Outcomes After Assisted Reproductive Technology in Women With Cancer

A Systematic Review and Meta-analysis

Clare Meernik; Charles Poole; Stephanie M. Engel; J. Alejandro Rauh-Hain; Barbara Luke; Hazel B. Nichols

Hum Reprod. 2023;38(1):30-45.

Abstract and Introduction

Abstract

Study Question: What are the associations between a history of cancer and outcomes after ART?

Summary Answer: Compared to women without cancer, on average, women with cancer had a lower return for embryo transfer and a lower likelihood of clinical pregnancy and live birth after ART.

What is Known Already: Small, single-institution studies have suggested that cancer and its treatment may negatively affect ART outcomes.

Study Design, Size, Duration: We conducted a systematic review with meta-analysis of studies comparing ART outcomes between women with and without cancer. PubMed, Embase and Scopus were searched for original, English-language studies published up to June 2021.

Participants/Materials, Setting, Methods: Inclusion criteria required reporting of ART outcomes after controlled ovarian stimulation (COS) among women with a history of cancer compared to women without cancer who used ART for any indication. Outcomes of interest ranged from duration of COS to likelihood of live birth after embryo transfer. Random-effects meta-analysis was used to calculate mean differences and odds ratios (ORs) with 95% CIs and 95% prediction intervals (PIs). We assessed heterogeneity by age-adjustment, referent group indication for ART, study location and among women with breast cancer and women who initiated ART before cancer treatment. We used visual inspection, Egger's test and the trim-and-fill method to assess funnel plot asymmetry.

Main Results and the Role of Chance: Of 6094 unique records identified, 42 studies met inclusion criteria, representing a median per study of 58 women with cancer (interquartile range (IQR) = 159) and 114 women without cancer (IQR = 348). Compared to women without cancer, on average, women with cancer had a lower return for embryo transfer (OR: 0.22; 95% CI: 0.07, 0.74; 95% PI: 0.00, 64.98); lower likelihood of clinical pregnancy (OR: 0.51; 95% CI: 0.35, 0.73; 95% PI: 0.19, 1.35); and lower likelihood of live birth (OR: 0.56; 95% CI: 0.38, 0.83; 95% PI: 0.19, 1.69). Substantial among-study heterogeneity was observed for COS duration, gonadotropin dose, cycle cancellation, total oocytes and mature oocytes. Fertilization percentage showed less heterogeneity, but study-specific estimates were imprecise. Similarly, number of embryos showed less heterogeneity, and most studies estimated minimal differences by cancer history. Funnel plot asymmetry was observed for estradiol peak and oocyte maturation percentage.

Limitations, Reasons for Caution: Appreciable confounding is possible in 11 studies that lacked adequate control for group differences in age, and among-study heterogeneity was observed for most outcomes. Lack of data limited our ability to assess how cancer clinical factors (e.g. cancers other than breast, cancer stage and treatment) and ART cycle characteristics (e.g. fresh versus frozen embryo transfers and use of gestational carriers) may affect outcomes.

Wider Implications of the Findings: Women with cancer may be less likely to achieve pregnancy and live birth after embryo transfer. Further examination of reproductive outcomes and sources of heterogeneity among studies is warranted to improve evidence of the expected success of ART after a cancer diagnosis.

Study Funding/Competing Interest(S): This research was supported in part by R01 CA211093 and P30 ES010126. C.M. was supported by the University of North Carolina Lineberger Cancer Control Education Program (T32 CA057726) and the National Cancer Institute (F31 CA260787). J.A.R.-H. was supported by the National Cancer Institute (K08 CA234333, P30 CA016672). J.A.R.-H. reports receiving consulting fees from Schlesinger Group and Guidepoint. The remaining authors declare no competing interests.

Registration Number: N/A.

