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Impact of the levonorgestrel-releasing intrauterine device on controlled ovarian stimulation outcomes
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
Impact of the levonorgestrel-releasing intrauterine device on controlled ovarian stimulation outcomes Amanda J. Adeleye, M.D., Lusine Aghajanova, M.D., Ph.D., Chia-Ning Kao, M.S., Marcelle I. Cedars, M.D., and Mark V. Sauer, M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California
Objective: To report differences in ovarian stimulation outcomes in women using a levonorgestrel-releasing intrauterine device (LNGIUD). Design: Retrospective cohort study. Setting: University-based infertility practice. Patient(s): Female patients pursuing either social oocyte cryopreservation or oocyte donation. Intervention(s): Chart review of all female patients presenting from January 1, 2012, to June 30, 2017, for social oocyte cryopreservation or oocyte donation. Demographic data, cycle performance data, and the presence or absence of an LNG-IUD at the time of ovarian stimulation were compared. Main Outcome Measure(s): Total oocyte yield and total mature oocyte yield. Secondary measures included clinical pregnancy rate and live birth rate in recipients of donor oocytes. Result(s): Univariate analysis of predicted oocyte yield and mature oocyte yield showed no significant difference between subjects with and without an LNG. When controlling for history of recent hormonal contraceptive use, initial antral follicle count (AFC), age, body mass index (BMI), gonadotropin dose, and stimulation day/protocol, no significant differences were seen in total oocyte yield or mature oocyte yield in the presence or absence of an LNG-IUD. Univariate analysis of the effect of LNG-IUDs on the predicted clinical pregnancy rate and live birth rate did not significantly differ for oocyte recipients. Controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation day/protocol also showed no significant differences in the predicted clinical pregnancy rate and live birth rate. Conclusion(s): LNG-IUDs do not affect cycle performance in women undergoing ovarian stimulation cycles. (Fertil SterilÒ 2018;-: -–-. Ó2018 by American Society for Reproductive Medicine.) Key Words: Levonorgestrel, intrauterine device, oocyte stimulation, oocyte donation Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/31366-25439
L
evonorgestrel (LNG)–releasing intrauterine devices (IUDs) are an effective form of longacting reversible contraception (1). Because the popularity of intrauterine devices has increased in recent years, a growing proportion of women presenting for either social oocyte cryopreservation or oocyte donation may have an LNG-IUD in
place during controlled ovarian stimulation (2). These devices contain up to 52 mg LNG and function by releasing 20 mg local LNG to the endometrial cavity daily. In a retrospective study of 110 women, serum LNG levels were collected in women who had an LNGIUD placed from 20 days to 11 years before sampling. At 1 year after LNG-
Received December 12, 2017; revised March 14, 2018; accepted March 19, 2018. A.J.A. reports participation as a medical advisor for Carrot outside of the submitted work. L.A. has nothing to disclose. C.-N.K. has nothing to disclose. M.I.C. reports grants from Ferring Pharmaceuticals outside of the submitted work. M.V.S. has nothing to disclose. Reprint requests: Amanda J. Adeleye, M.D., 550 16th St, 7th floor, San Francisco, California 94107 (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2018 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.03.022 VOL. - NO. - / - 2018
IUD placement, the mean serum level of LNG was 191 71 pg/m,L whereas after 3 years of use, the mean LNG level was 134 41 pg/mL and decreased progressively over the subsequent years of sampling. The authors demonstrated a strong negative correlation between time of LNG-IUD placement and serum LNG levels (3). There has been some concern that either the local effects of LNG-IUDs may extend to the ovaries and have a direct impact on follicular maturation or that systemic levels may be high enough to affect ovarian stimulation (4). However, the general belief is that the mechanism of action of the LNG IUD is confined to the endometrium and cervical mucous. 1
ORIGINAL ARTICLE: ASSISTED REPRODUCTION Limited data exist about the fertility potential of oocytes collected in the presence of an LNG-IUD. In 1997, S€ oderstr€ om-Anttila et al. reviewed seven ovarian stimulation cycles in the presences of an LNG-IUD matched with 16 cycles without the device and found no difference in stimulation. Recent matched retrospective cohort studies have reported similar findings wherein there appears to be no impact of the LNG-IUD on ovarian stimulation outcomes (5, 6). The first case report of two successful pregnancies with the use of oocytes donated from a woman who had an LNG-IUD during stimulation was described in 2004 (7). Women pursing social oocyte cryopreservation typically do not intend to conceive in the near future. Furthermore, oocyte donors tend to be young women at the height of their reproductive potential. Both groups of women undergo similar treatment regimens of ovarian stimulation and during this time are known to be at risk for unintended pregnancy if they do not abstain from intercourse or use a barrier contraceptive method. It is important to understand if effective contraception, such as the LNG-IUD, commonly used by such individuals, impairs controlled ovarian stimulation and cycle performance. These data should assist providers in counseling patients regarding whether or not to remove their LNG-IUD before treatment. In the present study, we evaluated any potential impact that an LNG-IUD may have on controlled ovarian stimulation and/or pregnancy outcomes from donated oocytes.
UCSF Committee on Human Research, approved this study (IRB 17-22176).
Assessment of Antral Follicle Count We assessed antral follicle count (AFC) by measuring follicles 2–10 mm in mean diameter with the use of a GE Voluson S6 transvaginal ultrasound. An initial AFC was determined to be either the AFC assessed at initial consultation or, for patients who pursued multiple cycles, the last documented AFC unrelated to controlled ovarian stimulation collected within the year before the planned cycle. If an adequate initial AFC was not described, we used a baseline AFC obtained at the start of the controlled ovarian stimulation cycle.
