MLH Placental Transfer Drugs

8/2/2019 MLH Placental Transfer Drugs

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Placental Transfer of Drugs

Mark L. Harman, M.D.

University of Oklahoma College of Medicine TulsaDepartment of Obstetrics and Gynecology


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Objectives

Placental hypertensive disorders Definition & diagnosis Etiology (unknown) Pathophysiology Management


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NIH Working Group onHypertension in Pregnancy

Four main classes: Chronic hypertension

Preeclampsia and eclampsia Preeclampsia superimposed on chronic

hypertension

Gestational hypertension


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Chronic Hypertension

Definition: Hypertension that is observable before

pregnancy or diagnosed before twenty weeksof gestation.

Persistent blood pressure greater than 140/90 Hypertension first confirmed during

pregnancy that persists beyond 84 days afterdelivery


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Preeclampsia

Increased blood pressure with proteinuria Requires systolic blood pressure 140 mm Hg or

higher or diastolic pressure of 90 mm Hg or higher

Proteinuria Urinary excretion of at least 300 mg of protein in a24-hour specimen

Correlates with 1+ dipstick reading.


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Severe Preeclampsia

BP of 160 mm Hg systolic orhigher or 110 mm Hgdiastolic or higher on 2occasions at least 6 hoursapart while pt is on bed rest

Proteinuria of 5 g or higherin a 24-hour urine specimenor 3+ or greater on two

random urine samplescollected at least 4 hoursapart

Oligouria of less than 500mL in 24 hours

Cerebral or visualdisturbances

Pulmonary edema orcyanosis

Epigastric or right upperquadrant pain

Impaired liver function Thrombocytopenia Fetal growth restriction


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Panel 1 Maternal and fetalcomplications in severe pre-eclampsia

Maternal complications Abruptio placentae Disseminated

coagulopathy/HELLP syndrom(10-20%)

Pulmonaryoedema/aspiration (2-5%)

Acute renal failure (1-5%) Liver failure or haemorrhage

(


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Eclampsia

Definition:

The occurrence of seizures that cannot beattributed to other causes in a woman withpreeclampsia or gestational hypertension.


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Symptom Frequency (%)

HeadacheHyperreflexiaProteinuriaEdemaClonusVisual signsEpigastric pains

83808060464520

Frequency of Symptoms Preceding Eclampsia

Adapted from Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr: Reassessment of intravenous MgSO therapy in preeclampsia-eclampsia. Obstet Gynecol 57:199-202, 1981; with permission from the American College of Obstetricians and Gynecologists.


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Diagnosis of Superimposed Preeclampsia

In women with documented hypertension andno proteinuria before 20 weeks gestation

New onset proteinuria, defined as the urinaryexcretion of 0.3 g of protein or more in a 24-hour specimen


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Diagnosis of Superimposed Preeclampsia

In women with hypertension and proteinuria before20 weeks gestation

A sudden increase in proteinuria

A sudden increase in blood pressure in a womanwhose blood pressure has previously been wellcontrolled

Objective evidence of involvement of multiple organ

systems, such as thrombocytopenia, an increase inliver transaminases to abnormal levels, or suddenworsening of renal function


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Gestational Hypertension

Definition:

A woman who has no proteinuria and a bloodpressure elevation detected for the first timeduring pregnancy


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HELLP Syndrome

Pathophysiologic changes of preeclampsia canoccur in the absence of hypertension andproteinuria

Reduced organ perfusion Consider HELLP a variant of preeclampsia More often in older white multiparous women


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Pregnancy-Related Hypertension

Eclampsia Survivorship. Survival times are plotted for women witheclampsia in the first pregnancy (solid line) and those with eclampsia in alater pregnancy (dashed line). Survival of women with first-pregnancy

eclampsia was not different from survival of a control group.


