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Regulation of sodium and total body water metabolism in pregnancy
Regulation of sodium and total body water metabolism MARY :I.
JANE
C.
GRAY,
BRUCE
ETHAN
MUNRO, A.
H.
IRVING
Burlington,
SAMUEL
SIMS,
M.D. M.D. M.D.
MEEKER,
M.D.
Vermont
SOLOMON,
MAMORU Montreal,
in pregnancy
P1r.D.
WATANABE, Quebec,
M.D
Canada
Material
A I, T II o u G H differences in the metabolism of salt and water may exist in the pregnant woman as compared with the nonpregnant, the nature and magnitude of these changes and the mechanisms controlling them remain to be delineated. In some recent studies’, “, ’ evidence has been presented which shows that retention of sodium is one of the characteristics of toxemia of pregnancy, while other publications have appeared which seem to refute this43 5 Most confusing of all has been the report by Robinson,G in which it is claimed that the incidence of pre-eclampsia is lower in women given a high salt diet, and that salt is beneficial in the treatment of pre-eclampsia once it develops. The present study was undertaken in an attempt to define the role of dietary sodium in salt and water retention during normal pregnancy. From the Departments of Obstetrics crnd Gynecology and Medicine, linirlersity of Vermont College of Medicine, the Department of Experimental Medicine. McGill llniuersity. and the University Clinic, Royal Victoria Hospital. These studies were supported in part linited States Public Health Service Grants GM-03745, AM-04329, and ,4M-03805 from the Institute of .4rthritis and Metabolic Diseaxc.
and
methods
Twenty-eight normal pregnant women were followed for 1 month while living at the Elizabeth Lund Home for unmarried mothers. During this time, daily estimates 01 the dietary sodium intake were obtained through the cooperation of the subjects under the supervision of a research dietitian. Total body water, sodium space, total exchangeable sodium, aldosterone secretor) rate, creatinine clearance, and 24 hour urinary sodium excretion were determined in each subject. Initial studies were carried out between 28 and 33 weeks of pregnancy and repeated 4 weeks later. The standard “low salt” diet at the home contained an average of 150 mEq. of sodium (Na) per day. Half of the subjects maintained this diet and thrl others were permitted additional salt from weighed saltcellars. Both groups were romparable with respect to weight, age. and stage of gestation. It was found that the average quantity of sodium added in this manner was only 32.6 mEq. per day. ‘I’hc~rcfore, an effort was made to increase tllc, sodium intake by means of syrups. capsules. and tablets. Calculations are based on the total quantity of sodium ingested from all sources. All of the subjects studied were ambulatory
by
760
Sodium
Table I. Changes period
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 “0 21 22 23 24 "5 "6 27 28
in water,
sodium,
space, and aldosterone
secretion
and
water
761
in pregnancy
over a 4 week
of gestation
33 37 31 35 32 36 32 36 30 34 28 32 33 37 30 34 31 35 30 34 31 35 31 35 32 36 32 36 28 32 35 39 31 35 33 37 31 35 31 35 32 36 33 37 32 33 31 35 31 35 28 32 29 33 32 36
121 I?? 122 130 132 133 153 157 157 158 160 160 161 165 174 174 180 185 187 195 196 196 206 207 217 218 219
225
48.6 50.9 67.2 68.0 48.8 48.6 58.0 58.4 76.8 78.8 70.9 73.2 74.1 74.9 62.0 63.3 57.7 60.5 59.5 60.7 62.4 62.3 61.6 63.6 68.6 70.5 57.3 58.8 67.7 65.5 49.5 52.0 51.3 53.3 66.0 67.9 59.1 59.7 57.8 58.6 72.5 74.3 65.3 69.9 59.3 60.2 85.5 87.7 60.5 61.8 70.9 72.3 63.4 68.8 63.9 63.8
