Trans-signaling by cytokine and growth factor receptors

OBJECTIVE: to compare methotrexate (MTX) to laparoscopic salpingotomy for conservative management of ectopic pregnancy (EP). DESIGN: prospective randomized study. PATIENTS: eighty-nine patients were randomized into 2 groups using a random number table. Inclusion criteria were an EP visualized by ultrasound with a pretherapeutic score < or = 13 as assessed by 6 criteria graded from 1 to 3: gestational age, hCG level, P level, abdominal pain, volume of the hemoperitoneum, and diameter of the hematosalpinx. INTERVENTIONS: 1 mg/kg of MTX injected transvaginally into the ectopic pregnancy without anaesthesia or IM administration (1.5 mg/kg) when EP cannot be safely or easily punctured (group 1) versus laparoscopic salpingotomy (group 2). RESULTS: the success rates defined by hCG levels returned to normal (< 10 mlU/mL) were 43 out of 46 in group 1 and 40 out of 43 in group 2. Medical treatment was significantly associated with shorter post-operative stay (24 vs 46 hours). hCG return to normal was quicker after laparoscopic treatment (13 vs 29 days). Reproductive performances were similar in both groups. CONCLUSIONS: in selected cases of EP with a pretherapeutic score < or = 13, MTX treatment appeared to be as safe and efficient as was conservative treatment by laparoscopy, an expectant management should be offered as a treatment option only in women fulfilling the criteria for a good prognostic.     

Intramesosalpingeal injection of oxytocin in conservative laparoscopic treatment for tubal pregnancy: preliminary results

The objective of this study was to evaluate the efficacy of the local use of oxytocin as adjuvant treatment in conservative surgery for tubal pregnancy. The patients were 25 women with laparoscopic diagnosis of tubal pregnancy who were candidates for salpingotomy. Before salpingotomy, each patient was randomly allocated to intramesosalpingeal injection of 20 IU oxytocin diluted to 20 ml with saline solution or 20 ml saline solution. The surgeon then proceeded with salpingotomy and removal of the pregnancy according to the usual technique. The main outcome measures were bleeding during salpingotomy, ease of removal of the pregnancy, bleeding at the site of the pregnancy, and need for recourse to salpingectomy. Twelve women were randomized to the oxytocin group and 13 to the control group. Examination of the surgeons' assessments of the difficulties encountered at the different stages of surgery revealed statistically significant differences between the oxytocin group and controls in each variable. In particular, the amount of endosalpingeal bleeding after removal of the pregnancy was less in the oxytocin group. In one control patient, persistent bleeding due to incomplete trophoblast removal forced the surgeon to perform salpingectomy. Our results indicate that intramesosalpingeal injection of oxytocin facilitates the performance of conservative laparoscopic treatment for tubal pregnancy.     

Evaluation of serum inhibin A as a surveillance marker after conservative management of tubal pregnancy

Tubal pregnancy is now commonly managed by laparoscopic salpingostomy or systemic methotrexate. A disadvantage of such conservative management is the need for appropriate follow-up, with serial measurement of serum concentrations of human chorionic gonadotrophin (HCG), to exclude persistent ectopic pregnancy (PEP). Concentrations of inhibin A, also a placental product, are significantly increased during pregnancy and the half-life of inhibin A is significantly shorter than that of HCG. To assess the suitability of inhibin A as a marker of PEP, we studied 16 women who had undergone surgery for a tubal pregnancy, measuring HCG and inhibin during follow-up. The mean +/- SEM time taken to achieve non-pregnant concentrations of inhibin A was significantly shorter than for HCG (4.2 +/- 0.8 days versus 21.6 +/- 4.4 days respectively; P < 0.001 Wilcoxon signed rank test). However, in all women the inhibin A concentration increased rapidly after reaching a nadir, reflecting the return of ovarian function, complicating the interpretation of results. In four women inhibin A was almost undetectable preoperatively, while the corresponding HCG concentration was high. These data suggest that inhibin A will not be a useful marker for PEP but that it may provide a more accurate preoperative assessment of trophoblast viability than HCG, thereby improving management.     

