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Windle WF. Physiology of the Fetus. (1940) Saunders, Philadelphia.

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Chapter XII Fetal Motor Reactions and Reflexes

MANY provisions are made during intrauterine like to assure survival akter birth. A number ok these depend upon development of the ketal nervous system. 0ne function ok vital im— portance to all species is respiration and this has been emphasized by separate consideration in another chapter. 0ther kundamental activities involving the somatic motor mechanisms ok the body are sucking and swallowing which are well developed in all mammals at birth, crying which is encountered in most ok them, and locomotion which occurs to a variable extent. ln addition to these instinctive motor reactions, a number ok reflexes which some have thought ok as purposekul or protective have their genesis during prenatal like. The amount of kunctional independence at— tained within the uterus depends upon the degree ok matssdtion reached in the nervous system and varies within wide limits.

DEVELOPUENT OF FEEDING RBÄCTIONS

Coordinated movements ok suclcing and swallowing are kully kormed in viable premature human inkants, and may be seen in the common laboratory animals considerably before birth. In— deed, suclcing appears to be one ok the kew reactions endowing the tiny newborn opossumKs 2 Feeding reactions may be said to begin with the iirst movements ok the jaw.3- 4 Opening and closing ok the mouth appear -in cat fetuses only about 25 mm. long, roughly comparable with the 9 weelcs human. The tongue can be protruded almost this early but its sides do not. curl until several days later. similar observations have been made in guinea pigss and sheepäs In the latter species, closure ok the jaws is the only response obtained by touching the tongue between the 41st and 49th days ok gestation. Throat movements occurring in briek rhythms follow jaw closure at 49 days. The tongue ok the fetal sheep curls at about 70 days. These early simple activities are the korerunners ok a number ok more complex movements whose

173 174 PHYSIOLOGY OF THE« FETUS

integration ultimately accomplish suclcing, chewing and biting in the cat, sheep and guinea pig. The early components of the feeding reacti0n have not been thoroughly studied in human fetuses but lip movements which may be related to suclcing have been seen at about 1o weelcs and later.7- Es 9

True suclcing is rhythmical in the cat and involves a coordins ation or integration of tongue, lip, jaw and throat movements. Furthermore, alternate forward thrusts of the limbs and side to side head movements enter into the feeding reaction to a remarlcable extent in the newborn kirren. However, the rhythrnical suclcing of the fetus is accomplished without participation of the limbs until late in the fetal period. Coronios4 observed pursing of the lips around the tip of a glass stimulator in specimens 43 mm. long, and at 54 mm. the first deftnite sucking coordinated with head and forelimb movements was encountered. The response continues to improve and appears to be fully developed and vigorous at least one weelc before birth of the lcitten.

The actual contractions of muscles which occur in swallowing are diiIicult to observe and can be seen only in late fetuses. These movements have been reported in sheep of so days gestation and we have seen them in the human fetus at 14 weelcs. Undoubtedly they occur even earlie»1·. When the abdominal wall of a cat fetus 25 to zo mm. long is opened the stomach may be seen to be well lilled with iluid. In specimens a little larger, brought out into the air, bubbles soon appear in this Organ. This early fetal swallowing of the cat is in no way remarlcable when a comparison is made wich ehe aik-hkeekhihg, suekihz 23 day «emhkye" ek khe opossum. »

swallowing of amniotic lluid does not seem to occur under perfectly normal physio1ogic conditions in the fetal guinea pig until about the 42nd day of gestation. This has been demonstrated by roentgenologic studiesso made after injecting thorotrast into the amniotic sac (see chapter VII) . The frequency of swallowing and the amount of iluid talcen into the fetal stomach increase with age. It may be concluded that the feeding mechan —ism, lilce that for respiration, has its genesis in the early part of the fetal period well in advance of the time it is normally called

into use. FETAL MOTOR RBACTIONS AND REFLEXES 175

DEVELOPMENT OF POSTURE AN D PROGRESSION

Mammalian locomotion is a complicated act requiring cooperation of many groups of muscles and exquisite integrative development within the Central nervous System. Nevertheless, it too has its genesis in ear1y prenatal life. Establishment of erect posture is prerequisite for wallcing. It involves the coming into action of righting reflexesz afkerent impulses for these arise in the slcin and muscles of the neclc and body, in the labyrinths and, for higher mammals including the cat, in the retina. Maintenance of erect posture requires the presence of static or postural tonus to establish the proper neurologic balance between flexor and extensor muscle groups in order that the force of gravity be successfully opposed. After these conditions have been met, progression becomes possible by alternately and rhythmically changing the balance in such a way that flexion-extension stepping movements of the limbs are performed. Developmentally, however, the various components of a locomotor reaction are not laid down in utero in the sequence just stated.3

1t is evident that alternation of trunlc movements is fairly well developed in the fetus before there is evidence of a postural mechanism. At the time bilateral flexion of the neclc and upper trunk can be induced in cat embryos less than 20 mm. long, the forelimbs move at the shoulders with the contractions of the trunlc muscles. No rhythmicity manifests itself in these bilateral trunk movements before the 25 to 28 mm. stage. Active, arrhythmic alternation of the forelimbs can be induced in 3o to 35 mm. fetuses with considerable regularityz in fact, crossed ex— tension responses begin to appear at 25 mm.

The bilateral trunk flexions, synchronized more or less pas— sively with the limbs, are forerunners of squirming movements. Early in development the resemblance between squirming and aquatic locomotion is rather strilcing At birth the lcitten utilizes side to side movements in its crawling-search reaction. The reflex crossed extension following active flexopwithdrawal of one forelimb foreshadows the act of steppi·ng. squirming and stepping are distinct from one another until the cat fetus has reached a length of about 50 mm., at which time the first integrated activity vaguely resembling the act of crawling can be seen. synchronized stepping movements of all fourjegs are not encountered 176 pnYsrohooY oF THE FETUs

before 8o mm.,I1 and even at birth the hind limbs are imperfectly coordinated with the forelimbsU Rhythmicity of forelimb stepping movements improves as the time of birth approaches. Kittens 95 to ioo mm. long delivered two weelcs prematurely manage to crawl very credibly.

Development of Progression difkers according to species in respect to late stages of developmenh but there is a surprising amount of similarity at Erst. 1t requires no great imagination to see a resemblance between the side to side head movements and coordinated forelimb activities by means of which the opossum

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Fig. 63.-Record of muscle tonus in a sheep fetus at 144 days gestation delivered at caesarean Section with placental circulation intact. In the Erst, third and iifth

records, the fetus lay quietly in a warm saline bath. In the second and fourth records it was lifted into the air and impulses began to flow to the muscle-s. (Bak croft: Irish Joutx Med. sei» 1935.)

«embryo" reaches the mother’s pouch at birth and the side to side necl(, trunlc and forelimb movements of the so mm. cat fetus. similar reactions have been observed in rat13- «« and guinea pig fetuses.5 The records are very incomplete in the human, but we have seen Hexor withdrawal of one leg accompanied by crossed extension of the opposite leg in 4o mm. specimens Rhythmicity of stepping has not been reported until much later in fetal life and even at birth behavior of a locomotor type is most ineffectuaL

Development of postural tonus has not been studied thorough1y. 1t is probable that muscle tone as we know it in the adult is not present at all in utero under nor-mal physiologic conditions. The FETAL Mosron KEACTIONS AND nEFLExEs 177

fact that rhythmical respiratory movements can occur toward the end of gestation without aspiration of a signiftcant amount of amniotic fluid demonstrates that the fetal chest is not held tonically in an elevated position which it must assume after birthLE The absence of afferent stimulation in utero is unquestionably an important factor in maintaining tonus at a low level. As illus— trated in Fig. 63, it was found that action potentials from fetal muscles appear when a fetus is lifted out of its warni saline bath and disappear again when it is returned to the bathJC The relation of anoxemia to thresholds of nervous activity and to tonus has been discussed in the preceding chapter.

How early in prenatal life postural tonus can be induced ex— perimentally is not deiinitely known, but an indication of it may be seen in cat fetuses about 50 mm. long. It was noticed that re » lease from their membranes was followed by straightening of the

back and extension of all limbs in such a way that they appeared to stretch. Full term birth posture, i.e., extension of the head and forelimbs," seem to be induced in part by a similar release of tension when the membranes burst. A factor in development of muscle tonus may be observed in the sustained fetal movements during anoxemia. sustained extensor movements are sometimes so marked in cat fetuses only 30 mm. long that they resemble the decerebrate condition.

Decerebration of cat fetuses results in hyperextension of the limbs during the last three weeks of prenatal life.3- IS 0ne or two weeks before birth deiinite decerebrate rigidity appears in the forelegs of specimens in which the brain has been cut through from the rostral border of the mesencephalon to the rostral border of the pons. When the level of the transection passes farther for— ward, leaving the region of the red« nucleus intact, decerebrate rigidity fails to appearRss IV Postural tonus can be called forth in the human fetus by decerebration20 and there too it seems to be more especially related to the midbrain and lower centers than to the higher parts of the nervous System. Decerebrate rigidity in the rabbit after birth is illustrated in« Fig. 64.

