Transvaginal intratubal insemination, ectopic pregnancy and treatment by single-dose parenteral methotrexate.

We report a case of a woman with ectopic pregnancy with fetal cardiac activity after ovulation induction and transvaginal intratubal insemination by tactile sensation. The patient was successfully treated by single-dose methotrexate (MTX) (77 mg or 50 mg/m2 given intramuscularly). Control hysterosalpingograms showed no tubal patency on the involved side. Potential advantages and hazards of transvaginal intratubal insemination and single-dose MTX for ectopic pregnancy are discussed.     

Successful treatment of an advanced interstitial pregnancy by sequential systemic and local administration of methotrexate

A patient is presented with an advanced interstitial pregnancy,diagnosed by transvaginal ultrasound and confirmed by laparoscopy.Amenorrhoea at the time of diagnosis was 57 days. Methotrexatewas given systemically (4x50 mg i.m.). Because of persistingviability of the fetus, systemic methotrexate treatment wasfollowed by local instillation of methotrexate into the gestationalsac (50 mg). Follow-up revealed rapid human chorionic gonadotrophinregression but slow regression of fetal remnants.     

A validation of the most commonly used protocol to predict the success of single-dose methotrexate in the treatment of ectopic pregnancy

BACKGROUND: Currently, the likely success of single-dose methotrexate (MTX) (50 mg/m(2)) for the treatment of ectopic pregnancy is indicated by a >15% decrease in hCG from days 4-7 after administration. The aim of this study was to assess this protocol and to develop new rules that could be used to predict the outcome at an earlier stage. METHODS: Data were collected prospectively. Women receiving MTX for an ectopic pregnancy had serum hCG and progesterone levels checked on days 1, 3, 4, 5 and 7. Other factors including age, gestational age, previous obstetric history and ultrasound findings were recorded. The women were followed up until the outcome of medical management was known. Univariate analysis was performed to determine the benefit of the '15% day 4-7 rule', as well as to develop new rules, which potentially could be used to predict the likelihood of success before 7 days. Historical and ultrasound variables were also analysed to identify the significant variables associated with successful conservative management. RESULTS: The success rate of single-dose MTX was 68.1% (47/69). A second dose was required in 18.8% (13/69) of cases, and it was successful in 84.6% (11/13). The 15% day 4-7 rule correctly predicted the outcome in 90.3% of cases [sensitivity 93.0%, specificity 84.2%, positive predictive value (PPV) 93.0% and negative predictive value (NPV) 84.2%, Fisher exact test P-value < 0.0001]. New rules were developed based on the percentage change day 4-5 and logistic regression models incorporating day 5 hCG levels and ultrasound findings. These new rules did not outperform the current 15% day 4-7 rule. CONCLUSIONS: We have confirmed that a 15% decrease in serum hCG between day 4 and day 7 is a very good indicator of the likely success of MTX. The development of new rules did not significantly improve our ability to predict a successful outcome at an earlier stage.     

Local injection of methotrexate dissolved in saline versus methotrexate suspensions for the conservative treatment of ectopic pregnancy

To compare the local injection of methotrexate (MTX) dissolvedin saline and MTX suspensions for the laparo-scopic treatmentof ectopic pregnancy in terms of success rate and postoperativetubal patency. A total of 26 patients with unruptured ectopicpregnancies were selected from among 60 women with ectopic pregnanciesadmitted to the Nagasaki University clinic. Of these patients,12 were treated with MTX dissolved in saline solution (solutiongroup) and 14 with MTX suspensions consisting of lipiodol (LPD)with phosphatidylcholine (PC) added as a dispersing stabilizer(suspension group). Except for one case treated under transvaginalguidance, all the patients were treated by laparoscopy. Persistentectopic pregnancy was recognized in seven cases (58%) in thesolution group but in only two cases (14%) in the suspensiongroup. Moreover, rupture occurred in two cases in the solutiongroup but in no case in the suspension group. A patent treatedtube was found in seven of 10 cases in the saline group andin 10 of 12 cases in the suspension group. During the follow-upperiod of 6–31 months, five women in the saline groupand three women in the suspension group had an intrauterinepregnancy. In this study, the local injection of MTX is consideredto be a reasonable method for the treatment of unruptured ectopicpregnancy, and the MTX suspension seems to be more effectiveand useful than MTX solution.     

