Philadelphia Reflections

Determining the Sex of The Human Fetus in Utero

Chapter One.

Determining the Sex of The Human Fetus in Utero

Stuart B. Blakely, M.D.

Binghamton, N.Y.

(Reprinted from

The American Journal of Obstetrics and Gynecology,

St. Louis, Vol. 34, No. 2, Page 322, August, 1937)

The diagnosis of fetal sex had intrigued interest and baffled solution for centuries before the twentieth-century invention of ultrasound, which of course greatly simplified the matter. In fact, the new technology was so cheap and simple, it essentially eliminated the question without the fanfare usually associated with such a revolution. Among peoples of all ages and areas, efforts had been made in vain to bridge the tantalizingly narrow gap between the observer and the child in its mother's womb. Classifications of means and methods employed in fetal sex diagnosis and discussions of them in each group, immediately transformed from a catalog of "superstitions" into more mundane investigations--the original purpose of this paper-- only a few decades ago. A straightforward review, however sharply revised for more contemporary viewpoints, shows how calmly astounding insights may sometimes be accepted even though they had been universal mysteries for generations.

While the logic of primitive thought is often vulnerable, it is not inferior to much that is current today. Regarding the diagnosis of fetal sex, one might fancy that it proceeded somewhat as follows, although not, necessarily, as a line of conscious reasoning. Marked changes from normal are evident in pregnant women. These changes must be due to the action or influence of the growing products of her conception. These changes vary in different women and in the same women in different pregnancies. Some of these variations must be due to some difference in the fetus. The only confidently obvious difference between a fetus and newborn is sex which must also exist before birth. This difference, I.e. sex, is almost surely the cause of at least some of these variations. The male is profoundly different from the female and has been considered to be of greater value, strength, and importance. The effect of a male fetus on the mother must likely be different in kind as well as degree, although not necessarily in timing. Therefore, the signs and symptoms of a male pregnancy probably do differ in character and degree from those a female pregnancy, but probably less than once was conjectured.

All means that have ever been used to diagnose fetal sex may be placed in two great classes: supernatural and natural.

The means employed in THE FIRST CLASS were the prophetic interpretation of numerology (still existing as late as the sixteenth century in countries as far apart as China and Italy), astrology and dreams; of the examination of the entrails of sacrificed animals and of the flight of birds; of "ordeals"; of chance happenings and occasions; and of magic formulas and other procedures. Material on this phase of the subject can be found in the first volume of Ploss-Bartels. It is interesting that the use of strictly supernatural means to determine fetal sex was never persistent or extensive, compared with the second class. I have not met nor heard of a survivor. Legendre records a French folk belief in a curious mixture of lunar influence and numerology.

The SECOND CLASS, comprising the natural means to diagnose fetal sex, from time out of mind to very present, may be further divided into three broad groups. Group 1. The supposed origin of the male from the right side of the uterus, the female from the left; and the changes in the right side of the pregnant woman's body ascribed to or imagined to result from, such origin.

Group 2. The position, outlines, attitude and activities of the fetus during pregnancy and labor.

Group 3. The effect of a male fetus on the total maternal organism; i.e. the reactions of the female body to the introduction of a male element. This is the largest and most important group.

Group 1.

A notion of antiquity was that the human uterus consisted of right and left cavities, as is normal in many animals which were the chief source of the ancients' ideas of anatomy. Since the right side has always been considered the stronger, superior and "holier" side and the male the stronger, superior and more valuable sex even in its mother womb, it followed that the male must develop in the right side of the uterus, the female in the left. Hippocrates taught that "The Male fetus is usually seated in the right, the female in the left side of the uterus. " After it became known that the human uterus is not normally duplex, the idea became current that the male came from the right ovary, the female from the left. This must have been, however, a comparatively recent development, for knowledge of the part played by the ovary and him ova in reproduction is not old. Through historic time this idea is found scattered from China to Europe; right-handed signs and symptoms point to male pregnancy. There is more pain or heaviness or more or earlier movement in, or more prominence of, the women's right side, if pregnant with a male. The right breast is larger, "softer" and more sparkling with a wider pupil. All blood vessels on the right side of the body are fuller and beat more forcibly (the sublingual being especially mentioned), and the right pulse is stronger. The right shoulder is lower, and the right thigh thicker. The woman starts off first with her right foot and supports herself more with the right hand. Salt does not melt on the right nipple, and the right nostril tends to bleed. Many, if not all, of such ideas, may be found in the "e Secretis Mulierum", a book ascribed to Albertus Magnus (1193-1280), which was widely used in the scholastic time of medieval medicine.

