Paper - A comparative study of the birth mortality in the albino rat and in man

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King HD. A comparative study of the birth mortality in the albino rat and in man. (1921) Anat. Rec. 20(4): 321-353.

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A Comparative Study of the Birth Mortality in the Albino Rat and in Man

321 322 HELEN DEAN KING

A Comparative Study Of The Birth Mortality In The Albino Rat And In Man

Helen Dean King

The Wistar Institute of Anatomy and Biology

321 322 HELEN DEAN KING

A Comparative Study Of The Birth Mortality In The Albino Rat And In Man

Helen Dean King

The Wistar Institute of Anatomy and Biology

Literature dealing with birth statistics for man contains numerous references both to the number and to’ the sex of the stillborn; but in none of this literature, nor in any of the many works covering various phases of animal breeding, is there any detailed information regarding birth mortality in other mammals. It has seemed worth while, therefore, to record the data for stillbirths in the albino ,rat that have been collected in the course of an extensive series of breeding experiments carried on in the animal colony of The Wistar Institute of Anatomy and Biology. Life processes in the rat accord in many ways with those for man, as Donaldson (’06, ’08, ’18) has pointed out, and the data given in the present paper indicate that there is also a close agreement in their normal sex ratio, in their birth mortality, and in the sex proportions of the stillborn.

The collection of data regarding the birth mortality in the albino rat was begun June 1, 1913, and carried on uninterruptedly for four years; it was resumed the beginning of June, 1918, and discontinued June 1, 1919. In any investigation of this character it is essential that all of the individuals in a given litter should be recorded, if the data are to have much statistical value. This necessitates, in the case of the rat, an examination of the litters at birth, or shortly after, since stillborn young left for a longer time in the nest are sometimes destroyed. While it is known that the data for the great majority of litters included in this study are complete, there is a probability that some of the stillborn young were omitted from the records, since all litters could not be examined at or close to the time of birth. The magnitude of the probable error is not great enough, however, to affect the general conclusions that have been drawn, though more exact data might change somewhat the various percentages given. Normally, young rats begin suckling soon after their birth, and as at this time and for some days afterward the skin over the abdomen is semi-transparent, any milk in the intestinal tract is readily seen and is a sure indication that the individual was alive when born. There is, therefore, no difliculty in distinguishing the stillborn individuals from those that died later, even though the litter is not examined until a day or two after it is cast. Throughout this paper the word ‘stillborn’ is applied only to young rats that lived through the normal gestation period (twenty-one to twenty-three days) and died shortly before or during birth, and the mortality data given are for such individuals only. Only a very few cases of abortion have been found in the course of breeding experiments with the rat extending over a period of eleven years and comprising many thousands of individuals; none of these are included in the present study.

THE NORMAL PERCENTAGE OF STILLBIRTHS

During the period in which the birth mortality statistics for the albino rat were being collected, a total of 253 litters were found in which one or more individuals were stillborn. Data for these litters, arranged according to the year in which the records Were taken, are given in table 1.

The data given in table 1 show that there was considerable variation in the number of stillbirths occurring in different years. Such variation was to be expected, since the total litter production in the colony varied greatly from year to year (table 2). The

. percentage of stillbirths in the total number of individuals in volved, however, is remarkably constant for all sets of data, as the range of variation is from 20 to 26.2 per cent only (table 1). Since in each year that records were taken at least one-fifth of the young in a considerable number of litters were dead at

birth, it is evident that the mortality was not due to chance, but L

to some disturbance in the metabolism of the mother that tended to involve the litter as a whole. BIRTH MORTALITY IN THE RAT AND IN MAN 323

In order to show the normal percentage of stillbirths in the entire colony, data for the total litter production during the period that the mortality records were taken are given in table 2.

TABLE 1

Data for living and for stillborn young in 253 litters of albino rats. Groups arranged according to the year in which the records were taken

L1 rum YOI 'NG s'r1LLn< mp: roux 3 TOTAL YEAR NUISEER “UEEER Number Number gffigzgé LHTERS YOUNG Males Females °€:‘1%l)es Males Females °£‘:"l?)10e3 in total

females. females Efuggggrg 1913-1914 29 225 81 99 81 .8 25 20 125.0 20 .0 1914-1915 78 570 222 225 98 .7 70 53 132.1 21 .6 1915-1916 35 289 121 104 116.3 36 28 128.6 22 .1 1916-1917 51 339 135 115 117.4 48 41 117.1 26.2 1918-1919 60 394 152 148 102.8 55 39. 141.0 23 .8 253 1,817 711 691 102 .9 234 181 129 .3 22 .8

TABLE 2

Showing the total number of individuals, including the stillborn, that were produced in a colony of albino rats during a period of five years

1913-1914 899 6,677 3,379 3,298 102 .5 45 0.67 1914-1915 945 7,065 3,690 3,375 109.3 123 1.74 1915-1916 828 6,443 3,273 3 ,170 103 .2 64 0.99 1916-1917 1,023 7,131 3,597 3 ,534 101.8 89 1.25 1918-1919 625 4,354 2,217 2 ,137 103.7 94 2.16

4,320 31,670 16,156 15,514 104.1 415 1 31

As table 2 shows, from 600 to 1000 litters of albino rats were born each year during the period covered by the investigation. The percentage of stillbirths in the total. litter production varied considerably in different years, and for the 31,670 births _was 1.31 per cent. Assuming, for reasons to be given later, that at most only 8 per cent of the stillbirths that occurred were not recorded, it would appear that the normal birth mortality in the colony, under existing conditions of environment and of nutrition, was not greater than 2 per cent. 324 HELEN DEAN. KING

During the past seventy-five years an extensive literature has appeared dealing with the birth statistics for man in various countries of the world. From the data given in this literature, Nichols (’07) has compiled a table showing the living and the stillbirths throughout the world during the period from 1751 to 1903. In the enormous total of 447,019,579 births recorded, 13,635,986, or 3.04 per cent, were stillbirths. From a statistical standpoint the various sets of data used by Nichols are not of uniform value, since the laws regarding the registration of births vary greatly not only in different countries, but in different sections of the same country (as in the United States), and therefore many of the records are known to be incomplete. The records of stillbirths, especially, are very faulty, partly because in many countries their registration is not required and partly because the data obtained include fetuses aborted at various stages of gestation. With reference to human births, it may be noted, the word ‘stillborn’ is used to designate fetuses that are at least seven months of age when born; fetuses aborted at earlier stage of development are not ordinarily included in birth statistics.

More recent series of statistics show a birth mortality for man varying but slightly from that given, by Nichols. Thus Auerbach (’12) states that in over 100,000 births as registered in Budapest, 3.3 per cent were stillbirths, and Terry (’17) has shown that in a total of 449,744 births recorded in Massachusetts during 1910 to 1914 there were 15,911, or 3.2 per cent, of stillbirths.

In certain countries in which the laws regarding the registration of births are relatively strict, the percentage of stillbirths is somewhat higher than that given by Nichols. For example, statistics for Prussia during the period from 1872 to 1881 show, according to Dfising (’84), that the stillbirths formed 4.67 per cent of the total of 10,577,478 births; birth statistics for the United States during 1918 show 356 per cent of stillbirths in a total of 1,412,283 births (Davis, ’20).

