Strategies to reduce multiple pregnancies during medically assisted reproduction
2020; Elsevier BV; Volume: 114; Issue: 4 Linguagem: Inglês
10.1016/j.fertnstert.2020.07.022
ISSN1556-5653
AutoresChristina Bergh, Mohan S. Kamath, Rui Wang, Sarah Lensen,
Tópico(s)Reproductive Biology and Fertility
ResumoMultiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates. Although this procedure is used successfully in many countries, it ought to be implemented broadly to improve the health of the children. One at a time should be the normal routine. Multiple birth rates after fertility treatment are still high in many countries. Multiple births are associated with increased rates of preterm birth and low birth weight babies, in turn increasing the risk of severe morbidity for the children. The multiple birth rates vary in different countries between 2% and 3% and up to 30% in some settings. Elective single-embryo transfer, particularly in combination with frozen-embryo transfer and milder stimulation in ovulation induction/intrauterine insemination, to avoid multifollicular development is an effective strategy to decrease the multiple birth rates while still achieving acceptable live-birth rates. Although this procedure is used successfully in many countries, it ought to be implemented broadly to improve the health of the children. One at a time should be the normal routine. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/30523 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/posts/30523 The aim of all fertility treatments is the delivery of a healthy baby. Different medically assisted reproduction treatments exist to reach this goal, including in vitro fertilization (IVF), intracytoplasmic sperm injection (ICSI), oocyte donation (OD), ovulation induction (OI), and ovarian stimulation with intrauterine insemination (OS-IUI). Despite the high success rate of assisted reproductive technologies (ART), with more than 9 million children born worldwide (1European Society of Human Reproduction and EmbryologyART fact sheet.https://www.eshre.eu/-/media/sitecore-files/Press-room/ART-fact-sheet-2020-data-2016.pdfDate: 2020Google Scholar), high multiple birth rates present a substantial problem. A Finnish study suggested more than 20 years ago that it is possible to achieve satisfactory live-birth rates by transferring only one embryo at a time (2Vilska S. Tiitinen A. Hyden-Granskog C. Hovatta O. Elective transfer of one embryo results in an acceptable pregnancy rate and eliminates the risk of multiple birth.Hum Reprod. 1999; 14: 2392-2395Crossref PubMed Scopus (276) Google Scholar). Randomized controlled trials (RCTs) later confirmed this finding, in particular when fresh and frozen cycles were combined to yield a cumulative live-birth rate (3Thurin A. Hausken J. Hillensjo T. Jablonowska B. Pinborg A. Strandell A. et al.Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization.N Engl J Med. 2004; 351: 2392-2402Crossref PubMed Scopus (536) Google Scholar, 4McLernon D.J. Harrild K. Bergh C. Davies M.J. de Neubourg D. Dumoulin J.C. et al.Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.BMJ. 2010; 341: c6945Crossref PubMed Scopus (51) Google Scholar). Although many countries now have adopted a single-embryo transfer (SET) policy, thereby reducing multiple births dramatically and improving maternal and perinatal outcomes, there is a huge variation in multiple births after ART around the world, ranging from 2% to 3% to more than 30% (5Newman J. Fitzgerald O. Paul R. Chambers G. Assisted reproductive technology in Australia and New Zealand 2017. National Perinatal Epidemiology and Statistics Unit, University of New South Wales Sydney, Sydney2019https://npesu.unsw.edu.au/sites/default/files/npesu/surveillances/Assisted%20Reproductive%20Technology%20in%20Australia%20and%20New%20Zealand%202017.pdfGoogle Scholar, 6Q-IVF: Nationellt kvalitetsregister for assisterad befruktning. MedSciNet AB, 2019https://www.qivf.seDate accessed: June 1, 2019Google Scholar, 7De Geyter C. Calhaz-Jorge C. Kupka M.S. Wyns