The mechanism by which the righting reaction evolves likewise has its development in the early fetus, but the actual accomplishment of righting has not been observed until after postural

«tonus and alternate stepping movements can be induced« Cat 178 PHYs1oLooY OF THE FETUs

fetuses 75 to 1oo mm. long try to hold their heads up and turn their jaws parallel to the ground when they are placed upon a Hat surface. The general impression gained is that they could right themselves save for the weakness of their muscles. Between 1oo and 1 Io mm., they are actually able to right the head in respect to the surface on which they 1ie, but they are completely disoriented when placed in warm water beyond their depth. No evidence of vestibular function was obtained in cat fetuses less than iio mm. in lengtlr Neither rotation of the specimens nor destruction of one or both labyrinths experimentally had any efkect before this time. It was concluded that the vestibular right Fig. 64.———l)ecerebrate rigidity in a young rabbiL The midbrajn was sectioned through the rostral border of the superior colliculus and rostral third of

the pons.

ing reflex appears about the 54th day of prenata1 life in the cat and that a body righting reklex precedes it by at least four days. The latter is activated by akferent impulses from the skin and deep tissues of the body and necl(. Visual impulses play no part in righting reactions until Some time after birth of the kitten whose eyes remain closed for several days. ln the newborn kitten the vestibular righting reflex is still incompletely developed.22 Development of a body righting reaction before the vestibular mechanism begins to function has been conHrmed in other species. In the sheep, which is more mature than the cat at birth and has a longer gestation period, righting is accomplished relatively ears FETAL MOTOR REACTIONS AND RBFLBXES 179

lier.3 0rientation in respect to gravity, seen in the opossum at the time of birth, which is long before the vestibular mechanism is functional, is an interesting related phenomenonks

In all animals in which fetal studies have been made, three components essential for locomotion—righting, postural tonus and alternate synchronous limb movements—have been developed by the time of birth. All three are present in some form well before the end of the gestation in most species, thus providing a factor of safety against the danger of premature interruption of

intrauterine life. DEVELOPMENT OF EYE REFLEXES

We have considered the prenatal development of motor mechanisms for respiration, feeding, posture and locomotion in some detail. 0ther equally interesting fetal activities could be studied profttably, but at the present time little is known about them. some observations on movements of the eyes and eyelids have been made but they are incomplete.

The eyeballs move behind closed lids in the fetuses of several species. such movements can be seen at the middle of the gesta— tion period in guinea pigss when the face is stimulated in the neighborhood of the eyes. somewhat later, postural changes elicit eye movements. Reactions to light appear during the third quarter of prenatal life. In the cat, eye movements in response to vestibular stimulation were not obtained before birth.« Most l(ittens 5 to 7 days old showed ocular nystagmus during and after stimulation of the labyrinthine afferents by rotation.

Contraction of the orbicularis oculi muscle can be elicited in cat and guinea pig fetuses at about the middle of the gestation period. The palpebral reflexes for protection of the eye have their genesis in these movements and are well developed in late fetal life, as can be determined by opening the eye experimentally and stimulating the cornea. Contraction of the human orbicularis oculi was seen at about 12 weelcs (4o mm.) when the eye region was touched.

Very little is known about the early development of light reflexes. The iris of guinea pig fetuses contracts in response to light early in the last third of prenatal life. The visual mechanism of this animal is more advanced than that of the cat or man at birth. 180 pnvstohoov oF THE: Fnrus

DEVELOPMENT OF PALMAR AND PLANTAR REFLEXES

several investigatorsUss 28 have studied the movements of the digits of the hand which ente·r into the prehension reaction of the fetus. These constitute the palmar or grasp reflex. HoolcerV observed Hexion of the iingers but not the thumb when the palm of a human fetus of 11 weelcs was touched, and it may occur even earlier. At 12 weelcs the. fetus formed a true list by flexing the thumb and fingers. Later, around 16 weelcs, when the iingers were held in a flexed posture stimulation of the palm brought about tightening of the iingerss Thumb movements were never as marked as those of the iingers and apposition of the thumb did not occur until after birth. Eikective sustained gripping of objects with the lingers began to manifest itself around 18 weelcs but even at 25 weelcs it was not strong. The grasp reflex appears to have two componentst iinger closure and gripping

The genesis of the human plantar reflex has interested many because of its practical importance in neurologic diagnosis. Although several have studied it in prenatal life,25-29 Minlcows slci’s7s S« 30 observations have been the most complete. spontaneous dorsal ilexion of the great toe characterized the early fetal period. No responses to stimulating the sole of the foot were obtained before Io weelcsz at this time one specimen exhibited a plantar flexion of the foot right after delivery. This was of very brief duration and when it was no longer elicitable, due to progressive asphyxiation of the specimen, only direct muscle responses could be obtained.

In fetuses of 1 1 to« 15 weelcs gestation, stimulating the sole of the foot sometimes produced dorsal flexion of the foot or of the great toe with spreading of the others. These responses, which constitute the Babinski phenornenon, were obtainable only when local anesthesia had been used and in the first few minutes of the observations. General anesthesia and progkessive asphyxia led to an inversion of the response, in which the same type of stimulus brought about plantar instead of dorsal Hexion. section of the cervica1 spinal cord or brain stem did not alter the plantar re— flexesz they could be observed for longer periods before they changed from the dorsal to the ventral type of response. There was only slight indication that higher centers participated in the dorsal form of plantar reflext before— 6 months gestation. FETAL MOTOR REAcTIONs AND REFLEXES 181

Minlcowslcis named the earIy period up to i6o mm. C. H. length the neuromuscular stagez the period between 160 and i8o mm. he called the spinal stagez the period between 190 and 270 mm., the tegmento-spinal stagez and the remainder up to birth,

the pal1ido—cerebello-teg-inentosspinal stage. These divisions were»

set somewhat arbitrarily, for the number of observations was limited and the physiologic conditions of specimens varied to a great extent. The phenomenon of inversion of the response has been discussed in chapter XI. The subject of plantar responses of infants and young children has been thoroughly reviewed recemiy by Richakds and Ikwixxss «

OTHER REFLEXES

Throughout the literature, mention has been made of many other reactions and reflexes not only in experimental animals but also in human fetusesF For the most part, the course of development of the slcin, tendon, deep neclc and other reflexes has not been followed completelsy and these activities do not Iend themselves to signiücant discussion for this reason. Here are Helds which future investigations may be expected to explore very proütably.

REFERENCES CJITED

i. Hartman, c. G. i9eo. Anat. Ren, i9: e5i. e. Mccradzz E. i938. The Embryology of the Opossunn Wistar Press, Philadelphia

. Windle, W. F. sc A. M. Griklin igzn J. comp. Neur., se: i49.

. Coronios, J. D. i933. Genetic PsychoL Monog., i4: e83.

. carmichaeh L. i934. Ibid., i6: 337.

. Barcrofn J. sc D. I-I. Bari-on. i93g. J. comp. Neur., 7o: 477. Minlcowskh M. i9ee. sehr-v. med. Wchnschn, se: 7ei, 75i. Minkowskh M. i938. Abderhaldecks I-Iandb. biol. Arbeitsmetlk Abt.

V, Teil 5 B: zu. g. Hooken D. i936. Yale J. Biol. sc Med., s: 579. o. Becken R. F., W. F. Windle, E. E. Barth sc M. D. Schule. i94o. sur-g. Gyn. sc Obst., 7o: sog.

ii. Brown, T. G. i9i5. J. Physiol» 49: Los.

te. Tilney, F. sc L. casamajon i9e4. Arch. Neur. sc Psychjat., ie: i.

i Z. swenson, E. A. i9e6. Thesis, Unin Kam.

i4. Angulo y Gonzalen A. W. i93e. J. comp. Neur., 55: 395.

i z. I-Ienderson, Y. i938. Adventures in Respiration, Williams sc Willcins,

Baltimore. is. Barcroln J. i935. Irish J. Med. sei» series 7, i: e89. i7f Rudolpln L. sc A. c. 1vy. i933. Am. J. Obst. Gyn., es: 74.

Pf« EVEN«

l 182 PHYsmLooY oF THE. FETUs

18. Windle, W. F. 1929. J. comp. Neun, 48: 227.

19. Langworthzz 0. R. 19291 Contrilx Emb., so: 127.

so. Minlcowslcjs M. I921. Ren Neun, igsu I1o5, I235.

tu. Winde, W. F. Z: M. W. Fish. 1932 J. comp. Neun, 54: 85.

u. Gen-Michael, L. i934. Genetic Psychoh 44: 453.

as. Larsell, 0., E. Mccrady s: A. A. Zimmermann. 1935. J. Comp. Neun, 632 os 24. Fish, M. W. s: W. F. Winde. 1932. J. Comp. Neun, 54: 1o3.

es. Bot-cito, M. sc G. Artom. 1924. Ast-eh. di sei. Bio1., z: 457.

es. I-Iool(et, D. i938. Proc. Am. PhiL soc» 79: 597.

27. Krabbe, K. «1912. Rest. Neuro1.. 24: 434.

as. Bersoh I-I. 192i. sehn« Arclx Neun Z: Psychiat., s: 47.

29. I-Ioo1:er, D. 1939. Atlas ok Early Human Fetal Behavior (Pkivate1y Printed).

so. Minkowslch M. 1926. c. R. cong. Med. Alienistes Neurologistes Geneve so: got.