Treatment of interstitial pregnancy with methotrexate: report of an unsuccessful case

Until now, the traditional management of interstitial pregnancyhas been surgical. Lately, we have advocated conservative treatmentwith methotrexate as an option for infertility patiants. Thisis the first publication of a rupture with abundant intra-abdominalbleeding during systemic treatment with methotrexate of a patientwith an interstitial pregnancy. Signs of therapy failure arediscussed.     

Intra-uterine insemination, cervical pregnancy and successful treatment with methotrexate

Cervical pregnancy is rare but one of the most dangerous ofall pregnancy complications. The aetiology of cervical implantationis unclear and because of the fear of profuse haemorrhage abdominalhysterectomy has been historically considered the standard therapy.We report here an unusual case of an infertile woman with cervicalectopic pregnancy after ovulation induction with gonadotrophinsand intra-uterine insemination. The patient was successfullytreated with parenteral methotrexate without significant morbidity.It is concluded that chemotherapy should be initially consideredin most cervical pregnancies either as the sole form of treatmentor to improve the chances of success in alternative conservativemeasures.     

Single progesterone assay for early recognition of abnormal pregnancy

Serum progesterone and human chorionic gonadotrophin (HCG) were analysed using a time-resolved fluoroimmunoassay in an unselected group made up of 158 women with clinical suspicions of abnormal early gestation. Only cases in which endovaginal sonography had failed to localize the pregnancy were included. A single HCG determination had no diagnostic value. On the other hand, a critical progesterone level of 30 nM was determined below which no viable intrauterine pregnancies were found. Eighty-eight per cent of the ectopic pregnancies (n = 97) and 83% of the spontaneous abortions had progesterone levels below this limit. The discriminatory efficacy of one single progesterone determination was independent of the actual HCG level and serial determinations of progesterone did not increase the discriminatory power.     

Transvaginal intratubal methotrexate treatment of ectopic pregnancy. Report of 100 cases

Between November 1988 and December 1993,100 patients with acommon, unruptured ectopic pregnancy were treated with 1 mg/kginjection of intratubal methotrexate under transvaginal sonographiccontrol. Patients were not excluded from this series on thebasis of the size of the adnexal mass, the term of ectopic pregnancyor initial p-human chorionic gonadotrophin (HCG) concentrations.Patients were excluded following uncertain diagnosis, signsof a ruptured ectopic pregnancy, or a significant haemoperitoneumon ultrasound scans. The mean age of the patients was 29.5 years(range 20–41). The mean gestational age and initial HCGconcentration were 7.5 weeks (5–11) and 11 614 mlU/ml(192-105 000 respectively). Of the 100 patients, 22 (22%) hadan ectopic pregnancy with active cardiac activity. Completeresolution was obtained in 78 out of these 100 ectopic pregnancies.Of these, 66 patients (85%) needed only one intratubal methotrexateinjection, and 12 patients (15%) required a second i.m. methotrexateinjection of 1 mg/kg. In this study, local treatment with onesingle intratubal methotrexate injection was successful in only66% of patients. The mean resolution time for reduction of p-HCGconcentrations was 23.5 days (range 7-40). There was no statisticallysignificant correlation between initial (J-HCG concentrationsand outcomes after methotrexate treatment of ectopic pregnancyin our study. Where embryonal heart beats were observed, thesuccess rate of the procedure was 40.9% (nine out of 22 cases).In the absence of cardiac activity, or when ultrasound examinationshowed no embryo, the success rate achieved was 84.6% (66 outof 78 cases) (P < 0.01). In all, 34 patients were consideredto be incompletely cured after only one intratubal methotrexateinjection: 12 patients required a second i.m. injection, a stagnationof {i-HCG concentrations was observed in 15 patients, abdominalpain occurred in six patients, and one patient suffered tubalrupture with haemoperitoneum. A total of 22 patients requiredsecondary surgical managment (salpingectomy). No biochemicalor clinical side-effects of methotrexate treatment occurred.Tubal alteration ascribable to methotrexate injection occurredin one patient in our study. Out of 75 patients in this serieswho wished to conceive, 21 (28%) became pregnant within 1 yearwith the following outcomes: 11 pregnancies at term, three miscarriages,one induced abortion and six recurrent ectopic pregnancies (fouroccurred on the same side). Our findings suggest that treatmentof common unruptured ectopic pregnancy without prior selectionof patients, by a single intratubal methotrexate administrationwas associated with a 66% success rate. This was dependent onlyon the presence of embryonal heart beats and there was no correlationbetween the success rate and initial fi-HCG concentrations.Successful outcome after methotrexate administration for ectopicpregnancy could be perfected by way of an improved selectionof patients based on inactive embryonal hearts and absence ofa visualized embryo.     

