Combination of gefitinib and methotrexate to treat tubal ectopic pregnancy (GEM3): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. METHODS: We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. FINDINGS: Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference -0·01, 95% CI -0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. INTERPRETATION: In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. FUNDING: National Institute of Health Research.

The efficacy of mifepristone combined with methotrexate for the treatment of ectopic pregnancy: a systematic review and meta-analysis.

OBJECTIVE: Systematically evaluate the clinical efficacy of mifepristone combined with methotrexate therapy for ectopic pregnancy (EP), analyze the experimental designs, put forward improvement ideas. METHODS: RCTs of mifepristone combined with mifepristone for EP until January 2022 in six databases were searched. The primary outcome indicator was the cure rate. RevMan 5.4 was used to analyse and the online GRADEpro tool was used to assess the certainty of the evidence. RESULTS: Twenty-five RCTs involved 2263 patients. The cure rate was higher in the investigational group (OR = 4.09, 95%CI: [3.20, 5.22]), time of vagina stopped bleeding (MD = -11.21, 95%CI: [-11.85, -10.57]) and time of abdominal pain disappeared (MD = -6.24, 95%CI: [-6.63, -5.86]) were shorter in the investigational group, ß-HCG level (MD = -585.32, 95%CI: [-609.62, -561.03]) was lower and diameter of the mass (MD = -1.23, 95%CI: [-1.40, -106]) was smaller in the investigational group. The certainty of the evidence for most outcomes was moderate or high, and only one was low. CONCLUSIONS: The combination of mifepristone and methotrexate can improve the efficacy of ectopic pregnancy without amplifying the toxic side effects. Larger scale and better design of the randomized controlled trials are needed.KEY MESSAGESIn recent years, the increase in ectopic pregnancies and their impacts on female fertility makes physicians have to find an effective medical treatment as soon as possible that can avoid surgery.The mifepristone combined with methotrexate therapy for EP has better curative effects on improving the cure rate, lowering ß-HCG level, reducing the mass, and alleviating symptoms of abdominal pain and bleeding, without amplifying the toxic side effects.Literature with high quality is lacking, and well-designed, large-scale and high-quality multicenter randomized controlled trials are needed.

Future Perspectives of Ectopic Pregnancy Treatment-Review of Possible Pharmacological Methods.

Ectopic pregnancy, that is, a blastocyst occurring outside the endometrial cavity of the uterus, affects nearly 2% of pregnancies. The treatment of ectopic pregnancy is surgical or pharmacological. Since surgical management is associated with numerous serious side effects, conservative treatment is sought. The treatment of choice in the majority of cases is based on pharmacotherapy with methotrexate (MTX) in a single- or multi-dose regimen. Although the efficacy of methotrexate reaches between 70 and 90%, its use requires specific conditions regarding both the general condition of the patient and the characteristic features of the ectopic pregnancy. Moreover, MTX can cause severe adverse effects, including stomatitis, hepatotoxicity and myelosuppression. Therefore, clinicians and researchers are still looking for a less toxic, more effective treatment, which could prevent surgeries as a second-choice treatment. Some studies indicate that other substances might constitute a good alternative to methotrexate in the management of ectopic pregnancies. These substances include aromatase inhibitors, especially letrozole. Another promising substance in EP treatment is gefitinib, an inhibitor of EGFR tyrosine domain which, combined with MTX, seems to constitute a more effective alternative in the management of tubal ectopic pregnancies. Other substances for local administration include KCl and absolute ethanol. KCl injections used in combination with MTX may be used when foetal heart function is detected in cervical ectopic pregnancies, as well as in heterotopic pregnancy treatment. Absolute ethanol injections proved successful and safe in caesarean scar pregnancies management. Thus far, little is known about the use of those substances in the treatment of ectopic pregnancies, but already conducted studies seem to be promising.

Ovarian hyperstimulation syndrome following GnRH agonist trigger-think ectopic.