The data for human births in one year in selected cities of the United States, as collected by The Children’s Bureau of the U. S. Department of Labor, form a unique and valuable series (Duke, ’15; Duncan and Duke, ’17; Allen, ’ 19; Dempsey, ’19). Although BIRTH MORTALITY IN THE RAT AND IN MAN 325

the number of births recorded is very small when contrasted with the large numbers given above, the great care taken to make these records as complete as possible gives to the data great statistical value.

Birth statistics for four selected cities, as collected by The Children’s Bureau, are given in table 3.

TABLE 3

Summary of human births in one year based on data collected by the U. S.Children’s Bureau in selected cities of the United States. 1,. Brockton, Mass.; 2, Johnstown, Pa.; 3, Manchester, N. H.; 4, Saginaw, Mich.‘

LIVING rocrm BTILLBORN romm TOTAL NUMBER P NUMBER or MALES er cent on mm» mg mg; 5:": BIRTHS FEMALES ‘ - c?‘ 5? O -8 9 <3‘ 9 0 es in total 1_nd1- to 100 indz- to 100 number of viduals females vrduals females young

1,247 105.77 1,210 623 587 106.13 37 18 19 94.73 2.96 1,551 110.16 1,463 761 702 108.40 88 52 36 144.44 5.67 1,643 101.10 1,564 781 783 99.74 79 45 34 132.35 4.80 1,015 107.99 981 507 474 106.92 34 20 14 142.85 3.34

kC‘~CA'Jl~Dr—A

5,456 105.96 5,218 2,672 2,546 104.94 238 135103 131.06 4.36

‘ Statistics of births during one year in a fifth city, Waterbury, Conn., have also been published by the Children’s Bureau (Hunter, ’18). The data given show a total of 2,654 births of which 3.2 per cent were stillbirths. Sincesex data are given for only 53 of the 86 stillborn young, this series of data is excluded from table 3.

As shown in table 3., the percentage of stillbirths in the various cities concerned varied from 2.96 (Brocton) to 5.67 (Johnstown), and in the total of 5,456 births recorded there were 238, or 4.36 per cent, of stillbirths. In this series, therefore, the birth mortality is considerably higher than that in any series of data previously cited, yet in each of the papers in which the birth statistics are given it is stated that the number of stillbirths recorded is probably too low, owing to the great difficulty experienced in obtaining accurate information regarding such births. It has been estimated that at least 5 per cent of stillbirths are never recorded, even in localities in which the laws regarding their registration are most rigidly enforced. 326 HELEN DEAN KING

Although the birth mortality in domestic animals would seem to be a matter of considerable importance to the stock breeder, there are only a few scattered references to it in works dealing with various phases of stock breeding, and practically no data having statistical value are available for analysis. According to Bernoulli (’41), records for Europe covering a period of ten

years show that from 10 to 15 per cent of calves were dead at‘

birth. As, however, a very great proportion of these deaths were undoubtedly abortions due to infectious disease, the normal birth mortality, among full-term fetuses is yet to be determined.

Fairly complete records regarding living foals have been kept in various studs throughout Europe for many years, but data for the stillborn are very meager. Records compiled by Hoffman (’85) show that in a total of 1,556 foals, 87, or 5.6 per cent, were stillborn: Goehlert (’84), quoting Baumeister, states that on the average 6 per cent of all foals are born dead: 4 per cent of these are cases of abortion and 2 per cent are of foals at the end of term. In neither of these papers are any data given that show the sex proportions among the stillborn young.

Available evidence thus seems to indicate that in the higher mammals from 2 to 4 per cent of full—term fetuses are dead at birth, and it is probable that at least half of this mortality is due either to disease or to mechanical injury at birth.

THE SEX RATIO IN STILLBORN YOUNG

It is a matter of considerable interest whether the sex ratio, i.e., the number of males to each 100 females, in the stillborn is the same as that in the living young. For if there is a pronounced and constant difference between these two ratios, there must be some disparity between the ‘sexes that is an important factor in the birth mortality.

In order to make possible a comparison between the sex ratio for the living and that for the stillborn young of the albino rat, it is necessary to ascertain the sex ratio that is normal for the species. Cuénot (’99) gives 105.6 males to 100 females as the sex ratio in thirty litters of albino rats; records for over 10_00 litters of stock Albinos, as collected by King and Stotsenburg (’15), BIRTH MQRTALITY IN THE RAT AND IN MAN 327

show a sex ratio of 107.5 males to 100 females; while the data as given in table 2 of the present paper indicate a sex ratio of 104.1 males to 100 females in a total of 31,670 births.

The normal sex ratio for any species can be obtained only by

ascertaining the sex proportions among all of the offspring of a‘

considerable number of females kept under favorable conditions of environment and of nutrition during the entire period of their reproductive activity. None of the sex ratios for the albino rat as given above can, therefore, properly be taken as the norm, since none of them are based on completes series of data. Records covering the complete breeding history of a number of stock albino females have recently been obtained, however, and they show that the sex ratio in the newborn, including those dead at birth, is about 107 males to 100 females. This ratio, therefore, is the one that will be taken as the norm for comparison with the sex ratio in the stillborn.

On referring to table 1 it is found that in each year that mortality data for the albino rat were recorded there was a very great excess of males among the stillborn. While the number of stillbirths in any year was relatively small, the fact that in each set of records the sex ratio varies from the norm in the same direction and to a very considerable degree adds materially to the value of the data. In the total of 415 stillbirths recorded the sex ratio was 129.3 males to 100 females. This ratio is 26 points above that for the living young in the litters concerned, and as it is 22 points higher than the sex ratio taken as the norm (107 males to 100 females) the deviation is much too great to be considered as within the limits of normal variation. Granting that the records for stillbirths are incomplete, there is no reason to suppose that the sex ratio in the unrecorded stillborn would differ materially from that for the recorded stillborn as given in table 1. The evidence at hand, therefore, indicates that in the rat the mortality at birth is far greater among the male than among the female young.

According to Rauber (’00), as early as the year 1660 Graunt showed that more boys than girls were born in the city of London, and this finding has been confirmed by practically every collector 328 HELEN DEAN KING

of human birth statistics since that time. Nichols’ very comprehensive table of birth statistics, to which reference has already been made, shows a sex ratio of 105.5 males to 100 females in over four hundred million living births. More recent data give practically this same ratio: thus data for 171,297 living births of white and colored children in Cuba during the period from

1904 to 1906, as given by Heape (’09), show a ratio of 105.46 .

males to 100 females; while among the 465,655 births in Massachusetts from 1910 to 1914 the sex ratio is 105.41 males to 100 females (Terry, ’17).. Statistical evidence from many different sources thus seems to warrant’ the conclusion that in all civilized countries of the World there is an excess of males among the living young; the ratio which may be considered as the norm being about 105.5 males to 100 females. This ratio, as several investigators have pointed out, is remarkably constant and is maintained “through periods of war and of peace, of famine and of plenty, and under a great variety of racial and of climatic conditions; the variations, as a rule, being not greater than one per cent” (Pike, ’07).