28.5 36.5 34.4 36.4 30.9 30.8 34.1 33.7 33.5 35.3 36.5 37.4 40.6 43.6 33.1 39.0 34.0 34.5 34.7 35.9 27.1 3-1.2 35.8 4-z.+ 36.1 43.9 38.0 35.8 29.5 35.0 28.2 30.4 37.9 34.0 34.6 37.0 32.3 34.0 31.3 31.8 36.0 40.8 33.6 43.5 31.8 36.7 34.5 43.9 32.0 31.2 37.3 42.1 38.7 44.4 33.1 32.7
14.7 15.0 16.5 16.1 13.3 13.5 17.0 16.5 18.3 20.2 18.1 19.3 19.4 20.6 15.4 16.0 14.7 17.1 16.7 19.1 16.3 16.2 16.5 19.4 18.5 19.1 16.1 20.0 16.7 17.1 14.9 15.6 14.8 15.3 16.5 16.9 16.4 16.3 15.0 14.6 19.7 20.5 15.5 19.7 15.6 17.4 21.3 21.5 15.2 17.6 18.3 19.0 18.7 21.0 16.4 15.8
2,340 :!,380 "$50 :!,610 ".240 L!,250 2,580 :!,950 2,880 3,170 :! ,880 1,150 .1,080 3,090 2,740 2,600 ,:570 2,690 2,970 3,170 2,760 2.590 1,600 1,940 3,090 2.490 3,190 2,600 2,550 2.520 2.600 2,090" ",YlJO 2,610 2.560 2,490 2.520 2.330 2,460 3,280 3,400 2,490 2,850 2.490 2,790 3,420 3,300 2,618 2,662 2,930 2,950 3,050 3,180 2,610 2,410
1,070 1,170
940 2,380
2,910 810 910 1,040 3 10 570 1,030 2.3 6 0 570 390 711) 880 1,511) 550 970 1.810 1,000 1.211) 1.260 2,060 780 860 I ,-k-3 0 2,6-l 0
I .t20 1,600 940 1.360 530 1,380 l.?l(f 6-&O 2.510 2.850
780 710 600 2,640 1,690
762
Gray
et al.
July 15. 196$ .4m. J. Obst. & Gynec.
Table period
II. A summary of net changes in 28 pregnant women studied for a 4 week during the third trimester of pregnancy according to average Na intake Change per month (average and range) Sodium No. of 3 hour Total exchange Aldosterone ingested Weight DLO Na space sodium secretory rate
(mEq./day)
&is
Table
III.
13
gestation 30 to 31 32 to 33 34 to 35 36 to 37 38 t0 39 Total Average
(liters)
+1.3 (-0,2+tlo;2.3)
+0.9 (-0.4:2”,; 1.8)
(-‘.2t,t;2.5)
(-2.U;;
(-0.1 to+5.4)
(-0.8 to’+lO.O)
6.1)
9
Salt and water 3 hour
Weeks
(liters)
(Kg.)
6
127 (121 to 133) 167 (153 t0 187) 209 (195 to 225)
Na
% body weight
26.2 26.5 27.1 27.4 27.8 26.8
in normal
space I No.
11 la 16 12 4 61
Total !
body
% body weight
52.8 55.0 55.0 57.7 60.3
pregnant
Cm&.)
+0.4 (-0.5 tot1.9) +I.4 (-0.1 to+3.9) +2.6 (-0.6 to+6.2)
(&day)
+210 (- 40 to+590) +120 (-170 to+700)
+780 (t100 to+1,450) +350 (-960 to+1,330)
(-20;t:0+357)
(-86Otoy
860)
women
water Total No.
14 la 19 13 5 69
55.4
and carried out routine activities. A control blood sample was drawn and an intravenous infusion of 5 per cent dextrose in water started. Approximately 3 ,LLCof Na-22 in an isotonic saline solution was given intravenously from an accurately calibrated burette, followed by approximately 40 ml. of 99.5 per cent deuterium oxide, also prepared as an isotonic saline solution. The details of the administration of the tritiated aldosterone have been previously described.7 A 24 hour blood sample was taken for the determination of serum sodium and calculation of total exchangeable sodium. All urine was collected for at least 48 hours and an aliquot of each day’s urine used to determine Na-22 excretion and total sodium excretion. Sodium was measured with a flame photometer, using an internal lithium standard. With each group of analyses an internal control of pooled urine or serum was run. Three and 24 hour sodium spaces were determined by comparing the radioactivity in 2 ml. aliquots of serum and urine with that of appropriately diluted standards, using a well-
exchange
mEq./Kg.
51.3 48.8 48.2 47.3 47.5
13 18 19 11 5 66
48.8
41.5 42.0 42.9 43.6 44.3 42.9
Na No.
12 17 19 12 4 64
Serum mEq./L.
140.3 139.7 137.8 136.3
Na I No.
