Book - Contributions to Embryology Carnegie Institution No.1-1

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A personal message from Dr Mark Hill (May 2020)  
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I have decided to take early retirement in September 2020. During the many years online I have received wonderful feedback from many readers, researchers and students interested in human embryology. I especially thank my research collaborators and contributors to the site. The good news is Embryology will remain online and I will continue my association with UNSW Australia. I look forward to updating and including the many exciting new discoveries in Embryology!

Mall FP. On the fate of the human embryo in tubal pregnancy. (1915) Contrib. Embryol., Carnegie Inst. Wash. Publ. 221, 1: 1-104.

   Fate of the Human Embryo in Tubal Pregnancy: Introduction | Acknowledgments | Tubal pregnancy with normal embryos | Tubal pregnancy with pathological embryos | Tubal pregnancy with pathological ova | Fertility and sterility | Implantation in tubal pregnancy | Normal implantation in uterus | Normal embryos in the tube | The trophoblast | Normal embryos from 6 to 9 mm in length | Normal embryos over 9 mm long | Conclusions regarding normal implantation | Pathological embryos in tubal pregnancy | Pathological ova in tubal pregnancy | Degeneration of villi and chorion | Summary | Cause | Normal implantation | Tubal pregnancy containing pathological embryos | Pathological ova | Addendum | Description of the individual specimens | Bibliography of papers cited | Explanation Plates 1, 2, and 3
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Cause Of Tubal Pregnancy

According to Williams, it is now generally admitted that tubal pregnancy is due to a preceding salpingitis, which interferes in some way with the downward movement of the fertilized ovum. This idea had previously been put forward by Schroeder and Tait, but as it was not definitely known at that time that fertilization takes place in the tube, the theory did not seem to explain fully the occurrence of tubal pregnancy and therefore did not meet with immediate acceptance. More careful anatomical studies by Williams and other investigators demonstrated that under certain conditions and in certain cases tubal pregnancy was due to normal diverticula from the tube lumen, which caught up the fertilized ovum in its passage towards the uterus. Nevertheless, subsequent studies have demonstrated that this would account for a very small number of cases, leaving the cause in the larger number to be explained in some other way.


The view held at the present day is supported by proof that in many cases a tubal pregnancy has been preceded by pelvic inflammatory trouble. Thus Diihrssen, Mandl and Schmidt, Klistner, Petersen, Runge, and others were able to elicit a history of gonorrheal salpingitis or of inflammatory lesions of the appendages in more than two-thirds of their cases. But, again, after it had been demonstrated that the arrest of the ovum was not always due to the destruction of the cilia by the inflammatory process, great difficulty was experienced in explaining the connection between the two conditions. In 1912, however, Opitz found definite histological inflammatory lesions in two-thirds of his specimens, and, even when they were absent, noted that the tips of many of the folds of the mucosa had become fused together, so that the section showed in places the cribriform appearance characteristic of the so-called follicular salpingitis, and as similar lesions were frequently present in the opposite non-pregnant tube, he held that they afforded a very satisfactory explanation for the arrest of the ovum. He assumed that some of the canals inclosed between the adherent folds communicated freely with the main lumen of the tube, but ended blindly at the other extremity, so that if a fertilized ovum were arrested in a cul-de-sac a tubal pregnancy would develop.


The same observer examined with great care 23 cases and found that in nearly all of them the folds of the tube were hypertrophiecl and grown together at many points, forming in transverse sections a network in the tube lumen. At other points there were outgrowths of the epithelial tube, forming glandlike structures in the muscular wall. All these changes he believed to be due to some earlier inflammatory process which had brought about the production of numerous pockets which could easily have arrested the ovum. He also found that in the majority of cases there had been sterility before tubal pregnancy had taken place. Many of the instances were in women who had borne several children, and then after a lapse of years had had a tubal pregnancy. In multiparae tubal pregnancy seldom followed immediately after marriage. These observations, taken in connection with the clinical signs of pelvic inflammation, would indicate that a slow inflammatory process had taken place before pregnancy occurred in the tube. In general, our own specimens confirm Williams's view that the chief cause of tubal pregnancy is due to a condition improperly called " follicular salpingitis." These "follicles " are in reality partitions formed by adherent folds which with the lower power of the microscope give the appearance of follicles. This condition, however, is not always present and certain investigators even deny its occurrence, but whenever I have examined with care a portion of the tube between the pregnancy and the uterus, I have nearly always found marked changes in the form of the lumen of the tube wall, either with follicular formation or numerous outpouchings of the epithelial lining. In some instances I found multiple lumina; in one there were as many as 20.