Protocols The majority of patients, 79.5%, were stimulated with the use of a GnRH antagonist protocol. Antagonists included cetrorelix or ganirelex acetate and were started between cycle days 6 and 8 when the lead follicle was R12 mm. A minority of patients were treated with a leuprolide acetate (Lupron)–based protocol. In such cases, subjects were treated with 10 U Lupron daily beginning in the midluteal phase and then decreased to 5 U or discontinued at the commencement of gonadotropins. Criteria for hCG trigger included two follicles R17–18 mm with consideration of the cycle day and E2 level. A small number of patients (8.06%) underwent clomiphene citrate or letrozole flare protocols (Table 1).
MATERIALS AND METHODS
Outcome Measures
Study Population
Primary outcome measures included the total oocyte yield and mature oocyte yield. Because conventional IVF was used in a large proportion of donated oocytes, the number of mature oocytes could be determined only in subjects who completed ovarian stimulation for the purposes of oocyte cryopreservation or intracytoplasmic sperm injection with the use of donated oocytes. Secondary outcome measures included predicted fertilization rate, blastocyst progression rate, blastocyst transfer rate, clinical pregnancy rate, and live birth rate from donated oocytes collected in the presence or absence of an LNG-IUD. In a given cycle, pregnancies may have occurred after either a fresh or frozen-thawed embryo transfer.
All patients who sought oocyte cryopreservation or who donated oocytes at the Center for Reproductive Health at the University of California San Francisco (UCSF) from January 1, 2012, to June 30, 2017, were eligible for this retrospective cohort study. Potential subjects who pursued fertility preservation for a diagnosis of malignancy or who had previously demonstrated infertility as documented in the patient chart were excluded. All eligible cycles were included for evaluation. Eligibility determination and data collection were performed by means of electronic chart review. Patient protocols included both agonist and antagonist protocols, which were categorized and accounted for in analysis. The
TABLE 1 Characteristics of patients undergoing ovarian stimulation in the presence or absence of a levonorgestrel-releasing intrauterine device (LNGIUD). Subject characteristic Age, y BMI, kg/m2 Initial AFC No. of stimulation days Total FSH dose Peak E2 Peak E2 per oocyte collected
LNG-IUD absent (n [ 1,028)
LNG-IUD present (n [ 45)
P value
32.77 5.92 23.04 3.58 18.39 9.70 9.82 1.52 1,863.31 761.96 3,289.0 1,589.14 194.41 108.40
33.14 4.54 22.79 2.69 19.15 8.76 10.30 3.66 2,091.86 773.03 2,600.69 1,266.18 150.42 51.50
.60 .60 .60 .39 < .05 < .01 < .01
Note: Values are reported as mean standard deviation. AFC ¼ antral follicle count; BMI ¼ body mass index; FSH ¼ follicle stimulating hormone. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
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Fertility and Sterility® Statistical Analysis Demographic parameters between the subjects with and without an LNG-IUD were tested with the use of a Student t test or chi-square/Fisher test, as appropriate. The impact of an LNG-IUD on total oocytes and mature oocytes collected as well as fertilization rates from donor oocytes were tested with the use of a mixed analysis of covariance (ANCOVA) model. A logistic regression model was used to test the effect of the LNG-IUD on blastocyst transfer rates and pregnancy outcomes. A cycle was deemed to be successful if any oocyte from a cycle, after either fresh or frozen-thawed embryo transfer, resulted in a clinical pregnancy or live birth. All models included within-subject effects to account for the subset of subjects who completed multiple cycles. Models controlled for potential confounding effects, including a history of combined contraceptive use at the time of initial AFC, age, body mass index (BMI), initial AFC, length of cycle, stimulation regimen, and total gonadotropin dose. All testing was performed at the 0.05 level of significance. Statistical analysis was performed with the use of SAS v9.4.
RESULTS Patient Characteristics A total of 1,074 women who underwent 1,487 cycles of controlled ovarian stimulation were included in this study. Forty-five subjects had an LNG-IUD, representing 4.2% of the study population. Subjects with an LNG-IUD contributed 68 cycles, representing 4.6% of all cycles analyzed. There was no difference in age, BMI, stimulation protocol, or number of stimulation days between cycles conducted in the presence and those in the absence of an LNG-IUD. Subjects with an LNG-IUD exhibited lower peak E2 levels (P< .01), lower peak E2 level per follicle (P< .01), and higher total FSH dose per cycle (P< .05) (Table 1). The majority of cycles, 79.7%, used an antagonist protocol (Table 2).
Levonorgestrel Intrauterine Devices Do Not Impact Oocyte Yield In a simple ANCOVA model, there were no differences in predicted oocyte yield or mature oocyte yield between subjects with and without an LNG-IUD (P¼ .55 and P¼ .57, respec-
TABLE 2 Characteristics of cycles in the presence or absence of a levonorgestrel-releasing intrauterine device (LNG-IUD). Cycle characteristic LNG-IUD absent LNG- IUD present P value Treatment group Lupron 17.6 (250) 22.1 (15) Antagonist 79.7 (1130) 77.9 (53) Mini IVF 2.7 (39) 0 (0) Combined hormonal contraception at initial AFC No 70.2 (987) 100 (68) Yes 29.8 (419) 0 (0) Donor cycles 39.6 (563) 44.1 (30)
.30
< .01 .38
Note: Values are reported as % (n). AFC ¼ antral follicle count; IVF ¼ in vitro fertilization. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
VOL. - NO. - / - 2018
tively). When controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation days and protocol, the predicted mean number of oocytes collected in subjects with an LNG-IUD was 15.74 (95% confidence interval [CI) 12.81–18.66] compared with 16.99 (15.89–18.08) in subjects without an LNG-IUD. There were no differences in total oocyte yield (P¼ .41) or mature oocyte yield (P¼ .49) in the presence or absence of an LNGIUD. When comparing antagonist protocols with either agonist or ministimulation protocols, antagonist-based protocols were associated with a higher total oocyte yield (Table 3).
