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Effects of oral contraceptive pretreatment on IVF outcomes in women following a GnRH agonist protocol

  • Author Footnotes
    1 These authors contributed equally to this work.
    Lan Xu
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Centre for Reproductive Medicine, Shandong University, Centre for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Lingling Ding
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Centre for Reproductive Medicine, Shandong University, Centre for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
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  • Jingjing Jiang
    Affiliations
    Centre for Reproductive Medicine, Shandong University, Centre for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
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  • Peihao Liu
    Affiliations
    Centre for Reproductive Medicine, Shandong University, Centre for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
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  • Daimin Wei
    Correspondence
    Corresponding authors.
    Affiliations
    Centre for Reproductive Medicine, Shandong University, Centre for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
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  • Yingying Qin
    Correspondence
    Corresponding authors.
    Affiliations
    Centre for Reproductive Medicine, Shandong University, Centre for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University, National Research Centre for Assisted Reproductive Technology and Reproductive Genetics, The Key Laboratory of Reproductive Endocrinology (Shandong University), Ministry of Education, Jinan, China
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  • Author Footnotes
    1 These authors contributed equally to this work.
Published:August 16, 2019DOI:https://doi.org/10.1016/j.rbmo.2019.08.002

      Abstract

      Research question

      Does oral contraceptive pretreatment impact IVF–embryo transfer cycle outcomes in women following the gonadotrophin-releasing hormone agonist (GnRHa) protocol?

      Design

      This retrospective study was designed to compare cycle outcomes after oral contraceptive pretreatment versus the standard protocol in women within the GnRHa long protocol or the GnRHa short protocol. A total of 2052 women undergoing their first IVF treatment with the GnRHa long protocol and 3557 women with the GnRHa short protocol between 2012 and 2017 were enrolled.

      Results

      No significant differences in the rates of clinical pregnancy (long protocol: 49.2% versus 46.7%; short protocol: 39.4% versus 38.0%) or live birth (long protocol: 44.3% versus 41.3%; short protocol: 32.8% versus 31.4%) after fresh embryo transfer were observed between the oral contraceptive group and the control group in either the long protocol or the short protocol.

      Conclusions

      Oral contraceptive pretreatment has no effect on IVF outcomes in either the GnRHa long protocol or short protocol.

      Keywords

      Introduction

      Oral contraceptives are widely used in IVF–embryo transfer (IVF–ET) (
      • Garcia-Velasco J.A.
      • Bermejo A.
      • Ruiz F.
      • Martinez-Salazar J.
      • Requena A.
      • Pellicer A.
      Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol versus the long protocol: a randomized, controlled trial.
      ;
      • Hauzman E.E.
      • Zapata A.
      • Bermejo A.
      • Iglesias C.
      • Pellicer A.
      • Garcia-Velasco J.A.
      Cycle scheduling forin vitro fertilization with oral contraceptive pills versus oral oestradiol valerate: a randomized, controlled trial.
      ;
      • Weisman Z.
      • Dirnfeld M.
      • Lissak A.
      • Sorokin Y.
      • Abramovici H.
      Oral contraceptive pills and follicular fluid hormones in anin vitro fertilization program.
      ). Oral contraceptives consisting of oestrogen and progesterone inhibit endogenous FSH and LH secretion through a negative feedback mechanism (
      • Cohen B.L.
      • Katz M.
      Pituitary and ovarian function in women receiving hormonal contraception.
      ) and thus suppress gonadal function and synchronize the follicle cohort (
      • Cedrin-Durnerin I.
      • Bstandig B.
      • Parneix I.
      • Bied-Damon V.
      • Avril C.
      • Decanter C.
      • Hugues J.N.
      Effects of oral contraceptive, synthetic progestogen or natural oestrogen pre-treatments on the hormonal profile and the antral follicle cohort before GnRH antagonist protocol.
      ;
      • Gonen Y.
      • Casper R.F.
      Prediction of implantation by the sonographic appearance of the endometrium during controlled ovarian stimulation forin vitro fertilization (IVF).
      ). Oral contraceptive pretreatment is frequently used for scheduling cycles in patients undergoing a gonadotrophin-releasing hormone agonist (GnRHa) protocol, and it has been reported that oral contraceptives significantly reduce weekend oocyte retrievals (
      • Barmat L.I.
      • Chantilis S.J.
      • Hurst B.S.
      • Dickey R.P.
      A randomized prospective trial comparing gonadotrophin-releasing hormone (GnRH) antagonist/recombinant follicle-stimulating hormone (rFSH) versus GnRH-agonist/rFSH in women pretreated with oral contraceptives beforein vitro fertilization.
      ;
      • Huirne J.A.
      • Hugues J.N.
      • Pirard C.
      • Fischl F.
      • Sage J.C.
      • Pouly J.L.
      • Obruca A.
      • Braat D.M.
      • van Loenen A.C.
      • Lambalk C.B.
      Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.
      ).
      Recent studies have investigated the effects of oral contraceptive pretreatment prior to different ovarian stimulation protocols on cycle outcomes, and it has been reported that oral contraceptives used for menses induction prior to the GnRH antagonist protocol are associated with poor outcomes after fresh embryo transfer, including a lower live birth rate, a lower pregnancy rate and a higher pregnancy loss rate (
      • Farquhar C.
      • Rombauts L.
      • Kremer J.A.
      • Lethaby A.
      • Ayeleke R.O.
      Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques.
      ;
      • Griesinger G.
      • Venetis C.A.
      • Marx T.
      • Diedrich K.
      • Tarlatzis B.C.
      • Kolibianakis E.M.
      Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis.
      ;
      • Wei D.
      • Shi Y.
      • Li J.
      • Wang Z.
      • Zhang L.
      • Sun Y.
      • Zhou H.
      • Xu Y.
      • Wu C.
      • Liu L.
      • Wu Q.
      • Zhuang L.
      • Du Y.
      • Li W.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.
      ). However, there is still insufficient evidence for the effect of oral contraceptive pretreatment on cycle outcomes in women undergoing the GnRHa long protocol or the GnRHa short protocol.
      In the present study, a retrospective analysis was performed to assess the effect of oral contraceptive pretreatment on IVF–ET outcomes in women undergoing the GnRHa long protocol or the GnRHa short protocol.