31. Richards T. W. Z: O. c. Irwin. 1935. Unisn Iowa stud. child Welkare, u (No. 1): I. « CHAPTER XIII

THE FETAL sENsEs

IN discussing sensory mechanisms before birth the be1ief is not implied that the fetus is consciously aware of any sensation either in utero or after removal. Interest lies solely in whether or not the various endiorgans and afkerent neurons can function before birth. This is determinable by observation of the reflex motor effects of stimuli of different kinds applied to the fetus. It is seldom possible to be certain of the nature of neurons stimu1ated. Whether they conduct painful or tactile atkerent impulses, or even whether exteroceptive or proprioceptive, following a given stimulus is usually undeterminable.

Almost everyone who has studied fetal movements has contributed information to this subject, but it is impossible to evaluate and coordinate all the data. We are faced in most in— stances with the task of trying to synthesize experiments performed under good and bad conditions to arrive at some lmowledge of the- subject. No one would thinlc of accepting results in adult physiology of sense org-ans obtained in animals under narcosis and asphyxia Yet that is the lcind of data predominating in respect to the fetus.

It would seem that variations among species as well as in animals of the same species by different investigators are explainable td a very great extent on the basis of experimental methods used to study fetuses. When specimens are examined without using a general anesthetic and when they are exposed very quickly it is found that they are excitable by much milder forms of stimuli than must be used a minute or so later when anoxemia has begun to afkect them.I Furthermore, grossly undetectab1e deterioration of the physio1ogic condition of fetuses after delivery, even when the placental circulation remains intact, aEects some sensory nerves more than others and appears to alter synaptic mechanisms in such a way that motor responses change their Character. These efkects are especially well illustrated in human fetuses at hyster 183 184 PHYsmLooY oF THE: FETUs

otomy performed under local anesthesia. The human fetus of the third and fourth monthsslies quietly within its crystal clear amnion. A very little pressure, such as follows tapping the membrane lightly, causes it to malce quiclc jerlcy movements of arms, legs and other parts. When the stimulus stops, the movements stop. 0n the other hand, when the placenta is detached and the fetus removed from its membranes it· executes «spontaneous" squirming movements which are more sustained and tonic than those seen at first. Fewer slcin regions are sensitive to the lighter forms of stimulation than was the case in amnio. Excitability diminishes rapidly. Most human fetuses have been studied after removal from the uterus2s Z« 4 and it was only recently that the opportunity arose to observe them at the moment of delivery while the placenta was intact and before the amnion was rupturedP consequently our lcnowledge of sensation in human fetuses is still very incomplete. ·

THE FETAL sKIN As A RECBPTOR ORGAN

(a) Pnsssunx Touckt Am) Pan(

Motor function precedes sensibility.·3—8 1n mammalian embryos it is always possible to obtain contractions of slceletal muscles by stimulating them directly before any of the sensory neurons can be activated. spontaneous movements of the chick embryo occur in advance of the reactions which follow stimulating the surface of the body,9- 10 but this is not the case in mammals.

The superlicial epithelium with its underlying mesenchymal connective tissue serves as a receptor organ in early fetal life. Nerves course beneath the epithelium and end under it in primitive free terminations before any reflexes can be elicited in mammalian embryos.1I-I2 They appear in the face and forelimbs before they can be seen in the hind limbs and tail. Reflex responses follow stimulating them in cat embryos about 14 mm. long, Ibut the stimuli must be somewhat stronger at that time than later. Mild faradic shoclcs call forth responses before it is possible to obtain them by touching the epithelium with a single hair or a soft brush. A little later, in specimens about 15 mm. or 16 mm. long, touching with a single hair often serves adequately, providing the stimulus is placed directly over a spot supplied by primitive afkerent nerve übers. stimulation with a little brush THE FETAL sENsEs 185

made up of soft hairs is more often effective than a single punctate stimu1us,7-8-13-I4 because there is greater chance of pressing upon one of the sparse endings with it.

It is relatively easier to lind reflexogenous spots upon the face than upon the limbs. Furthermore, -responses to stimulating endings in the forelimb disappear before those from the face, under the influence of progressive anoxemiaJ Consequently, the failure to elicit fetal movements by punctate stimulation of the epithelium of a limb does not prove the absence of a response-producing mechanism in the limb unless careful consideration is given to experimental conditions.

With further growth the number of nerve endings in the con— nective tissue beneath the epithelium increases and the Ebers begin to penetrate the epithelium itself. It becomes progressively easier to lind points whose stimulation elicits motor responses. Development proceeds in a cephalo-caudal direction in the body and proximodistally in the limbs. 0n the other band, rising thresholds, either in the endings themselves or in the central nervous System, soon bring about a condition of diminishing excitability of many cutaneous surfacesJs

0ne is scarcely justiiied in classifying the early sensory func· tions as touch or pain. strictly spealcing, the fetus experiences no sensation whatsoever; it simply responds automatically, reflexly, in the early part of prenatal life. It is true that the neurons are activated by external environmental changes and may be considered exteroceptive, but there is nothing about their structure and nothing about the response itself which would indicate that some subserve pain and others touch or cutaneous pressure.

It is the opinion of some investigators that both pain and touch are difkerentiated in late fetal life. Very little difkerence could be observed in cat fetuses between responses elicited by coarse but innocuous stimuli and ones which produced demonstrable trauma until after the 45th day of gestationJ Even at full term, pain, touch and pressure are not well differentiated Raney and carmichaels have dealt with the question of localization to tactual stimuli in relation to the genesis of space perception in the rat. They found greater speciiicity of response as the time of birth approached. 186 PHYsIoLooY or THE FETUS

(b) Tauf-www ssnsmvrrr

Only one attempt has been made to study the eifect of tempera— ture stimulation systematically throughout the entire fetal periodss Physiological saIine solutions of different temperatures were applied in drops upon six representative cutaneous areas of guinea pig fetuses and the motor responses were recorded with a motion—picture camera. The parts stimulated were vibrissae area, ear, shoulder, rump, forepaw and hind paw. Control tests were made with the solution at body temperature. Responses were obtained throughout most of the fetal period but the warmer or cooler the solution the greater their number. Cold solutions

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appeared to be a little nsore effective than warm during the early part of the motile period. sensitivity increased with age to some extent but the growth of hair modified the effectiveness of stimuIation in the older specimens Furthermore, there »was evidence of sensitivity spreading from cephalic to caudal and from pro-c— imal to distaI parts as development progressed. Fig. 65 illustrates

the relative eEectiveness of solutions of Various temperatures used in three age groups of fetuses.

PROPRIOCEPTIVE FUNCTION IN THE PETUS It is quite possible that afferent nerves of the deeper fetal cis— sues such as muscles and joints become functionaI very early. Some of the first responses of mammglian embryos may resu1t THE FETAL sENsEs 187

krom their activation. Movements ok the primitive limbs can be induced by bending the limbs or by tapping on them. They can lilcewise be obtained without touching the embryos at all by tapping lightly upon the fluid filled amniotic sac containing a specimen, but one does not know what nerves are being stimulated. since akkerent neurons are present in the connective tissue just underneath the epithelium, it is just as likely that the response is due to exteroceptive as to proprioceptive stimulation.

Nevertheless there are many observations suggesting that primitive endings in the muscle are capable ok being stimulated by the middle ok the gestation period or a little latet. The stretch— ing ok the ketus upon opening the amniotic vesicle and thus changing the pressure upon the specimen is a case in point. 0ther observations on the development ok muscle tonus and the tonic neclc and body righting rellexes leave no doubt that proprioception is present, and well kormed, considerably bekore birth.

1n newborn rats whose spinal cords were sectioned completely during intrauterine like it was often very diklicult to determine by physiologic tests that nerve pathways had been interr"upted. The animals responded to stimulation ok points below the level ok section much as did their unoperated litter mates.I7 It was suggested that in these very immature animals reflex movements below the lesion were responsible kor stimulating proprioceptive endings in muscles above, setting up proprioceptive reilex movements ok which the rats were aware and in this way acquainting

«the rats, as it were, with what was happening in a part ok the body

from which no direct messages could be received. The spread ok activity krequently seen in much less mature mammalian ketuses ok other species suggests a mechanism ok a similar sort. Ik proprioceptive kunction plays a part in the responses ok the early human ketus it is certain that it does not require highly specialized neuromuscular spindles because these structures do not appear until about the third monthÄs

Function ok the vestibular mechanism begins rather late in ketal like ok the can« In other species it may be present relatively earlier, as seems to« be thes case in the sheepJs However, caution must be exercised in attempting to determine its presence, kor righting reflexes and eye movements can be induced by stimulat188 PHYsmLoeY oF THE FETUs

ing other receptors such as those of the neck and body. The righting reiiexes have beens discussed in the preceding chapter.

OLPACTORL GUSTATORY AND VISCERAL sENsEs

The olfactory apparatus is made ready during prenatal life, but it is doubtful if adequate stimuli are ever present in utero where no air comes into contact with the nasal recept0rs. In the newborn and prematurely born human infant, various observers have obtained evidence of olfactory function.20s 21 It has been pointed out, however, that common chemical receptors of the trigeminal nerve are readily stimulated by strongly aromatic materials and they must not be confused with true olfactory phenomena.

Taste has been demonstrated at birth in man as well as in lower animals, but it is doubtful if dikkerentiation between sour, salt and bitter is very well formed. The day old lcitten can distinguish between millc and a mixture of millc and sodium chloride.22 The experiments of De snooks who injected saccharin solution into the amniotic sac of women sukkering from polyhydramnios, seem to indicate that the fetus responded to the sweet taste and swallowed unusually large quantities of the amniotic fluid.

