BackgroundPublic funding for fertility services within the United Kingdom is limited, and therefore, strict guidance exists regarding who can be offered treatment under the National Health Service (NHS). Body mass index (BMI) is a universal criteria adopted by both the public and private sector.This study addresses an important aspect of the impact of a raised BMI on fertility treatment outcomes. We standardise the analysis of the data by only including studies incorporating the WHO BMI criteria; the current reference point for clinicians and clinical commissioning groups in ascertaining which group of patients should receive treatment. This study is an update of the previous systematic review performed in 2010, with the inclusion of a larger number of cycles from central databases such as the Society for Assisted Reproductive Technology (SART).MethodsAn electronic literature search was conducted through the Cochrane, Medline and Embase libraries. Data extraction for each outcome measure was pooled and expressed as an odds ratio with 95% confidence intervals. Where clinical heterogeneity was evident, the random effects model was used to calculate the risk ratio and a fixed effects model was used for the remaining studies. A p value < 0.05 was considered statistically significant.ResultsA total of 49 studies have been identified and included in this systematic review. Overweight and obese (BMI ≥ 25 kg/m2) women have a statistically significant lower live birth rate (OR 0.81, 95% CI 0.74–0.89, p < 0.00001) following Assisted Reproductive Technology (ART) when comparisons are drawn to women with a normal BMI. An increase is also demonstrated in the number of miscarriages experienced by women with a BMI ≥ 30 kg/m2 (OR 1.52, 95% CI 1.28–1.81, p < 0.00001).ConclusionAlthough this review concludes that a clear impact of BMI on ART outcomes is demonstrated, there remains questions as to the pathophysiology underlying these differences. This review supports the government’s stringent criteria regarding BMI categories under which NHS funding is made available for ART, through a clear description of poor reproductive outcomes in women with a BMI ≥ 30 kg/m2.

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 &lt; 0.001). The failed fertilisation rate was marginally higher in IVF treatment cycles (17.3%, 95% binomial exact 16.9 to 17.7%) when compared to ICSI treatment cycles (17.0%, 95% binomial exact 16.6 to 17.4%); however, this did not reach statistical significance (P = 0.199). The results followed a similar trend when analysed for all autologous ovarian response categories with a higher rate of failed fertilisation in IVF treatment cycles (4.8%, 95% binomial exact 4.7 to 4.9%) when compared to ICSI treatment cycles (3.2%, 95% binomial exact 3.1 to 3.3%) (P &lt; 0.001). LIMITATIONS, REASONS 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.

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 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.