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Studies on the circulation in pregnancy
AMJZRICAN JOURNAL
48
OF W3STETRICS ANIl QYNECOI.(h:Y REFEREN(lES
Browne, J. S. L., and Venning, E. X.1.: Aim. J. Pllysiol. 116: 18, 1936. (2) Do&Is, E. C. : AM. J. OBST. & GYNW. 30: 302, 1935. (3) Frank, Iz. T.: Ibid. 32: 168, 1936. (4) Geschickter, C. F., Lewis, Dean, an,d Hartman, C. G.: AnI. J. Cancer 21: 828, 1934. (5) Goldberger, M. A.: AM. .J. 0~s~. & GPNEC. 33: 1093, 1937. (6) Mazer, C., Merunze, D. R., and lsraeZ, S. L.: J. A. M. A. 105: 257, 1935. (7) Robinson, A. L., D&now, M. 2f., and deffcoate, T. B. A.: &it. M. J. 1: 749, 1935. (8) Savage, J. X., and Wylie, H. B.: AN. J. OBST. & GYIVJK. 33: 771, 1937. (9) Schmdovitz, &l. J., and Wylie, H. R.: J. T,ab. & Clin. Med. 21: 210, 1935. (10) &de, E.: Endocrinology 21: 594, 1937. (II) Smith, G. V., ad Kennard, J. H. : Proc. Moe. Exper. Biol. & Med. 36: 508, 1937. (12) Smith, G. V., and Smith, 0. W. : Surg. Gynec. Obst. 61: 175, 1935. (13) Idem: New Eng. J. Med. 215: 908, 1936. (14) Smith, 0. W., and Smith, G. V.: AM. J. OBST. & GPNW. 33: 365, 1937. (15) Steinkamm, E., and Giesen, TV.: Zentralbl. f. Gyn%k. 60: 369, 1936. (16) Witherspoon, J. T.: Proe. Sot. Exper. Biol. Rr Med. 29: 1063, 1932. (17) WY&e, H. B., and Savage, J. B. : In preparation for publication. (18) Birman, S, A.: IIlinois M. J. 70: 198, 19X. (1)
LOMBARD AND GREENE
STUDIES 111.
STREETS
OX THE CIltCULATION
KI,OOD VOLUME
CHANGES
IX PREGNANCY
IN NORMAL
PRWNANT
WOMEN
K. JEFFERSON TIIOMSON, M.D., MOUNT MCGREGOR, N. Y., A. HIRSHEIMER, MD., DAYTO'K. OHIO, JOHN G. GIBSON, ZND, M.D., BOSTO'N, MASS., AND WIIXAX 11. EVASS, JR., M.D., DETROIT, MICH. (From
the Departments of Obstetrics nnti Xediciw, Cardiac Clinic nml Research Laboratory, Boston the Medical
Clinic
of the Pefu
Bent
Rrigham
Rarcnrd
Medical
Lyi~lg-in
Hoqifal,
Hospitul,
School;
the
and
Boston,
N ANY consideration of the altered physiology of the circulation during normal pregnancy, notably the low level of the solid constituents of the blood, the diminished viscosity of the blood, the changes in cardiac output and velocity of blood flow, and the frequent occurrence of edema, it is important to know what variations, if any, occur in the plasma and blood volume. Such information is likewise useful in evaluating certain pathologic conditions frequently associated with cardiac disease and the “toxemias” of pregnancy ; particularly pregnancy. Dieckman and Wegner, who contributed a valuable blood volume study in 1934,l pointed out in their review of the literature the conflicting findings of previous investigators in this field. They cited important criticisms: First, none of the earlier studies included an adequate number of det,erminations on the same individuals during the ante- and post-partum periods, conclus’ions having been drawn from the analysis of disparate groups ; and second, the methods used were various and of doubtful accuracy, in some instances in technique, elsewhere in calculations based on the patients’ weights without due regard to the undeterminable quantity of the uterus and its contents and to maternal edema. It should be emphasized, in addition, that it is unlikely that a reliable estimate of the blood volume changes occurring in pregnancy can be obtained by the comparison of single
I
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observations on many individuals in the several periods of gestation with the average normal nonpregnant volume whether absolute or in terms of body weight, since the range of volume in normal persons is great, Dieckmnn and Wegnerr found an increase in the plasma and total blood volumes in the second trimester of pregnancy and at term, as compared to the first trimester which amounted to a maximum of 25 per cent for plasma and 20 per cent for total blood volume. They also reported a post-partum decrease, not always manifest early in the puerperium, as compared to the last ante-par-turn determination (actually, however, in their Group A patients, followed throughout pregnancy and the puerperium, 6 of the 13 showed a higher postpartum total blood volume than at the last ante-partum observation! ). The plasma volume increase was relatively greater than that of the red cell volume. These anthers, while they were of the opinion that repeated determinations on the same individual checked closely and were significant, conceded that the KeithRowntree method,2 which they used, was liable to distinct errors.
The use of the original Keith-Rowntree method in this clinic produced such variable results that no definite conclusions could be drawn as to the behavior of the blood volume in pregnant women.” When, therefore, a new method which satisfactorily avoids the pitfalls of the earlier dye methods became available by the work of Gregersen, Gibson, and Stead,” another study of the blood volume in pregnancy seemed indicated. PROCEJDURE
The subjects for this study were obtained from the prenatal clinic of the Boston Lying-in Hospital, and were chosen at random, the only basis of selection being the duration of pregnancy and freedom from medical or obstetric complications. Observations were made at frequent intervals throughout pregnancy, usually about six weeks apart, and at least once post partum, usually at two weeks. The observations on individual patients varied between two and six, with an average of four. The data usually taken at each visit were: weight, arterial blood pressure, pulse and respiratory rates, venous pressure, circulation time, subcostal angle, hemoglobin, red blood cell count, hematocrit, vital capacity, blood volume, and occasionally, basal metabolic rate. Every patient at each visit received a careful physical examination of the heart, lungs, abdomen, and extremities. All patients were studied under basal conditions of fasting and resting, Blood volume and venous pressure observations were preceded by at least thirty minutes: bed rest, and circulation time measurements by at least sixty minutes’ bed rest. Vital capacities were determined according to the routine described fully in a separate paper.4 In presenting our data, the duration of gestation has been calculated back from the actual day of delivery, the duration of a full-term pregnancy being taken as 280 days, or ten lunar months. METHODS
With the exception of the blood volume method which is described below, the other determinations were carried out exactly as described in a previous report.5 Blood volumes were determined by the method developed by Gregersen, Gibson, and Stead,3 as adapted to clinical use by Gibson and Evans,6 in which the plasma approximately 100 attempts, 75 “satisfactory” observations on the blood volume on normal pregnant yomen at the Boston Lymg-in Hospltal by Dr. Mandel . The results from this study tended to show that the total blood volume increased during pregnancy and diminished after delivery. It was felt by him, however, since checks on the same sample were so difficult to obtain and since the percentage error in the method was so great, that the results of the study were unreliable. *In ger;jo;$z