In more recent anatomical studies by Wallgren reference is frequently made to inflammatory conditions accompanying tubal pregnancy, but it is not clearly stated whether these conditions should be viewed as the cause or the effect of the misplacement of the ovum. Wallgren gives a very detailed description of four cases which he had studied in complete serial sections, thereby enabling him to give a comprehensive view of the condition of the tube wall. It is clear that such a method is more satisfactory than when occasional sections cut from different portions of a greatly enlarged tube are examined, yet I do not believe that as much is to be gained through the very laborious work of complete sets of serial sections as Wallgren would lead us to believe. Any marked alteration in the tube wall would probably cover a large area and therefore could be found in individual sections, as I have myself found and as is indicated by the studies of Opitz.


The various earlier beliefs regarding the implantation of the ovum in the uterus namely, that it must be clasped by a decidua made it extremely difficult to understand how the ovum could become attached to the tube where no decidua or only a poorly developed one appears. This difficulty, however, has now been fully overcome, since it has been shown by von Spee and by Peters that the normal ovum burrows through the mucous membrane and implants itself against the muscular wall of the uterus, the decidua forming later. A similar condition could easily take place in the tube, and an abundant experience shows us that, in case the ovum is not detached, it rapidly burrows through the thin tubal wall and causes an early rupture. 8uch an active process must necessarily be accompanied by a severe reaction, and this may account for the severe inflammatory process seen in the neighborhood of the implanted ovum in the tube. Wall.ui-cn recognizes all this and also admits that in the attachment of the ovum to the tube wall then; must be a large number of variations. He finds himself unable to describe a single normal type of implantation, for in some instances it may be due to a kink in the tube wall, in others to a congenital diverticulum, while in still others the cause may be a constriction due to an inflammatory process. For this reason he does not exclude chronic inflammation of the tube, which in some way may cause a constriction of its lumen. In fact, he is not inclined to admit that tubal pregnancy is usually due to salpingitis. The chief reason for this statement seems to be that he could not determine whether or not the marked inflammatory process observed was primary or secondary. In a study of the normal tube beyond the region of the pregnancy he was unable to confirm the work of Opitz, for in most instances he found that there is but slight change in the tube wall between the ovum and the uterus. Furthermore, in specimens containing the older embryos he did not find that the change was more pronounced than in those containing the smaller ones. To me this does not seem to be an argument against the view of Opitz.


In the earlier part of this paper it was stated that the specimens with numbers below 500 usually came to the laboratory without the tube wall, or in the examination the tube wall was omitted; later on, in specimens somewhat above 500, the tube wall was at first occasionally examined, and finally the complete examination was added to the routine. Hence it follows that in general the condition of the tube wall can be considered systematically only in the second half of the tubal pregnancies. As far as this examination has now been carried on, we can in general confirm the work of Opitz, namely, that the folds of the tube wall are hypertrophic, inflamed, and united at their tips, giving on transverse sections a reticulated appearance; in other words, they show a " follicular salpingitis." This is frequently the condition found in the uterine end of the tube, which often appears to be abnormal. When normal it is lined with delicate folds which are in no way attached to one another, nor do they obstruct the tube lumen. However, if such specimens be examined with great care, we frequently find, at the periphery of the greatest dilatation, a mass of hypertrophic and adherent folds, forming a localized follicular salpingitis, and for our purpose this is sufficiently marked to account for the lodgment of the ovum within the tube. We can readily imagine that the protrusion formed by the enlarged folds, as well as the pockets between them and the tube wall, might arrest the ovum in its descent. It may be that on account of this enlargement the cilia could not propel the ovum, nor could this be brought about by a vermicular action of the muscular wall of the tube, provided it still acts normally. Even if we admit that the ovum does have the power to wander, it would be difficult to understand how it could escape from one of these pockets in case it got caught in it. In other words, it seems quite clear that frequently localized changes in the mucous membrane of the tube are sufficiently marked in many of the cases to account for the arrest of the ovum in the tube. On the other hand, there is another possibility, namely, that the localized follicular salpingitis is due to the presence of the ovum, which in its attachment to the tube produces a marked inflammatory reaction and changes which are expressed by the hypertrophy and adhesion of the folds. If this objection could be removed definitely, it would be found that localized salpingitis is common in inflamed and adherent tubes without pregnancy. Proof of this can not be produced at present, but we already have other evidence which points in the same direction. When the ovum develops normally in the tube and becomes well adherent to the wall, the inflammatory reaction is usually slight and does not appear to be due to infection, whereas, in those cases in which the tubal folds are adherent, there is often a very marked inflammatory reaction, indicating that a bacterial infection exists; in fact, the accumulation of leucocytes is often so great as to form abscesses. This would seem to indicate that the inflammation, which expresses itself in the changes of the tube wall, in turn causes the arrest of the ovum.