Available statistics for the sex of stillborn children are admittedly very incomplete, yet millions of such births have been recorded and they invariably show a fairly uniform sex ratio that differs in a marked degree from the sex ratio which is the norm for the living young. A few series of investigations may be cited to indicate the trend of such statistics in general. In the 13,635,986 stillbirths compiled by Nichols there were 131.6 males to each 100 females, the range of variation in the number of males being from 130 to 140 in the great majority of cases. In the records for stillbirths in various countries of Europe, as tabulated by Lewis and Lewis (’06), the number of males to 100 females varies from 120 to 170, with the average around 130; Heape’s (’09) data for Cuban births shows a sex ratio of 144.45 males to 100 females among the stillborn, While Hirsch (’13) gives 127.9 as the number of males to 100 females in the stillborn young recorded in Germany during 1908 to 1909; and, finally, the birth statistics of the United States for the year 1918 indicate a sex ratio of 137.1 males to 100 females among the stillborn (Davis, ’20). BIRTH MORTALITY IN THE RAT AND IN MAN 329

All of the various series of records given above show that the sex ratio in the stillborn is much higher than that in the living young, and sex statistics for aborted fetuses indicate that the excess of boys becomes greater the earlier the month of pregnancy in which the fetus dies (Rauber, ’00; Nichols, ’07; Auerbach, ’12; Carvallo, ’12). This latter fact is of great importance, since it indicates that one, at least, of the chief causes for the excessive mortality among males at birth must be sought in conditions that exist in early rather than in late stages of gestation.

In 1841 Bernoulli called attention to the fact that the sex ratio at birth is not the ratio in which the young are conceived, and he concluded that the true sex ratio for man is about .108.2 males to 100 females. This ratio is practically the same as the ‘primary’ sex ratio recently calculated by J endrassik (’11) and by Schultz (’ 18). The fact that in man the sexes are very evidently not conceived in equal numbers is a decided stumbling-block in the way of any theory of sex determination that postulates chance as the chief factor in deciding whether a given ovum shall become male or female. Morgan (’19) has recently offered the following explanation for the constant sex ratio in man:

Since male babies die oftener than females, the difference has been said to be an ‘adaptation,’ with the implication that it calls for no further explanation. Several possible solutions suggest themselves. The male-producing sperm bearing the sex—chromosome may more frequently develop abnormally than the female—producing sperm. Again, since the spermatozoa must, by their own activity, travel the entire length of the oviduct to ‘reach the egg as it enters the tube, the greater size or weight of the female—producing sperm may give a slight advantage to the male-producing sperm in the long trip up the tube. This would lead to an excess of males.

Since there is no evidence at present that one kind of spermatozoa is more active or more inclined to be abnormal than the other, it must be admitted that the above explanation for the male excess in human offspring is not an entirely satisfactory one.

A comparison of the sex ratios found in the newborn of the rat with the corresponding ones for man‘ show that they agree closely in all cases. The sex ratio that is normal for the living young at birth is practically the same in both species, being about 105.5 330 HELEN DEAN -KING

males to 100 females; in both species, also, the sex ratio in the stillborn is much higher than that in the living young, averaging about 130 males to 100 females. This striking similarity in the sex ratios of two such widely separated mammals as the rat and man is a matter of considerable theoretical interest, and it may have a practical bearing as well, since through carefully controlled experiments on the lower form it may be possible to obtain information that will help to check the appalling birth mortality among human ofispring.

Although a considerable body of statistics has been collected by Diising (’84) and by Wilckens (’86), among others, regarding the normal sex ratio in domestic animals, practically no information is available concerning the sex proportions in the stillborn. In fact, the only reference to this subject that I have been able to find is in a paper by Goehlert '(’82) which deals chiefly with the inheritance of coat color in the horse. Goehlert states that in

135,826 living foals born in various studs throughout Europe the sex ratio was 96.57 males to 100 females. Then follows this significant statement: “Derselbe steigert sich bei den todtgeborenen auf 106 bis 107 Hengst gegen 100 Stutenfohlen.” The data on which the above statement is based are not given, but if they are extensive and accurate enough to have statistical value, they indicate that the sex ratio in stillborn foals is some 10 pointshigher than that in living foals. Thus in man, in the rat, and in the horse, the only mammals for which data are at present available, the birth mortality is apparently far greater among the male than among the female young. It is not improbable that future investigations will show that this condition is characteristic of the Mammalia generally.

SEASONAL VARIATIONS IN THE PERCENTAGE OF STILLBIRTHS

It has been claimed by Diising (’84) that seasonal variations in temperature, through their action on nutritive conditions, affect not only the sex of developing fetuses, but the percentage of stillbirths as well.

The desirability of "recording data for stillborn rats according to the month of the year in which birth occurred was not realized BIRTH MORTALITY IN THE RAT AND IN MAN 331

when this investigation was begun, consequently only the data collected during the last year can be grouped by seasons as shown in table 4.

Stillbirths were recorded in the colony during every month of the year, the smallest number (3) being found in May, the largest (14) in September. On grouping the data as shown in table 4, it is seen that the 94 stillbirths were very evenly distributed throughout the different seasons, the variation in number being from 21 (spring) to 25 (autumn). The percentage of stillbirths in the total litter production, however, shows a wide range of variation in different seasons, being nearly twice as great in

TABLE 4

Showing the percentage of stillbirths in the albino rat colony from June 1, 1918, to June 1, 1919. Data arranged according to the season of the year in which birth occurred

PERCENTAGE

TOTAL TOTAL NUMBER STILLBIRTKI SEASON NUMBER OF NUMBER 0!’ OF IN TOTAL LITTERE YOUNG ETILLBIRTHB NUMBER OF‘ YOUNG

Spring (March to May) . . . . . . . . . . . . . 183 1,349 24 1.78 Summer (June to August). . . . . . 166 1,134 21 1.85 Autumn (September to November). . 120 821 1 25 3.04 Winter (December to February). . . . _ 156 1,050 24 2.28 625 4,354 94 2 16

autumn (3.04) as in summer (1.78). The data given in table 4 are, of course, too few to have much statistical value, but they seem to indicate that the percentage of stillbirths tends to vary somewhat with the season, reaching its highest point in the autumn months. Lacking adequate means of (heat regulation, rats suffer severely from high temperature, and the young born late in summer and in the autumn are, as a rule, inferior to those born at other seasons as regards their power of growth, resistance to disease, fertility, and longevity. It is not surprising, therefore, to find that this lowering of the physical tone of the animals at a definite season of the year is followed by an increase in the birth mortality. 332 HELEN DEAN KING

From an analysis of the data for over ten million births occurring in Prussia from 1872 to 1881, Diising (’84) concludes that “bei den Kindern, welche im Anfang des Jahres erzeugt und im Herbst geboren werden, zeigen sich die wenigsten (3.6 per cent), dagegen bei denen, welche im F rlihjahr gezeugt und in Winter "geboren werden, die meisten tot-geburten (4.4 per cent).” Other groups of statistics for human births do not support Diising’s conclusions, however, Thus, data compiled by Davis (’20) show that in the birth registration area of the United States during 1918 the lowest percentage of stillbirths occurred during the summer (3.07 per cent), and the highest in the autumn (3.79 per cent); while birth statistics for the city of Philadelphia covering a period of ten years (Sozinskey, ’85) and also thosefor Boston during 1891 to 1910 (Whipple, ’19) indicate no appreciable variation in the rate of stillbirths during different seasons of the year.