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volume is actually determined and the total blood and red cell volumes calculated from the plasma volume and the hematocrit value. This method employs a blue azo dye, Evans Blue (T-1824),7 and is a modification of the Keith-Rowntree method.2 It minimizes errors inherent in earlier techniques, resulting from variations in the time required for complete mixing of the dye in the blood stream, where volume calculation is based on the dye concentration uf a single sample iaken three to six minutes after dye injection. Furthermore, incalculable errors arising from variations in the rate of disappearance of dye from the blood stream are eliminated. Colorimetric estimations of the dye concentration of serum samples are made with the spec trophotometer, thus eliminating errors arising from inequality in dye concentration The use of a blue dye minimizes errors due to between standard and samples.* hemolysis of samples and affords an accurate spectrophotometric method of correcting for such occasional hemolysis as may occur. Minor modifications of the method as described by- Gibson and Evans6 were employed; the infiltration of skin at the site of venipunrture with procaine without adrenalin (gratefully acknowledged by the patients) and, occasionally, the use of 0.5 per cent sodium citrate in normal saliue solution to inhibit clotting in the needle between sampling. of vein damage by it were enNo systemic reactions to the dye, nor evidences countered. Accidental injection of the dye cxtravenously produced local diseoloration, but little or no discomfort and no tissue reaction or necrosis. None of the patients showed sufficient generalized coloration of the skin and subcutaneous tixsues from the dye (average dose 10 mg.) to be apparent to the casual observer. Relatively large doses of dye (30 mg.) were given to F patients in labor. Spcctrophotometric examination of the amniotic fluid and cord serum of 3 showed no dye. In none could dye he detected in microscopic examination of the membranes and placentas prepared by special technique to show the presence of this dye histologiIt was therefore assumed that the disappearance of the dye from the blood cally.* stream is not influenced by passage to the ovum. Evans and Gibson0 have showed that any influence of occult edema on the accuracy of the blood volume determinations may be disregarded. Duplicate red blood cell counts and hemoglobin determinations were made from oxalated venous blood (no stasis) obtained at the first venipuncture, using certified pipettes and counting chambers and a Sxhli hemoglohinometer calibrated by the oxygen capacity method, so that 100 per cent represents IS.6 gm. of hemoglobin per 100 cc. whole blood. RESUL’TS
The data here presented (Table I) were derived from 56 observations (40 ante and 16 post partum) on 14 patients whose pregnancies were entirely normal. In this group there were 9 primiparas and 5 multiparas, varying in age from 20 to 34 years, with an average age of 25.1 years. One patient in the series who delivered twins, although included in Table I, is not considered in the general analysis. The plasma volume was actually determined in this study. From it, by means of the hematocrit value, the total blood and cell volumes were calculated. Although for general physiologic purposes the chief concern is the state of the total blood volume, there is special interest in the plasma volume in pregnancy, since there is a reported disproportionate increase between it and the cell volume resulting in the “hydration” phenomenon. *Sections of the placenta and membranes were prepared according to the method of Dr. Harold L. Weatherford, Dept. of Anatomy, Harvard Medical Schoo$ in which tissues were tied in fluid composed of acetic acid 4.0 cc.. trlchlomcetic acKl 2.4) %m., sodium chloride 0.5 gm.. corrosive sublimate 6.0 gm., 37 per cent forma% 20.0 c.c., water 80.0 cc. ; run through paraffin and stained with Mayer’s ~racarmme in 70 per cent akohol, The authors are i%%bkl to PP. I;frx%h H. Nubile. re&dent pathologist, Boston Lying-in Hospital, for thege histologic lxeparations and eXa%Uinations.
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51
VOLUME
There is a progressive increase in plasma volume from early pregnancy through the ninth lunar month, when the maximum is reached. This amounts to an increase of 65 per cent above the average normal nonpregnant value (Chart l), During the tenth month there is a definite decrease to 50 per cent above the normal nonpregnant level. Post partum this decrease continues so that by the end of the second
Chart I.-The average total blood, plasma and cell Volume in normal pregnant women. The heavy perpendicular line represents delivery and separates the anteand Post-partum periods. Note that the maximum increase occurs in the ninth lunar month. with a deflnite diminution before delivery.
/ t c
1NO ;T ‘pi”6 -
2 PA‘Ul 3
ANTE PA
Chart Z.-The total blood volume in normal pregnant women. The flne connected lines represent curves of individual patients; the heavy line represents the curve of average values. The heavy perpendicular line represents delivery and separates the ante- and post-partum periods. Note that all of the ante-partum values are above ;y average normal nonpregnant value, whereas post partum they group closely about
post-partum week the normal nonpregnant level is reached. The plasma volume varied between 2,620 and 4,470 c.c., an average of 3,710 C.C. ante partum and between 2,010 and 3,050 c.c., an average of 2,106 C.C.post partum. The range of plasma volume determined by the same method in a group of 28 normal nonpregnant women of the same age group is from 1,880 to 2,860 c.c., an average of 2,370 C.C.
52
AMEXICAN
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7.3 7.5 0.’ 4.3 8.5 3.i 8.c 1 7.c I 4.1 s. , 8.2
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1510 1180 1880 2010 1640
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2960 1400 16: 150s 1090 1470 i 500 3510 is70 1110 -1570 1440 c350
1350 3010 !930 3330 1020 ?370 !620 1120 ?755 !290 2800 !5XO
i% 1040 1900 1660 !400 1340 ?OlO -1440 3315 1540 E
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65.7 74.2 --49.0 48.R 53.9 41.2 42.2 Ez 44.3
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ZI
-
I .-
12.30 9.83 10.14 10.45 8.11 10.61 9.98 9.36 9.36 10.14 11.90 10.61 8.15 10.92 12.17 10.92 9.67 9.36 9.83
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~ :I: 90
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Delivered Apr. 7, 1936 BirthO”mxSweight of baby
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12, 1935
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June 17, 1936 weight of baby 6 pounds,
Delivered June 10. 1936 Birth weight of baby 6 pounds,
ii::: 7.8( I 9.67 9.52 10.30 1 10.45
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Delivered May Basal metabolic + 6% Birth weight of o”nceS Delivered March Basal metabolic -8% Birth weight of Delivered
1% .9.05 9.05
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----
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1% I 9.5‘ -- 3.18~100607.5~~~ 4.64 12.01 100
REMARKS Dee 1 1935 weight’ oi baby
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TkIDelivered
Delivered June 5. 1936 Birth weight of baby ounces
9
12
9 pounds,
7
Delivered June 23, 1936 Birth weight of baby 8 pounds, O”IlCeS
4
Delivered May 14, 1936 Birth weight of baby 7 pounds, ounces Delivered Feb. 10, 1936 Birth weight of baby 8 pounds, ounces Delivered June 24, 1936 Birth weight of baby 7 pounds, O”nCeS Delivered March 23, 1936 Birth weight of baby 7 pounds, ounces Birthivered weightFeb. of26, baby1936 7 pounds, Del ounce Delivered May 28, 1936 Birth weight of baby 7 pounds.
13%
1~ 11%
4% 3/ 2%
ounceS T;ign36pregnancy.
Delivered
Birth weights of babies ounces and 6 pounds
March
3,
6 nounds. 15% IO.% ounces
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Total Blood Volzcwle.--Chart 2 shows the individual course of each paGent’s total blood volume and the average curve for the group. The total blood volume varied between 4,OiO and ti.830 C.C. ante partum, with an average value of 5,117 c.c., as compared with the range of a group of normal nonpregnant individuals of from 3,110 to 4,870 c.c., with an average of 3,920 C.C. It is significant that every ante-partum observation was above the average normal nonpregnant control value. The normal nonpregnant values, on the other hand, are closely approached by the post-pa&m range of from 3,140 to 4,720 c.c., an average of 3,987 C.C. The curve of variation of the individual total blood volume did not in all patients, nor at every observation, parallel the curve of average values, although the same trend was unmistakable in most instances (Chart 2). This is also true of the plasma and cell volumes. There was a progressive increase in total blood volume t,o the ninth lunar month, at which t,ime the average increase was 45.5 per cent above the average of the normal nonpregnant group (Chart 1, Table II). During the tenth month there was a definite diminution in total blood volume to 32.4 per cent above There was a prompt return to normal nonpregthe normal nonpregnant level. nant limits by the second week post partum (Charts 1 and 2).
