Placental Transfer of Drugs

Mark L. Harman, M.D.

University of Oklahoma College of Medicine Tulsa Department of Obstetrics and Gynecology

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

NIH Working Group on Hypertension in Pregnancy

Four main classes: Chronic hypertension Preeclampsia and eclampsia Preeclampsia superimposed on chronic hypertension Gestational hypertension

Chronic Hypertension
Definition: Hypertension that is observable before pregnancy or diagnosed before twenty weeks of gestation. Persistent blood pressure greater than 140/90 Hypertension first confirmed during pregnancy that persists beyond 84 days after delivery

 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 a 24-hour specimen Correlates with 1+ dipstick reading.

Severe Preeclampsia
BP of 160 mm Hg systolic or higher or 110 mm Hg diastolic or higher on 2 occasions at least 6 hours apart while pt is on bed rest Proteinuria of 5 g or higher in a 24-hour urine specimen or 3+ or greater on two random urine samples collected at least 4 hours apart Oligouria of less than 500 mL in 24 hours Cerebral or visual disturbances Pulmonary edema or cyanosis Epigastric or right upper quadrant pain Impaired liver function Thrombocytopenia Fetal growth restriction

Panel 1 Maternal and fetal complications in severe pre-eclampsia

Maternal complications
Abruptio placentae Disseminated coagulopathy/HELLP syndrom (10-20%) Pulmonary oedema/aspiration (2-5%) Acute renal failure (1-5%) Liver failure or haemorrhage (<1%) Stroke (rare) Death (rare) Long-term cardiovascular morbidity

Neonatal complications
Preterm delivery (15-67%) Fetal growth restriction (10-25%) Hypoxia-neurologic injury (<1%) Perinatal death (1-2%) Long term cardiovascular morbidity associated with low birth weight (fetal origin of adult disease)

Magnitude of risk depends on gestational age at time of diagnosis, delivery, severity of disease process, and presence of associated medical disorder

Eclampsia
Definition: The occurrence of seizures that cannot be attributed to other causes in a woman with preeclampsia or gestational hypertension.

Frequency of Symptoms Preceding Eclampsia

Symptom Frequency (%)

Headache Hyperreflexia Proteinuria Edema Clonus Visual signs Epigastric pains

83 80 80 60 46 45 20

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

Diagnosis of Superimposed Preeclampsia

In women with documented hypertension and no proteinuria before 20 weeks gestation New onset proteinuria, defined as the urinary excretion of 0.3 g of protein or more in a 24hour specimen

Diagnosis of Superimposed Preeclampsia

In women with hypertension and proteinuria before 20 weeks gestation
A sudden increase in proteinuria A sudden increase in blood pressure in a woman whose blood pressure has previously been well controlled Objective evidence of involvement of multiple organ systems, such as thrombocytopenia, an increase in liver transaminases to abnormal levels, or sudden worsening of renal function

Gestational Hypertension
Definition: A woman who has no proteinuria and a blood pressure elevation detected for the first time during pregnancy

HELLP Syndrome
Pathophysiologic changes of preeclampsia can occur in the absence of hypertension and proteinuria Reduced organ perfusion Consider HELLP a variant of preeclampsia More often in older white multiparous women

Pregnancy-Related Hypertension

Eclampsia Survivorship. Survival times are plotted for women with eclampsia in the first pregnancy (solid line) and those with eclampsia in a later pregnancy (dashed line). Survival of women with first-pregnancy eclampsia was not different from survival of a control group.

Hypertension in Pregnancy
5-10% of all pregnancies Part of deadly triad
Hypertension Hemorrrhage Infection

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 by 12 weeks postpartum

Pre-eclampsia
A pregnancy-specific syndrome of reduced tissue perfusion due to vasospasm and endothelial activation Proteinuria is the surrogate objective marker that defines the system wide endothelial leak which characterizes pre-eclampsia syndrome Thrombocytopenia - caused by a platelet activation and aggregation and microangiopathic hemolysis from severe vasospasm

 Abnormal lab findings and more severe the hypertension or proteinuria, the more certain the diagnosis and adverse outcomes

Atypical Pre-eclampsia
All aspects of the syndrome BUT without hypertension or proteinuria (?HELLP syndrome)

Eclampsia
Generalized seizures before, during or after labor 10% of eclamptics seize without proteinuria Seizures that develop after 48 hours postpartum make up less than 10% of cases of eclampsia

Superimposed Pre-eclampsia on Chronic Hypertension

All chronic hypertensive disorders predispose May develop earlier in pregnancy, tend to be more severe and often have IUGR

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

Panel 2 Risk factors for pre-clampsia Couple-related risk factors

Limited sperm exposure Primipaternity Pregnancies after donor insemination, oocyte donation embryo donation Protective effect of partner change in the case of previous pre-eclamptic pregnancy Maternal or pregnancy-related risk factors Extremes of maternal age Multifetal gestation Pre-eclampsia in previous pregnancy Chronic hypertension or renal disease 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

