Use of fibrinolytic agents in the prevention of postoperative adhesion formation.

OBJECTIVE: To review the events leading to the formation of adhesions, to describe the development of fibrinolytic agents, to review more than a century of research on the use of fibrinolytic agents in adhesion prevention, and to look at future aspects of adhesion prevention. RESULTS: A better understanding of the pathogenesis of adhesion formation has resulted in the use of fibrinolytic agents in their prevention. Fibrinolytic agents promote fibrinolytic activity during the early period after peritoneal trauma during which an increased formation of fibrin is seen in combination with a deficiency of endogenous fibrinolytic activity. Initially, chemical attacks on fibrin (fibrolysin and hypertonic glucose), foreign digestive ferments (pepsin, trypsin, and papain), and stimulation of intraperitoneal leukocytosis (amniotic fluid) were used. Development of new thrombolytic agents was soon followed by experiments in animal adhesion models and clinical studies to examine their antiadhesion properties. Plasmin preparations (plasmin, actase, and fibrinolysin) and plasmin activators (streptokinase, urokinase, and tissue-type plasminogen activator) were found to be efficacious in preventing adhesion formation in the greater part of reviewed animal and clinical studies. CONCLUSION(S): From the current literature, it can be concluded that postoperative intraperitoneal administration of thrombolytic agents can significantly decrease adhesion formation. Given the large number of experimental studies in animals, future studies should focus on the clinical use of fibrinolytic agents in the prevention of postsurgical adhesion formation.

Complications of hysteroscopy: a prospective, multicenter study.

OBJECTIVE: To estimate the incidence of complications of diagnostic and operative hysteroscopic procedures in the Netherlands and describe their nature. METHODS: Data on complications were recorded by 82 hospitals in 1997. Participating hospitals had a 100% response rate. Any unexpected events that required intraoperative or postoperative intervention were defined as complications in two groups: approach (entry-related) and technique-related (caused by surgical instruments). RESULTS: Thirty-eight complications occurred among 13,600 hysteroscopic procedures (rate 0.28%). Diagnostic hysteroscopic procedures had a significantly lower complication rate (0.13%) than operative procedures (rate 0.95%; P <.01). Fluid overloads of distention medium were recorded five times (rate 0.20%). The most frequent surgical complication was perforation of the uterine cavity (rate 0.76%). Approximately half the perforations (18 of 33) were entry-related. Bleeding caused by perforation was seen in 0.16% of cases. Incidences of complications were: intrauterine adhesiolysis 4.48%, endometrium resection 0.81%, myomectomy 0.75%, and removal of a polyp 0.38%. CONCLUSION: Diagnostic hysteroscopic procedures had very low complication rates, so are safe procedures with which to evaluate intrauterine pathology. Operative hysteroscopic procedures were more risky, but the removal of polyps had a very low complication rate (12 times lower than synechiolysis). Half the complications were entry-related, so attention has to be paid to the method of entry with the hysteroscope (ie, no unnecessary dilation of cervix and introduction of the scope under direct vision). The other half of complications were related to surgeons' experience and type of procedure.

Complications of laparoscopy: a prospective multicentre observational study.

OBJECTIVE: To determine the incidence and describe the complications of laparoscopic procedures in The Netherlands. DESIGN: A nationwide prospective multicentre observational study. METHODS: Data on complications were registered from 1 January to 31 December 1994 by 72 hospitals. Any unexpected or unplanned event requiring intra-operative or post-operative intervention was defined as a complication. Complications were classified in two groups: approach and technique related complications. Complication rates were compared with these already published. RESULTS: Of 25,764 laparoscopic procedures, 145 complications occurred (rate 5.7 per 1000 [/1000]); two deaths occurred. In 84 women laparotomy was necessary (rate 3.3/1000). In 83 cases (57%; 95% CI for approach = 49-65%) the complication was caused by the surgical approach; in 62 cases (43%) the technique was at fault. Haemorrhage of the epigastric vein and intestinal injury, often requiring laparotomy (90% of cases) were the most frequently observed complications. The complication rate was 2.7/1000 for diagnostic laparoscopic procedures, 4.5/1000 for sterilisation and 17.9/1000 (chi 2 = 127; dF = 2; P < 0.001) for operative laparoscopy. The highest incidence was registered for complications occurring during laparoscopic (assisted) hysterectomy. Stepwise logistic regression analysis showed that previous laparotomy and surgical experience were associated with complications requiring laparotomy. CONCLUSIONS: Most complications occurred during operative laparoscopic procedures (rate 17.9/1000). Residents in training are required to learn diagnostic laparoscopy and sterilisation and this training programme results in a fall in the risk of the complications. However, operative laparoscopic procedures are still hazardous, especially laparoscopic hysterectomy. Women with a previous laparotomy are particularly at risk.

