Assessment of Ovarian Function in Phase 3 (Neo)adjuvant Breast Cancer Clinical Trials: A Systematic Evaluation

BACKGROUND: Loss of ovarian function is a recognized adverse effect of chemotherapy for breast cancer and of great importance to patients. Little is known about the ovarian toxicity of newer cancer treatments. This study examined whether breast cancer clinical trials include assessment of the impact of trial interventions on ovarian function. METHODS: Eligible trials were phase III (neo)adjuvant trials of pharmacologic treatments for breast cancer, recruiting between June 2008 and October 2019, which included premenopausal women. MEDLINE, EMBASE, Clinicaltrials.gov, and EudraCT were searched. Data were extracted from trial publications, protocols, databases, and a survey sent to all trial chairs. Tests of statistical significance were 2-sided. RESULTS: Of 2354 records identified, 141 trials were eligible. Investigational treatments included chemotherapy (36.9%), HER2 targeted (24.8%), endocrine (12.8%), immunotherapy (7.8%), cyclin-dependent kinase 4/6 inhibitors (5.0%), and poly-ADP-ribose polymerase inhibitors (2.8%). Ovarian function was a prespecified endpoint in 13 (9.2%) trials. Forty-five (31.9%) trials collected ovarian function data, but only 33 (23.4%) collected posttrial-intervention data. Common postintervention data collected included menstruation (15.6%), pregnancy (13.5%), estradiol (9.9%), and follicle-stimulating hormone levels (8.5%). Only 4 (2.8%) trials collected postintervention anti-müllerian hormone levels, and 3 (2.1%) trials collected antral follicle count. Of 22 trials investigating immunotherapy, cyclin-dependent kinase 4/6 inhibitors, or poly-ADP-ribose polymerase inhibitors, none specified ovarian function as an endpoint, but 4 (18.2%) collected postintervention ovarian function data. CONCLUSIONS: The impact of pharmacologic interventions on ovarian function is infrequently assessed in phase III breast cancer (neo)adjuvant trials that include premenopausal women. Trialists should consider inclusion of ovarian function endpoints when designing clinical trials, given its importance for informed decision making

School-age outcomes among IVF-conceived children: A population-wide cohort study.

BackgroundIn vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception.Methods and findingsCausal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring ConclusionsIn this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians

School-age outcomes among IVF-conceived children: A population-wide cohort study

Background In vitro fertilisation (IVF) is a common mode of conception. Understanding the long-term implications for these children is important. The aim of this study was to determine the causal effect of IVF conception on primary school-age childhood developmental and educational outcomes, compared with outcomes following spontaneous conception. Methods and findings Causal inference methods were used to analyse observational data in a way that emulates a target randomised clinical trial. The study cohort comprised statewide linked maternal and childhood administrative data. Participants included singleton infants conceived spontaneously or via IVF, born in Victoria, Australia between 2005 and 2014 and who had school-age developmental and educational outcomes assessed. The exposure examined was conception via IVF, with spontaneous conception the control condition. Two outcome measures were assessed. The first, childhood developmental vulnerability at school entry (age 4 to 6), was assessed using the Australian Early Developmental Census (AEDC) (n = 173,200) and defined as scoring Conclusions In this analysis, under the given causal assumptions, the school-age developmental and educational outcomes for children conceived by IVF are equivalent to those of spontaneously conceived children. These findings provide important reassurance for current and prospective parents and for clinicians. In a population-wide cohort study, Dr Anthea C Lindquist and colleagues, examine school-age outcomes among IVF-conceived children in Australia. Author summary Why was this study done? More than 8 million children have been conceived globally with the assistance of in vitro fertilisation (IVF). Some studies suggest these children have an increased risk of congenital abnormalities, autism spectrum disorder, developmental delay, and intellectual disability. Educational and school-age developmental outcomes following IVF conception have not yet been adequately characterised. What did the researchers do and find? Using statewide, linked population data from Victoria, Australia, we investigated the school-age developmental and educational outcomes for children born following IVF-assisted conception. The study examined 2 separate assessments of school-age development and educational outcomes among 585,659 children, including 11,059 children who were conceived via IVF. This study was designed and performed within a causal framework, in order to produce the best possible estimate of exposure effect using observational data. We found no difference in school-age childhood developmental and educational outcomes between IVF- and spontaneously conceived children. What do these findings mean? These findings provide reassurance for current and prospective parents, as well as clinicians who are involved in IVF. This information may be useful in providing informed consent and education to those considering IVF and those with children conceived via IVF

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Tables A and B. Table A. Sensitivity analysis–NAPLAN (exempt multiply imputed). Table B. Sensitivity analysis–NAPLAN (exempt excluded). (DOCX)</p

Results of final causal model.

Results of final causal model.</p

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Tables A and B. Table A. Sensitivity analysis–AEDC (special needs multiply imputed). Table B. Sensitivity analysis–AEDC (special needs excluded). (DOCX)</p

STROBE guideline checklist.

(DOCX)</p