1987 Developmental Stages In Human Embryos - Introduction

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O'Rahilly R. and Müller F. Developmental Stages in Human Embryos. Contrib. Embryol., Carnegie Inst. Wash. 637 (1987).

Online Editor Note  
O'Rahilly R. and Müller F. Developmental Stages in Human Embryos. Contrib. Embryol., Carnegie Inst. Wash. 637 (1987).

The original 1987 publication text, figures and tables have been altered in formatting, addition of internal online links, and links to PubMed. Original Document - Copyright © 1987 Carnegie Institution of Washington.

See also the later 2010 paper by the same authors - O'Rahilly R & Müller F. (2010). Developmental stages in human embryos: revised and new measurements. Cells Tissues Organs (Print) , 192, 73-84. PMID: 20185898 DOI.

Links: Embryonic Development | Carnegie Collection | Carnegie Embryos | Ronan O'Rahilly | Fabiola Müller

1987 Stages: Introduction | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | References | Appendix 1 | Appendix 2 | Historic Papers | Embryonic Development
Historic Disclaimer - information about historic embryology pages 
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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)

Introduction

Franklin Mall 01.jpg

Franklin Mall (1911)


The norm should be established; embryos should be arranged in stages.

Franklin P. Mall

The combined use of fixation, sectioning with a microtome, and reconstruction from the resultant sections first enabled Wilhelm His, Senior, to begin to elucidate thoroughly the anatomy of individual human embryos. Indeed, His may rightfully be called the “Vesalius of human embryology” (Müller and O'Rahilly, 1986a).


Although fixatives other than spirits were introduced early in the nineteenth century, formalin was not employed until the 1890s. His devised a microtome in about 1866. (A microtome had already been employed as early as 1770.) The wax plate reconstruction technique of Born (1883), introduced in 1876, has undergone numerous modifications over the years. These, as well as graphic reconstruction, have been discussed in a number of publications, e.g., by Gaunt and Gaunt (1978). Florian, who used graphic reconstruction of the human embryo to great advantage, elaborated the mathematical background in Czech in 1928. (See also Fetzer and Florian, 1930.)


It has been pointed out that “the idea of working out a complete account of the development of the human body was always before the mind of His,” and his collaborator, Franz Keibel, proposed to provide “an account of the development of the human body, based throughout on human material” (Keibel and Mall, 1910) rather than from the comparative standpoint. The result was the Manual of Human Embryology edited by Keibel and Mall (Keibel and Mall, 1910, 1912), which was an important step in the goal of seeking precision in human embryology. The hope was expressed that, subsequently, a second attempt, “whether made by us or by others, will come so much nearer the goal” (ibid.).

The Carnegie Collection

Mall's collection of human embryos, begun in 1887, later became the basis of the Carnegie Collection (Mall and Meyer, 1921). Mall (1913) stated his indebtedness to His in the following terms:

“We must thank His for the first attempt to study carefully the anatomy of human embryos, but his work was planned on so large a scale that he never completed it…. Thus we may trace back to him the incentive for Keibel's Normentafeln, Minot's great collection of vertebrate embryos and mine of human embryos.”


In more recent years the Carnegie Collection has benefited enormously from the meticulous investigations of Bartelmez, the technical adroitness of Heuser, and the donation of, as well as research on, remarkably young specimens by Hertig and Rock. The microtomy of Charles H. Miller and William H. Duncan, the reconstructions by Osborne O. Heard, the artwork by James F. Didusch, and the photography of Chester F. Reather and Richard D. Grill, have each played a key role in the establishment of the superb embryological collection on which the present monograph is so largely based. In George W. Corner's apt comparison, the Collection serves “as a kind of Bureau of Standards.”