Levonorgestrel Intrauterine Devices Do Not Affect Laboratory or Pregnancy Outcomes A total of 608 donor cycles resulted in 583 fresh or frozenthawed embryo transfers. Because some intended parents also planned to use a gestational carrier who had yet to complete evaluation at the time of oocyte donation, there were fewer transfers than donor cycles. For all cycles in which oocytes were appropriately inseminated, there was at least one embryo that was appropriate for transfer. A univariate model showed no difference in the predicted fertilization rates between oocytes collected in the presence or absence of an LNG-IUD (P¼ .64). In an adjusted model, patients with an LNG-IUD were predicted to have a fertilization rate of 74.5% (95% CI 69.1%–90.0%). Patients without an LNGIUD had a predicted fertilization rate of 74.6% (71.5%– 77.7%; P¼ .98). For oocyte donation cycles, at least four good-quality day 3 embryos were required to allow embryos to develop to the blastocyst stage in extended culture. To assess blastocyst progression rate, only cycles in which all embryos were intended to be maintained in extended culture were included for analysis. In an unadjusted model, there was no difference in the blastocyst progression rate (P¼ .67) between the two groups. After adjusting for confounders, there remained no difference between the two groups (P¼ .52). The predicted blastocyst progression rate was 53.2% (95% CI 42.0%–64.5%) for embryos conceived from oocytes collected in the presence of an LNG-IUD and 49.4% (46.9%–51.9%) in cycles without an LNG-IUD. The vast majority of oocyte donation cycles resulted in embryos that progressed to the blastocyst stage, and all extended culture cycles resulted in at least one blastocyst that was appropriate for transfer (Table 4). When an LNGIUD was present, the predicted blastocyst transfer rate was 80.2% compared with 75.7% when the LNG-IUD was absent. There was no difference in the blastocyst transfer rate between the two groups after an unadjusted logistic regression (P¼ .43) or when adjusting for confounders (P¼ .74). A univariate logistic regression showed no statistically significant impact of LNG-IUD use on clinical pregnancy (P¼ .62) or live birth rate (P¼ .77) for donor oocyte recipients. When controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation day/protocol, the predicted clinical pregnancy rate from oocytes collected in the presence of an LNG-IUD was 90.5% (95% CI 66.9%–97.8%) and in the absence of an 3
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
TABLE 3 Comparison of oocyte yield in the presence and absence of a levonorgestrel-releasing intrauterine device (LNG-IUD). Oocyte outcome No. of subjects Total oocytes retrieved No. of subjects with oocytes cryopreserveda Mature oocytes retrieved
LNG-IUD absent
LNG-IUD present
1,028 16.99 (15.89–18.08) 641 9.84 (8.84–10.83)
45 15.74 (12.81–18.66) 32 10.89 (7.96–13.83)
P value .41 .49
Note: Values are reported as predicted mean (95% confidence interval), unless specified otherwise. Models are controlled for history of recent hormonal contraceptive use, initial antral follicle count, age, body mass index, gonadotropin dose, and stimulation days/protocol. a Maturity of donor cycle oocytes was not assessed, because most were conventionally inseminated. Donor oocyte cycles are not included in this analysis. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
LNG-IUD was 84.5% (80.2%–87.9%). The predicted live birth rates from oocytes collected in the presence or absence of an LNG-IUD were 78.1% (47.7%–93.3%) and 75.2% (70.3%– 79.5%), respectively (Table 4). There were no significant differences in clinical pregnancy (P¼ .48) or live birth (P¼ .82) rates between the two groups.
DISCUSSION Among women using contraception in the United States from 2010 to 2013, 10.7% used an intrauterine device according to recent CDC estimates (2). Furthermore, as the popularity of social oocyte cryopreservation and oocyte donation continue to increase, it is likely that many clinicians will face the question of how to manage such patients with an LNG-IUD present. The present study sought to describe any impact of an LNGIUD on ovarian stimulation. Furthermore, we aimed to describe clinical pregnancy and live birth rates with oocyte donation. There was no difference in oocyte yield or mature oocyte yield when oocytes were collected in the presence or absence of an LNG-IUD. These findings are consistent with previous studies comparing conventional ovarian stimulation with cycles with a luteal phase or random start. Despite higher P levels in the luteal phase start, there was no difference in the oocyte yield between these protocols (8). Among recipients of donor oocytes, there was no difference in predicted fertilization, blastocyst progression, or blastocyst transfer rates between oocytes collected in the presence or absence of an LNG-IUD. Furthermore, clinical
pregnancy and live birth rates were not affected by the presence of an LNG-IUD. Previous results in a smaller retrospective cohort study similarly showed no impact of LNGIUDs on stimulation outcomes (9). These findings are in keeping with the presumed mechanism of action of LNGIUDs, which prevent pregnancy by a direct effect on cervical mucus and the endometrium. Although our study focused on healthy women, these results may be valuable to women seeking fertility preservation after a recent diagnosis of cancer. This group of women would have similar patterns of contraceptive use at diagnosis, and maintaining an LNG-IUD during ovarian stimulation for fertility preservation would aid in preventing unintended pregnancy in this population. Two intriguing findings revealed in data analyses were unrelated to the intended outcome measures. First, the peak E2 level and peak E2 level per follicle were lower in subjects with an LNG-IUD. Although the numbers of mature oocytes were not significantly different between the groups, it is possible that unobserved biologic factors related to endogenous E2 production may contribute to this disparate finding. For example, previous studies have demonstrated higher E2 levels per follicle in subjects of Asian descent (10). Alternatively, some studies have shown that stimulation cycles using pretreatment with the use of oral contraceptives may experience greater pituitary suppression or require more days of stimulation and higher gonadotropin doses (10, 11). Because many women with LNG-IUDs have irregular menses, oral contraceptives are often used to time stimulation cycles.