Introduction

Cancer treatment can increase the risk of infertility for many of the roughly 1.3 million reproductive-age women diagnosed with cancer each year (Lee et al., 2006; Levine et al., 2015; Poorvu et al., 2019; International Agency for Research on Cancer, 2020), which can lead to increased psychosocial distress, poorer mental health and lower quality of life (Lee et al., 2006; Deshpande et al., 2015; Anazodo et al., 2019; Logan et al., 2019). ART is clinically recommended for women with cancer who want to preserve their fertility before cancer treatment, or who are not able to naturally conceive after treatment (Ethics Committee of the American Society for Reproductive Medicine, 2018; Oktay et al., 2018; Practice Committee of the American Society for Reproductive Medicine, 2019; Lambertini et al., 2020). ART procedures include oocyte or embryo cryopreservation for fertility preservation, and embryo transfer to attempt pregnancy using fresh (non-cryopreserved) embryos or previously cryopreserved embryos that have been thawed (Centers for Disease Control and Prevention, American Society for Reproductive Medicine, Society for Assisted Reproductive Technology, 2017). However, evidence of reproductive success after ART in cancer populations has been limited (Dolmans et al., 2019; Lambertini et al., 2020). Women with cancer are often counseled using ART data from the general population, though it is unclear how prior exposure to cancer or its treatments may affect outcomes (Levine et al., 2015; Lambertini et al., 2016; Practice Committee of the American Society for Reproductive Medicine, 2019; Mulder et al., 2021).

Two meta-analyses comparing ART outcomes by cancer history have been previously published (Friedler et al., 2012; Turan et al., 2018). However, neither assessed study characteristics contributing to among-study heterogeneity, outcomes among women who initiated ART after cancer treatment, nor pregnancy or birth outcomes. Our systematic review and meta-analysis sought to fill these evidence gaps and contribute novel data to the comparison of ART outcomes between women with and without cancer.

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Abstract and Introduction
Methods
Results
Discussion
References