Chart 3 .-The total blood volume in C.C. per kg. bodv weight in normal pregnant women. The fine connected lines represent the curves of individual patients; the heavy line the curve of average values. The heavy perpendicular line represents delivery and separates the ante- and postqartum periods. Note that on this basis of presenting the data the blood volume returns well toward “normal” during the tenth lunar month. No obvious difference was noted in the curves of blood volume changes as between primiparas and multiparas. It is of interest to note the total blood volume changes with respect to weight change in this group of patients. Accordingly, the total blood volume has been calculated in cubic centimeters per kg. of body weight (Tables I, II). Even on this basis the values during pregnancy in most instances are above those of the normal nonpregnant control group. The individual and average curves (Chart 3) are similar to those for the observed total blood volume. The maximum increase for total blood volume in terms of cubic eeatimeters per kg. of body weight is 25.2 per cent over the normal nonpregnant level. The predelivery decreaw is coxtMer&ly aecentuatea by this method of presenting the data, the decrease being from 25.2 per cent in the x&r&h luxxar month to 7.7 per cent oyer the normal nqxegaant level in the tenth lunar month. The average values during pregnancy ax all above the normal nonpregxu& average of 71.7 C.C. per kg. of body weight, whelteaa fhe postpartum values are slightly below this figure (Table II). For purposes of comparison, the course of the average total blood volume, total blood W&IBM in cubic centimeters per kg. of body weight, plasma volume, pla+%na volume in cubic centimeters per kg. of body weight, cell volume, and the avenge hemeglobin, hem&o&t and red blood cell count values are presented in T&J& 11.
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CIRCULATION
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PREGNANCY
II
The average total blood volume, total blood volume in cubic centimeters per kg. body weight, plasma volume, plasma volume in cubic centimeters per kg. body weight, cell volume, hemoglobin, red blood cell count and hematocrit in normal pregnant women at varying intervals during pregnancy and the puerperium. DAYS
- 4500 83.2
EO121 4715 80.6
120. 91 4899 82.8
3186 58.5
3245 57.5
3332 56.3
1314 9.58 3.26
1452 9.79 3.52
:30.53
t11.02
151t Total blood volume in C.C. Total blood volume in IX. per kg. body weight Plasma volume in C.C. Plasma volume in C.C. per kg. body weight Total cell volume in cc. Hemoglobin in grams Red blood cell count in millions per c. mm. of blood Hematocrit in per cent
ANTE
-
= I
PARTUM go-
-
DAYS PAR
POST UM
60J01 5705 90.0
30-O --
O-30
30t
5190 77.2
se4 69.7
4052 66.2
3665 59.2
3913 61.7
3620 52.8
2507 44.2
2600 41.8
1567 IO.16 3.41
1740 9.76 3.49
1805 9.95 3.44
1681 11.23 3.75
1460 11.03 4.19
1452 10.71 3.72
--32.07
- c11.98
$1.34
32.43
36.80
35.21
61 5405 87.1
.
Cell VoZzlme.-It should be pointed out that in taking hematocrit readings no effort was made to read the level of packed red cells separate from the white cell and platelet layers, and our figures thus represent total blood cell volumes, though of course the red blood cells comprise the predominant part. Practically, the total cell volume may be considered the red cell volume in the absence of disease, involving either the platelet or white cell components of the blood. The calculated cell volume of the blood varies during pregnancy. The changes observed, although relatively small, are similar in trend to those in the plasma and total blood volumes (Chart 1). Both the early pregnancy and the postpartum values average slightly below the nonpregnant average. During the ninth lunar month, when the cell volume increase is maximum, it amounts to 16.5 per cent over the average of the normal nonpregnant control group. It is evident then that there is actually an increase in the total number of red cells late in pregnancy (Chart 1). Despite this increase, however, a relative (‘anemia” (on basis of red blood cell and hemoglobin content per unit volume of blood) develops during pregnancy as a result of the failure of the cell volume to increase in the same proportion as the plasma volume (Chart 1) .* Red Blood Cells and HemogZobin.-Analysis of the red blood cell counts and hemoglobin values, obtained from venous blood samples, shows a greater fluctuation between observations on the same individual, and a greater lack of absolute parallelism of the individual changes to the average changes for the group than that encountered in the blood volume determinations (Table I). This may be accounted for by actual individual variations in hematopoiesis and hemoglobin formation, or by the lesser accuracy of the methods used in their determination, or both. Again, the trend is nevertheless quite evident. In inverse relation to the plasma volume, the red cells and hemoglobin per unit volume of blood are below the average normal nonpregnant levels throughout pregnancy. During the tenth lunar month a return toward normal begins, which continues on through the puerperium. This predelivery increase in hemoglobin and hematocrit has been described before.59 11 Simultaneous observations on venms pressare (arm), circzllation time (arm to carotid, pulmonary and venous), vital capacity, szlbcostal angle, and arterial blood pressure are presented in Table I. The values of these functions are within “normal” limits and their behavior in this group of patients is similar to that of normal pregnant women described elsewhere.&, 5 *None
of the
patients
in
this
series
received
any
antianemic
therapy.
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Ederncc occurred in Y of 11~ 14 patients, WWdllj’ during the kdSt two nlont11;; of pregnancy (Table 1). Dgspnea otzurred in 11 of lhe l-1 CXW’R. Nrither horn any constant relationship to changes in the blood volume, although both edema and dyspnea were present, for the most part, late in prrgnancg rvhcn the blood volunx was usually at relatively high lercls. DISCTTSSION
This study shows that there is an increase in the plasma, reel ceil and total blood volumes late, as compared to early in pregnancy, and an increase beginning early in pregnancy as compared to the nongravid state. The average normal values, as determined in a control study in 28 normal nonpregnant women of an age group comparable to the series of eases herein studied, are 2,370 C.C. for plasma volume, 1,550 C.C. for cell volume and 3,920 C.C. for total blood volume. Gibson and EvanslO have showed that the total blood volume of normal nonpregnant individuals bears a definite relationship to height. Based on their prediction values, the average of the total blood volumes of the 14 cases comprising this series in relation to height is 4,043 KC., a value which compares favorably with the average total blood volume of 3,920 C.C. of the control group. This also corresponds well with the average -values of 3,964 C.C. at two weeks post. partum and 4,052 C.C. at later post-partum observations. There are definite indications that a decrease in blood volume usually occurs in the last weeks of pregnancy, before the onset of labor. (Charts 1, 2, 3, Table I.) This correlates with observations from this showing a relative increase in the solid eleclinic” and elsewhere,ll ments of the blood just before term. There is a marked post-partum decrease in the total blood and plasma volumes usually evident early in the puerperium. Since estimations of the blood loss at delivery are notoriously inaccurate they were omitted in t-his series. Kane of the patients, however, had excessive bleeding and can be presumed to have lost less than 500 C.C. of blood, an amount far less than t,he actual diminution in the total blood volume as bet.ween predelivery and postdelivery values which was found to a,verage 1,226 CL While for nonpregnant individuals the interpretation of blood volume values in terms of relation to body weight or surface area is of some comparative value, in pregnancy, this does not obtain for the weight is constantly changing due more or less to indeterminable and independent factors. The wide range of observation during pregnancy of 62.8 to 106.3 C.C. per kg. of body weight in this series demonstrates this contention. While the blood is unquestionably more dilute during pregnancy than in the nongravid state, there are numerous evidences that the increased volume is not due to simple hydration. The formed and unformed solid elements of the blood decrease in concentration reciproeally with, but not in, the same degree as the increase in plasma volume. The mechanisms for blood cell formation and for the maintenance of the physicoehemical balance of the blood apparently still
THOMSON
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PREGNANCY
5’i