Long-term analysis of peritoneal plasminogen activator activity and adhesion formation after surgical trauma in the rat model.

OBJECTIVE: Recent literature has shown that a common pathway in postsurgical adhesion formation is a transient reduction in local plasminogen activator activity, shortly after peritoneal trauma. This deficit in fibrinolysis permits deposited fibrin to become organized into fibrous, permanent adhesions. Although adhesion formation is a process that continues beyond the first postoperative days, long-term analysis of this theory has not been performed. DESIGN: A standardized peritoneal adhesion model in the rat. MAIN OUTCOME MEASURE(S): Long-term analysis of the peritoneal fibrinolytic activity (extraction technique) was related to the extent of postsurgical adhesion formation, up to 1 year postoperatively. RESULT(S): Total and tissue plasminogen activator activity were significantly increased at days 3 and 8, and 1 month postoperatively. A mean adhesion percentage of 75% per peritoneal defect was found to persist throughout all evaluation times, which was directly related to the increase of fibrinolysis. CONCLUSION(S): In contrast to the classical concept that adhesion formation is related to a reduction in fibrinolysis, an impressive increase of the fibrinolysis was found to be associated with the persistence of adhesions.

Perception of diagnosis and openness of patients about infertility.

The perception of the diagnosis of infertility and the openness of patients about infertility was investigated among 108 infertile couples. Husbands and wives answered a structured questionnaire. The perception of diagnosis was in 38% of the cases different from the medical diagnosis. Patients perceived the diagnosis of male infertility more frequently, and the diagnosis of female infertility less frequently, than these diagnoses were made. Also there are significant differences in the perception of diagnosis between husbands and wives. Among the respondents there is a tendency to ascribe the diagnosis of infertility to themselves. It is important that physicians make sure that the patients have understood the received information. Family and friends are in almost all cases informed about the infertility problem, colleagues and acquaintances in about 60% of the cases, neighbors in about 40% of the cases. The reaction to openness is positive. Husbands are less open about male infertility than about female infertility. A selective choice of confidants and a subtle way of conveying the information generally lead to a positive reaction to the disclosure of infertility.

A survey on (operative) laparoscopy in The Netherlands in 1992.

OBJECTIVE: A quantitative inventory of (operative) laparoscopic surgery practiced by Dutch gynecologists in 1992 was made. METHODS: A written inquiry was mailed to all 145 departments of Obstetrics and Gynecology (including 28 teaching hospitals), where all 630 practicing gynecologists in The Netherlands are established. The questionnaire included questions about diagnostic laparoscopies, sterilizations, laparoscopy for infertility reason and operative laparoscopies. General information about follow-up training of the practitioner was also collected. All data were analyzed and comparisons were made between teaching and non-teaching hospitals. Statistical significance was calculated with the chi-square test. RESULTS: The response rate was 78%. A total of 419 respondents represented in 99 clinics reported performing 33,676 laparoscopic procedures, which makes an average of 80 procedures per physician per year. Distribution of procedures showed that 36% was for diagnostic laparoscopy, 33% for tubal sterilization, 19% laparoscopy for infertility work-up and 12% counted for therapeutic laparoscopy. Comparison of procedures in teaching hospitals (n = 27) and non-teaching hospitals (n = 72) showed only slightly more diagnostic laparoscopies for infertility in the first and more tubal-sterilizations in the latter. A statistically significant difference was found for the ring or clip sterilization in teaching hospitals, compared with the coagulation technique in non-teaching departments (P < 0.001). More difficult laparoscopic procedures such as ovarian cystectomy and conservative surgery of ectopic pregnancy were more frequently performed by those who had followed additional laparoscopic training (P < 0.02). CONCLUSIONS: The results of this survey are representative for (operative) laparoscopic practice of gynecologists in the Netherlands, because of the high response rate. Relatively, a small proportion of all laparoscopic procedures performed in 1992 are due to the therapeutic laparoscopy (12%). The great majority of therapeutic laparoscopic procedures was reported by a relatively small number of practitioners. Gynecologists who followed an additional laparoscopic training (30%) performed statistically more difficult laparoscopic procedures.

