Book - Physiology of the Fetus 15
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Windle WF. Physiology of the Fetus. (1940) Saunders, Philadelphia.
1940 Physiology of the Fetus: 1 Introduction | 2 Heart | 3 Circulation | 4 Blood | 5 Respiration | 6 Respiratory Movements | 7 Digestive | 8 Renal - Skin | 9 Muscles | 10 Neural Genesis | 11 Neural Activity | 12 Motor Reactions and Reflexes | 13 Senses | 14 Endocrine | 15 Nutrition and Metabolism | Figures
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Chapter XV Fetal Nutrition and Metabolism
Paraplacental Nutrition
THE maternal organism not only breathes and excretes for the ketus but it also digests kood and kurnishes nutriments needed kor the growth ok the new individual. In early stages ok development the intimacy between embryo and mother is slight, and until a close approximation to the endometrium is ekkected nutrition can not be accomplished by direct processes which characterize the older and more advanced types ok placental circulatory Systems. An intermediate substance ok transient nutritional value to the early embryo is provided by secretion ok the uterine glands, by transudation and especially by erosion ok the endometrium and production ok tissue detritus in response to implantation ok the newly arrived blastocyst. To this paraplacental nutriment, the name histotrophe may be applied.I-4
In mammals with relatively simple epithelio-chorial and syn— desmo-chorial p1acentas, such as the horse and sheep, quite a different histotrophic material bathes the chorionic surkace throughout gestation. This, the «uterine mi11c," is composed predominantly ok secretions and transudates from the intact uterine epithelium. Its high kat- content gives it the appearance ok dilute millc.
It is doubtkul ik histotrophic nutrition can be ok real signikicance in man and other primates for more than a kew days during implantation) A yollc-sac placenta develops early in the rat, and with it a more eiiicient mechanism kor nutrition. The passage ok substances through the yollcssac epithelium ok the rat has been demonstrated very clearly.0- 7 0ne can not consider that the processes involved are entirely histotrophic in those animals in which uterine millc is laclcing.
With the kormation ok endothelio-chorial, hemo—chorial and hemo-endothelial (deciduate) placentas in carnivores, primates and rodents, histotrophe plays only a. Jninor and transient part
206 FETAL NUTRITION AND MBTABOLISM 207
and nutrition becomes possible largely by processes similar to those occurring in the tissues ok the body itseltl The substances which pass more directly from one blood stream to the other have been designated hemotrophe. Thus Bonet’s term «embryotrophe" has given way to a more usekul classiiicatiom
Bmbryofrophe Eistotrophe klemotrophe l . I . I . I « I Ikansient Uterme milk. Diikusible Nitrogenous substances endometrial Nutrition substances substances (e.y., lipids) detritus, etc. throughout (gases, ok high truly Nutrition kor gestation in dextrose and molecular absorbed b)implanting ungulatea inorganic weight which trophoblast blastoeyssz eompounds) are diikuss and yolkssac requiring no ible but epitheliunh resynthesia require
resynthesia
PLACENTAL PERMEABEITY
N utrition ok the fetus is closely dependent upon the manner and ekkiciency with which materials are transmitted across the placental barrier. It must be born in mind that the physiologic characteristics ok the placenta are not constant throughout development, nor are they the same in all species ok mammals. Furthermore, the chorio-allantoic attachment is not the only means ok contact between the ketus and motherz in some species, e.g., the rat, a yollosac placenta ok very dilkerent structure is known to serve concomitantly throughout gestationsk The term «the placenta« rekers as a rule to the combined ectoplacenta and yollc— sac placenta when used in rekerence to kunctioxx Density and number ok tissue layers separating maternal and fetal blood streams vary, as was pointed out in Chapter I. For these reasons one must exercise caution in attempting to draw conclusions regarding the permeability ok one type of placenta based upon experiments with a different type.
The subject ok placental permeability is much too extensive ito be discussed in detail, but a few signiiicant observations can be considered such observations inquire into the characteristics ok materials which make their way across the living membranes, and into the nature ok the processes involved in their passage.
Particulate matten even when microscopic in size, kails to pass 208 PHYSIOLOGY oF THE: FETUs
the most advanced hemo-endothelial placentas. Formerly there was much discussion of this, but the fact is now well establishedF certain ultræmicroscopic particles in colloidal solutions do pass, and the dye trypan blue seems to be one lying on the borderline between the transmissible and non—transmissible substances in the hemo-endothelial placentas. This dye does not traverse the endothelio-chorial type found in the cat.?
That a relationship exists between the molecular weight of substances and their ability to pass through placentas can scarcely be doubted. 0xygen, carbon dioxide and many chemical com— pounds of low molecular weight traverse membranes of all placentas. Tabulation of data available ·up to 1931 will be found in N eedham’s10 «Chemical Embryology" (Table 227) . From this it appears that the thinner the barrier, the more permeable it is to materials of large molecular size. 0n the other hand, it has been demonstrated that the thin chorionic trophoblast plates of the early rat placenta are actually less permeable than the much thiclcer yoll(-sac epithelium to the dye, toluidin blue.
