- Email: [email protected]
The ratio of urea nitrogen to total nonprotein nitrogen in the blood in normal pregnancy
THE
RATIO
OF UREA
NITROGEN BY W. DENIS,* (E‘rom
the
IN PH.D.,
Departments
NITROGEN
THE
BLOOD
IN
E. L. KING, of
TO TOTAL
KD.,
Bio-Chmistry Tulane
Mcdicinc,
NORMAL
NONPROTEIK PREGNANCY
AXD FRANCES BRIGGS, M.Sc.
and of
Obstetrics
of
the
School
of
University)
I
N MOST samples of normal blood about 50 per cent of the total nonprotein nitrogen is accounted for by the urea nitrogen, although variations of from 35 to 55 per cent have been rec0rded.l During the past decade there have been published the reports of numerous investigations dealing with the chemistry of the blood in pregnancy and incidentally with the problem of the relative conoentrations of urea and of nonprotein nitrogen in this condition. The results of these investigations are practically unanimous in the findings regarding the low absolute concentrations of nonprotein nitrogen and of urea in the blood in normal pregnancy and also in the majority of casesof abnormal conditions. But the observations regarding the relative concentrations of these fractions are rather diverse. Thus certain investigators have found. that the ratio of urea nitrogen to nonprotein nitrogen in the blood of normal pregnant women is much smaller than in the blood of the nonpregnant individual;” others have found this abnormality only in the blood in eclampsia and other pathologic conditions3 while on the other hand the results of several investigations are available which would indicate that this ratio is the same in pregnant and in nonpregnant subjects.l The lowered ratio of urea nitrogen to nonprotein nitrogen of the blood in pregnant women (if it exists) is of considerable interest both from the theoretical and from the practical side. The relation of the liver to urea formation has long been stressed by physiologists, while t,he occurrence of pathologic changes in this organ has been noted at autopsy in a sufficient number, of cases of eclampsia to warrant the view that in certain pathologic cases at least, the damage to the liver may be sufficiently severe to give rise to an abnormal concentration of some of the constituents of the blood and perhaps even the urine. On the other hand it is difficult to account for the fact that in normal pregnancies the ratio of urea nitrogen to nonprotein nitrogen should be lower than in the case of nonpregnant individuals. Two theories may be mentioned, the first of which, advanced some years ago by Folin,’ suggests that the pregnant organism may be extremely susceptible to the toxic effects of certain waste products and in self-defense may be compelled to Beep these waste products at a sub-*Dr. lIenis rliecl on January IO., 1939. In her ilwth. scirntiflc medicine, especial13 in the field of biochemistry, sustamed a great loss. (E. r,. K.)
386
DENIS,
KING,
BRIGGS:
BT,OOD
IN
NORMAL
387
PREGNANCY
normal level; the second that in order to nourish the fetus properly the maternal blood must contain a relatively higher proportion of amino acids and polypeptids than does that of the nonpregnant individual. In view of the diversity of results which have been obtained by the earlier investigators it has seemed worth while to carry on a relatively extensive series of observations on the ratio of urea nitrogen to total nonprotein nitrogen in women at different stages of pregnancy and also for the first two months postpartum. In a few cases we have been able to obtain a series of samples of blood from the same women taken at intervals during all or a considcrable portion of the period of gestation. In order to check our analytic methods we have also included in each series of 10 to 15 samples of blood taken from pregnant subjects the blood of one nonpregnant individual either male or female. TABLE
MONTHS PRRGNANT -~
I.
