PLASMAPROTEINS IN TOXEMIASOF PREGNANCY

BY HAROLDC. MACK(From the Departments of Obstetrics and Gynecology, Harper Hospital and Herman Kiefer

Hospital, Detroit, Mich.)

AND

BY ABNERR. ROBINSON, MARGARETE. WISEMAN, ERNESTJ. SCHOEB, ANDICIE G. MACY

(From the Research Laboratory, Children's Fund of Michigan, Detroit)

(Submitted for publication December 26, 1950; accepted, April 2, 1951)

Numerous studies of the toxemias of late preg-nancy have consistently demonstrated the as-sociation of pre-eclampsia and eclampsia withdisturbances of protein metabolism indicated byderangements in the protein composition of theblood. Whether these changes in themselvescause the symptoms of toxemia or are secondaryto the elusive "toxic" factor has not been de-termined. Many circumstances are known toprovide the basis for protein deficiency within thehuman body, by increasing the tissue requirementfor protein or by interfering with assimilation andutilization of an intake which would otherwise beadequate (1, 2). Evidence relating to the possiblerelationship of nutritional disturbances to the oc-currence of toxemia is contradictory (3-9). Inan excellent analysis of the problem of comparingconflicting reports in the literature, M0ller-Chris-tensen and Thygesen (10) emphasized the inti-mate connection between changes in protein bal-ance and accompanying shifts in water and saltbalances, and suggested the possibility of derange-ment in function of the adrenal in protein metabo-lism in toxemia. A complex explanation involv-ing the presence of a toxic protein (an atypicaleuglobulin) in the circulating blood during men-struation, labor, and toxemia of pregnancy hasbeen advanced by Smith and Smith (11, 12).

While a relationship between disturbed proteinmetabolism and toxemia of pregnancy has beenestablished, the evidence does not show that thedisturbance results from dietary protein deficiency.Dieckmann (13) believes that hypoproteinemia isneither the cause of pre-eclampsia and eclampsia,nor the cause of edema. Novak and Lustig (14)caution against identification of the hypopro-teinemia of pregnancy with hypoproteinemia dueto malnutrition and believe that within limits it

is a physiologic condition. The finding by Bibb(15) that most women who developed toxemiahad some previously existing hypoproteinemiawould be expected. Despite suggestive data, theo-ries relating toxemia to nutritional deficiency fail,as do all other hypotheses advanced, to explainmany features of this disorder, notably its singu-lar predilection for the primigravida. Our in-creased understanding in the past few years of theimportance of interrelationships among variouscomponents of the food intake may provide a keyto further elucidation of the role of nutrition intoxemias of pregnancy, but it seems likely thatboth nutritional and physiologic factors may beinvolved, the number varying perhaps with stillother conditions. Certainly, even with respect tothe part played by well-established changes inblood proteins, eclampsia remains "the disease oftheories."

The conflicting reports in the literature and therecent development of the electrophoretic tech-nique of analysis were responsible for the decisionto determine the distribution of plasma proteinsin the blood of women during pregnancy, at de-livery, and in the puerperium. A preceding publi-cation (16) reported the distribution of proteinsin the plasma of healthy women during the men-strual cycle, during successive stages of normalpregnancies, and postpartum, demonstrating theshifts in plasma protein composition which arecharacteristic of uncomplicated gestation. Thesame techniques were employed under comparableconditions in investigations of the protein con-stituents of the blood plasma of women whosepregnancies were complicated by toxemia andother gestational disturbances. The results dem-onstrate some of the causes of the wide variationsencountered in the literature and indicate profit-

609

6H. C. MACK, A. R. ROBINSON, M. B. WISEMAN, B. J. SCHOEB, AND I. G. MACY

able directions for further study. Subsequentpapers will record results of determinations ofplasma proteins in samples from subjects withrenal and liver diseases, hypertension, diabetes,and other conditions.

PROCEDURE

This report presents the results obtained from analysesof blood samples from 29 private and clinic patients ad-mitted to the obstetrical services of Harper Hospital andHerman Kiefer Hospital, Detroit. All were studied firstin the last trimester of pregnancy after toxemia had de-veloped. The methods of obtaining blood samples, prepa-

ration, and analysis were identical with those described(16). The buffer solution (barbital) used was 0.1 Nwith respect to sodium diethylbarbiturate and 0.02 N withrespect to diethylbarbituric acid. Electrophoretic re-

cordings were made with a Tiselius instrument employingthe Longsworth scanning mechanism and a three-pieceTiselius cell with a single, long center section. Determi-nations were run for three hours at 10 C. and a potentialgradient of about 6 volts/cm.