A very close parallelism exists between the ability of colloidal dye solutions to diffuse in iilms of 2o to 30 per cent gelatin and the efliciency of their transmission from the mother to the fetuses of rats and mice.U These and other observationsW have frequently been cited as evidence that the placenta acts largely in the capacity of an ultra-iilter. There is ample evidence, however, that the fat solubility of materials in the blood streams, their pH and ionic charges at the membrane play important röles in governing placental permeability. "Furthermore, one can not tell whether the experiments with colloidal dyes demonstrate passage through the ectoplacenta, the yolldsac placenta or a combination of both.
Although a number of investigations have led» to the conclusion that species differences exist at term in respect to permes ability of dye solutions,9 other chemical solutions« and antibodiesss few experiments have been concerned with the changes talcing place throughout the course of development of any one species. Recently, however, it was demonstrated that the permeability of the rabbit’s placenta to agglutinins and hemolysins in— creases during the course of gestation.14 The ratio of the titre of the fetuses to that of the mother plotted against the gestation-age forms a sigmoid curve (Fig. 68)'. Permeability is clearly related FETAL NUTRITION AND METABOLISM 209
to the changing histologic structure of the placenta during gestationss «
The two principal theories concerning the nature of the placental barrier merit further study. Many recent observers have favored the view that it is essentially an inert semipermeable membrane, but advocates of the concept of a vital function are not lacking. A preformed rcgulatory mechanism, inferring a secretory process, has been suggcstedJs
Those who favor the ultra-iilter theory believe that substances pass from mother to fetus, or in the reverse direction, by diffusion and filtration, that physical processes alone govern the transmission and that molecular size plays an important part in determining which shall and which shall not cross the barrier.
Fig. 68.—Permeability of the rabbit placenta to antibodies at different times during prenatal life. (Rodo1fo: J. Exp. Zool» Vol. 68, 1934.)
This seems to be well established for gases, dextrose and a number of chemical compounds of relatively low molecular weight, including some of the products of fetal metabolism. The subject has been reviewed by schlossmanW who concludes that, aside from endocrine activities, there is not the slightest reason to believe that the placenta and its chorionic epithelium has a truly secretory function. He believes that even in the instances of seemingly vitalistic activities, physical principles in the last analysis can ex— plain transmission. Nevertheless it is reasonable to adhere to the concept of absorption in the trophoblast.. The recent studies on metabolism of lipids provide strong circumstantial evidence for the vitalistic theoryäs
With the recognition of functional properties of the yollc-sac in some animals, the question of secretory function talces on re— newed interest. In structure as well as in physiologic reaction to perfusion of the maternal blood vessels with various chemical and dye solutions, the yollcssac placenta of the rat appears to be an organ for absorptionks 7 When more attention has been paid to the functions of this organ, as well as to factors of age and species differences, our knowledge of the passage of the nutriment from mother to fetus will undoubtedly be advanced far beyond its present state.
UETAZOLISM oF cumoknmmrns
The body of the fetus is bui-It from chemical substances which are available in the mother’s blood. Energy needed by the fetus is derived from the same source. Indeed, all the prenatal require· ments are met by processes of intermediary metabolism. The most readily available substance is carbohydrate in the form of dextrose which serves as the important energy source for the fetus.
Dextrose can pass from mother to fetus across the placental barrier in all mammalskHs Human fetal bloodssugar concentration is always a little lower than that of the mother near term. For example, Morriss found averages of 1 15 mg. per cent in the fetus and 132 Ins. per cent in the motherkl indicating that there is a gradient of flow towards the fetus. A similar condition pre— vails in most mammalssks 23 but not in the pig and cow in which the concentration is lower in maternal than in fetal blood.23- 24 The reason for these species differences is not clear, but they may be related to placental structural variations and to histotrophe as an intermediate nutriment. Much of our information has been obtained at the end of gestation or is based on averaged data of different prenatal ages. A more complete study is available in the incubating chiclc.25 The blood-sugar concentration maintains a reasonably constant level up. to the 16th day; thereafter it rises and surpasses the adult level at about hatching time, which is the 21st day. Fetal blood—sugar concentration varies with gestation age in mammals too. For example, it decreases toward term in the cow but increases markedly in the spguinea pig and rabbitkss 27
It is apparent that a simple filtration across the placental barrier is not the only mechanism governing the blood-sugar level in the fetus.