UREA NITROGEN, NONPROTEIN SPECIMENS OF BLOOD FROM
"iE;Ca&
1
1
NONPROTEIN NITROGEb MQ. PER loo C.C. BLOOD MINIMAXIMUM I MUM -~ 24.0
I
NITROGEN
UREA PER MAXIMUM 10.4
i 4 5 6 ;: 9
59 16 it
49 52 47
27.2 24.6 26.2 26.0 26.1 27.2 28.5 27.3
20.7 19.0 17.5 19.3 18.2 17.5 16.7 17.1
23.3 21.8 23.2 22.0 22.3 21.3 21.8 22.1
AND
162 NORMAL
OF THE
SAME
IN
239
WOMEN
RATIO URF,A NI'PROQEN TO NONPROTEIN NI!TROGEN PER (EENT 1 AVERMAXII MINIAVER1 MUM -- ABE ~~-AGE 1 MUM
NITROGEN MG. loo C.C. BLOOD I MINIMUM I 6.1
9.9 8.9 10.0
5.0 4.7
13.0
5.1
11.0
5.0 4.7
11.7 12.5
RATIO
PREGNANT
5.9
4.9
10.0 8.3 7.5
I
I
/
46.0
1
8.1 7.3 7.4 7.5 6.8 7.2
29.6
43.5 40.6 42.0 43.5 52.0
25.0 26.0 25.0 22.2 24.2
23.9 22.6
1
41.7 35.5 34.3 34.3 33.0 33.4 33.0 32.8 32.6
Our determinations of urea and of nonprotein nitrogen were I nade by the methods of Folin and Wu. 5 During the course of the investigation frequent check analyses were run on urea solutions of known concentrations, and during the latter part of the work check analyses were also made by the recently published manometric method of van Slyke.” Our clinical material was obtained from the colored out-patient clinic and colored obstetric wards of the New Orleans Charity Hospital. The samples of blood were all obtained at about the same time in the morning and were brought immediately to the laboratory and analysed at once. Our observations have extended over a series of 316 samples of blood taken from 162 normal pregnant women from the first to the ninth month of gestation, 55 samples of blood taken from 55 women from eleven hours to five months after delivery, and (as a check on our analytic technic) 14 samples of blood from 14 nonpregnant individuals. The ages of our subjects varied from fourteen to thirty-seven years,
UREA
1:: 150
27.1 23.8 28.6 26.1 30.4 30.7
35 42 49 60
32.4
31.6 27.9 21.4 30.0 28.6
MAXIMUM
29.7
NUMBER OF CASES
II.
.-
31.6 23.1 23.8 18.5 25.3 23.7 22.2 21.5
20.7
19.8
24.5 19.7 20.6
MINIiWUM
21.8 30.8 24.2 20.8 25.4 23.9 20.0 24.0 20.4 28.6 22.2 32.0 26.3 25.5 21.2 27.0 24.9 25.9 25.5 32.0
PER
AVERAGE-___.
MG.
NONPROTEIN
NITROUEN C.C. BLOOD
NITROGEN,
ZZZ NONPRUTI CIb I 101 I - 0
Ii
17
i
; 3 4c ii 7
0.5
'AMEbTER DELIVERY (DAYS)
TABLE UKEA
16.6 14.2 11.8 10.5 11.3 11.3 13.9 11.1 9.9
102 9.6
iti
9.4 11.5
11.5
E 7:5
1E 10:s
MINIMUM
12.2
-
MG. BLOOD
--
PER
OF THE
8.0 7.9
9.1
RATIO
NITROGEN
AND
MASIMUM-
III
I
NITROGEN,
E 9:0 13.2 8.3 14.1 10.9 11.7 9.1 10.6 10.9 11.8 10.4 14.3
k6'
;:;
6.1 8.6
C.C.
IN
AVERACE -___-..
1ou
SAME
55 l:HL:.<
47.5 43.0 44.3 39.8 42.3 47.6 46.5
51.1
32.6 43.5 41.0 48.0 41.1
MAXIMUM ----.-.
K.\TIO
POSTPARTUN:
-
CASFS
-
36.4 34.0 41.5 41.5 39.0 40.2 43.0 34.5
27.9 39.2 32.3 33.6 34.6
MINIMUM
TO NUNPROTYlN PER CENT
- -.-___.
27.9 30.2 40.7 37.4 38.4 39.2 34.5 35.4 44.0 46.0 37.4 43.8 41.6 42.3 42.R 39.4 41.3 44.9 41.4 44.6 _--_..
AVERAGE
NITROGEN
.-.----^--.-
~_
DENIS,
KING,
BRIGGS
:
BLOOD
the majority being between eighteen ber of previous pregnancies recorded erable proportion of primiparae.
