Table I.

Main characteristics of the studies included in the present meta-analysis.

Reference	Country	Years	Study design	Patients exposed to COS or ART, n	Patients not exposed to COS or ART, n	Timing of ovarian stimulation n, (%)	FP strategy and concomitant medications	Mean/median follow-up time in FP vs no FP cohort	Matching criteria for choosing controls/ controlling factors	Baseline differences between study populations and controls	Outcomes	Risk of bias*
Azim et al. (2008) 1	USA	2002–2007	Prospective nonrandomized controlled study	79	136	Before adjuvant chemotherapy	COS + AI (100%)	FP: 23.4 months (7.5–63.6) No FP: 33.05 months (4.5–63.6)	N.R.	No statistically significant differences between populations	Delay to treatments, recurrence rate, RFS	Moderate
Kim et al. (2016) 1	USA	2002–2014	Prospective nonrandomized controlled study	120	217	14 (11.7) Before surgery 106 (88.3) After surgery	COS + AI (100%)	FP: 5 years (±2.1) No FP: 6.9 years (±3.6)	N.R.	FP patients had lower node involvement (p=.02) than controls	Recurrence rate, RFS	Moderate
Chien et al. (2017) 2	USA	2010 –2017	Retrospective study	34	48	Before neoadjuvant chemotherapy	N.R.	FP: 79 months No FP: 79 months	N.R.	No statistically significant differences between populations	Delay to treatments, recurrence rate, RFS	Moderate
Rodriguez‐Wallberg et al. (2018)	Sweden	1999–2013	Retrospective cohort study	148	378	23 (15.5) Before neoadjuvant chemotherapy 123 (83.1) Before adjuvant chemotherapy 2 (1.3) N.R.	COS ± AI (46%)	FP: 5.8 years (0.3–17.9) No FP: 5.8 years (0.3–17.9)	Age at diagnosis; adjustments for confounders: tumor size, node involvement, estrogen receptor status and chemotherapy administered	No statistically significant differences between populations	Recurrence rate	Low
Muñoz et al. (2019)	Spain	2008–2016	Ambispective cohort study	148	111	20 (13.5) Before neoadjuvant chemotherapy 128 (86.5) Before adjuvant chemotherapy	COS + AI (100%)	FP: 5 years No FP: 5 years	Patients with same characteristics but who did not want to preserve their fertility	No statistically significant differences between populations	DFS	Moderate
Letourneau et al. (2020) 2	USA	2007–2017	Retrospective cohort study	207	122	85 (41.1) Before neoadjuvant chemotherapy 122 (58.9) Before adjuvant chemotherapy	COS + AI or TAM in hormone-receptor positive breast cancer	FP: 42 months (2–114) No FP: 46 months (10–132)	Demographic, reproductive health, cancer treatments and tumor characteristics considered as potential confounders and included in the multivariable survival analysis in case of P < 0.2	No statistically significant differences between populations	Recurrence rate, DFS	High
Vriens et al. (2020)	The Netherlands	2008–2015	Prospective cohort study	34	84	Before adjuvant chemotherapy	COS + AI (100%)	FP: 52 moths (48–58) No FP: 51 months (42–63)	N.R.	FP patients had lower tumor size at diagnosis (P = 0.04)	Recurrence rate, DFS	Moderate
Marklund et al. (2021)	Sweden	1994–2017	Retrospective cohort study	425	850	105 (24.7) Before neoadjuvant chemotherapy 320 (75.3) Before adjuvant chemotherapy	N.R.	FP: 5.8 years (±4.2) No FP: 5.2 years (±4)	Age at diagnosis (5-year periods), time of diagnosis (3-year periods) and health care region	FP patients were younger (P < 0.001), estrogen receptor positive (P = 0.034), and received more chemotherapy (P = 0.002)	MR	Moderate
Moravek et al. (2021)	USA	2005–2018	Retrospective cohort study	150	165	39 (26.0) Before neoadjuvant chemotherapy 111 (74.0) Before adjuvant chemotherapy	COS without any AI or TAM	FP: 4 years (0.48–12.40) No FP: 6.19 years (0.72–11.12)	N.R.	No statistically significant differences between populations	Delay to treatments, recurrence rate, MR	High
Fredriksson et al. (2021)	Sweden	2005–2014	Retrospective cohort study	126	126	Before adjuvant chemotherapy	COS ± AI	FP: N.R. No FP: N.R.	Age at breast cancer diagnosis ±5 years, tumor size and node involvement	No statistically significant differences between populations	Recurrence rate, RFS	Moderate
Greer et al. (2021)	USA	2007–2017	Retrospective cohort study	123	149	37 (30.1) before neoadjuvant 86 (69.9) before adjuvant chemotherapy	COS ± AI (60.2%) or TAM (3.3%)	FP: 50 months (32–71) No FP: 49 months (31–75)	N.R.	More FP patients were BRCA mutation carriers (P = 0.021)	Delay to treatments, DFS, OS	Moderate
Goldrat et al. (2015)	Belgium, Italy, Spain and Denmark	2000–2009	Retrospective cohort study	25	173	After adjuvant chemotherapy	ART	FP: 102 months (81–131) No FP: 107 months (85–123)	N.R.	Patients not exposed to ART were younger (P = 0.009) and higher grade 3 tumors (P = 0.033)	Recurrence rate	Moderate
Rosenberg et al. (2019)	Sweden	1982–2014	Retrospective cohort study	37	148	After adjuvant chemotherapy	ART	FP: 10.3 years (±4.2) No FP: 10.7 years (±4.4)	Breast cancer stage and year of diagnosis (±5 years)	No statistically significant differences between populations	Recurrence rate	Low
Condorelli et al. (2021b)	Belgium	2006–2016	Retrospective cohort study	39	73	After adjuvant chemotherapy	ART	FP: 9.4 years (4.5–22.2) No FP: 12.1 years (6.8–19.8)	BRCA status, breast cancer stage, anticancer treatments and age	ART patients were younger than controls (P < 0.001)	Recurrence rate, RFS	Low
Condorelli et al. (2021a)	Europe, USA and Israel	2000–2012	Retrospective cohort study	22	146	After adjuvant chemotherapy	ART	FP: 7.5 years (3.0–16.0) No FP: 8.8 years (2.5–18.4)	N.R.	ART patients were older (P = 0.004), had lower grade (P = 0.008) and higher hormone-receptor positive (P = 0.016) tumors	DFS, OS	High

AI, aromatase inhibitors; COS, controlled ovarian stimulation; DFS, disease-free survival; FP, fertility preservation; MR, mortality rate; N.R., not reported; OS, overall survival; RFS, relapse-free survival; TAM, tamoxifen.

^*Quality assessment and risk of bias performed using the Newcastle-Ottawa Assessment Scale.

¹Partially overlapping population.

²Partially overlapping population.