Late complications after systemic methotrexate treatment of unruptured ectopic pregnancies: a report of three cases

BACKGROUND: The use of methotrexate (MTX) by systemic administration in the treatment of unruptured ectopic pregnancy has been reported as a safe and effective method. CASES: We report three cases (one hematosalpinx and two pelvic hematocoeles) of complications after the use of MTX in the treatment of unruptured ectopic pregnancies. All three cases came to our observation for pelvic pain, abnormal bleeding and a pelvic mass after an interval of 3-5 months, subsequent to the disappearance of symptoms and normalization of serum human chorionic gonadotropin beta-subunit (beta-hCG) levels. CONCLUSIONS: These findings suggest that: (a) such complications should be considered before selecting the mode of treatment for ectopic pregnancy; and (b) that an early ultrasonographic control should be performed after MTX treatment even when the decline in beta-hCG levels suggests a successful resolution. This would permit an early diagnosis of these late complications.     

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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.     

Successful treatment of advanced interstitial pregnancy with methotrexate and hysteroscopy. A case report

BACKGROUND: Data concerning medical treatment of interstitial ectopic pregnancies are scarce. These pregnancies are characterized by late and serious clinical manifestations. We report a case of advanced interstitial pregnancy treated successfully by combining methotrexate (MTX) and hysteroscopy. CASE: A routine ultrasonic evaluation of a 10-week pregnancy revealed a right interstitial gestational sac 58 mm in diameter and containing an embryo with a crownrump length of 29 mm and embryonic heartbeats. Serum beta-human chorionic gonadatropin (hCG) level was 97,950 mIU/mL. The patient was treated with a systemic MTX/leucovorin regimen. At the end of the one-week course, no embryonic cardiac activity was detected, and a decrease in beta-hCG levels commenced. Persistent trophoblastic tissue, manifested by a low (26 mIU/mL) beta-hCG level in plateau, was successfully removed by way of hysteroscopy. CONCLUSION: Early detection of interstitial pregnancy may facilitate conservative medical treatment.     

Randomized trial of conservative laparoscopic treatment and methotrexate administration in ectopic pregnancy and subsequent fertility

Methotrexate treatment was compared to laparoscopic salpingotomy for conservative management of ectopic pregnancy in a prospective randomized study. One hundred patients were randomized into two groups using random numbers. Inclusion criteria were an ectopic pregnancy visualized by ultrasound with a pre-therapeutic score <13 as assessed by the following six criteria, graded from 1 to 3: gestational age, human chorionic gonadotrophin (HCG) concentration, progesterone concentration, abdominal pain, haemoperitoneal volume and diameter of the haematosalpinx. The treatments were either 1 mg/kg of methotrexate injected transvaginally into the ectopic pregnancy without anaesthesia or administered i.m. when the pregnancy could not safely or easily be punctured (group 1), or laparoscopic salpingotomy (group 2). Success was defined as the return to normal (<10 mIU/ml) of HCG concentrations. Treatment was successful for 45 of 51 patients in group 1 (88.2%) and 47 of 49 in group 2 (95.9%). Medical treatment was significantly (P < 0.05) associated with shorter postoperative stay (24 compared with 46 h), but HCG returned to normal more quickly after laparoscopic treatment (13 compared with 29 days). Spontaneous reproductive performance was similar in both groups, but overall intrauterine pregnancy was higher, and repeat ectopic pregnancy lower, after methotrexate treatment. In selected cases of ectopic pregnancy, with a pre-therapeutic score <13, methotrexate treatment appeared as safe and efficient as conservative treatment by laparoscopy and was associated with improved subsequent fertility.     