Appraisal of history, physical, and laboratory findings,and postpartum outcome are usually necessary to permitsome degree of accuracy in evaluation. Hence, finalclassification of the patients was determined only afterpostpartum observations were available. The patientsstudied fell into the following categories according to the

TABLE I

Data from medical records of 29 patients with toxemias of pregnancy

Mother Infant

Subject* Blood pressure Total weightAge Parity Term Albu__gain_uring_Weigh|(Ages|Gravida |gestation dAbu-|dema egxaindring S Weigt(Yrs)Gmida(.iks.) Whn Ps- mnuria pregnancy (gin.)

admitted partumt ~b.

Mild pre- 3 31 1/1 42 164/100 125/70 + ++ 15 M 3005eclampsia 18 18 1/1 42 170/120 142/90 + 0 44 F 3288

27 26 2/3 41 140/100 132/80 + + + 22 M 382744 25 1/1 37 154/104 120/70 + + + + 24 M 228247 24 1/1 40 144/90 108/60 + + + 34 F 371452t 41 1/5 38 174/90 160/100 + + + 38 F 311853 26 1/1 42 155/80 122/80 + + + 43 M 348773 26 1/2 40 180/100 150/90 ++ + 28 F 385678 23 1/1 35 146/104 105/70 + + + + + 22 F 1502**

108 34 1/1 41 160/90 120/70 +++ + 50 F 3062118 26 1/2 35 174/120 120/90 + + + + + 30 F 1474123 28 2/2 41 152/92 120/90 + ++ 23.5 F 3799

Severe pre- 4 19 1/1 39 184/100 112/78 +++ ++ 37 F 3090eclampsia 171 37 4/4 32 155/90 138/90 +++ ++ 53 M 1502**

M 1361**2411 18 1/1 39 162/118 124/80 + +++ 21 M 22683111 35 2/3 37 190/100 150/90 + ++ + + 23 F 207032 38 3/3 39 180/110 115/75 + ++ 0 8 F 192837 23 1/2 43 170/110 146/104 +++ +++ 22 F 2041

M 26658711 20 1/1 38 190/120 130/88 ++++ +++ 31 F 2948

M 246694 29 1/1 35 180/120 138/90 +++ ++ 10 F 992**

10711 26 3/5 30 190/120 140/90 ++ +++ F 3175**169 35 1/2 34 198/100 130/90 + + + + ++ 20 F 1502170 41 2/4 38 190/110 145/95 +++ ++++ 12.5 F 1602171 26 0/1 35 170/100 132/70 ++ + +++ 36 M 2211**

Eclampsial 211 18 1/1 38 180/120 160/110 ++++ ++ 13 F 326014 26 1/1 35 140/110 110/64 ++ + 13 M 150264 36 6/7 42 215/115 130/90 + + ++ + + 60 F 396982 23 1/1 33 160/100 130/80 + ++ + ++++ M 2495

111 18 1/1 35 160/110 122/70 ++++ ++ 37 M 2098

* Subjects 4, 18, 31, 37, 107, 170, and 171 are negroes; subject 47 is Mongolian.t Approximately six weeks.

Four previous spontaneous abortions; stilbestrol therapy during pregnancy.I Rh negative-high titer.1 No prenatal care. Abruptio placentae occurred with subjects 24, 107, and 171. Subject 31 previously was hyperten-

sive.¶ Convulsions occurred three times with subject 2; twice with each of the other patients.** Stillborn.

610

PLASMA PROTEINS IN PREGNANCYTOXEMIAS

clinical classification proposed in 1939 by the AmericanCommittee on Maternal Health: mild pre-eclampsia, 12cases; severe pre-eclampsia, 12 cases; eclampsia, fivecases. Pertinent information from the clinical historiesof the patients is summarized in Table I.

