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Serum protein concentrations in pregnancy
Serum protein concentrations II. Concentrations
HIRAM
W.
Gainesville,
Florida
in cord
serum
MENDENHALL,
and amniotic
in pregnancy fluid
M.D.
Employing the technique of single radial immunodiflusion, the concentrations of 8 serum proteins have been measured in cord serum and amniotic fluid, and compared to the levels in maternal serum and in sera of nonpregnant women. A significant decrease in albumin, IgA, IgM, ceruloplasmin, and transferrin concentration was obserued in cord serum. IgG and a,-antitrypsin concentrations were significantly elevated in both maternal and cord serum above the nonpregnant concentration. All proteins were detected in amniotic fluid in low concentration.
ELECTROPHORETIC technique&* and analyses33 * have demonstrated antigenic the presence of serum proteins in cord serum and amniotic fluid early in gestation and have stimulated investigations concerned with their origin and the factors which regulate their presence and concentration. The evidence to date, from both in vivo and in vitro studies,5, 6 suggests that the fetus synthesizes its own serum proteins with the notable exception of Immunoglobulin G, and that the proteins detected in amniotic fluid represent a transudate from the maternal plasma.? Investigation of regulatory factors by experimental manipulation in the human is limited for various reasons. That as it may be, in an attempt to gain some insight into this area, it seems reasonable to investigate cord serum protein patterns in normal as well as pathologic states affecting the mother and/or fetus. In Part I of this series of reports,* concentrations of 8 proteins were examined in
From the Department Gynecology, University College of Medicine.
of Obstetrics of Florida
8
maternal serum. Utilizing the technique of single radial immunodiffusion, concentrations in maternal serum, cord serum, and amniotic fluid have been analyzed in the same population. The data collected form the basis of this report. Materials
and
methods
Preparation of purified protein antigens, antisera, standards, and the modified technique of single radial immunodiffusion havr been described in Part I of this study. Cord blood was collected by gravity flow from the severed umbilical cord, usually prior to placental separation, and the serum stored as previously described. Amniotic fluid was obtained by aspiration either at the time of cesarean section or from the forewaters during labor. It was centrifuged promptly, and the fluid separated from the cellular debris. In measuring concentration of cord serum IgM, a more dilute preparation of antiserum in agar was found to be necessary than when maternal serum concentration was determined. In several instances, concentrations could be determined only as being less than a certain level, and, accordabsolute values are not reported. ingly, While approximate values could be estimated, the lower limits of reliability for the various protein concentrations with the antisera employed are as follows: albumin, 60
and
This work was supported in part by the 1967 National Institutes of Health General Research Support Grant No. 5-SOI-FR-05362-07 at the University of Florida College of Medicine. 581
582
Mendenholl
Amer.
mg. per cent; IgG, 40 mg. per cent; IgA, 10 mg. per cent; IgM, 4 mg. per cent; transferrin, 15 per cent of normal reference serum (NRS) ; ceruloplasmin, 20 per cent NRS; cy,-macroglobulin, 25 per cent NRS; and a,-antitrypsin, 15 per cent NRS. A normal reference serum (NRS) was prepared from 25 nonpregnant women. Results Table I shows concentrations of 8 proteins in normal reference sera, maternal sera, cord sera, and amniotic fluid. Cord serum, term infants. Albumin concentration is significantly higher in fetal serum than in maternal serum (column 3) and approaches the normal nonpregnant
Table I. delivery (range). per cent measured
February J. Obstet.
15, 1970 Gynrc.