IN
NORMAL
389
PREGNANCY
and twenty-two years. The numranged from 0 to 8 with a consid-
In the interest of space economy we have refrained from tabulating all our results, but in Table I have presented the maximum, minimum VARIATION
OF THE RATIO
2
33 kIr:
UREA
NITROGEN: PREGNANCY
NONPROTEIN
3 --.--
30
-
Ratio
-.--
..-. --
Month -.--..
.._.-_--
-____.--___
NO. ---~
78.
- K O
$
8
DURING
4
----&gJ#Mf--
25
NITROGEN
9 of --. Prennancg. .2 -...- .____________ Fig.
----__.___
1.
and average figures obtained on our antepartum series, while in Table II we give the same data for our postpartum observations. In 24 cases we were able to obtain several samples of blood at intervals of a month or more during the antepartum period, and in several instances it was also possible to repeat these observations after delivery. Several curves prepared from the data obtained in these latter cases are presented in Figs. 1 and 2.
390
THE
AMERICAN
JOURNAL
OF
OBSTETRICS
AND
GYNECOLOGY
STJMMAEY
Our results may be briefly summarized. In the normal pregnant woman there was observed in the majority of cases a slight decrease in the concentration of nonprotein nitrogen of the blood which is accompanied by a relatively large decrease in the urea nitrogen fraction. VARIATION
_--
OF THE EATIO
Wm.4
NITROGEN: pREi3NANCP
Month
of
Pregnsmy.
Bitanth
of
Pregnanoy.
5-.--_.-.---.---
NONPROTEIN
SITR~C~EN
I%RING
--. EIonth
of
Pregnancy.
No.
. ...-..--__. .---
-_
---9 Eonth
of
44.
_-.--_ -=Yi--
Pree;nsnay. Fig.
2.
Values for urea nitrogen of over 10 mg. per 100 C.C. of blood were noted in lsas than 4 per oent of 5 m;ar‘ of urea titrogen per XI0 0.c. of Q =gr su& abnormal vales a~ the one jtuat, &ted were aheoked by reg~&&I Balyaes, so- t&at we felt rea#ortab3y me that they were not t&e to andytic errors.
DENIS,
KING,
BRIGGS
:
BLOOD
IN
NORMAL
391
PREGNANCY
The average figures presented in Table I show a slight but gradual decrease in the ratio of urea nitrogen to nonprotein nitrogen during the course of pregnancy, while the results on postpartum blood given in Table II indicate an equally definite and gradual rise in this ratio. This fall in the urea nitrogen, nonprotein nitrogen ratio during the advance of pregnancy with the subsequent rise during the postpartum period is also shown graphically in Figs. 1 and 2. The following figures in the different types of cases studied also offer further evidence for our conclusion that in pregnancy the ratio of urea nitrogen to total nonprotein nitrogen in the blood is lower than in nonpregnant individuals. Average ratio of urea nitrogen to nonprotein nitrogen in the blood: In In In In
162 normal pregnant women 55 women eleven hours to five 4 normal nonpregnant women 10 normal men
months
after
delivery
33.1 42.6 45.6 45.5
REFERENCES 1. Folin, 0.: Physiol. Rev. 2: 469, 1922. 2. Folin, 0.: Mellon Lecture, Univ. of Pittsburgh, 1917. Stander, H. J.: Bull. Johns Hopkins Hosp. 36: 133, 1924. 3. Killian, J. A., and Sherwin, C. P.: Aa6. J. OBST. & GYNEC. 2: Caldwell, W. E., and Lyle, W. G.: AM. J. OBST. & GYNEC. 2: Harding, V. J., and Drew, K.: J. Obst. & Gynec. Brit. Emp. Harding, V. J., Allen, K. D., and Van Wyck, H. B.: J. Obst. Emp. 31: No. 4, 1924. 4. Plass, E. D.: J. Biol. Chem. 56: 17, 1923. Plass, E. D.: Bull. Johns Hopkins Hosp. 35: 345, 1924. Bunker, C. W. O., and Mundell, J. J.: J. A. M. A. 83: 836, 5. Folin, O., and Wu, H.: J. Biol. Chem. 38: 81, 1919. 6. Van Slyke, D. D.: J. Biol. Chem. 73: 695, 1927.
