovascularaccidents(CVA).

• Placentalabruption.

• Decreases during the first trimester,

• Reaching its lowest point at 20 weeks,

• Returns to pre-pregnancy levels during

the third trimester.

Classification

Pre-eclampsia

Eclampsia

Preeclampsia superimposed

on chronic hypertension

Chronic hypertension

with pregnancy

Gestational hypertension

BloodPressure≥140/90mmHgontwoormoreoccasions- inapreviouslynormotensivepatient- after20weeksgestation- withoutproteinuria- returningtonormal12weeksafterdeliveryAlmosthalfofthesedeveloppreeclampsiasyndrome

GESTATIONAL HYPERTENSION

GESTATION ≥ 20 WEEKS

SUSTAINED HYPERTENSION ( ≥ 140/90)

No proteinuria

DEFINITION

SYMPTOMS

EXAMINATION

GESTATIONAL HYPERTENSION

Sustained B.P No proteinuria

NONE

Unremarkable

GESTATIONALHYPERTENSION

CRITERIA FOR MILD GESTATIONAL HYPERTENSION

Blood Pressure > 140 to < 160 mm Hg, systolic> 90 to < 110 mm Hg, diastolic

Proteinuria < 300 mg per 24-hr collection

Platelet count > 100,000/mm3

Liver enzymes Normal

Maternal symptoms Absent

IUGR / Oligohydramnios Absent

• It is defined as hypertension of at least 140/90mm Hg

recorded on two separate occasions at least 4 hours

apart and in the presence of at least 300mg protein in a

24 hour collection of urine, arising after the 20th week of

gestation in a previously normotensive woman and

resolving completely by the 6th postpartumweek.

Preeclamsia GestationalHypertension Proteinuria

RISK FACTORS for PREECLAMPSIA

DEMOGRAPHIC

OBSTETRICS

MEDICAL

NULLIPARA(Age extremes <20yrs ,>35yrs )

1. Multiple gestation2. Molar pregnancy3. Non-immune

hydrops

1. Diabetes mellitus2. Chronic HTN3. Renal disease4. SLE

Genetic

GeneticPredisposition

FamilyHistory

Race&EthnicityMoreCommon inblack&Asians

Pregnancybyovumdonation

Age&Parity

Teenagepregnancy<18yrs

Age>35yrs

Longintervalbetween

pregnancy>10years

Nulliparity

PartnerFactors

Changeofpartner

Limitedspermexposure

Pregnancybydonor

insemination

Partner fatheredaneclampticpregnancy

PregnancyFactors

Multiplepregnancy

Hydatiformmole

Hydrops fetalis

Fetalchromosomalanomaly

(trisomy13)

UnderlyingMedicalDiseae

Chronichypertension

Diabetesmellitus

RenalDisease

Cardiovasculardisease

Hyperthyroidism

MetabolicSyndrome

Others

ObesityBMI>35kg/m2

Psychologicalstress&strainSmoking

Previoushistoryofpreeclamsia

• Hyperhomocysteinemia ,

• Autoimmune disease

• Antiphospholipid antibodies,

• Thrombophilia

MILDPREECLAMPSIA

GESTATION ≥20WEEKS

SUSTAINEDHYPERTENSION(≥140/90)

Proteinuria(≥300mg/24hr)

SYMPTOMS

EXAMINATION

PATHO-PYSIOLOGY

NONE

NONE

DiffuseVasospasmCapillaryinjury

LABORATORY FINDINGS

MANAGEMENT

Proteinuria (1-2+)Hemoconcentration

< 36 wks Conservative>36 wks MgSO4 and

Delivery

GESTATIONALHYPERTENSION

GESTATION ≥20WEEKS

SUSTAINEDHYPERTENSION(≥140/90)

NOPROTEINURIA

MILDPREECLAMPSIA

SUSTAINEDHYPERTENSION( ≥140/90)

Proteinuria( ≥300mg/24hr)

GESTATION ≥ 20WEEKS

BLOODPRESSURE

PROTEINURIA

SYMPTOMS

≥160/110

≥ 5grams

1. Headache2. Epigastricpain3. Visualchanges

LABORATORYFINDINGS

SIGNS

DICElevatedLiverenzymes

1. Pulmonaryedema2. Oliguria3. cyanosis

• new onset of seizures or unexplained coma

during pregnancy in patients with pre-existing

preeclampsia and without pre-existing

neurological disorder.

• addition of convulsions in a womanwith preeclampsia

• occurs in 0.5-4% of deliveries

• 25% have eclamptic seizures before labour, 50% duringlabour, and 25% after delivery.