Trophoblast tissue culture of human intrauterine and ectopic pregnancies and treatment with methotrexate.

The application of drugs for conservative treatment of patients with ectopic pregnancy has been used worldwide for several years. In-vitro studies, however, are very few. We therefore examined the effects of methotrexate on trophoblast tissue cultures derived from intrauterine and ectopic pregnancies. Methotrexate was administered either 12 h or 6 days after initiation of the culture. Human chorionic gonadotrophin (HCG) levels were measured in the culture medium. All cultures showed secretion of HCG within the first 16 days. Methotrexate concentrations less than 3.8 x 10(-4) mol/l had no effect on HCG secretion. Cultures of ectopic pregnancies required a concentration about 10x higher to induce an equivalent reduction of HCG levels compared to intrauterine pregnancies. A few intrauterine and ectopic pregnancies showed no reduction of HCG values after treatment. These results suggest that data obtained from studies on intrauterine pregnancies may not be transferable to ectopic pregnancies in all instances. In some regimens approximately 8 days are required before the effect becomes measurable. In combination with our clinical data, we therefore recommend not to repeat a methotrexate dose too early in treatment of patients with ectopic pregnancies. The possibility that non-responding patients could exist should be kept in mind.     

Pregnancy: A comparison of methotrexate versus laparoscopic surgery for the treatment of ectopic pregnancy: a cost analysis

This study was a cost analysis of direct medical costs of themethotrexate management versus laparoscopic surgery in the treatmentof ectopic pregnancy. A total of 40 patients treated from January1991 to October 1994 with methotrexate were compared with another40 patients treated at the same hospital by laparoscopy fromApril 1986 to June 1994. Medical records for all these patientswere received and hospital databases were used to retrieve informationon cost Treatment cost included the primary treatment, hospitalizationand outpatient follow-up necessitated by treatment, complicationsand secondary treatment in cases of treatment failure. The costrelated to diagnosis was excluded. The direct medical costsfor methotrexate and laparoscopy groups were based on successrates of 72.5 and 95% respectively. The total cost of methotrexatetreatment was Canadian $35 180 compared with Canadian $73 440for the laparoscopic treatment. The mean ± SE cost perpatient was Canadian $880 ± 160 in the methotrexate groupcompared with Canadian $1840 ± 150 in the laparoscopicgroup (P 0.001). The mean ± SE cost per patient withmethotrexate success was Canadian $330 ± 67 comparedwith Canadian $2330 ± 220 per patient with methotrexatefailure (P = 0.001). A complete assessment of methotrexate treatment,including cost-benefit and cost-effectiveness, is warranted.     

Successful treatment with methotrexate of five vital interstitial pregnancies.