12 14 13 11 50
138.8
type scintillation counter. The calculation of total exchangeable sodium was made using the method of Forbes.* Deuterium oxide concentrations were determined by the falling drop method, modified after that described by Fetcher.g The method of determining the aldosterone secretory rates and some of the results obtained have been reported previously.7 Results Using the dietary sodium as a guide, the normal pregnant women were arbitrarily divided into three groups: one group consisting of those subjects who had consumed less than 135 mEq. of sodium per day (average 127)) a second gro’up which included the subjects who ingested from 153 to 187 mEq. per day (average 167), and a third group containing those who had consumed more than 195 mEq. (average 209). These results are presented in Tables I and II. It may be noted that the women on higher sodium diets gained slightly more weight and retained more water, but their average net retention
Volume Number
89 6
of exchangeable sodium was less, and their average increase in aldosterone secretion less than that of the other groups. When the subjects who were studied initially at 30 and 31 weeks are compared with those started at 32 and 33 weeks, it is seen that an average of 108 mEq. of exchangeable sodium was retained in a 4 week period in the earlier group as compared with 162 mEq. during the latter period, indicating increased salt retention near term. Considerable individual variation in this pattern was noted. Table III presents a summary of the data relating sodium space, total body water, total exchangeable sodium and serum sodium to the progress of gestation during the third trimester. Although the differences between the individual groups are too small to be statistically significant, the constancy of the direction of change in each of the five consecutive groups represents a significant trend. There is a slight increase in both sodium space and total body water, expressed as per cent body weight, with progression of pregnancy. The relative increase in total body water exceeds that of the sodium space, so that the sodium space decreases when expressed as per cent total body water. There is a slight increase in total exchangeable sodium, expressed as milliequivalents per kilogram, with a concomitant fall in serum sodium. It would appear from these data that fluid retention exceeds salt retention in the latter portion of normal pregnancy. Comment
Salt retention has long been suspect as one of the factors contributing to the etiology of pre-eclampsia and eclampsia. This concept was given support by Dieckmann’slO experiments with intravenous salt loading, in which he found that some pre-eclamptic patients were unable to excrete a salt load as rapidly as the normal. This was later confirmed by both Willsonl* and Chesley,12 who noted that an occasional patient with pre-eclampsia could be made worse as a result of the test. Studies by Robinson,‘j in which she concluded that extra salt in the diet was essential for the health of the pregnant woman,
Sodium
and
water
in pregnancy
763
the fetus, and the placenta have, therefore, received little support. Although her patients lacked close supervision and it seems unlikely that they actually ingested as much salt as reported, the large number of women included in the series lends some weight to her conclusions. More recently Zuspan13 has confirmed the observation that salt loading is deleterious to the moderately severe preeclamptic patient, but can be handled by normal pregnant women and many of the mild pre-eclamptics. Mengert14 gave alternately low and high sodium diets to toxic women, and was unable to discern any clinical difference in the two groups. MacGillivrayX5 has recently shown that diuretics given during the latter portion of pregnancy cause a net loss of total exchangeable sodium which is of considerable magnitude, and he concludes that their use may be hazardous. WeseleylG has shown that the continuous use of the chlorothiazide type drugs does not reduce the incidence of pre-eclampsia. Among the questions that have remained unanswered, therefore, are these: Can the amount of salt in the diet of the pregnant woman influence the amount of sodium retained, and does this influence her chance of developing pre-eclampsia? Is salt restriction in the patient with borderline or frank toxemia of value in preventing progression of the condition? Finally, are we likely to influence significantly the ingestion of salt in the pregnant woman who is attempting to manage her diet at home? From Table II it may be seen that there is considerable variation in salt and water retention of normal pregnant women, regardless of the diet on which they are maintained. There was no increase in salt retention in the women who uere given extra salt in their diet, as compared to those on a diet in which no salt was added. This would support Zuspan’P and Mengert’P statements to the effect that the normal pregnant woman can handle a reasonable salt load without dificulty. It has been disappointing to find that in these long-term studies the average difference in salt intake in the groups was less than we
764
Gray
et al.