Developmental differences in catalase activity and hypoxic-hyperoxic effects on fluid balance in isolated lamb lungs

From these data, it seems highly likely that conservation of the involved tube does not substantially increase the risk of a future ectopic pregnancy, although it does slightly increase the chance of a subsequent intrauterine pregnancy. This advantage of conservative therapy is also demonstrable in patients with a repeat tubal pregnancy. Pregnancy rates after conservative operation still compare favorably with those after in vitro fertilization. There seems to be a slightly increased risk of persistent trophoblastic activity after laparoscopic conservative therapy compared with conservative surgical treatment by laparotomy, but prospective randomized data are lacking. The psychosocial and economic benefits of laparoscopic treatment are well established.     

Mifepristone in combination with methotrexate for the medical treatment of tubal pregnancy: a randomized, controlled trial

In the search for a more potent alternative to a single i.m. injection of methotrexate for ectopic pregnancy, a randomized trial was organized. The efficacy of a combination of methotrexate and mifepristone was compared with methotrexate alone in the treatment of unruptured tubal pregnancies. The diagnosis of an unruptured tubal pregnancy was confirmed laparoscopically in 50 patients during a 2 year period. Women were randomized to receive a single i.m. injection of 50 mg/m2 methotrexate alone or a single dose of 600 mg oral mifepristone in combination with the same dose of methotrexate. Both treatment protocols were successful in achieving the resolution of unruptured ectopic pregnancy (18/25 in the methotrexate group and 22/25 in the combination group) following the initial intervention. A second injection was needed in four (16%) cases in the methotrexate group and in one (4%) case in the combination group. Overall, a complete resolution was achieved in 22/25 and 23/25 cases respectively. Unruptured ectopic pregnancy resolved faster in women given the combination of methotrexate and mifepristone compared to women given methotrexate only (P = 0.01). The effect of the methotrexate and mifepristone combination was more pronounced in women with higher human chorionic gonadotrophin concentrations.     

Conservative management of extra-uterine pregnancy

Expectant management was studied in 35 patients representing 4.9% of all ectopic pregnancies during an 8 year period. Laparoscopy was performed in a first period to define the inclusion criteria: hematosalpinx < or = 2 cm and hemoperitoneum < or = 50 ml. In a second period, inclusion criteria used a predictive pretherapeutic score < or = 11 with a sonographic visualization of the ectopic pregnancy. This score involved six criteria graded on a scale from 1 to 3: gestational age, hCG and P level, existence of abdominal pain, size of hemoperitoneum and diameter of hematosalpinx assessed sonographically. The patients were on out-patients basis. Success rate was 85.7% (30/35 patients). When the pretherapeutic score was < or = 11 and the initial hCG level < 1,000 mUl/ml the success rate increased to 96%. Thirteen patients (87%) had patent tubes evaluated by hysterosalpingography on the side of the ectopic pregnancy. Twelve patients delivered one miscarriage occurred and none ectopic pregnancy was observed. Expectant management is a useful form of treatment for ectopic pregnancy in selected cases.     

A rapid direct latex agglutination test for HCG (author's transl)

792 urine samples from pregnant patients were investigated by a direct latex agglutination test (LA). Results of this slide test were compared with data derived from a haemagglutination inhibition test (HI). The same results were obtained by both pregnancy tests in 768 (96.7%) out of 792 urine samples. The pregnancy test was negative in 20 cases (2.5%) as assessed by HI, whereas a positive result was recorded with the LA in these cases. Seven were cases of early pregnancy and control tests performed by HI became positive at a later date. The remaining 13 (1.6%) of these patients belonged to a group of pathological pregnancies (missed abortion, threatened abortion, incomplete abortion and ectopic pregnancy). The slide test is more sensitive (1000 I.U. HCG/1 urine) than the HI (1500 I.U.HCG/1 urine). No false positive results were obtained with the LA; false negative results were registered in only 0.5% of cases. A semi-quantitative HCG determination was performed by means of the tube and slide test in 29 urine samples. However, agreement of the data by the two methods was relatively poor, owing to the higher sensitivity of the LA, with consequent inaccurate assessment of HCG excretion. Not much importance need be attached to this finding in view of the diagnostic and prognostic deficiencies of HCG determination. The new slide test was found to be a rapid, simple and accurate pregnancy test.     

