Toxemia Of Pregnancy

Charles Neal, D.O. Medical Director This protocol should be used for the patient in her third trimester of pregnancy that is exhibiting signs of PRE-ECLAMPSIA or ECLAMPSIA. The signs of toxemia include proteinuria (dark colored urine), excessive weight gain, and hypertension. The presence of two of these signs constitutes pre-eclampsia and all three constitutes eclampsia. The seizing patient in her third trimester of pregnancy should be assumed to be eclamptic and treated as specified below. However, consideration of another underlying etiology, such as: hypoglycemia, drug overdose, head injury, or fever should also be considered. Witnessed continuous convulsions (generalized tonic-clonic seizure or Grand Mal) or repeating episodes without regaining consciousness or sufficient respiratory decompensation demonstrates a need for immediate treatment.

Recently, among the staff of our department there was contentious controversy about the diagnosis of the disease process involving a patient aged 43, pregnant for the sixth time. She was admitted to the hospital during the twenty-first week of pregnancy because of the sudden onset of hypertension ranging in the average of 180 mm of mercury systolic and 110 diastolic, albuminuria amounting to 4,5 grams per 24 hours, and generalized edema. Laboratory studies were all within normal limits except for urinalysis which showed in addition to proteinuria, the presence of red blood cells in considerable quantity. The blood showed no evidence of nitrogen retention, including uric acid. Although no uniformity of the diagnosis was forthcoming, all agreed that continued hospitalization and bed rest were indicated. Under this program she improved, and after six weeks the blood pressure averaged 140 mm of mercury systolic and 85 diastolic, albuminuria diminished to a 24 hour excretion of less than 1 gram, and the edema, particularly of her face, largely vanished.
The staff, including those of the cognate medical services, agreed that the diagnosis was most likely acute glomerulonephritis, and recommended continued hospitalization until the termination of pregnancy. A distinguished obstetrician visited the hospital at this time and the detafls of the patient's condition were presented to him together with our diagnosis. He disagreed and stated that in his opinion the patient was suffering from severe preeclampsia.
The patient left the hospital against our advice and was not seen again until she responded to a telephone call to come for observation. The symptoms of hypertension, albuminuria, and edema were stfll present. Hospitalization was again enforced. Her blood pressure averaged 220 mm mercury systolic and 110 diastolic. The 24 hour *GynecoIogist-Obstetrician-in-chief, Department of Gynecology and Obstetrics, Henry Ford Hospital, excretion of albumin in the urine measured 2 grams, and edema of the dependent type was observed. Laboratory studies showed the urine to be free of red blood cefls, and there was no nitrogen retention in the blood except for uric acid which was elevated to 6 mgm per 100 cc. Under observation the uric acid continued to climb and reached a maximum of 11 mgm per 100 cc of blood. At about thirty-two weeks gestation intrauterine infant death occurred and one week later, labor commenced spontaneously. When discharged 10 days after delivery the blood pressure ranged in the high normal level, the urine contained a trace of albumin, and the edema had vanished.
The final diagnosis was acute glomerulonephritis with superimposed severe preeclampsia.

