The Role of the Placenta in Fetal Survival

The Role of the Placenta in Fetal Survival JOSEPH DANCIS, M.D.

The retention of the fetus within the mother for a prolonged period of time, characteristic of mammalian pregnancy, affords obvious advantages to the newborn in its fight for survival against a relatively inclement environment. In the evolutionary development of this method of reproduction, problems of extreme complexity had to be solved. The physiology of mother and fetus had to be modified to permit an intimate and hitherto novel relationship of two individuals, and the modifications had to be carefully selected so that they in turn would not pose a threat to either individual. In the course of evolving solutions to these problems a new organ was designed solely for use during pregnancy-the placenta. This presentation is not intended as a complete review of placental physiology, nor is the bibliography comprehensive. Such reviews are readily available. 39 • 47. 55 Instead, a selective survey of placental function is presented which, perhaps unduly, reflects the interests of the author. When the information permits, the potential role of the placenta in fetal survival is indicated. This is obviously the central "purpose" of the placenta, and such a viewpoint may hopefully add some interest and reason to what often threatens to become a dull cataloguing of observations.

MAINTENANCE OF PREGNANCl

The retention of the conceptus throughout pregnancy requires many profound physiologic changes in the uterus. These are induced primarily by the action of estrogens and progesterone. In many mammalian species From the Department of Pediatrics, New York University School of Medicine, New York City. The work of the author was aided by a grant from the National Institutes of Health, #HD-00462. The author is a Career Investigator of the National Institutes of Health.

477

JOSEPH DANCIS

PREGNANEDIOL

0 0

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75

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10

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o

40

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DAYS OF PREGNANCY Figure 4. Urinary excretion of hormone metabolites in pregnancy. (Modified from E. H. Veenning: Obst. & Gynec. Surv., Vol. 32. Reprinted from J. Dancis: J. Pediat., Vol. 55. C. V. Mosby & Company.)

these endocrine requirements are satisfied by the maternal ovaries, under the stimulation of trophic hormones from the pituitary. In the human species, by the end of the first trimester, the placenta fulfills these functions for both the trophic hormone and the steroids. The synthesis of chorionic gonadotropin by placenta has be ell demonstrated in tissue culture. 50 The urinary excretion of this hormOnE by the mother starts shortly after conception, reaches a peak in about twc months and then falls off rapidly to a relatively low level that is main· tained throughout pregnancy (Fig. 4). The time course parallels closel) the waxing and waning of the cytotrophoblast (Langhans') layer, be· lieved to be the site of origin of this hormone. Curiously, the materna blood level of this hormone is considerably higher than that found ir cord blood, indicating a "one-way" transfer. Estrogens and progesterone are synthesized in large amounts, prob ably by the syncytial trophoblast. Evidence for their synthesis b) placenta was first obtained by biological studies. 1 , 49 Only recently ha the biochemist been able to fill in some of the metabolic details. The ovary can synthesize both estrogen and progesterone from l simple two carbon precursor, acetate. Nevertheless all efforts to redupli

THE

ROLE OF THE PLACENTA IN FETAL SURVIVAL

479

cate this with the placenta have been unsuccessful. The metabolic pathway from acetate to progesterone passes through cholesterol. Perfusion experiments of human placenta have been unable to demonstrate any significant conversion of acetate to cholesterol.84 But cholesterol is easily available to the placenta from both the maternal and fetal circulations, and the placenta can complete the conversion to progesterone. 48 The synthesis of estrogens involves an interesting interplay of placental and fetal metabolism. The human fetus develops a thick adrenal cortex occupied largely by distinctive cells forming the "fetal zone." This atrophies shortly after birth. Its function has been a mystery, though the time sequence indicated that it must be related to antepartum existence. It has recently been demonstrated that the fetal adrenal synthesizes a wide variety of steroids, none of which has the unsaturated "A" ring characteristic of estrogens; however, the placenta is capable of completing the conversion. 42 This circumstantial evidence for the biosynthetic pathway of the estrogens of pregnancy has been rendered fairly firm by observations in the anencephalic monster.19 The anencephalic monster often lacks the fetal zone of the adrenal cortex, and the level of estrogens in maternal urine is very low. In those rare anencephalic monsters with a normal fetal zone, the estrogen levels are also normal. There is still no satisfactory proof that the placenta can synthesize any hormones other than the above-mentioned three, though interesting evidence has now been presented for a protein hormone related immunologically to growth hormone. 28