While right-sided signs and symptoms are no longer valued in fetal sex diagnosis, a bit of the old belief still lingers in the theory of the ovarian or ovular determination of sex. The idea that sex is determined by the egg still lives and will not die, and among men of scientific training. As a matter of fact, the last word on the subject has not been spoken. Otto Schoener published his theory in 1909 and his results in 1924 and 1925. It has given rise to a large volume of German literature. Schoener held, and still holds, that the right and left ovaries alternate continuously in their activities (an idea suggested by Bischoff in 1844); that the human ovum possesses its sex "Anlage" before fertilization; and that the sex "Anlage " changes, --possibly better said, appears--, in each ovary in the following sequence: right ovary, male; left ovary, female; right ovary, female; left ovary, male. The cycle is repeated ad infinitum. E. Rumley Dawson proposed the hypothesis that male and female determining ova are discharged from the ovaries alternately, male from the right and female from left. Both these men claim that, after the first pregnancy, it is possible to quite accurately foretell the sex of future children by a careful history of the menses (actual and missed), assisted by the palpation of an enlarged tender ovary due to the presence of the corpus luteum of pregnancy. The difficulties of these theories are quite apparent; e.g., menstruation is not always associated with ovulation nor vice versa, and the sex of children after unilateral oophorectomy does not always conform to the rules. Through many years of observing pregnant women, I have never been able to determine any right-sided signs or symptoms peculiar to male pregnancy, nor evidence of either definitely alternating ovarian activity or of ovular determination of sex. It is probably safe to deny their existence, though dogmatic statements about the physiology of sex are dangerous.

Group 2.

The position, outlines, attitude and activities of the fetus during pregnancy and labor.

Hippocrates held that the boy moves in the womb at three months, the girl at four. This idea, with variations in the actual number of the months, was once widespread. It was also thought that labor was slower with a female child. These conceits are entirely consistent with a belief in male superiority. The girl was supposed to be born "face-up," looking at the rib whence she came, a bit of Genesis perhaps, or reminiscent of the usual position at coitus.

In this group belong two modern "natural" means that have been employed in an effort to solve the problem: the x-ray (two procedures) and the rate of the fetal heart. Roentgenologists agree that the ossification of the skeleton of the female is more advanced than that of the male throughout intrauterine life; it has been suggested that this fact might be utilized to foretell fetal sex. Visualization of the fetus in utero (including the outlines of the soft parts), by rendering the amniotic fluid opaque through the injection of strontium iodide into the amniotic sac, occasionally permits the diagnosis of fetal sex, if a true lateral view of the breach is obtained (menses).

In 1859, on the basis of a study of one hundred cases, Frankenhauser suggested that fetal sex might be determined by the rate of the fetal heart in the last three months of pregnancy, a persistently slow rate (averaging 124 or less a minute) indicating a boy, and a persistently more rapid rate averaging 144 or more a minute) -- a girl. A large number of observations have been made with corresponding literature. If the male fetal heart is slower, it must be due to some peculiar influence of male sex itself, maleness per se, for which I know of no evidence; or because the male is heavier or bulkier, but the average difference in the birth weights of the sexes would seem to be too slight to have much effect; or the result of some hormonal action, as yet unknown. It is generally conceded today that the method is of no, or at least of very little value, if for no other reason than that the usual fetal heart rate falls between the figures given and so into the uncertain class. Many of the laity express a wistful faith in it. Some physicians for unworthy or obscure reasons, encourage this faith by professing, at least not denying the same. Nevertheless, it may lay claim to having been a really intelligent effort to solve the problem.

Group 3

The effects of the male fetus on the total maternal organism cells and organs, their functions and secretions.

In pregnancy, mother and child are a biologic unit. If the mother's own hormones produce well-recognized phenomena, why may not be added fetal hormones (which she surely receives) alter these phenomena in degree or character? If the male fetus introduces into her economy new or "foreign" hormones, why may these not alter her response; and, if harmful (as we know they may be), why may they not meet hormonal or humoral resistance (be protective?)? The maternal response to pregnancy may be physical, or biochemical (using the term in a broad sense), or both. Her reactions may be quantitative, qualitative or both. A discussion of these two possible types of reaction now follows.

