Vol. 28, No.3, March 1977 Printed in U.S.A.

FERTILITY AND STERILITY Copyright © 1977 The American Fertility Society

TUBAL PREGNANCY AND INFERTILITY

RICHARD A. BRONSON, M.D.* Department of Obstetrics and Gjmecology, University of Pennsylvania School of Medicine, Pennsylvania Hospital, Philadelphia, Pennsylvania 19107

Once in every hundred pregnancies or so, implantation occurs in an ectopic location, usually within the fallopian tube. Within weeks; ifundetected, the abnormally located embryo will either abort through the infundibulum of the tube or rupture through its wall. The outcome of this event is often hypovolemic shock, destruction of an-oviduct, and loss of fertility. Approximately onethird of such women are nulliparous. Over 50% will subsequently be unable to conceive. In the young woman attempting to become pregnant, this is particularly tragic, the more so if she has undergone reconstructive tubal surgery to improve fertility. Many factors have now combined to increase the incidence of ectopic pregnancy. Highly effective methods of contraception have led to an increasing frequency of premarital sexual relations. Not only is a younger population exposed to pregnancy, but also to venereal disease and its sequelae, pelvic inflammatory disease, infertility, and ectopic gestation. The intrauterine device has also raised the apparent incidence of tubal pregnancy by inhibiting intrauterine implantation. 1 In addition, the technical capabilities of infertility surgery have improved, so that tubal patency is being restored in a group of women at high risk for extrauterine pregnancy. This article reviews the pertinent basic physiology of nidation, examines the causes of ectopic pregnancy in women at high risk, and discusses concepts of management, with the aim of maximizing fertility and diminishing the risks of recurrent ectopic pregnancy. Received February 2, 1977. *Present address: Department of Obstetrics and Gynecology, TripIer Army Medical Center, APO San Francisco, Calif. 96438. .

PHYSIOLOGY OF NORMAL NIDATION

During its first few days of existence, the fertilized egg lies free within the tubal fluid, a medium ideal for its continuing development. Soon, however, the embryo will become one of the most actively growing tissues, and the ingredients neces~ sary for growth will no longer be able to be obtained by simple diffusion. It is this increasing need for cellular building blocks, energy sources;_ and the transfer of metabolic wastes that man" dates the need for implantation of the embryo and its close association with the -maternal circulatory system. Fertilization occurs in the ampulla of the oviduct. By comparing the time of the luteinizing hormone surge with the first appearance of eggs within uterine flushings performed serially, Croxatto et al. 2 showed that the normal transit time of ova within the fallopian tube is 1 to 2 days. Implantation is intimately linked to tubal function, not only in providing the environment for the fertilized ovum to develop to an implantation stage embryo, but also in modulating ovum transport so that the embryo arrives within the uterine cavity at an optimal time. Embryo transfers per. formed in several species have revealed that the endometrium is receptive to implantation for only a short period in early pregnancy.3-S During the immediate postovulatory period, the endometrial glands begin to secrete glycogen. This is reflected at the light microscopic level in the formation of periodic acid-Schiff-positive subnuclear vacuoles, which form on the 2nd postovulatory day within the columnar cells lining the endometrial glands. Subsequently, these vacuoles rise to the apices of the cells that make up the glandular epithelium. Glycogen is extruded into the gland lumina, supplying a convenient energy 221