TRANSPLANTATION PROBLEMS

All vertebrates appear to have the faculty of recognizing foreign tissues that have been grafted onto them and of mounting a defensive rejection of these tissues. The foreignness of the tissue is dictated by its genetic composition. It has been suggested that this universal function of rejection is a fundamental defense of multicellular organisms against genetic aberrations within its own tissues which could be lethal to the host. In view of the fundamental nature of this reaction, it has been of some wonder to immunologists how the mother will tolerate a "foreign" fetus-foreign because it contains paternal genes-for the duration of pregnancy. The problem has been approached almost entirely in experimental animals, at times with apparently conflicting results probably as a reflection of varied experimental situations. Nevertheless some interesting suggestions concerning possible mechanisms have emerged. 4 • 31 1. The placenta is a barrier limiting the passage of fetal cells into the mother and reducing the likelihood of sensitization of the mother.

480

JOSEPH DANCIS

The clinical entity, erythroblastosis fetalis, makes it evident that this is an imperfect barrier. Although red blood cells do not carry transplantation antigens, it is a safe assumption that white cells, which do, travel the same route. 2. In the human being large numbers of trophoblast cells are released into the mother's blood during pregnancy.16 It has been suggested that this may serve to suppress the immune response of the mother. If this were true, tolerance to the fetus should also occur, and most investigators have failed to demonstrate this. 3. The trophoblast is nonantigenic. It serves therefore to protect the mother against stimulation by fetal tissue and, in the case of an inadvertent immune response by the mother, will protect the fetus against maternal rejection. The experimental evidence for this hypothesis was obtained in the mouse,45 using the ectoplacental cone harvested early in pregnancy. The artificial sensitization of the pregnant rabbit to the fetus fails to induce rejection, indicating some protection of the fetus derived from its location. 32 4. Although the trophoblast is bathed in maternal blood, this is generally a poor route for inducing a transplantation rejection. The formation of humoral antibodies 26 may actually "enhance" retention of the fetus by blocking the rejection process. This situation has been demonstrated with experimental tumors. When the placental barrier was breached artificially in rabbits with hyaluronidase,37 the reaction of the mother to fetal tissues was one of increased tolerance rather than rejection. 5. It has recently been reported that the administration of estrogens in large amounts will prolong the survival of trophoblast grafts in the human being. 29 This brief survey demonstrates the complexity of the problem. The suggestions are not mutually exclusive, and may actually be complementary. Most studies have stressed the risk to pregnancy of invasion of the mother by fetal cells. The risk to the fetus of invasion by maternal cells would appear particularly grave when the fetus's own immunologic defenses are incompletely developed. In the experimental animal this situation often leads to disease and death. Evidence has now been presented that, in the mouse, the placenta contains immunologically competent cells which may serve as a first line of defense. '*,12

TRANSFER OF ANTIBODIES

The human infant is born with fairly effective immunologic defenses. Even a small premature will form antibodies at birth,46, 54 and will '* ]. Dancis, G. W. Douglas and ]. Fierer: Immunological Competence of Mouse Placental Cells in Irradiated Hosts. Unpublished observations.

THE ROLE OF THE PLACENTA IN FETAL SURVIVAL

481

develop a delayed hypersensitivity ("tuberculin type") reaction when appropriately stimulated. 53 The latter response depends on cellular immunity, and is also involved in transplantation rejection. But the immunologic reactions are not as effective as they will be a few months after birth. The improvement in performance appears to be primarily a result of exposure to multiple antigens after birth, rather than maturation.l1 See also page 663. During this period of relative susceptibility, survival could be increased by receiving preformed antibodies directed against the multiple threats in the environment. The mammalian mother, who has survived these exposures herself, supplies the antibodies to her infant. The varied method of transfer among the several species demonstrates the resourcefulness of nature. 6 The ungulate receives its antibodies immediately after birth by absorbing them through the gut from its mother's colostrum. The mouse receives some antibodies before birth, but also obtains the main complement post partum. Rabbit and guinea pig fetuses develop a specialized membrane, the splanchnopleure, which transfers antibodies to the young in utero. In the human species, it is the placenta that fulfills this function.14 The human adult has three main classes of circulating antibodies: gamma2 (7S), beta2A (gammalA, 7S), and beta2M (gammalM, 19S). It is only the first group of antibodies that is found in significant amounts in cord blood, and is responsible for the high levels of gamma globulin with which the infant is born. 20 The method of transfer of such large molecules is not known. It has been attributed by electron microscopists to pinocytosis, a method of vacuolization and engulfing of material. But the method of transfer appears to be selective, and this is entirely unexplained. Table 1 presents a listing of antibodies and the relative titers found in cord blood.