RESULTSANDDISCUSSION

The means and ranges of concentrations of totalprotein and protein fractions in the plasma of bloodobtained prepartum, at delivery, and postpartumare given in Table II. The results, insofar as can

be determined, were not influenced by any form oftherapy prior to the time of blood sampling."The distribution of the total protein among theprotein fractions and the albumin/globulin ratiosare given in Table III. Values for womenwhosepregnancies were uncomplicated (normal) andfor non-pregnant women (16) are included forcomparison. Individual values for each woman

will be presented in a subsequent report.Numerous publications (10, 13, 14, 18-22) have

given the quantities of proteins in the blood innormal and toxemic pregnancies, based for themost part on the results of various salt fractiona-tion technics. All agree on the general pattern ofthe changes in the blood proteins, described as

"dyscolloidosis" by Seitz (19) and Eufinger (20)although the degree of alteration in toxemia andthe clinical significance of these changes are vari-ously interpreted. All agree that a definite hypo-proteinemia, greater than that observed in normalpregnancy, is found in the toxemias. Since thetechnics employed differ, and more especially, sincethere is no uniformity with which the various clini-cal types and degrees of toxemia are classified, pro-

tein values reported cannot be compared directly.In the preceding paper (16) we compared elec-

trophoretic results in normal pregnancies and post-partum with those for healthy non-pregnantwomen. The data showed that by six to 12 weekspostpartum (average, eight weeks) "the return ofthe plasma protein pattern toward normal is almostcomplete. .. ." If in healthy womenwhose preg-

1 In one patient, stilbestrol therapy as recommended bySmith (17) was employed in regularly increasing amounts(up to 125 mg. daily) from the seventh to the thirty-fifthmeek of gestation to prevent abortion. Despite continu-ous estrogen therapy and normal hormone excretion thispatient developed mild pre-eclampsia, with electrophoreticpatterns similar to those of other subjects with the same

type of toxemia.

nancies have been uncomplicated, the levels ofblood proteins five to six days postpartum are sig-nificantly different from non-pregnant values andhave not completely returned to normal levels byeight weeks postpartum, on the average, it seemsevident that accurate control data for women whohave had toxemias of pregnancy cannot be ob-tained from the same subjects sooner than eightor more weeks following delivery.

In pre-eclampsia and eclampsia mean concen-trations (Table II) in plasma of total protein, al-bumin, beta and gamma globulins tended to belower than comparable values in normal preg-nancy. The other globulin fractions showed trendsdissimilar to those of total protein, albumin, andgammaglobulin, with a tendency for values to behigher than in normal pregnancy.

In normal pregnancy mean values for fibrino-gen (phi globulin) in the third trimester werehigher than the average for non-pregnant women,showed little change at delivery and five or sixdays postpartum, and declined to below non-preg-nant levels by six to 12 weeks postpartum. Inpre-eclampsia a similar trend occurred at a some-what higher level, with levels six to 12 weeks post-partum approximating the average for non-preg-nant women. In eclampsia, however, the meansbefore and at delivery were higher than that of anyother group, at one to five days postpartum theaverage still was high, and six to 12 weeks post-partum the mean was higher than that of non-pregnant women. Both chemical and electropho-retic determinations of fibrinogen have disclosedlevels in toxemia even higher than the recognizedincrease in normal pregnancy. According toDieckmann (13), a falling fibrin level in eclampsiaimplies a grave prognosis, and Dillon and Schmitz(23) reported two instances of fatal fibrinogeno-penia in eclampsia. Among the cases of severepre-eclampsia for which data are reported in thispaper were three in which premature placentalseparation occurred. For these three patients,plasma fibrinogen levels were lower than those ofpatients in whom this complication did not occur.The levels, however, were not lower than meanvalues in uncomplicated pregnancy.

In a consideration of blood proteins in the toxe-mias of pregnancy two trends must be evaluated inrelation to concomitant manifestations of disturbedphysiologic function: their relation (1) to levels

611

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and trends in normal pregnancy and (2) to levelsin healthy non-pregnant women. Heretofore,comparable data have not been available whichwould permit comparison of the trends from pre-partum to recovery in eclampsia with the trendsin normal pregnancy or the comparison of trendsof protein concentrations in mild and severe pre-eclampsia at different times in relation to de-livery with values in normal pregnancy and fornon-pregnant women. Undoubtedly, in addition todifferences in method of sampling and analysis theprevious lack of values for various intervals pre-and postpartum, both in normal and complicatedpregnancies, has been responsible in large meas-ure for discrepant results in the literature. Theprogressively severe clinical picture described asmild pre-eclampsia, severe pre-eclampsia, andeclampsia suggests a progressive change in accom-panying internal conditions in the body. The datain Tables II and III show that such parallelismdoes not hold true for all protein fractions and forall times in relation to delivery. Likewise, the pro-tein values accompanying increased severity of theclinical picture do not consistently increase or de-crease in relation to comparable values for normalpregnant women.

