Fetal methotrexate and misoprostol exposure: the past revisited

BACKGROUND: Fetal aminopterin/methotrexate syndrome was described nearly 50 years ago when these agents were first used as abortifacients. Physicians essentially stopped using these agents when the associated anomalies were recognized. Over the last several years the use of methotrexate with or without misoprostol for management of ectopic pregnancy and medical terminations of pregnancy has increased. METHODS: A 23-year-old female sought a termination at eight weeks gestation. She was given methotrexate followed by misoprostol. RESULTS: The medical termination was unsuccessful. The patient elected to continue the pregnancy secondary to financial considerations. She presented at 39 weeks without intervening prenatal care. She was diagnosed with severe preeclampsia. At delivery the infant was hypotonic and growth restricted with multiple anomalies. CONCLUSIONS: Physicians are increasingly using methotrexate with or without misoprostol for treatment of ectopic pregnancies and medical terminations. Clinicians need to be aware of the characteristic teratologic effects of these two agents.     

Methotrexate therapy. Nonsurgical management of ectopic pregnancy.

Ectopic pregnancy has become a surgical epidemic over the past two decades. To minimize the morbidity, mortality, and financial burden created by this rapidly growing health problem, nonsurgical alternatives have been investigated, including treatment with methotrexate. We reviewed current literature to evaluate the safety, efficacy, and costs associated with methotrexate treatment of tubal pregnancy. To date, 17 studies have reported on 400 patients with tubal pregnancies treated with parenteral methotrexate; the overall success rate was 92% (95% confidence interval, 89% to 95%). Single-dose parenteral methotrexate has been shown to be safe, effective, and associated with minimal costs when used in carefully selected patients. A prospective, randomized clinical trial comparing medical and surgical management of ectopic pregnancy is needed to assess the risks, benefits, and costs of these two approaches.     

Teratogen update: methotrexate

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.     

Solitary luteinized follicle cyst of pregnancy. Report of a case with cytologic findings

BACKGROUND: Giant luteinized follicle cyst is a recently recognized cause of ovarian enlargement during pregnancy and the puerperium. Only rare cases of this clinical condition have been reported in the literature, and the cytologic features have not been previously described. CASE: A 34-year-old, pregnant woman presented at 10 weeks' gestation with a large, right ovarian cyst. Clinical management was initially conservative, but four weeks later the patient presented with acute abdominal pain. At laparotomy, the ovarian cyst was aspirated and a cystectomy performed. On cytologic examination, the presence of a luteinized follicle cyst of pregnancy was suggested. Subsequent histologic examination confirmed the diagnosis. CONCLUSION: This case illustrates the clinicopathologic features of a luteinized follicle cyst of pregnancy with special emphasis on the cytologic characteristics. The cytologic features are sufficient to establish the diagnosis in conjunction with the ultrasonographic appearance.     

Managing gynaecological emergencies with laparoscopy.

A consecutive series of 49 women (50 procedures), whose conditions were haemodynamically stable, presenting with acute lower abdominal pain, pelvic tenderness, and either a urine concentration of greater than 50 U/l beta human chorionic gonadotrophin or a pelvic mass shown by ultrasonography were treated with operative laparoscopy under video monitoring (videopelviscopy) as an alternative to laparotomy. Ectopic pregnancy, ovarian and non-ovarian cysts, pelvic adhesions, endometriosis, and fibroids were found, for which salpingotomy, salpingectomy and salpingo-oophorectomy, cystectomy, adhesiolysis, thermocoagulation, and myomectomy were carried out by laparoscopy. In one patient pelviscopy was repeated because of persistent tubal pregnancy after the fimbria was expressed. Laparotomies were carried out on three patients because treatment was not possible by laparoscopy and on a further patient two days after adhesiolysis had been attempted. These were the only serious complications. For the 46 cases (45 patients) in which operative laparoscopy was successful the mean stay in hospital was 1.9 days after operation, and this group of patients returned to normal activities and to work after an average of 2.3 and 2.6 weeks respectively. Most gynaecological emergencies that are managed by laparotomy can be treated by laparoscopy and benefit both patients and the health service.     

Anti-implantation effect of prostaglandins in the rat.