TABLE 4 Comparison of predicted laboratory and pregnancy outcomes in the presence and absence of a levonorgestrel-releasing intrauterine device (LNGIUD). Cycle outcome
LNG-IUD absent
LNG-IUD present
No. of cycles with fertilization Fertilization rate No. of donor cycles with a transfer Blastocyst progression ratea Blastocyst transfer rate Clinical pregnancy rate Live birth rate
639 74.6 (71.5–77.7) 555 49.4 (46.9–51.9) 75.7 (70.4–80.3) 84.5 (80.2–87.9) 75.2 (70.3–79.5)
31 74.5 (69.1–80.0) 28 53.2 (42.0–64.5) 80.2 (47.8–94.7) 90.5 (66.9–97.8) 78.1 (47.7–93.3)
P value .98 .52 .74 .48 .82
Note: Values are reported as predicted mean rate (95% confidence interval), unless specified otherwise. Models are controlled for history of recent hormonal contraceptive use, initial antral follicle count, age, body mass index, gonadotropin dose, and stimulation days/protocol. a The number of cycles included in the blastocyst progression rate analysis was limited to cycles with the intention for all embryos to be maintained in extended culture. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
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Fertility and Sterility® In women who are significantly suppressed with oral contraceptives, E2 levels may be lower during stimulation. Our data suggest that E2 levels may not be as predictive of maturity when an LNG-IUD is present, and further investigation is warranted. Second, there was a significantly higher number of oocytes retrieved in cycles with the use of an antagonist-based protocol. When subjects have a larger initial AFC, antagonist protocols are often used to allow for an agonist-based trigger when ovarian hyperstimulation syndrome is a risk. This treatment preference for antagonist-based protocols in this cohort of subjects with higher AFCs may account for the differences in oocyte yield between the two types of protocols.
CONCLUSION
Strengths
REFERENCES
This study represents a robust assessment of the impact of LNG-IUDs on ovarian stimulation and related outcomes. The diversity of protocols and age groups represented increases the generalizability of this study. This information will aid fertility clinics in providing appropriate counseling during an initial encounter, increasing patient experience and satisfaction with care. Patients can be counseled that the presence of an LNG-IUD during controlled ovarian stimulation should have no clinically relevant effect on the important outcomes of oocytes cryopreserved or clinical pregnancy potential.
The presence of an LNG-IUD during ovarian stimulation has no impact on total oocyte yield or mature oocyte yield in a healthy population without evidence of infertility. Furthermore, the LNG-IUD may not have an impact on pregnancy or live birth rates in recipients of oocytes collected in the presence of an LNG-IUD. Knowledge about the impact of LNG-IUDs on ovarian stimulation cycles may improve the experience and overall quality of life for women who desire to delay childbearing or donate oocytes and who desire also an excellent form of long-acting contraception. Finally, this approach may also have a measurable impact on health care costs associated with interruption in use and replacement of a long-active contraceptive device.
1.
2.
3.
4.
5.
Limitations Although this was the largest study to date to review the impact of LNG-IUDs on oocyte stimulation cycles, the number of cycles in which an LNG-IUD was present was still small. A power calculation showed that 45 cycles would be sufficient to demonstrate a significant difference of two oocytes between the groups with a power of 85%. However, this study was not powered to address the secondary outcomes of clinical or live birth rates. Serum levels of LNG may be higher in the first several months after LNG-IUD placement. As Seeber et al. demonstrated, there is a negative correlation between length of time since LNG-IUD placement and serum LNG levels (3). The length of time that an LNG-IUD was in place was variably reported in our medical records and could not be reliably assessed. In the future, a study that is able to review the impact of the time that an LNG-IUD was present, before stimulation, may be informative.
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6. 7.
8.
9.
10.
11.
American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 121: long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol 2011;118:184–96. Branum A, Jones J. Trends in long-acting reversible contraception use among U.S. women aged 15–44, NCHS data brief, no. 188. National Center for Health Statistics; 2015. Seeber B, Ziehr SC, Gschließer A, Moser C, Mattle V, Seger C, et al. Quantitative levonorgestrel plasma level measurements in patients with regular and prolonged use of the levonorgestrel-releasing intrauterine system. Contraception 2012;86:345–9. Barbosa I, Olsson SE, Odlind V, Goncalves T, Coutinho E. Ovarian function after seven years’ use of a levonorgestrel IUD. Adv Contracept 1995;11: 85–95. Friedenthal J, Maxwell S, Willson S, McCulloh D, Grifo J, Goldman K. The progestin-containing intrauterine device (IUD) during ovarian stimulation and oocyte retrieval: should it stay or should it go? Fertil Steril 2017; 108(Suppl 3):e12. McQueen D, Uhler M, Feinberg E. Impact of the levonorgestrel intrauterine device (LNG-IUD) on oocyte donation. Fertil Steril 2017;108:e233. Kailasam C, Akande V, Gordon UD. Levonorgestrel hormone releasing intrauterine system (Mirena) as a contraceptive in egg donors: case report. J Assist Reprod Genet 2005;22:137–40. Cakmak H, Katz A, Cedars MI, Rosen MP. Effective method for emergency fertility preservation: random-start controlled ovarian stimulation. Fertil Steril 2013;100:1673–80. €derstro €m-Anttila V, Tiitinen A, Hovatta O. Levonorgestrel-releasing intraSo uterine device can be used in oocyte donors during ovarian stimulation. Hum Reprod 1997;12:491–5. Huddleston HG, Rosen MP, Lamb JD, Modan A, Cedars MI, Fujimoto VY. Asian ethnicity in anonymous oocyte donors is associated with increased estradiol levels but comparable recipient pregnancy rates compared with Caucasians. Fertil Steril 2010;94:2059–63. Tran N, Aghajanova L, Kao C-N, Cedars MI, Rosen MP. Impact of pituitary supression on antral follicle count and oocyte recovery fter ovarian stimulation. Fertil Steril 2016;105:690–6.