Efficacy of methotrexate and misoprostol for early abortion

BACKGROUND: Medical termination of pregnancy (medical abortion) as an alternative to surgical abortion has many advantages since it does not require anesthetics and there is no risk of cervical laceration or uterine perforation. In the present study, we evaluated the efficacy of methotrexate and intravaginally administered misoprostol for early abortion. METHODS: The study population consisted of 32 women seeking abortion of a normal intrauterine pregnancy of 8 weeks or less documented by ultrasound. The dose of methotrexate was 50 mg/m2 intramuscularly and the dose of misoprostol was 800 micrograms intravaginally. The final outcome of treatment was evaluated on day 14 or 16, and an abortion was considered successful if pregnancy was terminated without a surgical procedure. RESULTS: Abortion occurred in only 23 (71.8%) of 32 women. There were 9 failures (28.1%); 3 were ongoing pregnancies (9.3%) and 6 were incomplete abortions (18.7%) requiring suction curettage. After the exclusion of treatment failures, the mean duration of vaginal bleeding was 16.3 +/- 2 days. No serious side effects occurred as a result of methotrexate and misoprostol treatment. CONCLUSION: The use of methotrexate and intravaginal misoprostol for the termination of pregnancy requires larger studies to determine the safety and efficacy of this medical abortion, a comparison with RU 486 in prospective controlled randomized trials is necessary.     

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.     

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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.     

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.     

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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.     

Systemic methotrexate therapy versus laparoscopic salpingostomy in tubal pregnancy. Part II. Patient preferences for systemic methotrexate

OBJECTIVE: To investigate patient preferences for systemic methotrexate therapy relative to laparoscopic salpingostomy in the treatment of tubal pregnancy. DESIGN: Preference assessment in controlled clinical study. SETTING: Four hospitals and one infertility clinic. PATIENT(S): Forty patients who had been treated for tubal pregnancy and 40 nonpregnant controls. INTERVENTION(S): Preference for methotrexate therapy relative to salpingostomy was established during an interview. Two scenarios were offered for methotrexate therapy: one with and one without preceding diagnostic laparoscopy. Hypothetical tubal patency rates after methotrexate therapy were varied in both scenarios until patients switched in their initial preference. MAIN OUTCOME MEASURE(S): Preference for systemic methotrexate therapy. RESULT(S): Only a few patients switched in their initial preference when the tubal patency rate after systemic methotrexate therapy was varied. Most preferred methotrexate therapy without an increase in the tubal patency rate in a scenario without preceding diagnostic laparoscopy. A small group never opted for methotrexate therapy even when it would guarantee a 100% tubal patency rate. CONCLUSION(S): Systemic methotrexate therapy would be preferred by most patients as part of a completely nonsurgical management strategy. Tubal patency was a decisive factor for treatment preference in a minority of patients only.     

Methotrexate hepatotoxicity

Hepatoxicity is a major adverse reaction that can occur during methotrexate treatment of the rheumatic diseases. The pathologic lesions are nonspecific and the pathogenesis is poorly understood. Early studies in psoriasis clearly established a relationship between hepatic injury and several risk factors, particularly alcohol use. Methotrexate hepatoxicity occurs less frequently in rheumatoid arthritis than previously reported in psoriasis patients. Consequently, the American College of Rheumatology guidelines for methotrexate monitoring do not recommend baseline and surveillance liver biopsies in low-risk patients. These guidelines seem to be useful and cost-effective.     

Clinical biochemistry of pregnancy

Major adaptations in maternal physiology and metabolism are required for successful pregnancy outcome. Hormonal changes initiated even before conception significantly alter maternal biochemistry early in pregnancy. Steroid hormones, peptide hormones, and prostaglandins interact to expand blood and plasma volume and modulate the maternal capacity to supply energy and nutrients to the fetoplacental unit. As gestation progresses, reference ranges for the concentration of many biochemical parameters change significantly from those found in the nonpregnant state. Gestation-specific reference ranges are essential for correct interpretation of tests used in screening, diagnosis, and monitoring during pregnancy. The use of clinical laboratory tests in the management of high-risk pregnancy are discussed from the perspective of testing before conception and during pregnancy.     

