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Background Tubal ectopic pregnancies can cause significant morbidity or even death. Current treatment is with methotrexate or surgery. However, methotrexate treatment can fail in approximately 30% of women. Gefitinib, an epidermal growth factor receptor inhibitor, may improve the effects of methotrexate. We assessed the efficacy of administering oral gefitinib with methotrexate, versus methotrexate alone, to treat a tubal ectopic pregnancy. Objectives To test the hypothesis a combination of gefitinib with methotrexate can increase resolution of stable tubal ectopic pregnancy without the need for surgery, compared with methotrexate alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting Fifty UK hospitals. Participants A target of 328 women with a stable, tubal ectopic pregnancy. Intervention Women were randomised to combination of methotrexate and gefitinib or methotrexate and placebo. All participants received a single intramuscular dose of methotrexate 50 mg/m2 and were randomised in a 1:1 ratio of oral gefitinib (250 mg daily for 7 days) or placebo. Main outcome measures The primary outcome was surgical intervention for resolution of ectopic pregnancy. Secondary outcomes were the need for an additional dose of methotrexate, time to resolution of the ectopic pregnancy, number of treatment-associated hospital visits, safety and tolerability, acceptability of treatment and return to menses. Results Between 2 November 2016 and 6 October 2021, 328 women were randomly allocated to methotrexate and gefitinib (n = 165) or methotrexate and placebo (n = 163). Three women in the placebo group withdrew. Surgical intervention occurred in 30% (50/165) of the gefitinib group and in 29% (47/160) of the placebo group (adjusted risk ratio 1.15, 95% confidence interval 0.85 to 1.58; adjusted risk difference −0.01, 95% confidence interval −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% confidence interval 0.75 to 1.40). The need for additional methotrexate doses, number of additional hospital visits, participant acceptability, time to return of menses and serious adverse events were similar in both groups. Diarrhoea and rash were more common in the gefitinib group. Conclusions The addition of gefitinib to standard medical management with methotrexate to treat tubal ectopic pregnancy is not clinically effective as it does not reduce subsequent surgical intervention and is associated with higher rates of reported symptoms than placebo. Limitations We were unable to investigate how different gefitinib doses or modes of delivery would impact on the results. Future work Questions that remain unaddressed relate to the use of methotrexate and gefitinib combination treatment for other extrauterine and uterine ectopic pregnancy, such as caesarean scar pregnancies, or in the management of choriocarcinoma. Trial registration This trial is registered as ISRCTN 67795930 and EudraCT 2015-005013-76. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme and will be published in full in Efficacy and Mechanistic Evaluation; Vol. 10, No. 1. The gefitinib and placebo were supplied by Astra Zeneca. See the NIHR Journals Library website for further project information. Plain language summary What was the question? A tubal ectopic pregnancy is where a fertilised egg is not growing in the womb. The pregnancy cannot be saved and the woman is at risk of losing her fallopian tube and if this pregnancy is left to grow can even die. Current treatment is with methotrexate or surgery. An operation can happen because either the ectopic pregnancy has ruptured and caused internal bleeding, the medical treatment has not worked and the ectopic pregnancy needs to be removed or the patient can chose to have an operation. However, methotrexate treatment can fail in approximately 30% of women. We carried out research to see if the addition of a new drug (gefitinib, a drug used for lung cancer) to methotrexate could lower the number of women needing an operation to remove their ectopic pregnancy. What did we do? We involved 328 women with a stable tubal ectopic pregnancy, who were being treated medically with methotrexate, and randomly assigned them to have methotrexate alone or a combination of methotrexate and gefitinib. The gefitinib was taken in tablet form for 7 days, and the methotrexate was given as an injection. We followed the women up in line with their clinical care until their ectopic pregnancy resolved or they had surgery to remove the ectopic pregnancy. What did we find? The addition of gefitinib to methotrexate did not reduce the number of women who required surgery to remove their ectopic pregnancy. More women taking gefitinib experienced side effects, such as a facial rash or diarrhoea. What does this mean? Treatment with methotrexate remains the only drug treatment option for ectopic pregnancy. More research is needed. Scientific summary Background Tubal ectopic pregnancy (EP) can cause significant morbidity or even death. Current treatment is with methotrexate (MTX) or surgery. However, MTX treatment can fail in approximately 30% of women. Preclinical studies have shown that tubal implantation sites express high levels of epidermal growth factor receptor (EGFR) and that gefitinib (an EGFR