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source for the implantation embryo. During the next 4 days, the stroma becomes more edematous, which may aid trophoblast penetration of the endometrium. Prior to implantation, the embryo has cleaved several times, developed a fluid-filled cavity (the blastocele), and differentiated into two distinct tissues: inner cell mass and trophoblast. The fetus will ultimately develop from the former, and the trophoblast will take part in the penetration of the endometrium and placenta formation. At this late preimplantation stage, the embryo, now termed a blastocyst, has become an ovoid structure approximately 0.2 mm in length. During its passage through the fallopian tube, the preimplantation embryo is surrounded by an acellular membrane, the zone pellucida. This structure has served to quarantine the embryo from the oviduct. It acts primarily to prevent contact of the embryo with the oviductal epithelium. If one removes the zona either mechanically or enzymatically, the embryo adheres to the oviductal epithelium and transport is prevented. 6 • 7 Implantation of the human blastocyst begins on the 6th postovulatory day. The very first stage of nidation, attachment of the trophoblast to the endometrial epithelium, has not been observed in humans, but is assumed to be similar to that in the rhesus monkey. The trophoblast overlying the inner cell mass hypertrophies and forms a syncytium, which penetrates into the endometrial stroma. As implantation progresses, in the human, more and more foci of syncytiotrophoblast form from the original thin trophoblastic shell of the blastocyst and penetrate into the endometrium, which is edematous but not decidualized. s Trophoblast also produces chorionic gonadotropin. 9 This glycoprotein shares with luteinizing hormone, the pituitary gonadotropin, the ability to bind to corpus luteum receptors and stimulate progesterone production. In the human, the placenta does not produce progesterone in amounts sufficient to maintain pregnancy until after the 6th week following fertilization. 10 The maintenance of pregnancy is dependent upon continued ovarian luteal production of progesterone stimulated by the trophoblastic gonadotropin. By the 9th postovulatory day, the blastocyst is completely implanted beneath the surface epithelium. The syncytiotrophoblast, derived from the inner, less-differentiated, cytotrophoblast,l1 forms the outer invasive margins of implantation. At this stage, the embryo is still not much larger than the original preimplantation

blastocyst (0.3 mm diameter). Toward the end of this day, the invading trophoblast digests the walls of hypertrophied endometrial capillaries near the implanting embryo. Maternal blood fills the lacunar spaces developing within the syncytiotrophoblast. Decidualization and glandular gestational hyperplasia are now prominent features within the endometrium. Endometrial stromal cells have hypertrophied, obliterating the previously extensive areas of interstitial edema. The borders ofthese cells come to lie in close contact, and intercellular junctional complexes may be seen in electron micrographs. 12 ETIOLOGY OF ECTOPIC PREGNANCY AND THE HIGH-RISK PATIENT

The common denominator in ectopic pregnancy is a delay in transport of the fertilized ovum from the site of ovulation to the uterus, giving time for the embryo to reach a stage of development in which invasive trophoblast has developed. It is now clear, however, that delayed tubal transport, while a necessary condition for tubal pregnancy, is not sufficient to explain the pathogenesis of ectopic implantation in humans. Ectopic pregnancy is exceedingly rare in other species, and even in the nonhuman primate it is rather uncommon. 13 The experimental production of delayed ovum transport, in several species, by the use of hormones or ligature of the oviduct fails to result in tubal implantation. 14• 15 That these embryos, confined to the oviduct, possess the capacity for development has been. demonstrated by transferring them to the uterus, where implantation proceeds normally. Our species, then, is peculiar in its propensity for tubal pregnancy. Decidual reactions are common within the fallopian tube during pregnancy, as demonstrated at postpartum sterilization. 16 It has been theorized that this capacity of the fallopian tube to undergo decidualization may playa role in ectopic implantation. Studies in rodents have provided evidence that trophoblast invasion may be modulated by decidualization of the endometrial stromaY Following implantation of blastocysts in the non. pregnant uterus, where the endometrium is unable to decidualize, penetration of the trophoblast occurs in an uncontrolled manner, through the uterine musculature, to reach the uterine serosa. IS Implantation within the human uterus, however, begins prior to decidualization of the endometrium, so that extrapolation of experiments in other species may not be valid.