PURPOSE: This study aims to report a case of ovarian hyperstimulation syndrome (OHSS) following GnRH agonist trigger for final follicular maturation. METHODS: This study is a retrospective chart review. RESULTS: We report the first case of OHSS following GnRH agonist trigger for final follicular maturation and freeze-all, masking extrauterine pregnancy (EUP). The present case report elucidates the feasibility of stimulating and recruiting ovarian follicles yielding mature oocytes during early pregnancy and the ability of GnRH agonist to trigger final follicular maturation during pregnancy, in the presence of high progesterone and hCG levels. CONCLUSIONS: Since OHSS almost always develops after hCG administration or in early pregnancy, its occurrence following GnRH agonist trigger should alert physician to search for either an inadvertent administration of exogenous hCG, or the endogenous secretion of hCG by pregnancy, e.g. EUP, or as part of a paraneoplastic syndrome.

Clinical predictors of failing one dose of methotrexate for ectopic pregnancy after in vitro fertilization.

PURPOSE: The aim of this study is to investigate the clinical predictors of failure of a single dose of methotrexate (MTX) for management of ectopic pregnancy after in vitro fertilization (IVF). METHODS: A retrospective cohort study was performed of women who conceived ectopic pregnancies following fresh or frozen IVF cycles at an academic infertility clinic between 2007 and 2014, and received intramuscular MTX (50 mg/m2). Successful single-dose MTX treatment was defined as a serum beta-human chorionic gonadotropin (hCG) decline ≥15% between days 4 and 7 post-treatment. Logistic regression models adjusted for oocyte age, number of embryos transferred, and prior ectopic pregnancy were used to estimate the adjusted odds ratio (OR) (95% confidence interval [CI]) of failing one dose of MTX. RESULTS: Sixty-four patients with ectopic pregnancies after IVF were included. Forty required only one dose of MTX (62.5%), while 15 required additional MTX alone (up to four total doses, 23.4%), and 9 required surgery (14.1%). By multivariable logistic regression, the highest tertiles of serum hCG at peak (≥499 IU/L, OR = 9.73, CI 1.88-50.25) and at first MTX administration (≥342 IU/L, OR = 4.74, CI 1.11-20.26), fewer embryos transferred (OR = 0.37 per each additional embryo transferred, CI 0.19-0.74), and adnexal mass by ultrasound (OR = 3.65, CI 1.10-12.11) were each correlated with greater odds of requiring additional MTX and/or surgery. CONCLUSION: This is the first study to report that in women with ectopic pregnancies after IVF, higher hCG-though well below treatment failure thresholds previously described in spontaneous pregnancies-fewer embryos transferred, and adnexal masses are associated with greater odds of failing one dose of MTX. These findings can be used to counsel IVF patients regarding the likelihood of success with single-dose MTX.

Associations of lifetime active and passive smoking with spontaneous abortion, stillbirth and tubal ectopic pregnancy: a cross-sectional analysis of historical data from the Women's Health Initiative.

OBJECTIVE: To examine the associations between tobacco exposure and adverse pregnancy outcomes using quantitative measures of lifetime active smoking and secondhand smoke (SHS) exposure. METHODS: Historical reproductive data on 80 762 women who participated in the Women's Health Initiative Observational Study were examined with a cross-sectional analysis. We assessed self-reported lifetime active and passive tobacco smoke exposure, self-reported spontaneous abortions, stillbirths and ectopic pregnancies. RESULTS: When compared with never-smoking women, participants who were ever active smokers during their reproductive years had ORs (OR) of 1.16 (95% CI 1.08 to 1.26) for 1 or more spontaneous abortions, 1.44 (95% CI 1.20 to 1.73) for 1 or more stillbirths, and 1.43 (95% CI 1.10 to 1.86) for 1 or more ectopic pregnancies. Never-smoking women participants with the highest levels of lifetime SHS exposure, including childhood >10 years, adult home >20 years and adult work exposure >10 years, when compared with never-smoking women with no SHS exposure had adjusted ORs of 1.17 (95% CI 1.05 to 1.30) for spontaneous abortion, 1.55 (95% CI 1.21 to 1.97) for stillbirth, and 1.61 (95% CI 1.16 to 2.24) for ectopic pregnancy. CONCLUSIONS: Women who were ever-smokers during their reproductive years had significantly greater estimates of risk for spontaneous abortion, stillbirth and tubal ectopic pregnancy. Never-smoking women with the highest levels of lifetime exposure to SHS had significantly increased estimates of risk for spontaneous abortion, stillbirth and tubal ectopic pregnancy.