Aristotle held that, since the female is on a lower developmental plane, a female pregnancy has less effect and makes less demand on the maternal organism than does a male pregnancy; that there is greater body warmth in a male pregnancy and therefore a better circulation; and that on these as a basis the diagnosis of fetal sex is possible. some observers today agree with Aristotle that a male pregnancy makes greater demands on the pregnant woman. There is claimed to be more iron in the male placenta; more adrenalin in male urine, and therefore (?) more in the urine of a woman pregnant with a male child. It is said that midwives in the Philippines used to prophesy the sex of the unborn child by the reaction of the pupil of a male dog's eye into which had been dropped some of the pregnant women's urine. Thinking along this line, I observed the pupillary reaction of twenty-five pregnant women on whom the Bercovitz test of pregnancy was done, to see if the contraction or dilatation of the pupil bore any relationship to the sex of the fetus. The results were negative.

The second idea, that the reaction of the pregnant woman to a male fetus is qualitatively different from that of a female fetus, is very old, runs as a common thread through most of the ancient methods of sex diagnosis, and is the basis of nearly all modern efforts to solve the problem. Hormones can and do pass the barrier of the placenta. Profound changes are produced in the pregnant woman's organ growth, circulation, skin, glands, etc.; she is often "rejuvenated". The origin must be in the fetus, a source of additional, possibly new and different, possibly even antagonistic hormones. If the fetus dies, these changes retrogress. There is no question but that a male hormone (using the singular for convenience) exists. There is some question when and in what quantity this hormone is first produced in the fetus. There is a still larger question if the male sex hormone, by circulating in the maternal bloodstream, induces or can induce recognizable specific changes in the mother's body, by acting as an antigen with the production of "antibodies" or by some hormonal effect. Every cell of the male fetus must differ from the female cells of the mother. The mother has no organ homologous with the fetal testis or the fetal tissues that produce male sex hormone. There is probably no antagonism between sex hormones as such, i.e., they do not neutralize each other when mixed together. But there does appear to be some sort of antagonism, direct or indirect, between the specific hormone of one sex and the specific hormone-producing organs or tissues of the opposite sex. Moore and Price reject Steinbach's and other's ideas of sex hormone antagonism; they admit that certain facts do point to such action but claim that the effect is indirect through the hypophysis. But compare the production of sterility by the parenteral injection of semen or even its vaginal absorption the production of agglutinins against spermatozoa, and the occurrence of freemartins and other phenomena to be discussed in the immediately following paragraphs. Does the introduction of maleness, e.g. a male fetus, into the female body produce quantitative or qualitative changes that can, possibly one might add, someday in the future, be recognized by the clinician or the laboratory worker? Is there any evidence that a male pregnancy has an effect on the mother, different in degree or character from that of a female pregnancy? In the attempt to answer these questions, let us examine further evidence which is closely bound up with the inescapable idea of some sort of sex antagonism.

Ancient relief. This must be neither, lightly regarded nor summarily ignored. The remarkable agreements of such beliefs among people widely separated in time, place and culture arrest attention. Somewhere in the welter, to be found someday by some seeing eye, maybe a little, or the little grain of golden truth. Not everything that we cannot prove scientifically is improbable.

The frequency of male abortions. The ratio of male to female abortions is at least 150 to 100. The cause must be in the "fruit". This may be the reason for nature's prodigality with male pregnancies because so many are destroyed by some unfavorable reactions to their presence in the maternal organism. Some women seem to abort all male conceptions, carrying only female to term; the reverse, at least in my personal experience, is rare. Male stillbirths are also more common, even after discounting the usual causes for this condition and the hazards of male birth itself. Cases of unexplained and of "habitual" death of fetus near or over term are 80 percent males. The excess of males among abortions and stillbirths is greatest during the first and last third of pregnancy; this may have something to do with the development of the interstitial cells in the fetal testis. While it is true that there are more male than female twins (1043:100; the ratio in single births, 1050-60: 100), due to the great preponderance of male pregnancies, the prenatal mortality of male twins is higher, and "as the number of individuals to a birth increases the relative proportion of males to females decreases. Nichols, who collected statistics of over 700,000 pairs of twins, has pointed out that the ratio of males to females decreases from 1059: 1000 in single births to 548:1000 in quadruplets. The Dionne's are girls, and so are most quadruplets of press renown. In sheep, there are over twice as many female as male triplets. For opposing view consult A.S. Parkes.