Regarding other visceral aiferent stimulation, nothing is known. 0ne can speculate that the normally occurring intestinal movements stimulate afkerent neurons. Perhaps the active swallowing of amniotic Auid by fetuses in the last months of gestation is reflexly controlled by» such a mechanism. Vigorous «hunger" contractions of the stomach are found in prematurely delivered mammals.24 .

IIEARING AND VISION

Hearing has been considered to be imperfect «at birth but seems to improve within a short time after the amniotic fluid and secretions drain from the middle ear.25 — Prematurely delivered infants show evidence of audition a little while after birth. Some investigators hold that the respiratory changes observed in the human infant concomitant with the production of sounds signify a functional auditory mechanism. «

Attempts were made by PeiperW to observe changes in intra— uterine activity associated with Hund. »Alt.hough it was diflicult THE FETAL sENsEs 189

to rule out stimulation of the fetus by the mother’s own responses, the evidence suggests that strong sounds may have initiated reflex movements of the fetus near term. 0thers have confirmed these results« We have found that very slight tapping upon the amnion at the time of hysterotomy under local anesthesia results in similar quiclc fetal movements even at a much earlier time in prenatal life) such stimuli need not be thought of as sound producing. It is possible that the strong sounds, especially in the case of tapping upon a metal bath tub in which the pregnant woman 1ay, were not in themselves the cause of the fetal responses, but that pressure was transmitted to the fetus as in our own ex— periments. 0n the other hand, sontag and Wallace have presented good evidence that the human fetus does react in utero to sound producing stimuli app1ied externally to the mother’s abdomen. The fetal responses (movements) became more marked as term approachedks Electrical responses have been re— corded from the fetal cochlea after auditory stimulation in guinea pigs of 52 days gestation.29 This was the earliest period at which this species reHd overtly to such stimuli.

Although there can be no stimulation by 1ight before birtln it is probable that the visual mechanism is functional t«o an imperfect degree in late prenatal life. 0bservations in premature infants indicate that some sort of differentiation of light and dark is present. Pupillary responses to strong light can be obtained in late fetal life.

REFERENCES cITED

r. Windle, W. F. sc R. F. Becken 194o. Arch. Neur. sc Psychiat., 43: ge. . Minkowslci. M. 1938. Abderhaldecks Handb. biol. Arbeitsmeth., Abt. V, Teil 5 B: Zu.

. Bolaflio, M. sc G. Artom. 1924. Arch. di sei. Biol., H: 457.

. Hoolcen D. 1936. Yale biol. sc Med., s: 579.

. Fit2gerald, E. sc W. F. Windle, unpublished observations

. Preyer, W. 1885. spedielle Physiologie des Embryo. Gnaden, Leipzig. . Windle, W. F. sc A. M. Griiiiw xgsn J. comp. Neun, se: 149.

. Raney, E. T. sc L. carrnichaeL 1934. J. Genetic Psychol., 45: Z.

g. 0rr, D. W. sc W. F. Windle. 1934. J. comp. Neur., 6o: 271.

to. lcuo, Z. Y. 1932 J. Exp. Zool» Hi: 395.

u. Windle, W. F. 1937. Proc. soc. Exp. Ziel. sc. Med., 36: 64o.

is. Windle, W. F. sc E. Fitzgerald. 1937. comp. Neun, 67: 493.

is. coronios, J. D. 1933. Genetic PsychoL Monog., I4: 283.

i4. carmichaeh L. 1933. In c. Murchisocks Handb. child Psychol., and

ed., clarlc Univ. Press, Worcester.

U

IN! GIVE-Abs 190

IOIAIOIOIIIAIOU Obschon-HiYPOVPSOPEVP PPYPOJTSIWI

PHYSIOLOGY OF THE FETUS

. Bat-Gott, J. s- D. H. Bau-on. 1939. J. comp. Neun, 7o: 477.

cartnichaeh L. s- G. F. J. Lehnen 1937. J. Genetic Psychol., so: 217. Hoolten D. s- J. s. Nicholas 193o. J. Comp. Neun, so: 413.

. cuajunco, F. 1927. contn Emb., 19: 45.

Winde, W. F. s- M. W. Fish. Igzn J. comp. Neun, 54: 85.

Peipetx A. 1928. Ergebw inn. Med. Kinderhlh 33: 5o4.

Frau, K. c» A. K. Nelson s- K. H. sun. 193o. The Behavior of the

Newborn Inkanr. Ohio state Univ. studies, No. to.

Pkalkmanm C. 1936. J. Genetic Psychol., 49: Si.

De snoo, K. 1937. Monatschtz Geburtsh. Gyn., 1o5: As.

carlson, A. J. s- I-I. Ginsburg. Ists. Am. J. Physiol» 38: 29.

Peterson, F. s- I.. I-I. Rainezu 191o. Bu11. N. Y. Lyingsin I-Iosp., 7: 99. Peipen A. 1925. Monatschtn Kind-Ethik» sey: 236.

. Fort-es, H. s. s- I-l. B. Fort-es. 1927. J. Gott-F. Psychol., 7: 353. . sontag, L. W. and R. Wallacn

child Developmeny 6: 253. 1938. Exp.

I935Rawdonismith A. F» L. carmichael and B. We1Iman.

Psychol., es: zzn CHAPTER XIV

THE FETAL ENDOCRINE GLANDS

Qui: lcnowledge of endocrine functions during prenatal life is fragmentary as may be expected from the fact that adult glands of internal secretion are still incompletely understood and their relationship to one another only partly determine-d. There seems to be little doubt that a few of the maternal hormones do influence embryonic deve1opment, but not all can pass the pla— cental barriers The present deftciency of information concem— ing placental transmission of hormones is a factor limiting any discussion of their activities in the fetus. Perhaps the secretions of the fetus itself are equally or more important than those of the mother for the well being and normal metabolism of the new individual. It is with their functions that we shall be especially concerned.

THE SUPRARENAL OORTBX

Among all the endocrine glands of the humazfetus the suprarenals manifest the most remarlcable peculiaritiesks 3 Exam— ination of them in the still—born infant reveals that they are proportionately very much larger than at any time after birthx in fact they form o.2 per cent of the entire body weight. Those of the adult constitute only o.o1 per cent.4 The reason for their great size is found in an hypertrophy of the innermost cortical cells

sforming a layer to which the names, X-zone, fetal cortex and

androgenic zone have been applied. Only the outer rim of the embryonic gland difkerentiates into the characteristic suprarenal cortex of the adult, and it does not come into prominence until after prenatal life.

The androgenic zone of the fetal suprarenal undergoes involution rapidly after birthF and as it disappears the size of the gland becomes actually -as well as relatively smaller. The growth curve of the human suprarenal gland is reproduced in Fig. 66.C The gland loses one—third of its birth weight during the first postnatal week, one-half in the first three months and fouplifths by the

191 192 PHYSIOLOGY OF THE FETUS

» end of the first year. Thereafter, a slow growth takes place and at puberty the suprarenal again attains the weight it had at the end of the fetal life ; but the androgenic Zone is no longer recognizable. This characteristically fetal part of the suprarenal gland has been identiiied in the cat,7 Inouse,8 rabbit9 and in one strain of rats.10 It seems to be absent, or at least not present as a comparable distinct layer of cells, in the albino rat and some other anitnals.

The physiologic signiHcance of the hypertrophiecl fetal cortex of the suprarenal gland is not understood. That it is closely re—

c« B «? 4 6 F J« ZZ « 36 II ZU . Ase f« Yes-·. Fig. 66.-—Growth of the human suprarenal glands (weight) during fetal like (c—B) and after birth. (scammon: «The Measurement of Maus« Und: dünn. Press.)

lated to other endocrine organs is quite certain. A possible influence of Inaternal sex hormones upon the growing feta1 suprarenal is suggestecl by the closely parallel growth curve of the uterus in prenatal and early postnatal life (Fig. 67) . Involution of the X-2one of young male Ihice is accomplished under the in— fluence of testicular horrnoneU

It has been suggested that the fetal suprarenaLgland elaborates an anclromirnetic substance.I2- I« Its ability to maintain the prostates of the castrated immature mouse and rat, which degenerate when gonads and suprarenals are removed, demonstrates THE FETAL ENDOCRINE GLANDS lgs

an andromimetic property quite clearly-P«- 15 «« Recentlzy however, evidence has been advanced which indicates that carefully prepared extracts of fetal and of other X—2one—bearing glands do not have androgenic propertiesss but it is possible that the amount of suprarenal tissue extracted was too small to produce eifects. should it prove that androgens are laclcingx one would have to discard the attractive hypothesis that the androgenic cortex serves directly to protect the fetus against an excessive iniluence of maternal estrogens reaching it through the placental barrier.

a---»»! OF« Z Z 4 6 J« E) «? ««- Jö X r«AXJD Bär-«. Fig. 67.-Growth of the hutnan Uterus (length) during ketal like (c-—B) and after birth. (scammon: «The Measurement of Man," Univ. Minn. Press.)

