Gestational Exposure to Benzodiazepines and Z-Hypnotics and the Risk of Major Congenital Malformations, Ectopic Pregnancy, and Other Adverse Pregnancy Outcomes.

A small proportion of women with anxiety, insomnia, and other conditions may require benzodiazepines or z-hypnotics intermittently or daily sometime during pregnancy. This article provides an update on pregnancy outcomes associated with pre-gestational or gestational exposure to benzodiazepines and z-hypnotics based on results from 2 meta-analyses, 2 registry-based studies, and 2 large retrospective cohort studies. In summary, the meta-analyses found that exposure was associated with an increased risk of spontaneous abortion, induced abortion, preterm birth, low birth weight, small for gestational age, low Apgar scores at 5 min, and neonatal intensive care unit admission. Whereas meta-analyses and registry studies found that first trimester exposure to benzodiazepines and/or z-hypnotics was not associated with increased risk of congenital malformations, a nationwide observational study with 10 times as many exposed pregnancies as in all the previous studies combined found that first trimester exposure to benzodiazepines was associated with a small but statistically significantly increased risk of overall malformations as well as, specifically, cardiac malformations; in this study, analyses that examined the potential role of confounding by indication suggested that the adverse findings may not have been due to confounding. Finally, a large observational study found that exposure to benzodiazepines in the 90 days before conception was associated with an increased risk of ectopic pregnancy; in this study, as well, the findings were consistent in analyses that examined possible confounding by indication. In no reviewed study could residual confounding be ruled out. The take-home message is that benzodiazepine and z-drug exposure before and during pregnancy is associated with many adverse gestational outcomes, but it is unclear to what extent the findings are due to exposure to drugs vs exposure to the indication for treatment. Therefore, all treatment decisions need to be tailored to context and shared between health care professionals, patients, and their caregivers.

Ectopic Pregnancy Risk in Users of Levonorgestrel-Releasing Intrauterine Systems With 52, 19.5, and 13.5 mg of Hormone.

This study assesses the association between use of levonorgestrel intrauterine systems containing 52, 19.5, and 13.5 mg of hormone and ectopic pregnancy in a nationwide cohort study.

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.

Apoptosis versus necrosis in tubal ectopic pregnancies following Methotrexate.

Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and eventually fallopian tube rupture. Salpingectomy specimens were collected, analysed and divided into three equal groups: patients who received Methotrexate but who ultimately failed medical treatment, patients who had a viable ectopic pregnancy and patients with a self-resolving ectopic pregnancy that were operated due to other medical indications. The specimens were dyed using the Cleaved Caspase-3 (Asp175) Rabbit mA. Specimens were divided into three equal groups and analysed. The patients in self-resolving ectopic pregnancy group were older and had more pregnancies. Rates of apoptosis were found to be less than 1% per slide. Necrosis was not evident in any of the pathological specimens. It seems Methotrexate administration does not lead to a significant tubal necrotic reaction. Further studies are required.

Very early medical abortion: treatment with mifepristone and misoprostol before ultrasonographic visualisation of an intrauterine pregnancy.

INTRODUCTION: Abortion providers may be reluctant to commence abortion before ultrasound evidence of intrauterine pregnancy (IUP) due to concerns of missed ectopic pregnancy. In 2017, very early medical abortion (VEMA) was introduced at an abortion service in Edinburgh, UK. Following ultrasound, patients without confirmed IUP, and without symptoms or risk factors for ectopic pregnancy, could commence treatment immediately after baseline serum-human chorionic gonadotrophin (hCG) measurement, and return for follow-up serum-hCG a week later to determine treatment success (≥80% decline from baseline). This study aimed to compare clinical outcomes between two pathways: (1) VEMA; and (2) standard-of-care delayed treatment where treatment is only commenced on IUP confirmation by serial serum-hCG monitoring and/or repeat ultrasound. METHODS: A retrospective database review was conducted of VEMA eligible patients from July 2017 to December 2021. Study groups were determined by patient preference. Records were searched for abortion outcomes, duration of care, number of appointments (clinic visits, ultrasounds, serum-hCG) and clinical data entries. RESULTS: Of 181 patients included, 77 (43%) chose VEMA and 104 (57%) chose delayed treatment. 11/181 (6.1%) were lost to follow-up. Cohort ectopic prevalence was 4.4% and was not statistically different between groups (2.6% vs 5.8%, VEMA vs delayed group, respectively, p=0.305), as with complete abortion rates (93.3% vs 97.6%, p=0.256). All VEMA group ectopics were detected on the seventh day (from initial visit) while time-to-diagnosis for delayed group ectopics ranged from 7 days to 3 weeks. VEMA patients had significantly reduced duration of care (12 vs 21 days, p<0.001), number of visits (2 vs 3, p<0.001), ultrasounds (1 vs 2, p<0.001) and data entries (6 vs 9, p<0.001). CONCLUSIONS: VEMA is safe, effective and reduces the duration of care, number of appointments and clinical administrative time. It should be offered to medically eligible patients.

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.

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.

Optimizing an algorithm for the identification and classification of pregnancy outcomes in German claims data.