value (column 2). IgG levels are essentially the same in maternal and cord sera and higher in both than in the nonpregnant woman. IgA and IgM concentrations are markedly lower in cord serum. Ceruloplasmin and transferrin levels are considerably lower in cord sera than in either normal controls or in maternal sera. The 2 alpha globulins are present in cord sera in higher concentration than in the normal reference serum, and as regards a?-macroglobulin, in slightly higher concentration than in maternal serum. Cord serum, premature infants. In general, the serum concentrations of proteins synthesized by the fetus were similar in term and premature infants. When protein con-
Concentrations of serum proteins in normal reference serum, maternal sera, cord sera, and amniotic fluid mean, t 1 standard deviation, and Values in milligram per cent for albumin and immunoglobulins, and in normal reference serum for the other 4 proteins. N = number of samples
Cord Normal Protein Albumin
reference serzlm
serum
Term delivery, maternal serum
Term, vaginal delivery
Premature delivery
Amniotic fluid
N = 25 4,296 + 451 (3,600-5,200)
N = 49 3,144 + 709 (1,500-5,800)
N = 36 3,510 f 910 (2,400-6,200)
N = 17 3,308 + 917 (2,400-4,500)
N = 14 204 2 186 (90-800)
Immunoglobulin (I&+)
G
N = 25 1,248 5 408 (400-2,000)
N = 53 1,571 k 598 (530-2,900)
N = 37 1,612 f 367 ( 1,050-2,500)
N = 17 1,200 C 488 (370-2,100)
N = 14 91 + 14 (66-120)
Immunoglobulin (IpA)
A
N = 25 241 t 142 (47-600)
N = 48 242 k 146 (56-680)
N = 18 < 10
N = 10 < 10
N = 15 < 10
Immunoglobulin (IgM)
M
N = 25 89 2 28 (48-140)
N = 49 123 2 52 (46-300)
N = 37 8.7 + 1.7 (4.0-13.0)
N = 16 7.5 k 0.8 (5.4-10.0)
N = 24 < 10
N = 41 234 +_ 67 (100-380)
N = 25 41 + 10 (23-56)
N = 14 42 + 21 (18-92)
N = 12 < 20 (< 5-21)
Ceruloplasmin
N = 1 (pool 25 normals) 100%
of
Transferrin
N=l 100%
N = 41 160 + 49 (104-290)
N = 25 74 + 29 (43-165)
N = 14 64 + 17 (41-94)
N = 12 17 + (13-22)
a,-macroglobulin
N=l 100%
N = 41 110 + 34 (56-225)
N = 25 135 + 36 (92-225)
N = 14 112 + 42 (66-225)
N = 12 < 10
aI-antitrypsin
N=l 100%
N = 41 324 2 90 (200-660)
N = 25 180 2 60 (115-340)
N = 14 223 + 81 (115-360)
N = 12 < 30
Volume Number
106 4
Serum
protein
in pregnancy
583
.
. . 2400. .
.
2ocQBP E
.
.
.
. .
Mean of 37 Term ~~~-------~~~~--~~-----~~~---r--fT---r~~~~
.
.
Infants
.
.
. .
N. -------------
I 3 z
.
.--
.
VI 1200m
.o . .
.
. .
.
t
..f
.m
0” ”
.
8
:
l
0
l
.
l
.
.
8CKF
. .
400-
.
0 800
rzoo
I80
1
I
I
1
I
1
1
2000
2400
2800
3200
3600
4000
4400
WEIGHT
OF FETUS
AT
DELIVERY
I
4800
fgm)
Fig. 1. centrations were plotted against fetal weight throughout gestation, however, it was apparent in the population studied that increasing fetal size was associated only with increasing serum concentration of IgG (Fig. 1). Amniotic fluid. The concentrations of serum proteins in amniotic fluid were all lower than in control, maternal, and fetal sera. The levels more closely approximated those detected in cord sera rather than those in maternal sera. IgA, IgM, and a2-macroglobulin were present in especially low concentrations. Comment
As shown in Table I, it is apparent that a wide variety of serum proteins exists in measurable amounts in fetal serum and amniotic fluid. Furthermore, their concentrations appear independent of those detected in maternal serum. Various techniques have been used in de-
termining their origin. That the fetus can synthesize serum proteins has been established by studies showing incorporation of labeled amino acids into proteins5 and by detection of phenotypic differences between maternal and fetal transferrin, haptoglobin, and Gc-globulin. ‘9 lo Gitlin and associate9 have demonstrated the virtual impermeability of the placenta to all maternal proteins with the exception of IgG. This immunoglobulin appears to cross the placenta by a process of pinocytosisll and is apparently protected from complete degradation by virtue of the unique biochemical features of the class specific portion of its molecule, the Fc fragment. Interestingly, it is this portion of the molecule wherein IgG differs from IgA and IgM, immunoglobulins to which the placenta is essentially impermeable. The fetal pulmonary and gastrointestinal surfaces are exposed to proteins in the amniotic fluid, but the contribution to the fetal serum pattern from such a source
584
Mendenhall Amer.
