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The safety of conception occurring shortly after methotrexate treatment of an ectopic pregnancy
Abstract
The objective of this study was to determine whether a single or repeated injection of methotrexate (MTX) to treat ectopic pregnancy results in either teratogenicity or other bad obstetric outcome in the pregnancy that shortly follows treatment. Data were retrieved from the medical records of 314 women treated with MTX for ectopic pregnancy in our institute (2000-2006) included age, MTX dosage, interval between last MTX treatment to conception, results of ultrasonographic follow-up of the subsequent pregnancy, triple test, karyotype testing, pregnancy outcome, and newborn weight and Apgar score. A logistic regression model based on pregnancy outcome as the dependent variable and interval since last MTX treatment as the independent variable estimated the odds ratio for the safety of conception occurring shortly after the treatment. Complete information was obtained for 125 pregnancies. Forty-five pregnancies occurred within 6 months (mean 3.6+/-1.7) after the last MTX treatment. The outcome of these pregnancies was compared with that of 80 pregnancies which occurred > or =6 months (mean 23.6+/-14.7) after the last MTX treatment. The fetal malformation and adverse outcome rates for both groups were similar (odds ratio 1.003, 95% CI 0.98-1.02). According to a logistic regression analysis, the interval between the last MTX treatment for ectopic pregnancy had no effect on the outcome of the pregnancy that shortly followed it. The results of this study support the notion that conceiving within the first 6 months after treatment with MTX for ectopic pregnancy is safe and not associated with any increase in the examined adverse pregnancy outcome parameters.
... Indeed, it is safe for a later pregnancy. The fetal exposure to MTX from maternal organs is considered to be low and the outcomes of pregnancies shortly after MTX therapy, are almost favorable (8). ...
... Nowadays, AMH is routinely measured in multiple occasions especially for infertility evaluation. Measurement of AMH is considered a highly effective approach of assessing ovarian reserve because of its independence of the menstrual cycle as well as the higher inter-cycle and intra-cycle reproducibility (8). ...
Background:
The aim of this study was evaluation of the impact of single-dose methotrexate (MTX) treatment on ovarian reserve in women with ectopic pregnancy (EP) undergoing infertility treatment in Iranian population.
Materials and methods:
This prospective cohort study was done between March 2015 and March 2017 in Tehran General Women Hospital, Tehran, Iran. We enrolled 20 patients with EP who conceived during infertility treatment and received a single-dose MTX (50 mg/m2) intramuscularly. Serum anti-Mullerian hormone (AMH), 17 beta-estradiol (E2), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and antral follicle count (AFC) on transvaginal ultrasonography, were evaluated before and 8 weeks after administration of MTX.
Results:
AMH did not significantly vary after the administration of MTX, compared to before treatment value (P=0.36). FSH, E2 and AFC changes were not statistically significant, while increment of LH was significant (P=0.02).
Conclusion:
Results indicated that single-dose MTX treatment did not reduce ovarian reserve in women with EP. Further randomized controlled clinical trial studies with larger sample sizes, by using multiple dosages of MTX, and with long-term follow up are suggested to be done.
... Hemorragia vaginal e contrações uterinas foram os motivos mais comuns para procurar cuidados hospitalares. Apenas 8% das mulheres relataram efeitos colaterais gastrintestinais 19 [27][28][29] . ...
... Já o metotrexato, outro fármaco utilizado como abortifaciente, atua bloqueando a enzima diidrofolato redutase, envolvida na produção de tiamina durante a síntese de DNA, e age sobre o citotrofoblasto interrompendo o processo de implantação 21 . É um antifolato amplamente utilizado para o tratamento da leucemia linfoblástica aguda, sendo também aplicado no tratamento de artrite reumatóide e de outras doenças inflamatórias, pois age como anti-inflamatório e imunomodulador 27 . ...
span style="color: #221e1f; font-size: xx-small;">
A prática clandestina do aborto pode provocar diversos efeitos prejudiciais à saúde da mulher. Em muitos casos, a situação política, social e religiosa do Brasil favorece a automedicação e a procura por preparações caseiras e populares para induzir o aborto. Atualmente, medicamentos e plantas são alguns dos
métodos empregados para interromper a gestação. Observa-se uma diversificação na legislação do aborto entre os países, com tendência à menor restrição na interrupção da gravidez em países desenvolvidos. É fundamental o envolvimento da iniciativa pública em programas de educação e planejamento familiar da população para que esta esteja capacitada a avaliar suas escolhas e os riscos aos quais se expõe. O objetivo do presente trabalho foi realizar uma revisão bibliográfica e análise crítica dos aspectos toxicológicos de fármacos e de plantas utilizados como abortifacientes, considerando também os riscos associados quando não há um acompanhamento médico efetivo. </span
... This "astute clinician method", as suggested by Carey et al., [2009]; cannot be used for assessing possible associations to relatively common malformations such as cardiovascular malformations. The authors do not discuss several papers that do not support the hypothesis that low-dose methotrexate be a clinically important teratogen [Lewden et al., 2004;Svirsky et al., 2009;Martin et al., 2014;Weber-Schoendorfer et al., 2014]. In a prospective study by Weber-Schoendorfer et al. [2014] which included 324 women with low-dose methotrexate exposure from 12-month preconception throughout first trimester, a sta-tistically significant odds ratio of 3.1 (95% CI 1.03-9.5) ...
... There were a total of two cardiovascular malformations. No increased risk was observed among 136 preconception only exposures, which is in accordance with other studies [Svirsky et al., 2009;Weber-Schoendorfer et al., 2014]. The latter study was published online on 28 April 2014 and may understandably have eluded the present author group. ...
... Hemorragia vaginal e contrações uterinas foram os motivos mais comuns para procurar cuidados hospitalares. Apenas 8% das mulheres relataram efeitos colaterais gastrintestinais 19 [27][28][29] . ...
... Já o metotrexato, outro fármaco utilizado como abortifaciente, atua bloqueando a enzima diidrofolato redutase, envolvida na produção de tiamina durante a síntese de DNA, e age sobre o citotrofoblasto interrompendo o processo de implantação 21 . É um antifolato amplamente utilizado para o tratamento da leucemia linfoblástica aguda, sendo também aplicado no tratamento de artrite reumatóide e de outras doenças inflamatórias, pois age como anti-inflamatório e imunomodulador 27 . ...
... Hemorragia vaginal e contrações uterinas foram os motivos mais comuns para procurar cuidados hospitalares. Apenas 8% das mulheres relataram efeitos colaterais gastrintestinais 19 [27][28][29] . ...
... Já o metotrexato, outro fármaco utilizado como abortifaciente, atua bloqueando a enzima diidrofolato redutase, envolvida na produção de tiamina durante a síntese de DNA, e age sobre o citotrofoblasto interrompendo o processo de implantação 21 . É um antifolato amplamente utilizado para o tratamento da leucemia linfoblástica aguda, sendo também aplicado no tratamento de artrite reumatóide e de outras doenças inflamatórias, pois age como anti-inflamatório e imunomodulador 27 . ...
A prática clandestina do aborto pode provocar diversos efeitos prejudiciais à saúde da mulher.
Em muitos casos, a situação política, social e religiosa do Brasil favorece a automedicação e a procura por
preparações caseiras e populares para induzir o aborto. Atualmente, medicamentos e plantas são alguns dos métodos empregados para interromper a gestação. Observa-se uma diversificação na legislação do aborto entre os países, com tendência à menor restrição na interrupção da gravidez em países desenvolvidos. É fundamental o envolvimento da iniciativa pública em programas de educação e planejamento familiar da população para que esta esteja capacitada a avaliar suas escolhas e os riscos aos quais se expõe. O objetivo do presente trabalho foi realizar uma revisão bibliográfica e análise crítica dos aspectos toxicológicos de fármacos e de plantas utilizados como abortifacientes, considerando também os riscos associados quando não há um acompanhamento médico efetivo.
... Antim€ ullerian hormone was not routinely measured on multiple occasions in our practice and was therefore unable to be compared between cycles. Antim€ ullerian hormone is considered to be another highly effective method of assessing ovarian reserve because of its independence of the menstrual cycle as well as the higher intercycle and intracycle reproducibility (18,19). Oriol et al. (15) did include a comparison of antim€ ullerian hormone level before and after treatment and did not find a decrease in levels, although the sample size (n ¼ 14) was small. ...
... Limited evidence demonstrates the clinical significance of the time to clearance. Svirsky et al. (19) found no difference in the adverse pregnancy outcome when conception took place within 6 months after the last MTX treatment (n ¼ 45) and when the interval was more than 6 months (n ¼ 80). However, McLaren et al. (17) demonstrated a decreased number of oocytes retrieved when IVF was performed within 180 days of MTX administration (n ¼ 20). ...