      Materials and methods

      Study population

      A retrospective analysis was carried out on a total of 2052 women undergoing their first IVF treatment with the GnRHa long protocol and 3557 women with the GnRHa short protocol between 2012 and 2017 at the Reproductive Hospital Affiliated to Shandong University.
      For the long protocol, the inclusion criteria were undergoing the first fresh cycle, age between 20 and 35 years, regular ovulatory menstrual cycles (25–35 days) and basal serum FSH <10 IU/l. Subjects with abnormal karyotypes, congenital or acquired uterine malformations, or a history of ovarian surgery, endometriosis or polycystic ovary syndrome (PCOS) according to the Rotterdam criteria were excluded.
      For the short protocol, the inclusion criteria were undergoing the first fresh cycle, age between 20 and 40 years, and basal serum FSH <15 IU/l. The exclusion criteria were the same as for the long protocol.
      The key baseline characteristics of the population were matched between two groups. In the long protocol, age and body mass index (BMI) were matched, and in the short protocol, age and FSH were matched.

      Ethics approval

      All study procedures were approved by the Institutional Review Board of the Centre for Reproductive Medicine of Shandong University on 8 January 2018 (reference number: 1813).

      Study procedures

      The study centre generally uses oral contraceptives for the purposes of avoiding ovarian cysts and double down-regulation. In this study, according to oral contraceptive pretreatment or not, all patients were divided into an oral contraceptive group and a control group within the long protocol and short protocol, respectively. In the oral contraceptive groups, some patients received 0.15 mg desogestrel and 0.03 mg ethinyl oestradiol and some patients received 3 mg drospirenone and 0.03 mg ethinyl oestradiol.
      The oral contraceptive groups started with oral contraceptives on Day 3–5 of the menses of the previous cycle for 21 consecutive days, and then the standard GnRHa long protocol or short protocol was begun for ovarian stimulation. In brief, patients undergoing the long protocol were treated with GnRHa to down-regulate the functions of the pituitary gland on Day 21 of the previous menstrual cycle. After down-regulation of the pituitary gland, gonadotrophin was initiated with a starting dose of recombinant FSH ranging from 75 to 225 IU, and the dose of gonadotrophin was modulated according to the patient's ovarian response. For patients undergoing the short protocol, GnRHa was started on Day 1–3 of the menstrual cycle after the oral contraceptive withdrawal bleeding, and gonadotrophin administration was initiated on the second day of GnRHa administration and continued until the day that human chorionic gonadotrophin (HCG) was administered.
      In the control groups undergoing the long protocol, GnRHa was initiated at the mid-luteal phase of the previous menstrual cycle (5–7 days after ovulation). For the short protocol, GnRHa was administered on Day 1–3 of the spontaneous menstrual cycle.
      For patients undergoing long protocol, a transvaginal ultrasound scan was performed on Day 21 prior to the IVF cycle and again early in the cycle of ovarian stimulation to detect ovarian cysts; for patients using short protocol, ultrasound scans were conducted before ovarian stimulation. Ovarian stimulation was started only if there was no functional ovarian cyst.
      As soon as two leading follicles reached ≥18 mm, HCG (6000–8000 IU, Livzon Pharmaceutical Group) was administered to trigger maturation of oocytes, and oocyte retrieval was performed 34–36 h later. Luteal phase support with 20 mg dydrogesterone oral twice daily combined with 200 mg progesterone oral/vaginally once daily was administered for 2 weeks from the day of oocyte retrieval. Morphologic criteria were used for embryo scoring (
      • Puissant F.
      • Van Rysselberge M.
      • Barlow P.
      • Deweze J.
      • Leroy F.
      Embryo scoring as a prognostic tool in IVF treatment.
      ), and two good-quality embryos were transferred on Day 3. If pregnancy was achieved, the luteal phase support was maintained until week 10 of pregnancy.