PGF2alpha and PGE2 have been instilled in small amounts (5mug) into the uterine horns of pregnant rats at different intervals following mating. Unilateral as well as bilateral injections have been used. Three parameters have been taken into consideration at laparotomy performed on the 13th day of pregnancy: a) the number of implantation sites; b) the number of viable fetuses; and c) the number of corpora lutea present on the ovarian surface. Both PGs proved able to inhibit implantation, to affect the development of embryos and to exert some luteolytic activity when given between D-1 and D-6 of pregnancy.     

A case of left interstitial pregnancy after left adnexectomy--why surgical management?

Interstitial pregnancy is a rare condition of tubal pregnancy with a mortality rate of 2-2.5% [4] that can easily be misdiagnosed. The prevalence of interstitial pregnancy is 0.8% in normal population and it increased during the past few decades due to reproduction techniques development even up to 11% in groups of women after in vitro fertilization. A comprehensive MEDLINE and OLDMEDLINE search covering years 1950-2005 using query terms "interstitial", "pregnancy" and "adnexectomy" identified only 10 cases reported in worldwide literature. The first treatment of interstitial pregnancy used to be a resection of the uterus body via laparotomy. Along with the evolution of sensitive biochemical assays, imaging technologies and the development of operative techniques, the management of interstitial pregnancy became less invasive. We report a case of spontaneous left interstitial pregnancy after left adnexectomy due to left ovarian tumor of borderline malignancy.     

Early detection of ovarian cancer: preliminary results of the Yale Early Detection Program.

Eighty-four women at high risk for ovarian cancer by having first-degree relatives with epithelial ovarian cancer participated in a newly established, early ovarian cancer detection program at Yale University. Participants were to be evaluated with physical examinations and circulating tumor markers at entry and every six months thereafter. Endovaginal ultrasound and color Doppler flow studies were to be performed at three and nine months following entry into the program. In addition, women were encouraged to follow American Cancer Society guidelines for mammography. Stool was checked for occult blood. Endometrial sampling was offered to post-menopausal women. No participant has developed an ovarian cancer since entering the program. One woman has been diagnosed to have breast cancer. False-positive levels of circulating tumor markers (CA 125, 4/84 [4.8 percent]; lipid-associated sialic acid in plasma, 13/84 [15.5 percent]; NB/70K, 4/84 [4.8 percent]; and urinary gonadotropin fragment, 1/65 [1.5 percent]) were observed on entry into the program. Low resistive indices (less than 0.5) were documented in 8/91 (8.8 percent) ovaries studied by the color Doppler flow technique. One participant underwent a laparotomy based on a false-positive endovaginal ultrasound examination. Tests now being employed in community practice have a high likelihood of being associated with false-positive results. Therapeutic interventions based on isolated abnormal tumor markers or ultrasound studies obtained from women with family histories of ovarian cancer may lead to inappropriate surgery. It is necessary for cancer centers to develop expertise in ovarian cancer detection techniques to advise physicians in their geographic areas appropriately about the significance of the abnormal screening test.     

Anti-implantation effect of prostagiandins in the rat

PGF₂ and PGE₂ have been instilled in small amounts (5 μg) into the uterine horns of pregnant rats at different intervals following mating. Unilateral as well as bilateral injections have been used. Three parameters have been taken into consideration at laparotomy performed on the 13th day of pregnancy: a) the number of implantation sites; b) the number of viable fetuses; and c) the number of corpora lutea present on the ovarian surface. Both PGs proved able to inhibit implantation, to affect the development of embryos and to exert some luteolytic activity when given between D-1 and D-6 of pregnancy.     

Monitoring ovarian response of Booroola Assaf ewe lambs to PMSG, using ultrasonography and serum estradiol

Ovarian size was determined for 30-day-old ewe lambs treated with pregnant mare serum gonadotropin (PMSG; 1000 IU) using ultrasonography and was compared with direct measurement at laparotomy. Ultrasonography was found to be an accurate and reliable method for estimating ovarian size, and a significantly high correlation was found between the methods (R=0.96, P<0.01). Forty-eight hours following PMSG treatment, serum estradiol levels increased from below detectable levels to a value of 72.8 +/- 27.4 pg/ml (mean +/- SEM). A high correlation was found also between estradiol levels and ovarian size measured at laparotomy and by ultrasound, with a correlation coefficient of 0.94 and 0.80, respectively. It is suggested that a differential increase in ovarian size and estradiol secretion in immature ewe lambs treated with PMSG may reflect the different stages of ovarian development in individual animals. Noninvasive methods such as ultrasonography and measurements of serum estradiol may be utilized in the estimation of ovarian response.     