From available evidence it would appear that the birth mortality in man is but little influenced by the season of the year in which either conception or birth occurs. Since man has a highly developed mechanism for heat regulation, moderate changes of temperature have Very little effect on body metabolism and therefore cannot, under ordinary circumstances, influence the nutrition of the "fetus, as Diising claims.

POSTNATAL MORTALITY

Since deaths that occur among the young within a few days after birth are traceable, in many cases, to prenatal causes that are responsible for a certain proportion of stillbirths, a brief consideration of postnatal mortality is included in the present paper.

Little exact information is available, as yet, regarding the mortality among young rats during the Week after birth. The number of such deaths in any large colony is considerable, but what proportion of them is due to prenatal causes cannot be determined, since a great part of such mortality is always due to causes that are purely accidental, such as smothering of the young by the crowding of adults into the nest when they are cold or BIRTH MORTALITY IN THE RAT AND IN MAN 333

frightened and death from exposure or starvation when the young leave the nest and are not carried back by the mother.

Records kept from June 1, 1918, to June 1, 1919, show that ninety-eight rats died within three days after birth from causes that were undetermined. As during this year 4,250 living young were born in' the colony, the postnatal mortality was 2.3 per cent, or slightly greater than the birth mortality during the same period (table 2), Although the great majority of these deaths were undoubtedly accidental, some of them were unquestionably due to prenatal causes that so affected the constitutional vigor of the individual that death was inevitable. Occasionally litters are cast in which one or more of the members are very much under normal size. These small individuals are the so-called ‘runts,’ which are frequently found among multiparous mammals, and since they are usually unable to compete with the larger and more vigorous individuals of the litter in their efforts to obtain food, they generally die within a few days after birth. Under very favorable conditions some of these undersized individuals are able to survive and to reach maturity, but they never attain the size of the normal members of the litter and they are usually sterile (King, ’16). Since runts are found most frequently in very large litters cast by young females and in litters cast by females that are not in good physical condition, they are evidently individuals with relatively low initial vitality that were subjected to conditions inimical to growth during the intrauterine period; the weaker among them die soon after birth, those that survive are among the physically unfit that generally ‘drop out’ at a relatively early age.

Among the 98 young recorded as dying shortly after birth there were 42 males and 56 females, or a sex ratio of 75 males to 100 females as contrasted with a sex ratio of 141 males to 100 females in the stillborn young found during the same period (table 1). The marked difference between these two ratios is readily explicable. Factors responsible for the great excess of males among the stillborn can act only to a very limited extent in influencing the sex ratio in the young that die after birth, and postnatal mortality due chiefly to accidental causes might be ex334 HELEN DEAN KING

pected to take a heavier toll from the females, since at birth the females are somewhat smaller, as a rule, than the males (Donaldson, ’06; Jackson, ’13; King, ’15).

The question of postnatal mortality among human offspring involves so many different factors that an adequate consideration of the subject cannot be attempted here. The many investigations that have been made show that the mortality is very high during the first month after birth, averaging about 5 per cent of all young. About one-fourth of these deaths, it has been estimated, are due to improper care or to disease, the remaining can be attributed to premature birth, injuries at birth, or to congenital debility (Ashby, ’ 15; Hunter, ’18; Eastman, ’19; Dempsey, ’19).

Sex statistics for infants dying under one year of age, as collected by a number of investigators in various countries (Diising, ’84; Rauber, ’0O; Prinzing, ’06; Nichols, ’07 ; Dutton, ’10; Pinard et Magnan, ’13;Kroon, ’17; Ashby, ’15; Davis, ’l8, ’19, etc.), all show that infant mortality is considerably greater among boys than among girls, and that, while it varies considerably in different localities and under different conditions, on the average about 120 boys die to each 100 girls.

A comparison of the findings for the rat with those for man shows that in both forms the postnatal mortality is somewhat higher than the birth mortality; in the rat this mortality is chiefly due to accidental causes that seemingly tend to kill more females than males, while in man infant mortality is traceable in many cases to ‘congenital debility’ which is apparently far more fatal to males than to females.

CAUSES OF BIRTH MORTALITY

Barring accidents, there are six leading causes to one or another of which practically all stillbirths in mammals can be ascribed: 1) malposition of the fetus leading to abnormal development; 2) infectious -disease; 3) mechanical obstruction to birth, including size of the fetus; 4) physical condition of the mother; 5) age of the mother; 6) congenital debility. The part played by these various factors in the birth mortality in the rat and in man will be discussed briefly in the following sections. BIRTH MORTALITY IN THE RAT AND IN MAN

a. M alposition of the fetus and disease as causes of birth mortality

Faulty implantation is responsible for the abnormal development of many ova in the rat (Huber, ’15), but these ova, as a rule, die at an early stage and are absorbed in situ. Little is known, as yet, regarding the death in utero of older embryos. The examination of a number of gravid females indicates that this phenomenon is not as common in the rat as it is in many other multiparous mammals (Stahl and Henneberg, ’02 ; Hammond, ’14). So-called ‘monsters,’ which arise through faulty implantation and consequent inadequate nutrition of the embryo, comprise about 1 per cent of all human fetuses at birth (Mall, ’08), but they are very rare among newborn rats. In the course of an examination of over 50,000 young rats I have found but four such fetuses, and in all of these the body appeared perfectly normal, but the head was hydrocephalic.

Infectious diseases are responsible for an appalling number of deaths among human offspring and among the young of cattle, but no cases are known, as yet, in which stillbirths in the rat could be ascribed to this cause. Neither the rat scourge, so-called ‘pneumonia,’ nor other diseases common to the rat are transmitted to the fetus as far as is known. From the evidence at hand, therefore, infectious disease can be eliminated as a cause of stillbirth in the rat, though illness of the mother, as will be shown later, is a potent factor in birth mortality.

b. The size of the fetus as a cause of birth mortality

Since the size of the fetus is an important factor in human birth mortality (Diising ’84; Nichols, ’07; Dutton, ’10; Hirsch, ’13), it is conceivable that this factor may also play a role in the birth mortality in the rat. The following series of observations was made to determine this point.

Fifty-nine litters of rats, in which one or more members were stillborn, were obtained at birth. Each of the young rats was taken from the mother as soon as it was cast, the placenta was removed, and the body weight taken immediately. Data regarding the age and general physical condition of the mother at

THE ANATOMICAL RECORD, VOL. 20, NO. 4 336 HELEN DEAN KING

the time of parturition were also recorded, since these factors had to be taken into account as possible causes of birth mortality.