In-vitro fertilization: the experience of treatment, pregnancy and delivery.

The present study compares the evidence of pregnancy and delivery among in-vitro fertilization (IVF) parents (45 couples), other formerly infertile parents (35 couples) and fertile parents (35 couples). All deliveries concerned primaparous women and singleton births. In addition, the burden of fertility treatments was investigated. Results show that the psychological burden of the treatments exceeds the physical burden. Fertility treatments were judged very worthwhile. Complications during pregnancy were more frequently reported by IVF mothers and other initially infertile mothers than by fertile mothers. However, controlling for the older age in both formerly infertile groups (IVF and non-IVF), no significant difference was found. No differences appeared regarding the evaluation of the development of the delivery. IVF parents and other infertile parents evaluated the pregnancy as more stressful than fertile parents. However, mothers experienced their delivery as more exceptional, and fathers experienced the pregnancy as more exceptional. In addition, IVF fathers enjoyed the pregnancy more than fathers from the other groups.

Involuntarily childless couples: their desire to have children and their motives.

Long-term infertile couples often reflect seriously on their desire for a child. By investigating involuntarily childless couples we might get a better understanding of the intensity of the desire for the first child, the motives behind this desire and the difference between men and women in these respects. In this study among 108 couples with a mean infertility period of 8.6 years, the desire for children was still very strong especially among the women. Also, there were differences between men and women as to their motives for having a child. The most frequent motives for wanting a child are part of the categories happiness and well-being. Motives within the categories social control and continuity were seldom mentioned. Among women with the most intense desire for a child, motives within the categories motherhood and identity-development were very important.

Natural course of postsurgical adhesions.

To evaluate the natural course of postsurgical adhesion formation, a descriptive animal study was performed in a standardized rat adhesion model, involving the uterine horn and peritoneal side wall. Extent and type of postsurgical adhesion formation was evaluated at increasing postoperative time intervals up to 1 year, both through inter- and intra-animal observations (laparotomy and repeated-laparotomy group). The extent of the adhesions was found to be similar while the type of the adhesions changed markedly, especially during the early observation periods. From day 1 until 1 month post- operatively, the adhesions became increasingly more organized and vascular and were separable with sharp dissection only. From the present study it was concluded that spontaneous lysis of postsurgical adhesions, once they are established, does not seem to occur. The most optimum time for surgical intervention when scheduled to lyse newly formed adhesions will be between 8 days and 1 month after the initial procedure.

Factors influencing the well-being of long-term infertile couples.

The aim of the study was to investigate factors that may influence the well-being of long-term infertile couples. One hundred and eight childless couples with a long-term infertility completed a structured questionnaire. Three groups of independent variables were discerned: sociodemographic factors, factors associated with infertility and the desire to have a child, and personality characteristics. The effect of these variables upon seven dimensions of (negative) well-being: depression, anxiety, hostility, health complaints, guilt/blame, self-esteem and sexuality was investigated. Strong negative feelings concerning infertility and a high degree of femininity were associated with a low level of well-being (among women as well as among men). To a lesser extent, secrecy with regard to infertility and being the infertile partner (among men) and still pursuing medical treatment (among women) were related to a lower sense of well-being. Recognition of these relations may help in the counselling of infertile couples.

Long-term infertile couples: a study of their well-being.