The association between smoking and ectopic pregnancy: why nicotine is BAD for your fallopian tube.

Epidemiological studies have shown that cigarette smoking is a major risk factor for tubal ectopic pregnancy but the reason for this remains unclear. Here, we set out to determine the effect of smoking on Fallopian tube gene expression. An oviductal epithelial cell line (OE-E6/E7) and explants of human Fallopian tubes from non-pregnant women (n = 6) were exposed to physiologically relevant concentrations of cotinine, the principle metabolite of nicotine, and changes in gene expression analyzed using the Illumina Human HT-12 array. Cotinine sensitive genes identified through this process were then localized and quantified in Fallopian tube biopsies from non-pregnant smokers (n = 10) and non-smokers (n = 11) using immunohistochemistry and TaqMan RT-PCR. The principle cotinine induced change in gene expression detected by the array analysis in both explants and the cell line was significant down regulation (P<0.05) of the pro-apoptotic gene BAD. We therefore assessed the effect of smoking on cell turnover in retrospectively collected human samples. Consistent with the array data, smoking was associated with decreased levels of BAD transcript (P<0.01) and increased levels of BCL2 transcript (P<0.05) in Fallopian tube biopsies. BAD and BCL2 specific immunolabelling was localized to Fallopian tube epithelium. Although no other significant differences in levels of apoptosis or cell cycle associated proteins were observed, smoking was associated with significant changes in the morphology of the Fallopian tube epithelium (P<0.05). These results suggest that smoking may alter tubal epithelial cell turnover and is associated with structural, as well as functional, changes that may contribute to the development of ectopic pregnancy.

[Cervical pregnancy: a rare case of reimplantation after abortion. A case report]. / La réimplantation cervicale de la grossesse, une complication méconnue des interruptions volontaires de grossesse. À propos d'un cas.

Cervical pregnancy is a rare form of ectopic pregnancy defined by the implantation of the blastocyst in the cervical canal. Most of the cervical pregnancies have been reported in patients with a history of vacuum curettage or caesarean section. The authors report a case of cervical pregnancy occurred after a failure of medical abortion. A literature review discusses the possibility of a cervical secondary implantation and describes the management of such pregnancies.

Tabaquismo durante el embarazo / Smoking during pregnancy

El tabaquismo durante el embarazo ha sido relacionado a muchas patologías obstétricas y neonatales, como desprendimiento de placenta, placenta previa, embarazo ectópico, aborto, parto prematuro, síndrome de distress respiratorio del recién nacido, bajo peso de nacimiento, muerte súbita, síndromes neurocognitivos, entre otros. En relación a la patología respiratoria el tabaquismo durante el embarazo produce alteraciones en la función de la vía aérea, traducido por flujos espiratorios disminuidos, sibilancias recurrentes y asma bronquial, hiperreactividad bronquial, mayor frecuencia de hospitalizaciones e infecciones respiratorias bajas. Finalmente es fundamental aplicar medidas tendientes a evitar el tabaquismo en las mujeres embarazadas y en el producto de la concepción.

Anticoncepción hormonal de emergencia y embarazo ectópico: caso clínico / Emergency contraception and ectopic pregnancy: clinical case

El riesgo de embarazo ectópico después de anticoncepción de emergencia es un hecho conocido y con el aumento de la demanda por este método, es esperable un mayor número de casos en el futuro. Se presenta un caso de embarazo ectópico después del fracaso de la anticoncepción de emergencia con levonorgestrel.