Classifications:
Preeclampsia is divided into two degrees of severity -mild and severe, and eclampsia is divided into convulsive and non-convulsive.
Preeclampsia has been defined as toxemia which arises after the twenty-fourth week of gestation characterized by a systolic rise in blood pressure to 160 mm of mercury, and a diastolic rise to 100, The 24 hour urine excretion contains less than 0.6 gram of protein, and edema is slight or absent.
Severe preeclampsia is the same condition characterized by higher elevation of blood pressure, excretion of larger quantities of protein and obvious edema. This inane differentiation of preeclampsia into two grades has about the same degree of meaning as do the yellow and red lights of our traffic signals in Michigan, and if ignored, about the same resufl. The importance of the differentiation lies in the warning significance to the obstetrician. Although mfld preeclampsia is a phase of the disease in which the obstetrician has moderate leeway for the employment of conservative therapeutic measures on a home treatment basis, severe preeclampsia demands immediate bed rest, preferably in a hospital and the most cautious care. In each instance the objective is to modify the intensity of the symptoms so as to prevent the development of eclamptic convulsions, the highly lethal phase of the disease. Committees on Maternal Mortality reach their highest degree of vituperation when obliged to study a death from eclampsia when the records show gradual progression through the phases of mild to severe preeclampsia to actual eclampsia and death without evidence of the obstetrician having recognized the significance of the warning signs and not having instituted appropriate therapy. Pathology: Probably no better reason exists for dividing toxemia into preeclampsia and eclampsia than comes from a study of pathology. In preeclampsia, necropsy studies have been most unrewarding. Few. if any pathologic lesions have been recognized which can be considered specific.
Although no precise pathological lesion has been identified there has been rather general acceptance of the functional and structural associated changes present in the preeclamptic phase of the disease. Vasospasm, particularly arteriolar spasm, appears to be common denominator present in all visceral pathologies. Garberi stated that these changes in the blood vascular sy.stem are evidence of a widespread under-lying abnormal vasopressor activity or arteriospasm. In effect, according to Garber, this change causes decreased blood flow, anoxemia, and increased capillary permeability with edema and stasis leading to thrombosis, hemorrhage, ischemia and necrosis. Unfortunately, these last four: thrombosis, hemorrhage, ischemia and necrosis are pathologic findings in eclampsia and not preeclampsia. It is a clinical fact that preeclampsia, no matter how severe, fails to cause these lesions; while eclamptic convulsions, no matter at what level of blood pressure they may occur, frequently cause them.
Some observations of interest were recently reported by Pollack and his group^ showing the results of kidney biopsy performed in patients having preeclampsia. They recognized three lesions of which one was completely reversible, one partially reversible, and one permanent.
The reversible lesion occurred in the uncomplicated preeclampic patient and was characterized by swelling of the glomerular tuft, widening of the basement membrane from swelling which involved the basement membrane, the endothelium and the epithelium, many narrow capillary lumens, vacuoles in the glomerular tuft, and no evidence of a mucopolysaccharide over the basement membrane. In this group of patients the glomeruli appeared large, and crowded Bowman's capsule. These lesions were completely reversible, and after delivery, re-biopsy showed absence of swelling of the glomerular tuft and return of the thin delicate basement membrane.
The second group of patients, partially reversible, showed the same findings plus sclerotic thickening of the basement membrane. After delivery all findings disappeared except sclerosis of the basement membrane.
The third group of patients, which showed permanent disease pathology, was composed of patients having known vascular sclerosis. Most had diabetes. Here sclerosis was permanent.
Pollack differentiated the findings in the preeclamptic group as changes within the basement membrane and not a deposit over the membrane as was observed by Fahr, Bell, Sheehan and others in patients having eclamptic convulsions.
The pathology in convulsive eclampsia, in contrast, is definite, varied and widespread. In turn, pathologists have directed attention to the kidneys, liver, brain, and other viscera recognizing thrombosis, hemorrhage, ischemia, and necrosis as the basic pathologic lesion.
The cause still remains obscure and each has his pet theory. Perhaps sufficient importance has not been given to the pathogenic potentialities of the convulsive act per se, which is an acute catabolic mechanism. In 1949 Dillon and Schmitz^ reported afibrinogenemia following fulminating eclamptic convulsions, a condition which never occurs unless actual tissue injury is incurred. Realizing that fibrinogen depression is preceded by the fibrinogen-fibrin conversion to insoluble fibrin gel, and possible embolism, gives credence to this pathogenic mechanism as a potential lethal factor. Moreover, there appears to be no reason why the mucopolysaccharide coating over the basement membrane of Bowman's capsule, as observed by BelH and others', could not be adherent fibrin gel. That convulsions do cause fibrinogen depression was ob-