The body weight records for the 306 living and for the 137 stillborn young in these fifty-nine litters are shown in table 5. For purposes of later analysis the data are arranged in three groups according to the physical condition of the mother at the time of parturition.

TABLE 5

Sea: and body-weight data for living and for stillborn young in fifti —nine litters of albino rats. Groups arranged according to the physical condition of the mother at the time of parturition

uvnm YOUNG STILLBORN roam; Average Average PHYSICAL Num- Average bod Number AVGT9-Z9 body Percentcounrrrom or l_:eI"i_0f bgfilty H weig t of weli3§)<11€’a“ weight age stillln 1' W61 34 - ~ ' ' g MOTHER viduals individuals 1gir5ie§lt1;fs" mdwlduals individuals 1355331518‘ tol%3i§.if§10 etc ‘5 o"9o"9o"9c?‘9o"9o"9y°ung gma. gms. gms. gms. gms. gms. gms. gms.

1 Good 68 5l4.574.284.914.52 21 21 4.203.754.504.11 26.1 2 P001‘ 43 604.244.l74/154.42 46 28 4.154.084.404.31 41.8 3 Good, but fe maleyoung 43 414.l23.844.534.40 12 9 3.563.803.853.85 20.0

.1541524.414.134.664.39 79 58 4.113.814.363.99 30.9

In table 5 the final averages, computed from individual not from grouped data, confirm the findings of Donaldson ‘(’06), of Jackson (’13), and of King (’15), that in the rat the living male is heavier at birth than the living ‘female. They show, also, that this same relation is found among ‘the stillborn; the difference between the body weights of the two sexes averaging about 0.30 gram in each case.

In each of the three groups given in table 5, the living young, both males and females, have a heavier birth weight than the stillborn young, the final averages indicating a difference of 0.30 gram for each sex. Obviously the body-weight relations between the living and the stillborn young would be just the reverse of that shown above if the size of the individual is a determining cause of birth mortality. When the average body weights for BIRTH MORTALITY IN THE RAT AND IN MAN 337

the largest of the living and the largest of the stillborn in each group are compared, the result shows conclusively that the size of the fetus is not a cause of death at birth, since in all three groups the average body weight of the largest living individual of both sexes exceeds that of the largest stillborn individual in the corresponding group. In this instance, also, the final averages show a difference of 0.30 gram in favor of the living young.

In man multiple births are the exception, not the rule as in the rat, so in this respect conditions in these two species are radically different. It is not so much the weight of the fetus as the size of the head that is responsible for the death of many infants, particularly boys. The deaths from this cause and those due to other forms of mechanical'obstruction to birth comprise about 10 per cent of all human stillbirths, according to various observers.

The data given in table 5 show that the stillbirths formed 30.9 per cent of the total of 443 births in fifty-nine litters of albino rats. In collecting these data there was no error, gince the litters were obtained at the time of birth and all of the young recorded. In the total of 253 litters containing stillborn young that were obtained during a period of five years, the birth mortality among 1817 individuals, as registered, was 22.8_ per cent (table 1). The difference between these two sets of data would seem to indicate that at most 8 per cent of the stillbirths in the colony were not recorded. This error is not sufficiently large to invalidate any of the conclusions drawn from the records as they stand.

a. The physical condition of the mother as a cause of birth mortality

It requires but little experience in the handling of albino rats to determine from the general appearance of an animal whether or not it is in good physical condition. Alert animals of large size, having clear eyes and thick, glossy hair, are usually in excellent condition and free from disease. On the other hand, labored breathing, rough hair, dark red eyes, sluggish movements, and relatively light body weight are all evidences of poor physical condition and generally indicate that the animal is in an advanced stage of ‘pneumonia.’ 338 HELEN DEAN KING

Table 6 shows the age, body weight, and general physical condition of the fifty-nine albino females that gave birth to the young whose body—weight data are given in table 5.

The first group in table 6 comprises twenty females that were apparently in good physical condition at the time of parturition, as was indicated not only by their general appearance and behavior, but also by the fact that they weighed, on the average, over 15 grams more than the ‘standard’ body weight for breeding females of the same age (Donaldson, ’15). The average body weights of their young at birth exceeded those of the young cast by females in poor condition (cf. group 1 and group 2; table 5), thus adding more evidence that “rats in good physical

TABLE 6

Data regarding the age, body weight, and general physical condition of the fifty-nine female albino rats that cast the litters recorded in table 6

STANDARD B0 DY WE [GET

AVERAGE FOR AVERAGE

AVERAGE AGE BODY WEIGHT

  or 

‘ PARTURITION PARTURITION ‘(igg';‘_L:‘:):?: ’15) days ems. gms. 1 Good 20 202 224 .4 209 A 1 2 Poor 26 244 190 .7 220 ,0 3 Good; but female very young 13 99 143.7 146.2

condition bear young with a birth weight considerably above that of the young cast by females in poor condition” (King, ’ 15). Each female in this group gave birth to a litter that contained, on the average, two stillborn to six living young (table 5). Since these stillbirths cannot be ascribed either to mechanical obstruction to birth, to abnormal development, nor to infectious disease, it would appear that they must have been caused by some other prenatal condition that adversely affected the vitality of the young.

Examining the history of the mothers, as kept on record cards, it was found that five of the females in this group were nursing young at the time that the litter containing stillborn young was BIRTH MORTALITY IN THE RAT AND IN MAN 339

east; eight of the females gave birth to very large litters containing ten or more members; three females were over fifteen months of age at the time of parturition. No reason can be assigned for the presence of stillborn young among the offspring of the remaining four females in this group. It is possible, perhaps, that these females were in early stages of ‘pneumonia’ which had not as yet altered either their general appearance or their body weight, but had already affected their body metabolism in such a way

. as to adversely influence the development of the fetal young.

The second group in table 6 comprises twenty-six females that were obviously in bad physical condition at the time that their litters were cast. These females were, on the average, some 30 grams under the ‘standard’ body Weight for breeding females of the same age, and the birth weights of their young were very low (table 5). It is of interest to note that the percentage of stillbirths in the total number of young cast- by these females was relatively very high (cf. group 1 and group 2; table 5). The majority of the females in this group were obviously suffering from ‘pneumonia;’ three of them were in such an advanced stage of the disease that they had to be killed as soon as the litter was cast.

d. The age of the mother as a factor in birth mortality

It has already been shown that litter size in the albino rat is influenced to a considerable extent by the age of the mother (Slonaker, ’12; King, ’16 a), and it is possible that the viability of the young at birth may also be affected by this same factor.

As already noted, three of the females in the first group of table 6 were over fifteen months of age when casting a litter that contained stillborn young. These females appeared to be in good physical condition, yet their litters were very small, and seven of the eleven young cast were dead at birth. The third group of table 6 comprised thirteen females that had an average age of only ninety-nine days when casting their first litter. Although each of these females was seemingly in good health, twenty-one in the total of 105 young were stillborn (table 5). 340 HELEN DEAN KING

Since none of the females in these two groups showed any evidence of disease at the time of parturition, it is probable that the age of the mother, and not incipient ‘pneumonia,’ was the chief factor responsible for the high birth mortality in their young. The age ofieighteen months marks approximately the end of the reproductive activity of the albino female, and toward its close, as at its beginning, there seems to be a strong tendency for the females to cast fewer individuals in a litter and a relatively greater proportion of stillborn young. This phase of the subject will be discussed later.