The risk of ectopic pregnancy after emergency contraception is known and with the increased use of this treatment, we might expect more cases in the future. One case of ectopic pregnancy after failure of emergency contraception with levonorgestrel is presented.

Safety of quinacrine contraceptive pellets: results from 10-year follow-up in Vietnam.

BACKGROUND: This study was conducted to evaluate long-term safety of quinacrine pellets for nonsurgical sterilization among women in Vietnam. STUDY DESIGN: Observational cohort study of 2735 women who had quinacrine insertions between 1989 and 1993 compared to 1623 women who received an intrauterine device (IUD). RESULTS: Cumulative follow-up times for the quinacrine and IUD cohorts were 28,697 and 17,382 person-years, respectively, and losses to follow-up were 6% and 7%, respectively. Quinacrine users had a higher incidence of ectopic pregnancy compared to IUD users (risk ratio, 2.2; 95% confidence interval, 1.06-4.54); the risks of cancer, hysterectomy, pelvic/gynecologic surgery and death were similar in the two groups. Two quinacrine insertions appeared to lower the risk of ectopic pregnancy to that of surgical tubal occlusion. CONCLUSIONS: Use of quinacrine in this cohort appeared to have minimal health risks. Other research, including preclinical studies, needs to be considered in an overall evaluation of whether the combination of safety and efficacy provide a basis for quinacrine's approval by appropriate regulatory agencies.

Ectopic pregnancy in a breast cancer patient receiving trastuzumab.

Cervico-isthmic pregnancy is a rare form of ectopic pregnancy with a poor obstetrical prognosis, whose mechanism remains unclear. Preclinical data indicate that HER-2 plays a major role in embryo implantation. We report a case of cervico-isthmic pregnancy occurring during treatment with trastuzumab (Herceptin, a monoclonal antibody to HER-2). A 43-year-old woman presented with abnormal vaginal bleeding, while she was receiving trastuzumab for the last 14 months as an adjuvant therapy for a node-positive, HER-2 positive breast cancer. The diagnosis of evolutive cervico-isthmic pregnancy was confirmed by iterative ultrasonographic examinations. Given the poor obstetrical prognosis, the patient underwent voluntary abortion. The use of trastuzumab during pregnancy is still poorly documented, and its safety is not yet established. Given the importance of HER-2 in embryo implantation and fetal development, its putative role in this abnormal embryo implantation should be discussed.

Ectopic pregnancy with postcoital contraception--a case report.

The incidence of ectopic pregnancies is increasing. Common risk factors are tubal pathology, previous tubal surgery, previous ectopic pregnancy, intrauterine device use and embryo transfer. Levonelle-2, a progesterone-only postcoital contraceptive works by a combination of mechanisms including ovulation inhibition, prevention of fertilization, and inhibition of implantation. It is 85% effective and there have been 12 reported cases of ectopic pregnancy in the UK with its use. It is believed that progesterone slows the intratubal migration of the fertilized ovum. In the case reported here, a woman presented with an ectopic pregnancy after use of Levonelle-2 as postcoital contraception; there were no clinical predisposing risk factors. In the absence of any histological evidence of tubal damage, we suspect that the levonorgestrel from Levonelle-2 could have been responsible for delayed embryo transfer which resulted in the ectopic pregnancy.

Six cases of women with diethylstilbestrol in utero demonstrating long-term manifestations and current evaluation guidelines.

Diethylstilbestrol (DES), a nonsteroidal estrogen, was widely used in the United States from 1940 through 1971 to prevent pregnancy loss. In the late 1960s, an association was made with an increased incidence of clear cell adenocarcinoma in young women exposed in utero to DES. Additional study of these women over the next 35 years has shown an increased risk of other health problems including intraepithelial neoplasia, ectopic pregnancy, first trimester spontaneous abortion and second trimester pregnancy loss. The National Institutes of Health continues to fund studies to follow cohorts of DES-exposed mothers, daughters, sons and third generation children. The Centers for Disease Control have conducted a large DES Education Project and have established guidelines for management. The following six cases studies illustrate common problems seen in DES exposed daughters and management of problems encountered.

