Secondary sex ratio in assisted reproduction: an analysis of 1 376 454 treatment cycles performed in the UK.

STUDY QUESTION: Does ART impact the secondary sex ratio (SSR) when compared to natural conception? SUMMARY ANSWER: IVF and ICSI as well as the stage of embryo transfer does impact the overall SSR. WHAT IS KNOWN ALREADY: The World Health Organization quotes SSR for natural conception to range between 103 and 110 males per 100 female births. STUDY DESIGN SIZE DURATION: A total of 1 376 454 ART cycles were identified, of which 1 002 698 (72.8%) cycles involved IVF or ICSI. Of these, 863 859 (85.2%) were fresh cycles and 124 654 (12.4%) were frozen cycles. Missing data were identified in 14 185 (1.4%) cycles. PARTICIPANTS/MATERIALS SETTING METHODS: All cycles recorded in the anonymized UK Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All singleton live births were included, and multiple births were excluded to avoid duplication. MAIN RESULTS AND THE ROLE OF CHANCE: The overall live birth rate per cycle for all IVF and ICSI treatments was 26.2% (n = 262 961), and the singleton live birth rate per cycle was 17.1% (n = 171 399). The overall SSR for this study was 104.0 males per 100 female births (binomial exact 95% CI: 103.1-105.0) for all IVF and ICSI cycles performed in the UK recorded through the HFEA. This was comparable to the overall SSR for England and Wales at 105.3 males per 100 female births (95% CI: 105.2-105.4) from 1991 to 2016 obtained from the Office of National Statistics database. Male predominance was seen with conventional insemination in fresh IVF treatment cycles (SSR 110.0 males per 100 female births; 95% CI: 108.6-111.5) when compared to micro-injection in fresh ICSI treatment cycles (SSR 97.8 males per 100 female births; 95% CI: 96.5-99.2; odds ratio (OR) 1.16, 95% CI 1.12-1.19, P < 0.0001), as well as with blastocyst stage embryo transfers (SSR 104.8 males per 100 female births; 95% CI: 103.5-106.2) when compared to a cleavage stage embryo transfer (SSR 101.2 males per 100 female births; 95% CI: 99.3-103.1; OR 1.03, 95% CI 1.01-1.06, P = 0.011) for all fertilization methods. LIMITATIONS REASONS FOR CAUTION: The quality of the data relies on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst stage embryo transfers. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date evaluating the impact of ART on SSR. The results demonstrate that, overall, ART does have an impact on the SSR when assessed according to the method of fertilization (ICSI increased female births while IVF increased males). However, given the ratio of IVF to ICSI cycles at present with 60% of cycles from IVF and 40% from ICSI, the overall SSR for ART closely reflects the population SSR for, largely, natural conceptions in England and Wales. STUDY FUNDING/COMPETING INTERESTS: The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Wellbeing of Women, the European Union and Finox. TRIAL REGISTRATION NUMBER: Not applicable

Ist der Kliniksarzt eine unabhängige Variable bzgl. der Ergebnisse des Embryotransfers bei standardisierter direkter Supervision? Eine 5-jährige beobachtende Kohortenstudie