The occurrence of freemartins, in cattle and more rarely in other animals. A bovine freemartin, probably meaning "farrow heifer," is the female co-twin of a normal bull calf; the female of two-sexed twins. Cattle breeders from Roman times have known that such females are usually sterile, 87 percent or more (some observers claiming even 100 percent) instead of the normal incidence of less than 10 percent. Lillie has shown beyond all questions that a freemartin is a "blighted" female calf fetus with undeveloped or deformed sexual organs (usually internal only), and often with more or less male characteristics due to saturation with antagonistic male sex hormone from it co-twin which interferes with the normal female development. This is possible and occurs only when the chorionic or placental anastomosis between the binovular twins is early and extensive. Either the male shows an earlier sex differentiation and an earlier sex hormone is more "powerful". The former of these ideas suggest that sex is not absolutely determined by the spermatozoon but is profoundly influenced by the environment; the latter, again, the ancient thought of male superiority. Williams, in personal communication, reports "Quintuplets with two males and an asexual. Ten individuals with 4 males and six sexless. There were 8 abortions and two viable young (the twins)." Hartman believes that the process can be reversed in which a male co-twin is sterilized and made more or less asexual or intersexual (sexual intergrade) by the female. He calls these "reciprocal freemartins", and rather believes that both types do occur in man and may explain some cases of intersexuality (Novak). Contrary to a belief once held in rural England, no diminished fertility in the female of two-sexed human twins has been observed because a comparable placenta anastomosis does not occur in man. Sir J.Y. Simpson collected the married history of 123 women born co-twins with males and found that only 11 had no offspring.

Fetal malformations. As a whole, there are probably more male than female fetuses that are, malformed. Dr. D. P. Murphy of Philadelphia, in personal communication, says, "if you were able to secure figures on the sex ratio of 500 cases of any given type of defect you might well find... that the defects in most cases afflict the two sexes about equally." But the available figures show strange sex ratios of congenital deformities. Curiously enough, deformities of the brain and cord, and of congenital hip dislocation are much more common in the female. M.S. Michel of Minneapolis reported in 1928, 57 cases of craniorachischisis, of which 85 percent were female; Malpas, 44 cases of anencephaly with 70 percent females, and 80 of hydrocephalus and spina bifida with 57 percent of that sex. Of 5,494 cases of congenital hip dislocation, 84 percent were females. On the other hand of 3,309 club feet, 65 percent were males. Of 507 cases of harelip-cleft palate gathered from various sources, 55 percent were males. Ballantyne reports the sex ratio of his malformations as follows: iniencephalies, 1 male to 21 females (5 percent males); anencephalies, 10 to 30; genal fissure, 41 to 26; harelip, 180 to 118; diaphragmatic hernia, 47 to 20; preauricular appendages, 21 to 12. These percentages are approximate. He states that there are more female cyclopia and united twins; but more male urinary umbilical fistulas and polydactylies; of extroversion of bladder, male: female: "6 or 7:1"; of transposition of viscera, "2:1." I have not been able to secure much evidence for the suggestion that most pseudohermaphrodites are primarily males, the course of whose early sex differentiation has been altered by the antagonistic sex hormones of the mother. Such evidence would be very interesting. In 980 cases of placenta previa, the male-female sex ratio was 124: 100. While fetal malformations are not good witnesses to any distinctive effect of maleness on the maternal organism, still sex in some way would seem to play a part in their production.

The relation between male pregnancy and toxemia. An old belief, still alive, was that the pregnant woman vomits more if her baby is a boy. David suggests that the cause of the vomiting is something transmitted to the child from the father that is foreign to her blood; that the more the child resembles the father, the more the mother vomits; and that the pigmentation of the other parallels that of the child. In all this, no direct mention of sex diagnosis. Herrmann reports in 1,442 cases of eclampsia a ratio of male to female children of 122:100 (normal ratio, 105:100); in the last four months of pregnancy, this ratio rose to 156: 100; and in those eclamptic individuals with twins, to 173:100.