Pre-eclampsia
Reduced risk
Placenta previa Smoking

Eclampsia
Incidence is decreased with better care Incidence in developed countries 1:2,000 Incidence in US 1:3,250 deliveries

Etiology of Pre-eclampsia
Abnormal trophoblastic invasion Maladaptive immunological tolerance
Graft rejection

Maternal maladaption to cardiovascular or inflammatory changes Genetic factors

Abnormal Trophoblastic Invasion

Normally uterine spiral arterials remodel when invaded by endovascular trophoblasts
Replace vascular muscular and endothelial linings to enlarge diameter

Abnormal Trophoblastic Invasion

Pre-eclampsia Shallow invasion
Decidual vessels, not myometrial vessels, become lined by trophoblasts The abnormally narrow lumen impairs placental blood flow

Magnitude of defective trophoblast invasion correlates with severity of hypertension

Immunological Factors
Graft rejection? Immune mediated?
Impaired formation of blocking antibodies in first pregnancy More risk with increased paternal antigenic load
Molar pregnancy Trisomy 13

Pathogenesis
Vasospasm Vascular constriction causes increased resistance and hypertension Endothelial cell damage causes interstitial leakage Diminished blood flow from maldistribution with ischemia causes necrosis, hemorrhage and end-organ changes

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 be related to pre-eclampsia

Pathogenesis
Prostaglandins Pre-eclampsia
Decreased endothelial prostacyclin production Increased thromboxane A2 secretion by platelets

These cause vasoconstriction

Pathophysiology
Blood/coagulation Decreased platelets Hemolysis
Increased LDH Schizocytosis Spherocytosis Reticulocytosis

HELLP syndrome indication of hepatocellular necrosis

Peripheral blood smear from a patient with a microangiopathic hemolytic anemia 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 thrombocytopenia is due to enhanced destruction. Courtesy of Carola von Kapff, SH (ASCP).

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 a nucleated red cell (green arrow). Courtesy of Carola von Kapff, SH (ASCP).

Pathophysiology
Kidney Decreased renal perfusion Decreased GFR Oliguria Proteinuria ATN
Rarely caused by pre-eclampsia alone Often co-existent hemorrhagic hypotension

Pathophysiology
Liver AST, ALT changes are the hallmark Hepatic hematoma If fatal eclampsia
periportal hemorrhage in the liver periphery

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

Prevention
Overall, no effect Low salt diet Calcium or fish oil supplementation Antihypertensive drugs Antioxidants Antithrombotic agents
Low dose aspirin with or without heparin?

Pre-eclampsia Management
Objective Prevent seizures Prevent intracranial hemorrhage Prevent organ damage Deliver a healthy baby

Pre-eclampsia Management
If not delivered Perform frequent antenatal testing Outpatient vs. hospitalization
Either is appropriate for the women with mild de novo hypertension with or without non-severe pre-eclampsia

Pre-eclampsia Management
Delayed Delivery No data suggests that expectant management is beneficial for the mother Absence of convincing evidence that perinatal outcomes are markedly improved by average prolongation of pregnancy of one week

Seizure Management
All pregnant women with convulsions should be considered to have eclampsia until other causes are excluded
Epilepsy Meningitis Cerebral tumor Ruptured cerebral aneurysm Cysticercosis

Seizure Management
Maternal hypoxemia and lactic acidemia caused by convulsions often cause fetal bradycardia after a seizure Fetal heart tones usually recover in 3-5 minutes

Seizure Management

Management of Severe Hypertension

Treat if systolic > 160 mm Hg or diastolic > 110 mm Hg Antihypertensive agents
Hydralazine Labetalol Nifedipine

Management of Severe Hypertension

Hydralazine 5 mg initial dose Follow by 5-10 mg doses at 15-20 minute intervals Dose not limited Goal decrease diastolic blood pressure to 90-100 mm Hg

Management of Severe Hypertension

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

Management of Severe Hypertension

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

Drugs for Treatment of Hypertensive Emergencies

Time Course of Action
Drug Onset Maximum Duration Intramuscular Dosage 10-50 mg Intravenous Dosage 5-25 mg Interval between Doses 3-6 hr Mechanism

Hydralazine

10-20 min

20-40 min

3-8 hr

Direct dilatation of arterioles Direct dilatation of arterioles And veins

Sodium Nitroprusside

0.52-2 min

1-2 min

3-5 min

____

IV solution: 0.01 g/L; IV infusion rate: 3-4 mg/kg/min 20-50 mg 3-6 hr

Labetalol

1-2 min

10 min

6-16 hr

____

a- and BAdrenergic blocker Calcium channel blocker

Nifedipine

5-10 min

10-20 min

4-8 hr

____

10 mg orally

4-8 hr