Five patients with vital, unruptured interstitial pregnancies of less than 3 cm maximum diameter were treated successfully with methotrexate and leucovorin rescue. Four pregnancies showed cardiac activity. Diagnosis was established with transvaginal ultrasonography in all patients. The human chorionic gonadotrophin serum levels were measured to monitor the effectiveness of therapy. This is the first publication on methotrexate treatment for interstitial twin pregnancy and the first on instillation of methotrexate after puncture and aspiration of interstitial pregnancy. In all cases, total and uneventful regression of trophoblast tissue was achieved. No adverse reactions were observed. The advantages and drawbacks of these therapeutic approaches are discussed. Methotrexate appears to be an effective medical non-surgical treatment for unruptured interstitial pregnancy with or without cardiac activity, and preserves reproductive potential.     

Diagnosis and treatment of ectopic pregnancy by retrograde selective salpingography and intraluminal methotrexate injection: work in progress

Selective retrograde trans-cervical salpingography was carried out in four patients in whom ectopic pregnancy was suspected. The Fallopian tube was catheterized using a catheter set designed in our centre. The 6F catheter was placed in the cornua and an inner coaxial catheter was easily introduced into the proximal portion of the Fallopian tube, guided by tactile impression. Contrast medium was then injected and a round haloed mass was seen. Thereafter, the Fallopian tube was catheterized using a metallic guidewire until its tip was adjacent to the ectopic pregnancy. The coaxial catheter was then advanced along the guidewire and after removal of the latter, 5-35 mg of methotrexate was injected into the Fallopian tube. This new procedure was simple, well tolerated and had no side effects. A tubal pregnancy was demonstrated and surgery was avoided in all cases.     

Pregnancy: Laparoscopy: a dispensable tool in the diagnosis of ectopic pregnancy?

Laparoscopy is regarded as the final decisive diagnostic testin suspected ectopic pregnancy. The new non-invasive diagnosticmethods of transvaginal sonography and serum human chorionicgonadotrophin (HCG) monitoring now challenge this pivotal roleof laparoscopy. In this prospective study the diagnostic valueof an algorithm, combining transvaginal sonography with an HCGcut-off level between 1000 and 1500 IU/I (IRP) was tested in208 consecutive women at risk for ectopic pregnancy. Three diagnosticcategories are designated by the algorithm: intra-uterine pregnancy(n = 73), ectopic pregnancy (n = 89), and trophoblast in regression(n = 46). The latter category represents patients in whom nopregnancy could be located by transvaginal sonography, withan initial HCG concentration < 1500 IU/I, declining duringfollow-up. The algorithm has a sensitivity of 0.97, a specificityof 0.95, a likelihood ratio for a positive test of 19.4, anda likelihood ratio for a negative test of 0.03. The describeddiagnostic strategy thus proved extremely reliable in the safemanagement of patients at risk for ectopic pregnancy, and renderslaparoscopy obsolete.     

Non-surgical treatment of ectopic pregnancy in the sole remaining tube

We reported on three successive cases of intrauterine term pregnancyobtained in patients with an ectopic gestation in their solitaryremaining tube who were treated by three different non-surgicalconservative methods: parenteral methotrexate, local injectionof methotrexate combined with systemic administration, and expectantmanagement respectively. The opposite tube had been removedbecause of previous tubal ectopic pregnancy. The cases, whichwere at a high risk of repeated ectopic implantation, are unequivocalproof of intact function of a tube after conservative non-surgicalprocedures for ectopic pregnancy. Thus, our report adds furtherevidence favouring the feasibility, the safety and fertilitypotential of these procedures for selected unruptured tubalgestations.     