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Impact of the levonorgestrel-releasing intrauterine device on controlled ovarian stimulation outcomes Amanda J. Adeleye, M.D., Lusine Aghajanova, M.D., Ph.D., Chia-Ning Kao, M.S., Marcelle I. Cedars, M.D., and Mark V. Sauer, M.D. Division of Reproductive Endocrinology and Infertility, Department of Obstetrics, Gynecology, and Reproductive Sciences, University of California, San Francisco, California
Objective: To report differences in ovarian stimulation outcomes in women using a levonorgestrel-releasing intrauterine device (LNGIUD). Design: Retrospective cohort study. Setting: University-based infertility practice. Patient(s): Female patients pursuing either social oocyte cryopreservation or oocyte donation. Intervention(s): Chart review of all female patients presenting from January 1, 2012, to June 30, 2017, for social oocyte cryopreservation or oocyte donation. Demographic data, cycle performance data, and the presence or absence of an LNG-IUD at the time of ovarian stimulation were compared. Main Outcome Measure(s): Total oocyte yield and total mature oocyte yield. Secondary measures included clinical pregnancy rate and live birth rate in recipients of donor oocytes. Result(s): Univariate analysis of predicted oocyte yield and mature oocyte yield showed no significant difference between subjects with and without an LNG. When controlling for history of recent hormonal contraceptive use, initial antral follicle count (AFC), age, body mass index (BMI), gonadotropin dose, and stimulation day/protocol, no significant differences were seen in total oocyte yield or mature oocyte yield in the presence or absence of an LNG-IUD. Univariate analysis of the effect of LNG-IUDs on the predicted clinical pregnancy rate and live birth rate did not significantly differ for oocyte recipients. Controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation day/protocol also showed no significant differences in the predicted clinical pregnancy rate and live birth rate. Conclusion(s): LNG-IUDs do not affect cycle performance in women undergoing ovarian stimulation cycles. (Fertil SterilÒ 2018;-: -–-. Ó2018 by American Society for Reproductive Medicine.) Key Words: Levonorgestrel, intrauterine device, oocyte stimulation, oocyte donation Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/31366-25439
L
evonorgestrel (LNG)–releasing intrauterine devices (IUDs) are an effective form of longacting reversible contraception (1). Because the popularity of intrauterine devices has increased in recent years, a growing proportion of women presenting for either social oocyte cryopreservation or oocyte donation may have an LNG-IUD in
place during controlled ovarian stimulation (2). These devices contain up to 52 mg LNG and function by releasing 20 mg local LNG to the endometrial cavity daily. In a retrospective study of 110 women, serum LNG levels were collected in women who had an LNGIUD placed from 20 days to 11 years before sampling. At 1 year after LNG-
Received December 12, 2017; revised March 14, 2018; accepted March 19, 2018. A.J.A. reports participation as a medical advisor for Carrot outside of the submitted work. L.A. has nothing to disclose. C.-N.K. has nothing to disclose. M.I.C. reports grants from Ferring Pharmaceuticals outside of the submitted work. M.V.S. has nothing to disclose. Reprint requests: Amanda J. Adeleye, M.D., 550 16th St, 7th floor, San Francisco, California 94107 (E-mail: [email protected]). Fertility and Sterility® Vol. -, No. -, - 2018 0015-0282/$36.00 Copyright ©2018 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2018.03.022 VOL. - NO. - / - 2018
IUD placement, the mean serum level of LNG was 191 71 pg/m,L whereas after 3 years of use, the mean LNG level was 134 41 pg/mL and decreased progressively over the subsequent years of sampling. The authors demonstrated a strong negative correlation between time of LNG-IUD placement and serum LNG levels (3). There has been some concern that either the local effects of LNG-IUDs may extend to the ovaries and have a direct impact on follicular maturation or that systemic levels may be high enough to affect ovarian stimulation (4). However, the general belief is that the mechanism of action of the LNG IUD is confined to the endometrium and cervical mucous. 1
ORIGINAL ARTICLE: ASSISTED REPRODUCTION Limited data exist about the fertility potential of oocytes collected in the presence of an LNG-IUD. In 1997, S€ oderstr€ om-Anttila et al. reviewed seven ovarian stimulation cycles in the presences of an LNG-IUD matched with 16 cycles without the device and found no difference in stimulation. Recent matched retrospective cohort studies have reported similar findings wherein there appears to be no impact of the LNG-IUD on ovarian stimulation outcomes (5, 6). The first case report of two successful pregnancies with the use of oocytes donated from a woman who had an LNG-IUD during stimulation was described in 2004 (7). Women pursing social oocyte cryopreservation typically do not intend to conceive in the near future. Furthermore, oocyte donors tend to be young women at the height of their reproductive potential. Both groups of women undergo similar treatment regimens of ovarian stimulation and during this time are known to be at risk for unintended pregnancy if they do not abstain from intercourse or use a barrier contraceptive method. It is important to understand if effective contraception, such as the LNG-IUD, commonly used by such individuals, impairs controlled ovarian stimulation and cycle performance. These data should assist providers in counseling patients regarding whether or not to remove their LNG-IUD before treatment. In the present study, we evaluated any potential impact that an LNG-IUD may have on controlled ovarian stimulation and/or pregnancy outcomes from donated oocytes.
