Dana B. McQueen, M.D.a, Karine Matevossian, D.O. b, Sedona Speedy, M.D. a, Meike L. Uhler, M.D.c, Eve C. Feinberg, M.D.a
a Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, Northwestern University, Chicago, IL
b Department of Obstetrics and Gynecology, Advocate Aurora Lutheran General Hospital, Park Ridge, IL
c Fertility Centers of Illinois, Chicago, IL
Background: Intrauterine devices (IUDs) are a widespread method of contraception and
commonly utilized by oocyte donors. Removal and replacement of the IUD prior to oocyte
donation is costly and requires additional procedures, which could deter donors who undergo the
procedure electively. Therefore, it is important to understand if the presence of an IUD impacts
oocyte donation outcomes.
Objective: The aim of this study was to investigate the potential impact of the LevonorgestrelIUD (LNG-IUD) on ovarian stimulation, fertilization, and pregnancy outcomes from donated
Study Design: All oocyte donation cycles (N=1,615) from 2010 – 2016 were reviewed for the
presence of a LNG-IUD in a private practice setting. Only anonymous donors < 30 years old
were included. Controls were matched 2:1 by the date of stimulation. A third cohort of donors
with a copper IUD was also analyzed. The first embryo transfer resulting from the oocyte
donation cycle was used for pregnancy outcome calculations. Continuous variables were
compared with a student’s t-test and ANOVA and categorical variables were compared with
Fisher’s exact test.
Results: The study included16 donors with a LNG-IUD, 32 matched controls and 16 donors with
a copper IUD. The total gonadotropin dose, peak estradiol (E2) and number of days of
stimulation were not statistically different between the LNG-IUD group and controls. The
cancellation rate was 12.5% (2/16) in the LNG-IUD group vs. 6.3% (2/32) in controls and 0%
(0/16) in the copper IUD group (NS). The mean number of oocytes retrieved was not significantly
different between groups: (LNG-IUD 20, controls 22, and copper IUD 21). The clinical
pregnancy rate in the LNG-IUD group was significantly higher than controls, 86% vs 52%,
P=0.04. There was no difference in live birth rate, 71% vs 48%, P=0.2.
Conclusions: The presence of a LNG-IUD did not significantly impact ovarian responsiveness
and live birth rate compared to matched controls. These findings suggest that the presence of the
LNG-IUD among oocyte donors did not impact outcomes.
Intrauterine devices (IUDs) are a widespread method of contraception, especially among younger women aged 15-34 years old. As a result, clinicians are likely to encounter women presenting for oocyte donation with an IUD in place. Removal and replacement of IUDs prior to oocyte donation is costly and requires additional procedures, which could deter donors who undergo the procedure electively. Oocyte donors are typically young (<35 years) and fertile and often desire a method of contraception. Therefore, it is important to understand if the presence of an IUD impacts oocyte donation outcomes.
There are several types of IUDs commercially available, including Levonorgestrel (LNG)-releasing IUDs (Mirena®) and non-hormonal copper IUDs (Paragard®). The LNG-IUD has a T-shaped plastic frame and a reservoir containing 52 mg of levonorgestrel (LNG). It initially releases 20 µg/day of LNG, producing a high endometrial concentration but a low plasma concentration of progestin. Contraception with the LNG-IUD is primarily achieved by delivering progestin locally within the endometrium causing endometrial decidualization and atrophy, and thickening cervical mucus, which prevents sperm penetration. However, there is evidence that the LNG-IUD also alters ovulation and hypothalamic pituitary ovarian function. The mean serum level of LNG at one year after LNG-IUD placement is 191±71 pg/mL and decreases to a level of 133±38 pg/mL at 6 years after placement. The systemic effects of LNG pose a theoretical risk to ovarian responsiveness and oocyte quality. Conversely, the copper IUD exerts its contraceptive effects by inducing a local inflammatory response in the absence of hormones.
The aim of this study was to investigate the potential impact of the LNG-IUD and copper IUD on ovarian stimulation, fertilization, and pregnancy outcomes from donated oocytes. Previous research has shown that the presence of LNG-IUDs did not affect oocyte yield in patients undergoing ovarian stimulation. 8 However, to date, there have been no matched studies comparing the LNG-IUD to the copper IUD in ovarian stimulation cycles.
MATERIALS AND METHODS
Institutional Review Board (IRB) approval was obtained from New England IRB. All women undergoing oocyte donation at a single center, Fertility Centers of Illinois, from 2010-2016 were screened for the presence of a LNG-IUD or copper IUD. Only anonymous donors < 30 years old were included. Controls without a LNG-IUD or copper IUD were matched 2:1 by the date of stimulation to the LNG-IUD group. Each donor was included only once in the analysis.
The donors in both groups underwent similar ovulation stimulation protocols using gonadotropins and a gonadotropin-releasing hormone (GnRH) antagonist protocol. Embryo transfer for the recipients was performed using a leuprolide acetate downregulation protocol with estrogen patch and intramuscular and vaginal progesterone supplementation.
Information on baseline characteristics, ovarian stimulation and cycle outcomes was collected by chart review. The first embryo transfer resulting from the oocyte donation cycle was used for pregnancy outcome calculations. A clinical pregnancy was the proportion of oocyte recipients with an intrauterine gestational sac visible on ultrasound after the 6th week of gestation. A live birth was the proportion of embryo transfers resulting in a live birth of one or more living infants.
Continuous variables were compared with a student’s t-test and categorical variables were compared with Fisher’s exact test.
Between 2010 and 2016, 1,615 oocyte donors underwent stimulation at Fertility Centers of Illinois. All charts were reviewed and 16 donors with a LNG-IUD, 16 donors with a copper IUD and 32 matched controls were included for analysis.