Recombinant tissue type plasminogen activator treatment of thrombosed mitral valve prosthesis during pregnancy

PURPOSE: Prosthetic heart valve thrombosis occurring during pregnancy is a life-threatening complication. Surgical treatment requires clot removal under cardiopulmonary bypass (CPB) and carries a high mortality. We describe the successful use of thrombolytic therapy for recurrent thrombosed valve prosthesis in a pregnant patient. CLINICAL FEATURES: A 32-yr-old patient whose pregnancy was complicated by two episodes of a thrombosed St Jude mitral prosthesis is reported. The first episode occurred at 20 wk of pregnancy during the change of oral anticoagulant therapy (acenocoumarol 4 mg a day) to sc heparin. As the patient was in cardiogenic shock, the valve thrombus was treated by clot removal under CPB., with a cross clamp time of 32 min, a perfusion pressure above 70 mmHG. There was no fetal cardiac rhythm during CPB which lasted < 45 min. The second episode occurred at the 28th gestational week in a patient in cardiogenic shock and because reoperation was thought to carry too high a risk, the thrombus was successfully treated with 50 mg recombinant tissue plasminogen activators (rtPA) i.v. Following this, the course of pregnancy was uneventful and carried to term and the patient delivered vaginally. Pain relief was achieved with intravenous patient-controlled analgesia with alfentanil (bolus 100 mug; lock out = five minutes). Although rtPA has been used before, this is the first report in which pregnancy was carried to term and standard vaginal delivery performed. CONCLUSION: This case provides evidence for the efficacy and relative safety of rtPA as thrombolytic therapy in the treatment of haemodynamically compromised valve heart thrombosis in pregnancy.     

Successful pregnancy after spontaneous remission of familial pulmonary alveolar proteinosis

In this report we describe a case of a successful pregnancy in a 19-year-old patient suffering from the familial form of pulmonary alveolar proteinosis, a very rare pulmonary disorder. The pregnancy course was complicated by preterm labour. The outcome and management are discussed.     

Methotrexate and misoprostol to terminate early pregnancy

BACKGROUND: Although medical termination of pregnancy is available in Europe and China as an alternative to surgical termination, political and social factors have blocked medical approaches to pregnancy termination in the United States. Methotrexate, which is toxic to trophoblastic tissue, has been used safely to treat unruptured ectopic pregnancies. This report describes the use of a single low dose of methotrexate followed by intravaginal misoprostol for the medical termination of early pregnancy. METHODS: Women seeking termination of pregnancy were selected for this study on the basis of their good general health, emotional stability, and a pregnancy of 63 days or less in duration. Each woman received an intramuscular dose of methotrexate (50 mg per square meter of body-surface area). Five to seven days later, 800 micrograms of misoprostol was administered intravaginally. If abortion did not occur after seven days, the women was offered a second dose of misoprostol or vacuum aspiration. Successful abortion was defined as a complete termination of pregnancy within seven days after the first or second administration of misoprostol. RESULTS: A total of 171 of the 178 women enrolled in the study (96 percent) had successful medical abortions. Twenty-five women (14 percent) did not have an abortion after the first dose of misoprostol and received a second dose. Eighteen subsequently had complete abortions, but seven required suction curettage. In all seven women who required suction curettage, there was histologic evidence of disruption in the conceptus. No important side effects or complications were noted. CONCLUSIONS: The combination of methotrexate and misoprostol represents a safe and effective alternative to invasive methods for the termination of early pregnancy.     

The role of scientific societies

Ectopic pregnancy is one of the most common and dangerous complications of the early pregnancy period. Until now diagnosis has been late because major symptoms occur after tubal rupture and so only demolitive surgery has been possible. At present, with the appearance of ultrasound in obstetrics an earlier diagnosis of this pathology can be made before tubal rupture so medical treatment has become possible. We treated a series of twelve patients with early ectopic pregnancy (9 tubal and 3 with no localized site of implantation) with intramuscular 0.5 mg/kg methotrexate and oral 0.1 mg/kg of folic acid (Citrovorum Factor) on alternate days, in the attempt to reduce hospitalization and obtain more effective and safer medical management. We observed a fall in serum beta-HCG levels after one cycle of treatment in 11 out of 12 patients and after two cycles of therapy in the remaining case. Minimal side-effects were observed in four cases. Three pregnancies occurred after treatment before the advised interval time and ended in blighted ovum. Methotrexate systemic therapy can be considered an elective treatment and a sufficiently safe management in early unruptured ectopic pregnancy when a good clinical selection of patients is performed.     

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.     