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Penetration of the endometrial (or tubal) epithelium appears to be a critical step in implantation, and may be the factor determining whether tubal implantation will occur. Experimentally produced extrauterine pregnancies have been studied in rodents. It has been found that blastocysts possess the capacity for growth at ectopic sites within the parenchyma of the kidney, spleen, and testis. I9, 20 On the other hand, fertilized rat and mouse eggs given access to the peritoneal cavity implant only rarely.21 This appears to be due to the inability of rodent trophoblast to penetrate intact epithelium. Uterine implantation of blastocysts can occur in the nonpregnant uterus, but only if the endometrial epithelium has been previously damaged. It appears that, during normal pregnancy, alterations occur within the endometrial epithelium, perhaps under the influence ofthe various steroid hormones, that allow trophoblast penetration. 22 Clinical experience has amply documented the fact that, following tubal abortions in humans, ectopic gestations may go on to implant within the peritoneal cavity and continue to grow. This observation would suggest that human trophoblast has the capacity to penetrate peritoneum, a phenomenon which has not been seen in experimental animals. This increased invasiveness of human trophoblast could be an important factor leading to tubal implantation. Diverse causes may contribute to delay in ovum transit and lead to a high risk of tubal implantation. These factors include peritoneal adhesions and tubal diverticula (the sequelae of salpingitis), congenital diverticula, fibrosis associated with the operative trauma of tubal reconstructive surgery, and, in theory, functional aberrations in tubal motility. At laparotomy for ectopic pregnancy, residua of pelvic inflammatory disease have been evident in 30% to 50% of cases. 23 In the remaining 50% of women, the adnexa appear normal. The external appearance of the fallopian tube may not, however, be a true reflection of its normalcy. A significant amount of bridging of the tubal plicae, destruction of the tubal mucosa, and fibrosis of the wall of the fallopian tube can occur without the development of peritoneal adhesions or hydrosalpinx. In two large series, histologic examination of apparently normal tubes involved with ectopic pregnancy revealed the presence of diverticula in high frequency, although it was unclear whether these were formed on a congenital basis or were acquired secondary to endosalpingitis. 24,25

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Transperitoneal migration of the ovum has also been implicated, in roughly 20% to 50% of cases, by the finding of a corpus luteum in the contralateralovary.26 It is not known how often following ovulation ovum pickup occurs by the fimbria of the contralateral fallopian tube that is on the side opposite the ruptured follicle. Experimental evidence in the guinea pig suggests that this event may occur following 15% of ovulations,27 thus it is unclear whether the finding of a corpus luteum contralateral to a tubal pregnancy is merely a reflection of normal, crossed, ovum pickup or indicates that trans peritoneal migration of the ovum predisposes to ectopic pregnancy. Grant28 has suggested that women who exhibit recurrent cornual spasm during tubal patency testing are at greater risk for ectopic pregnancy. There is a large body of experimental evidence to suggest an interplay among catecholamines, prostaglandins, and gonadal steroids in modulating tubal motility.29, 30 Although no convincing clinical data are available, in theory an imbalance in any of these factors could lead to a functional delay in ovum transport. Experience has been uniform that there is an increased chance of recurrent ectopic gestation and a high incidence of infertility following tubal pregnancy.31, 32 Ten to twenty per cent of pregnancies which occur in women who have had prior tubal pregnancy will be recurrent ectopic tubal gestations. Diverse causes may lead to both the initial occurrence of tubal pregnancy and predispose to a later recurrence. In only certain instances may these factors be corrected by operative intervention. Damage to the adnexal structures subsequent to ectopic gestation or secondary to pre-existing salpingitis is amenable to surgical correction. If normal anatomy could be restored and all postoperative adhesions prevented, the incidence of ectopic pregnancy would be greatly diminished. Indeed, the risk of tubal pregnancy following all types oftubal reconstructive surgery is dependent upon minimizing postoperative adhesion formation. The incidence of ectopic pregnancy following infertility surgery varies markedly from series to series. Many factors, including surgical technique, the type of procedure performed, and regimens to suppress fibroplasia, interact, leading to a resultant risk of ectopic pregnancy. In theory, the incidence of ectopic pregnancy would be greatest following those reconstructive procedures which predispose to delayed ovum transport and least in cases that minimize this possibility. During cornual implantation of the fallopian tube