antagonist) augments MTX-induced regression of pregnancy-like tissue. Clinical evidence from uncontrolled phase I and II trials has raised the possibility that a combination of MTX and gefitinib could be a more effective medical treatment than MTX alone to treat stable tubal EP. Objectives To test the hypothesis, a combination of gefitinib with MTX can increase resolution of stable tubal EP without the need for surgery, compared with MTX alone. Design A randomised, double-blind, placebo-controlled, multicentre, superiority trial. Setting This trial took place in 50 hospitals in the UK. Participants A target of 328 women with a stable, tubal EP. Intervention Participants were randomly assigned in a 1:1 ratio to receive either gefitinib and MTX or matched placebo and MTX with the use of minimisation to balance trial-group assignments according to baseline human chorionic gonadotropin levels (

Abstract Background Endometriosis is a common benign condition, which is characterized by the growth of endometrial-like tissue in ectopic sites outside the uterus. Laparoscopic excision of the disease is frequently carried out for the treatment of severe endometriosis. Pelvic adhesions often develop following surgery and they can compromise the success of treatment. Ovarian suspension (elevating both ovaries to the anterior abdominal wall using a Prolene suture) is a simple procedure which has been used to facilitate ovarian retraction during surgery for severe pelvic endometriosis. The study aims to assess the effect of temporary ovarian suspension following laparoscopic surgery for severe pelvic endometriosis on the prevalence of post-operative ovarian adhesions. Methods A prospective double blind randomised controlled trial for patients with severe pelvic endometriosis requiring extensive laparoscopic dissection with preservation of the uterus and ovaries. Severity of the disease and eligibility for inclusion will be confirmed at surgery. Patients unable to provide written consent, inability to tolerate a transvaginal ultrasound scan, unsuccessful surgeries or suffer complications leading to oophorectomies, bowel injuries or open surgery will be excluded. Both ovaries are routinely suspended to the anterior abdominal wall during surgery. At the end of the operation, each participant will be randomised to having only one ovary suspended post-operatively. A new transabdominal suture will be reinserted to act as a placebo. Both sutures will be cut 36 to 48 hours after surgery before the woman is discharged home. Three months after surgery, all randomised patients will have a transvaginal ultrasound scan to assess for ovarian mobility. Both the patients and the person performing the scan will be blinded to the randomisation process. The primary outcome is the prevalence of ovarian adhesions on ultrasound examination. Secondary outcomes are the presence, intensity and site of post-operative pain. Discussion This controlled trial will provide evidence as to whether temporary ovarian suspension should be included into the routine surgical treatment of women with severe pelvic endometriosis. Trial registration ISRCTN: ISRCTN24242218

Abstract Background For most tubal ectopic pregnancies (EP) surgery is the treatment of first choice. Whether surgical treatment should be performed conservatively (salpingostomy) or radically (salpingectomy) in women wishing to preserve their reproductive capacity, is subject to debate. Salpingostomy preserves the tube, but bears the risks of both persistent trophoblast and repeat ipsilateral tubal EP. Salpingectomy, avoids these risks, but leaves only one tube for reproductive capacity. This study aims to reveal the trade-off between both surgical options: whether the potential advantage of salpingostomy, i.e. a better fertility prognosis as compared to salpingectomy, outweighs the potential disadvantages, i.e. persistent trophoblast and an increased risk for a repeat EP. Methods/Design International multi centre randomised controlled trial comparing salpingostomy versus salpingectomy in women with a tubal EP without contra lateral tubal pathology. Hemodynamically stable women with a presumptive diagnosis of tubal EP, scheduled for surgery, are eligible for inclusion. Patients pregnant after in vitro fertilisation (IVF) and/or known documented tubal pathology are excluded. At surgery, a tubal EP must be confirmed. Only women with a tubal EP amenable to both interventions and a healthy contra lateral tube are included. Salpingostomy and salpingectomy are performed according to standard procedures of participating hospitals. Up to 36 months after surgery, women will be contacted to assess their fertility status at six months intervals starting form the day of the operation. The primary outcome measure is the occurrence of spontaneous viable intra uterine pregnancy. Secondary outcome measures are persistent trophoblast, repeat EP, all pregnancies including those resulting from IVF and financial costs. The analysis will be performed according to the intention to treat principle. A cost-effectiveness analysis will be performed within a decision analysis framework, based on costs per live birth, including IVF treatment whenever a spontaneous pregnancy does not occur. Patients' preferences will be assessed using a discrete choice experiment. Discussion This trial will provide evidence on the trade off between salpingostomy and salpingectomy for tubal EP in view of the pros and cons of both interventions and will offer guidance to clinicians in making the right treatment choice. Trial registration Current Controlled Trials ISRCTN37002267