To evaluate the effects of methotrexate (MTX) on the future fertility of women undergoing IVF by comparing ovarian reserve and ovarian responsiveness in the IVF cycle before and after an ectopic pregnancy (EP) treated with MTX.
Retrospective cohort study.
Private reproductive endocrinology and infertility practice.
Sixty-six women undergoing IVF before and after receiving MTX for an EP.
Methotrexate administration and ovarian stimulation.
Markers of ovarian reserve (day 3 FSH, antral follicle count), measures of ovarian responsiveness (duration of stimulation, peak E2 level, total dose of gonadotropins, number of oocytes retrieved, fertilization rate), and time from MTX administration to subsequent IVF cycle.
There were no differences after MTX administration in body mass index (BMI), FSH, or antral follicle count. A greater dose of gonadotropins was used in the cycle after MTX, but there were no differences in numbers of oocytes retrieved or high quality embryos transferred. As expected, there was a slight increase in age in the subsequent IVF cycle. The pregnancy rates (PR) were comparable to the average PRs within the practice when combining all age groups.
Methotrexate remains the first line of therapy for medical management of asymptomatic EP and does not compromise ovarian reserve, ovarian responsiveness, or IVF success in subsequent cycles.
... W badaniach randomizowanych porównujących postępowanie zachowawcze z operacyjnym wykazano, że stosowanie protokołu ze stałymi wielokrotnymi dawkami metotreksatu (1 mg/kg i.m. w dniu 0, 2, 4, i 6 podawany naprzemiennie z kwasem foliowym p.o. 0,1 mg/kg, w dniu 1, 3, 5, 7) cechuje się nieznacznie lepszym efektem końcowym w postaci obniżenia kosztów hospitalizacji w porównaniu do postępowania laparoskopowego. Postępowania takie powinno być oferowane dla pacjentów z koncentracją β-hCG poniżej 3000 mIU/ ml [32]. ...
Wstęp: Od kilku lat obserwuje się gwałtowny wzrost częstości wy-stępowania ciąż pozamacicznych. Wczesna diagnostyka ciąż pozama-cicznych opiera się na połączonej ocenie ultrasonograficznej z warto-ściami stężeń β-hCG w surowicy krwi. Wyróżnia się dwie metody leczenia ciąż pozamacicznych: operacyjne oraz farmakologiczne. Postępowanie farmakologiczne w przypadku ciąży ektopowej polega na podawaniu an-tagonisty kwasu foliowego-metotrek-satu (MTX). Celem badania była ocena sku-teczności terapii pacjentek ze zdia-gnozowaną ciążą pozamaciczną le-czonych zachowawczo. Materiał i Metodyka: Badaniem objęto 126 pacjentek z rozpoznaną ciążą pozamaciczną. Do zachowaw-czego leczenia, metodą pojedynczej dawki MTX, ciąży ektopowej zosta-ło zakwalifikowanych 97 pacjentek. W przypadku braku satysfakcjo-nującego obniżenia stężeń β-hCG w surowicy krwi podawano kolejne dawki, aż jego uzyskania lub wystą-pienia objawów niepożądanych. U 25 pacjentek zastosowano z wyboru leczenie operacyjne. 4 pacjentki zo-stały objęte postępowaniem wycze-kującym bez wdrożenia terapii meto-treksatem, ze względu na naturalny szybki spadek β-hCG. Za sukces terapeutyczny uznawa-no spadek wartości β-hCG<0,2 mIU/ ml po włączeniu terapii zachowaw-czej bez konieczności wykonywania zabiegów operacyjnych. Wyniki: Pacjentki przydzielone do obu grup badawczych tj z i bez zastosowania metotreksatu (MTX+ i MTX-) charakteryzowały się po-dobnymi cechami demograficznymi. Stwierdzono istotne statystycznie różnice odnośnie przebytego lecze-nia operacyjnego (p=0,013)-w grupie MTX(-) 63% vs w grupie z MTX(+) 34% pacjentek przebyło wcześniejsze ope-racje z otwarciem jamy brzusznej. Introduction: For several years there has been a rapid increase in the prevalence of ectopic pregnancies. Early diagnosis of ectopic pregnancy is based on a combined assessment of transvaginal ultrasound examination with serum β-hCG concentrations. There are two methods of treatment ectopic pregnancies: surgical and conservative. Conservative treatment of ectopic pregnancy involves the application-folic acid antagonist-methotrexate (MTX). The aim of the study was to evaluate the efficiency and effectiveness of the treatment of patients with a diagnosis of ectopic pregnancy treated conservatively. Material and Methods: The study included 126 patients diagnosed with ectopic pregnancy. 97 patients were qalified for conservative single dose MTX treatment. Consecutive doses were applied until a satisfactory reduction of blood serum β-hCG concentrations or side effects occurrence. In 25 cases the surgical treatment of choice was used. 4 patients were treated conservatively without MTX application, due to rapid decline of β-hCG. Decrease of β-hCG<0.2 mIU/ml after conservative therapy, without using surgical procedure, was considered as a therapeutical success. Results: Patients classified to two study groups: with and without methotrexate (MTX + and MTX-) had similar demographic characteristics. Statistically significant differences in the case of earlier abdominal cavity surgery (p=0.013)-group MTX (-) 63% in the group of MTX (+) 34%. 88 patients (90,72%) of treated with methotrexate MTX (+) were effectively cured without the need of surgery. Among 11 patients (9,28%) of MTX (+) accured complictions which require surgical treatment. We observed significant higher difference between β-hCG serum concentration from the
... The primary consideration that would justify the need for an alternative to MTX is the need to delay pregnancy following its use. However, due to the absence of conclusive scientific evidence, the optimal length of waiting period before attempting to conceive again remains a matter of contention [26,27]. As a result, a wide range of possible durations for this period has been proposed, varying from its omission to as long as 6 months [6,9,10]. ...
Objectives:
Inhibition of estradiol production by letrozole may interfere with physiological effects of progesterone necessary to maintain the pregnancy. Treatment of tubal pregnancy (TP) with letrozole would allow to avoid the disadvantages of methotrexate (MTX). The aim was to compare the effectiveness of letrozole with MTX in the management of TP.
Material and methods:
A prospective open-label cohort study was conducted among women with TP and increasing B-human chorionic gonadotropin (B-hCG) concentrations. MTX was administered in a single dose of 100 mg intravenously, while letrozole in a dose of 5 mg orally for 10 days. Blood parameters (B-hCG, hemoglobin, creatinine, urea, transaminases, bilirubin) were tested on days 0, 4 and 7.
Results:
Out of 22 eligible women, 14 received MTX and received 8 letrozole. Mean age, lesion diameter, gestation age in the MTX vs letrozole arm were: 31 vs 32 years (p = 0.3), 13.2 vs 16.3 mm (p = 0.1), 7 + 1 vs 7 + 0 weeks (p = 0.6), respectively. In case of 4 women treated with letrozole and in 2 treated with MTX (4/8, 50% vs 2/14, 14.3%, p = 0.07) the treatment was unsuccessful. There were no significant differences in blood parameters on days 0, 4 and 7 between both arms, except for the increasing urea concentration in the letrozole arm (p = 0.01).
Conclusions:
Even though the results did not reach statistical significance, it is likely that a larger study sample would confirm the trend of letrozole being less effective. The results did not support the use of letrozole in the studied regimen as an alternative to MTX.
... Otherwise, if endometrial biopsy does not contain chorionic villi and/or β-hCG levels do not decline after uterine evacuation, the pregnancy is presumed to be extrauterine and can be treated medically with methotrexate [32][33][34]. Te main arguments of such policy are: to restrict the use of methotrexate and its side efects, to allow a shorter time to pregnancy resolution, to bring more accurate fertility counseling and to avoid the need of delaying a subsequent pregnancy due to time required to methotrexate washout [32,35]. Moreover, it has been shown that empirical treatment of a presumed EP is inaccurate and may result in unnecessary treatment of miscarriages with methotrexate in up to 40% of cases [34]. ...
In the last decade, the widespread use of transvaginal ultrasound and the availability of highly specific serum assays of human chorionic gonadotropin (hCG) have become mainstays in the evaluation of early pregnancy. These tests have revolutionized the management of pregnancies of unknown location and markedly reduced the morbidity and mortality associated with the misdiagnosis of ectopic pregnancy. However, despite several advances, their misuse and misinterpretations are still common, leading to an increased use of healthcare resources, patient misinformation, and anxiety. This narrative review aims to succinctly summarize the β-hCG dynamics in early gestation and provide general gynecologists a practical approach to patients with first-trimester symptomatic pregnancy.