THE PLACENTA AS A "BARRIER"

The importance of maintaining some discrete distinction between mother and fetus has been indicated above. The placenta fulfills this function effectively. Although some cells do penetrate this barrier, thev are relatively few. In similar fashion the placenta serves as an effective, although incomplete, barrier against microorganisms. After the injection of bacteriophage into pregnant guinea pigs, microorganisms are regularly found in the fetus, but in relatively low concentration. 52 Bacteriophage was used because it is not pathogenic to mammals, and therefore invasion of the fetus can be assumed to have occurred in the absence of placental pathology.

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Maternal-Fetal Titer oj Antibodies

t-:l

UN DETERCLASS

SUBGROUP

TYPE ANTIBODY

EQUAL

LESS

MINED BUT

NONE

IN FETUS

PRESENT

IN FETUS

IN FETUS

Bacteria ............ Bacillary dysentery (shigellosis) Colon bacillus (E. coli) Diphtheria bacillus H. pertussis H. influenzae Pneumococcus Staphylococcus

Streptococcus

Tetanus bacillus Typhoid bacillus

Bactericidal Agglutinin Antitoxin Agglutinin Bactericidal Bactericidal Antistaphylolysin Antitoxin Anticapsular agglutinin Antistreptolysin Antitoxin Agglutinin Antitoxin Anti-H agglutinin Anti-O agglutinin

X X

X

X X X

X X X X X X X X X

Actinomycetes .... , M. tuberculosis

Complement-fixing

X

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Complement-fixing "Positive M.K.R. test"

X

Sporozoa. . . . . . . . .. Coccidiodomycosis Histoplasmosis Toxoplasmosis Rickettsia. . . . . . . . .. Q fever (R. burneti)

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Maternal-Fetal Titer oj Antibodies (Continued) UNDETER-

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PRESENT

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Viruses. . . . . . . . . . .. Adenovirus Complement-fixing "Immune or protective" Chickenpox (varicella) ECHO virus (types 1,2,8,11 and 20) Neutralizing Neutralizing Herpes simplex Influenza A Neutralizing Neutralizing Influenza B Lymphogranuloma venereum Complement-fixing Complement-fixing Measles Complement-fixing Mumps Agglutination-inhibition Poliovirus (types 1, 2 and 3) Neutralizing Smallpox (vaccinia) Hemagglutination-inhibition Japanese B. encephalitis Neutralizing Neutralizing and complementSt. Louis encephalitis fixing Neutralizing and complementWestern equine encephalitis fixing Allergens. . . . . . . . .. Blocking Skin sensitizing Autoantibodies and miscellaneous. . . .. Thyroid Platelet

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MINED BUT

NONE

PRESENT

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These antibodies represent conglutinin; blocking; albumin or protein form; Coombs or antiglobulin reacting; incomplete; and the antibodies detected by the enzymatic treatment of red cells Other blood group systems At one time or another all of these antibodies have been reported to have caused erythroblastosis fetalis. In general these antibodies are rare and the degree to which they pass the placenta is not known

Anti-Rh conglutinins (blocking) Anti-Rho(D), anti-RhA , anti-Rhc , and anti-RhO Anti-hr'( c), anti-hr"( e), antirh"(E), anti-rh'(C), anti-rhW(CW), and anti-hr(f) Anti-K Anti-k, anti-M, anti-S, anti-s, antiMi", anti-VW, anti-Fy', anti-Jk', anti-Lea, anti-Lub, anti-Be", anti-Ca, anti-Dia, anti-Yen, antiWr a, anti-Jobbins, anti-Becker, anti-Good, Anti-Ge

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486

JOSEPH DANCIS

The placenta therefore serves as a mechanical barrier which probably could be protective against minor bacteremias-minor to the mother, but potentially fatal to the fetus. Nevertheless, if the defenses of the mother are breached by a serious sepsis or if the placenta is involved in the pathologic process, lethal invasion of the fetus may occur. N or is the placenta an effective barrier against other maternal disturbances. Osmotic and electrolytic imbalances in the mother may be reflected in the fetus. 3 ,13 Teratogens, commonly man-made, against which evolutionary defenses cannot be expected, may make use of the same functions of placental transport that are normally essential to the welfare of the fetus.