Serologic studies. These, while not conclusive, evidence a difference between male and female blood and serum greater than that afforded by chance.

The foregoing would seem to justify the conclusion that the introduction of the male element into the female body does produce effects. The mechanism by which the male fetus is protected against the antagonistic sex hormones of the mother is, at times, more or less broken down. Sufficient means and knowledge are not yet at hand to recognize such effects definitely and permit practical sex diagnosis.

The ancient ideas of the qualitative effects of a male pregnancy on the mother comprise a large number of "natural" means to diagnose fetal sex. Hippocrates said that "a woman with a child, if it is a male, has a good color; with a sense of well-being. The face is brighter, the color better, the skin clearer; she is cheerful (Arabian), happy (Indian), and untroubled (Jewish). Many of these may be explained by the belief that the increased heat production, held to be associated with male pregnancy, quickened the circulation and heightened metabolism; suggestion and wishful thinking may have played a role. Finally, however, with these as with many other ancient ideas about fetal sex diagnosis, we may be standing on the edge of an unexplored field of endocrinology.

Freckles, pigmentation, and vomiting were sometimes stated to indicate a boy, though Hippocrates held that freckles meant a girl. While "liver spots," a blotchy skin and a bad or pallid color were usually interpreted to mean a girl, pigmentation, in general, pointed to a boy. There was a widespread belief that the lack of pigmentation of the lineal alba below the naval meant a girl. The endocrinologists have here food for speculative thought. It was also an old idea that the desires of the pregnant women are an expression of the desires or will of the fetus often expressed in dreams. In India, if the pregnant woman dreamed of men's food, the baby would be a boy; in Russia, dreaming of a spring or well, meant a girl; of a knife or club, a boy (Freud?). There was no agreement in the interpretation of changes in sexual desire during pregnancy. Incidentally, the subjective sensations of the pregnant woman have never been considered of great value as evidence in fetal sex diagnosis; but this may be another entirely unexplored clinical field.

The most interesting "natural" means in Group 3, anciently used to foretell sex, have been the supposed effects of the fetus on the pregnant women's excretions: urine, milk, and sputum. A generation ago no one would have dreamed that the diagnosis of pregnancy was possible by an examination of the urine. But in ancient Egypt about 1350B.C. according to the Berlin Medical Papyrus, both pregnancy and sex could be determined by this means. "To see if the women are pregnant or not pregnant: barley and wheat are moistened daily with the women's urine, like dates or pastry in two bags. If they either generate, so will she give birth; if the wheat germinates, so will it be q boy; if the barley germinates, so will it be a girl; if they do not generate, so is she not pregnant." The idea had found its way to Europe by the seventeenth century. "Make two holes in the ground, in one place some wheat, in the other barley, wet with the women's urine and cover with earth. If the wheat sprouts first, the women have a male fetus; if the barley first, a female." The test is mentioned in the old English book, The Experienced Midwife. The manager repeated the experiment in 1933 and reported 8- percent correct prognostications, but his findings have not been corroborated. If any difference in the effect of male and female pregnant urine on the growth of these seeds does exist, it must depend on the presence of some substance produced, directly or indirectly, by the fetus.

There was a curiously widespread idea that the milk (sometimes specified as of the right breast) of a woman pregnant with a male was "tough" and thick. The test was to drop or squirt the milk onto a smooth surface, e.g. glass, a sword or a heated metal plate. If it remained conical or "stood like peas" or clotted, a male pregnancy was indicated; if it spread out or flowed off, a female. If some of the milk dropped into clear water or urine fell to the bottom, a boy was to be born; if it floated or dissolved, a girl. Another test was to knead the milk with meal into a small loaf to be baked over a slow fire; if it shriveled up or burned, a boy; if it "puffed up," a girl. It appears that these tests were occasionally, but much more rarely, applied to blood and urine. Much of the foregoing is not strange to primitive thought about sex.