Links: Carnegie Collection

Embryological Seriation

His had made the first thorough arrangement of human embryos in the form of a series of selected individual embryos, numbered in the presumed order of their development. The same principle was followed in the published plates known as the Normentafeln, Page 2 edited by Franz Keibel from 1897 onward; the volume on the human (by Keibel and Elze) appeared in 1908. The limitations of the method are (l) that individual embryos cannot be arranged in a perfect series, because any given specimen may be advanced in one respect while being retarded in another, and (2) that it may prove impossible to match a new embryo exactly with any one of the illustrated norms. The need for a more flexible procedure than a mere Entwicklungsreihe soon became apparent in experimental embryology.

Embryonic Staging

In the words of Ross G. Harrison (Wilens, 1969), “the need for standardized stages in the embryonic development of various organisms for the purpose of accurate description of normal development and for utilization in experimental work has long been recognized.” Because “development is a continuous process with an indefinite number of stages” (ibid.), a certain number have to be chosen. Thus each stage “is merely an arbitrarily cut section through the time-axis of the life of an organism” (deBeer, 1958). It resembles, in Harrison's apt comparison, a frame taken from a cine-film. Stages are based on the apparent morphological state of development, and hence are not directly dependent on either chronological age or on size. Furthermore, comparison is made of a number of features of each specimen, so that individual differences are rendered less significant and a certain latitude of variation is taken into account.


Although embryonic staging had been introduced toward the end of the nineteenth century, it was first employed in human embryology by Franklin P. Mall (1914), founder of the Department of Embryology of the Carnegie Institution of Washington.


On the basis of photographs of their external form, Mall (1914) arranged 266 human embryos 2–25 mm in length in a series of fourteen stages, lettered from H to U. (A to G were to have been the earlier stages.)


Mall's successor, George L. Streeter, provided the definitive classification of human embryos into stages, which he termed “developmental horizons.” Attention was concentrated on embryos up to about 32 mm greatest length because it was believed that, during the fetal period, the rate of increment in size and weight might be large enough to provide an adequate index of relative development.


The original plan was “to cover as far as possible the earliest specimens up to fetuses between 32 and 38 mm. long, the stage at which the eyelids have come together,” and “twenty-five age groups” were envisioned (Streeter, 1942). Subsequently, Streeter (1951) decided that stage 23 “could be considered to mark the ending of the embryonic period” proper. The onset of marrow formation in the humerus was “arbitrarily adopted as the conclusion of the embryonic and the beginning of the fetal period of prenatal life. It occurs in specimens about 30 mm. in length” (Streeter, 1949). A scheme of the 23 stages, as modified and used in the present monograph, is provided in Table 0-1.


The term “horizon” was borrowed from geology and archaeology by Streeter (1942) in order “to emphasize the importance of thinking of the embryo as a living organism which in its time takes on many guises, always progressing from the smaller and simpler to the larger and more complex.” However, the somewhat infelicitous term “horizon” has now been replaced by “stage” because the latter is the simple term employed for all other vertebrate embryos. Not only was the term “stage” used decades ago by Harrison for Ambystoma and subsequently by Hamburger and Hamilton for the chick embryo, as well as by others for a variety of reptiles, birds, and mammals, but, even in the case of the human, the term “stage” was employed by Mall (1914) when he first staged the human embryo more than half a century ago. The term is simpler, clearer, of widespread usage, and can be employed as a verb (to stage an embryo) as well as a participial adjective (a staging system). Furthermore, it should be pointed out that such expressions as “at the 3-mm stage” should be replaced by “at 3 mm.” In other words, the length of an embryo is a single criterion that is not in itself sufficient to establish a stage. The term “stage” should be confined to its present-day usage in embryology (such as the 46 stages of Hamburger and Hamilton in the chick, and the 46 stages of Harrison in Ambystoma maculatum).


Additional alterations that have been made in the current work include the replacement of Roman by Arabic numerals and the elimination of the scientifically meaningless term “ovum.” Atlases based on the Carnegie system of staging have Page 3 been prepared by Blechschmidt (1973) and by Gasser (1975). Alternative systems of staging (discussed by O'Rahilly, 1973) are now obsolescent.