had hoped to achieve. Coaxing could not induce our women to add the quantities of salt which Robinson claims that her patients ~~scd, and our attempts to increase sodium intake by means of syrups, capsules, and tablets were only moderately successful. As these subjc,cts added salt to their diet, they rut back on those foods which contained larger anlounts of sodium. Whether this was df~liberatc~, or the result of subconscious Ilomeostntic mechanisms, is unknown. Desl)ite this limitation, it remains of interest that the group with the lower sodium intake rctaincd slightly more sodium and had a higher aldosteronr secretory rate than the supplenitmtcd group. In all groups there was increased retention of sodium during the last month of pregnancv , : compared to the preceding month. ‘Illis correlates with the period of increased alclosteronc~ secretion reported previously.’ Sccrctory levels wcrc elevated as early as the fifteenth \c-eck of pregnancy, with a relatively Imiform rate from the twenty-eighth to tllirty-tifth week of gestation. and a further increase during the last 4 weeks. Aldosterone secretion responded to changes in dietary sodium in much the same manner in pregnant wolnen as in the nonpregnant indil.-idrlal. It lvould appear, therefore, that such nlcasl1rc of control as it is possible to exert in an institutional kitchrn or through minor \.ariations in diet at home can be expected to ham littlc if any cfl’cct upon the net retention of sodilun in normal pregnancy. ‘1’11~ changes in sodium space. total body watc’r. total exchangeable sodium, and serum soclilun with progression of pregnancy are seen to 1~2 consistent from 30 weeks to term. Tllere is a gradual incrcasc in sodium space
and total body water when expressed as peg cent body weight. The increase in sodium space is relatively less than that of total hod) water. suggesting water retention in excess of sodium retention. This is supported by thr drop in serum sodium during this same period of time; a totally independent dctermination using the flame photometer and unrelated to isotope dilution techniques. Hrandstetter and Schuller’7 have found :I drop in many serum electrolyte concentrations as pregnancy progresses. The small but consistent increase in retrntion of exchangeable sodium, expressed a!: millieyuivalents per kilogram, during the last 8 weeks of pregnancy suggests that some of the apparent conflicts in reported results in patients with toxemia of pregnancy may hr related to the week of gestation in which thcx patient was studied. This factor cannot IX% ignored in attempting to ascertain whethct sign&ant amounts of sodium are retainc,tl in pre-eclampsia as found by Dieckmann,” Plentl,l and MahrarQ or are not retained as maintained by MacGillivray’ and Davcy. ’ Summary
Twenty-eight normal pregnant women were placed under constant dietary supervision for 1 month during the last trimester of pregnancy. The amount of sodium retained could not be influenced by differences in the average quantity of sodium ingested during this time. Some increase in sodium retention was noted during the last month of gestation. None of these women developed pre-eclampsia. There was an increase in both sodium space and total body water with progress of pregnancy, with a relatively greater incrtbasc in water than in sodium space.
REFERENCES 1. 2. 3.
Plentl. A. .4., and Gray, M. J.: Anl. J. OBST. s( GYNEC. 78: 472, 1959. Dieckrnann. W. J.. and Pottinger, R.: AM. J. OBST. & GYNEC. 74: 816. 1957. Mahran, M.: J. Obst. & Gynaec. Brit. Comm. 68: 597, 1961.
MacGillivray, I., and Buchanan, T. J.: Lanret 2: 1090, 1958. Davey. D. A., and O’Sullivan, W. J.: Path. Microbial. 24: 642, 1961. Robinson, M.: Lancet 1: 178, 1958. Watanabe, M., Meeker, C. I., Gray, M. J”,
Sodium
8. 9. IO.
Il.
Sims, E. A. H., and Solomon, S.: J. Clin. Invrst. 42: 1619, 1963. Forbes, G. B., and Perley, A.: J. Clin. Invest. 30: 558, 1951. Fetcher, E. S., Jr.: Indust. & Engin. Chem. (Anal. Ed.) 16: 412, 1944. Dieckmann, W. J., Pottinger, R. E., and Rynkiewicz. L. M.: AM. J, OBST. & GYNEC. 63: 783, 1952. Willson, J. R., Williams, J. M., Jr., and Havashi. T. T.: Ant. 1. OBST. & GYNEC. 73: 30.’ 195f. Chesley, L. C., Valenti, C., and Rein, H.: Metabolism 7: 575, 1958. ”
12.
13. 14. 15.
16. 17.
Zuspan, Gynec. Mengert,
and
water
in pregnancy
765
F. P., and Bell, J. D.: Obst. & 18: 530, 1961. W. F., and Tacchi, D. A.: Anf. J. OBST. & GYNEC. 81: 601, 1961. MacGillivray, I., Hytten, F. E., Taggart, N., and Buchanan, T. J.: J. Obst. & Gynaec. Brit. Comm. 69: 458. 1962. Weseley, A. C., and Douglas, G. W.: Obst. & Gynec. 19: 355, 1962. Brandstetter, F., and Schuller, E.: Arch. Gynlk. 193. 420, 1959.
