No additional risk of congenital anomalies after first-trimester dydrogesterone use: a systematic review and meta-analysis.

STUDY QUESTION: Is exposure to dydrogesterone a risk factor for congenital anomalies when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in assisted reproductive technology (ART)? SUMMARY ANSWER: Dydrogesterone, when given in the first trimester for recurrent/threatened pregnancy loss or as luteal support in ART, is not a relevant additional risk factor for congenital anomalies. WHAT IS KNOWN ALREADY: Despite large clinical trials and meta-analyses that show no association between dydrogesterone and congenital anomalies, some recently retracted publications have postulated an association with teratogenicity. Dydrogesterone is also often rated as less safe than bioidentical progestins. STUDY DESIGN SIZE DURATION: A systematic review was conducted according to a pre-specified protocol with searches on Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Clinicaltrials.gov. The search was limited to human studies, with no restrictions on language, geographical region, or date. The search algorithm used a PICO (Population, Intervention, Comparison, Outcome)-style approach combining both simple search terms and medical subject heading terms. As congenital anomalies are mostly reported as secondary outcomes, the search term 'safety' was added. PARTICIPANTS/MATERIALS SETTING METHODS: Interventional study and observational study (OS) designs were eligible for inclusion. Inclusion criteria were: women >17 years old treated for threatened miscarriage, recurrent pregnancy loss, and/or ART; the use of dydrogesterone in the first trimester compared with placebo, no treatment or other interventions; and reporting of congenital anomalies in newborns or infants ≤12 months old (primary outcome). Two authors (A.K., M.R.N.) independently extracted the following data: general study information, study population details, intervention and comparator(s), and frequencies of congenital anomalies (classification, time of determination, and type). Risk of bias focused on the reporting of congenital malformations and was assessed using the Cochrane Risk of Bias Tool Version 2 or the ROBINS-I tool. The GRADEproGDT platform was used to generate the GRADE summary of findings table. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 897 records retrieved during the literature search, 47 were assessed for eligibility. Nine studies were included in the final analysis: six randomized controlled trials (RCTs) and three OSs. Among the RCTs, three had a low risk and three a high risk of bias. Two of the OSs were considered to have a serious risk of bias and one with critical risk of bias and was excluded for the evidence syntheses. The eight remaining studies included a total of 5070 participants and 2680 live births from 16 countries. In the meta-analysis of RCTs only, the overall risk ratio (RR) was 0.92 [95% CI 0.55; 1.55] with low certainty. When the two OSs were included, the overall RR was 1.11 [95% CI 0.73; 1.68] with low certainty. LIMITATIONS REASONS FOR CAUTION: The studies included in the analysis do not report congenital anomalies as the primary outcome; reporting of congenital anomalies was often not standardized. WIDER IMPLICATIONS OF THE FINDINGS: This systematic literature review and meta-analysis provide clear reassurance to both clinicians and patients that dydrogesterone is not associated with congenital anomalies above the rate that might be expected due to environmental and genetic factors. The results of this work represent the highest current level of evidence for the question of congenital anomalies, which removes the existing uncertainty caused by poor quality and retracted studies. STUDY FUNDING/COMPETING INTERESTS: Editorial support was provided by Highfield Communication Consultancy, Oxford, UK, sponsored by Abbott Products Operations AG, Allschwil, Switzerland. A.K., J.A.G.-V., L.P.S., J.N.v.d.A., and J.F.S. received honoraria from Abbott for preparation and participation in an advisory board. J.A.G.-V. received grants and lecture fees from Merck, Organon, Ferring, Gedeon Richter, and Theramex. M.R.N. has no conflicts of interest. J.N.v.d.A. and J.A.G.-V. have no other conflicts of interest. A.K. received payment from Abbott for a talk at the IVF Worldwide congress on 22 September 2023. J.F.S. has received grants from the National Institutes of Health, royalties/licences from Elsevier and Prescient Medicine (SOLVD Health), consulting fees from Burroughs Wellcome Fund (BWF) and Bayer, honoraria from Magee Women's Research Institute, Wisconsin National Primate Research Centre, University of Kansas and Oakridge National Research Laboratory, Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support to attend meetings for the International Academy of Human Reproduction (IAHR). J.F.S. has patents related to diagnosis and treatment of PCOS and prediction of preterm birth. J.F.S. participates on advisory boards for SOLVD Health, Wisconsin National Primate Research Centre, and FHI360, was the past President board member of the Society for Reproductive Investigation, has a leadership role for the following organizations: Scientific Advisory Board, SOLVD Health, EAB Chair for contraceptive technology initiative, FHI360, EAB member, Wisconsin National Primate Research Centre, Advisory Board for MWRI Summit, Chair of BWF NextGen Pregnancy Research Panel, Medical Executive Committee at the Howard, and Georgeanna Jones Foundation, and is Vice President, IAHR. L.P.S. has received consulting fees from Shield Pharmaceuticals, Scynexis, Organon, Natera, Celula China, AiVF, Agile, Daiichi Sankyo, American Regent, and Medicem, honoraria from Agile, Daiichi Sankyo/American Regent, and Bayer, and travel support from BD Diagnostics. L.P.S. participates on the data safety monitoring board for Astellas and is a Chair of DSMB for fezolinetant. Abbott played no role in the funding of the study or in study design, data collection, data analysis, data interpretation, or writing of the report. TRIAL REGISTRATION NUMBER: PROSPERO 2022 CRD42022356977.