Background: Caesarean scar ectopic pregnancy (CSEP) is associated with significant maternal and foetal morbidity. However, the optimal treatment remains unknown. Objectives: The aim of this study was to review outcomes reported in studies on CSEP treatment and outcome reporting quality. Search Strategy: We reviewed 1270 articles identified through searching PubMed, MEDLINE and Google Scholar from 2014 to 2024 using the search terms 'caesarean scar ectopic pregnancy and caesarean scar pregnancy'. Selection Criteria: We included all study types evaluating any form of CSEP treatment, with a sample size of ≥ 50, where diagnosis was described, and the article was in English. Data Collection and Analysis: Two authors independently reviewed studies and assessed outcome reporting and methodological quality. The relationship between outcome reporting quality and publication year and journal type was assessed with univariate and bivariate models. Main Results: A total of 108 studies, including 17 941 women, were included. 83% of all studies originated from China. Studies reported on 326 outcomes; blood loss (86%), need for additional intervention (77%) and time for serum hCG to normalise post treatment (69%) were the most common outcomes. A primary outcome was clearly defined in 11 (10%) studies. The median quality of outcome reporting was 3 (IQR 3–4). No relationship was demonstrated between outcome reporting quality and publication year (p = 0.116) or journal type (p = 0.503). Conclusions: This review demonstrates that there is a wide variation in outcomes reported in studies on CSEP treatment. Development and implementation of a core outcome set by international stakeholders which includes patients is urgently needed to enable high‐quality research that is both useful and relevant to patients. [ABSTRACT FROM AUTHOR]

Objective: To report the outcome of cesarean scar pregnancy (CSP) undergoing treatment. Methods: MEDLINE, Embase and CINAHL databases were searched. Inclusion criteria were women with CSP undergoing treatment. The primary outcome was successful treatment for CSP, defined as no need for additional medical or surgical strategies. Secondary outcomes were the type of additional treatment (surgical or medical), need for blood transfusion, emergency laparotomy, hysterectomy, post-treatment complications. All these outcomes were explored in women undergoing single and compound treatments for CSP. Furthermore, we performed a separate sub-group analysis only including studies which reported on the outcomes of elective treatments. Random effects meta-analyses were used to analyze the data and results reported as pooled proportions or odd ratio (OR). Results: 176 studies (13431 women with CSP undergoing treatment) were included. Successful treatment after primary intervention was achieved in 86.2% (95% CI 82.3–89.7) of women with CSP undergoing treatment with ultrasound guided suction curettage, 72.4% (95% CI 64.8-79.3) with systemic MTX, 81.6% (95% CI 72.3–89.3) with local MTX, 83.9% (95% CI 66.7–95.6) with interventional radiology, 90.42% (95% CI 82.9–96.0) with hysteroscopy, 96.1% (95% CI (92.3–98.6) with laparoscopy and 92.6 with high intensity focused ultrasound (95% CI 78.2–99.6). Post-treatments complications were reported in 3.5% (95% CI 1.7–6.0) of women treated with systemic MTX, 5.9% (95% CI 0.8–15.1) with local MTX or KCl, 1.2% (95% CI 0.1–3.5) with interventional radiology, 1.4% (95% CI 0.4–2.9) with hysteroscopy, 5.5% (95% CI 0.4–25.7) with high intensity focused ultrasound and in none of the cases treated with ultrasound guided suction curettage. When considering compound treatments, successful resolution of CSP was achieved in 91.9% (95% CI 88.0–95.10) of women treated with interventional radiology followed by curettage, 83.3% (95% CI 68.8–93.8) with systemic MTX and curettage, 79.4% (95% CI 56.3–95.2) with local MTX and curettage, 96.2% (95% CI 92.3–98.7) with curettage followed by single or double balloon insertion in the uterine cavity, 98.3% (95% CI 95.9–99.7) with high intensity focused ultrasound followed by curettage, 91.1% (95% CI 3.4–97.0) with interventional radiology followed by removal of CSP with hysteroscopy, 64.3% (95% CI 13.8–99.2) with interventional radiology and systemic MTX and in 95.5% (95% CI 92.9–97.5) with curettage and hysteroscopy. When considering studies reporting a comparison between different treatments, there was no difference between systemic vs local MTX in the primary outcome. Curettage was associated with a higher chance of achieving a successful treatment. Conclusions: A multitude of treatments for CSP have been reported in the published literature. All treatments described for CSP are apparently equally effective in treating this condition. The findings from this systematic review highlight the need for adopting a common definition and outcome reporting of CSP to better elucidate its natural history, estimate the magnitude of maternal complication after treatment and design appropriately powered RCT to elucidate the optimal treatment of CSP according to its ultrasound phenotype and gestational age at treatment, in terms of effective resolution of the condition and risk of post-intervention complications. [ABSTRACT FROM AUTHOR]