The placenta and liver are important depots for carbohydrate storage in prenatal life. As early as 1858, Claude Bernard demonstrated that the placenta contains glycogen and serves as a «transitory liver« for the embryoks It has been clearly shown that the glycogen content of the placenta is high in the early part of fetal life whenlittle or none is in the liver. Only the maternal portion of the placenta contains it.29 A time is reached, however, when glycogen storage becomes active in the fetal liver; when this occurs there is a corresponding reduction of storage in the placenta. This crossing over takes place after the elapse of 75 per cent of the total gestation time in the rat, 82 per cent in the chiclc and 91 per cent in the rabbitPHI The glycogen content of the fetal liver rises rapidly toward the end of gestation and is especially high a few days before birth.22 Nevertheless, the amount of liver glycogen is inconstant at any given period in the fetus and. varies with the food intalce of the mother. Following 24 hours of fasting in the rat at full term, the pealc of maternal liver glycogen was reached about four hours sooner than that of the fetuses« When the average glycogen content in the mother’s liver was o.29 per cent of the total liver weight (fasting1eve1) , that of the fetuses was 4.95 per cent. At the pealc of storage after feeding, average values of 3.1 per cent and 1o.6 per cent were found in the mothers and fetuses respectively. These differences are truly remarlcable.
Glycogenic function begins after secretion of bile has startedFs It has been thought to begin at almost precisely the time the is— lands of Langerhans differentiate and begin to supply insulin to the fetal bloodZss ZHC However, it has been demonstrated re— cently that the livers of incubating chiclcs contain glycogen at Ieast as early as the 7th day of incubation, although the pancreatic islands do not appear until the Iith day.3·3 In livers of pig and sheep fetuses, likewise, glycogen has been observed before the pancreatic islands are formed. Glycogen is distributed evenly throughout the chiclc liver after island tissue makes its appearance, but is conlined to the cells around large veins in earlier embryos. Nearly all livers show glycogen on the seventh, eighth and ninth days and again after thirteen days, but in the interven212 PHYSIOLOGY oF THE. FETUs
ing period fewer contain it. There is no detectable change in the blood-sugar concentration at this time of rapid glycolysis, even though the metabolic rate increases and the respiratory quotient approaches unity. These facts suggest very strongly a relative increase in utilization of carbohydrates as an energy source between the Ioth and izth days of incubation, and they indicate that the fetal liver supplies some of this material at this period during which endocrine functions of thyroid, suprarenal and pancreas are just becoming established. «
The passage of carbohydrate from mother to fetus is a s1ow process under normal conditions, but it can be accelerated greatly by injecting insulin into the fetus.37 When this was done it was found that the glycogen or total carbohydrate content of livers and muscles of dog fetuses was not infiuenced significantly However, the lactic acid concentration of the fetal blood was raised a few hours after insulin injection and the difference between its level in the umbilical artery and vein was increased many times above the normal. About three-fourths of the dextrose which passed from the dog to its fetuses to compensate for the experimental fetal insulin hypoglycemia returned to the mother as lactic acid.22 "
The fetal dog is reported to be highly resistant to insulin and the fetal sheep and goat scarcely respond at all to doses as great as 415 units per kilogram. An insulin antagonistic substance seems to be present in their blood.22- 23 Although insulin fails to deplete the fetal liver glycogen in dogs, sheep and goats when given to the fetuses, it·has been observed to do so in rats when injected into the mother-PS Adrenalectomy of pregnant rats simii lar1y leads to depletion of the fetal liver glycogenks Apparently the fetus practices a rigid glycogen economy at theexpense of its mother’s dextrose, drawing upon its own liver store only in emergencies.
Well nourished fetuses are supplied with good stores of fat. Do they acquire this by transfer through the placenta or must it be synthesized from simpler materials? Perhaps the fetus is able to synthesize some from carbohydrates or amino acids, but these are not the only sources. Certaimlipids are passed from the mother’s blood to that of the fetus by poorly understood mechanisms and thus become available for construction of fat. To what extent lipids are oxidized by the mammalian fetus for energy is not known. They form the principal source of energy in birds during the greater part of the period of incubationKo
It has been quite deiinitely determined that the fat which is fed to a pregnant animah and which is absorbed and stored in its tissues, does not pass through the placenta unchanged When stained by sudan III or some other similar dye before feeding, the body fat becomes intensely colored, but there is not the least color in the fetuses.39-4I Regardless of the degree of saturation of the fatty acids available from material fed to the mother, the fetal fat has an almost unalterable degree of saturation.42 It is quite different from that of the mother in respect to melting point and chemical composition, in that it contains much more palmitic and less oleic and stearic acids.43
Other lines of evidence suggest that there is no direct passage of lipids across the placenta! membranes. A marked difference in fatty acid content of maternal and fetal blood has been found.