In considering the causes responsible for stillbirths among human offspring, the age of the mother is a factor that is usually ignored or assigned a very minor role. Various series of reliable statistics, however, indicate that the birth mortality is relatively high in children of very young and of very old mothers, so evidently the age factor has greater influence in this respect than is generally assumed. The trend of statistical evidence on this point is shown by the following examples. Whipple’s (’19) analysis of the birth statistics for the city of Boston during the period from 1891 to 1910 shows that: “The percentage of stillbirths arranged according to the age of the mother gave the very high percentage of 11.1 per cent for mothers under 20 years of age, 4 per cent for age group 20-24, 5.1 for 25-29 years, 4.4 for 30-39 years, and 3.3 for ages over 40.”

Far more comprehensive data regarding the effect of the age of the mother on birth mortality among the young are given by Davis (’20) in his study of the births in the registration area of the United States during the year 1918. In a total of 1,372,329 births in which the age of the mother was ascertained, there were 46,122 stillbirths. The percentage of stillbirths was 3.9 for mothers under twenty years of age, 3.2 per cent for mothers from twenty to thirty-nine years, and 5.4 per cent for mothers over forty. This study indicates that the percentage of stillbirths is much higher in children born to mothers at the beginning and at the end of the reproductive period, and its findings are confirmed by the birth statistics gathered by The Children’s Bureau

(Duke, ’15; Duncan and Duke, ’17; Allen, ’19; Dempsey, ’19),' BIRTH MORTALITY IN THE RAT AND IN MAN

which have already been given in table 3 of the present paper. They are shown again in table 7, arranged according to the age of the mother at the time that the birth of her child occurred. It will be noted that table 3 gives a total of 5,456 births, while table 7 registers only 5,452 births. This discrepancy is due to the fact that in four cases the age of the mother was not ascertained.

Nearly 90 per cent of the births registered in table 7 were those to women between twenty and thirty—nine years of age, the remaining 10 per cent were evenly divided between women that Were under twenty and over forty. As this is about the normal distribution of births relative to the age of the mothers, a comparison of the percentages of stillbirths as given seems permissible.

TAB LE 7

Data for human births, collected by the U. S. Ch1'ldren’s Bureau (table 3), arranged according to the age of the mother at the time of parturition

PER CENT

”°3§§§'fn‘a°” ’°§$”n§'§§§§”“ WING BIRTHS BTMBIRTES 33'??? ‘$3313? OF BIRTHS

Under 20 282 263 19 6 .95 20 to 39 4,882 4,683 199 4.07 40 and over 288 268 20 6.94 5,452 5,214 238 4 .36

Table 7 shows clearly that in this set of records, as in those given by Whipple and by Davis, the percentage of stillbirths is correlated with the age of the mother. In table 7 the stillbirths formed only 4.07 per cent of all births to Women at the zenith of

the child-bearing period, while they were increased to nearly 7 .

per cent in the births to women at the extremes of the reproductive period.

When the data in table 7 are arranged according to the order of the birth, as is shown in each of the papers in which the separate sets of data are given, it is found that the percentage of stillbirths is higher for the first births and for those after the sixth than for the intermediate births. A series of birth statistics arranged in this manner is, of necessity, an age series, and it is 342 HELEN DEAN KING

more probable that the observed variations in the percentage of stillbirths depend on the age factor rather than on the number of the pregnancy.

It has been claimed that the high birth mortality in children of very young mothers is due chiefly to the mother’s ignorance of the proper hygienic laws that should be observed by pregnant women. This explanation cannot be offered to account for the increase in the percentage of stillbirths among the children of women over forty, however, since births at this age are rarely those of the first pregnancy. It seems probable that both at the beginning and at the end of the reproductive period physiological conditions incident to age are responsible in great part for the high birth mortality among the children born at this time.

e. Congenital debiltty as a cause of birth mortality

Stillbirths among human offspring not traceable to a welldefined cause are generally ascribed to ‘congenital debility,’ this term being used to indicate a lack of sufficient vitality in the fetus to render postnatal existence possible. Various series of investigations show that a very considerable proportion of stillbirths are attributed to this cause. For example, in 201 cases of stillbirths at term studied by Brothers (’96), over 50 per cent were classed as due to ‘congenital debility,’ while Waldvoge1’s (’13) studies led to a similar conclusion.

In the sense in which the term ‘congenital debility’ is used above, practically all stillbirths in the rat might properly be grouped under this heading, since in all cases so far found impaired vitality of the fetal young was seemingly the direct cause of the birth mortality; the underlying cause is discussed in the following section.

GENERAL DISCUSSION

This study has shown that in two important respects the statistics for the birth mortality in the albino rat accord in a most striking manner with those for man: 1) the sex ratio in the living young at birth is practically the same in both forms (about 105.5 BIRTH MORTALITY IN THE RAT AND IN MAN 343

males to 100 females); 2) the great excess of males among human stillborn finds its parallel in the high sex ratio which characterizes the stillborn of the rat (129 males to 100 females). In one respect only the birth records for these two forms do not agree. The normal percentage of stillbirths in human offspring (4 to 5 per cent) is at least twice that in the albino rat (table 2). This difference, however, is readily explicable. Factors which are responsible for about one—half of all human stillbirths, i.e., mechanical obstruction to birth, accidents, faulty implantation, and infectious disease, ordinarily play little, if any, part in the birth mortality in the rat. If stillbirths due to these causes are eliminated, the birth mortality among human offspring falls to about 2 per cent, which is close to the percentage of stillbirths which is seemingly normal for the albino rat when large numbers of breeding animals are kept under fairly uniform conditions of environment and of nutrition. The stillbirths in man which thus seem comparable to those in the rat, are those that, in general, are attributed to ‘congenital debility,’ this term, as already stated, being used to indicate that the fetus possesses such a low state of vitality at the end of term that it is incapable of independent existence. From the evidence at hand the great proportion of stillbirths in the rat can be attributed to the same cause.

The question at once arises as to the cause of this impaired vitality in the fetus and whether it is possible to control it so that the percentage of stillbirths will be materially decreased. If we consider those cases in the albino rat in which the stillborn young were obtained at the time of birth and the age and physical condition of the mothers noted (tables 5 and 6), it is found that the great majority of them occurred in litters of females that were suffering from disease, chiefly ‘pneumonia,’ or in those of females at the extremes of the reproductive period, while in a few cases the litters were very large or were cast by females that were suckling young at the time of parturition. Extensive series of breeding experiments extending over a period of a dozen years and covering the birth of many thousands of rats lead me to believe'that practically all stillbirths in this animal occur under 344 HELEN DEAN KING

one or another of these conditions. The one factor which seemingly might have afiected the vitality of the fetal young in all of these cases is malnutrition. _

The nutrition of the fetal young is a very complex process, and in its broadest sense it includes the absorption and the assimilation of food by the mother as well as its transmission through the placenta to the young. Any factor or physiological condition that adversely affects the normal metabolic processes upon which any phase of embryonic nutrition depends therefore indirectly influences the development of the young and may impair their vitality to a greater or less extent.