JANE
C.
GRAY,
BRUCE
ETHAN
MUNRO, A.
H.
IRVING
Burlington,
SAMUEL
SIMS,
M.D. M.D. M.D.
MEEKER,
M.D.
Vermont
SOLOMON,
MAMORU Montreal,
in pregnancy
P1r.D.
WATANABE, Quebec,
M.D
Canada
Material
A I, T II o u G H differences in the metabolism of salt and water may exist in the pregnant woman as compared with the nonpregnant, the nature and magnitude of these changes and the mechanisms controlling them remain to be delineated. In some recent studies’, “, ’ evidence has been presented which shows that retention of sodium is one of the characteristics of toxemia of pregnancy, while other publications have appeared which seem to refute this43 5 Most confusing of all has been the report by Robinson,G in which it is claimed that the incidence of pre-eclampsia is lower in women given a high salt diet, and that salt is beneficial in the treatment of pre-eclampsia once it develops. The present study was undertaken in an attempt to define the role of dietary sodium in salt and water retention during normal pregnancy. From the Departments of Obstetrics crnd Gynecology and Medicine, linirlersity of Vermont College of Medicine, the Department of Experimental Medicine. McGill llniuersity. and the University Clinic, Royal Victoria Hospital. These studies were supported in part linited States Public Health Service Grants GM-03745, AM-04329, and ,4M-03805 from the Institute of .4rthritis and Metabolic Diseaxc.
and
methods
Twenty-eight normal pregnant women were followed for 1 month while living at the Elizabeth Lund Home for unmarried mothers. During this time, daily estimates 01 the dietary sodium intake were obtained through the cooperation of the subjects under the supervision of a research dietitian. Total body water, sodium space, total exchangeable sodium, aldosterone secretor) rate, creatinine clearance, and 24 hour urinary sodium excretion were determined in each subject. Initial studies were carried out between 28 and 33 weeks of pregnancy and repeated 4 weeks later. The standard “low salt” diet at the home contained an average of 150 mEq. of sodium (Na) per day. Half of the subjects maintained this diet and thrl others were permitted additional salt from weighed saltcellars. Both groups were romparable with respect to weight, age. and stage of gestation. It was found that the average quantity of sodium added in this manner was only 32.6 mEq. per day. ‘I’hc~rcfore, an effort was made to increase tllc, sodium intake by means of syrups. capsules. and tablets. Calculations are based on the total quantity of sodium ingested from all sources. All of the subjects studied were ambulatory
by
760
Sodium
Table I. Changes period
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 “0 21 22 23 24 "5 "6 27 28
in water,
sodium,
space, and aldosterone
secretion
and
water
761
in pregnancy
over a 4 week
of gestation
33 37 31 35 32 36 32 36 30 34 28 32 33 37 30 34 31 35 30 34 31 35 31 35 32 36 32 36 28 32 35 39 31 35 33 37 31 35 31 35 32 36 33 37 32 33 31 35 31 35 28 32 29 33 32 36
121 I?? 122 130 132 133 153 157 157 158 160 160 161 165 174 174 180 185 187 195 196 196 206 207 217 218 219
225
48.6 50.9 67.2 68.0 48.8 48.6 58.0 58.4 76.8 78.8 70.9 73.2 74.1 74.9 62.0 63.3 57.7 60.5 59.5 60.7 62.4 62.3 61.6 63.6 68.6 70.5 57.3 58.8 67.7 65.5 49.5 52.0 51.3 53.3 66.0 67.9 59.1 59.7 57.8 58.6 72.5 74.3 65.3 69.9 59.3 60.2 85.5 87.7 60.5 61.8 70.9 72.3 63.4 68.8 63.9 63.8