The lipid content of red blood corpuscles is about the same in infant and adult. However, the blood plasma contained on the average 948 mg. per cent in the former and 737 mg. per cent in the latter in one series of estimations.44 Average values in another series of human newborn infants appear in Table 23345
Tut-D 23
Lusrv couposrrron or Gut-arm) Fuss«
kapu- Nswkom Isgsggskezkszks mg.Xl00 ce. mg.Xl00 Oe. »Ja« value« Tom! lipids ........... .. 589 -i- 87 198 -s- 80 84 Neutral fat . . . . . . . . . . . . . 154 - 42 90 - 50 58 Tom! kam— acids ...... .. 353 -i- 56 140 - 57 40 Totul eholesteroL . . . : . . . 162 -I- 32 84 -l- 15 2l» Bster eholesterol . . . . . . . . 115 -I- 27 A) -s- 12 l7 Iüsee eholesterol . . . . . . . . . 47 -I- 7 14 -s- 7 80 Phospholipid . . . . . . . . . . . . 196 -l- 23 6l- -I- 32 31
0n the other band, the blood passing to the fetus from the placenta is richer in certain lipids than that returning from the fetusKC The difference must represent lipids used or stored by the growing fetus. Averages of 15 analyses are given in Table 24310 Tut-n 24 Lan) contes-im« or« Ema-m Unten-Iehr- conv Bnoov
Artery Vein
Ins! 100 Oe. mgjlllll ee. Phospholipid . . . . . . . . . . . . . . . . . . . . . . . . 16«0 204 Free cholesterol . . . . . . . . . . . . . . . . . . . . . . 55 64 Ester cholesterol . . . . . . . . . . . . . . . . . . . . . 8 18
Neutral kat . . . . . . . . . . . . . . . . · . . . . . . . . 116 121
Phospholipids are always talcen up in large amounts, and smaller amounts of free cholesterol may be absorbed by the human placenta. cholesterol esters pass to the fetus when they are present in sulficient quantities in the mother’s blood. Neutral fats have been thought to pass in both directions. Lipids continue to be added to the static placental blood by the placenta after birth of the child. Without malcing a positive statement concerning the mechanism involved, it may be said that a significant passage of lipids across the placental barrier takes place in the human near term. It has been estimated that a well nourished fetus takes up about 50 grams of lipids a day at full term, 40 grams of which are in the form of phospholipids.
The lipid eempesikieh ek khe pieeehkä and kekus ek the kahhik at various stages in gestation has been reported« The phospho— lipid and free cholesterol concentration increase rapidly in the fetus up to the middle of gestation and then more slowly until about the final weelc at which time the rate increases again. Up to the middle of gestation, the placental concentration of« phos— pholipid decreases while that of ester cholesterol increases. Beyond the midpoint in gestation, the reverse was found. slight increases in neutral fat and free cholesterol were encountered in the placenta throughout gestation. The results suggest that there is a greater demand for phospholipid by the fetus than can be met by the placenta in the middle of gestation. and a late secondary demand which is compensated near term by increased placental ability to supply it.
Large amounts of fatty acids are accumulated in the liver by the guinea pig fetus.48 Early irxgestation the liver contains about the same proportion as that of the adult, which is approximately 2 to 4 gramsx its liver fatty acid concentration is already increasing, and at a few days before birth (8o grams weight) the value reaches 15 grams per cent, while the mother’s liver shows no change. It drops again to the adult level within 3 or 4 days after birth.
The lipids of the fetal liver are much more unsaturated than those in other fetal tissues and less so than those of the mother’s liverfs 0ne wonders whether the fetal liver is endowed with greater ability to desaturate fatty acids than is the mother’s liver or if it simply receives already desaturated acids from the plaöenta. The latter seems the more likely, and for the following reasons.
When the pregnant animals were fasted and then given phloridzin it was found that the fetal liver storage of fatty acids was increased in the early period of gestation (fetuses weighing 30 grams and less) , but no signiticant change occurred in the maternal liver with the dosage used. Furthermore, the fatty acid was less unsaturated than normal, as would be expected under influence of phloridzin with Inobilization of the connective tissue fat to the liver. Evidently the fatty acid in the fetal liver, norma1ly encountered, is not transported from the other fetal tissues but comes from the placenta.
Evidence has been presented recently that esterification of cholesterol by fatty acids takes place in the liver cells of the chick embryofk Histochemical tests indicated the presence of free cholesterol, ester cholesteroland cholesterol-fatty acid mixtures in the liver on the e1eventh day; but in chorio-allantoic grafts of the liver, in which the host was several days older than the graft, these substances appeared during the latter part of the seventh day. It is evident, therefore, that the fetal liver is prepared for its röle in lipid metabolism some time in advance of the day it actually begins to work.
METABOLISM OF PROTEIN
A great deal of information has been obtained in recent years regarding the metabolism of proteins in bird fetusesEo but we still know little about this process in mammals. There are three principal methods for approaching the question. The chemical composition of maternal and fetal blood can be compared, the composition of the embryo itself at different stages of development can be determined, and Hnally the initrogenous waste prod216 Ptivsxotocv oF THE FErUs
ucts of combustion in the fetus can be analyzed. We shall ex— amine evidence obtained in these ways.
Food proteins are digested and brolcen down into amino acids which are absorbed into the mother’s blood. These are used, not only for tissue metabolism of the mother’s own body, but they serve as a readily available material out of which the fetus builds its tissues. Some of the nitrogenous food material together with nitrogenous waste products can be determined analytically as the non-protein nitrogen of the fetal blood. It has been found that non-protein nitrogen concentration of maternal and fetal blood is practically identicaIZU This suggests that the compounds in question pass through the placenta by simple diffusion.