would appear negligible. As for the placenta itself being a possible source of fetal serum proteins, Dancis, Braverman, and Lind’ have demonstrated incorporation of amino acids into protein by placental tissue slices, but immunoglobulin production and albumin production could not be established. Furthermore, the alpha and beta globulins produced did not react to antisera against human serum proteins. Other dataI suggest that the placenta may be a potential source of immunoglobulins. The serum proteins in amniotic fluid have been stated to arise as a transudate from maternal serum by several investigators7* I3 As suggested by Schultze and Heremans,14 phenotypic analysis of proteins in fetal and maternal serum, and in amniotic fluid could establish the origin of amniotic fluid proteins but as yet such a study has not been performed. Studies with radioisotope-labeled material injected into the amniotic sac have produced conflicting data.‘“, lo If it is accepted that the fetus is largely responsible for synthesis of its own serum proteins, it becomes important to discover the regulatory factors involved in production of the serum protein concentrations detected. Undoubtedly, the genetic capabilities of the developing fetus are of major importance. The term fetus has a physiologic hypoproteinemia even more marked than that described in the mother, and yet it maintains a circulating albumin level higher than that in the mother. This finding would suggest that the influence of circulating estrogen on albumin levels, as discussed previous1y,s is either not operative in the fetus or that the placenta at least has a mitigating influence-by virtue of its handling of steroids. While the concentrations of IgG in fetal and maternal sera are similar, the proportion relative to total protein is higher in the fetus-a situation expected when considering this substance as one which is probably transferred across the placenta unaltered. The work of Hobbs and Davis,” and Hobbs and Yeung. lx demonstrated a lower level of
February 15, 1970 J. Obstet. Gynec.
IgG in the premature, “small for dates,” babies, and postmature infants. Their data strongly suggest that fetal IgG levels reflect one facet of the functional capacity of the placenta. A study by Thorn, McKay, and GrayIs revealed cord serum IgG and albumin concentrations to be positively related to birth weight-a finding not confirmed by our albumin analyses. Of interest is the finding by DiltP of significantly lower cord serum total protein and globulin levels in a group of infants who developed the respiratory distress syndrome. The low cord serum levels of ceruloplasmin noted may relate to altered steroid influence, relative immaturity of the hepatic cells responsible for protein synthesis, or a diminished stimulus for the production of an acute phase reactant. The higher than normal levels in cord serum of a,-macroglobulin and nl-antitrypsin do not permit a ready explanation or speculation at the present time. The very low levels of IgA and IgM found in cord serum (in the past often not detected because of insufficiently sensitive techniques) are perhaps best explained as reflecting the usual isolation from antigenic stimuli which the fetus in utero enjoys. The formerly held opinion that the fetus is immunologically incompetent has been compIetely disproved by investigations showing abundant production of IgA and IgM by the fetus when it is stimulated by exposure to an appropriate antigen, i.e., rubella, cytomegalovirus, or adult red cells administered intraperitoneally during intrauterine transfusion.?l-23 The factors relating to the transferrin concentrations present in cord serum are at present unknown. Other than these few bits of evidence concerning a few proteins, our knowledge of the mechanisms responsible for the observed concentrations of serum proteins in the fetus is severely limited. The author wishes to acknowledge the excellent technical assistance of Mrs. Julia Deere.
Volume 106 Number 4
Serum
protein
in pregnancy
585
REFERENCES
1. Bergstrand, C. G., and Czar, B.: &and. J. Clin. Lab. Invest. 9: 277, 1957. 2. Moore, D. H., Martin Du Pan, R., and Buxton, C. L.: AMER. J. OBSTET. GYNEC. 57: 312, 1949. 3. Scheidegger, J. J., Martin, E., and Riotton, G.: Schweiz. Med. Wchr. 86: 224. 1956. 4, Hitzig, W. H.: Schweiz. Med. ‘Wschr. 91: 1093,.1961. 5. Dancis, J., Braverman, N., and Lind, J.: J. Clin. Invest. 36: 398, 1957. 6. Gitlin, D.. Kumate, J., Urrusti, J., and Morales. C.: T. Clin. Invest, 43: 1938. 1964. 7. Abbas, T. Mx and Tovey, J. E.: Brit. Med. J, 1: 476, 1960. 8. Mendenhall, H. W.: AMER. J. OBSTET. GYNEC. Accepted for publication. 9. Rausen, A. R., Gerald, P. S., and Diamond, L. K.: Nature 191: 717, 1961. 10. Hirschfeld, J., and Lunell, N. 0.: Nature 196: 1220, 1962. 11. Bardawil, W. A., Toy, B. L., and Hertig, A. T.: AMER. J. OBSTET. GYNEC. 75: 708, 1958. 12. Good, R. A., Varco, R. L., Aust, J. B., and Zak, S. J.: Ann. N. Y. Acad. Sci. 64: 882, 1957.