... В некоторых источни ках указывается, что полное выведение МТ из организма происходит в течение 4-6 мес, а следовые количества мо гут сохраняться в печени и почках в течение 9-12 мес [34]. В ретроспективном исследовании, включившем пациенток после консервативного лечения ВБ, не выявлено различий в частоте пороков развития у плода при зачатии, наступив шем до или после 6 мес после введения МТ [35]. ...
An ectopic pregnancy is a medical emergency. Currently, surgery is the main method of therapy, and non-surgical management with methotrexate is considered an acceptable alternative. Methotrexate is a folic acid antagonist and has an inhibitory effect on the proliferation of trophoblast cells. There are various methotrexate regimens; the choice is based on the level of β-subunit of human chorionic gonadotropin, the location of the ectopic pregnancy and the patient's adherence to treatment. Therapy of ectopic tubal pregnancy with methotrexate is an effective and safe alternative to surgical treatment, does not affect the ovarian reserve and preserves the woman's fertility.
... Fortunately, the adverse effects of anti-folate agents, including PDX, on the reproductive system can be avoided (Hui et al., 2012). For instance, if anti-folate agent treatment was discontinued within 3 months preconception, the risks of adverse reproduction outcomes do not seem to occur, regardless of gender (Svirsky et al., 2009). However, considering the relatively short duration of therapeutic intervention in most of the viral infection, potential PDX toxicity on reproduction can be minimal. ...
... For commercial re-use, please contact journals.permissions@oup.com ectopic pregnancy is very limited (Svirsky et al., 2009;Elson et al., 2016;Lagarce et al., 2016). In addition, treatment with methotrexate or expectant management can take many weeks for the pregnancy to resolve, leading to a prolonged period of hospital follow up, uncertainty of treatment success and pregnancy avoidance for women. ...
Ectopic pregnancy is a risk of both spontaneous and assisted reproduction pregnancies. The majority of ectopic pregnancies abnormally implant within a fallopian tube (extrauterine pregnancies). In haemodynamically stable women, medical or expectant treatment can be offered. Currently accepted medical treatment is using a drug called methotrexate. However, methotrexate has potential adverse effects, and a significant proportion of women will still require emergency surgery (up to 30%) to remove the ectopic pregnancy. Mifepristone (RU-486) has anti-progesterone effects and has a role in managing intrauterine pregnancy loss and termination of pregnancy. On reviewing the literature and given progesterone’s pivotal role in sustaining pregnancy, we propose that we may have overlooked the role of mifepristone in the medical management of tubal ectopic pregnancy in haemodynamically stable women.
... The common side effects are proliferative active tissue and gastrointestinal reaction, such as flatulence, nausea and vomiting, stomatitis and the temporary rise of liver enzymes. Other side effects are bone marrow suppression, kidney damage, alopecia, dermatitis, pigmentation, drug-induced pneumonia, etc. MTX does not have adverse effects on long-term fertility and ovarian function [6]. Based on the guideline of BJOG [5], the patients treated with MTX are suggested to get pregnant again only 3 months after treatment. ...
Objective
Ectopic pregnancy is a life-threatening disease and is an important cause of pregnancy-related mortality. MTX is the primary conservative treatment medicine of ectopic pregnancy, and mifepristone is also a promising medicine. Through studying the ectopic cases at the third affiliated hospital of Sun Yat-Sen University, the study aims to analyze the indication and treatment outcome predictors of mifepristone.Methods
The data of 269 ectopic pregnancy cases treated with mifepristone during the year 2011–2019 were retrospectively collected. Logistic-regression analysis was used to analyze the factors affiliated with the treatment outcome of mifepristone. Then ROC curve was used to analyze the indication and predictors.ResultsThrough logistic-regression analysis, HCG is the only factor related to the treatment outcome of mifepristone. The AUC of ROC curve predicting treatment outcome with pre-treatment HCG is 0.715, and the cutoff value of ROC curve is 372.66 (sensitivity 0.752, specificity 0.619). The AUC of 0/4 ratio predicting the treatment outcome is 0.886, and the cutoff value is 0.3283 (sensitivity 0.967, specificity 0.683). The AUC of 0/7 ratio is 0.947, and the cutoff value is 0.3609 (sensitivity 1, specificity 0.828).Conclusions
Mifepristone can be used to treat ectopic pregnancy. HCG is the only factor related to the treatment outcome of mifepristone. Patients with HCG less than 372.66 U/L can be treated by mifepristone. If HCG descends more than 67.18% on the 4th day or 63.91% on the 7th day, it is more likely to have a successful treatment outcome. It is more precise to retest on the 7th day.
... 23 If MTX was discontinued within the 3 months preconception, the risks of adverse pregnancy outcomes do not seem to be increased. 24 Therefore, preconception counselling should not advise or encourage TOP due to prepregnancy MTX. ...
... However, MTX presence in hepatocytes has been reported as many as 116 days after use. 37 Due to this finding, a recommendation for a 3-month interval is reasonable. 6,38 The current evidence suggests that MTX does not have adverse effects on ovarian reserve or subsequent fertility. ...
... 37 Higher (chemotherapy or abortifacient) doses of methotrexate (>0.4 kg/week) have been associated with prenatal growth deformities (aminopterin syndrome), including growth retardation, large fontanelles, craniosynostosis, ocular hypertelorism, micrognathia and limb abnormalities and developmental delay. 38 Although the t 1/2 of methotrexate is 3-10 h and is undetectable in serum within 24 h, it is common to stop 12 weeks before conception as methotrexate may be stored in both kidneys (weeks) and the liver (months). The weekly folate supplementation should be increased to daily. ...
... Et retrospektivt studie fandt ingen forskel i hyppigheden af børn med medfødte misdannelser eller andre uønskede haendelser (aborter, for tidlig fødsel, lav fødselsvaegt) hos kvinder, der blev gravide mindre end 6 måneder efter MTX-behandling for ekstrauterin graviditet (n=45) sammenlignet med kvinder, der blev gravide mere end 6 måneder efter behandlingen (n=80). Forfatterne konkluderede, at graviditet inden for 6 måneder efter MTX-behandling synes at vaere sikkert (16). Et follow-up-studie fra Polen fandt, at 16 kvinder, som blev behandlet med MTX for ekstrauterin graviditet, efterfølgende blev gravide og fødte raske børn. ...
Sygehistorie 1: En kvinde har modtaget en enkelt dosis methotrexat 75 mg i.m. på grund af ekstrauterin graviditet. Tre måneder senere bliver kvinden gravid igen. Ifølge pro.medicin.dk skal graviditet undgås mindst 6 måneder (1) efter methotrexatbehandling, og der spørges nu til risikoen for teratogen eff ekt. Sygehistorie 2: En kvinde med psoriasis artritis har vaeret i behand-ling med methotrexat 20 mg ugentligt. Da kvinden ønsker at blive gra-vid, er behandlingen seponeret. Hun spørger nu, hvor laenge hun skal fortsaette med at anvende antikonception. Baggrund Methotrexat (MTX) er en folsyreantagonist, der anvendes ved et bredt spektrum af maligne lidelser, svaer psoriasis, reumatoid artritis og andre immuninfl ammatoriske sygdomme. MTX haemmer DNA-syntesen og Laegemidler Kontakt uhedegaard@health. sdu.dk Biografi Ida Berglund Kuhlmann er reservelaege, Dorthe Dideriksen og Ulla Hedegaard er kliniske farmaceuter, og Per Damkier er overlaege. Alle er ansat ved afde-ling for Klinisk Biokemi og Farmakologi, Odense Universitetshospital. Methotrexat – hvor lang tid forud for graviditet bør behandling undgås? Af Ida Berglund Kuhlmann, Dorthe Dideriksen, Ulla Hedegaard og Per Damkier Vi fortsaetter case-serien om laegemidler i almen praksis. Denne gang med spørgsmål og svarom tidspunkt for seponering af methotrexat forud for graviditet. RESUME: Anvendelse af methotrexat (MTX) under organogenesen er associeret med et spektrum af medfødte misdannelser i form af vaekst-haemning, nedsat forbening af kalotten, ufuldstaendig udvikling af den supraorbitale foramen, små lavtsiddende ører, kort underkaebe, abnormt udviklede ekstremiteter samt mental retardering. I denne artikel dis-kuteres, hvor lang tid efter afsluttet behandling med MTX der er risiko for teratogen eff ekt. Forfatterne konkluderer, at det med den tilgaenge-lige evidens ikke er muligt at estimere, hvor lang tid efter methotrexat-behandling graviditet bør undlades. Som en pragmatisk foranstaltning bør producenternes anbefaling på 3-6 måneder efterleves.