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for proximal obstruction, the interstitial and isthmic portions are excised. These segments of the oviduct are involved in the retention of the ovum within the fallopian tube, and their excision then might actually reduce the transit time of the embryo within the tube and lessen the chances for ectopic implantation. 33 The anastomotic site, however, is also subject to fibrosis and stricture, which of its own accord might contribute to delayed passage of the ovum into the uterine cavity. The balance of these opposing factors, in each patient, will determine the outcome of surgery. The state of the endosalpinx is also not a constant. Occlusion of the proximal fallopian tube could occur as a result of salpingitis isthmica nodosum, gonorrheal salpingitis, postabortal endometritis, or sterilization procedures. These factors may well explain the disparate incidence of ectopic pregnancy reported in several large series following tubal reimplantation (0% to 20%). The tubal mucosa would be expected to be least damaged in those cases in which cornual tubal reimplantation was carried out to reverse prior sterilization. Included in a series recently reported by Siegler and Perez34 were 22 pregnancies in 124 patients undergoing tubal implantation, of which two were ectopic. Hellman35 has reported 272 cases of tubal reimplantation for various causes (performed by 51 surgeons) with a 9% incidence of ectopic implantation (4 of 43 pregnancies). The incidence was 4% in Grant's series36 of 192 cases, while in Williams' survey37 of 107 conceptions following 639 implantations for all causes of isthmal or interstitial occlusion, 19% were ectopic. In cases of midsegment tubal reanastomosis, patency may be restored, allowing passage of sperm distally, yet stricture of the fallopian tube at the anastomotic site might narrow the lumen sufficiently to delay ovum transport. The incidence of ectopic pregnancy following this procedure again varies widely from series to series, but is in general higher than that reported for tubal reimplantation. An incidence of 50% has been reported in some of the earlier reports.38 With the use of finer sutures and microsurgical techniques, surgical trauma is minimized and an incidence closer to 10% to 20% is to be expected. 39 The incidence of ectopic pregnancy following salpingostomy is reported to be within the same range. The use of Silastic hoods or early hydrotubation has improved the success of these procedures, as far as patency and pregnancy rates are concerned. 40 The evidence is also suggestive

March 1977 that the risk of ectopic pregnancy is also lowered. Grant,36 in 103 patients, has reported tubal implantation in 3 of22 pregnancies following salpingostomyonly. No ectopic pregnancies were noted in 25 pregnancies in 53 cases of salpingostomy with early hydrotubation. 36 A STRATEGY TO MAXIMIZE FERTIlJTY

Tubal implantation is often a clear indication for salpingectomy. There is no argument with this approach when rupture of the pregnancy has led to hemorrhage and extensive tubal damage. On the other hand, when confronted with an unruptured ectopic gestation, an alternative approach would be to conserve the involved tube. The choice of approach in this case is a difficult one and must rest upon the individual merits of each case. Factors of primary concern are the patient's desire for future fertility, the state of the contralateral tube, and the underlying cause of the ectopic gestation. Thus, when a woman desires no future children, sterilization by excision of the involved tube and tubal ligation of the contralateral side are indicated. When maintenance of fertility is desired and the uninvolved side is grossly damaged, again, the decision to conserve the involved site is clear. Further experience must be gained before the best approach can be unequivocally stated in cases where the contralateral tube appears normal. Salpingectomy has been the more routine procedure of choice. If this policy is adopted, a word of caution is in order. It should be noted that the normal gross appearance of a fallopian tube does not exclude the possibility of tubal occlusion due to prior endosalpingitis. Thus intraoperative tubal lavage would be of benefit in making such a decision. There is a growing body of experience that conservation of the involved tube increases the likelihood of future fertility without increasing the subsequent risk of recurrent ectopic pregnancy.41-44 When such an approach is taken, various strategies are indicated, depending upon the site of tubal pregnancy. In roughly two-thirds of cases, implantation occurs within the ampulla of the fallopian tube. 45 In unruptured cases, or when loosely attached to the fimbria, the pregnancy may be expressed through the tubal ostium and bluntly separated from the tube. There is some controversy over this approach. Grant 28 has stated that the greatest success, in terms of maintenance of fertility and prevention of recurrent tubal pregnancy, is related to the least surgical