      Outcomes

      The primary outcome was the rate of live birth, which was defined as delivery of a viable neonate (≥28 weeks’ gestation). Secondary outcomes included biochemical pregnancy, clinical pregnancy and early pregnancy loss. Biochemical pregnancy was defined as a serum level of HCG of more than 10 mIU/ml at 14 days after embryo transfer. Clinical pregnancy rate was defined as the presence of an intrauterine gestational sac at 35 days after embryo transfer, and early pregnancy loss was defined as clinical pregnancy loss before 12 weeks. In addition, the parameters of the ovarian response were also analysed.

      Statistical analysis

      Data were analysed using SPSS Statistics for Windows, Version 21.0 (IBM Corp., Armonk, NY, USA). Numeric variables are presented as the mean ± SD, and categorical variables are expressed as numbers and percentages. For numeric variables, two groups were compared by Student's t-test for normally distributed data, and the Kruskal–Wallis test was used for non-normally distributed data. For categorical variables, the chi-squared test or Fisher's exact test were used to compare the difference between two groups. Multivariate logistic regression was used to adjust for the effects of baseline characteristics. P < 0.05 was considered statistically significant.

      Results

      Baseline characteristics

      As shown in Tables 1 and 2, age, basal FSH, basal LH, and basal antral follicle count (AFC) were comparable between the oral contraceptive group and control group in both the long protocol and short protocol. In women undergoing the long protocol, basal oestradiol levels were slightly lower in the oral contraceptive group compared with the control group (33.1 ± 12.5 versus 34.6 ± 12.8 pg/ml, P = 0.007). In women undergoing the short protocol, the oral contraceptive group had a higher BMI than the control group (23.4 ± 3.7 kg/m2 versus 22.9 ± 3.6 kg/m2, P < 0.001).
      Table 1Baseline characteristics of women treated with the long protocol
      CharacteristicsOCControl
      Number of patients10121040
      Age (years)29.2 ± 3.229.2 ± 3.3
      Primary infertility (%)652 (64.4%)633 (60.9%)
      BMI (kg/m2)22.5 ± 3.122.4 ± 3.2
      Basal FSH (IU/l)6.4 ± 1.36.5 ± 1.3
      Basal LH (IU/l)4.9 ± 1.94.9 ± 2.7
      Basal oestradiol (pg/ml)33.1 ± 12.534.6 ± 12.8
      Basal AFC12.8 ± 3.312.8 ± 3.3
      Indication for treatment (%)
       Tubal factor620 (61.3%)611 (58.8%)
       Male factor180 (17.8%)211 (20.3%)
       Tubal and male factors212 (20.9%)218 (21.0%)
      Values presented as mean ± SD or number (%).
      P < 0.05 was considered statistically significant.
      No statistically significant differences were found between the two groups, except for basal oestradiol (P = 0.007).
      AFC = antral follicle count; BMI = body mass index; OC = oral contraceptive.
      Table 2Baseline characteristics of women treated with the short protocol
      CharacteristicsOCControl
      Number of patients10902467
      Age (years)32.0 ± 4.532.1 ± 4.5
      Primary infertility (%)538 (49.4%)1224 (49.6%)
      BMI (kg/m2)23.4 ± 3.722.9 ± 3.6
      Basal FSH (IU/l)7.5 ± 2.17.5 ± 1.9
      Basal LH (IU/l)4.5 ± 1.84.5 ± 1.7
      Basal oestradiol (pg/ml)36.1 ± 14.736.0 ± 13.8
      Basal AFC9.6 ± 2.79.6 ± 2.4
      Indication for treatment (%)
       Tubal factor775 (71.1%)1728 (70.0%)
       Male factor148 (13.6%)315 (12.8%)
       Tubal and male factors167 (15.3%)424 (17.2%)
      Values presented as mean ± SD or number (%).
      P < 0.05 was considered statistically significant.
      No statistically significant differences were found between the two groups, except for BMI (P < 0.001).
      AFC = antral follicle count; BMI = body mass index; OC = oral contraceptive.