PURPOSE: For studying drug utilization and safety in pregnancy based on administrative health care data, the reliable identification and classification of pregnancy outcomes in the data is essential. We aimed to optimize an existing algorithm for the identification and classification of pregnancy outcomes in the German Pharmacoepidemiological Research Database (GePaRD) with a particular focus on births. METHODS: We reconsidered all codes used by the original algorithm and applied it to data of GePaRD from 2006 to 2014. Longitudinal records of pregnancies were used to identify targets for enhancing the algorithm's specificity. We checked the plausibility of the results, eg, regarding the age distribution of persons with pregnancy outcomes. Based on 20 longitudinal records of pregnancies, we compared the outcome classification by clinical experts with the results of the modified algorithm. RESULTS: Our algorithm identified 1 235 261 pregnancy outcomes in the database, with the majority (94%) being live births, classified as preterm (10%), term (78%), and (12%) births after the expected delivery date. The median age of pregnant women was 32 years (Q1 28; Q3 35). Implausible sequence of outcomes (for example, an induced abortion within a pregnancy categorized as ending in a live birth) were rare (0.03%). The case profile review by clinical experts resulted in the same outcome type and date as the algorithm in 95%. CONCLUSIONS: Our algorithm led to plausible results regarding the identification and classification of pregnancy outcomes. It will be an important foundation for studies on drug utilization and drug safety during pregnancy based on GePaRD.

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.

Embarazo cornual y metotrexato en multidosis / Cornual pregnancy and multidose methotrexate

El embarazo cornual es una patología poco frecuente pero con una elevada mortalidad si no se diagnostica precozmente. La ecografía vaginal permite un diagnóstico precoz y la realización de un tratamiento conservador con metotrexato, reduciendo la morbimortalidad materna. Presentamos un caso de una gestante diagnosticada de embarazo cornual derecho no accidentado que fue tratada con metotrexato multidosis con éxito

Cornual pregnancy is a rare condition but has high mortality unless diagnosed early. Early diagnosis with transvaginal ultrasound allows conservative treatment with methotrexate, thus reducing maternal morbidity and mortality. We report a case of an unruptured right cornual pregnancy successfully treated with multidose systemic methotrexate

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.

Revisión del tratamiento del embarazo ectópico sobre cicatriz de cesárea previa. Una localización poco habitual / Review of the treatment of ectopic pregnancy in a previous cesarean section scar. A unusual location

La gestación implantada sobre cicatriz de cesárea previa es una forma poco habitual de embarazo ectópico, pero cuya incidencia ha aumentado en los últimos años en relación con las técnicas de reproducción asistida. Precisa de un diagnóstico temprano para poder minimizar las posibles complicaciones que pueden ocurrir (metrorragia, hemoperitoneo, rotura uterina,..). Disponemos de diferentes opciones diagnósticas y terapéuticas que revisaremos en este trabajo y que elegiremos en función de las características individuales de cada paciente (AU)

The pregnancy implanted on cesarean scar is a rare form of ectopic pregnancy, but whose incidence has increased in recent years in relation to assisted reproduction techniques. Accurate early diagnosis is needed in order to minimize the possible complications that can occur (metrorrhagia, hemoperitoneum, uterine rupture,..). We have different diagnostic and treatment options that will be reviewed in this paper and we will choose based on the individual characteristics of each patient (AU)

[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.

Dispensing patterns and pregnancy outcomes for women dispensed selective serotonin reuptake inhibitors in pregnancy.

BACKGROUND: The safety of selective serotonin reuptake inhibitors (SSRIs) during pregnancy remains uncertain. The purpose of this study was to investigate dispensing patterns and pregnancy outcomes for women dispensed an SSRI in pregnancy. METHODS: Using data linkage of population-based health datasets from Western Australia and a national pharmaceutical claims dataset, our study included 123,405 pregnancies from 2002 to 2005. There were 3764 children born to 3703 women who were dispensed an SSRI during their pregnancy. RESULTS: A total of 42.3% of the women were dispensed an SSRI in each trimester, and 97.6% of the women used the same SSRI throughout the first trimester without switching. The women who were dispensed an SSRI were more likely to give birth prematurely (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.2-1.7), to have smoked during the pregnancy (OR, 1.9; 95% CI, 1.8-2.1), and parity>1 (OR, 1.7; 95% CI, 1.5-1.8). The singletons were found to have a lower birth weight than expected when other factors were taken into account (OR, 1.2; 95% CI, 1.1-1.3). There was an increased risk of major cardiovascular defects (OR, 1.6; 95% CI, 1.1-2.3). The children of women dispensed citalopram during the first trimester had an increased risk of vesicoureteric reflux (OR, 3.1; 95% CI, 1.3-7.6). Children born to women dispensed sertraline had a higher mean birth weight than those born to women dispensed citalopram, paroxetine, or fluoxetine. This pattern was also seen in birth length. CONCLUSIONS: Most women were dispensed the same SSRI throughout their pregnancy. We have confirmed previous findings with an increased risk of cardiovascular defects and preterm birth. New findings requiring confirmation include an increased risk of vesicoureteric reflux with the use of citalopram.

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.