75

The possibility that cortin or a cortin-like hormone is forrned by the feta1 suprarenal gland has received attention. Some investigators have reported that the survival times of adrenalectomized cats and dogs are prolonged during advanced pr«eg— nancy.I7szI9 Others failed to substantiate this at the end of gestation,20 but even if it is true there is no proof that a fetal secretion protected the mother. Progesterone maintains life and growth in ferrets and rats in the absence of suprarenal glands,2I-««’3 and the functional corpus luteum of pregnant adrenalectomized anirnals does the Same« Adrenalectomy of pregnant rats during gestation results in an increase in weight of the fetal glandsW as will be seen in Table ge.

IZ 194 Pnrsxoroor or THE: rETUs

Tanm 22

Tun Bringe-IS or Aussicht-Demut Denn-ro Pagen-mer III-on kur- Wntenks or rat; Fast-Hi« sur-Hauptn- Gunvs

Time of adrenaleetomy No. of Average Ist. Ave. set. of suprarenal of mothek litters of fetuses (gm.) glands of fetuses (mg.) « d« 9 o« 9 Unoperated eontrols . . . . . . 18 5 .84 5.t»)8 0.90 0.82 14th day of FeSUItIOIL . . . . 15 4 .96 4.78 LLZ I .l8 7th day of Feste-tion . . . . . . 10 4 .70 4.51 1.17 Lls

Attempts have been made to destroy the suprarenal g1ands by means of intrauterine surgery to observe effects on other fetal

endocrine organskk but it proved impossible to obtain clear—cut results because of the magnitude of technical difkiculties

THE SUPRARENAL MEDULLA

The medulla of the suprarena1 gland has an embryonic origin very different from that of the cortex. It is formed by cells which arise from the primordia of sympathetic ganglia and which begin to migrate into the already prominent cortical bodies at about seven weeks gestation in man. cells ok the suprarena1 medulla as well as of certain other small glandular bodies of similar embryonic origin (e.g., the aortic paraganglia) possess a retnarld able afkinity for chrome compounds with which they take on a brown color. This chromafkin reaction has been demonstrated to be elicitable iirst at about the time extracts of embryonic suprarenal tissue begin to produce pharmacologic responses characteristic of epinephrink749

Many have investigated the activities ok the embryonic -and fetal suprarenal medulla by this histochemical method as well as by other chemical and sensitive physiologic techniques Epinephrindilce reactions are obtainable from suprarenal extracts pre— pared from chiclc embryos as early as the eighth day of incubation although similar extracts of other embryonic tissues give negative resultsFHI Epinephrin is formed, or at least stored, in the medulla of the glands in many fetal mammals before the middle of gestation.32-39 The medullary cells show the chromaliin reaction at the 17th to 18th day in the pig and both physiologic and histochemical tests reveal the presence of an epinephrins lilce substance at the time migration of. iznedullary cells into the THE« FETAL ENDOCRINE GLANDS 195

cortical bodies is first observablekssfs The epinephrin content of fetal glands has been reported to be greater than in the adult; more was found in female than in rnale fetusesPs A correlation between appearance of. epinephrin in the suprarena1 of th«e rat and the origin of fetal movements has been suggestedxm but this seems to be coincidental.

In sharp contrast with results obtained in most rnamma1s, human fetal suprarenal extracts give negative or only very slightly positive tests for epinephrinJHss 4144 However, in- full term infants as well as prematures which lived for a short time somewhat more definite reactions were obtained. The near fai1— ure to obtain epinephrin-lilce responses from human fetal suprarenal extracts may be contrasted with the observation that the paraganglia yielded definite amounts of epinephrin in one in— stance:43

kluman suprarenal at birth - 0.0I arg. epinephrin per OR? Hm. Flur-d.

Etunan paraganglion at birth - 0.24 rag- epinephria per 0.1I Hm. sind.

Any relationship between low content of epinephrin and the presence of a very prominent androgenic cortical zone in man is

undetermined Im: sEx Blond-muss

An excellent consideration of embryologic development of sex with a review of all but the latest literature has appeared recentlyxss We are limited here to only a small part of this interesting subject.

The male gonads produce substances with androgenic properties in prenatal life. 1t was demonstrated that extracts prepared from the testes of fetal calves are similar to those from the adult and the hormonal yield per unit weight of tissue is greaterKS It is probable that the male sex glands begin to elaborate secretions about as soon as their sex can be differentiated, which is the sixth day in the incubating chiclc and the seventh weelc in man. The ovary is recognizable as such about a weelc later than the testes.

The best indication we have that fetal androgens are active in early prenatal life is that forthcoming from a study of freemartins in cattle.47s 48 The freemartin is an intersexed or mascu— linized female calf which deve1ops under conditions of chorionic fusion in which vascu1ar anastomoses are estab1ished between the 196 PHYSIOLOGY oF THE. FETus

placentas of adjacent male and female fetuses. The male is always a normal individual: It is believed that the hormone elab— orated by the fetal male gonadscirculates in the conjoined blood streams, acting upon the female twin’s Miillerian or female duct derivatives to inhibit their normal development and upon its Wolllian or masculine duct derivatives to stimulate their abnormal dilferentiatiom When vascular connections are not established between adjacent fetuses of opposite sex no freemartin results, but the calves are normal male and female.

A. similar freemartin condition has been described in swine.49 It should be noted that the placentas of both cattle and swine are relatively ineflicient from the standpoint of permeabi1ity. A high degree of placental fusion, apparently with vascular union, was observed in one instance of synchorial twinning in the cat.50 The fetuses were of opposite sexes, were sexually normal in every way, and were sulliciently advanced in development to make it appear certain that the female twin would not have become a freemartin. similarly synchorial twins of opposite sexes are encountered in other animals and man,51- 32 but freemartins have not been re— ported. It will probably be prolitable to- learn how the transmission of fetal male sex hormones across the placental barrier is related to the phenomenon in question. It is diflicult to see how the freemartin condition can be so limited unless the diffusibility of embryonic testicular hormones is greater in the deciduate types of placentas which therefore never allow hormones to accumulate in suilicient amounts to stimulate the Wolflian derivatives of the genetically female twin.

It would carry us too far alield to inquire deeply into the ex— tensive experimental studies on production of pseudohermaphrodism in the lower animals« success has been attained in mams mals at several laboratories recentlyks Injections of pregnant rats with large doses of testosterone and related preparations bring about abnormal development of the potentially male ducts of genetically female young. It is necessary to administer the hormone before the 16th day of gestation to obtain the most marked effects.54 This is about one day before the WolHian ducts begin to regress The intersexed individuals produced experimentally resemble the naturally occurring freemartins in certain particu lars. THE! FETAL ENDOCRINB GLANDS 197

Male ofkspring of rats receiving large doses of estrogens before the Izth day of gestation have been markedly feminizedPs Thus a converse of nature’s freemartin has been induced with excessive female sex hormones. The extent to which the mother’s own hormones may inliuence normal development of sex in the fetus is not understood. It is known that the fetal uterus exhibits a marked hypertrophy and diminishes in size after intimate contact with the mother is abolished by birth. The mammary glands of newborn infants of both sexes show enlargement and may secrete transientlys It is possible that this production of «witch milk" is stimulated by the same maternal hormonal mechanism that leads to the preparation of the mother’s breasts for lactation.

THE TEYROID GLAND

The ability of the fetal thyroid to secrete at an early period seems to have been established. Iodine has been identilied in the gland at the 2nd or zrd month of gestation in cattle, sheep and swiness and in man at least as early as the 6th month» The amount is said to increase toward the end of prenatal life but to be low as compared with the adult gland, perhaps because storage of colloid is not so marked in the fetus« There is no close correlation between the maternal and fetal blood content of hormone iodine, a fact which suggests that the fetus is secreting its own hormoneIs The presence of thyreoglobulin in the human fetus at the zrd and 4th months has been established by means of an immunologic precipitin reaction.59

Amphibian metamorphosis and growth can be inlluenced by extracts and transplants of avian and mammalian fetal thyroid glands. In several, it may be said that the thyroid« becomes active at about the time its structure begins to resemble that of the adult. This is on the iith day of incubation in the chickW In calves colloid is present as early as the end« and differentiation is comp1eted between the 4th and 6th prenatal monthsz at this time extracts serve to bring about metamorphosis in the axolotl, a salamander which normally retains the larval state throughout life.30 Extracts prepared from the glands of pig fetuses 7 cm. long proved to be inactive, but those from 9 cm. pig fetuses produced reactions comparable with adult thyroids; correlatively, the adult structure was nearly attained at 9 cm.» When bits of 198 PHYsmLooY oF THE: FETUS

the thyroid gland from a 3-months-old human fetus (1o cm. C. R. length) were transplanted into larvae of a toad, accelerated development took place, and trarisplants from 5-months-old human fetuses had more marked efkectsYs Control experiments with bits of fetal muscle gave negative results. It was found that the thyroid gland of the youngenfetus had already deve1oped col1oid Iilled vesicles.