      Ovarian response

      The starting dose of gonadotrophin, the duration of exogenous gonadotrophin stimulation and the total dose of gonadotrophin consumed were comparable between women in the oral contraceptive group and control group for both the long protocol and the short protocol (Tables 3 and 4, respectively).
      Table 3Stimulation cycle parameters of women treated with the long protocol
      CharacteristicsOC (n = 1012)Control (n = 1040)P-value
      Gn starting dose (IU/day)158.3 ± 37.3158.9 ± 36.2NS
      Duration of stimulation10.9 ± 1.611.0 ± 1.6NS
      Total FSH dose (IU)1718.0 ± 601.11764.7 ± 608.3NS
      At day of HCG trigger
       Oestradiol (pg/ml)4109.4 ± 2088.73939.7 ± 2044.1NS
       Progesterone (ng/ml)1.0 ± 0.41.0 ± 0.4NS
       LH (IU/l)2.2 ± 1.02.5 ± 1.2<0.001
       Endometrium (mm)11.2 ± 1.711.4 ± 1.80.015
      Retrieved oocytes12.8 ± 5.312.7 ± 5.0NS
      Fertilization rate (%)7972/12974 (61.4%)7674/13190 (58.2%)<0.001
      High-quality embryos4.4 ± 3.04.1 ± 2.80.015
      Cancellation rate, n/N (%)260 (25.7%)304/1040 (29.2%)NS
      Values presented as mean ± SD or number (%).
      P < 0.05 was considered statistically significant.
      Gn = gonadotrophin; HCG = human chorionic gonadotrophin; NS = not statistically significant; OC = oral contraceptive.
      Table 4Stimulation cycle parameters of women treated with the short protocol
      CharacteristicsOC (n = 1090)Control (n = 2467)P-value
      Gn starting dose (IU/day)200.4 ± 45.6199.8 ± 46.8NS
      Duration of stimulation9.9 ± 1.99.8 ± 1.8NS
      Total FSH dose (IU)1947.4 ± 770.01920.2 ± 727.7NS
      At day of HCG trigger
       Oestradiol (pg/ml)3231.9 ± 1830.93160.9 ± 1964.4NS
       Progesterone (ng/ml)1.0 ± 0.61.0 ± 0.5NS
       LH (IU/L)4.9 ± 2.75.4 ± 2.4<0.001
       Endometrium (mm)10.4 ± 1.910.6 ± 1.90.002
      Retrieved oocytes8.4 ± 4.58.3 ± 4.4NS
      Fertilization rate (%)5822/9146 (63.7%)12735/20432 (62.3%)0.029
      High-quality embryos3.0 ± 2.33.0 ± 2.4NS
      Cancellation rate, n/N (%)287 (26.3%)585 (23.7%)NS
      Values presented as mean ± SD or number (%).
      P < 0.05 was considered statistically significant.
      Gn = gonadotrophin; HCG = human chorionic gonadotrophin; NS = not statistically significant; OC = oral contraceptive.
      On the day of HCG trigger, oestradiol and progesterone levels in the oral contraceptive groups were comparable to the control groups for both the long protocol and short protocol. However, there was a statistical difference in LH level on the day of HCG trigger between oral contraceptive groups and control groups (long protocol: 2.2 ± 1.0 IU/l versus 2.5 ± 1.2 IU/l, P < 0.001; short protocol: 4.9 ± 2.7 IU/l versus 5.4 ± 2.4 IU/l, P < 0.001).
      Oral contraceptive pretreatment showed no influence on the numbers of oocytes retrieved or the total cancellation rate compared with control groups for either the long protocol or the short protocol (Tables 3 and 4, respectively). The oral contraceptive group showed a higher fertilization rate (61.4% versus 58.2%, P < 0.001) and more high-quality embryos (4.4 ± 3.0 versus 4.1 ± 2.8, P = 0.015) than the control group for the long protocol, but in women undergoing the short protocol no differences were observed in the fertilization rate or in the number of high-quality embryos.