Abdominal pregnancy in a baboon: a first case report

The abdominal pregnancy is a rare, but life threatening complication of ectopic embryo implantation. Only three cases of abdominal pregnancy have been previously described in primates: in a squirrel monkey, owl monkey and in a rhesus macaque. A 14-year-old wild-caught olive baboon (Papio cynocephalus anubis) was diagnosed at the ultrasound examination with advanced gestational age extrauterine pregnancy. At the initial laparotomy and necropsy the diagnosis of abdominal pregnancy was made on Studdiford's criteria. This case indicates the possibility of developing a model for further study of different types of ectopic pregnancy and indicates a cesarean section as a risk factor for abdominal pregnancy.     

A role for tumor markers in therapeutic decisions after chemotherapy induction of objective remission in stage III epithelial ovarian neoplasms

The management of advanced stage ovarian carcinomas is presently based on initial surgical debulking, multiple drug chemotherapy including cisplatinum, second-look laparotomy. Such an aggressive approach has improved objective response rates and expected survival time, but no dramatic change has been demonstrated as for definitive cure percentages. Many Authors have attempted to turn an optimal objective response to chemotherapy (no residual or minimal residual disease at second-look) into a definitive cure with irradiation. Some reports show satisfactory results, but a high incidence of bowel obstructive complications has been demonstrated, probably due to multiple surgical manipulations before radiotherapy. A reliable diagnostic tool, that could help to avoid the second-look laparotomy (whose inherent role in improving survival is not assessed) should be therefore useful. The possible role of serum tumor markers determinations, for this purpose, is here discussed on the ground of a series of 20 patients affected by stage III ovarian carcinoma. Following this experience, a valuable role seems attributable to CA 125 in monitoring tumor response. Patients achieving values under 35 U/ml before second-look laparotomy showed tumor residuals in the range O-microscopic- less than 1 cm., that is, neoplastic localizations reliable for consolidation radiation therapy.     

Progesterone receptor modulators and progesterone antagonists in women's health

Both progesterone receptor modulators (PRMs) as well as pure progesterone antagonists (PAs) have numerous proven and potential therapeutic applications in female health care. Mifepristone, a PRM with only marginal agonistic activity, together with a prostaglandin can terminate pregnancies of less than 9 weeks duration; mifepristone is also used in the preparation of women at later gestational stages whose pregnancies are terminated with prostaglandins or surgery. Mifepristone causes expulsion of the uterine contents following intrauterine fetal death and promotes dilation of the non-pregnant primigravid uterus. It is also effective in the treatment of missed abortion. Together with methotrexate, mifepristone can be used in the medical treatment of ectopic pregnancy. Both PAs and PRMs display antiproliferative effects on the endometrium. Because of this, they have application in the treatment of endometriosis, an estrogen-dependent condition. They may also be utilized to reduce myoma size, acting as both a PA and antiproliferative agent. Unlike GnRH agonists, long-term use in endometriosis and myoma is not associated with loss of bone and hypoestrogenism. PRMs may also be useful in IVF programs to prevent a premature LH surge and to delay the emergence of the implantation window. Some PRMs have potential use as hormone replacement therapy in women during menopause or in those with dysfunctional uterine bleeding.     

Targeted therapies in epithelial ovarian cancer: Molecular mechanisms of action

Ovarian cancer is the leading cause of death in women with gynecological cancer. Most patients are diagnosed at an advanced stage and have a poor prognosis. Currently, surgical tumor debulking, followed by platinum- and taxane-based chemotherapy is the standard treatment for advanced ovarian cancer. However, these patients are at great risk of recurrence and emerging drug resistance. Therefore, novel treatment strategies are required to improve outcomes for women with advanced ovarian cancer. A variety of molecular targeted agents, the majority of which are monoclonal antibodies and small-molecule protein-kinase inhibitors, have been explored in the management of ovarian cancer. The targets of these agents include angiogenesis, the human epidermal growth factor receptor family, ubiquitin-proteasome pathway, epigenetic modulators, poly(ADP-ribose) polymerase (PARP), and mammalian target of rapamycin (mTOR) signaling pathway, which are aberrant in tumor tissue. The antiangiogenic agent, bevacizumab, has been reported as the most effective targeted agent and should be included in the standard chemotherapeutic regimen for advanced ovarian cancer. PARP inhibitors, which are mainly used in breast and ovarian cancer susceptibility gene-mutated patients, and mTOR inhibitors are also attractive treatment strategies, either alone or combination with chemotherapy, for ovarian cancer. Understanding the tumor molecular biology and identification of predictive biomarkers are essential steps for selection of the best treatment strategies. This article reviews the molecular mechanisms of the most promising targeted agents that are under early phase clinical evaluation for ovarian cancer.     