Eclampsia PreeclampsiaSeizure/

Convulsion/Coma

rebra

SYMPTOMS

PATHO-PYSIOLOGY

RISKFACTORS SameasPreeclampsia

Cerebralvasospasm,ischemiaandedema

Generalizedtonic-clonicSEIZURES

ECLAMPSIA

LABORATORYFINDINGS

MANAGEMENT

• Proteinuria• Hemoconcentration• DIC• ElevatedLiverenzymes

1. StopconvulsionswithMgSO42. Promptdeliveryatanygestational

age3. LowerdiastolicBP90-100mm/Hg

ECLAMPSIA

MANAGEMENT

IVMgSO4– Topreventconvulsions(continue24hrspost-partum)

LOWERB.P(hydralazineorlabetalol)

INDUCELABOR(IVoxytocin andamniotomy )

• Bloodpressure≥140/90before20weeksofgestation.

OR

• persistenceofhypertensionbeyond12weeksafterdelivery.

CHRONICHYPERTENSION

GESTATION<20WEEKSORPrepragnancy

SUSTAINEDHYPERTENSION(≥140/90)

+/- PROTEINURIA

GOODPROGNOSIS

POORPROGNOSIS

WORSTPROGNOSIS

B.P140/90to179/109Noendorgandamage

KIDNEYS:RenaldiseaseEYES:RetinopathyHEART:LeftVentricularHypertrophy(B.P>180/110)

UncontrolledHTNChronicHTN+SuperimposedPIH

MANAGEMENTOFCHRONICHYPERTENSION

Ifantihypertensivemedsneeded- Methyldopa isdrugofchoice(orlabetalol)

Serialultrasounds(increaseriskofIUGR>30weeks)

Inducelaboratterm

DCantihypertensivemeds(ifB.P>100mmHgdiastolic)

SerialB.Pandurineprotein(watchforsuperimposedpreeclampsia)

• New-onsetproteinuria> 300mg/24hrsinhypertensivewomenbutnoproteinuriabefore20wks gestation.

• Asuddenincreaseinproteinuriaorbloodpressureorplateletcount<100,000/cumminwomenwithhypertensionandproteinuriabefore20wksgestation.

CHRONICHTNSUPERIMPOSEDPIH

CHRONICHYPERTENSION

WorseningBLOODPRESSURE

Worseningproteinuria

MANAGEMENTofChronicHTNandsuperimposedPIH

MgSO4– Topreventconvulsions(continue24hrspost-partum)

LOWERB.P- Diastolic90-100mmHg(hydralazineorlabetalol)

INDUCELABOR(IVoxytocin andamniotomy )

• HTNpatientswithhemolysis (H),elevatedliverenzymes(EL),lowplatelet count(LP)

• 4-12% ofpt.withseverepreeclampsiaandeclampsiadevelopHELLPsyndrome

• cardiovascularstabilization,correctionofcoagulationabnormalities,anddelivery

• PLTtransfusionbeforeorafterdeliveryifPLTcountis<20,000/mm3 (advisedat<50,000/mm3 beforecesarean)• <32weeksgestation;steroidtherapy

mayhelpstabilizematernalPLTcount

• Complex disease• Appearstobetriggeredbytheplacenta• Canoccurinmolar

pregnancieswherefetusabsent

• Canalsooccurinabdominalpregnancy(pregnancynotinuterus)

Stage03-8weeks

Stage18-18weeks

Stage220weeksto

birth

PoorImmunoregulationInadequatetolerancetofeto-paternalantigensduring conceptionandimplantation

PoorPlacentationDeficienttrophoblast invasionandspiralarteryremodelling

ClinicalmanifestationOveractivationofmaternalendothelium andsystemicinflammatorynetwork

OxidativeStress

EndoplasmicreticulumStressInflammatory

Stress

invasivecytotrophoblasts offetalorigininvadethe

maternalspiralarteries

transformsthemfromsmall-caliber resistancevesselstohigh-calibercapacitance vessels

capableofprovidingplacentalperfusion

adequatetosustainthegrowingfetus

Normal Pregnancy

cytotrophoblasts failtoadoptaninvasiveendothelialphenotype

invasionofthespiralarteriesisshallowandtheyremainsmallcaliber,

resistancevessels

placentalischemia

Preeclampsia

39

Defective implantation, poor Placentation

Successful implantation, but failed Placentation

Complete implantation failure Infertility

Miscarriage

Pre-eclampsia

Stage1:reducedplacentalperfusionAbnormalimplantation

Stage2:maternalsyndrome-hypertension-proteinuria-endothelialdysfunction

NORMALPREGNANCY

PREECLAMPSIA

Impair/inadequatetrophoblast invasiontothespiralarteries

Spiralarteriesretaintheircharecteristic (narrow,tortuous,highresistance)

Reducebloodsupplytoplacenta

Resultinplacentalhypoperfusion

AsacompensationHighBPinmaternal

Stage1:reducedplacentalperfusionAbnormalimplantation

Stage2:maternalsyndrome-hypertension-proteinuria-endothelialdysfunction

WHATGETSINTOMATERNALCIRCULATION???