13. 14.
15.
16. 17. 18. 19. 20. 21. 22.
23.
Brzezinski, A., Sadovsky, E., and Shafrir, E.: AMER. J.~ O~STET. G~NEC: 82: 800, 1961. Schultze. H. E.. and Heremans. T. F.: Molecular Biology ‘of Human Pro&s, Amsterdam, 1966, Elsevier Publishing Company, vol. I, p. 553. Dancis, J., Lind, J., and Vara, P.: In Villee, C. A., editor: The Placenta and Fetal Membranes, Baltimore, 1960, The Williams & Wilkins Company, pp. 185-187. Bangham, D. R.: J. Physiol. (London) 153: 265, 1960. Hobbs, J. R., and Davis, J. A.: Lancet 1: 757, 1967. Hobbs, J. R., and Yeung, C. Y.: Lancer 1: 1167, 1968. Thorn, H., McKay, E., and Gray, D.: Arch. Dis. Child. 42: 259, 1967. Dilts, P. V.: AMER. J. OBSTET. GYNEC. 97: 1145, 1967. Stiehm, E. R., Amman, A. J., and Cherry, J. D.: New Eng. J. Med. 277: 437, 1967. Alford, C. A., Schaefer, J. A., Blankenship, W. 1.. Straumfiord. J. V.. and Cassadv. G.: New&g. J. Med. i75: 437, 1967. ” Hobbs, J. R., Hughes, M. E., and Walker, W.: Lancet 1: 1400, 1968.
HIRAM
W.
Gainesville,
Florida
in cord
serum
MENDENHALL,
and amniotic
in pregnancy fluid
M.D.
Employing the technique of single radial immunodiflusion, the concentrations of 8 serum proteins have been measured in cord serum and amniotic fluid, and compared to the levels in maternal serum and in sera of nonpregnant women. A significant decrease in albumin, IgA, IgM, ceruloplasmin, and transferrin concentration was obserued in cord serum. IgG and a,-antitrypsin concentrations were significantly elevated in both maternal and cord serum above the nonpregnant concentration. All proteins were detected in amniotic fluid in low concentration.
ELECTROPHORETIC technique&* and analyses33 * have demonstrated antigenic the presence of serum proteins in cord serum and amniotic fluid early in gestation and have stimulated investigations concerned with their origin and the factors which regulate their presence and concentration. The evidence to date, from both in vivo and in vitro studies,5, 6 suggests that the fetus synthesizes its own serum proteins with the notable exception of Immunoglobulin G, and that the proteins detected in amniotic fluid represent a transudate from the maternal plasma.? Investigation of regulatory factors by experimental manipulation in the human is limited for various reasons. That as it may be, in an attempt to gain some insight into this area, it seems reasonable to investigate cord serum protein patterns in normal as well as pathologic states affecting the mother and/or fetus. In Part I of this series of reports,* concentrations of 8 proteins were examined in
From the Department Gynecology, University College of Medicine.
of Obstetrics of Florida
8
maternal serum. Utilizing the technique of single radial immunodiffusion, concentrations in maternal serum, cord serum, and amniotic fluid have been analyzed in the same population. The data collected form the basis of this report. Materials
and
methods
Preparation of purified protein antigens, antisera, standards, and the modified technique of single radial immunodiffusion havr been described in Part I of this study. Cord blood was collected by gravity flow from the severed umbilical cord, usually prior to placental separation, and the serum stored as previously described. Amniotic fluid was obtained by aspiration either at the time of cesarean section or from the forewaters during labor. It was centrifuged promptly, and the fluid separated from the cellular debris. In measuring concentration of cord serum IgM, a more dilute preparation of antiserum in agar was found to be necessary than when maternal serum concentration was determined. In several instances, concentrations could be determined only as being less than a certain level, and, accordabsolute values are not reported. ingly, While approximate values could be estimated, the lower limits of reliability for the various protein concentrations with the antisera employed are as follows: albumin, 60
and
This work was supported in part by the 1967 National Institutes of Health General Research Support Grant No. 5-SOI-FR-05362-07 at the University of Florida College of Medicine. 581
582
Mendenholl
Amer.