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manipulation, that is, expressing the conceptus through the tubal ostium. On the other hand, Timonen and Nieminen41 have presented evidence that the incidence of recurrent ectopic pregnancy is higher after this procedure than any other. Twenty-one per cent of women who became pregnant following expression of a tubal gestation through the tubal ostium had a subsequent extrauterine pregnancy, compared with 12% of women who had salpingostomy. They questioned whether squeezing the tube completely evacuated the ectopic pregnancy. Remaining trophoblastic tissue within the lumen might cause adhesions of tubal plicae that predispose to delayed ovum transit and subsequent tubal implantation. Tompkins46 advocates a linear incision on the antimesenteric aspect of the tube, with one blade of a straight scissors through the ostium. The tubal pregnancy is then evacuated under direct vision. Following achievement of hemostasis, the incision is left open and is not approximated, as this may be technically difficult because of mucosal edema. Closure of the salpingostomy may actually predispose to additional operative trauma to the tube. Kistner and Patton47 have also adopted this approach. This technique, while allowing the extrauterine pregnancy to be completely enucleated from the tubal lumen, would appear to increase the risk of fimbrial damage secondary to the surgical incision through the tubal ostium. In this author's opinion, a linear incision just proximal to the fimbria is least likely to traumatize that area. Jarvinen et al,42 have adopted use of a blunt curette to help evacuate all products of conception from the tubal lumen. The use of a narrow jet of saline applied to the tubal implantation site with a 23-gauge needle mounted on a syringe is helpful in defining individual bleeding points. Hemostasis should be scrupulous, to avoid later hematosalpinx. The use of electrocautery, particularly with a bipolar instrument, is particularly advantageous. Often, the involved portion of tube is quite friable, and fine suture easily pulls through. The author concurs with Hallatt23 that restoration of normal anatomy by closure of the salpingostomy is of benefit. It is not necessary to carry out a layer-by-layer closure, which may be technically difficult. Rather, interrupted seromuscular stitches of 5-0 Dexon, placed so that the knot is buried and tied loosely to just approximate the serosal edges, will achieve ultimate tubal patency. The lumen narrows appreciably in the proximal portion of the fallopian tube, making linear salpingostomy technically difficult. There is a great

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risk of incomplete evacuation of the products of conception, with increased risk of later tubal occlusion. Therefore, if the isthmal portion of the tube is involved, resection of the isthmus is in order. Cornual reimplantation may then be carried out at a later date. Although some advocates of tubal conservation have suggested that reconstructive surgery be carried out at the time of laparotomy for the ectopic pregnancy, there are good reasons for delay until a later elective laparotomy, even if conditions are stable. In cases of ectopic pregnancy, the adnexal structures may often be edematous and hyperemic, making this a suboptimal time for tubal reconstruction and predisposing to postoperative adhesion formation and tubal occlusion. In addition, the strategy of surgery could be altered, depending upon whether the involved tube were to remain patent or become occluded following the initial linear salpingostomy. Thus, while involving a need for future surgery, if maintenance of fertility is the desired goal it would be better to perform an elective laparotomy at a later date, at which time both the residue of the ectopic gestation and the pre-existing adnexal disease may be corrected. Unruptured ectopic pregnancy of the midportion of the fallopian tube could be treated by either resection and later end-to-end reanastomosis or by linear salpingostomy. Hallatt,23 Timonen and Nieminen,41 Jarvinen et al.,42 and Skulj et a1. 43 have each provided evidence that the latter approach will restore tubal patency and maintain fertility. Thirty per cent of women status-postsalpingectomy for ectopic pregnancy had normal term pregnancies in Timonen and Nieminen's seriesY In the group undergoing linear salpingostomy, 36% had term pregnancies. Of 92 patients in whom the involved fallopian tube was conserved, 76 had later documented bilateral tubal patency. In another study, 24 of 32 such patients had bilateral tubal patency. This would indicate that fallopian tubes involved by ectopic pregnancy can be salvaged without loss of patency. In the series reported by Timonen and Nieminen,41 12% of women following linear salpingostomy had recurrent ectopic pregnancy. This figure compares favorably with the quoted 9.5% recurrence rate in females following salpingectomy and would suggest that conservation of the involved tube does not increase the risk of recurrent disease. Another factor that leads one toward a policy of tubal conservation is the possibility of damage to the uninvolved contralateral tube as a conse-