      Treatment outcome

      The rates of live birth did not differ significantly between the oral contraceptive group and the control group for either the long protocol or the short protocol. In addition, no significant differences in clinical pregnancy rate or early pregnancy loss were observed between the oral contraceptive group and the control group for either the long protocol or the short protocol (Tables 5 and 6, respectively). Logistic regression analyses showed that the rates of clinical pregnancy and live birth were still comparable between the oral contraceptive group and the control group for both the long protocol and the short protocol after adjustment for the baseline characteristics (Table 7).
      Table 5Treatment outcome parameters of women treated with the long protocol
      CharacteristicsOC (n = 1012)Control (n = 1040)OR (95% CI)
      No. of cycles with ET749728
      In cycles with ET:
       Biochemical pregnancy rate549 (73.3%)532 (73.1%)1.01 (0.80–1.27)
       Clinical pregnancy rate498 (66.5%)486 (66.8%)0.99 (0.80–1.22)
       Early pregnancy loss rate33/498 (6.6%)40/486 (8.2%)0.79 (0.49–1.27)
       Live birth rate448 (59.8%)430 (59.1%)1.03 (0.83–1.27)
      In cycles with ovarian stimulation:
       Biochemical pregnancy rate549 (54.2%)532 (51.2%)1.13 (0.95–1.35)
       Clinical pregnancy rate498 (49.2%)486 (46.7%)1.10 (0.93–1.31)
       Live birth rate448 (44.3%)430 (41.3%)1.13 (0.95–1.34)
      P < 0.05 was considered statistically significant.
      No statistically significant differences were found between the two groups.
      CI = confidence interval; ET = embryo transfer; OC = oral contraceptive; OR = odds ratio.
      Table 6Treatment outcome parameters of women treated with the short protocol
      CharacteristicsOC (n = 1090)Control (n = 2467)OR (95% CI)
      No. of cycles with ET8031882
      In cycles with ET:
       Biochemical pregnancy rate506/803 (63.0%)1093/1882 (58.1%)1.23 (1.04–1.46)
       Clinical pregnancy rate430/803 (53.5%)937/1882 (49.8%)1.16 (0.99–1.37)
       Early pregnancy loss rate41/430 (9.5%)114/937 (12.2%)0.76 (0.52–1.10)
       Live birth rate358/803 (44.6%)774/1882 (41.1%)1.15 (0.98–1.36)
      In cycles with ovarian stimulation:
       Biochemical pregnancy rate506/1090 (46.4%)1093/2467 (44.3%)1.09 (0.94–1.26)
       Clinical pregnancy rate430/1090 (39.4%)937/2467 (38.0%)1.06 (0.92–1.23)
       Live birth rate358/1090 (32.8%)774/2467 (31.4%)1.07 (0.92–1.25)
      P < 0.05 was considered statistically significant.
      No statistically significant differences were found between the two groups, except for biochemical pregnancy rate in cycles with ET (P = 0.017).
      CI = confidence interval; ET = embryo transfer; OC = oral contraceptive; OR = odds ratio.
      Table 7Logistic regression analysis for the effect of OC pretreatment before ovarian stimulation on rates of clinical pregnancy and live birth, adjusting baseline characteristics
      OC group versus controlAdjusted OR (95% CI)
      Long protocol:
       Clinical pregnancy rate1.11 (0.93–1.32)
       Live birth rate1.13 (0.95–1.35)
      Short protocol:
       Clinical pregnancy rate1.05 (0.91–1.22)
       Live birth rate1.06 (0.91–1.24)
      P < 0.05 was considered statistically significant.
      For long protocol, adjusted baseline characteristics included age, BMI, basal FSH, basal oestradiol, primary or secondary infertility and indication for IVF/ICSI treatment.
      For short protocol, adjusted baseline characteristics included age, BMI, primary or secondary infertility and indication for IVF/ICSI treatment.
      All adjusted P-values were not statistically significant.
      BMI = body mass index; CI = confidence interval; ICSI = intracytoplasmic sperm injection; OC = oral contraceptive; OR = odds ratio.