28.5 36.5 34.4 36.4 30.9 30.8 34.1 33.7 33.5 35.3 36.5 37.4 40.6 43.6 33.1 39.0 34.0 34.5 34.7 35.9 27.1 3-1.2 35.8 4-z.+ 36.1 43.9 38.0 35.8 29.5 35.0 28.2 30.4 37.9 34.0 34.6 37.0 32.3 34.0 31.3 31.8 36.0 40.8 33.6 43.5 31.8 36.7 34.5 43.9 32.0 31.2 37.3 42.1 38.7 44.4 33.1 32.7
14.7 15.0 16.5 16.1 13.3 13.5 17.0 16.5 18.3 20.2 18.1 19.3 19.4 20.6 15.4 16.0 14.7 17.1 16.7 19.1 16.3 16.2 16.5 19.4 18.5 19.1 16.1 20.0 16.7 17.1 14.9 15.6 14.8 15.3 16.5 16.9 16.4 16.3 15.0 14.6 19.7 20.5 15.5 19.7 15.6 17.4 21.3 21.5 15.2 17.6 18.3 19.0 18.7 21.0 16.4 15.8
2,340 :!,380 "$50 :!,610 ".240 L!,250 2,580 :!,950 2,880 3,170 :! ,880 1,150 .1,080 3,090 2,740 2,600 ,:570 2,690 2,970 3,170 2,760 2.590 1,600 1,940 3,090 2.490 3,190 2,600 2,550 2.520 2.600 2,090" ",YlJO 2,610 2.560 2,490 2.520 2.330 2,460 3,280 3,400 2,490 2,850 2.490 2,790 3,420 3,300 2,618 2,662 2,930 2,950 3,050 3,180 2,610 2,410
1,070 1,170
940 2,380
2,910 810 910 1,040 3 10 570 1,030 2.3 6 0 570 390 711) 880 1,511) 550 970 1.810 1,000 1.211) 1.260 2,060 780 860 I ,-k-3 0 2,6-l 0
I .t20 1,600 940 1.360 530 1,380 l.?l(f 6-&O 2.510 2.850
780 710 600 2,640 1,690
762
Gray
et al.
July 15. 196$ .4m. J. Obst. & Gynec.
Table period
II. A summary of net changes in 28 pregnant women studied for a 4 week during the third trimester of pregnancy according to average Na intake Change per month (average and range) Sodium No. of 3 hour Total exchange Aldosterone ingested Weight DLO Na space sodium secretory rate
(mEq./day)
&is
Table
III.
13
gestation 30 to 31 32 to 33 34 to 35 36 to 37 38 t0 39 Total Average
(liters)
+1.3 (-0,2+tlo;2.3)
+0.9 (-0.4:2”,; 1.8)
(-‘.2t,t;2.5)
(-2.U;;
(-0.1 to+5.4)
(-0.8 to’+lO.O)
6.1)
9
Salt and water 3 hour
Weeks
(liters)
(Kg.)
6
127 (121 to 133) 167 (153 t0 187) 209 (195 to 225)
Na
% body weight
26.2 26.5 27.1 27.4 27.8 26.8
in normal
space I No.
11 la 16 12 4 61
Total !
body
% body weight
52.8 55.0 55.0 57.7 60.3
pregnant
Cm&.)
+0.4 (-0.5 tot1.9) +I.4 (-0.1 to+3.9) +2.6 (-0.6 to+6.2)
(&day)
+210 (- 40 to+590) +120 (-170 to+700)
+780 (t100 to+1,450) +350 (-960 to+1,330)
(-20;t:0+357)
(-86Otoy
860)
women
water Total No.
14 la 19 13 5 69
55.4
and carried out routine activities. A control blood sample was drawn and an intravenous infusion of 5 per cent dextrose in water started. Approximately 3 ,LLCof Na-22 in an isotonic saline solution was given intravenously from an accurately calibrated burette, followed by approximately 40 ml. of 99.5 per cent deuterium oxide, also prepared as an isotonic saline solution. The details of the administration of the tritiated aldosterone have been previously described.7 A 24 hour blood sample was taken for the determination of serum sodium and calculation of total exchangeable sodium. All urine was collected for at least 48 hours and an aliquot of each day’s urine used to determine Na-22 excretion and total sodium excretion. Sodium was measured with a flame photometer, using an internal lithium standard. With each group of analyses an internal control of pooled urine or serum was run. Three and 24 hour sodium spaces were determined by comparing the radioactivity in 2 ml. aliquots of serum and urine with that of appropriately diluted standards, using a well-
exchange
mEq./Kg.
51.3 48.8 48.2 47.3 47.5
13 18 19 11 5 66
48.8
41.5 42.0 42.9 43.6 44.3 42.9
Na No.
12 17 19 12 4 64
Serum mEq./L.
140.3 139.7 137.8 136.3
Na I No.