... 37 Higher (chemotherapy or abortifacient) doses of methotrexate (>0.4 kg/week) have been associated with prenatal growth deformities (aminopterin syndrome), including growth retardation, large fontanelles, craniosynostosis, ocular hypertelorism, micrognathia and limb abnormalities and developmental delay. 38 Although the t 1/2 of methotrexate is 3-10 h and is undetectable in serum within 24 h, it is common to stop 12 weeks before conception as methotrexate may be stored in both kidneys (weeks) and the liver (months). The weekly folate supplementation should be increased to daily. ...
The Australasian Psoriasis Collaboration reviewed methotrexate (MTX) in the management of psoriasis in the Australian and New Zealand setting. The following comments are based on expert opinion and a literature review. Low-dose MTX (< 0.4 mg/kg per week) has a slow onset of action and has moderate to good efficacy, together with an acceptable safety profile. The mechanism of action is anti-inflammatory, rather than immunosuppressive. For pretreatment, consider testing full blood count (FBC), liver and renal function, non-fasting lipids, hepatitis serology, HbA1c and glucose. Body mass index and abdominal circumference should also be measured. Optional investigations in at-risk groups include an HIV test, a QuantiFERON-TB Gold test and a chest X-ray. In patients without complications, repeat the FBC at 2-4 weeks, then every 3-6 months and the liver/renal function test at 3 months and then every 6 months. There is little evidence that a MTX test dose is of value. Low-dose MTX rarely causes clinically significant hepatotoxicity in psoriasis. Most treatment-emergent liver toxicity is related to underlying metabolic syndrome and non-alcoholic fatty liver disease or non-alcoholic steatohepatitis. Alcohol itself is not contraindicated, but should be limited to < 20 mg/day. Although MTX is a potential teratogen post-conception, there is little evidence for this pre-conception. MTX does not affect the quality of sperm. There is no evidence that MTX reduces healing, so there is no specific need to stop MTX peri-surgery. MTX may be used in combination with cyclosporine, acitretin, prednisone and anti-tumour necrosis factor biologics.
... Due to the concerns about methotrexate and its metabolites remaining in some organs and possibly affecting a future pregnancy or fetal development, several sources have arbitrarily recommended that women should wait 3-6 months to get pregnant after finishing therapy. [8][9][10] In previous studies, 11,12 the incidence of abnormal outcome (e.g. miscarriages, stillbirth, possible mole pregnancy) was found to be significantly higher in women who conceived within 6 months than in those who conceived 12 months after the treatment with methotrexate. ...
A clinical study was conducted in order to validate the effect of methotrexate on 30 patients with ectopic pregnancy (EP). A typical ultrasound appearance of multiple cysts of Naboth in the cervix was observed on six cases that are studied below. Endometrial sample with endogyn was retrieved from the six cases after the treatment with methotrexate was complete. The cytological results were studied and there were many changes found in the endometrial cells, in their cores, and some inflammatory cells as well. Two out of the six cases studied show more profound evidence. The cellular appearance of the endometrium after the treatment is discussed, in relation to the presence of multiple Nabothian cysts, as a result of inflammatory reaction, and the possibility of any influence in the capacity for a future pregnancy.
... Women were significantly older in the post-MTX cycle, though the mean age at the post-MTX cycle was relatively young (35.3 years) with a mean difference of only 0.6 years. Bold and * indicate significant findings Mean ± SD *P < 0.05 Whether this significant increase in age is due to time patients are counseled to wait after MTX before proceeding with another cycle [25,26] or it is influenced by other factors such as cost is unknown. After review of the first cycle, physicians may increase the dose and/or choose a more aggressive protocol with the aim of retrieving more oocytes and a better outcome. ...
Purpose:
The purpose of this research was to study whether methotrexate (MTX) as treatment for ectopic pregnancy (EP) impacts the future fertility of women undergoing assisted reproductive technology (ART) METHODS: In a systematic review and multi-center retrospective cohort from four academic and private fertility centers, 214 women underwent an ART cycle before and after receiving MTX as treatment for an EP. Measures of ovarian reserve and responsiveness and rates of clinical pregnancy (CP) and live birth (LB) were compared in the ART cycles prior and subsequent to MTX.
Results:
Seven studies were identified in the systematic review, and primary data from four institutions was included in the final analysis. Women were significantly older in post-MTX cycles (35.3 vs 34.7 years). There were no differences in follicle stimulating hormone, antral follicle count, duration of stimulation, oocytes retrieved, or fertilization rate between pre- and post-MTX cycles. However, post-MTX cycles received a significantly higher total dose of gonadotropins (4206 vs 3961 IU). Overall, 42 % of women achieved a CP and 35 % achieved a LB in the post-MTX ART cycle, which is similar to national statistics. Although no factors were identified that were predictive of LB in young women, the number of oocytes retrieved in the previous ART cycle and current AFC were predictive of LB (AUC 0.76, 0.75) for the older women.
Conclusions:
MTX does not influence ovarian reserve, response to gonadotropin stimulation, and CP or LB rate after ART. MTX remains a safe and effective treatment option for women with asymptomatic EPs.
... Hackmon and colleagues 32 discuss the conflicting evidence regarding conception after MTX administration and subsequent risk of spontaneous loss or congenital malformations. The most recent study from Svirsky and colleagues 33 did not demonstrate a difference in loss rates or birth defects in women who conceived at 6 months or less versus more than 6 months after receiving intramuscular MTX for ectopic pregnancy. Using this limited information, it seems reasonable to recommend a 3-to 6-month IPI after receipt of MTX for ectopic pregnancy before conceiving a subsequent pregnancy to avoid the potential risk of persistent long-acting antifolate metabolites and potential adverse pregnancy outcomes, although these have not been borne out by available evidence. ...
The interpregnancy interval (IPI) is the period of time between one birth outcome (live birth, miscarriage, stillbirth, or abortion) and conception of a subsequent pregnancy. Short IPI has been associated with obstetric, fetal, and maternal morbidity. While the literature has largely supported an ideal IPI of 18 to 23 months after live birth to minimize morbidity in a subsequent pregnancy, there are few references that can guide clinicians counseling patients about IPI after other pregnancy outcomes. In this article, we attempt to review, synthesize, and provide evidence-based IPI recommendations using the available literature.
... During embryonic development, MTX administration was found to be embryotoxic [20]. Systemic injections of MTX to pregnant rats have embryolethal effects as a function of embryonic development [21]. There is no literatures addressed the effect of low and high doses of methotraxate. ...
... During embryonic development, MTX administration was found to be embryotoxic [20]. Systemic injections of MTX to pregnant rats have embryolethal effects as a function of embryonic development [21]. There is no literatures addressed the effect of low and high doses of methotraxate. ...
... During embryonic development, MTX administration was found to be embryotoxic [20]. Systemic injections of MTX to pregnant rats have embryolethal effects as a function of embryonic development [21]. There is no literatures addressed the effect of low and high doses of methotraxate. ...
Abstract: Objective: The present study was carried out to evaluate potential adverse effects of the low and high doses of MTX through implantation and organogenesis. Materials and Methods: Pregnant female mice were given doses of 0, 0.13 and 0.42 mg/kg bw/week methotrexate orally on gestation day zero through day 15 along with vehicle-treated control. Status of gravid/non-gravid uterus, the number of corpora lutea in the ovary, implantation status, fetal resorption, fetal body weight, and external, visceral and skeletal malformations were recorded. Results: Maternal toxicity, as evidenced by reduction in body weight gain and signs of toxicity was observed at the low- and high-dose groups. Developmental toxicity that included significantly reduction in the number of live fetuses, mean fetal weight and increased resorption sites was observed only in the treated group of 0.42 mg/ kg bw/week. Also, there was significant increase in the incidence of fetuses with external, skeletal or visceral malformations in 0.42 mg/ kg bw/week dose group. It seems likely that marked maternal toxicity contributed to the observed fetotoxicity. Also, these results reveal that the malformations by MTX treatment are correlated to the disrupted circulating levels of reproductive hormones and histoarchitecture of ovary. Conclusion: The results suggest that the MTX had developmental toxicity and teratogenicity at high dose level, which could affect pregnancy, implantation and gestation. The no-observed-effect level (NOAEL) in the present study for developmental toxicity was 0.13 mg/ kg bw/week.
... Vinca alkaloids have been shown to cause aneuploidy in mouse and hamster oocytes (Russo and Pacchierotti, 1988;Tateno et al., 1995) and MI meitotic arrest in oocytes that have been observed to remain capable of fertilization, resulting in fetal abnormalities (Albanese, 1987). Concern has also been raised over the impact antimetabolites have on female germ cells; however, a retrospective study of women who conceived ,6 months after MTX treatment for ectopic pregnancy found no increase in fetal malformations or adverse outcomes (Svirsky et al., 2009). Paclitaxel inhibits mitosis by stabilizing microtubules and has been shown to result in aneuploidy in mouse oocytes (Mailhes et al., 1999). ...