mg. per cent; IgG, 40 mg. per cent; IgA, 10 mg. per cent; IgM, 4 mg. per cent; transferrin, 15 per cent of normal reference serum (NRS) ; ceruloplasmin, 20 per cent NRS; cy,-macroglobulin, 25 per cent NRS; and a,-antitrypsin, 15 per cent NRS. A normal reference serum (NRS) was prepared from 25 nonpregnant women. Results Table I shows concentrations of 8 proteins in normal reference sera, maternal sera, cord sera, and amniotic fluid. Cord serum, term infants. Albumin concentration is significantly higher in fetal serum than in maternal serum (column 3) and approaches the normal nonpregnant
Table I. delivery (range). per cent measured
February J. Obstet.
15, 1970 Gynrc.
value (column 2). IgG levels are essentially the same in maternal and cord sera and higher in both than in the nonpregnant woman. IgA and IgM concentrations are markedly lower in cord serum. Ceruloplasmin and transferrin levels are considerably lower in cord sera than in either normal controls or in maternal sera. The 2 alpha globulins are present in cord sera in higher concentration than in the normal reference serum, and as regards a?-macroglobulin, in slightly higher concentration than in maternal serum. Cord serum, premature infants. In general, the serum concentrations of proteins synthesized by the fetus were similar in term and premature infants. When protein con-
Concentrations of serum proteins in normal reference serum, maternal sera, cord sera, and amniotic fluid mean, t 1 standard deviation, and Values in milligram per cent for albumin and immunoglobulins, and in normal reference serum for the other 4 proteins. N = number of samples
Cord Normal Protein Albumin
reference serzlm
serum
Term delivery, maternal serum
Term, vaginal delivery
Premature delivery
Amniotic fluid
N = 25 4,296 + 451 (3,600-5,200)
N = 49 3,144 + 709 (1,500-5,800)
N = 36 3,510 f 910 (2,400-6,200)
N = 17 3,308 + 917 (2,400-4,500)
N = 14 204 2 186 (90-800)
Immunoglobulin (I&+)
G
N = 25 1,248 5 408 (400-2,000)
N = 53 1,571 k 598 (530-2,900)
N = 37 1,612 f 367 ( 1,050-2,500)
N = 17 1,200 C 488 (370-2,100)
N = 14 91 + 14 (66-120)
Immunoglobulin (IpA)
A
N = 25 241 t 142 (47-600)
N = 48 242 k 146 (56-680)
N = 18 < 10
N = 10 < 10
N = 15 < 10
Immunoglobulin (IgM)
M
N = 25 89 2 28 (48-140)
N = 49 123 2 52 (46-300)
N = 37 8.7 + 1.7 (4.0-13.0)
N = 16 7.5 k 0.8 (5.4-10.0)
N = 24 < 10
N = 41 234 +_ 67 (100-380)
N = 25 41 + 10 (23-56)
N = 14 42 + 21 (18-92)
N = 12 < 20 (< 5-21)
Ceruloplasmin
N = 1 (pool 25 normals) 100%
of
Transferrin
N=l 100%
N = 41 160 + 49 (104-290)
N = 25 74 + 29 (43-165)
N = 14 64 + 17 (41-94)
N = 12 17 + (13-22)
a,-macroglobulin
N=l 100%
N = 41 110 + 34 (56-225)
N = 25 135 + 36 (92-225)
N = 14 112 + 42 (66-225)
N = 12 < 10
aI-antitrypsin
N=l 100%
N = 41 324 2 90 (200-660)
N = 25 180 2 60 (115-340)
N = 14 223 + 81 (115-360)
N = 12 < 30
Volume Number
106 4
Serum
protein
in pregnancy
583
.