Amino acids of use to the fetus are relatively simple nitrogi enous compounds which are soluble in the blood p1asma, and it is known that they are highly ditkusible The human fetal plasma at term contains about 2 mg. of amino-acid nitrogen per Ioo cc. more than does that of its mother. In one 8 month premature infant the dilkerence was greater. This makes it seem probable that simple physical processes are not the only mechanisms involved in the passage of amino acids through the« placenta.
In the case of the nitrogenous waste products, ammonia, urea, uric acid and creatinine, the concentration in the two blood streams is almost identical and they probably pass from fetus to mother by purely physical processes.44 Table 25 summarizes some of the data on human subjects.
, TAVLD 25
Armut-n cost-knister- ops Ntstsnoonuovs coupounvs m sum« Bnoov or« IIUUAN Mosknmis AND Fsskusns ask Fuhr« Tut-tu«
Motheks blood Fetal blood No. of
mg.XI00 cc. mgJ 100 cc.« cases Nonsprotein nitrogen . . . . . . . . . . . . . 25.2 24 . 9 85 Amino-acid nitrogen (plqsma) . . . . . . 5.5 7.4 10
7 . 2 II .9 I premature
Urea and ammonia . . . . . . . . . . . . . . . 10.5 I0. 4 16 Uric acid . . . . . . . . . . . . . . . . . . . . . . .. s. 8 8.7 IT creatinine (plasma) . . . . . . . . . . . . . .« I .67 I .75 I8 - I . 70 I . 78 12
Results of analysis of embryonic tissues throughout the course of gestation demonstrate that the pig. builds very largely with FETAL NUTRlTlcN AND METABOLISM 217
nitrogenous compounds during its early prenatal like. The total nitrogen content ok the body per unit of dry weight decreases gradually from the 6 mm. to the so mm. stage and then remains constant throughout the remaining portion ok the gestation period. The decrease may be related to an increase ok other nonnitrogenous solids such as carbohydrates, lipids and inorganic salts. At the so mm. stage, when total nitrogen becomes constant, the embryo may be said to have attained chemical maturityFo
Tut-ti- 26 Aventin Witten-r am) Pvacnivsrhen contain« or· Wann, Ast! am) Nrsraoonu n: PreKarosse« l Embryo Ash Nitrogen Weiter« Lenglzh Weight P« com; Wes; Dry Wet Dry Ashckree mm. ging. per cent per eent per eent per eent per eent 24 . . . . . . . . . . . . . . 97 .4 . . . . . . . . . . . . . . . . . . . . . . . . .
647 . . . . . . .. 0 81 94.07 . . . . . . . . ·. 0 699 18 18
l0 . . . . . . . . 0 50 98.87 0 558 8.48 0 861 12 99 14 18
15 . . . . . . . . 0 98 91.88 0 775 9.00 l 061 12 81 18 52
R) . . . . . . . . 2 21 91.14 0 708 8.00 l 108 12 45 18 58
50 . . . . . . . . 6 55 91.65 l 086 12.41 0 910 10 91 12 45
60 . . . . . . .. 014 85 91.05 . . . . . . . . .. 0 966 l0 80
80 . . . . . . .. 26 00 91.59 . . . . . . . . .. 0 915 10 88
100 . . . . . . ·. 722 t 91.l8 . . . . . . . . .. 095 1078
110 . . . . . . .. 82 2 91.02 l so 14.50 0 972 10 82 12 65
120 . . . . . . .. 962 91.26 . . . . . . . . .. 0950 1087
160 . . . . . . .. 288 57 91.71 l 849 i 16.28 0 891 l0 75 12 84
200 . . . . . . .. 488 0 90.84 . . . . . . . . .. l 014 10 50
240 . . . . . . . . 725 0 88.7 2 58 2309 l 288 11 01 14 29
Interesting changes in the various kractions ok the total nitrogen have been observed. No signiiicant variation was apparent in amide, humin and cystine nitrogen but amino nitrogen concentration was increased and that ok the non-amino nitrogen decreased correspondingly during the early stages. There was a kall in arginine and histidine nitrogen and a deiinite rise in lysine nitrogen before the 30 mm. steige. Tyrosine showed a gradual decline throughout development. Glutathione, which is thought to aid in synthesis ok proteins, increased sharply until 30 mm. had been reached, after which it gradually decreased. Reciprocal ontogenetic variations in the nitrogenous substances arginine, histidine and lysine have been compared with somewhat similar 218 PHYsIoLocY oF THE FETUS
phylogenetic variationsPfs E! They may be correlated to some ex— tent with observations on tumor tissues, from which it appears that the younger types of neoplasms have the greater content of arg1n1ne.