Tubal Pregnancy with Normal Embryos

The minimal changes are found in the tube wall in cases in which the embryo is normal. They are more pronounced in the specimens containing pathological embryos and are most marked in those in which the embryo has been entirely destroyed and the ovum has undergone extensive degeneration.


In only 25 per cent of our specimens containing normal embryos have we data which bear upon their ages, and in only a few of these cases are there any observations on the condition of the tube wall. In 5 cases (Nos. 175, 179, 183, 387, 898) it is stated that tubal abortion had taken place. This would indicate that with the embryo normal, 10 per cent end in tubal abortion.


The first specimen (No. 109) contains a beautiful normal embryo and an extensive normal implantation of the chorion in the tube wall. This point is illustrated (plate 1) and will also be discussed more extensively later on in this article. The tube wall has not been examined with care, except where it is in apposition with the chorion. Here there is no indication of infection. The only point bearing upon this question is that the specimen came from an immoral woman.


A few additional data may be given of the specimens belonging to this group. In No. 183 there is a group of pockets in the tube wall to one side of the chorion. The same is true for specimen No. 503. In this the folds are very pronounced and each is filled with very large venous sinuses. In No. 790 there is a well-marked salpingitis. The tube folds are matted together. The chorionic membrane appears to be normal, but some of the villi are fibrous and degenerated. This specimen contains an embryo 20 mm. long, and is from a woman 28 years of age, who had been married 7 years, this being her first pregnancy. The history states that the year after her marriage she began to suffer with uterine trouble, and was operated upon by a surgeon who removed uterine polypi. Several years later she was operated upon twice for a similar condition. At the time of the operation it was found that the uterus was markedly enlarged. No doubt we are here dealing with an inflamed condition which may have been due to infection, the uterus being enlarged and the inflammatory condition expressing itself in the uterine end of the tube, which shows hypertrophy, the folds being matted together. In Nos. 867 and 898 the wall of the tube is markedly inflamed.

Tubal Pregnancy with Pathological Embryos

One-half of the specimens containing pathological embryos were accompanied with data bearing upon their age. A few data also were given regarding the condition of the lining of the tube. Specimen No. 479 came from a woman who had been suffering from pelvic attacks for at least four years. At the time of the operation it was found that the other tube was adherent to the appendix. In No. 524 a pathological embryo, 15 mm. long, was found within a large amniotic cavity surrounded by a hemorrhagic chorion at least 15 mm. thick. The tube wall around it was markedly inflamed, numerous abscesses being present. At one point within the sections made, the folds were very hypertrophic and the tips were adherent to one another, forming numerous pockets sufficient to account for the arrest of the ovary in the tube.


No. Template:CE697, which contains a small pathological embryo and a very hemorrhagic chorion, was surrounded by a slit which separated it from the tube wall. This space contained numerous folds of the tube which were united to one another, forming a reticulated zone of mucosa between the hemorrhagic mass and the muscular wall of the tube. Outpocketings and follicular salpingitis were found in the uterine end of the tube. There was no history of venereal infection or pathological change in the uterus, although the woman had aborted four times. However this may be, there was evidently a pathological condition of the tube wall sufficient to account for the tubal pregnancy.


No. 729 is an unusually interesting specimen containing a pathological embryo. The illustrations (plate 10) show a case of ruptured tubal pregnancy with the ovum still attached to the tube walls. Sections were cut through the middle of this specimen and through the tube on both the distal and central sides of the pregnancy. From the sections it is seen that the trophoblast is extremely active, eating its way through the muscular wall and into the sides of the large blood-vessels. In one instance one-half of a thick-walled artery has been eaten away, the other side, however, appearing to be perfectly normal. We have here a case in which the implantation was certainly sound. Sections through the uterine end of the tube show that the mucosa is thrown into folds, but they are not adherent to one another. The ephithelial lining, however, has formed diverticula into the muscular layer, giving a glandular appearance which will be discussed in speaking of the next group. This type of change is by no means uncommon; in one instance, instead of a single lumen, there are at least 20 lumina. Into one of these, if the main lumen should be missed, the ovum could easily implant itself. At any rate, we seem to have here a specimen of implantation in the muscular wall, because the ovum is burrowing through it so rapidly. The history of the case shows that rupture occurred at a point about 1 cm. from the uterus and that the outer end of the tube was matted together by adhesions. The woman had been married for 6 years and had been pregnant 4 times; the first two pregnancies had ended in an abortion at 6 weeks, and the third went to full term, ending in the birth of a healthy child. The patient had acquired syphilis 2 years before she was married; a gonorrheal infection was doubtful.