From the data in Table II it is readily under-standable that Lagercrantz (24) found a declinein total protein and albumin during the last monthof gestation but with values no lower than thosefor normal pregnancy in his group of unassortedpatients with various types and degrees of toxemia.Our study shows, on the contrary, little changein the mean quantities of total protein and albuminfrom the third trimester to delivery in normal preg-nancy (Table II). Thus, with a mean of normalvalues within a lower range than that found inour study, or with a mean for toxemia which bychance represented subjects whose levels rangedhigher for their degree of toxemia, it is understand-able that similar or even higher than normal levelsmight be found in other series of toxic women.Thus, also, the possible lowering of total proteinlevels in eclampsia during the five days immediatelyprepartum would be obscured and as well, thetrends we have observed toward lower concentra-tion of total protein and albumin with increasedseverity of pre-eclampsia.

Whether the lowered plasma protein concentra-tions in toxemia actually represent a real lo6s of

protein supplies in the body can be determinedonly by measurements of blood and plasma vol-ume, for which precise methods are not available.Studies of blood volume in pregnancy (25) haveconsistently shown an increase of plasma volumeof approximately 25 per cent subject, however,to great individual variations. In the evaluation ofdifferences in protein concentration and distribu-tion between womenwith and without toxemia thequestion is not whether blood volume increasesduring gestation but, rather, whether the increasevaries when toxemia occurs. Since rapid changesin water balance occur in toxemia, deductionsbased on averages of a few values are especiallysubject to error and valid conclusions can bereached only with results for a large number ofwomen or by following the same patients at fre-quent intervals, especially late in gestation andearly in the puerperium. The data obtained in thisinvestigation emphasize that confirmation or refu-tation of the numerous speculations which havebeen advanced will require more detailed study ofaccurately defined groups, both normal and ab-normal, at more frequent intervals, and with com-parable methods.

The data strongly suggest that the eclampto-genic syndrome is accompanied by alterations inthe plasma proteins which represent a modificationof changes which are physiologic in pregnancy.The deviations from normal in pre-eclampsia dur-ing the third trimester of pregnancy indicate thatchanges in the amounts and distribution of theplasma proteins may antedate the appearance ofclinical signs and symptoms of toxemia. However,no evidence was obtained of a relationship to die-tary protein inadequacy before or during preg-nancy. The fact that the eclamptogenic effects inthe third trimester, notably the increases in fibrino-gen and the alpha2 globulins and the decreases ingammaglobulin and albumin, occurred on the basisof percentages of total protein as well as in termsof plasma demonstrates that the alterations arenot reflections of changes in blood volume.

SUMMARY

The electrophoretic method is being used tostudy the plasma protein prepartum, at delivery,and postpartum in the blood of womenwhose preg-nancies are normal, and those whose pregnancies

614

PLASMAPROTEINS IN PREGNANCYTOXEMIAS

are complicated by toxemia, renal disease, hyper-tension, diabetes and other gestational disturb-ances. Means and ranges for total protein, albu-min, and alpha,, alpha2, beta, gamma, and phiglobulins are presented for 29 womenwho had mildeclampsia, severe pre-eclampsia, or eclampsia be-fore delivery.

The results stress the need for determinationsat narrower and more sharply defined intervalsprepartum and postpartum for larger groups ofpatients carefully grouped according to diagnosticcriteria and according to the severity of clinicalsymptoms.

Determinations of plasma proteins for non-pregnant women and for normal pregnant womenand patients with toxemia at intervals of a fewdays and six to 12 weeks postpartum emphasizethat normal non-pregnant levels of plasma proteinsare not achieved for several weeks after deliveryand determinations as early as ten days or twoweeks postpartum do not provide adequate "con-trol" data.

REFERENCES

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2. Stare, F. J., and Thorn, G. W., Protein nutrition inproblems of medical interest J.A.M.A., 1945, 127,1120.