With the two exceptions, marked vomiting which is still occasionally spoken of as sign of male pregnancy and sport with the pith ball, possibly the only other 'natural" means to diagnose fetal sex, existing in popular thought today, are the changes that "old women" think they discern in the shape and appearance of the pregnant woman's abdomen and back. There is by no means complete agreement; but in general, a hard, prominent, "high" and rounded and broad hip and back bespeak a male pregnancy. An abdomen sometimes described as "egg-shaped" is stated to indicate a female pregnancy. The origin and age of these ideas are not definitely known; some way has a phallic elusion from many wearied questionings and many observations, I am not willing to dismiss the matter as entirely without foundation. Possibly, an endocrine truth may be embodied in his popular persistent belief.

To digress a moment into veterinary medicine, cattle breeders have stated that the calf is more likely to be a male if the front quarters develop first in pregnancy and if the cow goes over term.

In modern times, excepting Frankenhaeuser's fetal heart study in 1859, there is no evidence that either science or scientific medicine concerned itself seriously, if at all, with the diagnosis of fetal sex in utero, until toward the end of the first decade of this century. Since then the problem has been attacked from many angles. Those in Groups 1 and 2 have already been the means employed; and the efforts, in the main, have followed the two ancient lines of thought about the effects of a male fetus on the maternal organism, the one, that they are quantitative; the other, that they are qualitative.

Excepting unsuccessful attempts to demonstrate a higher pH value in the blood of a woman pregnant with a male or a higher basal metabolic rate, the Manoiloff test is possibly the only modern example of the first idea, though not intentionally so in origin.

In ancient thought, all things had sex, which the study of language amply illustrates. The alchemists held that the elements were male and female. E. O Manoiloff, the Russian scientist, has revived that concept. He claims to be able to distinguish between male and female tissues and secretions (first in 1920), to determine the sex of the fetus by examination of the pregnant women's blood, to diagnose the sex of plants, and to separate male from female minerals. He claims sex differentiation from stone to man. As a matter of fact, female sex hormone has been recovered from minerals. Regarding fetal sex diagnosis, Manoiloff believes that a specific hormone from the fetal testis, or from the whole organism of the male fetus, passes into the maternal blood and changes its reaction. To the specially prepared blood is added an oxidizing agent, a reducing agent, an acid and an indicator. The results are determined by the absence or presence of color reaction. The idea of many investigators is that this test represents an oxidation-reduction process, of which the former predominates in the male, the latter in the female; that the substances involved parallelling the metabolic rate; and that the test is one of metabolic rate or level. It's quantitative, and not sex-specific. We are back again at the beginnings; one mark of sex is a difference in metabolic rate. Many modifications of the test have been made and its chemistry is complex; the necessary technic is delicate and subject to much possible error. Manoiloff's claim of 80 percent correct prognostications would seem overoptimistic.

A possible immunity reaction between the pregnant woman and her unborn male child has been the basis of most of the efforts of serology to solve the problem of fetal sex diagnosis during the past twenty-five years. It follows the second ancient idea that one of the effects of a male fetus on the maternal organism is a qualitative change, caused by the elaboration of specific substances, and is a predicated on the four following assumptions; (1) Even early in pregnancy there is sex differentiation in the fetus (morphologically, sex can be distinguished in a fetus 20 mm. Long and six weeks old), which becomes more marked as pregnancy advances. (2) The male secretions i.e. the "maleness," of the fetus passes into the mother's blood. (3) These secretions being "foreign" to her body cells and their products, act as antigens. (4) As a result, the mother produces "antibodies" against the invading "foreign" substances. The demonstration of these hypothetical "antibodies" has been attempted by precipitation reactions, agglutinations, complement fixation tests, the activity of ferments and allergic phenomena. The possibility must be constantly borne in mind that all such serologic tests may be invalidated by previous sensitization.

Petri experimented with precipitin reactions between a cow and steer serums and steer testis extract. Both serums gave precipitations when overlaid with the steer testis preparation, though stronger with the steer serum. The same results were obtained when antitesticular serum (from rabbits injected with this testis preparation) was tested against a cow and steer serums. Even after fractional precipitation of this antitesticular serum by cow serum until precipitation ceased, the addition of steer serum still gave a reaction. By these and other reactions he was able to determine the sex of serums in many cases, but the test was not dependable. Abraham from 1912 to 1914 conducted an extensive series of precipitin experiments. He injected rabbits with male and female pregnant serums and with male and female nonpregnant serums. Combinations and dilutions of serum from these sensitized rabbits were tested for precipitation against serums similar to those injected. His results were also not conclusive. His work stimulated investigation and his article contains an extensive bibliography.