Are health care providers who work with cancer drugs at an increased risk for toxic events? A systematic review and meta-analysis of the literature.

OBJECTIVE: A systematic review and meta-analysis was conducted to test the hypothesis that oncology health care workers are at an increased risk of cancer, reproductive complications and acute toxic events. DESIGN: A structured literature search of Index Medicus/ MEDLINE, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews and Healthstar was performed from 1966 to December 2004 for human epidemiological studies evaluating the risk of toxic events in health care workers exposed to cytotoxic drugs. Raw data and adjusted odds ratios (OR) reported in eligible studies were combined using a random effects model to calculate point estimates and 95% confidence intervals (CI) for each potential risk outcome. MAIN OUTCOME MEASURES: Adjusted OR for congenital malformations, stillbirths and spontaneous abortions among health care workers exposure to cytotoxic agents compared to a nonexposed control group. RESULTS: The systematic review identified 14 studies evaluating the outcomes of interest, seven of which were suitable for statistical pooling. Due to lack of evidence, we were unable to estimate a pooled OR for the risk of cancer and acute toxic events. However, no significant association was detected between exposure to cytotoxic drugs and; congenital malformations (OR = 1.64; 95% CI: 0.91-2.94) and stillbirths (OR = 1.16; 95% CI: 0.73-1.82). In contrast, an association was identified between exposure to chemotherapy and spontaneous abortions (OR = 1.46; 95% CI: 1.11-1.92). CONCLUSIONS: The results of this systematic review identified a small incremental risk for spontaneous abortions in female staff working with cytotoxic agents. Health policy decision makers should effectively communicate the magnitude of this risk to their staff and implement cost effective interventions for its reduction or elimination.

A randomized, double-blind, multicentre clinical trial comparing starting doses of 150 and 200 IU of recombinant FSH in women treated with the GnRH antagonist ganirelix for assisted reproduction.

BACKGROUND: Studies with the GnRH antagonist ganirelix in assisted reproduction have indicated that compared with traditional GnRH agonist downregulation protocols, slightly fewer oocytes are retrieved. In this study it was investigated whether an increase in the starting dose of recombinant FSH (rFSH) could compensate for this loss. METHODS: A randomized, double-blind, multicentre clinical trial comparing a starting dose of 150 and 200 IU of rFSH (follitropin beta), in women undergoing treatment with the GnRH antagonist ganirelix. RESULTS: In total, 257 women were treated with rFSH, of whom 131 received 150 IU and 126 women 200 IU. Overall, 10.3 oocytes were retrieved in the 150 IU group and 11.9 in the 200 IU group (P=0.051). This difference became significant when women with cycle cancellation before HCG administration were excluded. Nearly 500 IU of additional rFSH was given in the high-dose group (2014 versus 1541 IU). In the low-dose group, 4.6 high-quality embryos were obtained compared with 4.5 in the high-dose group. Vital pregnancy rates were similar (31 and 25% in the 150 and 200 IU-treated women, respectively). Serum concentrations of FSH, estradiol and progesterone were significantly higher in the high-dose group at day 6 of rFSH treatment and on the day of HCG administration. In the high-dose group, serum LH concentrations were higher at day 6 of rFSH treatment but lower at the day of HCG administration. CONCLUSION: By increasing the starting dose from 150 to 200 IU of rFSH, slightly more oocytes can be retrieved in GnRH antagonist protocols for assisted reproduction. However, because this did not translate into a higher number of high quality embryos, the clinical relevance of such a dose increase may be questioned.

Simultaneous intrauterine and ovarian pregnancy following treatment with clomiphene citrate.