6, 1921. 17, 1921. 30: No. 4, 1923. & Gynec. Brit.
1924.
RATIO
OF UREA
NITROGEN BY W. DENIS,* (E‘rom
the
IN PH.D.,
Departments
NITROGEN
THE
BLOOD
IN
E. L. KING, of
TO TOTAL
KD.,
Bio-Chmistry Tulane
Mcdicinc,
NORMAL
NONPROTEIK PREGNANCY
AXD FRANCES BRIGGS, M.Sc.
and of
Obstetrics
of
the
School
of
University)
I
N MOST samples of normal blood about 50 per cent of the total nonprotein nitrogen is accounted for by the urea nitrogen, although variations of from 35 to 55 per cent have been rec0rded.l During the past decade there have been published the reports of numerous investigations dealing with the chemistry of the blood in pregnancy and incidentally with the problem of the relative conoentrations of urea and of nonprotein nitrogen in this condition. The results of these investigations are practically unanimous in the findings regarding the low absolute concentrations of nonprotein nitrogen and of urea in the blood in normal pregnancy and also in the majority of casesof abnormal conditions. But the observations regarding the relative concentrations of these fractions are rather diverse. Thus certain investigators have found. that the ratio of urea nitrogen to nonprotein nitrogen in the blood of normal pregnant women is much smaller than in the blood of the nonpregnant individual;” others have found this abnormality only in the blood in eclampsia and other pathologic conditions3 while on the other hand the results of several investigations are available which would indicate that this ratio is the same in pregnant and in nonpregnant subjects.l The lowered ratio of urea nitrogen to nonprotein nitrogen of the blood in pregnant women (if it exists) is of considerable interest both from the theoretical and from the practical side. The relation of the liver to urea formation has long been stressed by physiologists, while t,he occurrence of pathologic changes in this organ has been noted at autopsy in a sufficient number, of cases of eclampsia to warrant the view that in certain pathologic cases at least, the damage to the liver may be sufficiently severe to give rise to an abnormal concentration of some of the constituents of the blood and perhaps even the urine. On the other hand it is difficult to account for the fact that in normal pregnancies the ratio of urea nitrogen to nonprotein nitrogen should be lower than in the case of nonpregnant individuals. Two theories may be mentioned, the first of which, advanced some years ago by Folin,’ suggests that the pregnant organism may be extremely susceptible to the toxic effects of certain waste products and in self-defense may be compelled to Beep these waste products at a sub-*Dr. lIenis rliecl on January IO., 1939. In her ilwth. scirntiflc medicine, especial13 in the field of biochemistry, sustamed a great loss. (E. r,. K.)
386
DENIS,
KING,
BRIGGS:
BT,OOD
IN
NORMAL
387
PREGNANCY
normal level; the second that in order to nourish the fetus properly the maternal blood must contain a relatively higher proportion of amino acids and polypeptids than does that of the nonpregnant individual. In view of the diversity of results which have been obtained by the earlier investigators it has seemed worth while to carry on a relatively extensive series of observations on the ratio of urea nitrogen to total nonprotein nitrogen in women at different stages of pregnancy and also for the first two months postpartum. In a few cases we have been able to obtain a series of samples of blood from the same women taken at intervals during all or a considcrable portion of the period of gestation. In order to check our analytic methods we have also included in each series of 10 to 15 samples of blood taken from pregnant subjects the blood of one nonpregnant individual either male or female. TABLE
MONTHS PRRGNANT -~
I.