Let us consider in. some detail the effect of thevarious factors

that are apparentlyuresponsible for stillbirths in the rat. The

rat scourge, ‘pneumonia,’ is a wasting disease, and as such profoundly affects all of the normal life processes in an animal affected with it. The living young cast by females having this diseasein an advanced stage are usually very small and emaciated at birth, and their vitality is at such a low state that they are difficult to rear even when suckled by a vigorous foster—mother. There can be no question but that the fetal young suffer throughout the entire _course of their intra-uterine existence from malnutrition, since the illness of the mother must interfere with her power to assimilate food and to transmit it to her offspring. With such a handicap to their normal development, it is not surprising that a large proportion of the young are not able to survive at birth.

The suckling of young, particularly if the litter is above the norm (seven) in size, is as a rule a severe strain on the nutritive reserve ‘of the mother, as is shown by the fact that she usually loses considerable Weight during this period unless she is in excellent health and abundantly supplied with food. Not infrequently a lactating female is also carrying a second litter. If one or both of theselitters are large, the amount of food that the mother can assimilate and supply to her young, in addition to her own needs, is inadequate for the proper nutrition of all of the individuals concerned. The result is that the suckling young usually grow very slowly and show every evidence of being unBIRTH MORTALITY IN THE RAT AND IN MAN 345

derfed, and the gestation period of the fetal young is lengthened from one to several days, owing doubtless to the fact that the implantation of the fertilized ova is delayed (King, ’13; Kirkham, ’16). Here again malnutrition is obviously a factor that impairs the vitality of the fetal young and tends to increase the proportion of stillbirths. A similar explanation can be offered for the presence of stillborn young in litters of exceptionally large size. In these cases the inadequate nutrition of the young is indicated by the fact that all members of the litter are, as a rule, of small size and under normal weight at birth.

The fact that the proportion of stillborn young in litters cast by very young and by very old females is markedly greater than that in litters cast by females at the height of their reproductive activity indicates that the age of the mother is a factor of importance in birth mortality. Donaldson (’06) has shown that one year of a rat’s life is equivalent to thirty years of human life. At the age of eighteen months, therefore, a female rat corresponds physiologically to a woman of forty-five years, and it can hardly be a coincidence that this age marks approximately the end of the reproductive activity in both species. The onset of puberty does not, however, correspond as closely in the two forms, since rats breed at three months of age. Age has a profound effect on all of the normal activities of the body, and it is not surprising, therefore, to find that the immaturity of the young mother and the physiological changes in the uterus incident to the approaching menopause seemingly inhibit the metabolic processes concerned with the nutrition of the fetal young. In such cases the young often suffer from impaired nutrition, and consequently the birth mortality among them is much greater than that among the offspring of females at the height of their reproductive activity. I

It has been repeatedly demonstrated that a mature, welldeveloped albino female that is in good physical condition at the time of conception, will, if abundantly supplied with proper food during the entire gestation period, cast a litter containing only living, vigorous young that have relatively heavy birth weights. A special experiment recently made to test this point has given 346 HELEN DEAN KING

rather astonishing results. The young cast by a mature female abundantly supplied with rich food during the gestation and lactating period were twice the normal weight at birth, and at thirty days of age, when weaned, they were over 200 per cent above the average weight of rat at this age. At sixty days of age the males in this litter had an average body weight of 260 grams, which is some 300 per cent above the ‘standard’ weight for males of this age. On the other hand, inadequate feeding of breeding females invariably leads to the production of small litters containing undersized individuals in which there is a high percentage of stillbirths. -This fact was fully demonstrated in the early stages of an inbreeding experiment with these animals which has been carried on for some years in our colony (King, ’18). Even when the food supply is ample, the present study has shown that in lactating females, in those carrying a very large litter, and in those suffering from disease or breeding at one extreme of the reproductive period, physiological conditions within the body of the mother may adversely influence the various processes upon which the nutrition of the young depends and thus lead in many cases to the death of a considerable proportion of the young at birth.

Conditions of human existence are so complex and so artificial in many cases that one would hardly venture to assert that the underlying cause of all cases of ‘congenital debility’ was malnutrition of the fetus due to the age or to some abnormal physical condition of the mother, yet the evidence at hand is strongly in favor of such a view. Inadequate nutrition of the young is certainly a potent factor in the birth mortality of the rat, and it probably plays an important role in the birth mortality of other mammals, including man. The maintenance of pregnant females under environmental and nutritive conditions favorable to the health of the mother and to the adequate nourishment of the fetal young throughout the entire gestation period, not merely near its close, Would, therefore, undoubtedly lead to the birth of more vigorous young and to a marked decrease in the number of abortions and of stillbirths. BIRTH MORTALITY IN THE RAT AND IN MAN 347

Whenever large groups of human birth statistics have been analyzed it has been found that the mortality among the males is very high, the sex ratio for the stillborn being at least 25 points higher than thatin the living young. This same phenomenon appears also when a large series of birth data for the rat are examined (table 1), and it likewise is present in statistics for the horse, if Goehlert’s (’82) records are reliable. Since the disparity between the sex ratios for the stillborn and those for the living young in these various groups of statistics is fairly constant and much too great to be considered as within the range of normal variation in the sex ratio, there must be some fundamental cause, founded on a difference in the constitution of the male and female organisms, that is responsible for the excessive mortality among the males at birth. ‘

Diising (’84) discusses this subject at considerable length, and he concludes that: “Die Knaben sterben also wahrend Fotalle— bens haufiger als die Madchen, weil viele derselben sich unter ungiinstigen Ernéihrungsverhaltnissen ausbilden, wiihrend sie, da sie durchschnittlich schwerer sind, sogar mehr Nahrung beanspruchen als die leichteren Madchen.” Since from the time that the sexes can be distinguished at about the sixth week of pregnancy the excess of males among aborted embryos is greater the earlier the age at which abortion occurs (Rauber, ’OO; Nichols ’07; Auerbach, ’12; Carvallo, ’12), inadequate nutrition cannot well be considered as the primary cause of the greater mortality among male fetuses in general.

A most suggestive hypothesis that may have a very important bearing on this problem has recently been advanced by Lillie (’17) in his study of the action of sex hormones in producing the ‘free-martin’ in cattle: “It seems probable that the disturbance of the equilibrium that protects the male from the sex hormones of the mother would result in malformations of the male sex characters to a degree commensurate with the extent of the disturbance. There is, therefore, here a possible explanation for the greater mortality among male foetuses.” Our knowledge of the action of sex hormones is as yet too meager to enable us to 348 HELEN DEAN KING

advance a definite theory regarding the influence of these factors on fetal mortality.