function as before pregnancy, although at a level too low to susta.in In the absence of nutritional deficiency the “normal” relationships. in pregnancy it is emphasized, however, that the total solid constituents of the blood are equivalent to or are greater than the normal nonpregnant values. Recently there have been specific studies of the water content of the blood during pregnancy, the results of which are in keeping with the results of this study. Feldman, Van Donk, Steenbock, and Schneiders,l’ made approximately monthly observations on 20 women during pregnancy on the hemoglobin, cell volume per cent, refractive index and lvater content of the blood. The water content reached a maximum a.t about 220 days’ gestation, while the ot,her values decreased up to the same point. Thereafter there was a tendency for these factors to remain unchanged until just before delivery, when there occurred a shift in the opposite direction. These authors concluded that the process of blood dilution is not an uncomplicated phenomenon because the reduction in protein cont,ent is far less than the reduction in total solids. It is interesting that in a similar study on gravid lactating cows they found no significant blood changes which makes it likely that the dilut,ion phenomenon is not concerned primarily with the physiology of lactation. Oberst and Plass,13 from average determinations on small groups of patients, nonpregnant, late in pregnancy, in early labor and seven to nine days post-partum, found a higher water content of the plasma and red cells with decreased specific gravity and plasma protein in the pregnant as compared with the nonpregnant. The cell volume and hemoglobin of the whole blood were decreased; whereas the hemoglobin content of the cells was increased. Early in labor the plasma and cells were slightly more concentrated, the specific gravity, proteins, cell volume and hemoglobin increased, while the water content decreased. After delivery the avera,ge values approached those of the nonpregnant group although the hematocrit and hemoglobin values remained increased and the water content of the cells and plasma decreased. It is interesting to speculate on the cause of the increase in blood volume during pregnancy though by neit.her this stucly nor those in the literature has any causal factor been demonstrated. The teleologic argument that the maternal organism is thereby prepared for the blood loss of parturition may be coincidentally true, but offers no explanaIt seems unlikely that the fetal respiratory exchange tion whatever. through the placenta benefits from a clilute maternal blood, although the fetal nutritional requirements may be more adequately met through an increased total blood volume. Neither purpose, however, provides a cause. It has been suggested that the vascular sinusoids at the placental site are in effect an arteriovenous fistula.14 Since an increased blood volume, and certain other circulatory changes which are observed in pregnancy, have been found in nonpregnant individuals with abnor-
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ma1 arteriovenous communications, the alterations in the circulation in pregnancy produced by the placenba might be a contributory factor. One patient, Case 19 (Table I), who had a “normal” twin pregnancy had the largest total blood volume encountered so far in our studies on pregnant women. Although many other factors are probably operative under such circumstances, the large placental circulation required for a twin pregnancy is consistent with this hypothesis. It must be pointed out, however, that the “hydration” phenomenon tiith low hematocrit values and the diminution in the solid constituents of the blood are not usually found in nonpregnant patients with abnormal arteriovrnous communications. Also, the predelivery decrease in blood volume demonstrated in this series is difficult to explain on such a basis, since the demonstrable morphologic cahanges, vascular degenerahion and infarctiou, in t.he placenta and placental site are not of sufficient degree to account for t,he marked blood volume changes. From these considerations it does not seem likely that. the behavior of the blood volume in pregnancy can be att.ributed solely to this mechanical factor. That some hormonal influence ma- affect the blood volume changes observed in pregnant women is possible. In this respect one notes that in some diseases in which there are factors of glandular dysfunction present, such as hyperthyroidism, mysedema, and diabetes insipidus, there is an altered blood volume. The increase observed in total blond volume early in pregnancy (in one normal patient not included in this series, on whom there were prepregnant data, a 5 per cent increase in total blood volume was present three weeks after conception, and a 12.5 per cent increase at seven weeks’ gestation), before any significant mechanical factors are likely to operate suggests this possibility; also the predelivery reduction in blood volume which is not clearly related to altered circulatory channels in t,he placenta or other known factors. Evidence that water balance, which is disturbed in normal pregnancy, is under hormonal control is also suggestive, Recent work of Smith and Smith,16 on serum prolan and estrin during the course of pregnancy is interesting, since the former shows a trend reciprocal to that observed in total blood volume. The endocrine and metabolic aspects of the problem require further investigation. CONCLUSIONS
In normal pregnancy: 1. There is a progressive increase in the plasma and total blood volume beginning early in pregnancy which reaches a maximum during the ninth lunar month. 2. During the tenth lunar month there begins a definite decrease in both the plasma and total blood volumes which by the end of the second postpartum week brings them close to the a,verage normal nonpregnant level.
JAMESON:
PREGNANCY
AND
59
TUBERCULOSIS
3. There is a definite absolute increase in the total cell volume during the latter months of pregnancy, but one that is distinctly less in proportion than the increase in plasma volume. 4. The disproportionate increase in plasma volume appears to be primarily accountable for the phenomenon of “hydration” of the blood in pregnancy. 5. Factors which might contribute to the blood volume changes in pregnancy are discussed. REFERENCES (1) Die&man, W. J., and Wegner, Keith, N. Y., Rowatree, L. G., 547,1915. (3) Gregersen, M. I., Gibson, 113: 54, 1935. (4) Thomson, K. J., and
C. R.: AN. J. OBST. & GYNEC. 53: 71, 1934. and Geraghty, J. T.: Arch. Int. Med. 16: J. G., and Stead, E. A.: Am. J. Physiol. (Proc.) Cohen,ilI. E.: Surg. Gynec. Obst. 66: 591,1938. (5) Cohen, M. E., and Thomson, K. J.: J. Clin. Investigation 15: 607, 1936b (6) Gibson, J. G., dnd, and Evans, W. A., Jr.: J. Clin. Investigation 16: 301, 1937. (7) Dawson, A. B., Evans, H. M., and Whipple, G. H.: Am. J. Physiol. 61: 232, 1920. (8) Gregersen, M. I.: To be published. (9) Evans, W. A., Jr., ad Gibson, J. G., .%d: Am. J. Physiol. 118: 251, 1937. (10) Gibson, J. G., .%d., and J. Clin. Investigation 16: 317, 1937. (11) Kiihnel, P.: Ztschr. Evans, W. A., Jr.: f. Geburteh. u. Gy&k. 90: 511, 1927. (12) Feldman, H., Van Don& E. C., Steenbock, H., and Schneiders, E. F.: Am. J. Physiol. 69: 115, 1936. (13) Oberst, F. W., and Pla.ss, E. D. : AM. J. OBST. & GYNEC. 31: 61, 1936. (14) Bwrwell, C. S.: South. M. J. 29: 1194, 1936. (15) Smith, 0. W., and Smith, G. V.: AM. J. OBST. & GYNEC. 33: 365, 1937. (2)
PREGNANCY
AND TUBERCULOSIS
A STUDY OF END RESULTS EDWIN
T
M. JAMESON,
B.S., M.D., F.A.C.S.,
SARANAC LAKE,
N. Y.
HE problem of the interrelationships between pregnancy and pulmonary tuberculosis is exceedingly complex, and notwithstanding the huge amount of work that has been done on the pathologic physiology of both conditions, we are still far from being able to answer many of the most fundamental questions. Why one woman takes a pregnancy or even repeated pregnancies “in her stride,” so to speak, with but little apparent alteration in her bodily economy while her sister is brought to the very door of death by the same biologic process, is a question to which we can no more give a categorical answer today than we can to that of why one patient with a given tuberculous lesion in her lungs succeeds in healing the lesion without difficulty and enjoys perfect health for the remainder of her life, while another with the same type of lesion goes down hill and finally succumbs in spite of all therapeutic measures at present available. One is reminded of Osler’s comparison of the evolution of tuberculosis in different individuals to the parable of the sower; the same comparison might almost be made with equal felicity to pregnancy. Given, then, two such variables, it is inevitable that they should react on one another in a variety of ways.
48
OF W3STETRICS ANIl QYNECOI.(h:Y REFEREN(lES
Browne, J. S. L., and Venning, E. X.1.: Aim. J. Pllysiol. 116: 18, 1936. (2) Do&Is, E. C. : AM. J. OBST. & GYNW. 30: 302, 1935. (3) Frank, Iz. T.: Ibid. 32: 168, 1936. (4) Geschickter, C. F., Lewis, Dean, an,d Hartman, C. G.: AnI. J. Cancer 21: 828, 1934. (5) Goldberger, M. A.: AM. .J. 0~s~. & GPNEC. 33: 1093, 1937. (6) Mazer, C., Merunze, D. R., and lsraeZ, S. L.: J. A. M. A. 105: 257, 1935. (7) Robinson, A. L., D&now, M. 2f., and deffcoate, T. B. A.: &it. M. J. 1: 749, 1935. (8) Savage, J. X., and Wylie, H. B.: AN. J. OBST. & GYIVJK. 33: 771, 1937. (9) Schmdovitz, &l. J., and Wylie, H. R.: J. T,ab. & Clin. Med. 21: 210, 1935. (10) &de, E.: Endocrinology 21: 594, 1937. (II) Smith, G. V., ad Kennard, J. H. : Proc. Moe. Exper. Biol. & Med. 36: 508, 1937. (12) Smith, G. V., and Smith, 0. W. : Surg. Gynec. Obst. 61: 175, 1935. (13) Idem: New Eng. J. Med. 215: 908, 1936. (14) Smith, 0. W., and Smith, G. V.: AM. J. OBST. & GPNW. 33: 365, 1937. (15) Steinkamm, E., and Giesen, TV.: Zentralbl. f. Gyn%k. 60: 369, 1936. (16) Witherspoon, J. T.: Proe. Sot. Exper. Biol. Rr Med. 29: 1063, 1932. (17) WY&e, H. B., and Savage, J. B. : In preparation for publication. (18) Birman, S, A.: IIlinois M. J. 70: 198, 19X. (1)
LOMBARD AND GREENE
STUDIES 111.