12 14 13 11 50
138.8
type scintillation counter. The calculation of total exchangeable sodium was made using the method of Forbes.* Deuterium oxide concentrations were determined by the falling drop method, modified after that described by Fetcher.g The method of determining the aldosterone secretory rates and some of the results obtained have been reported previously.7 Results Using the dietary sodium as a guide, the normal pregnant women were arbitrarily divided into three groups: one group consisting of those subjects who had consumed less than 135 mEq. of sodium per day (average 127)) a second gro’up which included the subjects who ingested from 153 to 187 mEq. per day (average 167), and a third group containing those who had consumed more than 195 mEq. (average 209). These results are presented in Tables I and II. It may be noted that the women on higher sodium diets gained slightly more weight and retained more water, but their average net retention
Volume Number
89 6
of exchangeable sodium was less, and their average increase in aldosterone secretion less than that of the other groups. When the subjects who were studied initially at 30 and 31 weeks are compared with those started at 32 and 33 weeks, it is seen that an average of 108 mEq. of exchangeable sodium was retained in a 4 week period in the earlier group as compared with 162 mEq. during the latter period, indicating increased salt retention near term. Considerable individual variation in this pattern was noted. Table III presents a summary of the data relating sodium space, total body water, total exchangeable sodium and serum sodium to the progress of gestation during the third trimester. Although the differences between the individual groups are too small to be statistically significant, the constancy of the direction of change in each of the five consecutive groups represents a significant trend. There is a slight increase in both sodium space and total body water, expressed as per cent body weight, with progression of pregnancy. The relative increase in total body water exceeds that of the sodium space, so that the sodium space decreases when expressed as per cent total body water. There is a slight increase in total exchangeable sodium, expressed as milliequivalents per kilogram, with a concomitant fall in serum sodium. It would appear from these data that fluid retention exceeds salt retention in the latter portion of normal pregnancy. Comment
Salt retention has long been suspect as one of the factors contributing to the etiology of pre-eclampsia and eclampsia. This concept was given support by Dieckmann’slO experiments with intravenous salt loading, in which he found that some pre-eclamptic patients were unable to excrete a salt load as rapidly as the normal. This was later confirmed by both Willsonl* and Chesley,12 who noted that an occasional patient with pre-eclampsia could be made worse as a result of the test. Studies by Robinson,‘j in which she concluded that extra salt in the diet was essential for the health of the pregnant woman,
Sodium
and
water
in pregnancy
763
the fetus, and the placenta have, therefore, received little support. Although her patients lacked close supervision and it seems unlikely that they actually ingested as much salt as reported, the large number of women included in the series lends some weight to her conclusions. More recently Zuspan13 has confirmed the observation that salt loading is deleterious to the moderately severe preeclamptic patient, but can be handled by normal pregnant women and many of the mild pre-eclamptics. Mengert14 gave alternately low and high sodium diets to toxic women, and was unable to discern any clinical difference in the two groups. MacGillivrayX5 has recently shown that diuretics given during the latter portion of pregnancy cause a net loss of total exchangeable sodium which is of considerable magnitude, and he concludes that their use may be hazardous. WeseleylG has shown that the continuous use of the chlorothiazide type drugs does not reduce the incidence of pre-eclampsia. Among the questions that have remained unanswered, therefore, are these: Can the amount of salt in the diet of the pregnant woman influence the amount of sodium retained, and does this influence her chance of developing pre-eclampsia? Is salt restriction in the patient with borderline or frank toxemia of value in preventing progression of the condition? Finally, are we likely to influence significantly the ingestion of salt in the pregnant woman who is attempting to manage her diet at home? From Table II it may be seen that there is considerable variation in salt and water retention of normal pregnant women, regardless of the diet on which they are maintained. There was no increase in salt retention in the women who uere given extra salt in their diet, as compared to those on a diet in which no salt was added. This would support Zuspan’P and Mengert’P statements to the effect that the normal pregnant woman can handle a reasonable salt load without dificulty. It has been disappointing to find that in these long-term studies the average difference in salt intake in the groups was less than we
764
Gray
et al.