      Discussion

      The present study found that pregnancy outcomes after fresh embryo transfer were not affected by the use of oral contraceptives in either the GnRHa long protocol or short protocol.
      With the widespread use of oral contraceptives in IVF cycles, concerns have been raised as to whether oral contraceptives can influence IVF cycle outcomes. Recent studies showed that oral contraceptive treatment prior to the GnRH antagonist protocol was associated with lower live birth rate and poorer IVF outcomes (
      • Farquhar C.
      • Rombauts L.
      • Kremer J.A.
      • Lethaby A.
      • Ayeleke R.O.
      Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques.
      ;
      • Griesinger G.
      • Venetis C.A.
      • Marx T.
      • Diedrich K.
      • Tarlatzis B.C.
      • Kolibianakis E.M.
      Oral contraceptive pill pretreatment in ovarian stimulation with GnRH antagonists for IVF: a systematic review and meta-analysis.
      ;
      • Wei D.
      • Shi Y.
      • Li J.
      • Wang Z.
      • Zhang L.
      • Sun Y.
      • Zhou H.
      • Xu Y.
      • Wu C.
      • Liu L.
      • Wu Q.
      • Zhuang L.
      • Du Y.
      • Li W.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.
      ). In this study, no effect of oral contraceptive pretreatment on IVF outcomes was observed.
      In this retrospective study with a large sample size (2052 patients with long protocol; 3557 patients with short protocol), the key baseline clinical characteristics between the two groups were matched. In the long protocol, age and BMI were matched, and in the short protocol, age and FSH. Although there were still baseline variables with a statistical between-group difference, such as oestradiol in the long protocol and BMI in the short protocol, most other baseline parameters showed no statistical difference between the two groups. Besides, multivariate logistic regression was used to adjust unmatched parameters to reduce possible bias, which might make the results more reliable. It is understood that further prospective studies and randomized trials are needed to confirm these results.
      In the long protocol, both oral contraceptives and GnRHa suppress gonadal functions, and it was found that although there was no difference in the number of retrieved oocytes between the two groups, the oral contraceptive group had a higher fertilization rate and a greater number of high-quality embryos than the control group. Consistent with previous studies, no difference was found in the number of retrieved oocytes in the oral contraceptive pretreatment groups compared with controls (
      • Huirne J.A.
      • Hugues J.N.
      • Pirard C.
      • Fischl F.
      • Sage J.C.
      • Pouly J.L.
      • Obruca A.
      • Braat D.M.
      • van Loenen A.C.
      • Lambalk C.B.
      Cetrorelix in an oral contraceptive-pretreated stimulation cycle compared with buserelin in IVF/ICSI patients treated with r-hFSH: a randomized, multicentre, phase IIIb study.
      ;
      • Kolibianakis E.M.
      • Papanikolaou E.G.
      • Camus M.
      • Tournaye H.
      • Van Steirteghem A.C.
      • Devroey P.
      Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients stimulated with GnRH antagonists and recombinant FSH for IVF.
      ;
      • Rombauts L.
      • Healy D.
      • Norman R.J.
      • Orgalutran Scheduling Study G.
      A comparative randomized trial to assess the impact of oral contraceptive pretreatment on follicular growth and hormone profiles in GnRH antagonist-treated patients.
      ). The higher fertilization rate and greater number of high-quality embryos in the oral contraceptive groups in the present study suggest a beneficial effect of oral contraceptive pretreatment; however, this beneficial effect did not lead to differences in pregnancy outcomes such as live birth rate, clinical pregnancy rate or early pregnancy loss. Even though the underlying mechanism remains unclear, the findings of this study clearly indicate that oral contraceptive pretreatment in the long protocol did not influence the quality of oocytes or IVF outcomes in ovulatory women.
      Similar to the patients in this study with the long protocol, a previous randomized controlled trial showed that oral contraceptive pretreatment could prevent ovarian cyst formation without affecting ovarian response or clinical pregnancy rates (
      • Biljan M.M.
      • Mahutte N.G.
      • Dean N.
      • Hemmings R.
      • Bissonnette F.
      • Tan S.L.
      Effects of pretreatment with an oral contraceptive on the time required to achieve pituitary suppression with gonadotrophin-releasing hormone analogues and on subsequent implantation and pregnancy rates.
      ). However, another prospective non-randomized study including 113 women with PCOS undergoing the GnRHa long protocol showed that oral contraceptive pretreatment was associated with lower clinical and ongoing pregnancy rates (
      • Decanter C.
      • Robin G.
      • Thomas P.
      • Leroy M.
      • Lefebvre C.
      • Soudan B.
      • Lefebvre-Khalil V.
      • Leroy-Martin B.
      • Dewailly D.
      First intention IVF protocol for polycystic ovaries: does oral contraceptive pill pretreatment influence COH outcome?.