UREA NITROGEN, NONPROTEIN SPECIMENS OF BLOOD FROM
"iE;Ca&
1
1
NONPROTEIN NITROGEb MQ. PER loo C.C. BLOOD MINIMAXIMUM I MUM -~ 24.0
I
NITROGEN
UREA PER MAXIMUM 10.4
i 4 5 6 ;: 9
59 16 it
49 52 47
27.2 24.6 26.2 26.0 26.1 27.2 28.5 27.3
20.7 19.0 17.5 19.3 18.2 17.5 16.7 17.1
23.3 21.8 23.2 22.0 22.3 21.3 21.8 22.1
AND
162 NORMAL
OF THE
SAME
IN
239
WOMEN
RATIO URF,A NI'PROQEN TO NONPROTEIN NI!TROGEN PER (EENT 1 AVERMAXII MINIAVER1 MUM -- ABE ~~-AGE 1 MUM
NITROGEN MG. loo C.C. BLOOD I MINIMUM I 6.1
9.9 8.9 10.0
5.0 4.7
13.0
5.1
11.0
5.0 4.7
11.7 12.5
RATIO
PREGNANT
5.9
4.9
10.0 8.3 7.5
I
I
/
46.0
1
8.1 7.3 7.4 7.5 6.8 7.2
29.6
43.5 40.6 42.0 43.5 52.0
25.0 26.0 25.0 22.2 24.2
23.9 22.6
1
41.7 35.5 34.3 34.3 33.0 33.4 33.0 32.8 32.6
Our determinations of urea and of nonprotein nitrogen were I nade by the methods of Folin and Wu. 5 During the course of the investigation frequent check analyses were run on urea solutions of known concentrations, and during the latter part of the work check analyses were also made by the recently published manometric method of van Slyke.” Our clinical material was obtained from the colored out-patient clinic and colored obstetric wards of the New Orleans Charity Hospital. The samples of blood were all obtained at about the same time in the morning and were brought immediately to the laboratory and analysed at once. Our observations have extended over a series of 316 samples of blood taken from 162 normal pregnant women from the first to the ninth month of gestation, 55 samples of blood taken from 55 women from eleven hours to five months after delivery, and (as a check on our analytic technic) 14 samples of blood from 14 nonpregnant individuals. The ages of our subjects varied from fourteen to thirty-seven years,
UREA
1:: 150
27.1 23.8 28.6 26.1 30.4 30.7
35 42 49 60
32.4
31.6 27.9 21.4 30.0 28.6
MAXIMUM
29.7
NUMBER OF CASES
II.
.-
31.6 23.1 23.8 18.5 25.3 23.7 22.2 21.5
20.7
19.8
24.5 19.7 20.6
MINIiWUM
21.8 30.8 24.2 20.8 25.4 23.9 20.0 24.0 20.4 28.6 22.2 32.0 26.3 25.5 21.2 27.0 24.9 25.9 25.5 32.0
PER
AVERAGE-___.
MG.
NONPROTEIN
NITROUEN C.C. BLOOD
NITROGEN,
ZZZ NONPRUTI CIb I 101 I - 0
Ii
17
i
; 3 4c ii 7
0.5
'AMEbTER DELIVERY (DAYS)
TABLE UKEA
16.6 14.2 11.8 10.5 11.3 11.3 13.9 11.1 9.9
102 9.6
iti
9.4 11.5
11.5
E 7:5
1E 10:s
MINIMUM
12.2
-
MG. BLOOD
--
PER
OF THE
8.0 7.9
9.1
RATIO
NITROGEN
AND
MASIMUM-
III
I
NITROGEN,
E 9:0 13.2 8.3 14.1 10.9 11.7 9.1 10.6 10.9 11.8 10.4 14.3
k6'
;:;
6.1 8.6
C.C.
IN
AVERACE -___-..
1ou
SAME
55 l:HL:.<
47.5 43.0 44.3 39.8 42.3 47.6 46.5
51.1
32.6 43.5 41.0 48.0 41.1
MAXIMUM ----.-.
K.\TIO
POSTPARTUN:
-
CASFS
-
36.4 34.0 41.5 41.5 39.0 40.2 43.0 34.5
27.9 39.2 32.3 33.6 34.6
MINIMUM
TO NUNPROTYlN PER CENT
- -.-___.
27.9 30.2 40.7 37.4 38.4 39.2 34.5 35.4 44.0 46.0 37.4 43.8 41.6 42.3 42.R 39.4 41.3 44.9 41.4 44.6 _--_..
AVERAGE
NITROGEN
.-.----^--.-
~_
DENIS,
KING,
BRIGGS
:
BLOOD
the majority being between eighteen ber of previous pregnancies recorded erable proportion of primiparae.