The agglutination or immobilizations of animal and human spermatozoa by the serums of pregnant women has been briefly investigated by me. While the degree of the reactions varied from what might be called complete to none whatsoever, even the markedly positive cases did not seem to be of value in fetal sex diagnosis. Of course, it can be argued that spermatogenesis is not a function of fetal life; that it is not known to what degree "maleness" is dependent on the external secretion of the testis; and that the serums might have been from patients already sensitized. References to other work of this character have not been found.

Complement fixation tests for diagnosing fetal sex were employed by Petri using an extract of the fetal testis, inactivated navel blood, and fresh guinea pig complement. All gave hemoptysis. Others have tried to solve the problem by this method which would seem to merit further investigation. I had a personal interview with an individual who believed that he had succeeded in this method. The New York Academy of Medicine scheduled for the Section of Obstetrics and Gynecology on April 28, 1925, a paper by Isaac Fried, M.D., entitled "The Serodiagnosis of the Sex of the Fetus During Pregnancy," "by invitation." The paper was withdrawn before the day of the meeting arrived. The author's interesting, but not at all convincing, complement fixation test, featuring a very complicated, possibly even fantastic, antigen, was published in the Medical Review of Reviews, August 1924. He claimed 100 percent correct prognostications.

The principle of the Abderhalden test (the formation of proactive (?) ferments against living foreign protein) has been extensively used in trying to foretell fetal sex. Using testis instead of placenta. Waldstein and Erkler in 1913 reported positive results from the action of pregnant serum on the testis, but they considered it due to previous semen absorption and made no mention of is possible to use in fetal sex diagnosis. In 1914 Franz Lehman first suggested that fetal sex might be determined by a modification of Abderhalden test. Later, he attacked the problem himself. Koenigstein of Schauta's clinic in Vienna in 1913 found that there was more destruction of fetal, infant, and steer testis by male than female pregnant serum. In 1917 Kraus and Saudek of Bruenn published their stimulating work done in 1913 and 1914. They employed carefully prepared (kosher) steer testis and pregnant serum, claiming nearly 80 percent correct prognostications. Schaefer of Bumm's clinic tested fetal and adult human testis and calf testis with pregnant serum; the best results were obtained with a fetal testis, but the conclusion reached was that he tests were not reliable. The most determined effort to use a modified Adberhalden test in fetal sex diagnosis was made in 1924 by Luettge and v. Mertz at Sellheim's clinic, the scene of Abderhalden's original work. for a "substrate" they used carefully prepared bull testis (later, a commercial product free from amino acids), which was incubated with the serum to be tested. The high molecular proteins were precipitated from the filtrate by alcohol, using this instead of dialysis. After further filtration, the final fluid was tested for split proteins, presumably produced by the antitesticular ferments in the male pregnant serum, by a ninhydrin color reaction. In 1925 I spent a day in their laboratory, and later in the same year, tried to duplicate their results at the Kilmer Pathological Laboratory. Our first seventeen serums were diagnosed (?) correctly; the next eight were wrong. A large literature for and against the method and its accuracy exists. The originators claimed over 78 percent, even up to 98 percent, correct prognostications. Those interested may consult their book. The optical interferometric method of Loewe-Zeiss has been used by many investigators, especially P. Hirsch, to test the serum after incubation, quantitatively.

Allergic skin reactions have been the basis of a number of attacks on the problem of fetal sex diagnosis. Lehman tried skin inoculations with extract of the animal testis; Koenigstein cutaneous injection of testicular extract in pregnant animals and pregnant women. Their results were not definite. Human semen and extracts thereof, preparations of the testis (both animal and human) and male fetal blood serum have been employed in skin tests on pregnant women by scarification and intradermal injection. The reactions have been sometimes negative, sometimes slightly to markedly positive, frequently bizarre. While the results have been too conflicting to permit definite conclusions as to their ultimate value in prognosticating fetal sex, they have been without question better than those afforded by chance. The most recent report is by Davis who injects intradermally a stock \testicular extract, grades the test by the resulting wheal and reports between 80 and 90 percent correct findings. It is a hope that all these puzzling skin reactions may be better understood when the workers in allergy shall have been able to put their house in order.