UCSF Committee on Human Research, approved this study (IRB 17-22176).
Assessment of Antral Follicle Count We assessed antral follicle count (AFC) by measuring follicles 2–10 mm in mean diameter with the use of a GE Voluson S6 transvaginal ultrasound. An initial AFC was determined to be either the AFC assessed at initial consultation or, for patients who pursued multiple cycles, the last documented AFC unrelated to controlled ovarian stimulation collected within the year before the planned cycle. If an adequate initial AFC was not described, we used a baseline AFC obtained at the start of the controlled ovarian stimulation cycle.
Protocols The majority of patients, 79.5%, were stimulated with the use of a GnRH antagonist protocol. Antagonists included cetrorelix or ganirelex acetate and were started between cycle days 6 and 8 when the lead follicle was R12 mm. A minority of patients were treated with a leuprolide acetate (Lupron)–based protocol. In such cases, subjects were treated with 10 U Lupron daily beginning in the midluteal phase and then decreased to 5 U or discontinued at the commencement of gonadotropins. Criteria for hCG trigger included two follicles R17–18 mm with consideration of the cycle day and E2 level. A small number of patients (8.06%) underwent clomiphene citrate or letrozole flare protocols (Table 1).
MATERIALS AND METHODS
Outcome Measures
Study Population
Primary outcome measures included the total oocyte yield and mature oocyte yield. Because conventional IVF was used in a large proportion of donated oocytes, the number of mature oocytes could be determined only in subjects who completed ovarian stimulation for the purposes of oocyte cryopreservation or intracytoplasmic sperm injection with the use of donated oocytes. Secondary outcome measures included predicted fertilization rate, blastocyst progression rate, blastocyst transfer rate, clinical pregnancy rate, and live birth rate from donated oocytes collected in the presence or absence of an LNG-IUD. In a given cycle, pregnancies may have occurred after either a fresh or frozen-thawed embryo transfer.
All patients who sought oocyte cryopreservation or who donated oocytes at the Center for Reproductive Health at the University of California San Francisco (UCSF) from January 1, 2012, to June 30, 2017, were eligible for this retrospective cohort study. Potential subjects who pursued fertility preservation for a diagnosis of malignancy or who had previously demonstrated infertility as documented in the patient chart were excluded. All eligible cycles were included for evaluation. Eligibility determination and data collection were performed by means of electronic chart review. Patient protocols included both agonist and antagonist protocols, which were categorized and accounted for in analysis. The
TABLE 1 Characteristics of patients undergoing ovarian stimulation in the presence or absence of a levonorgestrel-releasing intrauterine device (LNGIUD). Subject characteristic Age, y BMI, kg/m2 Initial AFC No. of stimulation days Total FSH dose Peak E2 Peak E2 per oocyte collected
LNG-IUD absent (n [ 1,028)
LNG-IUD present (n [ 45)
P value
32.77 5.92 23.04 3.58 18.39 9.70 9.82 1.52 1,863.31 761.96 3,289.0 1,589.14 194.41 108.40
33.14 4.54 22.79 2.69 19.15 8.76 10.30 3.66 2,091.86 773.03 2,600.69 1,266.18 150.42 51.50
.60 .60 .60 .39 < .05 < .01 < .01
Note: Values are reported as mean standard deviation. AFC ¼ antral follicle count; BMI ¼ body mass index; FSH ¼ follicle stimulating hormone. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
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Fertility and Sterility® Statistical Analysis Demographic parameters between the subjects with and without an LNG-IUD were tested with the use of a Student t test or chi-square/Fisher test, as appropriate. The impact of an LNG-IUD on total oocytes and mature oocytes collected as well as fertilization rates from donor oocytes were tested with the use of a mixed analysis of covariance (ANCOVA) model. A logistic regression model was used to test the effect of the LNG-IUD on blastocyst transfer rates and pregnancy outcomes. A cycle was deemed to be successful if any oocyte from a cycle, after either fresh or frozen-thawed embryo transfer, resulted in a clinical pregnancy or live birth. All models included within-subject effects to account for the subset of subjects who completed multiple cycles. Models controlled for potential confounding effects, including a history of combined contraceptive use at the time of initial AFC, age, body mass index (BMI), initial AFC, length of cycle, stimulation regimen, and total gonadotropin dose. All testing was performed at the 0.05 level of significance. Statistical analysis was performed with the use of SAS v9.4.
RESULTS Patient Characteristics A total of 1,074 women who underwent 1,487 cycles of controlled ovarian stimulation were included in this study. Forty-five subjects had an LNG-IUD, representing 4.2% of the study population. Subjects with an LNG-IUD contributed 68 cycles, representing 4.6% of all cycles analyzed. There was no difference in age, BMI, stimulation protocol, or number of stimulation days between cycles conducted in the presence and those in the absence of an LNG-IUD. Subjects with an LNG-IUD exhibited lower peak E2 levels (P< .01), lower peak E2 level per follicle (P< .01), and higher total FSH dose per cycle (P< .05) (Table 1). The majority of cycles, 79.7%, used an antagonist protocol (Table 2).