ANTI-ANGIOGENICFACTORS

ANGIOGENICFACTORS

Vascularendothelialgrowth(VEGF)includingplacentalgrowthfactor

Transforminggrowthfactor- beta(TGF-B)

Look aftermaternalendothelium

Solubleendoglin (sEng)

SolubleFMS-liketyrosinekinase-1(sFlt-1)

Releasedfromdiseasedplacenta

• 1.vasodialator& vasoconstrictor.

• 2.angiogenic andantiangiogenic factors.

FetalSyndrome

MaternalSyndrome47

Inadequate trophoblast invasion and defect remodeling of spiral arteries

Placental ischemia and inflammation

Systemic inflammation Apoptosis Oxidative

stress

Relase of placental

factor

Endothelial dysfunction

Pre-eclampsia

48

vasodialator

NO

PGI-2

vasoconstrictor

Angiotensin-II

Endothelin-I

ThromboxaneA2

placenta

Syncytiotrophoblast&endothelium

↓PGI2↑TXA2

VasoconstrictionPlateletaggregation↑Vasopressorresponse↑uterineactivity

Activatedendothelialcellspromotecoagulationandincreasevasopressorsensitivity

Widespreadcoagulationoccur(DIC)

Fibrindepositioninkidney&placenta

HPT&placentalinsufficiency

Cardiovascular

• Generalizedvasospasm• Increasedperipheralresistance• Reducedcentralvenous/

pulmonarypressure

Hematological

• Plateletactivationanddepletion• Coagulopathy• Decreasedplasmavolume• Increasedbloodviscosity

• Proteinuria• Decreasedglomerularfiltrationrate• Decreasedurateexcretion

Renal

Hepatic

• Periportalnecrosis• Subscapularhematoma

• Cerebraloedema• Cerebralhaemorrhages

CentralNervousSystem

OrganSpecificChangesassociatedwithPre-eclampsia

Organ Damage

utero-placenta IUGR

Hematological Epistaxis,DIClikefeatures,hemoconcentration

CNS Cerebraledema,cerebralhgeàseizures

Heart Subendothelial hge,focalnecrosis&hge,cardiomyopathy,heartfailure

Lungs Pulmonaryedema,hemorrhagicbrochopneumonia

Kidneys glomerularendotheliosis,oliguria

liver Subcapsular hge, ischaemiaàperiportalnecrosis,HELLP

Antihypertensivedrugsusedinpregnancyare

• Methyldopa

• Hydralazine

• labetalol

• RoutinelyusedinseverePE.

• Magnesiumsulphate:mostcommonlyused.

• Initiatedwithonsetoflabortill24hpostpsrtum.

• Forcaesarean,started2hrsbeforethesection

till12hrspostpartum.

itcanbegiveneitherIVorIM.IVhasgoodprognosis.

LoadingdoseforIVis4g.i.e.8mldilutedin12mlnormalsaline.This20mlisgivenin20minutes.

Maintenancedoseis20gi.e.40mldilutedin60mlnormalsalineandgivenatrateof1g/hr.

IMisalsoused.

LoadingdoseisasIV.

Maintenancedoseis5gevery4hrsinalternatebuttocksfor24hrs.

Mgso4actsonNMjunctionandinhibitentryofCa++ionsthusinhibitingexcitabilityofneurons.

• Maternal:flushingperspirationheadache,muscleweaknesspulmonaryoedema

• Neonatal:lethargyhypotoniarespiratorydepression

Management of MgSO4 Toxicity

Theonlydefinitivetreatment

Preeclampticpatientsdividedinto3categories

A- Preeclampsiafeaturesfullysubside

B- partialcontrol,butBPmaintainsasteadyhighlevel

C- persistentlyincreasingBPtosevereleveloraddition

ofotherfeatures

A:canwaittillspontaneousonsetoflabor

don’texceedExpectedDateofDelivery

B:>37wkterminatewithoutdelay

<37wk,expectantmanagementatleast

till34wks

C:terminateirrespectiveofPOG

startseizureprophylaxisandsteroidsif<34wks

Unlesscontraindicated:Eclampticwomenshouldundergonormalvaginaldelivery

Indicationsforcaesareansection-FetaldistressPlacentalabruptionUnfavourablecervixFailedinductionoflabourRecurrentseizures

• Urine:24hoururine,Proteinuria.