3. Siddall, A. C., Vitamin B1 deficiency as an etiologicfactor in pregnancy toxemias; preliminary com-munication. Am. J. Obst. & Gynec., 1938, 35, 662.

4. Ross, R. A., Perlzweig, W. A., Taylor, H. M., Mc-Bryde, A., Yates, A., and Kondritzer, A. A., Astudy of certain dietary factors of possible etiologicsignificance in toxemias of pregnancy. Am. J.Obst. & Gynec., 1938, 35, 426.

5. Whitacre, F. E., Loeb, W. M., Jr., and Chin, H., Acontribution to the study of eclampsia. Consider-ation of 200 cases. J.A.M.A., 1947, 133, 445.

6. Mastboom, J. L., Frequency of eclampsia in wartime.Nederl. tijdschr. v. geneesk., 1948, 92, 3604.

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8. Smith, C. A., Effect of wartime starvation in Hol-land upon pregnancy and its product. Am. J.Obst. & Gynec., 1947, 53, 599.

9. Kooser, J. H., Observations on the possible relation-ship of diet to the late toxemia of pregnancy.Am. J. Obst & Gynec., 1941, 41, 288.

10. Mfller-Christensen, E., and Thygesen, J. E., In-vestigation of the serum-protein balance in normaland toxemic pregnant women. J. Obst. & Gynaec.Brit. Emp., 1946, 53, 328.

11. Smith, 0. W., and Smith, G. V. S., A fibrinolytic en-zyme in menstruation and late pregnancy toxemia.Science, 1945, 102, 253.

12. Smith, 0. W., and Smith, G. V. S., Evidence for cir-culating menstrual "toxin" during menstruationand toxemia of late pregnancy. Proc. Soc. Exper.Biol. & Med., 1945, 59, 119.

13. Dieckmann, W. J., The Toxemias of Pregnancy.The C. V. Mosby Co., St. Louis, 1941.

14. Novak, J., and Lustig, B., Quantitative and qualitativechanges of the serum proteins in normal and toxemicpregnancy. The nature of the hypoproteinemia inpregnancy. J. Mt. Sinai Hosp., 1947, 14, 534.

15. Bibb, J. D., Protein and hemoglobulin in normal andtoxic pregnancies. Am. J. Obst. & Gynec., 1941,42, 103.

16. Coryell, M. N., Beach, E. F., Robinson, A. R., Macy,I. G., and Mack, H. C., Metabolism of women dur-ing the reproductive cycle. XVII. Changes inelectrophoretic patterns of plasma proteins through-out the cycle and following delivery. J. Clin. In-vest., 1950, 29, 1559.

17. Smith, 0. W., Diethylstilbestrol in the prevention andtreatment of complications of pregnancy. Am. J.Obst. & Gynec., 1948, 56, 821.

18. Plass, E. D., and Bogert, L. J., Plasma protein vari-ations in normal and toxemic pregnancies. Bull.Johns Hopkins Hosp., 1924, 35, 361.

19. Seitz, L., Biologie der Placenta; pathologischer Teil;die pathologische Biologie der Placenta und diewichtigsten chemisch-physikalischen und biologi-schen Grundlagen der Schwangerschaftstoxikosen.Arch. f. Gynak., 1929, 137, 322.

20. Eufinger, H., Die kolloidstruktur des Plasmas wiihrendder Gestation. I. Die Kolloidstabilitat des Plasmaswahrend der normalen Gestationsperiode. Arch. f.Gynak., 1928, 133, 452.

21. Eastman, N. J., The serum proteins in the toxemiasof pregnancy. Am. J. Obst. & Gynec., 1930, 19,343.

22. Rinehart, R. E., Serum protein in normal and toxemicpregnancy. Am. J. Obst. & Gynec., 1945, 50, 48.

23. Dillon, W. F., and Schmitz, H. E., Fulminatingeclampsia associated with fibrinogenopoenia andhemorrhage. Illinois M. J., 1949, 96, 255.

24. Lagercrantz, C., Electrophoretic analysis of serum inpregnancy and in pregnancy toxemia. Upsalalakaref. forh., 1945, 51, 117.

25. Dieckmann, W. J., and Wegner, C. R., Studies of theblood in normal pregnancy. III. Hemoglobin andcell volume co-efficients; erythrocyte volume, hemo-globin content and concentration; color, volumeand saturation indexes. Arch. Int. Med., 1934, 53,345.

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