Breast cancer incidence and mortality before and after implementation of the German mammography screening program.

Effective population-based mammography screening should impact breast cancer (BC) incidence, age and stage-specific incidence and BC mortality. We aim to investigate such effects in a time period of 10 years after implementation of the German mammography screening program. Data on 323,719 breast cancer patients from 2003 to 2014 for defined regions covering a population of 30 million inhabitants and official mortality data from 1998 to 2016 for almost the whole of Germany were used. We compared incidence and mortality rates for the prescreening time period (2003/2004) and the latest available data (2013/2014 and 2015/2016, respectively) and performed trend analyses using joinpoint regression models. In the screening exposed age groups (50-59 and 60-69 years), BC incidence showed a typical prevalence peak with the introduction of the mammography screening, mainly driven by an increase of early-stage BC. For Stage III and IV BC incidence in 2013/2014 was 24.2 and 23.0% (age group 50-59 years) and 28.3 and 24.2% (age group 60-69 years) lower than in the prescreening period. From 2003/2004 to 2015/2016 BC mortality decreased by 25.8 and 21.2%, respectively. As corresponding trends in nonexposed age groups were distinctly unfavorable, the reduction of late-stage BC incidence and BC mortality in the screening exposed age groups in Germany is most likely to be attributed to the introduction of the national mammography screening program. These positive effects are bought at the cost of a moderate occurrence of overdiagnosis, especially by a sharp increase of in situ cancers.

Delayed complications after placement of self-expanding stents in malignant esophageal obstruction: treatment strategies and survival rate.

PURPOSE: Placement of self-expanding metal stents is regarded as a safe and effective treatment in patients with incurable malignant esophagogastric obstruction. However, proceeding and possible benefit of re-interventions in patients with recurrent dysphagia due to delayed complications (>4 weeks after stent insertion) is unclear. PATIENTS AND METHODS: In 133 patients with malignant stricture of the esophagus or the esophagogastric junction 164 expandable metal stents were placed. About 89 patients were followed up until death. All tumor- or stent-related complications and consequent re-interventions were recorded. RESULTS: The overall incidence of delayed complications was 53.4% (71 of 133 pts.), with 34 patients (25.6%) experiencing more than one complication. Recurrent dysphagia due to tumor ingrowth (22%) or overgrowth (15%), bolus obstruction (21%), stent migration (9%), and development of esophagorespiratory fistula (9%) was successfully treated by dilatation (24%), placement of a second/third stent (27%), laser therapy (16%), and/or placement of a feeding tube (PEG, 19%). The median survival of patients with endoscopic therapy was significantly longer (222 +/- 26 days) compared to patients without re-intervention (86 +/- 14 days, P < 0.0001). CONCLUSIONS: Delayed complications after metal stent placement for malignant esophageal stricture are common, but can be treated successfully by endoscopic re-intervention in most cases. Regular interventional therapy may also improve survival.