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quence of ruptured ectopic pregnancy. About 50% to 60% of women with ectopic pregnancy will have residual damage of the uninvolved fallopian tube. Although pre-existing tubal disease predisposes to both ectopic pregnancy and infertility, Grant28 has presented evidence that tubal damage may also be sustained at the time of ectopic pregnancy, with periadnexal adhesions acquired during postoperative convalescence. Re stated that unclotted blood has been shown to produce inflammatory reactions within the tubal serosa and that blood clots may also organize and lead to adhesion formation rather than resorb. 28 A different approach has been advocated by Jeffcoate 48 to improve fertility following extrauterine pregnancy. Re has suggested that, if the contralateral tube and ovary appear normal, salpingo-oophorectomy should be performed on the involved side. Ris rationale was that, on the average, ovulation occurs 50% of the time from each ovary. Ova from the ovary remaining in situ following ipsilateral salpingectomy would probably be lost in the peritoneal cavity and not fertilized, or, iffertilized in the peritoneal cavity, transperitoneal migration to the opposite tubal ostium might increase the risk of ectopic pregnancy due to this delay in tubal ovum pickup. An approach that advocates removal of a normally functioning organ must be carefully scrutinized, however sound the theoretical arguments. Despite the advocacy of this policy more than 20 years ago, review of the reproductive experience of such women undergoing salpingo-oophorectomy, as compared with others treated solely with salpingectomy, has failed to reveal convincing evidence of an increase in fertility.32.49 Thus, while Bender50 found an increased conception rate when comparing salpingo-oophorectomy for ectopic pregnancy with salpingectomy (56.8% versus 42.7%, respectively), there was no difference in the rate of recurrence of tubal pregnancy (14% versus 16%). In another series, the conception rates were comparable for both groups, while the incidence of recurrent ectopic pregnancy was 59% following salpingo-oophorectomy versus 46% following salpingectomy.32 As the authors note, the extent of pre-existing tubal disease may influence the choice of operation performed as well as the ultimate outcome, so that the populations being compared may not truly be comparable. Recently, circumstantial evidence has been provided confirming the validity of this approach to improve fertility. In a study by Scott et al.,51 a number of patients with established infertility and extensive unilateral adnexal disease were

March 1977 treated by resection of the diseased tube and ovary, with subsequent restoration of fertility. In order to minimize the trauma done to the fallopian tubes by ectopic pregnancy, the following principles should be adhered to: There should be a high index of suspicion as well as utilization of those newer diagnostic modalities which would lead to early diagnosis of ectopic pregnancy prior to hemorrhage. The recent development of sensitive assays for human chorionic gonadotropin can enable one to detect pregnancy as early as 2 weeks following conception (the time ofthe first missed period).52 The immunologic agglutination pregnancy test is reliable only at human chorionic gonadotropin (RCG) concentrations above 700 IUlliter of urine, making this test highly unreliable in the diagnosis of extrauterine pregnancy. Indeed, prior studies have documented these pregnancy tests to be positive in only 50% of ectopic gestations. 53 Serum assays for RCG have not only an increased sensitivity, but also provide a quantitative determination of serum concentration. RCG levels during tubal implantation are generally lower and fail to rise to the same extent as compared with normal intrauterine pregnancies. 54 Low serum RCG levels have also been found in association with abnormal intrauterine gestations which are destined to abort, usually in the first trimester. Physical examination will often not be helpful in distinguishing between these possibilities, as the uterus may enlarge to 8 to 10 weeks' size on the basis of the hormonal changes of pregnancy, without the presence of a conceptus within the uterine cavity. In these cases, ultrasonography may be of value. B-scan of the uterus and adnexa may document a gestational sac within either the uterus or fallopian tube. Confirmatory evidence of an abnormal intrauterine pregnancy may be provided (e.g., irregular gestational sac). At approximately 10 weeks' gestation, the gestational sac fills the uterine cavity. The decidua capsularis fuses with the decidua vera, and at this time the sac is lost to ultrasonic visualization. A sonic ally blind period exists until 14 weeks, when the fetal head is detected. Examination under anesthesia and laparoscopy may often be necessary to differentiate a corpus luteum of pregnancy from a tubal gestation. In those cases where intra-abdominal bleeding is suspected, especially when sensitive assays for RCG are not available, culdocentesis still remains a simple means of sampling the peritoneal cavity.55 It is hoped that, by a combination of these