Diagnosing and management of iatrogenic moderate and severe ovarian hyperstymulation syndrome (OHSS) in clinical material

Severe ovarian hyperstymulation syndrome is a rare but potentially life-threatening complication in patients undergoing assisted reproductive techniques (ART). The pathogenesis of this condition is likely to be multifactorial. The aim of the retrospective study was to present management in moderate and severe iatrogenic ovarian hyperstymulation syndrome (OHSS) in clinical material. The study group was 19 women, admitted to the Department of Obstetrics and Gynecology in Central Clinical Hospital of Ministry of Interior and Administration in Warsaw from large outpatient infertility center "Novum" in Warsaw with moderate and severe OHSS between 14.07.2004 and 8.11.2005. Laboratory tests and ultrasound examination of the ovarian size and ascites were performed, abdominal circumference was measured. Patients were treated with rehydration with intravenous crystalloids and colloids, diuretics, antibiotics, anticoagulants and ultrasound-guided paracentesis if symptoms of ascites become severe (ascites causes pain and compromised pulmonary function). Oral intake of water was restricted, monitoring of fluid intake and output, and daily monitoring of body weight was performed. During treatment controlled laboratory tests were done. In one patient occurred intra-abdominal hemorrhage from ovarian rupture and laparotomy with oophorectomy was performed. The ovarian hyperstimulation syndrome is still a difficult diagnostic and therapeutic problem and more studies are required to elucidate pathophysiology of OHSS. Because of still unknown etiology treatment is empirical and in most of cases bases on experience of medical team. Thus, the management in individual patients varies according to the severity of ovarian hyperstymulation syndrome and its complications.     

Factors affecting pregnancy loss for single and twin pregnancies in a high-producing dairy herd

Our objective was to determine the magnitude of, and factors affecting, pregnancy loss for lactating Holstein cows on a commercial dairy farm when diagnosed with twin (n = 98) or single (n = 518) pregnancies using transrectal ultrasonography. Pregnancy losses were assessed with records of non-viable embryos at first pregnancy examination and embryo losses between the first (25-40 d after AI) and second (48 and 82 d after AI) post-breeding pregnancy examinations. Among cows diagnosed with single pregnancies, 3.7% were diagnosed with a non-viable embryo at first pregnancy examination, and 4.6% of those diagnosed with a viable embryo underwent pregnancy loss by the second examination. A total of 11.2% of cows diagnosed with twins experienced a single embryo reduction, whereas 13.3% lost both embryos. Overall, the total proportion of cows experiencing pregnancy loss or experiencing embryo reduction was greater for cows diagnosed with twin than single pregnancies (odds ratio; OR = 3.6), resulting in an embryo survival rate of 91.9% for cows diagnosed with single compared to 75.5% for cows diagnosed with twin pregnancies. Season of breeding and milk production were associated with pregnancy loss for single pregnancies, whereas CL number was associated negatively with embryo reduction and pregnancy loss for twin pregnancies. The risk of twinning and double ovulation among pregnant cows increased with days in milk (DIM), and the risk of double ovulation was greater for cows diagnosed with ovarian cysts and lacking a CL at initiation of an Ovsynch protocol. We concluded that in this herd, embryo reduction and pregnancy loss during early gestation was greater for lactating Holstein cows diagnosed with twin compared to single pregnancies. In addition, cows diagnosed with ovarian cysts and lacking a CL had an increased risk for double ovulation.     