. . 2400. .
.
2ocQBP E
.
.
.
. .
Mean of 37 Term ~~~-------~~~~--~~-----~~~---r--fT---r~~~~
.
.
Infants
.
.
. .
N. -------------
I 3 z
.
.--
.
VI 1200m
.o . .
.
. .
.
t
..f
.m
0” ”
.
8
:
l
0
l
.
l
.
.
8CKF
. .
400-
.
0 800
rzoo
I80
1
I
I
1
I
1
1
2000
2400
2800
3200
3600
4000
4400
WEIGHT
OF FETUS
AT
DELIVERY
I
4800
fgm)
Fig. 1. centrations were plotted against fetal weight throughout gestation, however, it was apparent in the population studied that increasing fetal size was associated only with increasing serum concentration of IgG (Fig. 1). Amniotic fluid. The concentrations of serum proteins in amniotic fluid were all lower than in control, maternal, and fetal sera. The levels more closely approximated those detected in cord sera rather than those in maternal sera. IgA, IgM, and a2-macroglobulin were present in especially low concentrations. Comment
As shown in Table I, it is apparent that a wide variety of serum proteins exists in measurable amounts in fetal serum and amniotic fluid. Furthermore, their concentrations appear independent of those detected in maternal serum. Various techniques have been used in de-
termining their origin. That the fetus can synthesize serum proteins has been established by studies showing incorporation of labeled amino acids into proteins5 and by detection of phenotypic differences between maternal and fetal transferrin, haptoglobin, and Gc-globulin. ‘9 lo Gitlin and associate9 have demonstrated the virtual impermeability of the placenta to all maternal proteins with the exception of IgG. This immunoglobulin appears to cross the placenta by a process of pinocytosisll and is apparently protected from complete degradation by virtue of the unique biochemical features of the class specific portion of its molecule, the Fc fragment. Interestingly, it is this portion of the molecule wherein IgG differs from IgA and IgM, immunoglobulins to which the placenta is essentially impermeable. The fetal pulmonary and gastrointestinal surfaces are exposed to proteins in the amniotic fluid, but the contribution to the fetal serum pattern from such a source
584
Mendenhall Amer.
would appear negligible. As for the placenta itself being a possible source of fetal serum proteins, Dancis, Braverman, and Lind’ have demonstrated incorporation of amino acids into protein by placental tissue slices, but immunoglobulin production and albumin production could not be established. Furthermore, the alpha and beta globulins produced did not react to antisera against human serum proteins. Other dataI suggest that the placenta may be a potential source of immunoglobulins. The serum proteins in amniotic fluid have been stated to arise as a transudate from maternal serum by several investigators7* I3 As suggested by Schultze and Heremans,14 phenotypic analysis of proteins in fetal and maternal serum, and in amniotic fluid could establish the origin of amniotic fluid proteins but as yet such a study has not been performed. Studies with radioisotope-labeled material injected into the amniotic sac have produced conflicting data.‘“, lo If it is accepted that the fetus is largely responsible for synthesis of its own serum proteins, it becomes important to discover the regulatory factors involved in production of the serum protein concentrations detected. Undoubtedly, the genetic capabilities of the developing fetus are of major importance. The term fetus has a physiologic hypoproteinemia even more marked than that described in the mother, and yet it maintains a circulating albumin level higher than that in the mother. This finding would suggest that the influence of circulating estrogen on albumin levels, as discussed previous1y,s is either not operative in the fetus or that the placenta at least has a mitigating influence-by virtue of its handling of steroids. While the concentrations of IgG in fetal and maternal sera are similar, the proportion relative to total protein is higher in the fetus-a situation expected when considering this substance as one which is probably transferred across the placenta unaltered. The work of Hobbs and Davis,” and Hobbs and Yeung. lx demonstrated a lower level of
February 15, 1970 J. Obstet. Gynec.
