Low versus atmospheric oxygen tension for embryo culture in assisted reproduction: a systematic review and meta-analysis  Carolina O. Nastri, Ph.D., Beatrice N. Nóbrega, M.D., Danielle M. Teixeira, M.D., Jowanka Amorim, M.Sc., Lívia M.M. Diniz, M.D., Marina W.P. Barbosa, M.D., Vanessa S.I. Giorgi, M.Sc., Vicky N. Pileggi, M.Sc., Wellington P. Martins, Ph.D.  Fertility and Sterility  Volume 106, Issue 1, Pages 95-104.e17 (July 2016) DOI: 10.1016/j.fertnstert.2016.02.037 Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Figure 1 Study flow chart for the three parts of the review: RCTs for the first and second part and observational studies for the third part of the review. Obs = observational studies; RCT = randomized controlled trial. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 1 Forest plot for live birth/ongoing pregnancy per randomized woman for the review of clinical outcomes. Comparison of “LowO2 versus AtmO2 during all embryo culture.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 2 Forest plot for clinical pregnancy per randomized woman for the review of clinical outcomes. Comparison of “LowO2 versus AtmO2 during all embryo culture.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 3 Forest plot for miscarriage per clinical pregnancy for the review of clinical outcomes. Comparison of “LowO2 versus AtmO2 during all embryo culture.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 4 Forest plot for live birth/ongoing pregnancy per randomized woman for the review of clinical outcomes. Comparison of “LowO2 versus AtmO2 after Day 2.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 5 Forest plot for clinical pregnancy per randomized woman for the review of clinical outcomes. Comparison of “LowO2 versus AtmO2 after Day 2.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 6 Forest plot for miscarriage per clinical pregnancy for the review of clinical outcomes. Comparison of “LowO2 versus AtmO2 after Day 2.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 7 Forest plot for fertilization per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 during all embryo culture.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 8 Forest plot for cleavage per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 during all embryo culture.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 9 Forest plot for top cleavage embryos per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 during all embryo culture.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 10 Forest plot for blastocyst per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 before Day 3 followed by low O2 in both groups.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 11 Forest plot for top blastocyst per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 before Day 3 followed by low O2 in both groups.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 12 Forest plot for cleavage embryos per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 only after Day 2.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 13 Forest plot for blastocyst per oocyte randomized for the review of laboratory outcomes. Comparison of “LowO2 versus AtmO2 only after Day 2.” A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 14 Funnel plot analysis of studies evaluating the effectiveness of LowO2 embryo culture on (A) live birth/ongoing pregnancy and (B) clinical pregnancy showing asymmetry. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 15 Cumulative meta-analyses of studies evaluating the effect of LowO2 embryo culture on (A) live birth/ongoing pregnancy and (B) clinical pregnancy showing a trend toward a decrease in the observed effect over time. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions

Supplemental Figure 16 Forest plot for live birth/ongoing pregnancy per randomized woman considering only the studies using the same incubator in both groups and comparing LowO2 and AtmO2 during all embryo culture. A/B = selection bias (sequence generation and allocation concealment); C = performance bias; D = detection bias; E = attrition bias; F = reporting bias; G = other bias. Fertility and Sterility 2016 106, 95-104.e17DOI: (10.1016/j.fertnstert.2016.02.037) Copyright © 2016 American Society for Reproductive Medicine Terms and Conditions