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Hypertension in Pregnancy

5-10% of all pregnancies Part of deadly triad

Hypertension Hemorrrhage Infection


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Gestational Hypertension

BP > 140/90 for first time at mid-pregnancy No proteinuria

50% of these patients develop preeclampsia Also known as transient hypertension if no

preeclampsia and blood pressure normal by12 weeks postpartum


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Pre-eclampsia

A pregnancy-specific syndrome of reduced tissueperfusion due to vasospasm and endothelialactivation

Proteinuria is the surrogate objective marker thatdefines the system wide endothelial leak whichcharacterizes pre-eclampsia syndrome

Thrombocytopenia - caused by a plateletactivation and aggregation and microangiopathichemolysis from severe vasospasm


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Abnormal lab findings and more severe thehypertension or proteinuria, the more certainthe diagnosis and adverse outcomes


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Atypical Pre-eclampsia

All aspects of the syndrome BUT withouthypertension or proteinuria (?HELLPsyndrome)


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Eclampsia

Generalized seizures before, during or afterlabor

10% of eclamptics seize without proteinuria Seizures that develop after 48 hours

postpartum make up less than 10% of cases of eclampsia


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Superimposed Pre-eclampsia onChronic Hypertension

All chronic hypertensive disorders predispose May develop earlier in pregnancy, tend to be

more severe and often have IUGR


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Pre-eclampsia

Incidence in nulliparous patients: 3-10% Risk factors

Younger and older patients Genetics, environmental, socio-economic, and

seasonal influences Multiple gestation Increasing BMI increases risk


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Panel 2 Risk factors for pre-clampsiaCouple-related risk factors

Limited sperm exposure Primipaternity Pregnancies after donor

insemination, oocyte donation

embryo donation Protective effect of partner

change in the case of previouspre-eclamptic pregnancy

Maternal or pregnancy-related

risk factors Extremes of maternal age Multifetal gestation Pre-eclampsia in previous

pregnancy

Chronic hypertension or renaldisease

Rheumatic disease Maternal low birth weight Obesity and insulin resistance

Pregestational diabetes mellitus Maternal infections Pre-existing thrombophilia Maternal susceptibility genes Family history of pre-eclampsia Smoking (reduced risk) Hydropic degeneration of

placenta


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Eclampsia

Incidence is decreased with better care Incidence in developed countries 1:2,000

Incidence in US 1:3,250 deliveries


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Etiology of Pre-eclampsia

Abnormal trophoblastic invasion Maladaptive immunological tolerance

Graft rejection Maternal maladaption to cardiovascular or

inflammatory changes Genetic factors


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Abnormal Trophoblastic Invasion

Normally uterine spiral arterials remodelwhen invaded by endovascular trophoblasts

Replace vascular muscular and endothelial liningsto enlarge diameter


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Abnormal Trophoblastic Invasion

Pre-eclampsia Shallow invasion

Decidual vessels, not myometrial vessels, becomelined by trophoblasts

The abnormally narrow lumen impairs placentalblood flow

Magnitude of defective trophoblast invasioncorrelates with severity of hypertension


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Immunological Factors

Graft rejection? Immune mediated?

Impaired formation of blocking antibodies in firstpregnancy

More risk with increased paternal antigenic load Molar pregnancy Trisomy 13


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Pathogenesis

Vasospasm Vascular constriction causes increased

resistance and hypertension Endothelial cell damage causes interstitial

leakage Diminished blood flow from maldistribution

with ischemia causes necrosis, hemorrhageand end-organ changes


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Pathogenesis

Endothelial cell activation Intact endothelium as anti-coagulant properties Intact endothelium blunts vascular smooth muscle

response to agonist by releasing nitric oxide N.O. is a vasodilator

Maintains low pressure feto-placental unit

Decreased N.O. synthetase expression may berelated to pre-eclampsia


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Pathogenesis

Prostaglandins Pre-eclampsia

Decreased endothelial prostacyclin production Increased thromboxane A2 secretion by platelets

These cause vasoconstriction


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Pathophysiology

Blood/coagulation Decreased platelets Hemolysis

Increased LDH Schizocytosis Spherocytosis

Reticulocytosis HELLP syndrome indication of hepatocellular

necrosis


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Peripheral blood smear from a patient with a microangiopathic hemolyticanemia with marked red cell fragmentation. The smear shows multiple helmet

cells (small black arrows), other fragmented red cells (large black arrow);microspherocytes are also seen (blue arrows). The platelet number is reduced;the large platelet in the center (red arrow) suggests that the thrombocytopeniais due to enhanced destruction.Courtesy of Carola von Kapff, SH (ASCP).