Table I. Characteristics of studies comparing ART outcomes among women with versus without a history of cancer.
First author (year)	Study period; country	Sample size		Cancer types^a	ART timing relative to cancer treatment	Referent indication for ART	Age at ART initiation mean (SD)		Comments regarding internal validity concerns
First author (year)	Study period; country	Cancer	Referent	Cancer types^a	ART timing relative to cancer treatment	Referent indication for ART	Cancer	Referent	Comments regarding internal validity concerns
Pal et al. (1998)	1995–1997; USA	5	12	gyn (3), other (2)	Prior	Tubal	31 (4.5)^b	31 (3.5)	None
Oktay et al. (2006)	2003–2005; USA	47	56	breast (47)	Prior	Tubal	36.4 (3.6)^b	36.9 (3.9)	None
Knopman et al. (2009)	2001–2006; USA	28	135	breast (10), gyn (9), heme (6), other (3)	Prior	Male	34 (5.1)^b	35.4 (3.5)	None
Klock et al. (2010)	2005–2008; USA	28	57	breast (11), gyn (1), heme (7), other (9)	Prior	Multiple	31.0 (5.3)^b	31.2 (4.6)	None
Michaan et al. (2010)	2002–2007; Israel	22	22	breast (12), heme (2), other (7)	Prior	Tubal	32.8 (5.7)^b	34 (4.2)	Groups additionally matched on period of treatment and COS protocol.
Michaan et al. (2010)	2002–2007; Israel	22	22	*n = 1 non-cancer	Prior	Tubal	32.8 (5.7)^b	34 (4.2)
Noyes et al. (2010)	2004–2009; USA	50	32	breast (12), gyn (22), heme (8), other (8)	Prior	Other	31 (7.1)	32 (5.7)	No age adjustment but groups were comparable.
Quintero et al. (2010)	1999–2007; USA	50	50	breast (28), heme (11), other (11)	Prior	Multiple	32.3 (5.0)^b	32.3 (5.0)	None
Werner et al. (2010)	2006–2010; USA	49	81	breast (10), gyn (21), heme (9), other (9)	Prior	Elective	30 (7.0)	36 (3.2)	Cancer group younger and no age adjustment.
Das et al. (2011)	2003–2010; Canada	39	48	gyn (7), heme (19), other (13)	Prior	Male	28.4 (5.5)^b	30.7 (2.1)	None
Robertson et al. (2011)	2001–2007; USA	26	921	breast (16), gyn (5), other (5)	Prior	Male	34.8 (5)	35 (4)	No age matching, but groups were comparable and total oocyte and embryo analysis adjusted for age, gonadotropin dose, peak estradiol, ICSI use and length of COS—no covariates were statistically significant, so only unadjusted summary statistics were presented.
Sabatini et al. (2011)	1997–2007; USA	28	393	breast (17), gyn (6), other (5)	Prior	Multiple	33.9 (3.4)	36.1 (3.9)	Cancer group younger, and no age adjustment reported except for birth analysis (report conducting age-adjusted analysis for pregnancy, but outcomes not reported). Birth analysis additionally adjusted for infertility diagnosis, prior IVF, and fertilization method.
Almog et al. (2012)	2000–2011; Israel	81	81	breast (42), heme (12), other (27)	Prior	Male	31.8 (4.8)^b	31.7 (4.7)	Groups additionally matched on date of COS.
Barton et al. (2012)	1998–2009; USA	53	7030	breast (17), gyn (8), heme (22), other (6)	After	Multiple	34.2 (19.3–43.9)^b,c	35.8 (19.3–43.9)^c	Additional adjustment for COS protocol and fertilization method, but did not change effect estimates by >10% so were not included in final models.
Das et al. (2012)	2003–2010; Canada	14	42	breast (1), gyn (3), heme (7), other (3)	After	Male	28.4 (4.5)^b	30.2 (2.6)	None
Domingo et al. (2012)	2007–2011; Spain	208	97	breast (143), heme (37), other (28)	Prior	Male	32.4 (4.9)^b	31.9 (5.3)	None
Garcia-Velasco et al. (2013)	2007–2012; Spain	340	560	breast, heme, other	Prior	Multiple	31.9 (5.1)	36.7 (4.2)	Cancer group younger and no age adjustment.
Fujimoto et al. (2014)	1999–2012; Japan	21	42	gyn (21)	After	Multiple	34 (30–39)^b,c	34 (29–41)^c	Groups additionally matched on date of ART.
Cardozo et al. (2015)	1997–2014; USA	63	122	breast (41), gyn (8), heme (5), other (9)	Prior	Tubal	33.7 (4.1)^b	34.5 (3.5)	Groups additionally matched on date of ART.
Goldrat et al. (2015)	2012–2014; Belgium	21	21	breast (21)	Prior	Multiple	31.7 (6.4)	32.3 (4.8)	No age adjustment but groups were comparable.
Lekovich et al. (2016)	2010–2013; USA	192	365	breast (99), gyn (15), heme (69), other (9)	Prior	Elective	31.8 (4.8)	36.5 (3.2)	Cancer group younger and no outcomes are reported after age adjustment (only P-values after age-adjustment reported).