C. Mocanu E. Motrenko T. et al.ART in Europe, 2015: results generated from European registries by ESHRE.Hum Reprod Open. 2020; 2020: hoz038Crossref PubMed Google Scholar). For non-ART treatments, including OI and OS-IUI, the high and varying multiple birth rate is also a big problem. We will summarize the literature on strategies to reduce multiple birth rates using both ART and non-ART. This narrative review is based on RCTs, systematic reviews/meta-analyses, and large observational studies, when relevant. In the early days of IVF, the process involved the transfer of multiple embryos to achieve what was considered "reasonable" pregnancy rates. As IVF success rates increased, attention turned to the increased risk of multiple pregnancy and consequently poorer obstetric and neonatal outcomes. Due to the high medical, economic, and social costs of multiple birth, various strategies were formulated with the aim of achieving a single healthy baby (8ESHRE Capri Workshop GroupMultiple gestation pregnancy. The ESHRE Capri Workshop Group.Hum Reprod. 2000; 15: 1856-1864Crossref PubMed Google Scholar). In IVF settings a strategy of reducing the number of embryos transferred was suggested, and ultimately elective single-embryo transfer (eSET) was proposed as a key method to reduce multiple pregnancy (9Practice Committee of Society for Assisted Reproductive Technology; Practice Committee of the American Society for Reproductive MedicineElective single-embryo transfer.Fertil Steril. 2012; 97: 835-842Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). Although there has been a gradual increase in the number of SET cycles being performed across the world, there is a substantial geographical variation in the uptake of the SET policy (7De Geyter C. Calhaz-Jorge C. Kupka M.S. Wyns C. Mocanu E. Motrenko T. et al.ART in Europe, 2015: results generated from European registries by ESHRE.Hum Reprod Open. 2020; 2020: hoz038Crossref PubMed Google Scholar, 10Adamson G.D. de Mouzon J. Chambers G.M. Zegers-Hochschild F. Mansour R. Ishihara O. et al.International Committee for Monitoring Assisted Reproductive Technology: world report on assisted reproductive technology, 2011.Fertil Steril. 2018; 110: 1067-1080Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 11Maheshwari A. Griffiths S. Bhattacharya S. Global variations in the uptake of single embryo transfer.Hum Reprod Update. 2011; 17: 107-120Crossref PubMed Scopus (112) Google Scholar). In Australia, New Zealand, and some Scandinavian countries, 90% of embryo transfers were SET in 2017 (5Newman J. Fitzgerald O. Paul R. Chambers G. Assisted reproductive technology in Australia and New Zealand 2017. National Perinatal Epidemiology and Statistics Unit, University of New South Wales Sydney, Sydney2019https://npesu.unsw.edu.au/sites/default/files/npesu/surveillances/Assisted%20Reproductive%20Technology%20in%20Australia%20and%20New%20Zealand%202017.pdfGoogle Scholar, 6Q-IVF: Nationellt kvalitetsregister for assisterad befruktning. MedSciNet AB, 2019https://www.qivf.seDate accessed: June 1, 2019Google Scholar). The United States also has reported an increasing use of SET; which is now at 71% of all transfers (12Centers for Disease Control and Prevention. Analyses of the National ART Surveillance System (NASS) data. Written communication with the Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention. April 29, 2020.Google Scholar). However, in many other areas multiple embryos are more often transferred. For example, in eastern Europe the SET rate is low, and consequently the SET rate for Europe was 38% of all transfers in 2015 (7De Geyter C. Calhaz-Jorge C. Kupka M.S. Wyns C. Mocanu E. Motrenko T. et al.ART in Europe, 2015: results generated from European registries by ESHRE.Hum Reprod Open. 2020; 2020: hoz038Crossref PubMed Google Scholar). However, there have been ongoing concerns regarding lower live-birth rates associated with SET compared with double-embryo transfer (DET) after a single fresh transfer (3Thurin A. Hausken J. Hillensjo T. Jablonowska B. Pinborg A. Strandell A. et al.Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization.N Engl J Med. 2004; 351: 2392-2402Crossref PubMed Scopus (536) Google Scholar, 4McLernon D.J. Harrild K. Bergh C. Davies M.J. de Neubourg D. Dumoulin J.C. et al.Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.BMJ. 2010; 341: c6945Crossref PubMed Scopus (51) Google Scholar, 13Van Montfoort A.P. Fiddelers A.A. Janssen J.M. Derhaag J.G. Dirksen C.D. Dunselman G.A. et al.In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial.Hum Reprod. 2006; 21: 338-343Crossref PubMed Scopus (170) Google Scholar). It should be acknowledged that this is perhaps not the most informative comparison for today's IVF practice, given the imbalance of embryos transferred and success of cryopreservation methods. Instead, fresh eSET with subsequent frozen transfer could be an effective policy in reducing multiple births and simultaneously yielding cumulative live-birth rates that are comparable with a single cycle of DET (3Thurin A. Hausken J. Hillensjo T. Jablonowska B. Pinborg A. Strandell A. et al.Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization.N Engl J Med. 2004; 351: 2392-2402Crossref PubMed Scopus (536) Google Scholar, 4McLernon D.J. Harrild K. Bergh C. Davies M.J. de Neubourg D. Dumoulin J.C. et al.Clinical effectiveness of elective single versus double embryo transfer: meta-analysis of individual patient data from randomised trials.BMJ. 2010; 341: c6945Crossref PubMed Scopus (51) Google Scholar). In three trials, one from Finland (n = 144), one from the Netherlands (n = 308), and one from the United States (n = 100), fresh eSET was compared with fresh DET, either at the cleavage or blastocyst stage (13Van Montfoort A.P. Fiddelers A.A. Janssen J.M. Derhaag J.G. Dirksen C.D. Dunselman G.A. et al.In unselected patients, elective single embryo transfer prevents all multiples, but results in significantly lower pregnancy rates compared with double embryo transfer: a randomized controlled trial.Hum Reprod. 2006; 21: 338-343Crossref PubMed Scopus (170) Google Scholar, 14Martikainen H. Tiitinen A. Tomas C. Tapanainen J. Orava M. Tuomivaara L. et al.One versus two embryo transfer after IVF and ICSI: a randomized study.Hum Reprod. 2001; 16: 1900-1903Crossref PubMed Scopus (328) Google Scholar, 15Abuzeid O.M. Deanna J. Abdelaziz A. Joseph S.K. Abuzeid Y.M. Salem W.H. et al.The impact of single versus double blastocyst transfer on pregnancy outcomes: a prospective, randomized control trial.Facts Views Vis Obgyn. 2017; 9: 195-206PubMed Google Scholar). All trials showed higher pregnancy/live-birth rates after DET, although not statistically significant in the Finnish trial, and statistically significantly lower multiple birth rates in the eSET group. In absolute figures the pregnancy/live-birth rates were increased up to almost double in the DET group while multiple pregnancy/birth rates were decreased from at highest 39% in the DET group to 0 in the eSET group. Two trials have compared the strategy of a fresh eSET followed by single frozen-embryo transfer (FET), compared with DET. The first RCT performed in the Nordic countries included women aged <36 years undergoing their first or second IVF, and had at least two good-quality cleavage-stage embryos available on the day of transfer (3Thurin A. Hausken J. Hillensjo T. Jablonowska B. Pinborg A. Strandell A. et al.Elective single-embryo transfer versus double-embryo transfer in in vitro fertilization.N Engl J Med. 2004; 351: 2392-2402Crossref PubMed Scopus (536) Google Scholar). Women assigned in the eSET arm (n = 330), underwent a fresh eSET followed by single frozen-thawed embryo transfer (if the fresh cycle did not result in a live birth). In the DET arm (n = 331), fresh transfer of two embryos was performed. After a single fresh cycle of eSET, the live-birth rate (27.6% vs. 42.9%; P<.001) was statistically significantly lower than after DET. However, there was no substantial difference in cumulative live births (38.8% vs. 42.9%; P=.30) following the SET strategy