Toxemia of Pregnancy
served from the fibrinogen profile obtained from a male who developed convulsions after injection of a drug. (Fig. No. 1) Generalized convulsion, Duration 25 min.
Normal saline 900cc As stated by Cosgrove', "lacking then a guide of any established knowledge of etiology and pathogenicity, the management and treatment of the late toxemias of pregnancy remain on exactly the same basis upon which our fathers established it. It presents three phases: prophylaxis, treatment of symptoms, and termination of pregnancy." Prophylaxis against the development of toxemia is a modern obstetric sophism. How can the disease be prevented when there is no knowledge of etiology? Can any obstetrician rightfufly state before a patient undertakes a pregnancy, that she will not develop toxemia? Until we know what destines a patient to develop toxemia, how can we tell her how to avoid it?
On the other hand clinical experience has shown that assiduous attention to the details recommended by good obstetrical teaching will prevent, in most instances, mild preeclampsia advancing to severe preeclampsia, and severe preeclampsia to convulsive eclampsia. This is the practical aim of modern obstetrics and is the reason for our constant obligation to continuously re-evaluate the problem by incorporating into the tried basic plans of therapy, new modalities of treatment , Because of the proclivity of the pregnant patient to retain excessive quantities of sodium and water, manifested clinically as unusual weight gain, assiduous prenatal care has as its objective: the detection, control or elimination of excessive weight gain, edema, and elevation in blood pressure.
Commonly related sodium and water retention are clinical problems of major concern, and the standard efforts of prevention include: restriction of sodium intake to less than 0.5 grams each day and relative limitation of fluid intake in quantities sufficient to insure urinary output of 2000 cc daily. Sudden increase in body weight and the development of edema occur in some patients after the slightest indiscretion. Treatment then must include efforts to eliminate the retained excessive quantities of sodium and water. To the basic plan of therapy must be added the use of such drugs as ammonium chloride for its diuretic effect, oral administration of magnesium sulfate for its dehydrating purgative effect, and sometimes mercurial diuretics. These methods have withstood the test of time, and although their limitations are recognized, this plan of therapy remains standard for preeclampsia.
New drugs and methods are available for appraisal. These are based upon new pharmacological knowledge and new physiochemical concepts. Clinical trial has been limited. Up for consideration are 1. diuretic of the carbonic anhydrase inhibitor type (Diamox) which selectively eliminates the cations, sodium and potassium, in addition to increased volumes of water: 2. cation exchange resins which selectively interfere with the absorption of cations, sodium and potassium; 3. the evaluation in pregnancy and toxemia of the influence of adrenocorticotrophic hormone (ACTH) and adrenal corticoids: and 4, determination of the clinical effectiveness of the newer antihypertensive drugs.

Carbonic Anhydrase Inhibitor:
Diamox is a potent carbonic anhydrase inhibitor. It functions by inhibiting the conversion of carbon dioxide and water to carbonic acid in the renal tubular cells. With a deficiency of hydrogen ions in the glomerular filtrate, the other cations, sodium and potassium, take hydrogen's place in the buffer systems of the glomerular filtrate and are excreted. As the result the urine becomes highly alkaline. Ashe and his group' reported favorable results using an intermittent treatment schedule consisting of 250 mgm daily for 5 days followed by a drug-free interval of two days. This schedule was continued until delivery. They reported no attributable fetal mortality nor maternal side-effects in 100 patients treated, and only 9 patients failed to respond.
Excessive and continuous use of Diamox will cause an inordinate loss of fixed base and result in decreased blood pH, hyperchloremic acidosis from retention of the chloride ion, and decreased CO2 concentration resulting from excessive ventilation and failure of production of carbonic acid.
Our experience with Diamox corresponds with that reported by Ashe and his group. We also observed rapid weight loss during the time of administration of Diamox. When the drug was discontinued, the patients rapidly regained the weight previously lost. We found it difficult to discontinue the drug during pregnancy. The concomitant use of ammonium chloride during Diamox therapy should be avoided because the chloride ion may augment the tendency to acidosis. Antihypertensive drugs may be given in conjunction with Diamox.