STREETS
OX THE CIltCULATION
KI,OOD VOLUME
CHANGES
IX PREGNANCY
IN NORMAL
PRWNANT
WOMEN
K. JEFFERSON TIIOMSON, M.D., MOUNT MCGREGOR, N. Y., A. HIRSHEIMER, MD., DAYTO'K. OHIO, JOHN G. GIBSON, ZND, M.D., BOSTO'N, MASS., AND WIIXAX 11. EVASS, JR., M.D., DETROIT, MICH. (From
the Departments of Obstetrics nnti Xediciw, Cardiac Clinic nml Research Laboratory, Boston the Medical
Clinic
of the Pefu
Bent
Rrigham
Rarcnrd
Medical
Lyi~lg-in
Hoqifal,
Hospitul,
School;
the
and
Boston,
N ANY consideration of the altered physiology of the circulation during normal pregnancy, notably the low level of the solid constituents of the blood, the diminished viscosity of the blood, the changes in cardiac output and velocity of blood flow, and the frequent occurrence of edema, it is important to know what variations, if any, occur in the plasma and blood volume. Such information is likewise useful in evaluating certain pathologic conditions frequently associated with cardiac disease and the “toxemias” of pregnancy ; particularly pregnancy. Dieckman and Wegner, who contributed a valuable blood volume study in 1934,l pointed out in their review of the literature the conflicting findings of previous investigators in this field. They cited important criticisms: First, none of the earlier studies included an adequate number of det,erminations on the same individuals during the ante- and post-partum periods, conclus’ions having been drawn from the analysis of disparate groups ; and second, the methods used were various and of doubtful accuracy, in some instances in technique, elsewhere in calculations based on the patients’ weights without due regard to the undeterminable quantity of the uterus and its contents and to maternal edema. It should be emphasized, in addition, that it is unlikely that a reliable estimate of the blood volume changes occurring in pregnancy can be obtained by the comparison of single
I
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49
observations on many individuals in the several periods of gestation with the average normal nonpregnant volume whether absolute or in terms of body weight, since the range of volume in normal persons is great, Dieckmnn and Wegnerr found an increase in the plasma and total blood volumes in the second trimester of pregnancy and at term, as compared to the first trimester which amounted to a maximum of 25 per cent for plasma and 20 per cent for total blood volume. They also reported a post-partum decrease, not always manifest early in the puerperium, as compared to the last ante-par-turn determination (actually, however, in their Group A patients, followed throughout pregnancy and the puerperium, 6 of the 13 showed a higher postpartum total blood volume than at the last ante-partum observation! ). The plasma volume increase was relatively greater than that of the red cell volume. These anthers, while they were of the opinion that repeated determinations on the same individual checked closely and were significant, conceded that the KeithRowntree method,2 which they used, was liable to distinct errors.
The use of the original Keith-Rowntree method in this clinic produced such variable results that no definite conclusions could be drawn as to the behavior of the blood volume in pregnant women.” When, therefore, a new method which satisfactorily avoids the pitfalls of the earlier dye methods became available by the work of Gregersen, Gibson, and Stead,” another study of the blood volume in pregnancy seemed indicated. PROCEJDURE
The subjects for this study were obtained from the prenatal clinic of the Boston Lying-in Hospital, and were chosen at random, the only basis of selection being the duration of pregnancy and freedom from medical or obstetric complications. Observations were made at frequent intervals throughout pregnancy, usually about six weeks apart, and at least once post partum, usually at two weeks. The observations on individual patients varied between two and six, with an average of four. The data usually taken at each visit were: weight, arterial blood pressure, pulse and respiratory rates, venous pressure, circulation time, subcostal angle, hemoglobin, red blood cell count, hematocrit, vital capacity, blood volume, and occasionally, basal metabolic rate. Every patient at each visit received a careful physical examination of the heart, lungs, abdomen, and extremities. All patients were studied under basal conditions of fasting and resting, Blood volume and venous pressure observations were preceded by at least thirty minutes: bed rest, and circulation time measurements by at least sixty minutes’ bed rest. Vital capacities were determined according to the routine described fully in a separate paper.4 In presenting our data, the duration of gestation has been calculated back from the actual day of delivery, the duration of a full-term pregnancy being taken as 280 days, or ten lunar months. METHODS
With the exception of the blood volume method which is described below, the other determinations were carried out exactly as described in a previous report.5 Blood volumes were determined by the method developed by Gregersen, Gibson, and Stead,3 as adapted to clinical use by Gibson and Evans,6 in which the plasma approximately 100 attempts, 75 “satisfactory” observations on the blood volume on normal pregnant yomen at the Boston Lymg-in Hospltal by Dr. Mandel . The results from this study tended to show that the total blood volume increased during pregnancy and diminished after delivery. It was felt by him, however, since checks on the same sample were so difficult to obtain and since the percentage error in the method was so great, that the results of the study were unreliable. *In ger;jo;$z
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volume is actually determined and the total blood and red cell volumes calculated from the plasma volume and the hematocrit value. This method employs a blue azo dye, Evans Blue (T-1824),7 and is a modification of the Keith-Rowntree method.2 It minimizes errors inherent in earlier techniques, resulting from variations in the time required for complete mixing of the dye in the blood stream, where volume calculation is based on the dye concentration uf a single sample iaken three to six minutes after dye injection. Furthermore, incalculable errors arising from variations in the rate of disappearance of dye from the blood stream are eliminated. Colorimetric estimations of the dye concentration of serum samples are made with the spec trophotometer, thus eliminating errors arising from inequality in dye concentration The use of a blue dye minimizes errors due to between standard and samples.* hemolysis of samples and affords an accurate spectrophotometric method of correcting for such occasional hemolysis as may occur. Minor modifications of the method as described by- Gibson and Evans6 were employed; the infiltration of skin at the site of venipunrture with procaine without adrenalin (gratefully acknowledged by the patients) and, occasionally, the use of 0.5 per cent sodium citrate in normal saliue solution to inhibit clotting in the needle between sampling. of vein damage by it were enNo systemic reactions to the dye, nor evidences countered. Accidental injection of the dye cxtravenously produced local diseoloration, but little or no discomfort and no tissue reaction or necrosis. None of the patients showed sufficient generalized coloration of the skin and subcutaneous tixsues from the dye (average dose 10 mg.) to be apparent to the casual observer. Relatively large doses of dye (30 mg.) were given to F patients in labor. Spcctrophotometric examination of the amniotic fluid and cord serum of 3 showed no dye. In none could dye he detected in microscopic examination of the membranes and placentas prepared by special technique to show the presence of this dye histologiIt was therefore assumed that the disappearance of the dye from the blood cally.* stream is not influenced by passage to the ovum. Evans and Gibson0 have showed that any influence of occult edema on the accuracy of the blood volume determinations may be disregarded. Duplicate red blood cell counts and hemoglobin determinations were made from oxalated venous blood (no stasis) obtained at the first venipuncture, using certified pipettes and counting chambers and a Sxhli hemoglohinometer calibrated by the oxygen capacity method, so that 100 per cent represents IS.6 gm. of hemoglobin per 100 cc. whole blood. RESUL’TS
The data here presented (Table I) were derived from 56 observations (40 ante and 16 post partum) on 14 patients whose pregnancies were entirely normal. In this group there were 9 primiparas and 5 multiparas, varying in age from 20 to 34 years, with an average age of 25.1 years. One patient in the series who delivered twins, although included in Table I, is not considered in the general analysis. The plasma volume was actually determined in this study. From it, by means of the hematocrit value, the total blood and cell volumes were calculated. Although for general physiologic purposes the chief concern is the state of the total blood volume, there is special interest in the plasma volume in pregnancy, since there is a reported disproportionate increase between it and the cell volume resulting in the “hydration” phenomenon. *Sections of the placenta and membranes were prepared according to the method of Dr. Harold L. Weatherford, Dept. of Anatomy, Harvard Medical Schoo$ in which tissues were tied in fluid composed of acetic acid 4.0 cc.. trlchlomcetic acKl 2.4) %m., sodium chloride 0.5 gm.. corrosive sublimate 6.0 gm., 37 per cent forma% 20.0 c.c., water 80.0 cc. ; run through paraffin and stained with Mayer’s ~racarmme in 70 per cent akohol, The authors are i%%bkl to PP. I;frx%h H. Nubile. re&dent pathologist, Boston Lying-in Hospital, for thege histologic lxeparations and eXa%Uinations.