Stages 10–23 were published either by Streeter (1942, 1945, 1948, and 1951) or at least with the aid of his notes (Heuser and Corner, 1957). “The earliest age groups” were wisely “to be reserved to the last, so that advantage may be taken of any new material that becomes available” (Streeter, 1942). These groups, stages 1–9, which were to have been completed by the late Chester H. Heuser, became the task of O'Rahilly (1973).

Embryonic Length

Because most embryos are received already in fixative, it is more practicable for comparisons to use measurement after fixation as the standard (Streeter, 1945). The most useful single measurement is the greatest length (G.L.) of the embryo as measured in a straight line (i.e., caliper length) without any attempt to straighten the natural curvature of the specimen (Mall, 1907) and preferably (for purposes of standardization) after two weeks in 10 percent formalin (Streeter, 1920). Up to stage 10, measurements are frequently made on accurately scaled models, although the results (because of shrinkage in preparing the sections) are then smaller (by 25 percent, according to Streeter, 1942). A particularly interesting study has been made of the shrinkage of (pig) embryos in the procedures preparatory to sectioning (Patten and Philpott, 1921). Careful technique (see Heard, 1957) is naturally to be encouraged in order to keep artifactual changes to a minimum.


Table 0-1. Developmental Stages in Human Embryos

Fig. 0-1. Diagram of endometrial-decidual and embryonic-fetal relationships in relation to time. The second ovulation shown, which is followed by fertilization, is that from which postovulatory age is calculated. The last menstrual period (L.M.P.), which occurred a variable time previously, marks the beginning of the “gestational interval” (asterisk), as defined by Treloar, Behn, and Cowan (1967), who consider pregnancy (gestation) to begin with implantation, whereas others use fertilization as the starting point. Postconceptual hemorrhage in phase with menstruation would result in an apparently short gestational interval. On the other hand, an unrecognized abortion preceding pregnancy, if no menstruation intervened, would result in an apparently long gestational interval. Such possibilities, together with variability in both premenstrual and postmenstrual phases of the cycle, render menstrual data unsatisfactory in the assessment of embryonic age.


The crown-rump (C.-R.) length appears to have been introduced into embryology by Arnold in 1887 (Keibel and Mall, 1910), although the sitting height had been used as a measurement in the adult by Leonardo da Vinci. In the human embryo, from about stage 12 onward it becomes practicable to use the C.-R. length, but this measurement is less satisfactory than, and should be replaced by, the G.L., which can be used from stage 6 throughout the remainder of the embryonic and also the fetal period (O'Rahilly and Müller, 1984a). Other mensural criteria, such as foot length during the fetal period, may be employed, particularly if the specimen has been damaged. The G.L. (like the C.-R. length) should always be stated in millimeters. Particularly in the case of larger embryos and all fetuses, the G.L. of a given specimen should always be stated in preference to, or at least in addition to, its supposed age.


The embryonic lengths given in Table 0-1 indicate the suggested norms. Where possible they are based on specimens graded as excellent and after fixation. It should be stressed, however, that the figures do not indicate the full range within a given stage, especially when specimens of poor quality are included.


Body weight has been somewhat neglected within the embryonic period proper, although some data are available (Witschi, 1956a; Jirásek, Uher, and Uhrová, 1966; Nishimura et al., 1968). By stage 23, the embryo weighs about 2 – 2.7 grams.

Embryonic Age

The supposed age, as dubiously estimated from the menstrual history, is seldom useful within the embryonic period proper, and such expressions as “at the 18-day stage” should have no place in present-day embryology. Moreover, allowance should be made, but generally is not, for considerable variability in both Page 5 premenstrual and postmenstrual (Stewart, 1952) phases of the menstrual cycle (Vollman, 1977), as well as for the possibility of incorrect identification of menstruation or erroneous interpretation of its absence (Treloar, Behn, and Cowan, 1967).


The ages of very early human embryos (those of the first 3–4 weeks) have been estimated chiefly by comparing their development with that of monkey conceptuses of known postovulatory ages (Rock and Hertig, 1944). Coital history, the condition of the corpus luteum, and the appearance of the endometrium are also taken into account (Rock and Hertig, 1948). More recently, ovulatory tests are providing additional information.