BACKGROUND Current options for female fertility preservation in the face of cytotoxic treatments include embryo, oocyte and ovarian
tissue cryopreservation. However these methods are limited by the patient age, status or available timeframe before treatment
and they necessitate invasive procedures. Agents which can prevent or attenuate the ovotoxic effects of treatment would provide
significant advantages over the existing fertility preservation techniques, and would allow patients to retain their natural
fertility without the necessity for costly, invasive and risky procedures. Recent studies have contributed to our understanding
of the mechanisms involved in cytotoxicity-induced ovarian follicle loss and highlight a number of agents that may be able
to prevent or reduce this loss.
... In retrospective studies, no differences were demonstrated in the frequencies of fetal defects between patients who conceived within 3 months (3.6 SD=1.7) into the MTX treatment as compared to those who conceived after a longer period of time (23.6 SD=14.7) [25]. The risk was equal to that of the general population. ...
The aim of the study was to assess fertility in patients diagnosed with ectopic pregnancy and treated with methotrexate, as well as safety and efficacy of conservative treatment. Also, risk factors of recurrent ectopic pregnancies were determined.
The study included 86 female patients with ectopic pregnancy hospitalized and treated in the clinic of Gynecological Endocrinology, UJCM, Cracow, between 2007 and 2011. A total of 73 patients received a single dose of MTX in the amount of 50 mg/m2 of body surface area. Serum b-hCG concentration was measured on days 4 and 7. The treatment was considered successful when b-hCG concentrations dropped to less than 0.2 mIU/ml without surgery.
Among 34 patients on follow-up, 8 (23.5%) did not attempt to conceive again, whereas 26 patients declared their wish to conceive again. The attempt proved to be successful in case of 16 women (61.53%), and they gave birth to healthy children. Average time to pregnancy was 14.9 months (SD +/- 10.9). The first pregnancy occurred after 6 months and the last after 35 months. No congenital birth defects were found in the newborns.
Systemic, conservative treatment with methotrexate is an effective and safe way of managing ectopic pregnancy even in cases with higher b-hCG concentrations. Most patients can be successfully treated without surgery thus they may even be treated in outpatient settings. High fertility can be maintained and is independent of the skills of the operators and access to laparoscopic techniques. Conservative treatment does not increase the risk of recurrent ectopic pregnancy but should be offered in wards that provide 24-hour surgical care.
... It is not clear how long conception should be delayed after successful treatment of ectopic pregnancy with methotrexate , inasmuch as the drug may persist in the liver for months. There is a study showing no difference in outcome in pregnancies conceived less than 6 months compared to more than 6 months after methotrexate therapy; however, there were only 45 pregnancies in the less-than-6-month group [Svirsky et al., 2009]. ...
A consideration of teratogenic exposures includes not only an agent (chemical, radiation, biologic) but an exposure level and timing of exposure. There are criteria by which exposures are evaluated for a causal connection with an abnormal outcome. We here review some teratogenic exposures and discuss how they were initially described and confirmed. We have limited our discussion to some of the exposures for which a connection to structural malformations has been accepted in some quarters, and we indicate some exposures for which a causal association awaits confirmation. We recommend that counselors find a reliable and updatable source of information on exposures during pregnancy.
Background:
Ectopic pregnancy is a major contributor to maternal morbidity and mortality across the globe.
Objective:
This study aims to investigate the clinical benefits of laparoscopic surgery in treating ectopic pregnancy, and its impact on tubal patency and reproductive outcomes.
Methods:
A clinical study was conducted to compare laparoscopic and medical conservative treatment for ectopic pregnancy. A total of 206 patients were treated for ectopic pregnancy at our hospital from January 2018 to June 2020. Among them, 46 underwent laparoscopic ipsilateral salpingectomy, 54 underwent laparoscopic ipsilateral salpingostomy with lesion removal, and 106 were treated conservatively with medication.
Results:
The age range and average age of each group are provided, with no significant differences in these general demographic characteristics (p> 0.05). Both the salpingostomy and medication groups had higher rates of ectopic pregnancy compared to the salpingectomy group, with statistically significant differences (p< 0.05). The comparison of ectopic pregnancy rates between the salpingostomy and medication groups showed no significant difference. Within three years, the salpingostomy group had 10 cases of recurrent ectopic pregnancy, with 2 cases on the same side, while the medication group had 18 cases, with 8 cases on the same side. At 3 months after the normalization of blood β-HCG, the salpingostomy group showed 43 cases of tubal patency (patency rate: 79.63%), while the medication group showed 57 cases (patency rate: 53.77%), with a statistically significant difference between the two groups (p= 0.01).
Conclusion:
Laparoscopic surgery for ectopic pregnancy offers significant clinical benefits over conservative medical treatment, including higher rates of tubal patency and improved reproductive outcomes. These findings support laparoscopic surgery as an effective approach for the management of ectopic pregnancy.
Based on the curriculum of the Royal College of Obstetricians and Gynaecologists' Advanced Training Skills Module in Fetal Medicine, this book provides a comprehensive knowledge base for all doctors practising in obstetrics and maternal-fetal medicine worldwide. It acts as a reference source for the many changing concepts in fetal medicine and is well-illustrated with images of normal and abnormal findings in pregnancy that will facilitate proper understanding of normal and pathological fetal development. Coverage includes embryology, fetal physiology; fetal anomalies; fetal diseases; prescribing and teratogenesis in pregnancy; termination of pregnancy; fetal growth and wellbeing; multiple pregnancy; the placenta and amniotic fluid; and diagnostic and therapeutic invasive procedures. Readers will benefit from the theoretical knowledge and vast clinical experience of the internationally renowned authorship. Overall this book will prepare you for dealing with congenital abnormalities detected during pregnancy, including the organization and supervision of screening programmes for structural and chromosomal anomalies.
RÉSUMÉ
Objectif
Fournir un algorithme fondé sur des données probantes pour orienter le diagnostic et la prise en charge de la grossesse de localisation indéterminée et de la grossesse ectopique tubaire ou non tubaire.
Population cible
Toutes les patientes en âge de procréer.
Bénéfices, risques et coûts
La mise en œuvre de la présente directive a pour objectif de bénéficier aux patientes ayant obtenu un résultat positif pour la sous-unité bêta de la gonadotrophine chorionique et de fournir aux médecins un algorithme normalisé pour l'expectative et le traitement pharmacologique ou chirurgical en cas de grossesse de localisation indéterminée et de grossesse ectopique tubaire ou non tubaire.
Données probantes
Les termes de recherche suivants ont été entrés dans les bases de données PubMed-Medline et Cochrane en 2018 : cesarean section, chorionic gonadotropin, beta subunit, human/blood, fallopian tubes/surgery, female, fertility, humans, infertility, laparoscopy, methotrexate, methotrexate/administration & dosage, methotrexate/therapeutic use, pregnancy (abdominal, angular, cervix, cornual, ectopic, ectopic/diagnosis, ectopic/diagnostic imaging, ectopic/drug therapy, ectopic/epidemiology, ectopic/mortality, ectopic/surgery, heterotopic, interstitial, isthmo-cervical, ovarian, tubal, unknown location), recurrence, risk factors, salpingectomy, salpingostomy, tubal pregnancy, ultrasonography, doppler ultrasonography et prenatal. Les articles retenus sont des essais cliniques randomisés, des méta-analyses, des revues systématiques, des études observationnelles et des études de cas. Des publications supplémentaires ont été sélectionnées à partir des notices bibliographiques de ces articles. Seuls les articles en anglais ont été examinés.
Méthodes de validation
Les auteurs ont évalué la qualité des données probantes et la solidité des recommandations en utilisant la méthodologie GRADE (Grading of Recommendations Assessment, Development and Evaluation). Voir l'annexe A en ligne (tableau A1 pour les définitions et tableau A2 pour l'interprétation des recommandations fortes et faibles).
Public visé
Obstétriciens-gynécologues, médecins de famille, urgentologues, sages-femmes, infirmières autorisées, infirmières praticiennes, étudiants en médecine, résidents et moniteurs cliniques.
Objective
To provide an evidence-based algorithm to guide the diagnosis and management of pregnancy of unknown location and tubal and nontubal ectopic pregnancy.
Target Population
All patients of reproductive age.
Benefits, Harms, and Costs
The implementation of this guideline aims to benefit patients with positive β-human chorionic gonadotropin results and provide physicians with a standard algorithm for expectant, medical, and surgical treatment of pregnancy of unknown location and tubal pregnancy and nontubal ectopic pregnancies.