Radiographic evaluation of the renal vasculature

The two main conservative treatment alternatives for tubal pregnancy, methotrexate administration and laparoscopic salpingostomy are under constant review. Recently, expectant management of tubal pregnancy has become increasingly popular. In this review, we assess the outcome of conservative management modalities for extrauterine pregnancy and compare the results of treatment with methotrexate and operative laparoscopy. Outcomes of extrauterine pregnancy were obtained from a review compiled from the English literature identified by directed Medline search. Methotrexate and laparoscopic salpingostomies yield good final treatment rates of 85-95% respectively and relatively low rates for further surgical complication (5-10% respectively). Tubal patency, as well as future fertility performance, are quite similar after both techniques. Although they appear to suit the demands of the 21st century, each one has its own benefits and contraindications. With adequate patient selection, expectant management of the tubal pregnancy is a reasonable approach with good results. Although the morbidity rate after tubal pregnancy treatment is decreasing and the main concern is to reduce the decline in fertility potential, the real future challenge remains prevention of the disease, especially among high risk patients, such as those undergoing infertility treatment.     

How to get the most from your iron supplement

BACKGROUND: Tubal effects of methotrexate injections have been poorly reported. CASES: Three fallopian tubes were examined with light microscopy 9-13 months after tubal methotrexate injection (one case) and intramuscular methotrexate injection (two cases) given for the treatment of unruptured ectopic pregnancies. No evidence of tubal damage was found. CONCLUSION: These three cases confirm previous experimental and clinical data showing the absence of a direct adverse effect of methotrexate on the fallopian tubes in the treatment of ectopic pregnancy.     

Analysis of three hundred fifteen ectopic pregnancies treated with single-dose methotrexate

OBJECTIVES: The objective of this study was to review the largest single series of ectopic pregnancies treated with single-dose methotrexate reported to date. STUDY DESIGN: A review of 315 patients with unruptured ectopic pregnancies treated with single-dose methotrexate 50 mg/m2 from March 21, 1990, to March 1, 1997, was performed. RESULTS: Overall 287 patients were successfully treated with methotrexate for a success rate of 90.1%. Six patients electively withdrew and requested surgery within 1 week of starting therapy. Excluding withdrawals the overall success rate was 92.9%. Ten patients with an ectopic pregnancy > 3.5 cm but < or = 4 cm in size were treated for a 90% success rate. Forty-four patients with positive ectopic cardiac activity were treated with an 87.5% success rate. CONCLUSIONS: This large series indicates that single-dose intramuscular methotrexate for treatment of ectopic pregnancy is associated with an excellent overall success rate.     

Medical management should be routinely used as primary therapy for ectopic pregnancy

It does not appear that methotrexate can or should be used to totally replace laparoscopic salpingostomy. However, given its success rate in selected patients, its cost-effectiveness, and its low incidence of side effects, methotrexate therapy certainly can be used as an alternative therapy. The next step in developing this treatment option will be to conduct a randomized clinical trial comparing laparoscopic salpingostomy with intramuscular methotrexate. This type of study will answer questions regarding the patient's health related quality of life and economic impact of the two treatment modalities. For now, it seems prudent to offer methotrexate to those patients with an unruptured ectopic gestational mass 3.5 cm or less in greatest dimension.     

Ectopic pregnancy--changing trends

This study is an attempt to have an overall view of the changing trends in the clinical presentation, diagnostic modalities and management of ectopic pregnancy over a period of three and a half decades. The incidence of ectopic pregnancy was one in 368 during the 15-year period from 1959-1973 (group A) and has increased to one in 160 during the latter part of the study period from 1988-1993 (group B). Medical termination of pregnancy, abortion, intra-uterine contraceptive device and previous tubal ligation were the important risk factors recently (group B). Unruptured tubal pregnancy was diagnosed in 9.8% (group B) as compared to only 3% in group A. However, as most of the patients came to the hospital with disturbed pregnancy, the use of ultrasonography and urine gravindex test was helpful in only 14% in the latter part of the study. The characteristic clinical features like pain abdomen with amenorrhoea, vaginal bleeding and positive culdocentesis were the most reliable diagnostic criteria in both the groups. There is an increasing trend towards conserving the tubes and methotrexate use recently.     