Objective: To compare the cumulative pregnancy rate (CPR) for experienced clinicians and trainees naive to the skill of embryo transfer (ET) during an assisted reproductive treatment (ART) cycle. To establish the minimum number of procedures required to achieve consistent outcomes.Method: A non-interventional retrospective observational cohort study looking at all consecutive ETs undertaken over a 5-year study period. The CPR was determined by a self-reported urinary home pregnancy test undertaken 16 days after oocyte retrieval.Results: The CPR did not differ between an experienced clinician (39%) and trainee (45%) for the first 50 (p=0.41) and last 50 (40.7% versus 42.7%) (p=0.81) ET procedures. The CPR for the individuals remained consistent with their peaks and troughs mirroring the overall success rate of the unit. This pattern continued when the data was further stratified for co-variables (age [=2]): CPRs for experienced clinicians was 65.7% (first 50 transfers) and 40.9% (last 50 transfers); CPR for trainees was 66.7% (first 50 transfers) and 53.6% (last 50 transfers); p=0.95 and p=0.37, respectively. The trainees, however, were more likely to use a stylet catheter with a 2-step transfer technique, with a cost over clinical implication. Furthermore, patients expressed a preference for an experienced clinician to perform their procedure, despite being informed that the grade of the clinician had no impact on the cycle outcome after an analysis of the unit's data.Conclusion: The clinician's grade and duration of service have not been shown to significantly impact the outcome of the ART cycle. The findings, however, should be interpreted with caution, as they reflect the culture of training in the unit, where there is a strong emphasis on adequate direct and indirect supervision. Furthermore, the relationship between the volume of work and outcomes is established in postgraduate medical education, with the exact number required to achieve clinical competence being dependent on the procedure and intensity of the workload.Hintergrund: Embryotransfer (ET) ist die letzte kritische Phase innerhalb des assistierten reproduktiven Behandlungszyklus (ART). Es wird zunehmend deutlich, dass ein atraumatisches Verfahren wichtig für das Erzielen eines erfolgreichen Ergebnisses ist, und somit sollten theoretisch die Erfolgsraten zwischen Kliniksärzten variieren, basierend auf ihrer Position und ihrem Dienstalter, die beide Maßeinheiten klinischer Erfahrung sind. Diese Studie vergleicht die kumulative Schwangerschaftsrate (CPR) erfahrener Kliniker mit der von Ärzten in der Ausbildung, die mit den Fertigkeiten des ET nicht vertraut sind.Methode: Nicht-interventionelle retrospektive beobachtende Kohortenstudie, die über einen 5-Jahres-Zeitraum alle durchgeführten konsekutiven ETs untersucht. Die CPR wurde durch einen Urinschwangerschaftstest festgestellt, der 16 Tage nach der Gewinnung der Oozyte durchgeführt wurde.Ergebnisse: Die CPR zeigte keine Unterschiede zwischen erfahrenen Kliniksärzten (39%) und Ärzten in der Ausbildung (45%) bei den ersten 50 (p=0,41) und den letzten 50 Verfahren (40,7% versus 42,7%) (p=0,81). Die CPR blieb für diese Personen konsistent hinsichtlich Spitzen und Tiefpunkten, die die Erfolgsrate der Abteilung widerspiegelten. Dieses Muster setzte sich fort, als nach Co-Variablen stratifiziert wurde (Alter [=2]): die CPR für erfahrene Kliniker lag bei 65,7% (erste 50 Transfers) und 40,9% (letzte 50 Transfers); die CPR für Ärzte in der Ausbildung lag bei 66,7% bzw. 53,6%; p=0,95 bzw. p=0,37. Ärzte in der Ausbildung neigten eher dazu, einen Mandrinkatheter mit 2-stufiger Transfertechnik zu verwenden mit klinischen Auswirkungen bzgl. Mehrkosten. Darüber hinaus präferierten die Patienten, das ein erfahrener Kliniker bei ihnen das Verfahren durchführen sollte, obwohl sie darüber informiert worden waren, dass nach Analyse der Daten die Dienstposition keinen Einfluss auf das Zyklusergebnis hat.Schlussfolgerung: Dienstliche Position und Dienstalter wirkten sich nicht signifikant auf das Ergebnis des ART-Zyklus aus. Die Ergebnisse sollten jedoch mit Vorsicht interpretiert werden, da sie die Ausbildungskultur in der Abteilung reflektieren, wo großer Wert auf adäquate direkte und indirekte Supervision gelegt wird. Außerdem wird das Verhältnis zwischen Arbeitsvolumen und Ergebnissen in der postgraduierten ärztlichen Ausbildung mit einer genauen Anzahl festgelegt, die nötig ist, um klinische Kompetenz zu erreichen in Abhängigkeit von Verfahren und Intensität des Arbeitsaufwands

Secondary sex ratio in assisted reproduction: an analysis of 1 376 454 treatment cycles performed in the UK.