Luke et al. (2016a)	2004–2009; USA	441	52985	breast (152), gyn (56), other (233)	Unknown	Multiple	34.9 (5.8)^b	35.3 (5.3)	Analysis of reproductive outcomes adjusted for age, parity, cumulative gonadotropin dose, infertility diagnosis and number of diagnoses, number of ART cycles, state of residency, and year of ART.
Luke et al. (2016b)	2004–2009; USA	270	68	breast (131), gyn (37), heme (64), other (37)	Unknown	Male	32.5 (5.5)	32.2 (4.2)	No age adjustment but groups were comparable.
Nurudeen et al. (2016)	2005–2012; USA	49	49	breast (35), gyn (1), heme (4), other (9)	Prior	Multiple	33.6 (4.8)^b	34.3 (4.6)	None
Pereira et al. (2016)	2005–2014; USA	220	439	breast (220)	Prior	Elective	35.7 (3.7)	36.7 (3.7)	No age adjustment but groups were comparable.
Quinn et al. (2017)	2009–2015; USA	191	398	breast (191)	Prior	Elective	34.9 (4.6)^b	36.4 (3.0)	COS length and peak estradiol adjusted for age and BMI; total oocytes, mature oocytes and maturation percentage analysis additionally adjusted for total gonadotropin dose and letrozole use.
Cobo et al. (2018)	2007–2018; Spain	1073	5289	breast (694), gyn (44), heme (191), other (144)	Prior	Elective	32.3 (3.5)	37.2 (4.9)	Cancer group younger and no age adjustment, though pregnancy and live birth outcomes were stratified by broad age categories; age-adjusted ORs were calculated, though residual confounding may be present.
Decanter et al. (2018)	2011–2014; France	90	180	breast (49), heme (25), other (16)	Prior	Male	29 (5)^b	29 (5)	Groups additionally matched on date of COS.
Dolinko et al. (2018)	2007–2014; USA	147	664	breast (79), gyn (8), heme (38), other (22)	Both	Male	31.7 (6.0)	34.6 (4.2)	No age matching but age-adjusted outcomes are reported.
Tsampras et al. (2018)	2009–2016; UK	157	2128	breast (80), gyn (8), other (69)	Prior	Male	30.3 (6.0)^b	32.0 (4.5)	None
Ben-Haroush et al. (2019)	2007–2017; Israel	313	105	breast (145), other (168)	Prior	Elective	29.8 (7.2)	36.0 (3.5)	Cancer group younger and no age adjustment.
de Moraes et al. (2019)	2010–2017; Brazil	23	164	breast (13), gyn, heme, other	Prior	Elective	31.0 (5.1)	35.7 (3.1)	Cancer group younger and no age adjustment.
Goldrat et al. (2019)	2012–2017; Belgium	23	24	breast (23)	Prior	Multiple	30.4 (3.8)	30.8 (3.9)	No age adjustment but groups were comparable.
Gunnala et al. (2019)	2010–2015; USA	176	600	breast (91), gyn (7), heme (42), other (36)	Prior	Elective	31.4 (5.5)	36.6 (3.0)	Cancer group younger and no age adjustment comparing cancer group vs. non-cancer group.
Rodriguez-Wallberg et al. (2019)	1998–2018; Sweden	382	180	breast, gyn, heme, other	Both	Multiple	30.9 (5.5)	27.1 (7.2)	Cancer group older; only outcome adjusted for age was return for embryo transfer.
Bercaire et al. (2020)	2015–2016; Brazil	69	92	breast (69)	Prior	Male	31.5 (4.1)^b	33.1 (7.1)	None
Kawwass et al. (2020)	2012–2016; USA	2715	26916	breast, heme, other	Unknown	Multiple	<35: 63%^b	<35: 25%	Cancer group younger; age-adjusted outcomes are reported though residual confounding may result from broad age categorization.
Nordan et al. (2020)	2007–2018; USA	10	30	other (10)	Prior	Male	30.4 (4.5)^b	30.5 (3.9)	Groups additionally matched on COS protocol.
Porcu et al. (2020)	2014–2019; Italy	46	181	breast (46)	Prior	Male	32.4 (4.1)	32.4 (2.8)	No age adjustment but groups were comparable.
Huang et al. (2021)	2010–2018; China	64	320	other (64)	After	Other	33.8 (4.3)^b	33.6 (3.9)	Groups additionally matched on BMI, infertility diagnosis, date of ART, COS protocol and type of embryo transfer. Reproductive outcomes further adjusted for free T4, TSH and fertilization method. Pregnancy outcomes were self-reported.
Hussein et al. (2021)	2009–2018; USA	96	75	breast (30), gyn (20), heme (24), other (22)	Prior	Elective	28.1 (7.0)	34.9 (5.5)	Cancer group younger and no age adjustment.
Tamauchi et al. (2021)	2009–2020; Japan	14	30	gyn (14)	After	Multiple	34.8 (29.0–40.4)^c	36.5 (22.9–42.8)^c	No age adjustment but groups were comparable.
Fabiani et al. (2022)	2016–2019; Italy	82	180	breast (52), gyn (9), heme (15), other (6)	Prior	Multiple	32.2 (4.3)^b	33.2 (5.1)	Groups additionally matched on date of ART.