IgG in the premature, “small for dates,” babies, and postmature infants. Their data strongly suggest that fetal IgG levels reflect one facet of the functional capacity of the placenta. A study by Thorn, McKay, and GrayIs revealed cord serum IgG and albumin concentrations to be positively related to birth weight-a finding not confirmed by our albumin analyses. Of interest is the finding by DiltP of significantly lower cord serum total protein and globulin levels in a group of infants who developed the respiratory distress syndrome. The low cord serum levels of ceruloplasmin noted may relate to altered steroid influence, relative immaturity of the hepatic cells responsible for protein synthesis, or a diminished stimulus for the production of an acute phase reactant. The higher than normal levels in cord serum of a,-macroglobulin and nl-antitrypsin do not permit a ready explanation or speculation at the present time. The very low levels of IgA and IgM found in cord serum (in the past often not detected because of insufficiently sensitive techniques) are perhaps best explained as reflecting the usual isolation from antigenic stimuli which the fetus in utero enjoys. The formerly held opinion that the fetus is immunologically incompetent has been compIetely disproved by investigations showing abundant production of IgA and IgM by the fetus when it is stimulated by exposure to an appropriate antigen, i.e., rubella, cytomegalovirus, or adult red cells administered intraperitoneally during intrauterine transfusion.?l-23 The factors relating to the transferrin concentrations present in cord serum are at present unknown. Other than these few bits of evidence concerning a few proteins, our knowledge of the mechanisms responsible for the observed concentrations of serum proteins in the fetus is severely limited. The author wishes to acknowledge the excellent technical assistance of Mrs. Julia Deere.
Volume 106 Number 4
Serum
protein
in pregnancy
585
REFERENCES
1. Bergstrand, C. G., and Czar, B.: &and. J. Clin. Lab. Invest. 9: 277, 1957. 2. Moore, D. H., Martin Du Pan, R., and Buxton, C. L.: AMER. J. OBSTET. GYNEC. 57: 312, 1949. 3. Scheidegger, J. J., Martin, E., and Riotton, G.: Schweiz. Med. Wchr. 86: 224. 1956. 4, Hitzig, W. H.: Schweiz. Med. ‘Wschr. 91: 1093,.1961. 5. Dancis, J., Braverman, N., and Lind, J.: J. Clin. Invest. 36: 398, 1957. 6. Gitlin, D.. Kumate, J., Urrusti, J., and Morales. C.: T. Clin. Invest, 43: 1938. 1964. 7. Abbas, T. Mx and Tovey, J. E.: Brit. Med. J, 1: 476, 1960. 8. Mendenhall, H. W.: AMER. J. OBSTET. GYNEC. Accepted for publication. 9. Rausen, A. R., Gerald, P. S., and Diamond, L. K.: Nature 191: 717, 1961. 10. Hirschfeld, J., and Lunell, N. 0.: Nature 196: 1220, 1962. 11. Bardawil, W. A., Toy, B. L., and Hertig, A. T.: AMER. J. OBSTET. GYNEC. 75: 708, 1958. 12. Good, R. A., Varco, R. L., Aust, J. B., and Zak, S. J.: Ann. N. Y. Acad. Sci. 64: 882, 1957.
13. 14.
15.
16. 17. 18. 19. 20. 21. 22.
23.
Brzezinski, A., Sadovsky, E., and Shafrir, E.: AMER. J.~ O~STET. G~NEC: 82: 800, 1961. Schultze. H. E.. and Heremans. T. F.: Molecular Biology ‘of Human Pro&s, Amsterdam, 1966, Elsevier Publishing Company, vol. I, p. 553. Dancis, J., Lind, J., and Vara, P.: In Villee, C. A., editor: The Placenta and Fetal Membranes, Baltimore, 1960, The Williams & Wilkins Company, pp. 185-187. Bangham, D. R.: J. Physiol. (London) 153: 265, 1960. Hobbs, J. R., and Davis, J. A.: Lancet 1: 757, 1967. Hobbs, J. R., and Yeung, C. Y.: Lancer 1: 1167, 1968. Thorn, H., McKay, E., and Gray, D.: Arch. Dis. Child. 42: 259, 1967. Dilts, P. V.: AMER. J. OBSTET. GYNEC. 97: 1145, 1967. Stiehm, E. R., Amman, A. J., and Cherry, J. D.: New Eng. J. Med. 277: 437, 1967. Alford, C. A., Schaefer, J. A., Blankenship, W. 1.. Straumfiord. J. V.. and Cassadv. G.: New&g. J. Med. i75: 437, 1967. ” Hobbs, J. R., Hughes, M. E., and Walker, W.: Lancet 1: 1400, 1968.