IN
NORMAL
389
PREGNANCY
and twenty-two years. The numranged from 0 to 8 with a consid-
In the interest of space economy we have refrained from tabulating all our results, but in Table I have presented the maximum, minimum VARIATION
OF THE RATIO
2
33 kIr:
UREA
NITROGEN: PREGNANCY
NONPROTEIN
3 --.--
30
-
Ratio
-.--
..-. --
Month -.--..
.._.-_--
-____.--___
NO. ---~
78.
- K O
$
8
DURING
4
----&gJ#Mf--
25
NITROGEN
9 of --. Prennancg. .2 -...- .____________ Fig.
----__.___
1.
and average figures obtained on our antepartum series, while in Table II we give the same data for our postpartum observations. In 24 cases we were able to obtain several samples of blood at intervals of a month or more during the antepartum period, and in several instances it was also possible to repeat these observations after delivery. Several curves prepared from the data obtained in these latter cases are presented in Figs. 1 and 2.
390
THE
AMERICAN
JOURNAL
OF
OBSTETRICS
AND
GYNECOLOGY
STJMMAEY
Our results may be briefly summarized. In the normal pregnant woman there was observed in the majority of cases a slight decrease in the concentration of nonprotein nitrogen of the blood which is accompanied by a relatively large decrease in the urea nitrogen fraction. VARIATION
_--
OF THE EATIO
Wm.4
NITROGEN: pREi3NANCP
Month
of
Pregnsmy.
Bitanth
of
Pregnanoy.
5-.--_.-.---.---
NONPROTEIN
SITR~C~EN
I%RING
--. EIonth
of
Pregnancy.
No.
. ...-..--__. .---
-_
---9 Eonth
of
44.
_-.--_ -=Yi--
Pree;nsnay. Fig.
2.
Values for urea nitrogen of over 10 mg. per 100 C.C. of blood were noted in lsas than 4 per oent of 5 m;ar‘ of urea titrogen per XI0 0.c. of Q =gr su& abnormal vales a~ the one jtuat, &ted were aheoked by reg~&&I Balyaes, so- t&at we felt rea#ortab3y me that they were not t&e to andytic errors.
DENIS,
KING,
BRIGGS
:
BLOOD
IN
NORMAL
391
PREGNANCY
The average figures presented in Table I show a slight but gradual decrease in the ratio of urea nitrogen to nonprotein nitrogen during the course of pregnancy, while the results on postpartum blood given in Table II indicate an equally definite and gradual rise in this ratio. This fall in the urea nitrogen, nonprotein nitrogen ratio during the advance of pregnancy with the subsequent rise during the postpartum period is also shown graphically in Figs. 1 and 2. The following figures in the different types of cases studied also offer further evidence for our conclusion that in pregnancy the ratio of urea nitrogen to total nonprotein nitrogen in the blood is lower than in nonpregnant individuals. Average ratio of urea nitrogen to nonprotein nitrogen in the blood: In In In In
162 normal pregnant women 55 women eleven hours to five 4 normal nonpregnant women 10 normal men
months
after
delivery
33.1 42.6 45.6 45.5
REFERENCES 1. Folin, 0.: Physiol. Rev. 2: 469, 1922. 2. Folin, 0.: Mellon Lecture, Univ. of Pittsburgh, 1917. Stander, H. J.: Bull. Johns Hopkins Hosp. 36: 133, 1924. 3. Killian, J. A., and Sherwin, C. P.: Aa6. J. OBST. & GYNEC. 2: Caldwell, W. E., and Lyle, W. G.: AM. J. OBST. & GYNEC. 2: Harding, V. J., and Drew, K.: J. Obst. & Gynec. Brit. Emp. Harding, V. J., Allen, K. D., and Van Wyck, H. B.: J. Obst. Emp. 31: No. 4, 1924. 4. Plass, E. D.: J. Biol. Chem. 56: 17, 1923. Plass, E. D.: Bull. Johns Hopkins Hosp. 35: 345, 1924. Bunker, C. W. O., and Mundell, J. J.: J. A. M. A. 83: 836, 5. Folin, O., and Wu, H.: J. Biol. Chem. 38: 81, 1919. 6. Van Slyke, D. D.: J. Biol. Chem. 73: 695, 1927.
6, 1921. 17, 1921. 30: No. 4, 1923. & Gynec. Brit.
1924.