Methotrexate in rheumatoid arthritis is frequently effective, even if re-employed after a previous failure

Effectiveness of therapy with individual disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is limited, and the number of available DMARDs is finite. Therefore, at some stage during the lengthy course of RA, institution of traditional DMARDs that have previously been applied may have to be reconsidered. In the present study we investigated the effectiveness of re-employed methotrexate in patients with a history of previous methotrexate failure (original course). A total of 1,490 RA patients (80% female, 59% rheumatoid factor positive) were followed from their first presentation, yielding a total of 6,470 patient-years of observation. We identified patients in whom methotrexate was re-employed after at least one intermittent course of a different DMARD. We compared reasons for discontinuation, improvement in acute phase reactants, and cumulative retention rates of methotrexate therapy between the original course of methotrexate and its re-employment. Similar analyses were peformed for other DMARDs. Methotrexate was re-employed in 86 patients. Compared with the original courses, re-employment was associated with a reduced risk for treatment termination because of ineffectiveness (P = 0.02, by McNemar test), especially if the maximum methotrexate dose of the original course had been low (<12.5 mg/week; P = 0.02, by logistic regression). In a Cox regression model, re-employed MTX was associated with a significantly reduced hazard of treatment termination compared with the original course of methotrexate, adjusting for dose and year of employment (hazard ratio 0.64, 95% confidence interval 0.42-0.97; P = 0.04). These findings were not recapitulated in analyses of re-employment of other DMARDs. Re-employment of MTX despite prior inefficacy, but not re-employment of other DMARDs, is an effective therapeutic option, especially in those patients in whom the methotrexate dose of the original course was low.     

Ovarian Failure and the Menopause

Long-term replacement therapy for ovarian deficiency or failure, including the menopause, has been widely debated. In the past, treatment, if indicated, was reassurance, sedation, and occasionally short-term estrogen therapy. Today, because of recent advances in steroid synthesis, the consequences of ovarian deficiency may be preventable.Ovarian function and failure are discussed, the apparent physiological renaissance of nine patients documented, and the methods of treatment detailed. Thirty-three patients, who took part in this program during the past two years, have continued treatment with enthusiasm, without major problems in management, and have shown evidence of improved physical and emotional well-being.Further unbiased long-term research, possibly using modern computer technique, is needed to decide between traditional and replacement therapy for the menopause.     

Restoration of fertility after treatment for cancer

The late effects of chemotherapy and radiation treatment on fertility are an important issue for long-term survivors of cancer who may not have started or completed a family at the time of diagnosis. Attempts at protecting reproductive function using hormonal manipulation have proved largely unsuccessful and other strategies have to be considered. For men, semen cryopreservation allows subsequent artificial insemination of a female partner or ivf but cryopreserved semen is a finite resource, does not allow natural conception and is not an option for prepubertal boys. In an effort to overcome this, research is in progress to investigate whether testicular cells harvested and cryopreserved before the start of chemotherapy can be reintroduced to the testis after treatment and resume normal spermatogenesis. This has been achieved in a mouse model and the results of experimental protocols in men are awaited with interest. For women, harvested mature oocytes are only poorly tolerant of the freezing process although immediate in vitro fertilization and cryopreservation of embryos can be successful. An experimental technique of great interest is the harvesting and cryopreservation of ovarian cortex before the start of sterilizing treatment. In ewes, the reimplantation of autologous ovarian cortical tissue into surgically castrated animals has resulted in resumption of oestrus, conceptions after normal matings and the birth of live offspring. Recently, ovarian function has been re-established using a similar technique in a patient following treatment for Hodgkin's lymphoma, but so far pregnancy has not been reported.     

Comparison of Immunochemical Methods with the Rat Ovarian Hyperemia Test in Routine Assays of Human Urinary Chorionic Gonadotropin

Positive rat ovarian hyperemia tests (AZ) in most cases of normal pregnancy agreed well with the positive results of commercial immunochemical in vitro assay methods. Immunochemically reactive and biologically undetectable urinary chorionic gonadotropin (HCG) was observed in one case of normal pregnancy, in one case of presumably normal pregnancy and in several cases of abortion. HCG excreted by a patient with choriocarcinoma was biologically active and immunochemically reactive; it became undetectable after methotrexate therapy. The in vitro tests have been successfully applied in quantitative gonadotropin assays. Negative bioassays and weakly positive immunochemical tests were observed in the urine of several patients in whom an increased pituitary gonadotropin output was suspected.