Little is known about placenta! transmission of the thyroid secretions. In swine, horses, cattle and sheep, animals with adeciduate placentas, it appears that there is no transmission. In geographical regions where iodine deliciency is prevalent the offspring of these animals are born in a state of athyreosis while the mothers show little or no evidence of the iodine lack.C4- S« It seems sthat the fetal requirements of iodine are greater than those of the mother and that the fetus cannot draw upon the mother’s hormone but must manufacture its own. Iodine feeding during pregnancy corrects this deliciency, and the newborn pigs are then normal. In man, on the other hand, it seems probable that the mother’s hormone is available to the fetus because it can traverse the placental barrier. Human infants born without or with atrophic thyroid glands exhibit none of the symptoms of myxe— dema, but a latent athyreosis soon manifests itself.S3-71

THE PARATIIYROID GLANDS

Practically nothing is known of function of fetal parathyroid glands. Injections of parathyroid hormone into dog fetuses bring on an elevation of the calcium level of the fetal, but not the maternal blood. This suggests that the parathyroid secretion does not pass the placenta in the species studied.72 Attempts have been made to determine the effects of fetal glands of dogs after thyroparathyroidectomy of the mothers. It was found that tetany de— veloped just as soon as it did in nonpregnant animalsJss ««

THE TIIYMUS

Although the thymus is usually considered with the glands of internal secretion, it is doubtful if it logically belongs there. By 3 months in man, the thymus has the appearance of a lymphoid organ with cortex and medulla already in evidence. There is no anatomical basis for the belie,f that the sgland elaborates a hormone THE« FBTAL BNDOCRINE GLANDS 199

and few attempts have been made to study the fetal thymus from the standpoint ·of its endocrine function.30s «« ««

Extracts of thymus seem to exert no elfects when fed to tadPoles, although opinion has been divided on this questions«- «« An extract of calf thymus, to which the name «thymocrescin" was given, has been reported to produce marked acceleration of growth in young rats when injected in daily doses as small as 1 .mg.79

Another extract prepared in an entirely different way resulted in even more marked effects in the hands of Rowntree and his colleaguesko This material was injected intraperitoneally in i cc. doses into rats over long periods including gestation and lactation; the young of succeeding generations were similarly treated. Elfects on the olkspring of the first animals were not signijicant but the second and subsequent generations showed remarkable changes. They were larger at birth, more of them survived and their postnatal development was delinitely speeded. The young rats became sexually mature precociously. Maximum effects were found in the eighth and tenth generations. It was necessary to keep giving the treatments and not miss a generation or the effects were promptly dissipated. From the more recent re— ports it seems that it was necessary to inject the extracts into females onlyFI

0ther investigators have attempted to reproduce these very interesting results. but so far no adequate confirmation has been reported» The biologic effects of certain iodine-reducing sub— stances (glutathione, ascorbic acid, cysteine) have been found to simulate those of the thymus extracts in certain particularsPI

Im; nrpopkkrsxs

A few studies have been made on placental transmission of hypophyseal extracts but we know Iittle about hormone elaboration by the fetus itself. When pituitrin was injected into rabbit fetuses no muscular contractions were observed in the mother.83 This suggests, but does not prove, that the substance failed to pass the placenta. Anterior lobe extract did not produce any evidence of its usual gonadotropic activity in the mother when it was introduced into the fetuses« Furthermore, this hormone failed to appear in the fetal fluids after it had been injected into 200 PHYSIOLOGY OF THE FETUS

the «mother; at least, the administration of these fluids to other adult rabbits fai1ed to bring about ovulatory changesss These experiments seem to show that there is very Iittle if any transmission of the large molecules of the anterior lobe gonadotropic factor even in the hemosendothelial type of p1acenta.

The fetal hypophysis seems to be capable of elaborating several active principlesPss VHV A pressor substance has been found at 6 months in man. similar studies have been made in fetuses of cattle, sheep and swine in which the response was found relatively earlier. The guinea pig uterine strip method served to demonstrate the oxytocic princip1e about as early as the pituitary glarid can be recognized macroscopicallzn It was found in appreciable amounts in pigs and sheep at term.

The melanophoreexpanding hormone has been identified in the fetal hypophysis It was found in the glands from calf fetuses of 3 months gestation but was not there at 2 months. It was present in pigs of only Zo mm. c. R. length.30- 88

Gonadotropic and growth promoting factors of the anterior lobe seem to make their appearance rather late in fetal life, and the former is later than the latter.90 In fetal pigs the gonadotropic response was obtained from glands at the 2o to 21 ern. stage, a short time before the end of gestation but was not found earlier. The general body growth response could be obtained at the 9 to 13 cm. stage which was just about the same time the thyroid hormone made its appearancesEs 90

SECRETIN

Extracts of the proximal portion of the fetal small intestine have been found to cause secretion of pancreatic juice when in— jected into adult animals with pancreatic Hstu1as.9I·9f The earliest period at which secretin has been obtained from the human fetus is 414 months. The exact source of the hormone is unknown and attempts to ascribe it to the chromalkn cells of the duodenum93 seem to be entirely unjustiöed

THE ENDOCRINE PANCREAS

The endocrine function of the pancreas is vested in the cells of the islands of Langerhans These make their appearance in the third month of human gestation but— it-.is not known how early THE FETAL ENDOCRINE GLANDS 201

they become capable of secreting. The acinar portion of the gland does not begin to produce its proteolytic ferment before about the 5th month,93 and Banting and Best took advantage of the fact that island tissue is functional earlier when they chose the pancreas of the fetal calf as a source of antidiabetic principle in their early search for insulin.97 Many have discussed the possibility that fetal insulin plays an important röle in carbohydrate metabolism of the fetus and have pointed to a correlation between the appearance of glycogen in the liver and the development of island tissue in the pancreassss 99 but the relationship is still somewhat unsatisfactorily established because the influence of maternal secretion acting through the placenta is diflicult to evaluate. It is said not to pass the placenta from fetal to maternal sides.83 Administration of insulin to pregnant cats failed to reduce the blood sugar level of the fetuses near term. This suggests that the pla— centa is impervious at the time, but at earlier stages similar results were not obtainedEoo Further discussion of this question will be found in Chapter XVI »

In birds, where all metabolic processes must be managed by the fetus itself, an insulin-like substance has been found in the unincubated eggJOI However, it is not present in the tissues of the early chick embryo until after the pancreatic islets are formed.

The ofkspring of diabetic animals are not diabetic and as a ruIe seem to possess healthy glandsW This is not always true in man where hypertrophy and hyperplasia of islands and postpartum hypoglycemic deaths are encountered in infants born of diabetic womenJos Although hyperplastic pancreatic islands are not. found in all instances, careful searching might show the condition to be more prevalent.

The possibility that during prenatal life fetal insulin can protect the diabetic mother has been discussed by several investigators. It was discovered by Carlson and his colleaguesIM W that the urine of completely pancreatectomized dogs remained free from sugar when the .operation was performed in late stages of pregnancy. This suggested that fetal island tissue had, supported both the mother and fetuses, for after parturition the mother exhibited glycosuria. These experiments have been adequately confirmedW and similar conditions app«arently occur in the human.I07 Completely depancreatized dogs maintained in 202 PHYSIOLOGY OF THE FETUs

good hea1th by diet and insu1in therapy can conceive and give birth to normal pups. They show an increased carbohydrate tolerance kor only about two weeks prior to labor. However, an even greater tolerance appears after birth during lactationz it would seem that the results previously ascribed entirely to ketal insulin are more probab1y due largely to increased utilization ok carbohydrates by the fetuses and, after birth, by the nursing puppies. We cannot be sure that the ketal insulin plays any part in protecting the diabetic mother. It is quite reasonable to suppose that it is more important kor the utilization ok sugar received by the

ketus krom the mother.

Glycogen appears in the liver ok the deve1oping chick at 7 days ok incubation. This is about three days before delinitive islands ok Langerhans make their appearance. Between the tenth and thirteenth days the glycogen content ok liver cells diminishes and

the metabolic rate and respiratory quotient increase, although there is no rise in the blood sugar concentration. Thus it appears that an increased utilization ok carbohydrate by the embryo is correlated with the advent ok kunction in suprarenal medulla. pancreatic islands and thyroid glandsÄss «

REFERENCES CITED

i. Needham, J. i93i. chemical Embryology, Macmillan, N. Y.

g. Gro11man, A. i93s. The Adrena1s, Williartis sc Wi1kins, Baltimore

z. Rogokk, J. M. 1932 chap. as, vol. 2 in cowdry: Special cytology, I-Ioeber, N. Y.

4. scammon, R. E. i923. Chap. z, vol. i in Abt: Pediatrics, saunders, Philadelphia. «

z. Elliott, T. R. sc R. G. Arnioun igi i. J. Path. sc Bach, is: 4si.

s. scammon, R. E. i93o.» Pt. IV in The Measurement ok Man. Univ. ok Minn. Press, Minneapolis

7. Davies, s. ig37. Quart. J. Mic. sci., so: si.

s. I-Ioward-Mil1er, E. i927. Am. J. Anat» 4o: 25i.

g. Roak, R. i935. J. Anat., 7o: ists.

io. Bacsich, P. sc s. J. Folley. i939. J. Anat» 73: 432.

ii. Martin, s. J. ig3o. Proc. soc. Exp. Bio1. sc Med., Es: 4i..

i2. Reichstein, T. i93s. I-Ielv. chi. Acta, i9: Les.

is. I-Ioward, E. i937. Am. J. Physiol» ii9: 339.

i4. BurrilL M. W. sc R. R. Greene. i93g. Proc. soc. Exp. Bio1. sc Meds., 403 IS? i5. I-Ioward, E. i939. Am. J. Anat., s5: io5.

is. Gersh, I. sc,A. Gro1lman. i939. Am. Physiol» us: 3ss.