To.xemia of Pregnancy Synthetic Resins:
Synthetic ion exchange resins have been used to some extent during the past five years in an attempt to control sodium retention and excessive water storage. They function by exchanging one ion for another. Two general types have been developed: anion resins which exchange one negatively charged ion for another negatively charged ion, and cation resins which exchange positively charged ions. In obstetrics most interest centers upon the cation, sodium, and there are two resins commercially available which function to remove sodium ions: (1) the sulphonic and (2) the carboxylic.
The ion exchange resins are mentioned, not because they possess any practical value in the treatment of toxemia of pregnancy (because they apparently have little or none,), but because of the attractive physiochemical mechanism whereby they function. For the present, let it suffice to recognize their potential vuale and be prepared to consider the problem afresh should more specific and efficient preparations become available in the future.

Adrenocorticotrophic Hormone and Adrenal Corticoids:
The similarity between the symptoms of toxemia of pregnancy and the physiological effects of ACTH and/or cortisone are striking. In non-pregnancy ACTH and/or cortisone can be expected to produce sodium retention, potassium excretion, elevated blood uric acid, increased excretion of 17-ketosteroids and occasionally albuminuria and hyperglycemia. Also frequently observed are hypertension, sudden weight gain, and edema. A shift of fluid from the extracellular to the intracellular compartment may occur. Many of these changes occur in pregnancy.
The relationship of adrenocorticosteroid metabolism to normal and toxemic pregnancies has been studied by several groups. Lloyd" noted increased excretion of poorly watersoluble corticoids in the urine of patients suffering from toxemia of pregnancy. Others' noted a toxemia-like condition in animals following administration of DOCA and a high salt diet.
Our group" made an effort to evalute the tolerance of the pregnant patient and her unborn infant to ACTH and cortisone. It was our opinion that the hormones neither significantly altered the course of toxemia of pregnancy nor caused its development.
The most striking observation was the apparent increased tolerance of the pregnant patient to ACTH and/or cortisone. None of the patients studied showed changes of significant deviation from normal in plasma potassium, plasma, chlorides, plasma sodium, blood sugar, and uric acid. The cause for increased tolerance to ACTH and/or cortisone during pregnancy is not known.
One must remember that these are potent drugs, and like new cars, their "horsepower" or potency is stepped up as the drugs are better prepared and new ones introduced. We are still concerned that the fetus in utero possibly does not withstand, with the same apparent degree of impunity as the mother, the maternal administration of these drugs. Recently five patients under our observation in whom ACTH and/or cortisone was administered during pregnancy suffered intrauterine fetal death concomitant with hormone therapy. In several instances this tragic event was unexpected and it was difficult not to impute ACTH and/or cortisone.

Antihypertensive
Drugs: In severe preeclampsia, impending convulsions threaten the patient and challenge the obstetrician. Increasingly severe hypertension, proteinuria and edema are the cardinal symptoms.
In severe preeclampsia, as in eclampsia, the objective of therapy is to prevent convulsions. With early delivery the ultimate objective, pre-delivery management has as its obligation, the responsibility of arresting and turning the aberrent physiological processes toward normal homeostatic levels. Evacuation of the uterus can then be accomplished with safety. In this phase, hypertension is the chief threat and arteriolar spasm the chief physiological deviation.
Hemodynamic factors concerned with arterial pressure are four in number: 1. cardiac output and cardiac force, 2. blood volume, 3. viscosity of the blood, and 4. peripheral resistance. These factors are under two types of control: neurogenic and humeral. In pregnancy, and in toxemia, the factors showing greatest deviation from normal are blood volume and increased peripheral resistance, A priori reasoning suggests that drugs useful for the treatment of critical hypertension of toxemia should reduce blood pressure without compromising blood flow through vital organs. Granted, that treatment is directed toward a symptom and not a cause, and drastic, precipitous hypotension may be as dangerous as hypertension, the stark fact remains that most deaths from toxemia result from convulsions, cerebral hemorrhage, left heart failure, and renal failure. Anti-hypertensive drug therapy has as its objective: control and not cure.
The drugs avaflable can be classified into four groups acording to their main point of action:

To.xemia of Pregnancy
The ideal drug for use in preeclampsia should have the following attributes: 1. lower blood pressure 2. maintain cardiac output 3. not effect cerebral blood flow 4. vasodilate 5. not effect renal blood flow 6. not be antidiuretic 7. not produce orthostatic hypotension 8. its use should be compatable with the use of other drugs 9. maintain patient alertness 10. have few side effects 11. leave no residual effects 12. leave no fetal side effects 13. have versatility of administration: I.V., Oral, I.M. 14. anticonvulsant 15. be capable of both rapid and gradual effects Using these critera, the drugs most useful for the treatment of preeclampsia are: hydrazinophthalazine (Apresoline), veratrum veridi and its purified extracts, rauwolfia serpentina, and its alkaloids, and magnesium sulfate, (parenteral).

Hydrazinophthalazine:
(Apresoline) causes mild tachycardia, is a vasodflator, reduces blood pressure, increases cardiac output, has relatively few sides effects, increases renal and cerebral flow, and does not change the blood volume. It is effective when administered by mouth and can be given intravenously to bed patients when prompt action is necessary. It is a valuable drug and appears to occupy the "number one" spot at the present time for treatment of hypertension of toxemia.

Veratrum Veridi:
This drug conforms to all the critera except for the disadvantage of causing more side effects. It appears that veratrum can be used to its greatest advantage as an emergency drug in situations characterized by dangerous hypertension. Veratrin extract given intravenously in an initial dose of 0.5 mgm augmented when necessary at half hour intervals by the administration of an additional 0.1 mgm will generally effect a prompt fall in blood pressure to less dangerous levels. The associated vagal stimulation causes slowing of the heart rate and nausea, which action can be negated through the administration of atropine. The drug is also effective when administered intramuscularly and orally. During intravenous administration, blood pressure should be recorded at 10 minute intervals and sudden extreme degrees of depression of arterial blood pressure should be avoided.

Rauwolfia serpentina:
This is a good drug which has the attributes of vasodilatation and mild sedation. Its disadvantage is its slow action. In toxemia rauwolfia is used most frequently in mild preeclampsia when it is given by oral administration to patients on a restricted ambulatory schedule. Here the mild sedative and hypotensive actions can be used to advantage.

Magnesium sulfate:
Magnesium sulfate when given orally is a dehydrating purgative and is useful in toxemia of pregnancy to aid in mobilization of extracellular body water. When given parenterally the pharmacological actions of magnesium sulfate are anticonvulsive and sedative. In toxemia of pregnancy its parenteral use is most effective for prevention impending convulsions. Magnesium sulfate when administered parenterally causes slight decrease in heart rate, mild vasodilatation, and slight lowering of the blood pressure. It does increase cerebral blood flow and renal blood flow. In these actions it is inferior to hydrazinophthalazine, veratrum and rauwolfia, but it can be in conjunction with these drugs for its synergistic action.
The other drugs mentioned have limited use in toxemia of pregnancy and some have definite disadvantages. Barbiturates lower blood pressure but they seriously reduce cerebral blood flow, oxygenation of the brain, and they do not relieve vasospasm. Morphine also reduces cerebral blood flow. The ganglionic blocking agents cause serious postural hypotension and the adrenergic drugs are most useful as diagnostic agents in patients suspected of having pleochromocytoma.

Conclusion:
It is important to remember the only cure for toxemia of pregnancy is termination of pregnancy as Cosgrove (6) stated. It is necessary to remember that it is the toxemic state that is inimical to both mother and fetus, and that termination of the pregnancy is most certainly salutary for the mother and probably so for the infant. For the infant the chance for survival from the state of prematurity is many times greater than is continued intrauterine survival should severe preeclampsia be prolonged or eclamptic convulsions intervene.