Study question Does ART impact the secondary sex ratio (SSR) when compared to natural conception? Summary answer IVF and ICSI as well as the stage of embryo transfer does impact the overall SSR. What is known already The World Health Organization quotes SSR for natural conception to range between 103 and 110 males per 100 female births. Study design, size, duration A total of 1 376 454 ART cycles were identified, of which 1 002 698 (72.8%) cycles involved IVF or ICSI. Of these, 863 859 (85.2%) were fresh cycles and 124 654 (12.4%) were frozen cycles. Missing data were identified in 14 185 (1.4%) cycles. Participants/materials, setting, methods All cycles recorded in the anonymized UK Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All singleton live births were included, and multiple births were excluded to avoid duplication. Main results and the role of chance The overall live birth rate per cycle for all IVF and ICSI treatments was 26.2% (n = 262 961), and the singleton live birth rate per cycle was 17.1% (n = 171 399). The overall SSR for this study was 104.0 males per 100 female births (binomial exact 95% CI: 103.1–105.0) for all IVF and ICSI cycles performed in the UK recorded through the HFEA. This was comparable to the overall SSR for England and Wales at 105.3 males per 100 female births (95% CI: 105.2–105.4) from 1991 to 2016 obtained from the Office of National Statistics database. Male predominance was seen with conventional insemination in fresh IVF treatment cycles (SSR 110.0 males per 100 female births; 95% CI: 108.6–111.5) when compared to micro-injection in fresh ICSI treatment cycles (SSR 97.8 males per 100 female births; 95% CI: 96.5–99.2; odds ratio (OR) 1.16, 95% CI 1.12–1.19, P &lt; 0.0001), as well as with blastocyst stage embryo transfers (SSR 104.8 males per 100 female births; 95% CI: 103.5–106.2) when compared to a cleavage stage embryo transfer (SSR 101.2 males per 100 female births; 95% CI: 99.3–103.1; OR 1.03, 95% CI 1.01–1.06, P = 0.011) for all fertilization methods. Limitations, reasons for caution The quality of the data relies on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst stage embryo transfers. Wider implications of the findings This is the largest study to date evaluating the impact of ART on SSR. The results demonstrate that, overall, ART does have an impact on the SSR when assessed according to the method of fertilization (ICSI increased female births while IVF increased males). However, given the ratio of IVF to ICSI cycles at present with 60% of cycles from IVF and 40% from ICSI, the overall SSR for ART closely reflects the population SSR for, largely, natural conceptions in England and Wales. Study funding/competing interest(s) The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Wellbeing of Women, the European Union and Finox. Trial registration number Not applicable.</p

ICSI does not improve reproductive outcomes in autologous ovarian response cycles with non-male factor subfertility

Study question Does the method of fertilisation improve reproductive outcomes in poor ovarian response (POR) cycles when compared to all other ovarian response categories in the absence of male factor subfertility? Summary answer ICSI does not confer any benefit in improving the clinical pregnancy or live birth (LB) outcome in autologous ovarian response cycles in the absence of male factor subfertility when compared to IVF. What is known already ICSI is associated with an improved outcome when compared to IVF in patients with severe male factor subfertility. Study design, size, duration A retrospective study involving 1 376 454 ART cycles, of which 569 605 (41.4%) cycles fulfilled the inclusion and exclusion criteria for all autologous ovarian response categories: 272 433 (47.8%) IVF cycles and 297 172 (52.2%) ICSI cycles. Of these, the POR cohort represented 62 641 stimulated fresh cycles (11.0%): 33 436 (53.4%) IVF cycles and 29 205 (46.6%) ICSI cycles. Participants/materials, setting, method All cycles recorded on the anonymised Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All fresh cycles with normal sperm parameters, performed after 1998 were included: frozen cycles, donor oocyte and sperm usage, intrauterine insemination cycles, preimplantation genetic testing (PGT) for aneuploidies (PGT-A), PGT for monogenic/single gene defects (PGT-M), PGT for chromosomal structural arrangements (PGT-SR) cycles, where the reason for stimulation was for storage and unstimulated cycles were excluded. Main results and the role of chance ICSI did not confer any benefit in improving the LB outcome when compared to conventional IVF per treatment cycle (PTC), when adjusted for female age, number of previous ART treatment cycles, number of previous live births through ART, oocyte yield, stage of transfer, method of fertilisation and number of embryos transferred in the POR cohort (adjusted odds ratio [a OR] 1.03, 99.5% confidence interval [CI] 0.96–1.11, P = 0.261) and all autologous ovarian response categories (aOR 1.00, 99.5% CI 0.98–1.02, P = 0.900). The mean fertilisation rate was statistically lower for IVF treatment cycles (64.7%) when compared to ICSI treatment cycles (67.2%) in the POR cohort (mean difference −2.5%, 99.5% CI −3.3 to −1.6, P Limitation, reason for caution The quality of data is reliant on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst-stage embryo transfers. The inability to link the treatment cycle to the individual patient meant that we were unable to calculate the cumulative LB outcome per patient. Wider implications of the findings This is the largest study to date which evaluates the impact of method of fertilisation in the POR patient and compares this to all autologous ovarian response categories. The results demonstrate that ICSI does not confer any benefit in improving reproductive outcomes in the absence of male factor subfertility, with no improvement seen in the clinical pregnancy or LB outcomes following a fresh treatment cycle. Study funding/competing interest(s) The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Bayer AG, Wellbeing of Women, the European Union and Finox. Trial registration number Not applicable.</p