compared with DET. There was a dramatic reduction in multiple births (0.8% vs. 33.1%; P<.001) after eSET compared with DET. The second RCT was based on a total of 175 women aged <38 years undergoing their first IVF cycle (16Lopez-Regalado M.L. Clavero A. Gonzalvo M.C. Serrano M. Martinez L. Mozas J. et al.Randomised clinical trial comparing elective single-embryo transfer followed by single-embryo cryotransfer versus double embryo transfer.Eur J Obstet Gynecol Reprod Biol. 2014; 178: 192-198Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar). Only cleavage-stage fresh or vitrified-thawed embryos were transferred. The cumulative live-birth rate was similar in both groups (38 of 84, 45.2% vs. 38 of 91, 41.8%; P=.60), but there was dramatic reduction in multiple pregnancy rate with the eSET approach (0 vs. 9 of 34, 26.4%; P<.05). A trial by Lukassen et al. (17Lukassen H.G. Braat D.D. Wetzels A.M. Zielhuis G.A. Adang E.M. Scheenjes E. et al.Two cycles with single embryo transfer versus one cycle with double embryo transfer: a randomized controlled trial.Hum Reprod. 2005; 20: 702-708Crossref PubMed Scopus (190) Google Scholar) investigated the effectiveness of two cycles of fresh SET (n = 54) versus single fresh cycle of DET (n = 53). They included women aged 38 years undergoing their first IVF cycle. Up to four DET cycles (n = 23) were performed in one arm; in the other, a maximum of three TET (n = 22) cycles were performed (15Abuzeid O.M. Deanna J. Abdelaziz A. Joseph S.K. Abuzeid Y.M. Salem W.H. et al.The impact of single versus double blastocyst transfer on pregnancy outcomes: a prospective, randomized control trial.Facts Views Vis Obgyn. 2017; 9: 195-206PubMed Google Scholar). No statistically significant difference was reported in the cumulative term live-birth rates after DET (47.3% vs. 40.5%) compared with TET. However, the multiple pregnancy rate was statistically significantly lower after DET (0 vs. 30%; P=.05). It was suggested that in women aged >38 years, a DET strategy could reduce multiple births and yield similar cumulative term live births compared with TET, at the cost of an increase in the number of treatment cycles. A large study involving retrospective analysis of 44,236 IVF cycles within the Human Fertilisation and Embryology Authority (HFEA) database reported that in women with ≥4 fertilized oocytes the live-birth rate did not statistically significantly differ after transfer of two instead of three embryos (21Templeton A. Morris J.K. Reducing the risk of multiple births by transfer of two embryos after in vitro fertilization.N Engl J Med. 1998; 339: 573-577Crossref PubMed Scopus (358) Google Scholar). However, the multiple birth rates were 4% to 11% lower compared with TET, depending on the age after DET. Further, a large observational study has indicated that the overall cumulative live-birth rates per oocyte aspiration are high (up to 45%), independent of women's age, when more than 15 oocytes can be retrieved and still keep a low multiple birth rate (22Magnusson A. Kallen K. Thurin-Kjellberg A. Bergh C. The number of oocytes retrieved during IVF: a balance between efficacy and safety.Hum Reprod. 2018; 33: 58-64Crossref PubMed Scopus (74) Google Scholar). In summary, eSET, particularly in combination with FET, appears to be a highly effective strategy for reducing risk of multiple births while still keeping high live-birth rates after IVF. However, the downside of eSET policy is additional cost of FET cycles and increased time to pregnancy. Ovulation induction and OS-IUI are recommended as the first-line treatment for couples with anovulation including polycystic ovary syndrome (PCOS) (23Teede H.J. Misso M.L. Costello M.F. Dokras A. Laven J. Moran L. et al.Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.Hum Reprod. 2018; 33: 1602-1618Crossref PubMed Scopus (583) Google Scholar, 24Teede H.J. Misso M.L. Costello M.F. Dokras A. Laven J. Moran L. et al.Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.Fertil Steril. 