The objective of the study was to investigate long-term infertile couples in regard to their well-being. The design of the study consisted of a structured questionnaire. Husband and wife answered a written questionnaire each in a different place in their home. Wives and husbands of 108 childless couples with a long-term infertility participated. Seven dimensions of (negative) well-being were measured: depression, anxiety, hostility, health complaints, guilt/blame, self-esteem and sexuality. Results showed that sexual behavior was (still) often ruled by the constraints of procreation. Also a third of the women reported as a consequence of infertility a low self-esteem concerning their womanhood. Infertile women were more anxious, more depressed, displayed more hostility and reported more health complaints. There was no similar difference between long-term infertile men and men in general. In conclusion long-term infertile women showed a significantly-lower level of well-being compared with women in general. A third of the infertile women and a fifth of the infertile men had serious well-being problems. This group can be considered as needing emotional help and counselling in learning to live with their childlessness.

Reversal of sterilization in women over 40 years of age: a multicenter survey in The Netherlands.

Microscopic reversal of sterilization in women is successful. Most infertility treatments, however, are bound to an age limit, which in the individual case is sometimes overstepped. To determine if reversal of sterilization in women greater than 40 years of age is justifiable, the data of nine centers of tubal surgery in the Netherlands were analyzed. In 78 women between 40 and 45 years, an intrauterine pregnancy rate of 45% and an ectopic pregnancy rate of 4% was reported. Whereas 26% of first pregnancies ended in a spontaneous abortion, the live birth rate (all healthy children) still amounted to 44%. The mean duration between operation and first pregnancy was 5.5 months. It is concluded that microscopical reversal of sterilization in women between 40 and 45 years is an acceptable infertility treatment.

PIP: Cases of all women over 40 attending 9 Dutch centers offering microsurgical tubal surgery for reversal of sterilization from 1987- 1988 were reviewed. 78 cases met the criteria of minimum 4 cm of healthy tube, and normal basal body temperature, semen analysis and postcoital testing. The patients' ages ranged from 40-45, mean 41. There were 38 pregnancies after surgery: 35 intrauterine and 3 ectopic, an initial pregnancy rate of 45% intrauterine pregnancy. 26 normal term births and 9 spontaneous abortion resulted. 7 of the women who miscarried and 1 of those with ectopic pregnancy subsequently bore term babies. Thus the overall live birth rate was 44%, in comparison to 66% among the total population of reanastomosis cases in these 9 centers. The total abortion rate, 26%, is similar to that seen in women over 40 from the general population. The mean duration to 1st pregnancy was 5.5 months. Best results were seen with women sterilized with rings or clips. A trend in successful pregnancy appeared in younger women.

In vitro fertilization at the Leiden Academic Hospital. Initial experiences.

At the Leiden University Hospital the first IVF treatment was initiated November 1st, 1985. In the following year 139 cycles with ovarian stimulation have been started with 75 patients. Thirty percent of these stimulations have been cancelled before oocyte retrieval due to suboptimal response. Totally 97 pick-ups have been carried out on 65 patients resulting in 78 embryo transfers to 54 patients. Fourteen clinical pregnancies were obtained. Four ended with a first trimester abortion, one was a tubal pregnancy and 9 are ongoing or have been already delivered.

Adhesion formation after tubal surgery: results of the eighth-day laparoscopy in 188 patients.

First-look laparoscopy (FL) on the eighth day after salpingostomy, fimbrioplasty, or adhesiolysis was performed in 188 patients. Behavior of postoperative adhesions and the occurrence of pregnancy after tubal surgery were compared with a similar group of 127 patients in whom no FL was performed. In greater than 50% of the cases (104/188), adhesions were found on the eighth postoperative day around both adnexa or the only remaining adnexum. Adhesions were mainly located between the ampulla and the ovary and between the ovary and the lateral pelvic wall or broad ligament. More than half of the adhesions that were separated at FL did not recur. It was concluded that FL significantly diminished the occurrence of permanent pelvic adhesions. The incidence of ectopic pregnancy after salpingostomy was significantly lower when FL was performed. FL on the eighth postoperative day can be regarded as a well-accepted procedure with few complications.

PIP: 1st-look laparoscopy (FL) on the 8th day after salpingostomy, fimbrioplasty, or adhesiolysis was peformed in 188 patients. Behavior of postoperative adhesions and the occurrence of pregnancy after tubal surgery were compared with a similar group of 127 patients in whom no FL was performed. In 50% of the cases (104/188), adhesions were found on the 8th postoperative day around both adnexa or only the remaining adnexum. Adhesions were mainly located between the ampulla and the ovary and between the ovary and the lateral pelvic wall or broad ligament. More than 1/2 of the adhesions that were separated at FL did not recur. It was concluded that FL significantly diminished the occurrence of permanent pelvic adhesions. The incidence of ectopic pregnancy after salpingostomy was significantly lower when FL was performed. FL on the 8th postoperative day can be considered a well-accepted procedure with few complications.