^aCancer types without a sample size indicates that this data were not reported in the study.
^bCancer and non-cancer referent groups were age-matched or the study reported age-adjusted outcomes.
^cMedian (range) reported.
COS, controlled ovarian stimulation; gyn, gynecologic cancer; heme, hematologic malignancy; TSH, thyroid-stimulating hormone.

Table II. Summary of ART outcomes comparing women with versus without a history of cancer. ^a
Outcome	# of studies	Sample size^b median (IQR)		Cochran's Q (P-value)	Random-effects variance (τ²)	MD (95% CI)^c	(95% prediction interval)
Outcome	# of studies	Cancer	Non-cancer	Cochran's Q (P-value)	Random-effects variance (τ²)	MD (95% CI)^c	(95% prediction interval)
Stimulation duration (days)	25	81 (158)	105 (375)	130.3 (<0.0001)	0.33	0.05 (−0.21, 0.31)	(−1.16, 1.26)
Total gonadotropin dose (IU)	29	50 (121)	97 (133)	369.7 (<0.0001)	378856.04	228.20 (−11.36, 467.77)	(−1059.38, 1515.79)
Peak estradiol (pg/ml)	17	40 (55)	97 (132)	n/a	n/a	n/a	n/a
Total oocytes	36	50 (135)	105 (291)	190.6 (<0.0001)	4.44	0.47 (−0.34, 1.29)	(−3.89, 4.84)
Mature oocytes	22	86 (141)	172 (288)	163.1 (<0.0001)	3.61	0.27 (−0.64, 1.18)	(−3.81, 4.35)
Maturation percentage	14	93 (1612)	89 (130)	n/a	n/a	n/a	n/a
Fertilization percentage	9	39 (37)	55 (74)	13.3 (0.10)	13.30	−1.81 (−5.73, 2.11)	(−11.65, 8.02)
Total embryos	10	46 (38)	151 (319)	11.3 (0.25)	0.09	−0.30 (−0.68, 0.08)	(−1.11, 0.51)
Outcome	# of studies	Sample size^a median (IQR)		Cochran's Q (P-value)	Random-effects variance (τ²)	OR (95% CI)^c	(95% prediction interval)
Outcome	# of studies	Cancer	Non-cancer	Cochran's Q (P-value)	Random-effects variance (τ²)	OR (95% CI)^c	(95% prediction interval)
Cycle cancellation	11	76 (181)	664 (3924)	77.9 (<0.0001)	0.83	1.85 (0.93, 3.67)	(0.20, 16.93)
Return for embryo transfer	4	466 (390)	423 (1512)	55.2 (<0.0001)	1.37	0.22 (0.07, 0.74)	(0.00, 64.98)
Clinical pregnancy	9	53 (54)	53 (645)	20.4 (0.009)	0.14	0.51 (0.35, 0.73)	(0.19, 1.35)
Live birth	10	42 (48)	50 (401)	23.7 (0.005)	0.19	0.56 (0.38, 0.83)	(0.19, 1.69)

^aSummary aggregation is not reported for outcomes demonstrating funnel plot asymmetry.
^bIn most studies, sample size represents the number of women, but in studies that reported outcomes at the cycle level, sample size represents the number of cycles.
^cReferent is women without a history of cancer.
IQR, interquartile range; OR, odds ratio.