Pregnancy: 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 withsuspected ectopic pregnancy, the diagnostic value of transvaginalsonography and serum human chorionic gonadotrophin (HCG) measurementswere analysed in detail. The absence of an intra-uterine gestationalsac obviously was the most constant sonographic finding amongpatients with ectopic pregnancy (n = 89), with a very high sensitivity(0.99) but a low specificity (0.41). The application of differentHCG cut-off levels improved specificity to 1.00 for values exceeding4500 IU/1. Clinical utility obviously decreased, as many patientspresented with HCG values well below this level. The additionaleffect of adnexal findings was analysed. Sonographic identificationof an ectopic pregnancy was very specific (0.99) but had lowsensitivity (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 questionedby the results of our analysis: whereas the combined use ofsonography and HCG measurements is shown to be of great benefit,the limitations are also documented, underlining the need forre-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 specificityand clinical utility.     

Tubal ectopic pregnancy: macrophages under the microscope

BACKGROUND: Ectopic pregnancy (EP) is a major reproductive health issue, whose underlying causes remain largely unknown. The unusual macrophage presence in the oviduct affected by EP could indicate macrophage contribution to the pathology. METHODS: Macrophages have important functions in reproduction that are reviewed in this work. They are needed for tissue remodelling and immune-regulatory roles, and are present both in the ovary and uterus. Numerous cytokines regulate monocytes recruitment, differentiation and function in the reproductive tract, among them leukaemia inhibitory factor (LIF), colony-stimulating factor 1 and transforming growth factor-beta are indispensable and non-redundant for reproductive outcome. Cytokine types and levels are modulated by estrogen, progesterone and seminal plasma, which drive the differentiation of monocytes to immunity cells or to immunosuppressed trophic and scavenging macrophages. RESULTS: Many risk factors for EP involve an inflammatory reaction that can induce the release of mononuclear phagocytes from the bone marrow and/or favour immunosuppressed trophic differentiation of newly recruited mononuclear phagocytes in the reproductive tract. These observations strengthen the hypothesis that immunosuppressed trophic and scavenging macrophages may have a role in EP onset. CONCLUSIONS: Macrophages may contribute to the regulation of tubal motility through prostaglandin production and induction of progesterone secretion. Considerations about LIF also suggest that macrophages may have a central role in ectopic receptivity.     

Pregnancy: Corpus luteum failure in ectopic pregnancy

The endocrinology of ectopic pregnancy was studied in orderto investigate the origin of the discordance in the circulatingamounts of human chorionic gonadotrophin (HCG) and those ofoestradiol and progesterone. Serial maternal blood samples wereobtained at 4–9 weeks gestation from 93 patients who becamepregnant following in-vitro fertilization and embryo transferincluding 10 ectopic, 21 anembryonic and 62 normal singletonpregnancies. The samples were analysed for HCG, Schwangerschaftprotein-1 (SP-1), pregnancy-associated plasma protein-A (PAPP-A),progesterone and oestradiol. In ectopic pregnancies, concentrationsof all substances analysed were significantly reduced comparedto singleton pregnancies from 5 weeks gestation (P < 0.05–0.001)but they were not significantly different from those of anembryonicpregnancies. In ectopic pregnancies, associations were foundbetween the concentration of both HCG and SP-1 and those ofprogesterone and oestradiol. No associations were found betweenPAPP-A and any other substances analysed. This may be due toinsensitivity of the PAPP-A assay; alternatively PAPP-A concentrationsmay be differentially reduced in ectopic pregnancy. These findingssuggest that progesterone and oestradiol are derived from thecorpus luteum in early ectopic pregnancy but that the corpusluteum fails rapidly and the dominant source of both hormonesbecomes the trophoblast as early as 5 weeks.     

Improved sensitivity and specificity of a single measurement of serum progesterone over serial quantitative beta-human chorionic gonadotrophin in screening for ectopic pregnancy.