Many attempts to study nitrogenous excretion in 1namma1ian fetuses have been made without notable success. It is impossible to account for all the nitrogen excretion because the greater part is passed through the placenta, dissipated in the mother’s blood and removed by her kidneys. some, but only a small part, is excreted by the fetal mesonephros and metanephros (see Chapter VI1l) and passed into the allantoic and amniotic fluids which can be recovered for analysis.
The urea content, in milligrams per ioo grams of human embryo, has been estimated to decrease as the gestation period advancesLo The amount of nitrogen per gram of fetus which is excreted into the fetal fluid of the ruminating mammals is lilcewise high in ear1y prenatal life, but decreases sharply and then remains at a low level throughout the greater part of gestationFfs I» A much clearer picture of nitrogenous metabolism of the embryo has been obtained from studies in the chiclc. There. a closed system makes it possible to obtain all the nitrogenous wastes which- accumulate in the allantoic sac.59-10 Uric acid begins to collect in the allantois on the iifth day of incubation. The chiclc makes eflicient use of the available protein, for about 96 per cent of that absorbed from the egg by the embryo during the first 13 days of incubation is retained in the embryonic tissues. Some protein is burned by the chiclcz in fact about« 6 per cent of all organic matter used for energy during the first two weelcs of incubation is protein.
0ne of the most interesting aspects of fetal protein metabolism is its comparative embryologysw Protein materials are used for energy in much greater amounts by embryos with an aquatic habitat than by those which are terrestrial. We may classify mammalian embryos in the aquatic group with those of ftshes, amphibians and many invertebrates, for they pour out their ex— cretions through the placenta into the limitless aqueous environment of the mother’s blood stream and l(idneys. The terrestrial group includes birds, some reptiles (e.g., lizards, snakes) , arthro— pods (e.g., insects) and molluslcs (e.g., land snails) . Aquatic embryos excrete nitrogen principally in« the— forth of ammonia and FETAL NUTRITION AND METABOLISM 219
urea which are very so1ub1e and diffusible end-products and require excessive use of water for their e1imination. From a teleo1ogical viewpoint, one may say that the terrestrial forms must conserve water and consequently have had to devise other methods of excreting nitrogen. Uric acid is the end-product in these embryos. If birds had retained urea excretion instead of resorting to uric acid, and if they had to store it all, their tissues would soon become high1y saturated with urea because this substance can dilfuse through the allantois into the body whereas uric acid is retained, concentrated and precipitated within the allantoic sac as the water is being absorbed and utilized. In their early development birds recapitulate aquatic stages in respect to their protein metabolism. During the first 5 days of incubation ammonia and urea are excreted, but on the lifth day a shift is made to uric acid and the embryo is thus spared a uremic fate.
Inorganic Metabolism
It is known that copper is stored in the human Iiver and its concentration and absolute amount is higher there at birth than at any subsequent time. Its concentration is greater at birth than at earlier prenata1 periods.34 copper is essential for hemoglobin synthesis and its mobilization in the fetal liver is thought to assure normal blood formation in the postnata1 nursing period during which the diet is delicient in this element. In contrast to conditions in man it has been reported that the late fetal pig liver shows no increase in percentage of copper as growth proceedsPsH The copper reserve of the liver is unusually low in the goat at birthFS In the incubating chick too the percentage of copper in the liver declines from the 12th day to hatching, although there is an increase in the actual amount present in the liver throughout» The difference between pig, goat and chick on the one hand and man on the other may be explained ,on the basis of placental permeability. The chiclc must utilize what store it has in the egg, the pig and goat get their copper from the histotrophe, but man, having a true placenta in which contact between maternal and fetal blood streams is intimate, may be able to draw heavily upon maternal stores.
It has been suggested that catabolism of maternal hemoglobin talces place in the human placenta to supply the pigment fraction of the hemoglobin molecule intact to the fetal circulationKs The iron content of the human placenta gradually increases during development.59 Iron is stored in« the liver during fetal life and for about two months after birth during which time there is an active physiologic postnatal hemolysis. Thereafter it declines in amount until the nursing period has passed.s4 Iron is excreted in the bile but is absorbed again in the fetal intestines.«4 As is true of copper, the iron reserve of the goat is low at birth," and the percentage concentration of iron declines in the liver of the incubating chicl(.37 The ratio of copper to iron in the chiclc’s tissues, other than the liver, stays constant throughout incubation. Nonhematin iron in the tissues is small. The metals are utilized and not stored in such large quantities in the liver for postnatal use as they are in the human fetus.
The efkect on fetal rats of iron deficient diets fed to the mothers has been investigated recently.·3«0- S! The first pregnancy brought on marked depletion of maternal liver iron but there was no anemia; with the advent of a second pregnancy an anemia did appear. The first litter of rat pups had normal hemoglobin values, but a reduction in total iron content of the entire body by about one-half the normal was evident. The second litter exhibited a reduction of the hemoglobin of the blood and the total iron content was only one-fourth normal. studies in the human« reveal that iron deficiency of the fetus may be related to that of the mother. Infants which are born of anemic mothers may exhibit hypochromic anemia during the first year. The normal full term infant has a good reserve of liver iron which is probably fully as important to it as the iron it may salvage from catabolism of its excess hemoglobin during the early postnatal period. If it were not for this fact, the human infant would probably exhibit more symptoms than it does when deprived of placental blood by the commonly practiced prompt c1amping of the umbilical cord at birth.