Ectopic pregnancy: criteria to choose therapy

The ectopic pregnancy (EP) could be treated by spontaneous resolution, or medical treatment or laparoscopic treatment. Spontaneous resolution of EP with beta hCG < 1,000 mUl/ml, plasmatic progesterone < 5 ng/ml had 74% success rate. Methotrexate (MTX) injection is the common Medical treatment of EP with beta hCG < or = 5,000 mUl/ml and mean diameter of EP < or = 3 cm: a single dose of 50 mg/m2 or 1 mg/kg intramuscular injection had 93.4% success rate; local injection under sonographic control (1 mg/kg) had 80.2% success rate. The surgical conservative treatment by laparoscopy had 94% success rate.     

Successful laparoscopic management of primary abdominal pregnancy

Overall, approximately 1% of ectopic pregnancies are abdominal pregnancies, which can be life-threatening even when surgical intervention with laparotomy is performed. We present a case in which abdominal pregnancy was successfully managed by operative laparoscopy. A 25 year old Japanese woman presented 6 weeks after her last menstruation with elevated basal body temperature, lower abdominal pain, and light vaginal bleeding. The urinary human chorionic gonadotrophin (HCG) concentration was 2137 IU/I, and laparoscopic findings (i.e. the implantation site was the posterior serosa of the uterus with normal adnexae) established a diagnosis of primary abdominal pregnancy. The gestational product was completely removed by laparoscopic surgery with no uncontrollable loss of blood. The urinary concentration of HCG declined rapidly and the patient made an uneventful recovery. Operative laparoscopy is a safe alternative for the management of appropriately selected patients with early abdominal pregnancy.     

Discriminability in length of lines in the Müller-Lyer figure

OBJECTIVE: To compare patients' health-related quality of life after systemic methotrexate therapy versus laparoscopic salpingostomy for tubal pregnancy. DESIGN: Multicenter randomized clinical trial. SETTING: Departments of obstetrics and gynecology of six Dutch hospitals. PATIENT(S): Hemodynamically stable patients with a laparoscopically confirmed unruptured tubal pregnancy without signs of active bleeding, who were randomly assigned to undergo either systemic methotrexate therapy or laparoscopic salpingostomy. INTERVENTION(S): Standard health-related quality of life questionnaires administered before and 2 days, 2 weeks, 4 weeks. and 16 weeks after confirmative laparoscopy. MAIN OUTCOME MEASURE(S): Health-related quality of life. RESULT(S): Health-related quality of life was impaired most severely 2 days after confirmative laparoscopy in both treatment groups and improved during follow-up. Health-related quality of life was impaired more severely after systemic methotrexate therapy than after laparoscopic salpingostomy. Medically treated patients had more limitations in physical functioning, role functioning, and social functioning; had worse health perceptions, less energy, more pain, more physical symptoms, and a worse overall quality of life; and were more depressed than surgically treated patients. CONCLUSION(S): Systemic methotrexate therapy had a more negative impact on patients' health-related quality of life than did laparoscopic salpingostomy. This negative impact on patients' health-related quality of life of systemic methotrexate therapy should be taken into account when deciding on the appropriate therapy for tubal pregnancy.     

Is luteal function maintained by factors other than chorionic gonadotrophin in early pregnancy?