Obstetric and gynecologic emergencies

This article reviews the pearls and pitfalls of obstetric and gynecologic emergencies occurring in women presenting to the emergency department. Some pitfalls include failure to screen for ectopic pregnancy, tachycardia as an unreliable indicator of a ruptured ectopic pregnancy, and the use of serum hCG as a testing procedure during pregnancy. Updates include serologic markers of ectopic pregnancy, ultrasonography in the emergency department, methotrexate treatment of ectopic pregnancy, traumatic placental separation, and fetomaternal hemorrhage.     

Cryptococcal pneumonia complicating pregnancy

In the present report we describe 4 previously healthy women who developed cryptococcal pneumonia during pregnancy, and 1 pregnant woman with cryptococcal meningitis. These cases illustrate a previously uncharacterized spectrum of cryptococcal disease. We also discuss 24 patients previously reported who had cryptococcal meningitis during pregnancy. Finally, we review the available data for each therapeutic option and present an algorithm for management based on appraisals of disease severity and risk to the unborn fetus. This report emphasizes the need for heightened awareness of cryptococcosis in the differential diagnosis of pneumonia, chest pain, and hypoxemia in the pregnant patient, but at present, there are insufficient epidemiologic data to determine whether incidences of pulmonary or disseminated cryptococcosis actually increase during pregnancy. The risk of congenital cryptococcosis to the unborn fetus is low, and the most likely mechanism whereby neonates acquire invasive fungal pulmonary infection is through aspiration. While it is unclear whether there is any real increased risk of spontaneous abortion or premature labor, the data indicate that overall fetal outcome depends on effective treatment of maternal infection. For patients with dense air-space consolidation, progressive pulmonary disease, or dissemination, antifungal therapy is necessary. Optimal treatment is determined by the acuity and severity of the clinical presentation. Amphotericin B (approximately 1 g) with or without flucytosine represents the choice for initial treatment of the more acutely ill patient with disseminated or progressive pulmonary cryptococcosis who requires hospitalization (whether during or after pregnancy). Oral fluconazole appears to be safe and effective alternative therapy after delivery for the less severely ill patient who can be managed on an outpatient basis. While the use of fluconazole during pregnancy generally appears safe in terms of fetal outcome (49, 58), the class C status and single report of fetal malformation (62) preclude confident recommendation for its use during pregnancy. The risks and benefits of this effective and generally less toxic drug should be discussed with the parents and weighed against the use of amphotericin B. For pregnant women with limited pulmonary cryptococcosis (segmental or nodular infiltrates) and no evidence of dissemination, we recommend close follow-up without antifungal therapy similar to the recommendation for normal hosts with minimal disease. However, it is important to note that there is no extensive experience upon which to base this recommendation for pregnant individuals (45, 55, 103, 108). It is prudent to use frequent physical examinations (for example, every 1-2 months), combined with chest roentgenograms and serum cryptococcal antigens to monitor progression and/or development of disease in both the mother and child for approximately 6 months postpartum. In conclusion, cryptococcosis during pregnancy presents a special challenge to the clinician. A balanced therapeutic approach holds great promise for successful maternal and fetal outcomes.     

The effects of D-23129, a new experimental anticonvulsant drug, on neurotransmitter amino acids in the rat hippocampus in vitro

Recent literature continues to promote the early use of disease-modifying antirheumatic drugs (DMARDs), especially the less toxic agents such as hydroxychloroquine. Reports of combination DMARD treatments have been disappointing, and careful attention must be paid to clinical trial design if the efficacy of combination therapies is to be established. Methotrexate retains its prominent role, and its mechanism of action has been the subject of many reports; its toxicity remains the most common reason for treatment termination. Guidelines for monitoring hepatic toxicity of methotrexate have been published and may help reduce the need for invasive biopsy procedures. Significant risk factors for methotrexate pulmonary toxicity remain difficult to identify. Large placebo-controlled studies of both sulfasalazine and hydroxychloroquine have been reported and have demonstrated the efficacy of these agents in the treatment of early rheumatoid arthritis. Awareness of drug-toxicity profiles is important for physicians who prescribe these agents.