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approaches, extrauterine pregnancy will be detected prior to tubal rupture and hemorrhage. At laparotomy, if tubal rupture has occurred, defibrinated blood clots, trophoblast, and decidua should be lavaged free of the peritoneal cavity with warm physiologic saline. Conservation of the involved fallopian tube should be practiced, as previously outlined, if the fimbriae have not been damaged and fertility is desired. Several series have advocated the use of postoperative hydrotubation with hydrocortisone in an attempt to maintain tubal patency and prevent periadnexal adhesions. Bilateral tubal patency rates of 75% to 80% have been achieved by using this methodology following conservation of the involved fallopian tube. 28 • 41, 42 While this technique has been objected to on theoretical grounds of an increased risk of pelvic infection, these fears have not uniformly been borne out. The status of the adnexal structures should be carefully evaluated postoperatively, especially when the involved fallopian tube cannot be salvaged. Hysterosalpingography may be performed after a period of convalescence, to document tubal patency. When normalcy of the adnexal structures is in doubt, and in those women who have failed to conceive within the year following their initial episode of extrauterine pregnancy, laparoscopy is indicated.

CONCLUSIONS

There is ample documentation that, for many women, tubal pregnancy is not a single, isolated event. Ten to twenty per cent of these women, subsequent to their inital surgery, will experience a recurrence of extrauterine implantation. Roughly 50% will be unable to~bear children. It is to be hoped that the increasing use of quantitative determinations of serum HCG, in conjunction with ultrasonagraphy and laparoscopy, will result in a greater yield of unruptured tubal pregnancies, diagnosed prior to the development of extensive tubal damage. This should then afford one greater opportunity to restore normal function of fallopian tubes bearing an ectopic gestation. An operative approach which con~ serves the involved tube, in conjunction with thorough postoperative evaluation of tubo-ovarian anatomy and later tubal reconstructive surgery where necessary, might well be expected to improve the now dismal reproductive outlook of many of these women.

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REFERENCES 1. Landesman R, Coutinho EM, Saxena BB: Detection of human chorionic gonadotropin in blood of regularly bleeding women using copper intrauterine contraceptive devices. Fertil Steril 27:1062, 1976 2. Croxatto HB, Diaz S, Fuentealba B, Croxatto HD, Carrillo D, Fabres C: Studies on the duration of egg transport in the human oviduct. I. The time interval between ovulation and egg recovery from the uterus in normal women. Fertil Steril 23:447, 1972 3. McLaren A, Michie D: Studies on the transfer on fertilized mouse eggs to uterine foster-mothers. 1. Factors affecting the implantation and survival of mature and transferred eggs. J Exp BioI 33:394, 1956 4. Noyes RW, Dickmann Z, Doyle LL, Gates AH: Ovum transfers, synchronous & asynchronous in the study of implantation. In Delayed Implantation, Edited by AC Enders. Chicago, University of Chicago Press, 1963 5. Chang MC: Development and fate of transferred rabbit ova or blastocysts in relation to ovulation time of recipients. J Exp ZooI14:197, 1950 6. Bronson RA, McLaren A: Transfer to the mouse oviduct of eggs with and without the zona pellucida. J Reprod Fertil 22:129, 1970 7. Modlinski J: The role of the zona pellucida in the development of mouse eggs in vivo. J Embryol Exp Morphol 23: 529, 1970 8. Hertig AT: The Human Trophoblast. Springfield Ill, Charles C Thomas, 1968 9. Catt KJ, Dufau ML, Vaitukaitis JL: Appearance ofhCG in pregnancy plasma following the initiation of implantation of the blastocyst. J Clin Endocrinol Metab 40: 537, 1975 10. Csapo AI, Pulkkinen MO, Wiest WG: Effects ofluteectomy and progesterone replacement therapy in early pregnant patients. Am J Obstet Gynecol 115:759, 1973 11. Tao TW, Hertig AT: Viability and differentiation of human trophoblast in organ culture. Am J Anat 116:315, 1965 12. Finn CA: The biology of decidual cells. Adv Reprod Physiol 5:1,1971 13. Lapin BA, Yakovleva LA: Comparative Pathology in Monkeys. Springfield Ill, Charles C Thomas, 1963, p 215 14. Bronson RA, Cunnane M: Transfer of uterine implantation blastocyst to the oviduct in mice. Fertil Steril 26: 455, 1975 15. Kirby DRS: The extrauterine mouse egg as· an experimental model. Adv Biosci 4:255, 1970 16. Hellman L: The morphology of the fallopian tube in the early puerperium. Am J Obstet Gynecol 57:154, 1949 17. Kirby DRS, Cowell TP: Epithelial-Mesenchymal Interactions, Edited by R Fleischmajer, RE Billingham. Baltimore, Williams & Wilkins Co, 1968, p 64 18. Cowell TP: Implantation and development of mouse eggs transferred to the uterus of non-progestational mice. J Reprod Fertil 19:239, 1969 19. Kirby DRS: The influence of the uterine environment on the development of mouse eggs. J Embryol Exp Morphol 10:496, 1962 20. Billington WD, Graham CF, McLaren A: Extrauterine development of mouse blastocysts cultured in vitro from early cleavage stages. J Embryol Exp Morphol 20:391, 1968 21. McLaren A, Tarkowski AK: Implantation of mouse eggs in the peritoneal cavity. J Reprod Fertil 6:385, 1963