THE PLACENTA AS AN ORGAN OF TRANSPORT

Before the development of a placental type of reproduction the size of the fetus and duration of gestation were limited by the amounts of nutrients that could be deposited in the egg. The mammalian egg provides very little stored food, the necessary materials for growth being derived from the mother through the placenta. To provide an adequate surface for the interchange, the maternal and fetal circulations are brought into close apposition within a system of villi and microvilli. The structures interposed between the maternal and fetal circulations have been called the placental membrane. In the human being these are very few-trophoblast (chorionic epithelium) and fetal endothelium. The term stresses the function of transport and suggests certain similarities with other membranes throughout the body. Highly specialized and specific mechanisms have been developed to aid the transfer of certain nutrients to the fetus. Gases diffuse readily through the placenta, a successful anesthesia in the mother being accurately reflected in the newborn. A free interchange of oxygen and carbon dioxide between mother and fetus is an obvious requirement to the survival of the fetus. There is still uncertainty as to the level of oxygen saturation of umbilical venous blood in utero, but it is likely that cord blood leaving the placenta is normally well oxygenated. Despite that, fetal tissues generally metabolize under hypoxemic conditions because of fetal shunts producing a mixing of oxygenated cord blood with venous blood from fetal tissues. The possible advantages to fetal development of such relative hypoxemia are not known, but it would not be surprising if some of the tissues of the prematurely born infant are at a disadvantage after birth from a surfeit of oxygen even in room air. Water also diffuses readily through the placenta, responding promptly to osmotic pressure changes. The behavior of electrolytes is more complex, the rates of transfer varying. Thus the induction of

THE

ROLE OF THE PLACENTA IN FETAL SURVIVAL

487

acidosis in the mother with ammonium chloride is followed rapidly by a fall in pH and carbon dioxide content in the fetus, but the fetal chloride level rises slowly over a period of hours,13 The mechanism of transport of univalent ions has been assumed to be simple diffusion. Nevertheless the induction of hypokalemia in the pregnant dog was not followed by a fall in fetal potassium, suggesting that the placenta was able to maintain the fetal level against a gradient,44 and protect the fetus against nutritional or pathologic deficiencies in the mother. Gradients are also maintained with those divalent ions that have been studied: iron,5 calcium24 and phosphorus. 2l In each instance the fetal level is higher than the maternal. Glucose is the principal source of energy for the fetus. The fetal blood level is lower than in the mother, not as a result of fetal consumption, but probably because the placenta maintains the gradient in this direction. Yet the net transfer of glucose is in the direction of the fetus and is facilitated by a stereo-specific transport mechanism. Thus D-xylose (a pentose with a configuration similar to glucose) is transferred more rapidly than L-xylose; and fructose, with the same molecular weight as glucose, is transferred much more slowly than the latter. ls ,25 Placental transport of glucose makes available virtually unlimited supplies from the mother. The injection of radioactive amino acids into the mother is followed within minutes by significant radioactivity in the fetal plasma, and this is readily incorporated into fetal proteins. 9 The level of amino acids in the fetal plasma is higher than the maternal level, and this is maintained by a stereo-specific transport mechanism in the placenta favoring the natural L-amino acids. as By this means the fetus is kept richly supplied with all the necessary amino acids for protein synthesis. As an incidental advantage, unrelated to the evolutionary process, the fetus suffering from a metabolic anomaly, such as phenylketonuria or maple syrup urine disease, is also protected before birth against an excess of the involved amino acids. The placenta serves to maintain a relatively constant ratio to the normal levels in the mother. The placenta also transfers proteins intact, 2,9,17 but in a much more limited fashion. In the case of gamma globulin, as indicated above, this source represents the infant's sole supply. By virtue of a long biological half-life of gamma globulin (20 to 30 days) and the assistance of a poorly defined transport mechanism in the placenta, enough is supplied to maintain a high fetal level. Significant amounts of albumin are also supplied, but the value of this function is not clear, because the fetus is capable of synthesizing its own serum albumin. lo Other serum globulins are also transferred, but their generally shorter half-lives make it unlikely that enough reaches the fetus to affect its economy (Fig. 5). Exceptions to this generalization, if they exist, have not yet been described. Although fetuses have been born with evidence of vitamin deficiency