A large series of chemical analyses of human fetuses has been summarized recently by swanson and Iob.02 content of nitrogen, calcium, iron and phosphorus throughout the greater part of prenatal life is illustrated in Fig. 69. The retention of these materials shows a similar pattern of gradually increasing quantities. The results indicate that there, can— be lit·kle··demand upon the mother’s reserve of the elements in question during the first halk ok presnancy. In kact it is not Juntil the last two or three months ok gestation that the ketal requirements become large.
« zoo M
PHOSPHORUS 2»L
s o 34587690345670910 Dom-r« »oui«-ZFig. 69.- tent ok nitrogen, iu1n,iron and phospho ok the hutnan ketus
between the « c! th and bitt . (swanson sc lob: Am. . bst. sc. cyn., Vol. 38,
1939. c. V. Mosby .
Fig. 7o.-E.tk ok changes in the cliet ok pregnant rats on calciu ncl phoss phorus content o eolksprinz (swanson Z: lob: Arn. J. Obs . sc Gynsp . 38, 1939, c. V. Mosby co.)
calcium and phosphorus are concerned in building skeletal structures. Their content in the ketus is iniiuenced by vitamin D in the mother’s diet and apparently by the amount ok exposure to sunlight.s«4 The eEects ok changing the diet ok pregnant rats in respect to vitamin D are illustrated in Fig. 7o. When the mother’s diet, fortiiied by vitamin D, is low in the required minerals the calcium and phosphorus content ok the ketal body approaches the normal level, but when the diet has in it the required amounts ok the minerals plus the vitamins the ketal calcium and phosphorus content exceeds the normal. Thus the ketal metabolism ok calcium and phosphorus is dependent upon that ok the mother and the transmission 'ok these substances to the ketus can be increased by vitamin D adminis·tration. In the human subject occurrence ok early congenital riclcets is illustrative ok maternal deiicienciesXE
Metabolism ok inorganic substances other than those we have already considered has been studied less eictensively. The most. marked changes in all inorganic compounds are encountered in the kourth lunar month in man. Bekore that time the ketus contains relatively little chlorine, potassium, sodium and magnesium, but these elements show a marked increase at the kourth monthFs
Energy Metabolism
Oxygen consumption in the ketus has been studied in various species and by various methods. The most signikicant data relative to amount and rateok utilization have been obtained in the incubating chiclc and in the sheep ketus. The amounts ok oxygen used and ok carbon dioxide given oE by the incubating chicl(·increase in proportion to growth in size ok the embryo. At six days ok incubation oxygen is consumed by the embryo (exclusive ok its membranes) at the rate ok o.o2 cc.Jgrn.Jmin. This rate de— clines as growth proceeds and by the nineteenth day reaches o.oi34 ccJgrnJminFC Barcrokt and his colleagueswi have estimated the rate ok oxygen consumption in the sheep ketus recently by a direct method. They obtained samples ok ketal blood at timed intervals akter occludingthei umbilica1 cord and determined FETAL NUTRITION AND METABOLISM 223
its oxygen content. In this way they observed the loss of oxygen in respect to time and could calculate its utilization per gram ok the ketal tissue without the complicating kactors ok the placenta and ketal rnembranes. Their data appear in Table 27. It will
Tat-m 27 Oxford: conswrrtorc m sauer« Ferner-s
Oxygen eonsumption
Fetal age Fetal weight days grams cc.-mirs. cc.Xgm.Xtain. III . . . . . . . . . . . . . . . . . . ·. I,200 4.6 0.0038
126 . . . . . . . . . . . . . . . . . . . .I 8,000 I2·s 0.004I
127 . . . . . . . . . . . . . . . . . . . . 2850 II .2 0. 0089
129 . . . . . . . . . . . . . . . . . . 2750 SZL 0.008I·«
Is7 . . . . . . . . . . . . . . . . . . . . 8,850 20.0 00052
138 . . . . . . . . . . . . . . . . . . . .k FOR) I5.5 0.0042
152 . . . . . . . . . . . . . . . . . . . . 2800 I6.4s 0.0048·«
’«'Authors’ values; errors present but souree unless-wo.