The sensitivity and specificity of a single serum progesterone measurement was compared against two beta-human chorionic gonadotrophin (HCG) measurements 48 h apart in screening for abnormal pregnancy, i.e. ectopic pregnancy, completed or incomplete abortion. Of 1120 patients in the first trimester presenting with a positive urinary pregnancy test, 116/1120 (10.4%) had an ectopic pregnancy, 755/1120 (67.4%) had ultrasonographically confirmed intra-uterine pregnancies, and 249/1120 (22.2%) had abnormal intra-uterine pregnancies documented as complete, incomplete or missed abortions. Of the ectopic pregnancies, 113/116 (97.4%) had a serum progesterone level less than 25 ng/ml while 516/755 (68.3%) viable intra-uterine pregnancies had a serum progesterone level greater than or equal to ng/ml. Of the 1120 patients screened, 402 (35.9%) had both a serum progesterone and two HCG measurements and were eligible for inclusion in this study. Setting a cut-off of 25 ng/ml, the sensitivity and specificity of a single serum progesterone measurement was then compared against two serial HCG measurements, utilizing receiver operating characteristic curves. This analysis demonstrated that a single serum progesterone measurement was significantly more sensitive (P less than 0.05) than two HCG measurements in screening for an abnormal pregnancy. In some patients, a single serum progesterone makes possible the diagnosis of ectopic pregnancy 2 days earlier than two HCG determinations because a second blood sample was not required. We conclude that a single serum progesterone measurement should be added to serial HCG determinations as a standard diagnostic screening test for ectopic pregnancy.     

Pregnancy: The prediction of ectopic pregnancy after in-vitro fertilization and embryo transfer

Data from 135 patients who suffered ectopic pregnancies andfrom 135 patients who progressed to singleton deliveries afterin-vitro fertilization and embryo transfer have been analysedretrospectively. The ectopic pregnancies represent all suchcases observed at Bourn Hall Clinic between 1983 and 1993. Thedelivered group was randomly selected from the same time period.The ectopic pregnancies included 20 heterotopic, eight ovarianand six bilateral tubal pregnancies; the remainder were singletontubal pregnancies. The aim of this study was to identify thevariables which differed systematically for the two groups ofpatients and to explore whether such variables could be usedto predict ectopic pregnancy at an early stage. The mean plasmaconcentration of human chorionic gonadotrophin and progesteronefor the ectopic pregnancy group was significantly lower thanthat for the singleton delivery group (P < 0.001). However,there was such a degree of overlap that it was impossible todevise a cut-off concentration for either hormone which wouldoffer a clinically useful predictor of ectopic pregnancy. Nevertheless,using the discriminant function analysis of these data, togetherwith the history of pelvic inflammatory disease, we could predictup to 90% of cases of ectopic pregnancy by day 23 after embryotransfer, long before ultrasound imaging would be useful.     

Spontaneous resolution of ectopic pregnancy in a surrogate after oocyte donation and frozen embryo transfer

A case of tubal pregnancy in a young and healthy woman participatingin a programme of in-vitro fertilization (IVF) gestational surrogacyis reported. The gestational surrogate was the 30 year old fertilesister of a 25 year old patient affected by stage 1 ovariancancer. After mandatory oncological consultation, the donorwas recommended to prospectively undergo controlled ovarianhyperstimulation cycles for embryo banking before being treatedby total hysterectomy. Available embryos were cryopreservedand after adequate endometrial preparation using artificialcycles of hormone replacement therapy, three thawed frozen embryoswere transferred to the surrogate. At 17 days following embryotransfer the surrogate was noted to have a negative -human chorionicgonadotrophin (HCG) serum concentration. All medication wassuspended and a few days later normal menstrual bleeding occurred.After 2 weeks, the (-HCG concentrations, performed as part ofroutine follow-up evaluation, were showing signs of trophoblastactivity (236 mIU/ml). Taking into account the stable conditionof the patient, a decision was made to undertake expectant managementAt 43 days after embryo transfer, a complete tubal abortionwas apparently seen in the posterior cul-de-sac by ultrasoundassociated with a subtle and short lasting pelvic pain. We stressthat this ectopic gestation was able to maintain prolonged viabilityin conditions of absent corpus luteum and exogenous steroidsupplementation.