TOXEMIA:
A BLOOD VOLUME DEFICIENT STATE

Edward Lichten, M.D.

555 South Old Woodward Suite #700
Birmingham, MI 48009 
248.593.9999

PATHOPHYSIOLOGY:

The Pathophysiology or cause of Toxemia, a pregnancy specific disease, is hypovolemia causing placenta hypoperfusion. The disease is characterized by new-onset of hypertension and proteinuria (protein in the urine), after 20 weeks of pregnancy. Pre-eclampsia is considered mild with blood pressures rising to above 140/90; the more sever forms will involve other organs such as kidney (renal failure), liver (HELLP syndrome), and the central nervous system (seizures).  The development of coagulation abnormalities such as DIC (diffuse intravascular coagulopathy) can lead to death. Toxemia is associated with 15% of premature births and 17.6% of maternal deaths even today worldwide.¹

The imbalance in angiogenic molecules is the rationale of the moment for the cause of toxemia. In experimental animals, the decrease in circulating estriol² may be more likely as the cause of volume deficiency and vasoconstriction. The vasoconstriction in the placenta would be the logical cause of the increase release of toxic vaso-constrictive elements to the mother that would hasten the delivery of the fetus.

LABORATORY MEASUREMENTS of PLACENTAL WALL INJURY

EXPERIMENTAL

• Plasminogen activator inhibitor-1 (PAI-1)

• Fibronetin, cellular

• Endothelin and altered prostacyclin/ thromboxane profiles.¹

CLASSICAL

• Hypertension: greater than 140/90 (mild); greater than 160/110 (severe)

• Proteinuria greater than .3gms in 24 hour urine

• Estriol/creatinine urine measurements (24 hour or random)

HELLP SYNDROME: increased mortality and morbidity

• Hemolysis

• Elevated liver enzymes

• Low platelets

EPIDEMIOLOGY:

The incidence ranges fro 2-6% in the United States in healthy young nulliparous (first term pregnancy) women. Three-fourths of cases are mild; one fourth severe. Pre-eclampsia often results in premature births: subsequent pregnancies have a 10% increase risk of pre-eclampsia and premature births. 

Women with connective tissue disorders (lupus, sarcoidosis, rheumatoid arthritis, etc.) are at greater risk for pre-eclampsia and complications. Women with renal disease, antiphospholipd syndrome and chronic hypertension increase the risk of pre-eclampsia and toxemia 10 to 20 fold.  Women over 40, obesity and a history of coagulation disorders increase risk as well. African American increase the risk by 50%; a family history increases the risk 5-fold. The homozygous presence of the angiotensinogen gene T235 increases risk 20 fold; versus 4 fold for heterozygousity.

TREATMENT

Standard treatment is taken from the Medscape website:

 If a patient presents with severe preeclampsia before 34 weeks' gestation, but appears stable and fetal condition is reassuring, expectant management may be considered provided they meet the strict criteria set by Sibai et al (see Laboratory values for preeclampsia and HELLP syndrome).⁴¹ This type of management should be considered only in a tertiary center. In addition, because delivery is always appropriate for the mother, some authorities consider delivery as the definitive treatment regardless of gestational age. However, delivery may not be optimal for a fetus that is extremely premature. Therefore, in a carefully chosen population, expectant management may benefit the fetus without greatly compromising maternal health.

All of these patients must be evaluated on a Labor and Delivery unit for 24 hours before a decision for expectant management can be made. During this period, maternal and fetal evaluation must show that the fetus does not have severe growth restriction or fetal distress. In addition, maternal urine output must be adequate. The woman must have essentially normal laboratory values (with the exclusive exception of mildly elevated liver function test results less than 2 times the normal value) and hypertension that can be controlled.

Fetal monitoring should include daily nonstress test and ultrasonography performed to monitor for the development of oligohydramnios and decreased fetal movement. In addition, fetal growth determination at 2-week intervals must be performed to document adequate fetal growth. In addition, a 24-hour urine collection for protein may be repeated. Corticosteroids for fetal lung maturity should be administered prior to 34 weeks.
 
Daily blood tests should be performed for LFTs, CBC, uric acid, and LDH. Patients should be instructed to report any headache, visual changes, epigastric pain, or decreased fetal movement.

Women with severe preeclampsia who are managed expectantly, must be delivered under the following circumstances:

• Nonreassuring fetal heart status
• Uncontrollable blood pressure
• Oligohydramnios with AFI of less than 5 cm
• Severe intrauterine growth restriction where estimated fetal weight is less than 5%
• Oliguria (<500 mL/24 h)
• Serum creatinine level of at least 1.5 mg/dL
• Pulmonary edema
• Shortness of breath or chest pain with pulse oximetry of <94% on room air
• Headache that is persistent and severe
• Right upper quadrant tenderness
• Development of HELLP syndrome

CLASSICAL TRAINING

Frederick P. Zuspan, M.D. was one of the individuals who promoted the use of magnesium sulfate in the treatment of both mild pre-eclampsia and severe (toxemia) cases.  His blood pressure lowering drug of choice as hydralazine. He also taught us the use of volume expansion with whole blood or salt-poor albumin³. Unfortunately, this information has been lost on the 'modern' generation that relies of pharmacologic agents. Our experience has been the lowering the blood pressure with stronger agents such as diazoxide and nitroprusside decreased the perfusion of the fetus resulting in more fetal distress and resultant fetal mental retardation.

The only 'cure' for pre-eclampsia and toxemia is delivery of the fetus. Caesarian sections are necessary 50% or more of the time. The toxemic patients remain at risk for seizures for days after delivery.  We continued magnesium sulfate into the post-partum period using the clinical picture of the patient's recovery (blood pressure, proteinuria).

For ADDITIONAL INFORMATION ABOUT STANDARD THERAPY, go to:

MAYO CLINIC                     www.MAYOCLINIC.org

MERCK MANUAL               www.merckmanual.com

National Institute of Health Public Library [pubmed.org]

REFERENCES:

1.  Warden M and B Eurele. Medscape. Toxemia. 2009.

2. WHO Chronicles 1986; 40(5): 175-83 

3. Brewer TH. Administration of Human Serum Albumin in Severe Acute Toxaemia of Pregnancy. British Journal Obstetrics and Gynecology. 1963 Dec; 70(6):1001-1004

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1442508/pdf/bmjcred00494-0003.pdf