be seen that, although the total amount ok oxygen consumed each minute rises sharply at the beginning ok the last quarter ok gestation, the rate ok utilization remains nearly constant throughout the period studied and averages o.oo43 cc.xgrn.jmin. (excepting the 129 day ketus) . This is a higher value than was obtained in earlier less satiskactory experiments in the Cambridge laboratoryss and by other investigators who have used indirect methods o»k estimation. The oxygen consumption ok human ketuses at terms bekore labor starts has been estimated to be 1.25 ccJkiloJminO
The ratio ok the amount ok carbon dioxide given olk to that ok cc. carbon dioxide
cc. oxygen embryos ok several species. This, the respiratory quotient, varies signiHcantly in the chiclc. Most deterrninations during the Hrst tive days ok incubation have given values in excess ok o.7, some ok them approaching unity. In vitro experiments on the iive day chiclc have demonstrated that the quotient is 1.o at this time« Between the sixth and ninth days ok incubation the respiratory quotient declines to approximately o.7, but it rises again toward unity between the tenth and thirteenth days. These fluc oxygen consumed ( ) has been determined in tuations have been taken to signify that the embryo utilizes carbohydrates almost exclusively for combustion up to five days, burns proteins very largely for the next few days and after the tenth day of incubation resorts to combustion of fat supplemented by rather large quantities of carbohydrateJo It should .be pointed out that in the chiclc, which excretes uric acid instead of urea after the lifth day, a respiratory quotient of o.7 rather than o.8 should be expected during combustion of proteins. For more detailed information, the reader should refer to original articlesJos W- ««
The respiratory quotient of guinea pig fetuses has been determined74 by direct measurement of the oxygen consumption and carbon dioxide evolution of the mother and her fetuses in utero before and after occluding the umbilical cords. Quotients of o.9 to 1.2 were obtained for the fetuses in most instances, and o.7 to o.9 in the mother. Coniirmatory results have been obtained by others« in experiments using whole rat embryos in vitro (mean R. O. .—.—. I.o4) . Respiratory quotients of this nature indicate that mammalian fetuses consume carbohydrates almost exclusively in their energy metabolism.
Many investigators have studied metabolism during pregnancy. especially in man, by indirect calorimetric methods.10 Mur1in75 observed a dog during two consecutive pregnancies, one pup being produced at the lirst and live pups at the second birth. An in— crease in caloric energy production due to the single fetus could be detected at the sixth weelcz it amounted to 9 per cent between the sixth and eighth weelcs. The total energy produced at full term was proportional to’ the weight of the offspring and was about equal to that required by the newborn pups (when calculated according to the law of slcin area·) . It amounted to 16.4 gm. cal.J1oo gar. in the single pregnancy and 16.8 gm. cahxioo gar. in the multiple pregnancy. The curve of total energy production of the dog and her pups showed no deflection at birth. The number of calories formed by the resting pregnant dog plus fetuses, placentas and membranes was very much the same as the sum of that produced after delivery by the lactating dog and her resting pups.
In the human not all investigators have found relationships quite so simple as those occurring in Mur1in’s experiments in the dog. some« have reported that excessive heat production in pregnancy results from some factors other than those of fetal growth. 0thers"- 78 have been able to account for all of the ex— cess on the basis of fetal heat production, fmding that the energy produced by the woman plus her fetus and its accessory structures at full term is equal to that produced by the lactating woman and the infant after birth. Recently, Enright and her associatessp reported that a greater post-partum drop in energy metabolism than is accountable on the basis of that produced by the fetus alone occurs in i 5-year-old females, amounting to about three times the probable basal energy requirements of infants. They concluded that in pregnant adolescents there appears to be some factor stimulating metabolism which results in a greater rise than occurs in more mature women. They suggested that this excessive energy production of immature -girls may be related to thyroid function, and have presented some evidence that feeding iodized salt diminished the rise in metabolism during pregnancy.
One point which has not been emphasized is worth consideration. The fetus in utero is quiescent and hypotonic whereas the newborn infant is active and its muscles possess good tonus. If the energy produced by the newborn is commensurately greater than that of the full term apneic, hypotonic, quiescent fetus use will have to conclude that more energy is produced by the woman (plus the accessory fetal structures but minus the fetus) than is produced by the post—partum lactating woman. The alternative assumption is that basal requirements of the hypotonic fetus are fully as great as in the newborn infant, and this seems unreason— able.
The various calorimetric studies suggest that the fetal metabolic rate remains fairly constant throughout the latter part of gestation, but during the early period while the embryo is very small no data are available« Postnatally the rate rises and reaches a pealc at about the Erst or second year in the human. similar postnatal pealcs have been observed in other animals such as the rabbit, mouse and some breeds of pigz others, notably the guinea pig, show an already declining metabolic rate at birth. These facts may be related to the maturity of the heat regulating mechanisms in the different species (see chapter VIII) . They suggest
«« Oxygen consumption of mammalian eggs during the one— to eights cell stages ainounts to o.ooo7z c.mm. per egg per hour. When gkowth in size begins the oxygen oonsumption increasesz on the eighth day of gestation in the rat it amounts to about «o.o1 c.mm. per hour. This increases to about o.2 drum. in the next two days that the metabo1ic rate may in rea1ity be increasing to some ex— tent throughout prenatal like in man and in the other animals with a postnatal pealc ok heat production and may have begun to decline in the others before birth.
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