Demographics compared between groups showed no significant difference in mean age between the LNG-IUD group, copper IUD group and controls (Table 1). Controls had a lower BMI compared to the LNG-IUD group (22 vs 24, P=0.05). The total gonadotropin dose, peak estradiol (E2) and number of days of stimulation were not statistically different between the LNG-IUD group and controls. The LNG-IUD group had a significantly lower peak E2 compared to the copper IUD group, P= 0.03. The cancellation rate was 12.5% (2/16) in the LNG-IUD group vs. 6.3% (2/32) in controls and 0% (0/16) in the copper IUD group (NS). It is interesting to note that both the donors in the LNG-IUD group and both donors in the control group were cancelled for a low response to stimulation.
The mean number of oocytes retrieved was not significantly different between groups: (LNG-IUD 20, controls 22, and copper IUD 21.) The percent of mature oocytes, fertilization rate and blast formation rate were not statistically different between the LNG-IUD group and controls. The LNG-IUD group had a significantly lower percent of mature oocytes compared to the copper IUD group, 68% vs 76%, p=0.02.
The clinical pregnancy rate in the LNG-IUD group was significantly higher than controls, 86% vs 52%, P=0.04. The difference in live birth rate did not reach statistical significance 71% vs 48%, P=0.2.
The presence of a LNG-IUD did not significantly impact ovarian responsiveness and live birth rate compared to matched-controls. These findings suggest that the presence of the LNG-IUD among oocyte donors does not impact outcomes.
Our findings are consistent with a prior case-series reported by Soderstrom-Anttila et al in 1997 (Table 2). The authors compared 7 oocyte donors with a LNG-IUD to 16 controls. They found that the presence of the LNG-IUD did not significantly impact the number of oocytes retrieved, fertilization rate or pregnancy rate.9 In a study by Adeleye et al. in 2018, 45 women with an LNG-IUD present were compared to 1028 subjects without an IUD, all of whom were undergoing either social oocyte cryopreservation or oocyte donation.8 They found no differences in oocyte yield, pregnancy rates or live birth rates and these outcomes were confirmed in our study. Adeleye et al, did find that donors with a LNG-IUD had lower peak E2 levels and a higher FSH dose per cycle but our study did not show these differences.8 In a study by Galvao et al. in 2019, 103 donor cycles with LNG-IUD were compared to 488 donor cycles with no IUD. The results showed no difference in the primary outcome of cumulative live birth rates between the two groups. They also found no difference in total embryo utilization rate, number of oocytes retrieved and number of days of stimulation.10 We did observe a trend toward an increased cancellation rate among donors with a LNG-IUD. While there was no significant difference in the number of oocytes retrieved, the potential increased risk of cancellation requires further investigation with a larger sample size.
The findings of this study are strengthened by a matched study design with both LNG-IUD and copper IUD users included. In addition, by restricting the study to anonymous oocyte donors, the heterogeneity of the sample is decreased. Our study is limited by sample size, as even in a busy private practice setting, relatively few donors underwent stimulation with an IUD in place because the current trend is to recommend removal prior to stimulation.
Our findings, taken with the prior literature, should reassure clinicians that there is no need to remove the LNG-IUD prior to ovarian stimulation. This has the potential to decrease unplanned pregnancies among oocyte donors, improve donor satisfaction and reduce the healthcare costs associated with removal and replacement of the LNG-IUD.
Future research should aim to study the LNG-IUD in a larger cohort, including women undergoing elective and medical oocyte cryopreservation. A well designed randomized controlled trial that stratifies patients into maintenance of IUD and removal of IUD is needed to answer this question.
In summary, this study demonstrates that the LNG-IUD does not negatively impact oocyte yield, fertilization rate, blast formation rate or live birth rate per transfer in the setting of oocyte donation. Therefore, oocyte recipients and intended parents can be counseled that live birth rates will not be decreased by using a donor with an IUD in place.
- 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.
- American College of Obstetricians and Gynecologists. ACOG practice bulletin no. 186: long-acting reversible contraception: implants and intrauterine devices. Obstet Gynecol 2017; 130:e251–69.
- Hurskainen R, Teperi J, Rissanen P, et al. Clinical outcomes and costs with the levonorgestrel-releasing intrauterine system or hysterectomy for treatment of menorrhagia: randomized trial 5-year follow-up. JAMA 2004;291(12):1456-1463
- Nilsson CG, Haukkamaa M, Vierola H, Luukkainen T. Tissue concentrations of levonorgestrel in women using a levonorgestrel-releasing IUD. Clin Endocrinol 1982;17(6): 529-536.
- J. Friedenthal, S. Maxwell, S. Willson, D. McCulloh, J. Grifo, K. Goldman. The progestin-containing intrauterine device (IUD) during ovarian stimulation and oocyte retrieval: should it stay or should it go? Fertil Steril, 2017;108: e12
- 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
- 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;86:345-349.
- Adeleye, A., Aghajanova, L., Kao, C.-N., Cedars, M., and Sauer, S. Impact of the levonorgestrel intrauterine device on controlled ovarian stimulation outcomes. Fertil Steril. 2018;110: 83–88
- Söderström-Anttila V, Tiitinen A, Hovatta O. Levonorgestrel-releasing intrauterine device can be used in oocyte donors during ovarian stimulation. Hum Reprod 1997;12:491-495.
- Galvao, A. Karakus, G. Racca, A. Santos-Ribeiro, S. Oocyte donation in donors with levonorgestrel intrauterine device: a good match? Reprod Biomed Online 2019;4:641-647.