Nos. 567, 784, 804, 846, 881, and 882 all show pathological changes in the tube wall. In No. 804 there are out-pocketings, in No. 846 the folds in the fimbriated end are adherent, in No. 881 there are out-pocketings with adherent folds, and in No. 882 there are out-pocketings in the uterine end of the tube and follicular salpingitis on the fimbriated end, with a history of gonorrhea.

Tubal Pregnancy with Pathological Ova

In the third group of tubal pregnancies containing pathological ova there are more specimens and also more data than in the first two groups. In this group there are 47 specimens, in 40 of which we have data. It is definitely stated that in 6 cases the tube wall was normal, while in 21 it was pathological. 1 In other cases the data are of a nature to indicate that some inflammatory process may have taken place. The histological studies, however, are not complete enough to bear upon this point. Table 3 gives the main facts of these cases. It is at once seen that the changes in the tubal wall are of two varieties: (1) those in which the folds grow into the lumen, and (2) those in which the ends of the epithelial lining grow away from the lumen into the muscular coat. In both cases pockets are formed. The two varieties are well illustrated in No. 418 and No. 472. In No. 418 the ovum and the organized clot are encircled with a zone of large folds, which are matted together, expressing a very pronounced follicular salpingitis. In the free tube lumen beyond the pregnancy the hypertrophied folds anastomose freely, forming a reticulum across the lumen. In No. 472, which is from a case of hysterectomy for pelvic disease, a few fibrous villi are found in one of the tubes. These lie in a cleft within a thick tube wall. From this cleft there are a few large gland-like outgrowths into the muscular wall, forming marked pockets into which an ovum could easily implant itself. The variations of these two varieties of outgrowths are seen in succeeding specimens (Nos. 488 and 513). In Nos. 515 and 517 we have indications of infection. In the first case an infected corpus luteum was found, and in the second there had been pelvic pain for a year. In a third case belonging to this group (No. 519) a large open cavity was found within the ovary.

Table 3. 47 cases of tubal pregnancy with pathological ova

(Table to be formatted)

Table 3. 47 cases of tubal pregnancy with pathological ova

(40 with data).

No.


Menstrual age, in weeks.


Remarks.


No.


Menstrual age in weeks.


Remarks.


298


3



734


2


20 lumina on uterine end. Diverticula.


361


7


Tubal abortion.


741


20


Tube abnormal.


367


2


Youngest child 11 years old.


754


1


Follicular salpingitis.


369


3



762


6


Adhesion. One child, 5 years old.


415


6



765a



5 previous pregnancies.


418


5


Follicular salpingitis.


772


4


Tube normal.


472



Multiple lumiua near uterus.


773



Tube abnormal.


488


6


Follicular salpingitis.


775



Tube abnormal (?).


613



Diverticula from lumen of tube.


777


11


Follicular salpingitis.


515



Infected corpus luteum.


787


6


Follicular salpingitis.


617



Pelvic pains for a year.


794


7


Tube wall normal.


519



Open cavity in ovary.


8096



Outpocketings.


540



Follicular salpingitis.


809c


2


"Fimbriated end inflamed.


553



Diverticula from lumen of tube wall.


816


5


Follicular salpingitis.


561


11



825


4(?)


Tube inflamed; gonorrhea.


570


6



835



Normal tube wall.


673


11



874


7


Follicular salpingitis.


686


% .


Tube inflamed. One child, 11 years old.


889


6


Marked inflammation.


720


7


Tube wall normal (?).


891


2


Marked inflammation.


726


12


Follicular salpingitis.


892


10


Outpocketings and follicular salpingitis.


  • The tube wall has been re-examined and found to be pathological in Nos. 507, 513, 561. 567, 602, 659, 694, and 765a.