i7. stewarch I-I. A. i9i3. Proc. i7th latet-nat. Gang. Magd» secr. z, Pt. g,

p- I73THE. FETAL ENDOGRINE GLANDS 203

ts. stewart, G. N. sc J. M. Rogolk t9es. Pt·oc. soc. Exp. Biol. sc Med» ee: sg4 and es: tgo.

t9. Rogokh M. sc G. N. stewarr. t9e7. Am. Physiol» 79: so8.

eo. cotsey, E. L. tge7. Proc. soc. Exp. Biol. sc Med» es: t67.

et. Gaunt, R» W. 0. Nelson sc E. Loomis. t9s8. Ibid» s9: st9.

ee. Gaum, R. sc H. W. I-Iays. t9s8. Science, 88: s76.

es. Greene. R. R., J. A. Wells sc A. c. Ivy. t9s9. Pt·oc. soc. Exp. Biol. sc

Med» 4o: 8s.

e4. Rogokh J. M. sc G. N. stewarr. tgeg. Am. J. Physiol» 88: t6e.

es. Ing1e, D. J. sc G. T. Fishetn t9s8. Proc. soc. Exp. Biol. sc Med» s9: t49. e6. Tobin, C. E. t9s9. Am. J. Anat» 6s: tst.

e7. Weymanth M. F. t9ee. Anat. Rec» e4: e99.

es. Howard-Miller, E. t9e6. Am. J. Physiol» 7s: e67.

es. 0lcuda, M. t9e8. Endocrin» te: s4e.

so. I-Iogben, L. T. sc F. A. E. Stets. t9es. Brit. Exp. Biol., t: t.

st. Lutz, B. R. and M. A. case. tges. Am. J. Physiol» 7s: 67o.

se. Langlois. J. P. and J. Rehns. t899. comp. Rend. soc. Biol., st: t46. ss. Fengetx F. t9te. J. Biol. chem., it: 489 and te: ss.

s4. cevolotto, G. t9t6. chem. Abstt·» to: tete.

ss. Mccord, c. P. t9ts. J. Biol. chem., es: 4ss.

s6. svehla, K. t9oo. A1ch. exp. Path. u. Phaxm» 4s: set.

s7. Moore, B. sc c. 0. Purinton. t9oo. Am. J. Physiol» 4: s7.

s8. Lewis, J. I-I. tgt6. J. Biol. chem., e4: e49.

s9. saito, s. t9e9. Toholcu J. Exp. Med» te: es4.

4o. Panlusatz D. s. t9st. Anat. Rec» 49: st.

4t. Ingietx A. sc G. schmorL 191 t. Miinch. med. Wochenschr» t9tt, e4os

(Abstt·.) . 4e. samelson, P. t9te. Ztschtn i. Kinderhllc» s: 6s. 4s. Elliott, T. R. Personal to G. Bat-get, t9t4. The simpler Natural Bases, Longmans Green, London (p. 9s). 44. Krametx D. t9t8. Monatschtx f. Kinderhllg t4: sst. 4s. Williety B. H. t9s9. chap. s in E. Allen’s «·sex and Internal secres tions," Williams sc Wilkins, Baltimore. 46. Womaclh E. B. sc F. c. Koch. t9st. Proc. end 1nternat. cong. set: Res» t9so, P. se9.

47. Linie, F. R. t9t7. Etcp. Zool» es: s7t.

48. Linie, F. R. t9e3. Biol. Ball» 44: 47.

49. I-Iughes, W. t9e9«. Anat. Rec» 4t: et s.

so. Wisloclus G. B. sc G. W. D. Hamletr. t9s4. Ibid» 6t: 97.

st. Hamlett. G. W. D. sc G. B. Wisloclti. t9s4. Ibiii» St: st..

se. Wisloclci, G. B. t9s9. Am. Anat» 64: 44s.

ss. Gt·eene, R. R» M. W. Burrill sc A. c. Iyy. t9s8. Am. Obst. sc Gyn»

s6: tos8.

s4. Butrill, M. W. sc R. R. Greene. tgs9. Am. J. Physiol» te6: 4se.

ss. Greene, R. R. sc M. W. Burrill. t9s9. Ibid» te6: sto.

s6. Nosalca, T. t9e7. chem. Abs» et: s9ts.

s7. Mauretx E. t9e7. Ztschtu i. Kinderhllc» 4s: t6s.

s8. Mcclendon, J. F. sc c. E. McLennam t9s9. Proc. soc. Exp. Biol. sc

Med., 4o: sss. sg. I-Ielctoett, L. sc K. schulhoL t9es. Proc. »Natl. Acad. sei» tt: 48t. eo4

. Wegelin, C. sc J. Abelin. . Thomas, E. sc E. Delhougne

. snyder, F. F. s: F. M. Hoskins.

. Leu-is, D. . snydeiy F. F. i9es. Am. J. Anat» 4i: s99.

. Bell, G. H. sc M. Robson. i9s7. Quart. J. EZcp. Physiol» e7: eo5. . sinith, P. sc c. Dortzbaclx . Hallion, L. 8c P. Lequeux. . camus, L. i9o6. Ibid., 6i: 59. . Pringle, H.

. Banting, F. G. s: c. H. Best. . Aron, M. . Port-in, R. sc M. Aron. i9e7. coinp. rend. soc. Biol., 96: e67. . Britton, s. W. i9so. Am. J. Physiol» 95: i78.

. shilcinamh Y. i9es. Tohoku J. Exp..Med.,sp io: i.

PHYSIOLOGY OF THE« FETUs

. Willieiy B. H. Personal to J. Needham. i9si. cheiii. Emb., Mac millan, N. Y.

. Abbott, A. C. 8c J. Prendergasr. . i9s7. can. Med. Assoc. J., s6: ees. . Rumph, P. 8c P. E. smith. i9e6. Anat. Ren, ss- es9.

. Schuhe, W» W. schmitt sc K. Hölldobler. . smith, G. E. s: I-I. Welch. i9i7. J. Biol. chem., e9: ei z. . smith, G. E. . siegen.

i9es. Endolcrin., e: e.

i9i9. Endocrin., s: e6e.

i9ei. Verh.«deuts. Gesel. Kinderhllsp ee: s64.

Kot-her, T. is9e. Deuts. Ztschr. chirurg.,-s4: 556.

i9ei. Arch. exp. Path. u. Pharm., sg: ei9. i9e4. Virchow’s Arch. path. Anat. u.

Physiol» e4s: eoi .

. Kraus, E. J. i9e9. Beitr. path. Anat. allg. Path., se: e9i. . sgalitzey K. i9ss. Ibid., ioo: es5. . Hoslcins, F. M. sc F. F. snyder.

i9e7. Proc. soc. Eis-P. Biol. sc Med., es: e64. ·

. Vassale, G. i9o5. Art-h. ital. biol., 4s: i77. . Werelius, A. i9is. Sarg. Gyti. sc Obst» i6: i4i. . Trinlca, L.

i9i4. Publ. biol. Ecole Hautes Etudes Vet. de Brno (in czechz cited by J. Needham, i9si) . —

. Macchiariilo, 0. i9so. Riv. ital. di Gin., ii: s57. . Gudernatsch, F. . Allen, B. M. i9eo. J. Exp. Zool., so: is9.

. Asher, L. i9ss. Abderhalden’s Handb. biol. Arbeits-method. Abt. s,

i9i4. Am. J. Anat., is: 4si.

Teil sB (e): 9e9.

. Rowntree, L. G., J. H. clarlc sc A. M. Hans-on. i9s4. science, so: e74. . Rowntree, L. G., A. steinberg, N. H. Einhorn 8c N. K. schaffen

i9ss. Endocrin., es: 584.

. Nelson, W. 0. i9s9. chap. ei, in E. Allen’s «sex and Internal Secre tions," Williams 8c IVillcinsk Baltimore i9e7. Anat. Rec., s5: es.

Wisloclci, G. B. sc F. F. snydeix i9se. Proc. soc. Exp. Biol. sc Med., so: i96. . Goodman, L. s: G. B. Wisloclci. i9ss. Am. J. Physiol» io6: ses. schlimperh H. i9is. Monatschix Geh. u. Gyn., ss: s.

i9i6. J. Exp. Med., es: 677.

i9e9. Anat. Rec., 4s: e77. i9o6. comp. rend. soc. Biol., 6i: ss.

i9ii. Physiol» 4e: 40 P.

. Koschtojanz c. i9si. Pllügeks Arch., ee7: s59. . parat, M. i9e4. comp. rend. soc. Biol., 9o: wes. . Ibrahim, J. i9o9. Biochem. Ztschr., ee: e4.

i9ee. J. Lab. s: Glitt. Med., 7: 464. i9es. comp. rend. soc. Biol., s9: is7, is9. THE FETAL ENDOCRINE GLANDS 205

me. Jos1in, E. P. 1915. Boston Mai. sc: Sarg. J., 173: 841.

1o3. smyth, F. s. 8e M. B. 01ney. 1938. J. Pediat., is: 772.

1o4. Car1son, A. J. 8e F. M. Drennam 1g11. Am. J. Physiol» es: 3g1.