Levonorgestrel Intrauterine Devices Do Not Impact Oocyte Yield In a simple ANCOVA model, there were no differences in predicted oocyte yield or mature oocyte yield between subjects with and without an LNG-IUD (P¼ .55 and P¼ .57, respec-
TABLE 2 Characteristics of cycles in the presence or absence of a levonorgestrel-releasing intrauterine device (LNG-IUD). Cycle characteristic LNG-IUD absent LNG- IUD present P value Treatment group Lupron 17.6 (250) 22.1 (15) Antagonist 79.7 (1130) 77.9 (53) Mini IVF 2.7 (39) 0 (0) Combined hormonal contraception at initial AFC No 70.2 (987) 100 (68) Yes 29.8 (419) 0 (0) Donor cycles 39.6 (563) 44.1 (30)
.30
< .01 .38
Note: Values are reported as % (n). AFC ¼ antral follicle count; IVF ¼ in vitro fertilization. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
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tively). When controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation days and protocol, the predicted mean number of oocytes collected in subjects with an LNG-IUD was 15.74 (95% confidence interval [CI) 12.81–18.66] compared with 16.99 (15.89–18.08) in subjects without an LNG-IUD. There were no differences in total oocyte yield (P¼ .41) or mature oocyte yield (P¼ .49) in the presence or absence of an LNGIUD. When comparing antagonist protocols with either agonist or ministimulation protocols, antagonist-based protocols were associated with a higher total oocyte yield (Table 3).
Levonorgestrel Intrauterine Devices Do Not Affect Laboratory or Pregnancy Outcomes A total of 608 donor cycles resulted in 583 fresh or frozenthawed embryo transfers. Because some intended parents also planned to use a gestational carrier who had yet to complete evaluation at the time of oocyte donation, there were fewer transfers than donor cycles. For all cycles in which oocytes were appropriately inseminated, there was at least one embryo that was appropriate for transfer. A univariate model showed no difference in the predicted fertilization rates between oocytes collected in the presence or absence of an LNG-IUD (P¼ .64). In an adjusted model, patients with an LNG-IUD were predicted to have a fertilization rate of 74.5% (95% CI 69.1%–90.0%). Patients without an LNGIUD had a predicted fertilization rate of 74.6% (71.5%– 77.7%; P¼ .98). For oocyte donation cycles, at least four good-quality day 3 embryos were required to allow embryos to develop to the blastocyst stage in extended culture. To assess blastocyst progression rate, only cycles in which all embryos were intended to be maintained in extended culture were included for analysis. In an unadjusted model, there was no difference in the blastocyst progression rate (P¼ .67) between the two groups. After adjusting for confounders, there remained no difference between the two groups (P¼ .52). The predicted blastocyst progression rate was 53.2% (95% CI 42.0%–64.5%) for embryos conceived from oocytes collected in the presence of an LNG-IUD and 49.4% (46.9%–51.9%) in cycles without an LNG-IUD. The vast majority of oocyte donation cycles resulted in embryos that progressed to the blastocyst stage, and all extended culture cycles resulted in at least one blastocyst that was appropriate for transfer (Table 4). When an LNGIUD was present, the predicted blastocyst transfer rate was 80.2% compared with 75.7% when the LNG-IUD was absent. There was no difference in the blastocyst transfer rate between the two groups after an unadjusted logistic regression (P¼ .43) or when adjusting for confounders (P¼ .74). A univariate logistic regression showed no statistically significant impact of LNG-IUD use on clinical pregnancy (P¼ .62) or live birth rate (P¼ .77) for donor oocyte recipients. When controlling for history of recent hormonal contraceptive use, initial AFC, age, BMI, gonadotropin dose, and stimulation day/protocol, the predicted clinical pregnancy rate from oocytes collected in the presence of an LNG-IUD was 90.5% (95% CI 66.9%–97.8%) and in the absence of an 3
ORIGINAL ARTICLE: ASSISTED REPRODUCTION
TABLE 3 Comparison of oocyte yield in the presence and absence of a levonorgestrel-releasing intrauterine device (LNG-IUD). Oocyte outcome No. of subjects Total oocytes retrieved No. of subjects with oocytes cryopreserveda Mature oocytes retrieved
LNG-IUD absent
LNG-IUD present
1,028 16.99 (15.89–18.08) 641 9.84 (8.84–10.83)
45 15.74 (12.81–18.66) 32 10.89 (7.96–13.83)
P value .41 .49
Note: Values are reported as predicted mean (95% confidence interval), unless specified otherwise. Models are controlled for history of recent hormonal contraceptive use, initial antral follicle count, age, body mass index, gonadotropin dose, and stimulation days/protocol. a Maturity of donor cycle oocytes was not assessed, because most were conventionally inseminated. Donor oocyte cycles are not included in this analysis. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
LNG-IUD was 84.5% (80.2%–87.9%). The predicted live birth rates from oocytes collected in the presence or absence of an LNG-IUD were 78.1% (47.7%–93.3%) and 75.2% (70.3%– 79.5%), respectively (Table 4). There were no significant differences in clinical pregnancy (P¼ .48) or live birth (P¼ .82) rates between the two groups.