THOMSON
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CIRCULATION
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51
VOLUME
There is a progressive increase in plasma volume from early pregnancy through the ninth lunar month, when the maximum is reached. This amounts to an increase of 65 per cent above the average normal nonpregnant value (Chart l), During the tenth month there is a definite decrease to 50 per cent above the normal nonpregnant level. Post partum this decrease continues so that by the end of the second
Chart I.-The average total blood, plasma and cell Volume in normal pregnant women. The heavy perpendicular line represents delivery and separates the anteand Post-partum periods. Note that the maximum increase occurs in the ninth lunar month. with a deflnite diminution before delivery.
/ t c
1NO ;T ‘pi”6 -
2 PA‘Ul 3
ANTE PA
Chart Z.-The total blood volume in normal pregnant women. The flne connected lines represent curves of individual patients; the heavy line represents the curve of average values. The heavy perpendicular line represents delivery and separates the ante- and post-partum periods. Note that all of the ante-partum values are above ;y average normal nonpregnant value, whereas post partum they group closely about
post-partum week the normal nonpregnant level is reached. The plasma volume varied between 2,620 and 4,470 c.c., an average of 3,710 C.C. ante partum and between 2,010 and 3,050 c.c., an average of 2,106 C.C.post partum. The range of plasma volume determined by the same method in a group of 28 normal nonpregnant women of the same age group is from 1,880 to 2,860 c.c., an average of 2,370 C.C.
52
AMEXICAN
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ANL)
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--
ME
i 2 -E
-
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65%
85. ‘7.! ,:.I ‘l:( 3.: b0.’ ip s4:t TG If 5s 8.: 7.: 9.: I.5 4.6
83.5 65.4 65.3 -_,i 1090 / 88.2 ‘4570 , 0 h970 / E.9’ 13 91:o ~_~~-__-4000 78.5 :::o” 81.4 5960 87.2 bi60 93.7 I4 4230 69.2 4920 88.6 SZUO 90.2 85.3 4970 14 82.6 i2 /,452O ._-14360 82.0 80.5 / 4900 ‘6150 88.3 is330 / 74.3 I2 13770 58.3 90.3 4390 4870 95.5 4945 95.5 4920 89.8 4970 85.3 9 13140 66.3 67.7 62.8
7.3 7.5 0.’ 4.3 8.5 3.i 8.c 1 7.c I 4.1 s. , 8.2
;i:i 59.4 85.9 95.3 I 06.3 79.7 75.8 85.6 67.7 dS.0 6R.I Gh 1
-/is 0.4 I 1.2 3.n 3.3 4.8 9.5
78.8 73.:: 89.5 83.8 74. I 90.0 71.2
9.f
--13
14 15
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63%
61%
24
j
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1-. i I I
2~
63% 63
;i
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68. I 59.1 65.2 85.6 78.8 88.6 69.2
4470 2920 3050 2790 3200
54.7 42.0 --_42.2
2360 1620 1670
34.45 35.80 35.28
79 63
;:9”: 3600 3650 1080 4550 2590 5360 3690 i 260 !680
58.9
1410
35.28
68
57.7 58.0 59.7 65.0 42.4
1510 1180 1880 2010 1640
29.10 30.X” 31.50 30.5; 38.75
“,:I 6U 65 ‘if?
2960 1400 16: 150s 1090 1470 i 500 3510 is70 1110 -1570 1440 c350
1350 3010 !930 3330 1020 ?370 !620 1120 ?755 !290 2800 !5XO
i% 1040 1900 1660 !400 1340 ?OlO -1440 3315 1540 E
i:g L-00. s mi 70.7 1370
65.7 74.2 --49.0 48.R 53.9 41.2 42.2 Ez 44.3
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ZI
-
I .-
12.30 9.83 10.14 10.45 8.11 10.61 9.98 9.36 9.36 10.14 11.90 10.61 8.15 10.92 12.17 10.92 9.67 9.36 9.83
3.39
-_
4.86 3.35 2.98 3.13
~ :I: 90
-_58
--i.i 9.4
1: 18
1 --
_~
--
--
:
0 i
Delivered Apr. 7, 1936 BirthO”mxSweight of baby
0 0 0 :
0 + + +0
0 0 0 0 0 I,
0
I ”0 IBirthounces
-~
: + 0 it
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I::;; I 8.74 I10.3r , 10.61 12.01 7 1% 12.01 10.92 ‘.11.8c 10.3( 1
-
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0 + +
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8 + 0
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10.14 10.61 10.31 I
;
0 0 + 0
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--
1,:::: 1-. 11.3c 8 9.6; 10.14 10.7f __ :: 9.95 I 12.1: ,
10
7 pounds,
13
11, 1936 rate on Feb. baby
5. 1936 rate on Nov. baby
12, 1935
7 pounds,
-60
8.5,
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--
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90 I ---70 I----
0 0
0 + -- 0 0 0 --
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25, 1935
7 pounds
June 17, 1936 weight of baby 6 pounds,
Delivered June 10. 1936 Birth weight of baby 6 pounds,
ii::: 7.8( I 9.67 9.52 10.30 1 10.45
9.6’
Delivered May Basal metabolic + 6% Birth weight of o”nceS Delivered March Basal metabolic -8% Birth weight of Delivered
1% .9.05 9.05
.-
8 Dounds.
----
.-
1% I 9.5‘ -- 3.18~100607.5~~~ 4.64 12.01 100
REMARKS Dee 1 1935 weight’ oi baby
!i! ” o-
.-
I
TkIDelivered
Delivered June 5. 1936 Birth weight of baby ounces
9
12
9 pounds,
7
Delivered June 23, 1936 Birth weight of baby 8 pounds, O”IlCeS
4
Delivered May 14, 1936 Birth weight of baby 7 pounds, ounces Delivered Feb. 10, 1936 Birth weight of baby 8 pounds, ounces Delivered June 24, 1936 Birth weight of baby 7 pounds, O”nCeS Delivered March 23, 1936 Birth weight of baby 7 pounds, ounces Birthivered weightFeb. of26, baby1936 7 pounds, Del ounce Delivered May 28, 1936 Birth weight of baby 7 pounds.
13%
1~ 11%
4% 3/ 2%
ounceS T;ign36pregnancy.
Delivered
Birth weights of babies ounces and 6 pounds
March
3,
6 nounds. 15% IO.% ounces
54
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Total Blood Volzcwle.--Chart 2 shows the individual course of each paGent’s total blood volume and the average curve for the group. The total blood volume varied between 4,OiO and ti.830 C.C. ante partum, with an average value of 5,117 c.c., as compared with the range of a group of normal nonpregnant individuals of from 3,110 to 4,870 c.c., with an average of 3,920 C.C. It is significant that every ante-partum observation was above the average normal nonpregnant control value. The normal nonpregnant values, on the other hand, are closely approached by the post-pa&m range of from 3,140 to 4,720 c.c., an average of 3,987 C.C. The curve of variation of the individual total blood volume did not in all patients, nor at every observation, parallel the curve of average values, although the same trend was unmistakable in most instances (Chart 2). This is also true of the plasma and cell volumes. There was a progressive increase in total blood volume t,o the ninth lunar month, at which t,ime the average increase was 45.5 per cent above the average of the normal nonpregnant group (Chart 1, Table II). During the tenth month there was a definite diminution in total blood volume to 32.4 per cent above There was a prompt return to normal nonpregthe normal nonpregnant level. nant limits by the second week post partum (Charts 1 and 2).