STUDY QUESTION Is acute haemoperitoneum that is managed conservatively a precursor of deep endometriosis? SUMMARY ANSWER Our study provides evidence to suggest that acute haemoperitoneum may lead to the development of deep endometriosis in a significant proportion of cases. WHAT IS KNOWN ALREADY A recent pilot study was the first to suggest that acute haemoperitoneum could be a precursor of deep endometriosis. However, the sample size was small, and the follow-up was not standardized owing to unknown rates of clot absorption and development of endometriosis. STUDY DESIGN, SIZE, DURATION This was a prospective observational cohort study conducted at a single centre over a 31-month period. A required sample size of 30 was calculated using results from a previous study, with a minimum of 15 women each in the groups with and without significant haemoperitoneum (study and control groups, respectively). A total of 59 women were recruited to the study and eight were lost to follow-up. The final sample comprised 51 women, 15 in the study group and 36 in the control group. PARTICIPANTS/MATERIALS, SETTING, METHODS All non-pregnant, premenopausal women aged 18–50 years who consecutively presented to our dedicated gynaecological diagnostic unit with severe acute lower abdominal pain were eligible for this study. We only included women who were clinically stable and were suitable for conservative management. Those with prior history or evidence of endometriosis on their initial ultrasound scan, previous hysterectomy, or bilateral oophorectomy were excluded. Participants had standardized follow-up visits for 6 months, with pelvic ultrasound scans and the British Society of Gynaecological Endoscopy pelvic pain questionnaires completed at each visit. The primary outcome was the sonographically confirmed presence of newly formed endometriosis. Secondary outcomes were the presence and change of pelvic pain symptoms and health-related quality of life (HR-QOL). MAIN RESULTS AND THE ROLE OF CHANCE After completion of follow-up, 7/15 (47%; 95% CI 21.3–71.4%) women presenting with acute haemoperitoneum (study group) developed sonographic evidence of deep endometriosis, compared to 0/36 (0%; 97.5% CI 0.0–9.7%) women in the control group. A ruptured functional haemorrhagic cyst was the most common cause of haemoperitoneum, occurring in 13/15 cases (87%). The time from the initial event to sonographic evidence of endometriosis varied from 2 to 6 months. The EuroQol visual analogue scores were not significantly different at baseline between the groups that developed and did not develop endometriosis [28 (interquartile range (IQR) 15–40, n = 6) vs 56 (IQR 35–75, n = 44), P  =   0.09], while the EuroQol-5D values were lower in the endometriosis group [−0.01 (IQR −0.07 to 0.19, n = 6) vs 0.62 (IQR 0.24–0.73, n = 44), P  =   0.002]. At 6 months, the EuroQol-5D scores were improved in both groups, but remained significantly lower in the endometriosis group compared to the no endometriosis group [0.69 (IQR 0.66–0.80, n = 6) vs 0.85 (IQR 0.76–1.00, n = 44), P  =   0.03]. There was no clinically relevant difference in the pelvic pain scores at either time point. LIMITATIONS, REASONS FOR CAUTION It remains uncertain whether minimal, superficial endometriosis existed at commencement of the study and had a role in the development of deep endometriosis. Although the ultrasound findings were in keeping with deep endometriosis, this was not confirmed histologically. The pelvic pain and HR-QOL findings could have been influenced by the baseline scores being taken when the patient was admitted with acute pain. Also, the sample size was too small to draw reliable conclusions regarding the impact of newly developed endometriosis on QoL. WIDER IMPLICATIONS OF THE FINDINGS Our study provides further evidence showing that significant haemoperitoneum may be a precursor of deep endometriosis. Haemodynamically stable women presenting with acute pelvic pain and significant haemoperitoneum should be counselled about the risk of developing deep endometriosis. Interventional studies should be carried out in the future to see whether laparoscopy and pelvic washout could prevent development of deep endometriosis. Preventative strategies, including treatment to suppress ovulation and formation of functional cysts, should be further investigated. This includes the combined and progesterone-only contraceptive pills. Larger future studies are also required to assess women over a longer period of time, with adjustment for confounding factors, to evaluate a possible effect on HR-QOL and pain symptoms. STUDY FUNDING/COMPETING INTEREST(S) Funding was obtained from The Gynaecology Ultrasound Centre, London, UK. TT received personal fees from GE, Samsung, Medtronic, and Merck for lectures on ultrasound. TT also received a postdoctoral grant from the South-Eastern Norwegian Health Authority (grant number 2020083). TRIAL REGISTRATION NUMBER researchregistry6472. [ABSTRACT FROM AUTHOR]