When an embryo has been staged, its presumed age in postovulatory days can be gauged from an appropriate table. The term “postovulatory age” (fig. 0-1) refers to the length of time since the last ovulation before pregnancy began. Because fertilization must occur very close to the time of ovulation, the postovulatory interval is a satisfactory indication of embryonic age. “Menstrual age,” on the other hand, is a misnomer in that it does not indicate age. Furthermore, for precise timing, the words “gestation,” “pregnancy,” and “conception” should be avoided because fertilization is not universally accepted as the commencement: some authors use implantation.


In Table 0-1, the ages are based on Hertig, Rock, and Adams (1956) for stages 2–7, on Heuser (1932a) for stage 8, on Ludwig (1928) for stage 9, on Heuser and Corner (1957) for stage 10, and on Olivier and Pineau (1962) for stages 11–23. The range is not indicated but (at least for stages 10–23) it was believed by Streeter to be ±1 day for any given stage. It should be noted, however, that from stage 14 onward, the ages become increasingly greater than those given by Streeter, which were based on comparisons with macaque embryos; it is now known that such comparisons are not warranted at these stages. Thus, by the time that the embryo reaches stage 23, there is general agreement that it is not 47 ± 1 days (Streeter, 1951) but rather at least 56 days (Witschi, 1956; Olivier and Pineau, 1962; Jirásek, Uher, and Uhrová, 1966; Jirásek, 1971). It has been confirmed ultrasonically in vivo that an embryo of 30 mm is normally aged 8 postovulatory weeks (Drumm and O'Rahilly, 1977).

Normality

The majority of the approximately 600 sectioned Carnegie embryos assigned to the 23 stages are listed as normal, although variations in, and even anomalies of, individual organs are known to occur. It should not be assumed, however, that every minor defect would necessarily lead to a recognizable anomaly in later life. In the present investigation, an effort has been made to note specifically the presence of frankly abnormal specimens. Nevertheless, it is still true that “as our knowledge of the normal becomes more complete, we find that more and more young embryos which formerly were regarded as normal are not really so ... it remains impossible even at the present time, to determine in all cases whether we are dealing with a normal or an abnormal specimen, even after it has been mounted in serial sections” (Meyer, in Mall and Meyer, 1921). It may be concluded that “The Borderland of Embryology and Pathology” (Willis, 1962) continues to be an important and fruitful area of investigation.

Terminology

In accordance with current practice in anatomical nomenclature, eponyms are avoided wherever possible.

The term anterior and posterior should never be used for the early embryonic period (stages 1–12) and are best avoided until considerably later. Terms considered unsuitable are listed in Table 0-2, together with suggestions for their replacement. Unfortunately the Nomina embryologica contains a number of inappropriate terms.

Graphs

Embryonic length is shown in figures 0-2 and 0-3, and the approximate diameter of the chorion is also provided in the latter. Relative sizes at weekly intervals are illustrated in figure 0-4.

Extension of Carnegie System

The attractive idea of using a standard system of staging throughout vertebrate embryology, as espoused by Emil Witschi, has been furthered by the recent appearance of an atlas for staging mammalian and chick embryos, based on the Carnegie system (Butare and Juurlink, 1987).


1987 Stages: Introduction | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 | 19 | 20 | 21 | 22 | 23 | References | Appendix 1 | Appendix 2 | Historic Papers | Embryonic Development
Historic Disclaimer - information about historic embryology pages 
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Pages where the terms "Historic" (textbooks, papers, people, recommendations) appear on this site, and sections within pages where this disclaimer appears, indicate that the content and scientific understanding are specific to the time of publication. This means that while some scientific descriptions are still accurate, the terminology and interpretation of the developmental mechanisms reflect the understanding at the time of original publication and those of the preceding periods, these terms, interpretations and recommendations may not reflect our current scientific understanding.     (More? Embryology History | Historic Embryology Papers)



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