Trudy C.M. Trimbos-Kemper

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.

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.

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.

Salpingotomy versus salpingectomy in women with tubal pregnancy (ESEP study): an open-label, multicentre, randomised controlled trial.

BACKGROUND Tubal ectopic pregnancy can be surgically treated by salpingectomy, in which the affected Fallopian tube is removed, or salpingotomy, in which the tube is preserved. Despite potentially increased risks of persistent trophoblast and repeat ectopic pregnancy, salpingotomy is often preferred over salpingectomy because the preservation of both tubes is assumed to offer favourable fertility prospects, although little evidence exists to support this assumption. We aimed to assess whether salpingotomy would improve rates of ongoing pregnancy by natural conception compared with salpingectomy. METHODS In this open-label, multicentre, international, randomised controlled trial, women aged 18 years and older with a laparoscopically confirmed tubal pregnancy and a healthy contralateral tube were randomly assigned via a central internet-based randomisation program to receive salpingotomy or salpingectomy. The primary outcome was ongoing pregnancy by natural conception. Differences in cumulative ongoing pregnancy rates were expressed as a fecundity rate ratio with 95% CI, calculated by Cox proportional-hazards analysis with a time horizon of 36 months. Secondary outcomes were persistent trophoblast and repeat ectopic pregnancy (expressed as relative risks [RRs] with 95% CIs) and ongoing pregnancy after ovulation induction, intrauterine insemination, or IVF. The researchers who collected data for fertility outcomes were masked to the assigned intervention, but patients and the investigators who analysed the data were not. All endpoints were analysed by intention to treat. We also did a (non-prespecified) meta-analysis that included the findings from the present trial. This trial is registered, number ISRCTN37002267. FINDINGS 446 women were randomly assigned between Sept 24, 2004, and Nov 29, 2011, with 215 allocated to salpingotomy and 231 to salpingectomy. Follow-up was discontinued on Feb 1, 2013. The cumulative ongoing pregnancy rate was 60·7% after salpingotomy and 56·2% after salpingectomy (fecundity rate ratio 1·06, 95% CI 0·81-1·38; log-rank p=0·678). Persistent trophoblast occurred more frequently in the salpingotomy group than in the salpingectomy group (14 [7%] vs 1 [<1%]; RR 15·0, 2·0-113·4). Repeat ectopic pregnancy occurred in 18 women (8%) in the salpingotomy group and 12 (5%) women in the salpingectomy group (RR 1·6, 0·8-3·3). The number of ongoing pregnancies after ovulation induction, intrauterine insemination, or IVF did not differ significantly between the groups. 43 (20%) women in the salpingotomy group were converted to salpingectomy during the initial surgery because of persistent tubal bleeding. Our meta-analysis, which included our own results and those of one other study, substantiated the results of the trial. INTERPRETATION In women with a tubal pregnancy and a healthy contralateral tube, salpingotomy does not significantly improve fertility prospects compared with salpingectomy. FUNDING Netherlands Organisation for Health Research and Development (ZonMW), Region Västra Götaland Health & Medical Care Committee.

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.

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.

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 patients 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.

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.

Preoperative predictors of postsurgical adhesion formation and the Prevention of Adhesions with Plasminogen Activator (PAPA-study): results of a clinical pilot study

OBJECTIVE To identify predictors of postsurgical adhesion formation in peritoneal fluid and plasma, and assess efficacy and safety of reteplase (recombinant plasminogen activator [r-PA]). DESIGN Prospective randomized study. SETTING University Medical Center. PATIENT(S) Twenty-six abdominal myomectomy patients with early second-look laparoscopy (ESL). INTERVENTION(S) Randomization to IP treatment with 1 mg reteplase in 300 mL Ringers lactate or 300 mL Ringers lactate only. Scoring of adhesions and collecting peritoneal fluid during both surgical procedures and collecting plasma samples at ten time points. MAIN OUTCOME MEASURE(S) Incidence, severity, and extent of adhesions at ESL. Concentrations of C-reactive protein (CRP), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and fibrin degradation products (FbDPs). RESULT(S) Significant correlation between the extent of uterine adhesion formation and preoperative plasma levels of CRP (r(s) = 0.558), PAI-1 (r(s) = 0.413), and the change in tPA concentration in peritoneal fluid from initial surgery to ESL (Delta+PA: r(s) = -0.636). No significant differences in adhesion scores between treatment and control groups. CONCLUSION(S) Our finding that preoperative plasma CRP and PAI-1-levels are significantly correlated with extent of adhesion formation points to a role of chronic inflammation in the disease process. Results are highly indicative for the paradigm that adhesions are caused by an insufficiency in peritoneal fibrinolytic capacity. For successful adhesion prevention therapy relatively high amounts of r-PA are required.

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.