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22. Schlafke S, Enders AC: Cellular basis of interaction between trophoblast and uterus at implantation. BioI Reprod 12:41, 1975 23. Hallatt JG: Ectopic pregnancy in perspective. Postgrad Med 44:100, 1968 24. Persaud V: Etiology oftubal ectopic pregnancy: radiologic and pathologic studies. Obstet Gynecol 36:257, 1970 25. Osiakina-Rojdestvenskaia AJ: The etiology of extrauterine pregnancy. Surg Gynecol Obstet 67:308,1938 26. Berlind M: The contralateral corpus luteum-an important factor in ectopic pregnancies. Obstet GynecoI16:51, 1960 27. Von Paeschke K-D, Haller J, Neeb U, Sievers U: Die tub are Fertilitat. Experimentaluntersuchungen zur ausseren Uberwanderung des Eies. Zentralbl Gynaekol 97:232, 1975 28. Grant A: The effect of ectopic pregnancy on fertility. Clin Obstet Gynecol 5:861, 1962 29. Spilman CH, Harper MJK: Effects of prostaglandins on oviductal motility and egg transport. Gynecol Invest 6: 186, 1975 30. Coutinho EM: Hormonal control of oviductal motility and secretory functions. In MTP International Review of Science Physiology Series, Vol 8, Edited by R Greep. London, Butterworths, 1974, p 133 31. Franklin EW III, Zeiderman AM, Laemmle P: Tubal ectopic pregnancy: etiology and obstetric and gynecologic sequelae. Am J Obstet Gynecol 117:220, 1973 32. Schoen JA, Nowak RJ: Repeat ectopic pregnancy. Obstet Gynecol 45:542, 1975 33. Aren, Hafez ESE: Utero-oviductal motility with emphasis on ova transport. Obstet Gynecol Survey 28:679, 1973 34. Siegler AM, Perez RJ: Reconstruction of fallopian tubes in previously sterilized patients. Fertil Steril26:383, 1975 35. Hellman LM: Tubal plastic operations. J Obstet Gynaecol Br Emp 63:852, 1956 36. Grant A: Infertility surgery of the oviduct. Fertil Steril 22:496,1971 37. Williams GFJ: Tubo-uterine implantation. Lancet 1:825, 1969 38. Siegler AM: Salpingoplasty: classification and report of 115 operations. Obstet Gynecol 34:339, 1969 39. Garcia C-R: Reconstruction of previously ligated fallopian tubes. Presented at the Twenty-Eighth Annual Meeting

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