DISCUSSION Among women using contraception in the United States from 2010 to 2013, 10.7% used an intrauterine device according to recent CDC estimates (2). Furthermore, as the popularity of social oocyte cryopreservation and oocyte donation continue to increase, it is likely that many clinicians will face the question of how to manage such patients with an LNG-IUD present. The present study sought to describe any impact of an LNGIUD on ovarian stimulation. Furthermore, we aimed to describe clinical pregnancy and live birth rates with oocyte donation. There was no difference in oocyte yield or mature oocyte yield when oocytes were collected in the presence or absence of an LNG-IUD. These findings are consistent with previous studies comparing conventional ovarian stimulation with cycles with a luteal phase or random start. Despite higher P levels in the luteal phase start, there was no difference in the oocyte yield between these protocols (8). Among recipients of donor oocytes, there was no difference in predicted fertilization, blastocyst progression, or blastocyst transfer rates between oocytes collected in the presence or absence of an LNG-IUD. Furthermore, clinical
pregnancy and live birth rates were not affected by the presence of an LNG-IUD. Previous results in a smaller retrospective cohort study similarly showed no impact of LNGIUDs on stimulation outcomes (9). These findings are in keeping with the presumed mechanism of action of LNGIUDs, which prevent pregnancy by a direct effect on cervical mucus and the endometrium. Although our study focused on healthy women, these results may be valuable to women seeking fertility preservation after a recent diagnosis of cancer. This group of women would have similar patterns of contraceptive use at diagnosis, and maintaining an LNG-IUD during ovarian stimulation for fertility preservation would aid in preventing unintended pregnancy in this population. Two intriguing findings revealed in data analyses were unrelated to the intended outcome measures. First, the peak E2 level and peak E2 level per follicle were lower in subjects with an LNG-IUD. Although the numbers of mature oocytes were not significantly different between the groups, it is possible that unobserved biologic factors related to endogenous E2 production may contribute to this disparate finding. For example, previous studies have demonstrated higher E2 levels per follicle in subjects of Asian descent (10). Alternatively, some studies have shown that stimulation cycles using pretreatment with the use of oral contraceptives may experience greater pituitary suppression or require more days of stimulation and higher gonadotropin doses (10, 11). Because many women with LNG-IUDs have irregular menses, oral contraceptives are often used to time stimulation cycles.
TABLE 4 Comparison of predicted laboratory and pregnancy outcomes in the presence and absence of a levonorgestrel-releasing intrauterine device (LNGIUD). Cycle outcome
LNG-IUD absent
LNG-IUD present
No. of cycles with fertilization Fertilization rate No. of donor cycles with a transfer Blastocyst progression ratea Blastocyst transfer rate Clinical pregnancy rate Live birth rate
639 74.6 (71.5–77.7) 555 49.4 (46.9–51.9) 75.7 (70.4–80.3) 84.5 (80.2–87.9) 75.2 (70.3–79.5)
31 74.5 (69.1–80.0) 28 53.2 (42.0–64.5) 80.2 (47.8–94.7) 90.5 (66.9–97.8) 78.1 (47.7–93.3)
P value .98 .52 .74 .48 .82
Note: Values are reported as predicted mean rate (95% confidence interval), unless specified otherwise. Models are controlled for history of recent hormonal contraceptive use, initial antral follicle count, age, body mass index, gonadotropin dose, and stimulation days/protocol. a The number of cycles included in the blastocyst progression rate analysis was limited to cycles with the intention for all embryos to be maintained in extended culture. Adeleye. Impact of LNG-IUD on ovarian stimulation. Fertil Steril 2018.
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Fertility and Sterility® In women who are significantly suppressed with oral contraceptives, E2 levels may be lower during stimulation. Our data suggest that E2 levels may not be as predictive of maturity when an LNG-IUD is present, and further investigation is warranted. Second, there was a significantly higher number of oocytes retrieved in cycles with the use of an antagonist-based protocol. When subjects have a larger initial AFC, antagonist protocols are often used to allow for an agonist-based trigger when ovarian hyperstimulation syndrome is a risk. This treatment preference for antagonist-based protocols in this cohort of subjects with higher AFCs may account for the differences in oocyte yield between the two types of protocols.
CONCLUSION
Strengths
REFERENCES
This study represents a robust assessment of the impact of LNG-IUDs on ovarian stimulation and related outcomes. The diversity of protocols and age groups represented increases the generalizability of this study. This information will aid fertility clinics in providing appropriate counseling during an initial encounter, increasing patient experience and satisfaction with care. Patients can be counseled that the presence of an LNG-IUD during controlled ovarian stimulation should have no clinically relevant effect on the important outcomes of oocytes cryopreserved or clinical pregnancy potential.
The presence of an LNG-IUD during ovarian stimulation has no impact on total oocyte yield or mature oocyte yield in a healthy population without evidence of infertility. Furthermore, the LNG-IUD may not have an impact on pregnancy or live birth rates in recipients of oocytes collected in the presence of an LNG-IUD. Knowledge about the impact of LNG-IUDs on ovarian stimulation cycles may improve the experience and overall quality of life for women who desire to delay childbearing or donate oocytes and who desire also an excellent form of long-acting contraception. Finally, this approach may also have a measurable impact on health care costs associated with interruption in use and replacement of a long-active contraceptive device.
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Limitations Although this was the largest study to date to review the impact of LNG-IUDs on oocyte stimulation cycles, the number of cycles in which an LNG-IUD was present was still small. A power calculation showed that 45 cycles would be sufficient to demonstrate a significant difference of two oocytes between the groups with a power of 85%. However, this study was not powered to address the secondary outcomes of clinical or live birth rates. Serum levels of LNG may be higher in the first several months after LNG-IUD placement. As Seeber et al. demonstrated, there is a negative correlation between length of time since LNG-IUD placement and serum LNG levels (3). The length of time that an LNG-IUD was in place was variably reported in our medical records and could not be reliably assessed. In the future, a study that is able to review the impact of the time that an LNG-IUD was present, before stimulation, may be informative.
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