488

JOSEPH DANCIS 100,000

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as a result of severe nutritional deprivation in the mother, it is not known whether this is a direct effect on the fetus or a reflection of the disturbed metabolism in the mother, There is a gross difference in the transfer across the placenta of lipid-soluble and water-soluble vitamins. The former are found in relatively low concentrations in fetal blood, This is true of vitamins A35 and E,51 the analytical methods for D having been inadequate until now to determine its blood concentrations. The water-soluble vitamins, however, are commonly found in higher concentration in fetal blood. This suggests transfer against a gradient, and one might assume an energy-requiring transport mechanism to accomplish it, Interesting suggestions concerning the mechanism for two of the vitamins have been presented. Ascorbic acid exists in the blood in two forms, dehydroascorbic acid and I-ascorbic acid. The placenta is freely permeable to the former, but not the latter. It would appear that the fetus is supplied with dehydroascorbic acid, which it converts to I-ascorbic, which now accumulates on the fetal side. 41 Riboflavin appears to utilize a similar mechanism. Flavin adenine dinucleotide is found in the maternal blood, and free riboflavin in the fetal blood. The placenta is impermeable to both forms, but can convert the former to the latter.36 A systematic study of lipid transfer has not yet been made. Acetate can cross the placenta, and the fetus can use this simple precursor to synthesize fats. 22 ,40 Of course, the freely available supplies of glucose could also serve as a source of acetate. Phospholipids and cholesterol are poorly transferred across the placenta. In contrast, the free fatty acids are transferred rapidly in both directions. This is probably necessary to sup/((0

/((0

H. Kayden and

J. Dancis: Unpublished observations.

THE ROLE OF THE PLACENTA IN FETAL SURVIVAL

489

ply the fetus with essential fatty acids, those that the mammal cannot synthesize. The fetus synthesizes its nucleic acids from simple precursors, receiving no significant supply of preformed nucleic acids from the mother.s This is not surprising in view of our current understanding of the function of nucleic· acids, that of transmitting and interpreting the genetic code. It is not known whether the fetus has any need for endocrines from the mother, though it does not seem likely. In fact, it would seem that the great excesses of hormones associated with pregnancy may be more of a problem than endocrine deficiencies. Chorionic gonadotropin appears to pass directly into the mother, the levels in cord blood never reaching very high levels. 30 Unconjugated estrogens15 and steroidsf> in general cross the placenta freely in both directions. Metabolism of estrogens reflects a complex interplay among mother, placenta and fetus. 33 Fetal tissues rapidly sulfurylate steroids, rendering them relatively impermeable to cell membranes and reducing their physiologic effect. Thus any estrogens arriving at the fetus from the placenta are rapidly "detoxified." On the other hand, sulfates coming from the fetus can be deconjugated by either the placenta or amnionchorion, facilitating their passage to the mother and eventual excretion. Some of the steroids synthesized in the fetal adrenal are sulfurylated, and in this form travel to the placenta, where they may be converted into estrogens. Desulfurylation will then activate the estrogens. Thyroxin and triiodothyronine are transferred across the placenta at slow rates,23 but the relatively long biological half-life suggests that a significant amount reaches the fetus. Nevertheless the fact that cretins may be born with stigmata of the disease indicates that the maternal supply is not adequate for fetal demands. Insulin is also transferred across the placenta,7 but again it is doubtful whether transfer is rapid enough to meet all the requirements of the infant. There is no direct information concerning other protein hormones. Knowledge concerning the transfer of excretory products is readily summarized. Urea is transferred through both the placenta and chorioamnion for final disposal by the mother.27 Bilirubin appears to behave much like estrogens, the un conjugated form being transferred rapidly and the conjugated form relatively slowly.43 This suggests an advantage to the fetus in the delay in development of the glucosiduronation mechanism.

CONCLUSION

We have touched briefly on some of the roles played by the placenta in contributing to the success of mammalian pregnancy. In so doing we .. M. Levitz, W. L. Money and

J. Dancis:

Unpublished observations.

490

JOSEPH DANCIS

have alluded on occasion to some of the interplay of function among mother, placenta and fetus. There are, no doubt, many subtle though vital features that remain to be uncovered. And, what must surely be a vast field, that of placental malfunction, has hardly been touched.