• Kidneyfunctions:serumcreatinine,urea,creatinineclearanceanduricacid.

• Liverfunctions:bilirubin,Enzymes

• Blood:CBC,HCt,HemolysisandPlateletcount(Thrombocytopenia).

• CoagulationProfile:Bleedingandclottingtime

• Convulsionsandcoma(eclampsia).• Cerebralhaemorrhage.• Renalfailure.• Heartfailure.• Liverfailure.• Disseminatedintravascularcoagulation.• Abruptio placentae.• Residualchronichypertensioninabout1/3ofcases.• Recurrentpre-eclampsia innextpregnancies.

a.Intrauterinegrowthretardation(IUGR).

b.Intrauterinefoetal death.

c.Prematurityanditscomplications.

• RegularAntenatalcheckup:rapidgaininweightrisingbloodpressureedemaproteinuria/derangedliverorrenalprofile• LowdoseAspirininHighriskgroup:↑PGsand↓TXA2• Calcium supplementation:noeffectsunlesswomenare

calciumdeficient• Antioxidants-VitaminC andE• Nutritionalsupplementation:zinc,magnesium,fishoil,

lowsaltdiet

v meningitisv encephalitisv spaceoccupyinglesionv electrolytedisturbancev vasculitisv amnioticfluidembolismv Medicationsv organfailurev stroke

N.B:Gradesofproteinuria (ing/L):Trace=0.1,1+=0.3,2+=1,3+=3,4+=10

Pregnancyinduced

Hypertension

GestationalHTN

● BP≥140/90mmHg●Noevidenceofunderlying

causeofHTN●Noassociatedsymptoms●Comestonormalwithin6

wksofdelivery

Pre-eclampsia

NonSevere Severe

Eclampsia

PreEclamsia+

Convulsion±

Coma

N.B:Pre-eclampsia isprincipallyasyndromeofsignsandwhensymptomsappearitis

usuallylate.Assessmentoftheseverityofpre-eclampsia

isgiveninthenextslide.

• ismostpromising,butcurrently,noneofthemiscompletelysuitableforclinicaluse.(Conde-Agudelo,2014;Kleinrouweler,2012;Myatt,2012a).

• Thesehavevalueforfetal-growthrestrictionbutnotpreeclampsia(ACOG,2013a).

• Asaresultofthesetrials,somemethodstopreventPreeclampsiahavebeentheorized…

UterineArteryDopplerVelocimetry(abnormalflowresistance/diastolicnotchin2nd/3rd

trimester)

Inpreeclampticmother:ShowingearlydiastolicNOTCHDecreasedEDF(due tohigh resistance)

Innormalmother

ABNORMALITIES NONSEVERE SEVEREBlood pressure ≥140/90mmHg but

<160/110mmHg≥160/110mmHg

Proteinuria ≤2+ ≥3+Oliguria Absent <400ml/dayHeadache Absent PresentVisual disturbances Absent PresentPlatelet count Normal Thrombocytopenia

(<100,000/mm3)HELLP syndrome Absent May be present

ALT,AST >70 IU/LLDH>600 IU/LBilirubin >1.2g/L

Serum transaminases(AST,ALT)

Normal (<40 IU/L) Elevated

Serum Creatinine Normal ElevatedEpigastric pain Absent PresentFetal growth restriction Absent ObviousPulmonary oedema Absent present

• Pre-eclampsia is a pregnancy specific

disorder .

• It can occur in absence of the fetus.

• The disease is cured by the removal of

the placenta .76

77

Genetic ModulatorsPre-existing

Vascular Pathology

Central players

Cytokines

Ros

78

q Hemoglobinandhematocritplateletcount:decreased,if<1lakhcoagulationprofile

q LFTs:indicatedinallpatientsq RFTs:raised(S.ureacreatinineisdecreasedinNormal

pregnancy)q UrineRoutine:proteinuria

OBSTETRICMANAGEMENT

1.Maternalevaluation

2.Fetalevaluation:

q Dailyfetalmovementcountq Ultrasoundq Dopplerultrasoundforfetalbloodflow

• Genetic factor• Immunologic factor• Endocrinologic factor• Nutritional factor• Infectious factor