      ). It could be speculated that this difference is explained by the different ovarian physiological situations and endocrine profiles of the patients included in these studies. PCOS patients are characterized by ovulatory dysfunction, polycystic ovary morphology and endocrine disorders, including hyperinsulinemia and hyperandrogenism, which contribute to endometrial dysfunction and increased miscarriage rate (
      • Giudice L.C.
      Endometrium in PCOS: Implantation and predisposition to endocrine CA.
      ;
      • Lizneva D.
      • Suturina L.
      • Walker W.
      • Brakta S.
      • Gavrilova-Jordan L.
      • Azziz R.
      Criteria, prevalence, and phenotypes of polycystic ovary syndrome.
      ). Therefore, it could be PCOS, not oral contraceptives, that resulted in the poor pregnancy outcomes in previous studies.
      When it comes to the short protocol, the results of this study also suggest that oral contraceptive pretreatment has no effect on cycle outcomes, except for a higher biochemical pregnancy rate in the oral contraceptive group compared with the control group. These results are consistent with a previous study by
      • Duvan C.I.
      • Berker B.
      • Turhan N.O.
      • Satiroglu H.
      Oral contraceptive pretreatment does not improve outcome in microdose gonadotrophin-releasing hormone agonist protocol among poor responder intracytoplasmic sperm injection patients.
      that showed comparable pregnancy rates, numbers of oocytes retrieved and numbers of high-quality embryos between the oral contraceptive pretreatment group and the non-pretreatment group in women undergoing the short protocol.
      Many studies have suggested that there is a continued effect of oral contraceptive pretreatment during the previous cycle on the LH concentration during ovarian stimulation. It has been reported that oral contraceptive pretreatment is associated with lower LH concentration on the day of HCG trigger (
      • Kolibianakis E.M.
      • Papanikolaou E.G.
      • Camus M.
      • Tournaye H.
      • Van Steirteghem A.C.
      • Devroey P.
      Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients stimulated with GnRH antagonists and recombinant FSH for IVF.
      ). In addition, a previous study by the current authors in women with PCOS also showed lower serum LH concentrations and thinner endometrium in the oral contraceptive pretreatment group compared with the non-pretreatment group (
      • Wei D.
      • Shi Y.
      • Li J.
      • Wang Z.
      • Zhang L.
      • Sun Y.
      • Zhou H.
      • Xu Y.
      • Wu C.
      • Liu L.
      • Wu Q.
      • Zhuang L.
      • Du Y.
      • Li W.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.
      ). In the present study, on the day of HCG trigger, although there was a statistical difference in LH concentrations between oral contraceptive groups and control groups for both the long protocol and the short protocol, the difference had no clinical relevance and might reflect the inherent weakness of attempting to match groups in a retrospective manner.
      LH is important for follicle development and oocyte maturation (
      • Hillier S.G.
      Gonadotrophic control of ovarian follicular growth and development.
      ), and
      • Kolibianakis E.M.
      • Papanikolaou E.G.
      • Camus M.
      • Tournaye H.
      • Van Steirteghem A.C.
      • Devroey P.
      Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients stimulated with GnRH antagonists and recombinant FSH for IVF.
      showed that persistently lower LH concentrations as a result of oral contraceptive pretreatment are associated with increased miscarriage rate. It has also been reported that lower LH concentrations caused by oral contraceptive pretreatment are associated with poor cycle outcomes in women undergoing the GnRH antagonist protocol (
      • Meldrum D.R.
      • Scott Jr., R.T.
      • Levy M.J.
      • Alper M.M.
      • Noyes N.
      Oral contraceptive pretreatment in women undergoing controlled ovarian stimulation in ganirelix acetate cycles may, for a subset of patients, be associated with low serum luteinizing hormone levels, reduced ovarian response to gonadotrophins, and early pregnancy loss.
      ;
      • Wei D.
      • Shi Y.
      • Li J.
      • Wang Z.
      • Zhang L.
      • Sun Y.
      • Zhou H.
      • Xu Y.
      • Wu C.
      • Liu L.
      • Wu Q.
      • Zhuang L.
      • Du Y.
      • Li W.
      • Zhang H.
      • Legro R.S.
      • Chen Z.J.
      Effect of pretreatment with oral contraceptives and progestins on IVF outcomes in women with polycystic ovary syndrome.
      ). However, in this work the LH concentrations in both the oral contraceptive and control groups were still within the physiological range and therefore did not influence oocyte quality or endometrial thickness, and thus cycle outcomes were unaffected in the oral contraceptive group compared with the control group.
      The endometrium is also a key factor during embryo implantation (
      • Mikołajczyk M.
      • Skrzypczak J.
      Endometrial receptivity– can it be diagnosed and controlled? and why does it matter?.
      ;
      • Oliveira J.B.
      • Baruffi R.L.
      • Mauri A.L.