1o5. car1son, A. J» J. s. Ort· 8e W. s. Jones. 1914. J. BioL Odem» 17: 19. 1o6. cuthberiz F. P., A. C. Ivy, B. L. Isaacs se: Gray. 1936. Am. J. Physiol»

us: 480. 1o7. Lawrence, R. D. 1929. Quart. J. Mai» es: 191. Los. Daltorh A. J. 1937. Anat. Ren, 68: 393. CHAPTER XV

FETAL NUTRITION AN D 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 transmis tIIIII--I tIIIIgIII ssIIZIIIs tgtZIIIIs I-IssUII

II Z( 2

O G

Z

Rotte-Pers! Fuss-Hofstaat Tit-se

Period of Gestaden-days

Fig. 68.—Permeability of the rabbit placenta to antibodies at different times during prenatal life. (Rodo1fo: J. Exp. Zool» Vol. 68, 1934.)

sion and that molecular size plays an important part in determining which shall and which shall not cross the barrier.10-U-17- 18 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

14 210 PHYSIOLOGY OF THE FETUs

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 lcnowledge 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 marlcedly in the spguinea pig and rabbitkss 27 FETAL NUTRITION AND METABOLISM 211

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 lcilogram. 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 einer—

gencies. METABOLISM 017 LIPIDs

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 FETAL NUTRITION AND METABOLISM 213

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

0ther lines of evidence suggest that there is no direct passage of lipids across the placenta! membranes. A marked dilkerence

«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 214 PITYSIOLOCLIY OF THE FETUS

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 phospholipidsås

The iipid 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 FETAL NUTRITION AND METABOLISM 215

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 lcidneys. 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.

IN ORGANIO IVIETABOLISM

It is lcnown 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 izth 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 220 PHYSIOLOGY OF THE FETUS

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 FETAL NUTRITION AND METABOLISM 221

« 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.) 222 PHYSIOLOGY OF THE« FETUS

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.

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 METÄBOLISM

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 224 PHYSIOLOGY OF THE« FETUs

tuations have been talcen 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 FBTAL NUTRITION AND METABOLISM 225

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 eightscell 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«

Is 226

PHYSIOLOGY OF THE FETUS

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.

REFERENCES CITED

. Meyer, R. i9e5. CentralbL Gyn» 49: i866. . Grossen 0. i9e7. Frähentwiclälung Eihautbildung und Placentatiom

Bergmanm München.

Grossen O. i933. Lancet, ee4: 999.

Bryce, T. H. i937. Edin. Med. J» 44: 3i7.

Wislockb G. B. sc G. L. streeten i938. conti·. Kind» 27- tBrunschwigz A. E. ige7. Anat. Rec» 34: e37.

Everett, J. W. i935. J. Exp. Zool» 7o: e43.

Wisloclch G. B. i9ei. Anat. Rec., ei: e9.

Wislockh G. B. i9ei. «Contr. Erim» i z: 9i.

N eedham, J. i93i. chemical Embryology, Macmillanp N. Y. shimidzm Y. i9ee. Am. ·J. Physiol» He: -eoe.

. cunningham, R. s. i9e3. Proc. soc. Exp. Biol. sc MAX» eot 343. . Römer, P. H. i9o5. Beitr. exper. Therap» g: is.

. Rodolio, A. i934. J. Exp. Zool» 68: ei z.

. Mossman, H. W. ige6. Am. J. Anat» 37: 433.

. Cunningham, R. s. igee. Am. J. Physio1»,6o: 448.

. Bremer, J. L. i9i6. Am. J. Anat» i9: i.79.

. Anselmino, K. J. i9e9. Arch. Gynäk.. i 38: 7io.

. schlossmann, H. i93e. Ergebn. Physiol» 34: 74i.

. cohnstein, J. sc N. Zuntz. i884. Plliigeks Arch., 34: i73.

Morriss, W. H. igi7. Johns Hoplcins Hosp. Ball» es: i4o.

. schlossmanm H. i938. J. Physiol» ge: eig.

. Passmore, R. sc H. schlossmann. i938. J. Physiol» 922 459.

. Aron, M. i9eo. compr. Rend. soc. Biol., 83: 63i, 1445- l447i . Zorn, C. M. sc A. J. Dalton. ig37. Am. J. Physiol» ii9: 6e7. . Aron, M. ige4. Arch. Internat. Physiol» ee: e73.

. snydeiy F. F. sc F. M. Hoslcins. . Bernard, C. i858. Ann. sei. Nat. (ser 4), io: in.

. Chipman, W. i9oe. stud. Roy. Victorian Hosp» Montreah WI- 1- M) i9e8. Anat. Rec» 38: es.

4, Gynec. i, pp. i-e6i. (Reprinted in Rep. Lab. Roy. Goll. Physicians Edin» vol. s, i9o3.)

. Lochhead, J. sc W. Cramer. i9o6. J. Physiol» 35: ii P. . Corey, E. L. i935. Am. J. Physiol» ne: e63.

. staat-r, H. A. sc G. M. Higgins 1935. Ibid., iii: 59o.

. sandstrom, R. H. ig34. Physiol. Zool» 7: Les.

. Aron, M. i9ee. Arch. Anat. Hist. Emb., i: 69.

. Potvin, R. sc M. Aron. . Dalton, A. J. i937. Anat. Rec., 68: IV.

. schlossmann, H. ig3i. Arch. Exp. Path. Pharmalm Izgk As. . Gorey, E. L. i935. Am. J. Physiol» its: 45o.

. Gage. s. H. sc s. P. Gage. · i»9g9. --Anat..Rsze·c» z: eo3.

i9e7. Comp. Rend. soc. Biol.. 96: e67. FETAL NUTRITION AND METABOLISM 227

4o. Meiidel, L. B. sc A. L. Daiiiels i9ie. Biol. chem., i z: 7i.

4i. . Wessoti, L. G. t9e6. Johns Hoplcins Hosp. Bull., 38: e37. 43« . slemons, J. M. . Boych E. M. t936. Am. J. Dis. child., He: i 3i9. . Boyd, E. M. sc K. M. Wilson. . Boyd, E. M. i935. Biochem. J» e9: 985.

. linrie, c. G. sc s. G. Graham. i9eo. J. Biol. chem» 44: e43.

. Dalton, A. i937. Anat. Rec» 67: 43i. «

. Willcersom V. A. sc R. A. Gorrtien i93e. Am. J. Phys10I-- tue: i53. . Rosedale, L. sc P. Morris. i93o. Biochetrx J., e4: ie94.

. ljnclsazy D. E. t9ie. . Fislce, C. I-I. sc E. A. Boyclen. i9e6. J. Biol. chem» 7o: 535.

. Ramagcz I-I., J. l-I. shelclon sc W. sheldoix i933. Proc. Roy. soc., Lotid.

Baum-um, E. J. sc O. M. l-lolly. t9e6. Am. J. Physiol» 75: 633.

Knopkelmachetz W. i897. Jahrb. Kitiderhllc., 45: i77. i9i9. Atti. J. Obst» so: i94.

i935. clin. Ins-est» 142 7 1hid., s: 79.

B., its: 3o8.

. Willcersoih V. A. i934. Biol. chem., io4: 54i. . Ramage, I-I. i934. Bioclietix J., es: i5oo.

. McFarlatie, W. D. sc l-I. l. Milne. . Schick, B. i9ei. Ztsclir. Kindes-thue, e7: est.

. I-lilgenbei·g, F. c. i93o. Ztschr. Geburtslx Gytiäk., 98: e9i.

. Parsoiis, L. G., E. M. Hiclcmans sc E. Fluch. ig37. Axch. Dis. chilclli»

t934. J. Biol. chem» io7: zog.

te: 369.

. L. i938. Am. J. Dis. child., 56: 975.

. swanson, W. W. sc V. lob. tg39. Am. J. Obst. sc Gyn» 38: 38e. . swanson, W. W. sc V. lob. i935. Am. J. Dis. chilc1» 49: 43.

. sontag, L. W» P. Munson sc E. I-Iukk. i936. lbicl., Hi: 3oe.

. lob, V. sc W. W. swatison. . Neeclham, J. t93e. Proc. Roy. soc» Loiicl» B, iio: 46.

. Barcroky J» J. A. Kennecly sc M. F. Masoix i939. J. Physiol» 95: e6g. . Baxcivktz J» L. B. Flexner sc T. Mcclurlciix . I-laselhorst, G. sc K. strombergen

t934. lbicl., 47: 3oe.

i934. lbicl., se: 49s. i93e. Ztsckm Geburtsh. Gynäk., ioe: i6

. Dicke-Ins, F. sc F. simeia i93o. Biocheitx J» e4: i got.

. Bohig c. sc K. A. Hasselbalch igo3. slcath Arch. Physiol» i4: 398. . l-lasselbalch, K. A. . Murray, H. A» Ji·. . Rohr, c. i9oo. Rand. Arch. Physiol» to: 4i3.

. Mut-litt, J. R. i9io. Am. J. Physiol» e6: i34.

. Rost-e, A. W. sc W. c. tzoyci. igzsr. J. Nutritioiy z: 55i.

. carpentetz T. M. sc J. R. Mut-Un. i9i i. Arch. litt. Mai» 7: i84.

. saiidikorch l» T. Wlieeler sc W. M. Boothbyc i93i. Am. J. Physiol»

i9oo. lbicl., to: III. i9e7. J. Gen. Physiol» to: 337.

96: tgi.

. Ein-ishr, L» V. V. cole sc F. A. Hitchcoclg t935. lbicl» its: eei. . Bot-II, E. J. sc J. s. Nicholas i939. scieiice, 9o: 4i i.

Book - Physiology of the Fetus 12

Chapter XII Fetal Motor Reactions and Reflexes