Chart 3 .-The total blood volume in C.C. per kg. bodv weight in normal pregnant women. The fine connected lines represent the curves of individual patients; the heavy line the curve of average values. The heavy perpendicular line represents delivery and separates the ante- and postqartum periods. Note that on this basis of presenting the data the blood volume returns well toward “normal” during the tenth lunar month. No obvious difference was noted in the curves of blood volume changes as between primiparas and multiparas. It is of interest to note the total blood volume changes with respect to weight change in this group of patients. Accordingly, the total blood volume has been calculated in cubic centimeters per kg. of body weight (Tables I, II). Even on this basis the values during pregnancy in most instances are above those of the normal nonpregnant control group. The individual and average curves (Chart 3) are similar to those for the observed total blood volume. The maximum increase for total blood volume in terms of cubic eeatimeters per kg. of body weight is 25.2 per cent over the normal nonpregnant level. The predelivery decreaw is coxtMer&ly aecentuatea by this method of presenting the data, the decrease being from 25.2 per cent in the x&r&h luxxar month to 7.7 per cent oyer the normal nqxegaant level in the tenth lunar month. The average values during pregnancy ax all above the normal nonpregxu& average of 71.7 C.C. per kg. of body weight, whelteaa fhe postpartum values are slightly below this figure (Table II). For purposes of comparison, the course of the average total blood volume, total blood W&IBM in cubic centimeters per kg. of body weight, plasma volume, pla+%na volume in cubic centimeters per kg. of body weight, cell volume, and the avenge hemeglobin, hem&o&t and red blood cell count values are presented in T&J& 11.
THOMSON
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55
PREGNANCY
II
The average total blood volume, total blood volume in cubic centimeters per kg. body weight, plasma volume, plasma volume in cubic centimeters per kg. body weight, cell volume, hemoglobin, red blood cell count and hematocrit in normal pregnant women at varying intervals during pregnancy and the puerperium. DAYS
- 4500 83.2
EO121 4715 80.6
120. 91 4899 82.8
3186 58.5
3245 57.5
3332 56.3
1314 9.58 3.26
1452 9.79 3.52
:30.53
t11.02
151t Total blood volume in C.C. Total blood volume in IX. per kg. body weight Plasma volume in C.C. Plasma volume in C.C. per kg. body weight Total cell volume in cc. Hemoglobin in grams Red blood cell count in millions per c. mm. of blood Hematocrit in per cent
ANTE
-
= I
PARTUM go-
-
DAYS PAR
POST UM
60J01 5705 90.0
30-O --
O-30
30t
5190 77.2
se4 69.7
4052 66.2
3665 59.2
3913 61.7
3620 52.8
2507 44.2
2600 41.8
1567 IO.16 3.41
1740 9.76 3.49
1805 9.95 3.44
1681 11.23 3.75
1460 11.03 4.19
1452 10.71 3.72
--32.07
- c11.98
$1.34
32.43
36.80
35.21
61 5405 87.1
.
Cell VoZzlme.-It should be pointed out that in taking hematocrit readings no effort was made to read the level of packed red cells separate from the white cell and platelet layers, and our figures thus represent total blood cell volumes, though of course the red blood cells comprise the predominant part. Practically, the total cell volume may be considered the red cell volume in the absence of disease, involving either the platelet or white cell components of the blood. The calculated cell volume of the blood varies during pregnancy. The changes observed, although relatively small, are similar in trend to those in the plasma and total blood volumes (Chart 1). Both the early pregnancy and the postpartum values average slightly below the nonpregnant average. During the ninth lunar month, when the cell volume increase is maximum, it amounts to 16.5 per cent over the average of the normal nonpregnant control group. It is evident then that there is actually an increase in the total number of red cells late in pregnancy (Chart 1). Despite this increase, however, a relative (‘anemia” (on basis of red blood cell and hemoglobin content per unit volume of blood) develops during pregnancy as a result of the failure of the cell volume to increase in the same proportion as the plasma volume (Chart 1) .* Red Blood Cells and HemogZobin.-Analysis of the red blood cell counts and hemoglobin values, obtained from venous blood samples, shows a greater fluctuation between observations on the same individual, and a greater lack of absolute parallelism of the individual changes to the average changes for the group than that encountered in the blood volume determinations (Table I). This may be accounted for by actual individual variations in hematopoiesis and hemoglobin formation, or by the lesser accuracy of the methods used in their determination, or both. Again, the trend is nevertheless quite evident. In inverse relation to the plasma volume, the red cells and hemoglobin per unit volume of blood are below the average normal nonpregnant levels throughout pregnancy. During the tenth lunar month a return toward normal begins, which continues on through the puerperium. This predelivery increase in hemoglobin and hematocrit has been described before.59 11 Simultaneous observations on venms pressare (arm), circzllation time (arm to carotid, pulmonary and venous), vital capacity, szlbcostal angle, and arterial blood pressure are presented in Table I. The values of these functions are within “normal” limits and their behavior in this group of patients is similar to that of normal pregnant women described elsewhere.&, 5 *None
of the
patients
in
this
series
received
any
antianemic
therapy.
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Ederncc occurred in Y of 11~ 14 patients, WWdllj’ during the kdSt two nlont11;; of pregnancy (Table 1). Dgspnea otzurred in 11 of lhe l-1 CXW’R. Nrither horn any constant relationship to changes in the blood volume, although both edema and dyspnea were present, for the most part, late in prrgnancg rvhcn the blood volunx was usually at relatively high lercls. DISCTTSSION
This study shows that there is an increase in the plasma, reel ceil and total blood volumes late, as compared to early in pregnancy, and an increase beginning early in pregnancy as compared to the nongravid state. The average normal values, as determined in a control study in 28 normal nonpregnant women of an age group comparable to the series of eases herein studied, are 2,370 C.C. for plasma volume, 1,550 C.C. for cell volume and 3,920 C.C. for total blood volume. Gibson and EvanslO have showed that the total blood volume of normal nonpregnant individuals bears a definite relationship to height. Based on their prediction values, the average of the total blood volumes of the 14 cases comprising this series in relation to height is 4,043 KC., a value which compares favorably with the average total blood volume of 3,920 C.C. of the control group. This also corresponds well with the average -values of 3,964 C.C. at two weeks post. partum and 4,052 C.C. at later post-partum observations. There are definite indications that a decrease in blood volume usually occurs in the last weeks of pregnancy, before the onset of labor. (Charts 1, 2, 3, Table I.) This correlates with observations from this showing a relative increase in the solid eleclinic” and elsewhere,ll ments of the blood just before term. There is a marked post-partum decrease in the total blood and plasma volumes usually evident early in the puerperium. Since estimations of the blood loss at delivery are notoriously inaccurate they were omitted in t-his series. Kane of the patients, however, had excessive bleeding and can be presumed to have lost less than 500 C.C. of blood, an amount far less than t,he actual diminution in the total blood volume as bet.ween predelivery and postdelivery values which was found to a,verage 1,226 CL While for nonpregnant individuals the interpretation of blood volume values in terms of relation to body weight or surface area is of some comparative value, in pregnancy, this does not obtain for the weight is constantly changing due more or less to indeterminable and independent factors. The wide range of observation during pregnancy of 62.8 to 106.3 C.C. per kg. of body weight in this series demonstrates this contention. While the blood is unquestionably more dilute during pregnancy than in the nongravid state, there are numerous evidences that the increased volume is not due to simple hydration. The formed and unformed solid elements of the blood decrease in concentration reciproeally with, but not in, the same degree as the increase in plasma volume. The mechanisms for blood cell formation and for the maintenance of the physicoehemical balance of the blood apparently still
THOMSON
ET
AL,. :
STUDIES
OK
CIRCULATION
IN
PREGNANCY
5’i