Nichols (’07) states that three explanations are open to consideration to account for the heavy mortality among boys at birth “ (a) the initial numerical preponderance of males; (b) the greater proportion of deaths of male fetuses occurring during parturition owing to their larger size; and (c) the intrinsically much greater mortality of males than of females in the earlier period of life, both antenatal and postnatal.” Nichols assigns only a minor

role to the first two of the causes enumerated above, and he concludes that:

Obviously the main cause of the great preponderance of male still .births resolves itself into the question of the comparative mortality or

death rate of the male and female sexes during the intrauterine period of existence. . . . . it is therefore obvious that the male constitution is intrinsically weaker, less hardy, and more susceptible to morbific and mortific influences, and has less vitality and resisting power against disease, than the female. The cause of this innate disparity of vitality between the two sexes we do not know; but the fact that it exists, that the antenatal mortality and death rate of males much

exceeds that of female fetuses, accounts for the great excess of male over female stillbirths.

In the light of the recent researches in heredity it is conceivable that the inherent dissimilarity between the sexes as regards their constitutional vigor, which has been discussed in detail by Geddes and Thomson (’01), may have its basis in the germinal structure of the fertilized egg. From the Work of Guyer (10) and of von Winiwarter (’12) on the spermatogenesis of man, and of Allen (’18) on the spermatogenesis of the rat, it is known that in both of these mammals the spermatozoa are dimorphic, one kind of spermatozoa having one more chromosome than the other; both kinds of spermatozoa are produced in equal numbers and both kinds, as far as known, are equally functional. The current theory of sex determination postulates that the spermatozoa containing the extra, or X-chromosome, are ‘female-producing’ ; those lacking it are ‘male-producing.’ The fertilized ovum that is to develop into a female thus contains two X-chromosomes, while that having only the X-chromosome received from the mother BIRTH MORTALITY IN THE RAT AND IN MAN 349

develops into a male. May not the difference in the constitutional vigor of the two sexes depend, in some Way, upon the fact that the chromatin content of the female ovum is greater than than of the male ovum? One might suggest, perhaps, that the excess of chromatin brought into the egg by the ‘female-producing’ spermatozoan influences the ensuing interaction of the chromatin and the cytoplasm in such a way that the embryo becomes endowed with a constitution that is more stable and more vigorous than that of the embryo developing from an egg in which the initial amount of chromatin is less. Such an hypothesis is, of course, only tentative. Until our knowledge of heredity and of the sex-determining mechanism is greatly increased it will be futile to theorize as to the probable cause for particular characters associated with one sex or the other which seemingly do not depend upon the action of specific genes.

The great excess of males among aborted and stillborn fetuses is readily explained if we assume that, from the time of conception, the embryo that is to develop into a male has a constitution inherently weaker than that of the embryo that is to become a female. During the gestation period many factors, such as disease, unfavorable environmental conditions, physiological changes incident to age, etc., may lessen the mother’s power of assimilating food and of transmitting it to her fetal young. Under these conditions, a male fetus possessing a relatively low initial vitality would be more severely handicapped by inadequate nutrition or by conditions unfavorable to normal development than would a female fetus having a greater initial vigor of constitution and more power to resist unfavorable environmental conditions. One, therefore, would expect to find the facts exactly as shown by various series of investigations cited in this paper, namely, that at all stages of gestation and at birth the mortality among the males is far greater than that among the females.

SUMMARY

1. Birth statistics collected during a period of five years show that in a total of 31,670 newborn albino rats 415, or 1.3 per cent, were stillborn. Allowing for the probable error in recording the 350 HELEN DEAN KING

data, it would appear that under normal environmental conditions not more than 2 per cent of rat fetuses are dead at birth.

The most accurate statistics available indicate that the normal birth mortality in man is about 4 per cent. There are no data of value regarding the percentage of stillbirths in other mammals.

2. The normal sex ratio in newborn albino rats, including the stillborn, is about 107 males to 100 females; in man the sex ratio for the living young at birth averages about 105.5 males to 100 females, and if the stillborn are added the sexratio rises to about 108 males to 100 females.

3. In each year that the mortality records for newborn rats were taken there was a pronounced excess‘ of males among the stillborn, the sex ratio in the total number of such individuals being 129.3 males to 100 females (table 1).

Large series of birth statistics collected in many different countries show that the sex ratio among stillborn children is very high, averaging about 130 to 140 boys to 100 girls. The excess of boys becomes greater the earlier the month of pregnancy in which the fetus dies.

4. In the rat the percentage of stillbirths seems to vary somewhat with the seasons, being least in the spring and greatest in the autumn months when the breeding animals are suffering from the devitalizing effects of high temperature during the preceding summer (table 4). The birth mortality among human offspring does not, apparently, vary to any appreciable extent at different periods of the year. ,

5. Data collected during one year show that the moritality among young rats during the first three days after birth was 2.3 per cent, or slightly greater than the birth mortality in the colony during the same period (2.16 per cent); infant mortality in man during the first month after birth is about 5 per cent}, or 1 per cent higher than the birth mortality.

Postnatal mortality in the rat is largely due to accidental causes which tend to kill more females than males; in man the death of many infants is traceable to prenatal causes which seemingly are more fatal to boys than to girls. BIRTH MORTALITY IN THE RAT AND IN MAN 351

6. Factors responsible for a considerable proportion of the stillbirths among human offspring, such as, infectious disease, faulty implantation, mechanical obstructions to birth, including the size of the fetus, apparently play no part, ordinarily, in the birth mortality of the rat.

7. From the data obtained it appears that malnutrition is directly responsible for most of the stillbirths in the rat. Factors influencing the ‘food supply of the fetal young, such as the physical condition and the age of the mother, the suckling of young, and the size of the litter carried, are therefore the chief causes of birth mortality in the rat.

8. Available evidence indicates that both in the rat and in man the male fetus is intrinsically weaker than the female, and therefore more susceptible to prenatal influences inimical to normal development. A tentative hypothesis is advanced that the difference in the constitutional vigor of the sexes has its basis in the different chromatin structure of the male and female zygote.

TEE ANATOMICAL RECORD, VOL. 20, N0. 4 352 HELEN DEAN KING

LITERATURE CITED

ALLEN, E. 1918 Studies in cell division in the albino rat (Mus norvegicus, Var. alb.). III. Spermatogenesis: the origin of the first spermatocytes and the organization of the chromosomes, including the accessory. Jour. Morph., vol. 31.

ALLEN, N. F. 1919 Infant mortality. Results of a field study in Saginaw, Mich., based on births in one year. Children’s Bureau, U. S. Dep’t of Labor, Washngton.

ASHBY, H. T. 1915 Infant mortality. Cambridge.

AUERBACH, E. 1912 Das wahre Geschlechtsverhaltnis des Menschen. Arch. Rassen- u. Geschlechaftsbiol., Bd. 9.

BERNOULLI, C. 1841 Handbuches der Populationistik.

BROTHERS, A. 1896 Infantile mortality during child-birth and its prevention. Philadelphia. '

CARVALLO, M. E. 1912 La masculinité dans les naissances humaines. Compte Rendu Assoc. Franc. pour d’Avancement des Sciences, T. 41.

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