2018; 110: 364-379Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar) and unexplained or mild male factor infertility (25Cohlen B. Bijkerk A. Van der Poel S. Ombelet W. IUI: review and systematic assessment of the evidence that supports global recommendations.Hum Reprod Update. 2018; 24: 300-319Crossref PubMed Scopus (42) Google Scholar, 26Practice Committee of the American Society for Reproductive MedicineEvidence-based treatments for couples with unexplained infertility: a guideline.Fertil Steril. 2020; 113: 305-322Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar), respectively. Therefore, these treatments are frequently used modalities for couples with infertility before IVF. The commonly used medications for OI and OS-IUI include oral agents such as antiestrogens (clomiphene citrate [CC]) aromatase inhibitors (letrozole), and injectable medications (gonadotropins). The biological mechanism of these medications involves processes to either increase the exogenous gonadotropin levels (gonadotropins) or increase the endogenous gonadotropins by blocking the estrogen receptor (antiestrogens such as CC) or by inhibiting the conversion of androgens to estrogen and thereby lowering the estrogen levels (aromatase inhibitors such as letrozole) (27Macklon N.S. Stouffer R.L. Giudice L.C. Fauser B.C. The science behind 25 years of ovarian stimulation for in vitro fertilization.Endocr Rev. 2006; 27: 170-207Crossref PubMed Scopus (375) Google Scholar). Consequently, increased gonadotropins levels can result in multiple follicular development and subsequent dizygotic multiple gestations. Data on non-ART treatments are not documented in many national registries, which makes such data of very limited availability, especially on OI. The most recent reports from registry data showed that twin delivery rates after IUI with the partner's sperm were 8.9% (triplet delivery rate 0.5%) in Europe in 2015 (7De Geyter C. Calhaz-Jorge C. Kupka M.S. Wyns C. Mocanu E. Motrenko T. et al.ART in Europe, 2015: results generated from European registries by ESHRE.Hum Reprod Open. 2020; 2020: hoz038Crossref PubMed Google Scholar) and 6% in China in 2016 (28Bai F. Wang D.Y. Fan Y.J. Qiu J. Wang L. Dai Y. et al.Assisted reproductive technology service availability, efficacy and safety in mainland China: 2016.Hum Reprod. 2020; 35: 446-452Crossref PubMed Scopus (40) Google Scholar). Earlier data from the International Committee for Monitoring Assisted Reproductive Technology showed that among 202,653 IUI cycles with the partner's sperm provided by 37 countries in 2011 (not including Australia, Canada, China, India, or the United States) the overall multiple delivery rate after IUI with the partner's sperm was 10.6%, ranging from 0 to 30% in different countries (10Adamson G.D. de Mouzon J. Chambers G.M. Zegers-Hochschild F. Mansour R. Ishihara O. et al.International Committee for Monitoring Assisted Reproductive Technology: world report on assisted reproductive technology, 2011.Fertil Steril. 2018; 110: 1067-1080Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar). It is worth noting that these data also include unstimulated IUI cycles and were calculated per delivery resulting from a single cycle. Therefore, the actual multiple birth rates after OS-IUI are likely even higher. The role of multifollicular development on multiple gestation is well understood. A meta-analysis of 14 studies including 11,599 IUI cycles showed that, compared with monofollicular IUI cycles, dual-, triple- and quadruple-follicular IUI cycles increased multiple pregnancy rates by 6%, 14%, and 10% points, respectively, while simultaneously increasing pregnancy rates by 5%, 8%, and 8% points, respectively (29Van Rumste M.M. Custers I.M. van der Veen F. van Wely M. Evers J.L. Mol B.W. The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis.Hum Reprod Update. 