REFERENCES 1. Allan, H., and Dodds, E. C.: Hormones in the Urine Following Oophorectomy during Pregnancy. Biochem. J., 29:285, 1935. 2. Bangham, D. R: The Transmission of Homologous Serum Proteins to the Foetus and to the Amniotic Fluid in the Rhesus Monkey. J. Physiol., 153:265, 1960. 3. Battaglia, F., Prystowsky, H., Smisson, C., Hellegers, A., and Bruns, P.: Fetal Blood Studies. XIII. The Effect of the Administration of Fluids Intravenously to Mothers upon the Concentration of Water and Electrolytes in Plasma of Human Fetuses. Pediatrics, 25:2, 1960. 4. Billingham, R E.: Transplantation Immunity and the Maternal-Fetal Relation. New England J. Med., 270:667, 1964. 5. Bothwell, T. H., Pribella, W. F., Finch, C. A., and Mebost, W.: Iron Metabolism in the Pregnant Rabbit. Iron Transport across the Placenta. Amer. J. Physiol., 193:615, 1958. 6. Brambell, F. W. R, Hemmings, W. A., and Henderson, M.: Antibodies and Embryos. London, Athione Press, 1951. 7. Buse, M. G., Roberts, W. J., and Buse, J.: The Role of the Human Placenta in the Transfer and Metabolism of Insulin. J. Glin. Invest., 41 :29, 1962. 8. Dancis, J., and Balis, M. E.: Reutilization of Nucleic Acid Catabolites. J. Biol. Ghem., 207:367,1954. 9. Dancis, J., and Shafran, M.: The Origin of Plasma Proteins in the Guinea Pig Fetus. J. Glin. Invest., 37:1093, 1958. 10. Dancis, J., Braverman, N., and Lind, J.: Plasma Protein Synthesis in the Human Fetus and Placenta. J. Glin. Invest., 36:398,1957. 11. Dancis, J., Osborn, J. J., and Kunz, H. W.: Studies of the Immunology of the Newborn Infant. IV. Antibody Formation in the Premature Infant. Pediatrics, 12:151, 1953. 12. Dancis, J., Samuels, B. D., and Douglas, G. W.: Immunological Competence of Placenta. Science, 138:382, 1962. 13. Dancis, J., Worth, M., Jr., and Schneidau, P. B.: Effect of Electrolyte Disturbances in the Pregnant Rabbit on the Fetus. Amer. .T. Physiol., 188:535, 1957. 14. Dancis, J., Lind, J., Oratz, M., Smolens, J., and Vara, P.: Placental Transfer of Proteins in Human Gestation. Amer. J. Obst. & Gynec., 82: 167, 1961. 15. Dancis, J., Money, W. L., Condon, G. P., and Levitz, M.: The Relative Transfer of Estrogens and Their Glucuronides across the Placenta in the Guinea Pig. J. Glin. Invest., 37:1373,1958. 16. Douglas, G. W., Thomas, L., Carr, M., Cullen, N. M., and Morris, R: Trophoblast in Circulating Blood during Pregnancy. Amer. J. Obst. & Gynec., 78:960, 1959. 17. Du Pan, R. M., Wenger, P., Koechli, S., Scheidegger, J. J., and Roux, J.: Etude du '. passage de la 'Y-globuline marquee a travers Ie placenta humain. GUn. Ghim. Acta, 4:110, 1959. 18. Folkart, G., Money, W. L., and Dancis, J.: Transfer of Carbohydrates across Guinea Pig Placenta. Amer. ]. Obst. & Gynec., 80:221, 1960. 19. Frandsen, V. A., and Stakeman, G.: The Site of Production of Oestrogenic Hormones in Human Pregnancy. III. Further Observations on the Hormone Excretion in Pregnancy with Anencephalic Fetus. Acta Endocrinol., 47:265, 1964. 20. Franklin, E. c., and Kunkel, H. F.: Comparative Levels of High Molecular Weight ( 19S) 'Y-Globulin in Maternal and Umbilical Cord Sera. J. Lab. & Glin. Med., 52:724,1958. 21. Fuchs, F., and Fuchs, A. R: Studies on the Placental Transfer of Phosphate in the

THE

22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48.

ROLE OF THE PLACENTA IN FETAL SURVIVAL

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