function as before pregnancy, although at a level too low to susta.in In the absence of nutritional deficiency the “normal” relationships. in pregnancy it is emphasized, however, that the total solid constituents of the blood are equivalent to or are greater than the normal nonpregnant values. Recently there have been specific studies of the water content of the blood during pregnancy, the results of which are in keeping with the results of this study. Feldman, Van Donk, Steenbock, and Schneiders,l’ made approximately monthly observations on 20 women during pregnancy on the hemoglobin, cell volume per cent, refractive index and lvater content of the blood. The water content reached a maximum a.t about 220 days’ gestation, while the ot,her values decreased up to the same point. Thereafter there was a tendency for these factors to remain unchanged until just before delivery, when there occurred a shift in the opposite direction. These authors concluded that the process of blood dilution is not an uncomplicated phenomenon because the reduction in protein cont,ent is far less than the reduction in total solids. It is interesting that in a similar study on gravid lactating cows they found no significant blood changes which makes it likely that the dilut,ion phenomenon is not concerned primarily with the physiology of lactation. Oberst and Plass,13 from average determinations on small groups of patients, nonpregnant, late in pregnancy, in early labor and seven to nine days post-partum, found a higher water content of the plasma and red cells with decreased specific gravity and plasma protein in the pregnant as compared with the nonpregnant. The cell volume and hemoglobin of the whole blood were decreased; whereas the hemoglobin content of the cells was increased. Early in labor the plasma and cells were slightly more concentrated, the specific gravity, proteins, cell volume and hemoglobin increased, while the water content decreased. After delivery the avera,ge values approached those of the nonpregnant group although the hematocrit and hemoglobin values remained increased and the water content of the cells and plasma decreased. It is interesting to speculate on the cause of the increase in blood volume during pregnancy though by neit.her this stucly nor those in the literature has any causal factor been demonstrated. The teleologic argument that the maternal organism is thereby prepared for the blood loss of parturition may be coincidentally true, but offers no explanaIt seems unlikely that the fetal respiratory exchange tion whatever. through the placenta benefits from a clilute maternal blood, although the fetal nutritional requirements may be more adequately met through an increased total blood volume. Neither purpose, however, provides a cause. It has been suggested that the vascular sinusoids at the placental site are in effect an arteriovenous fistula.14 Since an increased blood volume, and certain other circulatory changes which are observed in pregnancy, have been found in nonpregnant individuals with abnor-
58
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ma1 arteriovenous communications, the alterations in the circulation in pregnancy produced by the placenba might be a contributory factor. One patient, Case 19 (Table I), who had a “normal” twin pregnancy had the largest total blood volume encountered so far in our studies on pregnant women. Although many other factors are probably operative under such circumstances, the large placental circulation required for a twin pregnancy is consistent with this hypothesis. It must be pointed out, however, that the “hydration” phenomenon tiith low hematocrit values and the diminution in the solid constituents of the blood are not usually found in nonpregnant patients with abnormal arteriovrnous communications. Also, the predelivery decrease in blood volume demonstrated in this series is difficult to explain on such a basis, since the demonstrable morphologic cahanges, vascular degenerahion and infarctiou, in t.he placenta and placental site are not of sufficient degree to account for t,he marked blood volume changes. From these considerations it does not seem likely that. the behavior of the blood volume in pregnancy can be att.ributed solely to this mechanical factor. That some hormonal influence ma- affect the blood volume changes observed in pregnant women is possible. In this respect one notes that in some diseases in which there are factors of glandular dysfunction present, such as hyperthyroidism, mysedema, and diabetes insipidus, there is an altered blood volume. The increase observed in total blond volume early in pregnancy (in one normal patient not included in this series, on whom there were prepregnant data, a 5 per cent increase in total blood volume was present three weeks after conception, and a 12.5 per cent increase at seven weeks’ gestation), before any significant mechanical factors are likely to operate suggests this possibility; also the predelivery reduction in blood volume which is not clearly related to altered circulatory channels in t,he placenta or other known factors. Evidence that water balance, which is disturbed in normal pregnancy, is under hormonal control is also suggestive, Recent work of Smith and Smith,16 on serum prolan and estrin during the course of pregnancy is interesting, since the former shows a trend reciprocal to that observed in total blood volume. The endocrine and metabolic aspects of the problem require further investigation. CONCLUSIONS
In normal pregnancy: 1. There is a progressive increase in the plasma and total blood volume beginning early in pregnancy which reaches a maximum during the ninth lunar month. 2. During the tenth lunar month there begins a definite decrease in both the plasma and total blood volumes which by the end of the second postpartum week brings them close to the a,verage normal nonpregnant level.
JAMESON:
PREGNANCY
AND
59
TUBERCULOSIS
3. There is a definite absolute increase in the total cell volume during the latter months of pregnancy, but one that is distinctly less in proportion than the increase in plasma volume. 4. The disproportionate increase in plasma volume appears to be primarily accountable for the phenomenon of “hydration” of the blood in pregnancy. 5. Factors which might contribute to the blood volume changes in pregnancy are discussed. REFERENCES (1) Die&man, W. J., and Wegner, Keith, N. Y., Rowatree, L. G., 547,1915. (3) Gregersen, M. I., Gibson, 113: 54, 1935. (4) Thomson, K. J., and
C. R.: AN. J. OBST. & GYNEC. 53: 71, 1934. and Geraghty, J. T.: Arch. Int. Med. 16: J. G., and Stead, E. A.: Am. J. Physiol. (Proc.) Cohen,ilI. E.: Surg. Gynec. Obst. 66: 591,1938. (5) Cohen, M. E., and Thomson, K. J.: J. Clin. Investigation 15: 607, 1936b (6) Gibson, J. G., dnd, and Evans, W. A., Jr.: J. Clin. Investigation 16: 301, 1937. (7) Dawson, A. B., Evans, H. M., and Whipple, G. H.: Am. J. Physiol. 61: 232, 1920. (8) Gregersen, M. I.: To be published. (9) Evans, W. A., Jr., ad Gibson, J. G., .%d: Am. J. Physiol. 118: 251, 1937. (10) Gibson, J. G., .%d., and J. Clin. Investigation 16: 317, 1937. (11) Kiihnel, P.: Ztschr. Evans, W. A., Jr.: f. Geburteh. u. Gy&k. 90: 511, 1927. (12) Feldman, H., Van Don& E. C., Steenbock, H., and Schneiders, E. F.: Am. J. Physiol. 69: 115, 1936. (13) Oberst, F. W., and Pla.ss, E. D. : AM. J. OBST. & GYNEC. 31: 61, 1936. (14) Bwrwell, C. S.: South. M. J. 29: 1194, 1936. (15) Smith, 0. W., and Smith, G. V.: AM. J. OBST. & GYNEC. 33: 365, 1937. (2)
PREGNANCY
AND TUBERCULOSIS
A STUDY OF END RESULTS EDWIN
T
M. JAMESON,
B.S., M.D., F.A.C.S.,
SARANAC LAKE,
N. Y.
HE problem of the interrelationships between pregnancy and pulmonary tuberculosis is exceedingly complex, and notwithstanding the huge amount of work that has been done on the pathologic physiology of both conditions, we are still far from being able to answer many of the most fundamental questions. Why one woman takes a pregnancy or even repeated pregnancies “in her stride,” so to speak, with but little apparent alteration in her bodily economy while her sister is brought to the very door of death by the same biologic process, is a question to which we can no more give a categorical answer today than we can to that of why one patient with a given tuberculous lesion in her lungs succeeds in healing the lesion without difficulty and enjoys perfect health for the remainder of her life, while another with the same type of lesion goes down hill and finally succumbs in spite of all therapeutic measures at present available. One is reminded of Osler’s comparison of the evolution of tuberculosis in different individuals to the parable of the sower; the same comparison might almost be made with equal felicity to pregnancy. Given, then, two such variables, it is inevitable that they should react on one another in a variety of ways.