Follicular development during the luteal phase of the human menstrual cycle.

The aims of the present studies were to determine the number, size range, health, and steroidogenic activities of antral follicles in normal human ovaries during the luteal phase of the menstrual cycle. Steroidogenic activity was assessed from the levels of androstenedione, testosterone, and estradiol in follicular fluid and the levels of extant and FSH-stimulable aromatase activity and FSH-stimulable progestin synthesis in the granulosa cells. Data for luteal phase ovaries were compared to those obtained for ovaries from the late follicular phase. On average, 94% (range, 70-100%) of the luteal phase follicles (greater than or equal to 1 mm diameter) were atretic as assessed by oocyte viability and granulosa cell number. The largest healthy follicles during the mid- to late luteal phase were 4-4.5 mm in diameter; these contained high levels of aromatizable androgen (500-2000 ng/ml), low levels of estradiol (less than 10 ng/ml), and granulosa cells with an extant level of aromatase activity 200 times lower than that in a preovulatory follicle. Based on these biochemical criteria, healthy (luteal phase) follicles were not distinguishable from atretic follicles. Granulosa cells from the luteal phase follicles were responsive to FSH with respect to progesterone and estradiol biosynthetic activity; the aromatase system in the cells from the mid- to late luteal phase follicles was significantly more responsive to FSH than that in cells from late follicular or early luteal phase follicles (P less than 0.05). These data suggest that the number of healthy luteal phase follicles (greater than or equal to 1 mm diameter) available for subsequent preovulatory development is limited.

Management of infertile patients with unilateral tubal pathology by paradoxical oophorectomy.

Removal of a severely pathologic adnex to improve fertility in patients with strictly unilateral tubal disease is called paradoxical oophorectomy. This procedure was carried out in nine patients in our department. Seven of them became pregnant (78%). Four of these pregnancies occurred within a year, two during the 2nd year, and one during the 3rd year after the operation. These results were compared with the pregnancy rates in 15 patients with comparable tubal disease who were not operated on. Only four of these women became pregnant (27%); this difference is significant (P less than 0.05). Theoretic considerations and practical implications concerning paradoxical oophorectomy are discussed. We advise a wait of at least 2 years after diagnostic laparoscopy before performing paradoxical oophorectomy.

Etiological factors in tubal infertility.

An analysis was made of the history of 820 patients who underwent diagnostic laparoscopy for infertility reasons. Events in the patient's history related to abdominal surgery, infection of the genital tract, and endometriosis were compared with the incidence of tubal disease at laparoscopy. Salpingitis, puerperal endometritis, gynecologic operations such as ovarian cystectomy, wedge resection, and operative correction of uterine retroversion and appendicitis complicated by perforation of the appendix, inflammatory mass or appendiceal abscess, were all associated with a significantly higher incidence of tubal disease. In patients that had undergone an uncomplicated appendectomy, the occurrence of tubal abnormalities was not increased (42%), when they were compared with the group with a completely negative history (37%). Implications of these findings with relation to the prevention of tubal disease are discussed.

PIP: An analysis was made of the history of 820 patients who underwent diagnostic laparoscopy for reasons of infertility. Events in the patient's history related to abdominal surgery, infection of the genital tract, and endometriosis were compared with the incidence of tubal disease at laparoscopy. Salpingitis, puerperal endometritis, gynecologic operations such as ovarian cystectomy, wedge resection, and operative correction of uterine retroversion and appendicitis complicated by perforation of the appendix, inflammatory mass, or appendiceal abscess, were all associated with a significantly higher incidence of tubal disease. In patients who had undergone an uncomplicated appendectomy, the occurrence of tubal abnormalities was not increased (42%) when they were compared with the group with a completely negative history (37%). Implications of these findings with relation to the prevention of tubal disease are discussed.