      • Petersen C.G.
      • Borges M.C.
      • Franco J.G.
      Endometrial ultrasonography as a predictor of pregnancy in an in-vitro fertilization programme after ovarian stimulation and gonadotrophin-releasing hormone and gonadotrophins.
      ). In women undergoing the GnRH antagonist protocol, oral contraceptive pretreatment has been reported to be associated with asynchrony between the embryo and the endometrium, which might result in a thinner endometrium and lower clinical pregnancy rate (
      • Kolibianakis E.M.
      • Papanikolaou E.G.
      • Camus M.
      • Tournaye H.
      • Van Steirteghem A.C.
      • Devroey P.
      Effect of oral contraceptive pill pretreatment on ongoing pregnancy rates in patients stimulated with GnRH antagonists and recombinant FSH for IVF.
      ). Although in the current study there was a statistical difference in endometrial thickness between oral contraceptive groups and control groups for both the long protocol and the short protocol, the difference had no clinical relevance. Thus, it is likely that oral contraceptives have a negative effect on the endometrium in the GnRH antagonist protocol but do not significantly affect it in the GnRHa protocol. The difference suggests a smaller effect of oral contraceptives on the endometrium in the GnRHa protocol than the GnRH antagonist protocol, but the underlying mechanism behind this difference is uncertain and requires further exploration. Remarkably, patients enrolled in the present study had normal endometrium; therefore, for patients with thin endometrium or impaired endometrial receptivity the effects of oral contraceptives on the endometrium and pregnancy rate need more attention.
      In a recent meta-analysis,
      • Farquhar C.
      • Rombauts L.
      • Kremer J.A.
      • Lethaby A.
      • Ayeleke R.O.
      Oral contraceptive pill, progestogen or oestrogen pretreatment for ovarian stimulation protocols for women undergoing assisted reproductive techniques.
      concluded that oral contraceptives prior to the GnRH antagonist protocol have a significant adverse effect on cycle outcomes in both PCOS patients and healthy controls; however, the results of the current study indicate that oral contraceptive pretreatment has no effect on IVF outcomes in either the GnRHa long protocol or short protocol. Speculatively, this difference might be due to the time needed for the recovery of pituitary and ovarian activity after oral contraceptive suspension (
      • Klein T.A.
      • Mishell D.R.
      Gonadotrophin, prolactin, and steroid hormone levels after discontinuation of oral contraceptives.
      ;
      • van Heusden A.M.
      • Fauser B.C.
      Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives.
      ), which leads to different endocrine profiles when ovarian stimulation is started with different protocols. It has also been suggested that endocrine profiles at the beginning of ovarian stimulation play an important role in cycle outcomes (
      • Garcia-Velasco J.A.
      • Bermejo A.
      • Ruiz F.
      • Martinez-Salazar J.
      • Requena A.
      • Pellicer A.
      Cycle scheduling with oral contraceptive pills in the GnRH antagonist protocol versus the long protocol: a randomized, controlled trial.
      ;
      • Kolibianakis E.M.
      • Zikopoulos K.
      • Smitz J.
      • Camus M.
      • Tournaye H.
      • Van Steirteghem A.C.
      • Devroey P.
      Elevated progesterone at initiation of stimulation is associated with a lower ongoing pregnancy rate after IVF using GnRH antagonists.
      ).
      Despite the large cohort of patients that was enrolled in this study, a few limitations need to be mentioned. First, the data were retrospectively collected from only one clinical centre. Second, whether or not the patient underwent oral contraceptive pretreatment was completely dependent on the discretion of the clinician, without any strict criteria, and thus there might be a selection bias. Additionally, two types of oral contraceptives with different components were used in the study, and any differences in effect between the two oral contraceptive types were unclear.
      This large sample study suggests that oral contraceptive pretreatment prior to the GnRHa long protocol or short protocol has no effect on IVF outcomes.

      Acknowledgements

      The authors thank all of their colleagues for technical support. This study was supported by grants from the National Key Research and Developmental Program of China (2017YFC1001100) and the National Natural Science Foundation of China (81522018, 81430029, 81471509, 81771541, 81701404 and 31601198).

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      Biography

      Lan Xu is pursuing his PhD at the Center for Reproductive Medicine of Shandong University, which is one of the largest IVF centres in China and is a pioneer in IVF, oocyte cryopreservation, reproductive endocrinology and genetic diseases.
      Key message
      Oral contraceptive pretreatment has no effect on IVF outcomes in either the gonadotrophin-releasing hormone agonist (GnRHa) long protocol or short protocol. This study provided further information on oral contraceptive pretreatment in the GnRHa protocol.