Heterotopic pregnancy is increasingly being diagnosed since the advent of assisted reproductive technology involving the use of superovulatory drugs and/or in-vitro fertilization and the availability of high-resolution ultrasound scans. There are reports of Heterotopic tubal pregnancies following clomiphene use. Heterotopic ovarian pregnancies are however rare. Clomiphene citrate, which is widely used in the primary care setting to treat anovulatory infertility, is felt safe. We present a case of heterotopic ovarian pregnancy following treatment with clomiphene citrate. The diagnosis and management of heterotopic ovarian pregnancy are also discussed.

Continued follow-up of pregnancy outcomes in diethylstilbestrol-exposed offspring.

OBJECTIVE: To evaluate long-term pregnancy experiences of women exposed to diethylstilbestrol (DES) in utero compared with unexposed women. METHODS: This study was based on diethylstilbestrol-exposed daughters, the National Collaborative Diethylstylbistrol Adenosis cohort and the Chicago cohort, and their respective nonexposed comparison groups. Subjects who could be traced were sent a detailed questionnaire in 1994 that contained questions on health history, including information on pregnancies and their outcomes. We reviewed 3373 questionnaires from exposed daughters and 1036 questionnaires from unexposed women. RESULTS: The response rate was 88% among exposed and unexposed women. Diethylstilbestrol-exposed women were less likely than unexposed women to have had full-term live births and more likely to have had premature births, spontaneous pregnancy losses, or ectopic pregnancies. Full-term infants were delivered in the first pregnancies of 84.5% of unexposed women compared with 64. 1% of exposed women identified by record review (relative risk [RR] 0.76, confidence interval [CI] 0.72, 0.80). Preterm delivery of first births occurred in 4.1% of unexposed compared with 11.5% of exposed women, and ectopic pregnancies in 0.77% of unexposed compared with 4.2% of exposed women. Spontaneous abortion was reported in 19.2% of DES-exposed women compared with 10.3% in control women (RR 2.00, CI 1.54, 2.60). According to complete pregnancy histories (many women had more than one pregnancy), preterm births were more common in DES-exposed women (19.4% exposed versus 7.5% unexposed (RR 2.93 CI 2.23, 3.86). Second-trimester spontaneous pregnancy losses were more common in DES-exposed women (6.3% versus 1.6%; RR 4.25, CI 2.36, 7.66). More first-trimester spontaneous abortions occurred in DES-exposed women than in controls (RR 1.31, CI 1.13, 1.53), and DES-exposed women had at least one ectopic pregnancy more often than unexposed women (RR 3.84, CI 2.26, 6.54). CONCLUSION: Pregnancy outcomes in DES-exposed women were worse than those in unexposed women.

Quinacrine sterilization: an assessment of risks for ectopic pregnancy, birth defects and cancer.

Quinacrine sterilization (QS) involves transcervical insertion of quinacrine pellets using a modified Copper TIUD inserter. Pellets are placed at the fundus in the proliferative phase of the menstrual cycle. Efficacy is presently estimated at 1 pregnancy failure per 100 women at 2 years. Early complications are lower for QS than surgical sterilization and this is also true for risk of ectopic pregnancy with newer insertion protocols. The risk of birth defects is very low, when estimated from a model with reasonable assumptions for probability of insertion in a pregnant uterus or within 30 days of conception, probability of such exposed pregnancy being carried to term, and probability of quinacrine exposure to the fetus causing a birth defect. Although quinacrine is a mutagen it is unlikely to be a carcinogen. Concentrations of quinacrine in the uterus after transcervical insertion are higher than for oral administration for only a matter of a few hours, although this brief exposure is adequate to cause injury to the tubal epithelium, leading to inflammation and an occluding scar. Oral administration of quinacrine is accepted as non-carcinogenic. Each site of use of QS must make its own risk/benefit assessment. The benefits of any contraceptive that can raise contraceptive prevalence is greatest for developing countries.