Evidence
The following search terms were entered into PubMed/Medline and Cochrane in 2018: cesarean section, chorionic gonadotropin, beta subunit, human/blood, fallopian tubes/surgery, female, fertility, humans, infertility, laparoscopy, methotrexate, methotrexate/administration & dosage, methotrexate/therapeutic use, pregnancy (abdominal, angular, cervix, cornual, ectopic, ectopic/diagnosis, ectopic/diagnostic imaging, ectopic/drug therapy, ectopic/epidemiology, ectopic/mortality, ectopic/surgery, heterotopic, interstitial, isthmo-cervical, ovarian, tubal, unknown location), recurrence, risk factors, salpingectomy, salpingostomy, tubal pregnancy, ultrasonography, doppler ultrasonography, and prenatal. Articles included were randomized controlled trials, meta-analyses, systematic reviews, observational studies, and case reports. Additional publications were identified from the bibliographies of these articles. Only English-language articles were reviewed.
Validation Methods
The authors rated the quality of evidence and strength of recommendations using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. See online Appendix A (Tables A1 for definitions and A2 for interpretations of strong and weak recommendations).
Intended Audience
Obstetrician–gynaecologists, family physicians, emergency physicians, midwives, registered nurses, nurse practitioners, medical students, and residents and fellows.
ทบทวนหลักฐานทางวิชาการที่เกี่ยวข้องกับการคุมกำเนิดในสตรีหลังคลอด และ หลังแท้งบุตร
Ectopic pregnancy is defined as a pregnancy that occurs outside of the uterine cavity. The most common site of ectopic pregnancy is the fallopian tube. Most cases of tubal ectopic pregnancy that are detected early can be treated successfully either with minimally invasive surgery or with medical management using methotrexate. However, tubal ectopic pregnancy in an unstable patient is a medical emergency that requires prompt surgical intervention. The purpose of this document is to review information on the current understanding of tubal ectopic pregnancy and to provide guidelines for timely diagnosis and management that are consistent with the best available scientific evidence.
Objectives: To analyse the effectiveness and outcome of conservative treatment in cases of abnormally-located intrauterine pregnancies (cervical and cesarean scar).
Study design: A retrospective analysis was performed of 30 pregnant women hospitalized due to abnormally-located intrauterine pregnancies. The analysed group comprised 24 pregnant women with abnormally-located pregnancies. The patients were divided into two groups: the first group consisted of patients treated systemically with methotrexate, while the second of those treated locally by administration of methotrexate (MTX) and/or potassium chloride (KCl) by gestational sac puncture.
Results: The analysed group comprised 24 pregnant women with abnormally-located pregnancies. Eight patients were diagnosed with cervical pregnancy (CP) and 16 patients were diagnosed with cesarean scar pregnancy (CSP). Six patients were excluded from the study: two with spontaneous abortions, two heterotopic pregnancies and two cornual pregnancies. Twelve analysed patients underwent MTX systemic administration (five patients with CP, seven with CSP). In five patients, systemic treatment was ineffective; they were qualified for additional local therapy with gestational sac (GS) puncture and MTX or KCl administration to the sac and additional administration of MTX to the trophoblast area. In second group of 12 patients (three CP, nine CSP), local treatment (GS puncture with MTX or MTX + KCL) was used as the first line treatment. One patient underwent combined treatment (local + systemic).
Conclusions: Conservative treatment should be the gold standard procedure in abnormally-located intrauterine pregnancies. It is noticeable that MTX / KCl is more effective in a direct administration to the GS. In four cases, systemic MTX did not produce the desired effects. In these cases, the treatment was assisted by local administration of MTX or KCL, resulting in the termination of an abnormally-located pregnancy.
Objective:
To assess the risk of adverse pregnancy outcomes in subsequent pregnancies among women treated with methotrexate for ectopic pregnancy.
Methods:
In a retrospective single-center study, data were assessed for women treated with methotrexate for ectopic pregnancy at Asaf Harofe Medical Center, Zerifin, Israel, between May 2004 and May 2014.
Results:
Overall, 226 women were treated with methotrexate for ectopic pregnancy and subsequently conceived. The median time from treatment to conception was 10 months (range 1-120 months), and 127 women conceived within 12 months of treatment. Except for early missed abortion-which affected 23 (10.2%) pregnancies-adverse pregnancy outcomes such as fetal malformations were rare. The frequency of early abortion was lowest for women who conceived within 6 months of treatment with methotrexate (3/93, 3.2%), increased between 6 and 23 months (15/83, 18.1%), and remained high thereafter (7/50, 14.0%; P=0.006).
Conclusion:
The frequency of fetal malformation in a subsequent pregnancy was low among women treated with methotrexate for ectopic pregnancy. The frequency of early missed abortion was lowest during the first 6 months after treatment with methotrexate. This article is protected by copyright. All rights reserved.
Objective:
To evaluate the utility of an endometrial sampling protocol for the diagnosis of pregnancies of unknown location following in vitro fertilization.
Study design:
A retrospective cohort study of 14,505 autologous fresh and frozen in vitro fertilization cycles from 10/2007 to 9/2015 was performed; 110 patients were diagnosed with pregnancy of unknown location, defined as a positive human chorionic gonadotropin (hCG) without ultrasound evidence of intrauterine or ectopic pregnancy, and an abnormal hCG trend (<53% rise or <15% fall in two days). These patients underwent outpatient endometrial sampling with Karman cannula aspiration. Patients with hCG decline ≥15% within 24 hours of sampling and/or villi detected on pathologic analysis were diagnosed with failing intrauterine pregnancy and had weekly hCG measurements thereafter. Those with hCG declines <15% and no villi identified were diagnosed with ectopic pregnancy and treated with intramuscular methotrexate (50 mg/m2) or laparoscopy.
Results:
Across 8 years of follow-up, among women with pregnancy of unknown location, failed intrauterine pregnancy was diagnosed in 46 patients (42%) and ectopic pregnancy in 64 patients (58%). Clinical variables including fresh or frozen embryo transfer, day of embryo transfer, serum hCG at the time of sampling, endometrial thickness, and presence of an adnexal mass were not significantly different between patients with failed intrauterine pregnancy or ectopic pregnancy. In patients with failed intrauterine pregnancy, 100% demonstrated adequate post-sampling hCG declines, while villi were identified in just 46% (n=21). Patients with failed intrauterine pregnancy had significantly shorter time to resolution (negative serum hCG) after sampling compared to patients with ectopic pregnancy (12.6 vs 26.3 days, p-value<0.001).
Conclusion:
Using this safe and effective protocol of endometrial aspiration with Karman cannula, a large proportion of women with pregnancy of unknown location are spared methotrexate, with a shorter time to pregnancy resolution than those receiving methotrexate.
Pregnancy of unknown location (PUL) is a descriptive term for when a woman with a positive pregnancy test has a transvaginal ultrasound that cannot determine the site of the pregnancy. While the majority of women with PUL are subsequently diagnosed with a spontaneous abortion or viable intrauterine pregnancy, 7% to 20% of these women have an ectopic pregnancy. The potential for morbidity and mortality related to an ectopic pregnancy means that considerable care is necessary in the evaluation and management of women with PUL. In some cases, the location of the pregnancy is never determined and the PUL is categorized as resolving or persisting. Evidence suggests expectant management is a safe and effective approach for most women with PUL and should be the mainstay of care. However, in the case of persisting PUL, continued concern for ectopic pregnancy remains. Strategies for deciding when to intervene when a woman has a PUL are reviewed. A variety of clinical tools, including serum beta human chorionic gonadotropin (β-hCG), repeat ultrasonography, dilation and curettage (D&C), and empiric methotrexate therapy are discussed. Finally, a proposal is made that women with persisting PUL can be presented with the option of choosing expectant management, diagnostic D&C, or empiric methotrexate treatment.
Introduction:
Methotrexate (MTX) is a known teratogenic drug used off-label in the treatment of ectopic pregnancies (EP). As MTX polyglutamated derivatives remains into the cells during several weeks, it is recommended to avoid conception during 3 to 6 months following MTX therapy. We report the follow-up of pregnancies after preconceptional exposure to MTX for EP.
Material/methods:
Prospective cases of pregnancy occurring within 3 months after MTX injection for an EP recorded in the Terappel database were analyzed.