had hoped to achieve. Coaxing could not induce our women to add the quantities of salt which Robinson claims that her patients ~~scd, and our attempts to increase sodium intake by means of syrups, capsules, and tablets were only moderately successful. As these subjc,cts added salt to their diet, they rut back on those foods which contained larger anlounts of sodium. Whether this was df~liberatc~, or the result of subconscious Ilomeostntic mechanisms, is unknown. Desl)ite this limitation, it remains of interest that the group with the lower sodium intake rctaincd slightly more sodium and had a higher aldosteronr secretory rate than the supplenitmtcd group. In all groups there was increased retention of sodium during the last month of pregnancv , : compared to the preceding month. ‘Illis correlates with the period of increased alclosteronc~ secretion reported previously.’ Sccrctory levels wcrc elevated as early as the fifteenth \c-eck of pregnancy, with a relatively Imiform rate from the twenty-eighth to tllirty-tifth week of gestation. and a further increase during the last 4 weeks. Aldosterone secretion responded to changes in dietary sodium in much the same manner in pregnant wolnen as in the nonpregnant indil.-idrlal. It lvould appear, therefore, that such nlcasl1rc of control as it is possible to exert in an institutional kitchrn or through minor \.ariations in diet at home can be expected to ham littlc if any cfl’cct upon the net retention of sodilun in normal pregnancy. ‘1’11~ changes in sodium space. total body watc’r. total exchangeable sodium, and serum soclilun with progression of pregnancy are seen to 1~2 consistent from 30 weeks to term. Tllere is a gradual incrcasc in sodium space
and total body water when expressed as peg cent body weight. The increase in sodium space is relatively less than that of total hod) water. suggesting water retention in excess of sodium retention. This is supported by thr drop in serum sodium during this same period of time; a totally independent dctermination using the flame photometer and unrelated to isotope dilution techniques. Hrandstetter and Schuller’7 have found :I drop in many serum electrolyte concentrations as pregnancy progresses. The small but consistent increase in retrntion of exchangeable sodium, expressed a!: millieyuivalents per kilogram, during the last 8 weeks of pregnancy suggests that some of the apparent conflicts in reported results in patients with toxemia of pregnancy may hr related to the week of gestation in which thcx patient was studied. This factor cannot IX% ignored in attempting to ascertain whethct sign&ant amounts of sodium are retainc,tl in pre-eclampsia as found by Dieckmann,” Plentl,l and MahrarQ or are not retained as maintained by MacGillivray’ and Davcy. ’ Summary
Twenty-eight normal pregnant women were placed under constant dietary supervision for 1 month during the last trimester of pregnancy. The amount of sodium retained could not be influenced by differences in the average quantity of sodium ingested during this time. Some increase in sodium retention was noted during the last month of gestation. None of these women developed pre-eclampsia. There was an increase in both sodium space and total body water with progress of pregnancy, with a relatively greater incrtbasc in water than in sodium space.
REFERENCES 1. 2. 3.
Plentl. A. .4., and Gray, M. J.: Anl. J. OBST. s( GYNEC. 78: 472, 1959. Dieckrnann. W. J.. and Pottinger, R.: AM. J. OBST. & GYNEC. 74: 816. 1957. Mahran, M.: J. Obst. & Gynaec. Brit. Comm. 68: 597, 1961.
MacGillivray, I., and Buchanan, T. J.: Lanret 2: 1090, 1958. Davey. D. A., and O’Sullivan, W. J.: Path. Microbial. 24: 642, 1961. Robinson, M.: Lancet 1: 178, 1958. Watanabe, M., Meeker, C. I., Gray, M. J”,
Sodium
8. 9. IO.
Il.
Sims, E. A. H., and Solomon, S.: J. Clin. Invrst. 42: 1619, 1963. Forbes, G. B., and Perley, A.: J. Clin. Invest. 30: 558, 1951. Fetcher, E. S., Jr.: Indust. & Engin. Chem. (Anal. Ed.) 16: 412, 1944. Dieckmann, W. J., Pottinger, R. E., and Rynkiewicz. L. M.: AM. J, OBST. & GYNEC. 63: 783, 1952. Willson, J. R., Williams, J. M., Jr., and Havashi. T. T.: Ant. 1. OBST. & GYNEC. 73: 30.’ 195f. Chesley, L. C., Valenti, C., and Rein, H.: Metabolism 7: 575, 1958. ”
12.
13. 14. 15.
16. 17.
Zuspan, Gynec. Mengert,
and
water
in pregnancy
765
F. P., and Bell, J. D.: Obst. & 18: 530, 1961. W. F., and Tacchi, D. A.: Anf. J. OBST. & GYNEC. 81: 601, 1961. MacGillivray, I., Hytten, F. E., Taggart, N., and Buchanan, T. J.: J. Obst. & Gynaec. Brit. Comm. 69: 458. 1962. Weseley, A. C., and Douglas, G. W.: Obst. & Gynec. 19: 355, 1962. Brandstetter, F., and Schuller, E.: Arch. Gynlk. 193. 420, 1959.