Although fetal sex hormones must be the primary cause of any differences that may exist in the effect of fetal sex on the pregnant women, endocrinology to date has disappointed high hopes for solving the problem of fetal sex diagnosis. The male and female sex hormones are closely related chemically, their differentiation in the blood is difficult, and "both male and female stimulating substances can be extracted from both male and female urines" (personal communication from Dr. Carl R. Moore. With the cooperation of Mr. Jesse Briggs of the Kilmer Pathological Laboratory, I have carried on some observations of the number and prominence of the developed follicles in the Friedmann test, to determine any relationship to the sex of the child. The number of observations has been too small to warrant the ay conclusion. Dorn and Sugarman injected intravenously into immature male rabbits, whose tests must be in the inguinal canals and not in the scrotum, the urine of women pregnant in the last trimester of pregnancy. If later examination of the testes of the animal showed increased vascularity and cellularity and beginning spermatogenesis, they believed that they could conclude from their series of cases that the women were pregnant with a female fetus. They thought that they had discovered, in the urine of women carrying a female child, a true and hitherto undiscovered sex hormone which can stimulate the cells in the testicular tubules of the pubescent male rabbit and cause a precocious development." They claimed 94 percent, 80 out of 85 cases, correct prognostications. Other workers have not been able to duplicate their results. Mathieu and Palmar cite numerous references record the results of their own investigations which did not succeed in accurately diagnosing fetal sex and indulge in some interesting speculations. It was inevitable that the hormone test for pregnancy would be employed in an attempt to solve the problem. It is encouraging to remember that endocrinology is the merest infant in the world of medicine.

SUMMARY

All efforts ever made to diagnose the sex of the human fetus in utero may be placed into three groups.

Ancient beliefs about the diagnosis of fetal sex have almost entirely disappeared, but are still of interest, for ancient thought is the basis of nearly all modern attacks upon the problem.

More modern investigations of the problem have one or more representatives in each of the three groups. In the third group, serology and endocrinology have been the mean employed, with encouraging results.

Much thought has been expended and much work is done in this broad field, with its many converging paths of research, as evidenced by the appended bibliography, which is by no means complete.

In the first group are the beliefs that the male comes from the right side of the uterus or the right ovary, and that male pregnancies cause right-sided symptoms in the mother.

In the second group are the beliefs that the physical attributes of the fetus during pregnancy and labor differ in the sexes.

In the third group are the beliefs that the male fetus, through its secretions, affects the mother differently than does a female fetus. These differences in effect may be of degree or kind, and there is some evidence that they do exist. Sufficient knowledge and means are not now at hand to recognize these differences for practical use. This group is the largest.

Modern investigations of the problem have one or more representatives in each group. In the third group, serology and endocrinology have been the mean employed, with encouraging results.

Neither clinical observation, nor serology, nor endocrinology has solved the problem of the fetal sex diagnosis.

That much thought has been expended and much work is done in this broad field, with its many converging paths of research, as evidenced by the appended bibliography, which is by no means complete.

Neither clinical observation, nor serology, nor endocrinology has solved the problem of the fetal sex diagnosis.

CONCLUSION

The correct prognostication of fetal sex would satisfy a great curiosity and answer the pregnant woman's age-old question. It is true that it would not have great practical value. Research along other lines might well produce more solidly beneficent results. It may be true that such diagnosis, if possible early in pregnancy, might increase the incidence of induced abortions, though this does sound a bit timorous and farfetched. The parents made unhappy by knowing beforehand what they were going to have might easily be outweighed by those rejoicing in the knowledge that they would have a child of the sex they most desired. Its discovery might be exploited by the unscrupulous, as was salvarsan in its early history. All these and other objections have been raised. But the fact remains that no permanent harm has ever come by making the way of truth wider or smoother or straighter, or by pushing it a little farther. The diagnosis of fetal sex in utero is one of the unsolved problems of obstetrics. As such, it will remain a challenge. Someday, some eye will see clearly what men have as yet seen only through a glass darkly, or some laboratory worker will present the answer to us face to face. Clinical observation may come into its own someday, and what lies ahead in hormone study is not even dreamed of. The problem may still be solved.

Originally published: Wednesday, June 13, 2018; most-recently modified: Thursday, May 16, 2019