Results:
Data were obtained on 52 pregnant women. The median age of patients was 28 (18-38), and the median gestational age at inclusion was 7 weeks after last menstrual period (3-22). The time between the last MTX injection and conception ranged from 12 days to 13 weeks and the total MTX dose was between 40 to 210mg. Out of 45 pregnancies with known outcome, there were 39 live births (87%), 3 spontaneous abortions (6.7%) occurring 63 to 94 days after MTX administration, 2 elective terminations, and 1 medical termination after premature rupture of membranes, oligohydramnios and arthrogryposis (48mg of MTX 9 and 8 weeks before conception). Two additional cases of major malformations were observed among 40 examinable babies or fetuses: tetralogy of Fallot (MTX 6 weeks before conception), and cerebral ventriculomegaly with normal karyotype (50mg of MTX 9 to 13 weeks before conception). The resulting rate of major malformations was 7.5% (95% CI: 1.6-20.4).
Discussion/conclusion:
Although this prospective study shows a major malformation rate higher than expected in the general population, the observed malformations are not consistent with the typical pattern of methotrexate embryopathy. However, the case of tetralogy of Fallot is reminiscent of previously published cases with MTX exposure during early pregnancy. Owing to the small sample size, more powerful studies are needed to confirm or refute these findings.
Background. The loss of reproductive function is one of the most important adverse effects of chemotherapy. Folic acid deficiency may be harmful in pregnancy. Hence, it is imperative to investigate if leucovorin (LCN), a folinic acid supplementation and withdrawal of MTX treatment facilitate maintenance of pregnancy in albino rats. Aim. The aim of this study was to examine the role of ieucovorin (LCN) and withdrawal of MTX treatment in the protection of pregnancy at very early stage of pregnancy in MTX treated rats. Animals and Methods. Rats with regular ocstrous cycle were randomly divided into five groups (n=6) as follows: Control, MTXLD (low dose), MTXHD (high dose), MTXHD + LCN (leucovorin), and MTXHD + WD (withdrawal). Animals were treated intramuscularly (/'//;) on days 1-5 of pregnancy. MTXHD treatment was withdrawn and female rats showing regular cycle were caged with male rats. Laparotomy was performed on day 8 of pregnancy to note the number of implantation sites. Rats were sacrificed on day 20. Results. MTX significantly reduced maternal weights, number of corpora lutea. and implantation sites. 100% foetal resorption was prevalent in MTX treated groups. LCN supplementation did not help maintain pregnancy. While approximately 45% foetal resorption was observed in withdrawal group.
Methotrexate (MTX), a folic acid antagonist and DNA synthesis inhibitor in rapidly dividing cells, has been implicated in as a human teratogen, particularly when used in a high dose during the first trimester of pregnancy. Erroneous MTX treatment during pregnancy should prompt a thorough discussion and counseling of the patient regarding the risks of fetal exposure to MTX. Following MTX treatment, a 6-month interval before conception following the treatment should be advised. However, conception within less than 3–6 months subsequent to MTX treatment should not be considered as a definite indication for pregnancy termination.
Pregnancy of unknown location (PUL) is a common diagnostic challenge. The primary diagnostic goal is to ensure that the PUL is nonviable prior to proceeding with any invasive procedures. In nonviable PUL, there are several diagnostic and treatment strategies, which are generally quite safe. However, the management option that provides the most definite diagnosis is uterine curettage. We advocate use of uterine curettage in all cases of nonviable PUL because it limits exposure to a chemotherapeutic agent to only those who need it and it allows for the most accurate information for counseling the patient on prognosis of future pregnancies.
Methotrexate is a well known chemotherapeutic agent, extensively used for leukemia and other cancers. Although its efficacy
is wide, methotrexate can cause serious or life-threatening toxicities on liver, lungs, kidney, and immune system. Teratogenicity
is one of the methotrexate-induced side effects. So, we performed with JEG-3, human placenta choriocarcinoma cell line, to
identify the differentially expressed genes (DEGs) related to teratogenicity of methotrexate using an Agilent 44-K whole human
genome chip. Through the analysis of gene expression profiles, we identified 887 up-regulated genes and 828 down-regulated
genes above 1.5-fold by methotrexate. At IC30 doses recognized genes were functionally categorized as being involved in purine and pyrimidine biosynthetic process, cell
cycle arrest, and apoptosis. Functionally important purine and pyrimidine biosynthesis-related genes were further validated
by real-time RT-PCR. The results showed that GART, HPRT1, TYMS, and CTPS genes altered their expression levels by methotrexate.
Alteration of these genes may lead to methotrexate-induced teratogenicity, which caused by imbalance of nucleotide biosynthesis.
In conclusion, both gene expression profiles and functional analysis have identified potential gene-based biomarkers and provided
insights into the mechanism underlying the response of human placenta cell line to methotrexate exposure.
KeywordsMethotrexate-Teratogenicity-Nucleotide biosynthesis-Microarray
Crohn disease and ulcerative colitis commonly affect women in their childbearing years. Fortunately, advances in the field of inflammatory bowel disease have made successful pregnancy outcomes a reality for many women. These advances have led to family planning as a common discussion between gastroenterologists and inflammatory bowel disease patients. Common discussion topics are fertility, conception, medication safety, pregnancy, delivery, and breastfeeding although there are limited available data. Education and patient awareness have become vital factors in successful pregnancy outcomes.
Question:
My last pregnancy was diagnosed as ectopic, and I was treated successfully with intramuscular methotrexate (MTX) 8 weeks ago. I am currently planning for another pregnancy; however, I have read that MTX causes birth defects and that it stays in my body for a very long time, ranging from 1 to 12 months after treatment. When is it safe to conceive?
Answer:
We suggest that the outcomes of pregnancies conceived shortly after MTX therapy for extrauterine pregnancy are most likely to be favourable and similar to those pregnancies conceived 6 months after MTX treatment. However, as data are not sufficient to draw a definitive conclusion or to confirm the exact safe timing after MTX treatment, at least a 3-month waiting period is recommended for women who are planning pregnancy. Nevertheless, conception within 3 months of MTX treatment of extrauterine pregnancy should not be considered a definite indication of termination, and further targeted fetal anatomy assessment is recommended. Further retrospective and prospective studies are needed to define the safety period before 3 months and to solidify this recommendation.
To examine the possibility that cytotoxic drugs may cause sterility or congenital malformations in the offspring of women of childbearing age who are cured of cancer a study was conducted of the obstetric histories of 445 long term survivors treated in this unit with chemotherapy for gestational trophoblastic tumours between 1958 and 1978. After completing treatment 97% of those who wished for a pregnancy (49% of all women studied) conceived and 86% had at least one live birth. All these women had received methotrexate. Of the 47 women who wished to conceive and whose combination therapy included cyclophosphamide, 37 (79%) had a live birth. Women who received three or more drugs were less likely to have a live birth than those who received methotrexate alone or with only one other drug (p less than 0.001). There was no statistically significant excess of congenital malformations. These results are strong evidence that the cytotoxic drug regimens used in this unit for treating gestational trophoblastic tumours are compatible with the preservation of fertility in most women and not associated with any increase in congenital abnormalities.
Low-dose weekly methotrexate (MTX) is widely used in the treatment of rheumatoid arthritis1 and is now increasingly used in other rheumatic conditions, including systemic lupus erythematosus and juvenile arthritis. Because of its anti-metabolic and cytotoxic actions, questions of its safety in those of childbearing age are likely to become increasingly important. The aim of this review is to aid clinicians in the counselling and education of patients taking or about to start taking low-dose MTX. We examine the effects of MTX with respect to fertility, pregnancy and lactation, based upon information obtained using `Medline' search strategies from 1966 to 1997, hand search through the last ten years of the journal Teratology, source paper references and data from the UK National Teratology Information Service (NTIS) from 1992.
MTX is a derivative of the folic acid analogues. The importance of folic acid, a B group vitamin, in haematopoiesis was realized in the early 1940s, and by 1946 it had been synthesized and given its chemical term, pteroylglutamic acid.2 By the following year, the synthesis, anti-bacterial and anti-metabolic actions of its 4-amino derivative, aminopterin, had been described.3 The megaloblastic appearance of marrow in some cases of leukaemia, similar to that seen in folic acid deficiency, led early researchers to speculate that folic acid analogues could be useful in treating this form of malignancy. Paradoxically, it was found that a folate-deficient diet could cause depletion of leukaemic cell lines, which led to the use of the competitive analogues in haematological malignancies.4
In 1951, aminopterin was used for the first time for patients with a connective tissue disease, with six out of seven patients with rheumatoid arthritis experiencing some benefit. The authors commented, `The toxic effects of aminopterin place practical limitations on its use as a therapeutic agent'.5
MTX (amethopterin) …
Dr M.E. Lloyd, Department of Rheumatology, Frimley Park Hospital, Portsmouth Road, Frimley, Surrey GU16 5UJ
The prenatal effects of methotrexate (MTX) in rats and rabbits were assessed. It was found highly embryotoxic in postimplantation rat embryos; 0.3 mg/kg ip or less caused nearly total embryolethality with slight teratogenicity. Rabbit embryos were far more resistant to small doses of MTX than rats, but 19.2 mg/kg iv, when given during days 10 to 15 of gestation, produced little death and a constant spectrum of malformation in a high percentage of offspring. Cleft palate, skull defects, and severe fore- and hindlimb dysplasias, occurred with a high degree of regularity and were strongly dose and developmental-stage specific.