A very remarkable specimen is No. 734, which is from a tubal pregnancy with a menstrual history of two weeks (plate 9, fig. 2). The uterine end of the tube is markedly hypertrophied and shows large strands of muscular tissue, between which radiate numerous outgrowths of diverticula from the tube lumen; in fact, we may say that instead of one there are twenty lumina. A typical case of follicular salpingitis is shown in No. 726 (plate 8, fig. 5) . The tube lumen on the uterine side of the pregnancy is very large, about 5 mm. in diameter, and completely cut up by numerous anastomosing folds of its mucous lining. At some points the outgrowths are so numerous as to remind one very much of a section through the villi of the intestine. There is also evidence of infection. In the case of No. 488, which will be taken up in greater detail subsequently and for which we have a very complete history, the trouble must have originated from induced abortions, which caused pelvic trouble ending in two tubal pregnancies. Here also there is a follicular salpingitis.


Nos. 741 and 773 are especially interesting, since they indicate that the tubal pregnancy originated from a pocket in which the ovum had lodged. The first is from a long-standing pregnancy, the operation having taken place about 20 weeks after the last menstrual period. There was a large pus tube on the opposite side, while on the pregnant side was a well-organized clot containing the form of a degenerate ovum (plate 8) . On cross-sections the clot appears mottled, being oat up by numerous fibrous bands between which are fresh hemorrhages. The tube wall is also markedly inflamed. On one side the clot is penetrated by degenerated folds associated with a large mass of leucocytes. Apparently we are dealing here with secondary changes in the folds of a localized follicular salpingitis. This condition is also well represented in No. 773. Here the main part of the ovum is encircled by a crescentshaped shell composed of degenerated folds of the tube wall. The ovum had apparently eaten through the walls of one of these pockets, thus entering the main lumen of the tube, which became filled with blood, causing its distension. Lying within the lumen of the tube is a compartment from which the ovum has escaped. There has evidently been a destruction of the mucous folds which formerly produced this compartment.


Of the 9 specimens bearing numbers between 800 and 900, 8 show pathological changes in the tube wall. There are either outpocketings or a follicular salpingitis or both, often associated with a history of severe inflammation or sometimes of gonorrhea.


From the review of this group it is evident that a sufficient number of the specimens show alterations in the tube wall marked enough to allow the generalization that tubal pregnancy is usually caused by obstructions within the tube due to an inflammatory process. These changes are of two varieties; in the first, a morphological condition produces a hypertrophy of the folds within the tube, whereas in the second there is an outgrowth of the epithelial lining into the muscular coat. In both conditions pockets are formed in which the ovum lodges in its passage through the tube. Of course this does not exclude other mechanical factors, such as kinking, as the cause of tubal pregnancy.


In the older specimens examined, as, for instance, in No. 741, we see the later stage of this abnormal process, namely, the ovum eating its way through the walls of the pockets into the tube lumen. In practically all cases there is a very free hemorrhage in the tube lumen, and this helps to destroy the ovum. Finally, the ovum and clot may become completely separated from the tube wall, and if the mass is lodged within the fimbriated end it may be easily extruded into the abdominal cavity. On the other hand, if it has lodged in the uterine end this part of the tube does not appear to dilate so easily. The ovum eats into the muscular wall and usually produces perforation. In typical cases the ovum lies in the middle of the tube, and while it does not destroy the muscular wall, it becomes encircled with a mass of blood and ceases to grow. The clot organizes, and if it is not removed by the surgeon it gradually contracts and healing occurs. In many of these cases only a few degenerated villi are found in a highly organized clot.



Historic Disclaimer - information about historic embryology pages 
Mark Hill.jpg
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)
   Fate of the Human Embryo in Tubal Pregnancy: Introduction | Acknowledgments | Tubal pregnancy with normal embryos | Tubal pregnancy with pathological embryos | Tubal pregnancy with pathological ova | Fertility and sterility | Implantation in tubal pregnancy | Normal implantation in uterus | Normal embryos in the tube | The trophoblast | Normal embryos from 6 to 9 mm in length | Normal embryos over 9 mm long | Conclusions regarding normal implantation | Pathological embryos in tubal pregnancy | Pathological ova in tubal pregnancy | Degeneration of villi and chorion | Summary | Cause | Normal implantation | Tubal pregnancy containing pathological embryos | Pathological ova | Addendum | Description of the individual specimens | Bibliography of papers cited | Explanation Plates 1, 2, and 3



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