Serious hypertension üBP ≥ 160/110mmHg for at least 12hüProtein in the urine is over 5g/24h or +++~++++ üCreatinine level increasesüFunction of liver impaired obviouslyüFunction of the placenta impaired üFetus IUGR, asphyxia and even death

• GestationalHTN• TransientHTNofpregnancy

• Preeclampsia• Mild

• Severe

• Eclampsia• ChronicHTNprecedingpregnancy

• ChronicHTNwithsuperimposedpregnancy-inducedhypertension• Superimposedpreeclampsia• Superimposedeclampsia

ClassificationoftheAmericanCollegeofObstetriciansandGynecologists

Endothelial Dysfunction/Oxidant

StressFeto-Placental unit

Endocrine Dysfunction

Renal Dysfuntion Misc

Placental Perfusion/ Vascular Resistance

related TestsUterine Artery Doppler

Velocimetry

AT- III

ANPFree fetal DNAAdapted from Conde-Agudelo and associates (2009)

NO

YES

Neither forced nor restricted

• Gestational HTN :onlyifsevereHTN

• Preeclampsia :ü If diastolic pressure≥ 100mmof Hg OR, there is proteinuria OR, there is fetal compromise.ü37 completed weeks of gestation.

HEMOLYSIS(due to

passage of RBCs

through partially

obstructed vessel)

s)HEPATIC

DYSFUNCTION(due to

intravascular fibrin

deposition & sinosoidal

obst.)

Decreased Liver blood

flow

HELLP

SyndromeTHROMBO-CYTOPENIA

(due to platelet

aggregation & dipositionin the sites of endothhelial

damage)

Prompt delivery of fetus to achieve cure

Avoidance of diuretics & hyper osmotic agents

Limitation of I.V fluid

Intermittent antihypertensive to control BP judiciously

Control of convulsion by MgSO4 (IM/IV route)

Protection & supporting care during convulsionProtection in a railed

cotProtection of airway & prevention of tongue

biteCorrection of hypoxia &

acidosis

Managed in Eclampsia room.

88

“It is the most effective drug to control even recurrent seizures without any central nervous system depression to mother & fetus”

89

Magnesium sulphate

90

• Notusedtolowerbp• Produceintravascularvolumedepletion• Worsenmaternalhemoconcentration• Useislimitedtopresenceofpulmonaryedema(FUROSEMIDE)• Maybeusedinpersistentseverepostpartumhypertension

Enviromental

Genetics

CVS and inflammatory

changes

Maternal immunological

intolerance

Abnormal placental

implantaion

• Totalproteinin24hoursurine>300mg

• Protein:Creatinineratioinrandomsample>0.1

• Newonsetofhypertensionafter20weeks ofgestationwithoutproteinuria,followedbyreturnofB.P.tonormalwithin12weekspost-partum.

• Newonsetofhypertensionafter20weeksofgestationalongwithproperlydocumentedproteinuria,followedbyreturnofB.P.tonormalwithin12weekspost-partum.

PreeclamsiaGestational Hypertensio

nProteinuria

• Generalizedtonic-clonicseizure inapatientwithPreeclampsianotattributedtoanyothercause.

Eclampsia Preeclampsia

Seizure/Convulsion

/Coma

• Hypertensionbeforepregnancy/Diagnosedbefore20weeksofpregnancynotduetogestationaltrophoblasticdisease.

• Hypertensiondiagnosedafter20weeksbutpersistentafter12weekspostpartum

• Newonset proteinuriainhypertensivewomenbutnoproteinuria before20weeks'gestation

• Asuddenincrease inproteinuriaorbloodpressureorplateletcount<100,000/Linwomenwithhypertensionandproteinuriabefore20weeks'gestation

Primiparity Immunologicfactors PreviouspregnancycomplicatedbyPreeclampsia/Eclampsia/HELLP

FamilyhistoryofPreeclampsia BMI Pregnancyrelatedconditions

Primipaternity Sexualco-habituation Maternalinfection

Gestationalageatdeliveryof1st Pregnancy Socioeconomic status Smoking

Angiogenicfactor

• VEGF• TFG-beta• PlGF

Antiangiogenicfactor

• sFlt-1• sEng

Ø HistoryofPreeclampsiainpreviouspregnancyØ AdvancedmaternalageØ FamilyhistoryofPreeclampsiaØ Historyofplacentalabruption,IUGR,fetaldeathØ Obesity,BMI>35doublestheriskØ HypertensionØ DiabetesØ ThromboticvasculardiseasesØ MultiplegestationØ MolarpregnancyØ Smoking

Ø Largeplacenta

Ø Prolongedpregnancy

Ø Placentalhydrops

Ø Chromosomalabnormality