Methotrexate treatment of unruptured ectopic pregnancy is safe and effective and preserves reproductive potential. Previous protocols have required multiple methotrexate doses with or without citrovorum rescue. The purpose of this study was to determine whether patients with an unruptured ectopic pregnancy 3.5 cm or less in greatest dimension could be treated with single-dose intramuscular methotrexate (50 mg/m2) without citrovorum rescue. Thirty-one patients were eligible for this outpatient treatment protocol. One patient withdrew from follow-up, leaving 30 patients (96.8%) in the study group. Patients had a mean age of 28.5 years (range 18-37) and a mean gravidity of 3.0 (range 1-8); nine of 30 (30%) had previously undergone a salpingectomy for ectopic pregnancy. Pre-treatment hCG titers ranged from 130-16,700 mIU/mL (mean 4558). Pre-treatment transvaginal sonography visualized the ectopic in 28 of 30 patients (93.3%) and revealed cardiac activity in six patients. Patients were monitored with hCG titers three times per week for the first week, and then weekly until the hCG was less than 15 mIU/mL. A complete blood count and liver enzymes were obtained before treatment and on day 7. All patients had a continued rise in hCG titer for at least 3 days after methotrexate injection, although all levels began to decline by day 7. No patient required a second dose of methotrexate and no patient experienced any side effects. Twenty-nine of 30 patients (96.7%) were successfully treated. Six of 30 (20%) experienced an increase in lower abdominal pain between days 5-10, and two were hospitalized overnight for observation.(ABSTRACT TRUNCATED AT 250 WORDS)
The folate antagonist methotrexate (MTX), widely used in chemotherapy, is a well-documented teratogen. However, the mechanism by which it exerts its effects is still unclear. Specifically, we have examined the cytotoxicity of MTX in vivo and in vitro and have looked at the relationship between cytotoxicity and teratogenesis. The chick embryo was utilized to examine the effects of the drug administered to carefully staged embryos. Embryos were exposed at stages 18-22 and examined on day 11 of incubation. Wings were malformed in a stage-dependent manner while legs were affected similarly at each stage used. A modification of the 51chromium-release assay was used to test the toxicity of MTX to limb cells in vitro. None of the tissues tested showed measurable toxicity in vitro even though the drug kills cells in vivo, thereby suggesting that MTX may be metabolized differently in vitro. Malformations induced by MTX do not seem to be due to changes in the amount of cell death taking place in the limb but may be caused by a transient inhibition of cell division.
The folic acid analogue methotrexate (MTX) was evaluated for its embryotoxic potential in ICR mice on day 10 (stage 18) of gestation. No malformations were produced at doses shown to be embryotoxic in humans, rats, rhesus monkeys, and rabbits (0.3–10 mg/kg), although a significant increase in resorption rate was observed in litters treated with 10 mg/kg. Doses between the LD10 and the LD50 (25 and 50 mg/kg) produced a parallel increase in intrauterine death and congenital defects.
Women who had previously given birth to one or more infants with a neural-tube defect (NTD) were recruited into a trial of periconceptional multivitamin supplementation. 1 of 178 infants/fetuses of fully supplemented mothers (0.6%) had an NTD, compared with 13 of 260 infants/fetuses of unsupplemented mothers (5.0%).
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.
Our purpose was to report an expanded clinical trial with a nonlaparoscopic approach to ectopic pregnancy diagnosis combined with single-dose intramuscular methotrexate treatment.
A prospective cohort of 120 women with an ectopic pregnancy < or = 3.5 cm in greatest dimension was enrolled.
Patients had a mean age of 26.1 +/- 6.2 years, a mean gravidity of 3.2 +/- 1.6, and a mean parity of 0.97 +/- 1.0. The mean human chorionic gonadotropin titer before treatment initiation was 3950 +/- 1193 mIU/ml. Transvaginal ultrasonography visualized cardiac activity in 14 (11.7%) patients, with an ectopic mass visualized in 113 (94.2%). The mean time to resolution in the 113 (94.2%) subjects successfully treated was 35.5 +/- 11.8 days. Four (3.3%) patients required a second methotrexate dose on day 7. No biochemical or clinical side effects occurred. Posttreatment hysterosalpingograms demonstrated tubal patency on the ipsilateral side in 51 of 62 (82.3%) patients. Of those attempting pregnancy, 79.6% were pregnant, 87.2% intrauterine and 12.8% ectopic. The mean time to achieve pregnancy was 3.2 +/- 1.1 months.
This regimen requires minimal laboratory follow-up and eliminates leukovorin recovery, making it the regimen of choice for medical treatment of unruptured ectopic pregnancy.
Our purpose was to evaluate the effectiveness of single-dose intramuscular methotrexate in the treatment of ectopic pregnancies by physicians in the Department of Obstetrics and Gynecology of Northwestern Memorial Hospital and to compare the results with those of previously published studies.
A retrospective chart review was performed of 50 patients with ectopic pregnancies treated with single-dose methotrexate according to the protocol of Stovall et al. from January 1992 to February 1995.
The mean pretreatment level of beta-human chorionic gonadotropin was 1896.4 +/- 2399 mlU/ml. Only 32 women (64%) were successfully treated with a single dose of methotrexate. An additional 7 women required a second or third injection. The combined success rate for medical management of ectopic pregnancy with one to three doses of methotrexate was 78% (39 women). Pretreatment beta-human chorionic gonadotropin levels were significantly lower in women who responded to single-dose therapy than in those who required either two or three doses or who had failure of medical management (p = 0.0011). The mean time to resolution of beta-human chorionic gonadotropin was 26.5 +/- 17 days. Higher pretreatment levels correlated with longer resolution time (r = 0.83, p < 0.001). Eleven women (22%) with failure of medical management required surgery.
In our series single-dose methotrexate was only 64% successful. Women with a pretreatment beta-human chorionic gonadotropin level >5000 mlU/ml had a greater probability of requiring either surgical intervention or multiple doses of methotrexate. The potential for emergency surgery remains an important risk.
To evaluate reproductive outcome after ectopic pregnancy (EP) treated with methotrexate (MTX) and to assess the relative contribution of various risk factors to future fertility.
Telephone follow-up interviews in a cohort of patients treated for EP.
University hospital.
A cohort of 158 patients treated with MTX for tubal pregnancies between April 1991 and March 1999.
Assessment of fertility outcomes.
Cumulative pregnancy rates for intrauterine and ectopic pregnancies.
Thirty-two patients (20.2%) were lost to follow-up. Of 126 patients, 93 (73.8%) sought to become pregnant, and of these 93 women, 76 (81.7%) did. Sixty-four pregnancies were spontaneous, and 12 resulted from in vitro fertilization (IVF). No pregnancies occurred in the group not trying to become pregnant. Of the 64 spontaneous pregnancies, 52 (81.2%) were intrauterine, with 12 (18.7%) resulting in miscarriages, and 12 (18.7%) were recurrent ectopic pregnancies. The cumulative intrauterine pregnancy rate was 57.5% after 1 year and 66.9% after 2 years. The cumulative ectopic pregnancy rate was 15.4% after 1 year and 23.7% after 2 years. After adjusting for factors associated with fertility with a Cox regression, only one factor was associated with poor reproductive performance: previous history of infertility.
Within 1 year of seeking to become pregnant, more than half the women previously treated medically for EP conceived and had ongoing pregnancies. Our analysis indicates that fertility depends more on the patients' previous medical history than on her treatment for EP.
Methotrexate and misoprostol are frequently used in combination for medical termination of pregnancy. Despite their frequent use, published information about low-dose exposures to these known teratogens is sparse and neonatal follow-up data are limited. We present neonatal outcomes in three infants from two different women who had failed medical terminations with methotrexate and misoprostol.
A young gravida 1, para 0, presented with intrauterine pregnancy complicated by first-trimester exposure to oral methotrexate and vaginal misoprostol. Ultrasonography determined that the fetus had intrauterine growth restriction and ventriculomegaly. The infant had growth and developmental delays. A young gravida 4, para 3-0-0-3, also presented after first trimester exposure to methotrexate and misoprostol, and was found to have a twin gestation. The infants were noted to have multiple congenital anomalies, growth restriction, and developmental delay.
Even single doses of methotrexate and misoprostol used in medical termination of pregnancy can be associated with multiple congenital anomalies.