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Peripheral smears from two patients with microangiopathic hemolytic anemia,showing a number of red cell fragments (i.e., schistocytes), some of which take the

form of combat (red arrow), bicycle (thick black arrow), or football (blue arrow)"helmets." Microspherocytes are also seen (thin black arrows), along with anucleated red cell (green arrow).Courtesy of Carola von Kapff, SH (ASCP).


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Pathophysiology

Kidney Decreased renal perfusion Decreased GFR Oliguria Proteinuria ATN

Rarely caused by pre-eclampsia alone Often co-existent hemorrhagic hypotension


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Pathophysiology

Liver AST, ALT changes are the hallmark Hepatic hematoma If fatal eclampsia

periportal hemorrhage in the liver periphery


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Pathophysiology

Brain Normally auto regulated In pre-eclampsia: increased cerebral blood

flow Headache and scotoma due to

cerebrovascular hyperperfusion especially in

occipital lobes If history of eclampsia, patient may exhibit

excessive cognitive decline in 5 to 10 years


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Prevention

Overall, no effect Low salt diet Calcium or fish oil supplementation Antihypertensive drugs Antioxidants

Antithrombotic agents Low dose aspirin with or without heparin?


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Pre-eclampsia Management

Objective Prevent seizures Prevent intracranial hemorrhage Prevent organ damage Deliver a healthy baby


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If not delivered Perform frequent antenatal testing Outpatient vs. hospitalization

Either is appropriate for the women with mild denovo hypertension with or without non-severepre-eclampsia


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Delayed Delivery No data suggests that expectant management

is beneficial for the mother Absence of convincing evidence that perinatal

outcomes are markedly improved by averageprolongation of pregnancy of one week


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Seizure Management

All pregnant women with convulsions shouldbe considered to have eclampsia until othercauses are excluded

Epilepsy Meningitis Cerebral tumor Ruptured cerebral aneurysm Cysticercosis


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Seizure Management

Maternal hypoxemia and lactic acidemiacaused by convulsions often cause fetalbradycardia after a seizure

Fetal heart tones usually recover in 3-5minutes


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Seizure Management


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Management of Severe Hypertension

Treat if systolic > 160 mm Hg or diastolic > 110mm Hg

Antihypertensive agents Hydralazine Labetalol Nifedipine


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Hydralazine 5 mg initial dose Follow by 5-10 mg doses at 15-20 minute

intervals Dose not limited

Goal decrease diastolic blood pressure to90-100 mm Hg


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Labetalol Equivalent to Hydralazine 10 mg IV initially May repeat in 10 minutes with 20 mg IV Next 10 minute dose is 40 mg Next 10 minute dose is 40 mg If not adequate response, then 80 mg IV Maximum 220 mg IV per treatment cycle


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Nifedipine Equivalent to Labetalol 10 mg by mouth dose Repeat in 30 minutes if necessary

D f T f H i


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Drugs for Treatment of HypertensiveEmergencies

Drug Onset Maximum Duration IntramuscularDosage

IntravenousDosage

IntervalbetweenDoses

Mechanism

Hydralazine 10-20 min 20-40 min 3-8 hr 10-50 mg 5-25 mg 3-6 hr Directdilatation of

arteriolesSodiumNitroprusside

0.52-2 min 1-2 min 3-5 min ____ IV solution:0.01 g/L;IV infusionrate:3-4mg/kg/min

Directdilatation of arteriolesAnd veins

Labetalol 1-2 min 10 min 6-16 hr ____ 20-50 mg 3-6 hr a- and B-Adrenergicblocker

Nifedipine 5-10 min 10-20 min 4-8 hr ____ 10 mg orally 4-8 hr Calciumchannelblocker

Time Course of Action

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MLH Placental Transfer Drugs