Women with ectopic pregnancy (n = 14) and early embryonic arrest ('blighted ovum') (n = 9) were studied 16 days after conception, at a time when they were asymptomatic and serum concentrations of beta-human chorionic gonadotrophin (HCG) were in the normal range and increasing at an apparently normal rate. Serum progesterone and oestradiol concentrations were compared with those from normal women matched for gestational age and serum beta-HCG concentration whose singleton intra-uterine pregnancies proceeded normally beyond 20 weeks. Mean serum progesterone concentrations were significantly lower in the women with ectopic pregnancies than in matched controls (P < 0.002); however, there was no difference in the serum progesterone concentrations between women with blighted ova and matched controls. Statistically significant differences were not seen in serum oestradiol concentrations between either group and matched controls. Similarly there was no difference in serum progesterone or oestradiol concentrations in 20 women who conceived ectopic pregnancies and 20 women conceiving blighted ovum pregnancies and their matched intra-uterine controls when conception followed ovarian stimulation. The low serum progesterone concentrations seen in ectopic pregnancy suggest that there is a specific and selective deficiency in progesterone synthesis, which implies that factors other than HCG may influence luteal function.     

Variability of cutaneous lymphatic flow rates in melanoma patients

A woman with a small (6-mm gestational sac) interstitial pregnancy had complete resolution after medical therapy alone. A single cycle of methotrexate 50 mg/m2 was used as outpatient treatment without any operative procedure either for diagnosis or intervention. The guidelines that have evolved for selection of women for single dose methotrexate treatment for both intrauterine and tubal ectopic pregnancies may be applicable to interstitial ectopic pregnancy as well. A suggested framework for treatment decisions is presented.     

A 'potentially safer' route for puncture and injection of cornual ectopic pregnancies

Puncture and injection (usually by methotrexate) of ectopic pregnancies are relatively new modalities of treatment. Lately, these have been applied to cornual ectopic pregnancies. We describe here a proposed transvaginal ultrasound-guided puncture route, leading the needle into the cornual ectopic pregnancy, first traversing the myometrium and approaching the gestational sac from the medical aspect. After extracting the needle, there is potentially less chance for rupture and bleeding. In six of the seven injected cornual pregnancies, this technique was used without complication. The only one punctured from the lateral aspect bled and required laparoscopic intervention. This technique may enable the wider use of this treatment modality by lowering the complication rate caused by bleeding at the puncture site.     

Plasma albumin induces calcium waves in rat cortical astrocytes

At the end of the 19th century, ectopic pregnancy became a surgical procedure. A century later, one third of ectopic pregnancies are treated medically. In the meantime, early detection of ectopic pregnancy became possible due to sensitive serum hCG and progesterone combined assays with transvaginal sonography and a knowledge of risk factors. Consequently, a nonsurgical approach appears to be an attractive alternative to surgery. Expectant management is recommended with a plateau or decreasing hCG and an initial level < or = 1.000 mIU/ml in asymptomatic women. Medical treatment by local or parenteral methotrexate is recommended in patients with clear evidence of an unruptured pregnancy in based on initial hCG and progesterone level, size of hemoperitoneum, ultrasound diameter of hematosalpinx and absence of clinical pain. Laparoscopy remains the gold standard but in prospective randomized trials between medical treatment and laparoscopy, in selected patients, the non-surgical approach appears to be equivalent with a similar reproductive performance.     

Transvaginal sonography and human chorionic gonadotrophin measurements in suspected ectopic pregnancy: a detailed analysis of a diagnostic approach

In this prospective study among 208 high-risk patients with suspected ectopic pregnancy, the diagnostic value of transvaginal sonography and serum human chorionic gonadotrophin (HCG) measurements were analysed in detail. The absence of an intra-uterine gestational sac obviously was the most constant sonographic finding among patients with ectopic pregnancy (n = 89), with a very high sensitivity (0.99) but a low specificity (0.41). The application of different HCG cut-off levels improved specificity to 1.00 for values exceeding 4500 IU/l. Clinical utility obviously decreased, as many patients presented with HCG values well below this level. The additional effect of adnexal findings was analysed. Sonographic identification of an ectopic pregnancy was very specific (0.99) but had low sensitivity (0.56) because many ectopics were not detected. The additional effect of HCG values on these results was minor. The low HCG cut-off levels advocated in recent studies are questioned by the results of our analysis: whereas the combined use of sonography and HCG measurements is shown to be of great benefit, the limitations are also documented, underlining the need for re-evaluation at intervals of patients with low HCG values. The question of which cut-off level should be used in practice, however, hinges on a difficult choice between a certain specificity and clinical utility.