2008; 14: 563-570Crossref PubMed Scopus (121) Google Scholar). Therefore, the proposed strategies to reduce multiple gestation include the use of milder OI or OS strategies to prevent multiple follicular development, and upon observing that multiple follicles are developed, the cancellation of cycle or aspiration of excess follicles at the time of luteinizing hormone (LH) surge or human chorionic gonadotropin (hCG) trigger are alternative options (25Cohlen B. Bijkerk A. Van der Poel S. Ombelet W. IUI: review and systematic assessment of the evidence that supports global recommendations.Hum Reprod Update. 2018; 24: 300-319Crossref PubMed Scopus (42) Google Scholar). The choice of dose and type of OI medications are important. The optimal OI and OS-IUI strategy should aim to increase the cumulative live-birth rate without increasing the multiple pregnancy rate. The evidence from RCTs comparing different doses of the same medications are very limited. The consensus has been to start from a low dose to optimize monofollicular development, especially for gonadotropin protocols (23Teede H.J. Misso M.L. Costello M.F. Dokras A. Laven J. Moran L. et al.Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.Hum Reprod. 2018; 33: 1602-1618Crossref PubMed Scopus (583) Google Scholar, 24Teede H.J. Misso M.L. Costello M.F. Dokras A. Laven J. Moran L. et al.Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome.Fertil Steril. 2018; 110: 364-379Abstract Full Text Full Text PDF PubMed Scopus (385) Google Scholar, 26Practice Committee of the American Society for Reproductive MedicineEvidence-based treatments for couples with unexplained infertility: a guideline.Fertil Steril. 2020; 113: 305-322Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar). For women with PCOS, the most recent Cochrane review showed that, compared with CC, letrozole increased the live-birth rate (OR 1.68; 95% CI 1.42 to 1.99; 2,954 participants; 13 studies, moderate quality evidence) without increasing the multiple pregnancy rate (1.7% with CC vs. 1.3% with letrozole; OR 0.69; 95% CI 0.41–1.16; 3,579 participants; 17 studies) (30Franik S. Eltrop S.M. Kremer J.A. Kiesel L. Farquhar C. Aromatase inhibitors (letrozole) for subfertile women with polycystic ovary syndrome.Cochrane Database Syst Rev. 2018; 5CD010287PubMed Google Scholar). The findings are consistent with those from a subsequent individual participant data meta-analysis (31Wang R. Li W. Bordewijk E.M. Legro R.S. Zhang H. Wu X. et al.First-line ovulation induction for polycystic ovary syndrome: an individual participant data meta-analysis.Hum Reprod Update. 2019; 25: 717-732Crossref PubMed Scopus (31) Google Scholar). A network meta-analysis of 57 RCTs on 8,082 women with World Health Organization (WHO) II anovulation compared different first-line OI strategies; the analysis found that letrozole is the only treatment to show a statistically significantly higher live-birth rate with a low incidence of multiple pregnancy whereas gonadotropins ranked highest on increasing multiple pregnancy (32Wang R. Kim B.V. van Wely M. Johnson N.P. Costello M.F. Zhang H. et al.Treatment strategies for women with WHO group II anovulation: systematic review and network meta-analysis.BMJ. 2017; 356: j138Crossref PubMed Scopus (67) Google Scholar). In women who did not achieve pregnancy after the use of CC, another Cochrane review reported that gonadotropins increased live-birth rates compared with further application of CC (RR 1.24; 95% CI 1.05–1.46; one trial, N = 661, moderate quality evidence) without increasing multiple pregnancy (RR 0.89; 95% CI 0.33–2.44; one trial, N = 661) (33Weiss N.S. Kostova E. Nahuis M. Mol B.W.J. van der Veen F. van Wely M. Gonadotrophins for ovulation induction in women with polycystic ovary syndrome.Cochrane Database Syst Rev. 2019; 1CD010290PubMed Google Scholar). Only one trial of this comparison is available, and in this study if more than three dominant follicles (≥18 mm) were present the cycle was cancelled (34Weiss N.S. Nahuis M.J. Bordewijk E. Oosterhuis J.E. Smeenk J.M. Hoek A. et al.Gonadotrophins versus clomifene citrate with or without intrauterine insemination in women with normogonadotropic anovulation and clomifene failure (M-OVIN): a randomised, two-by-two factorial trial.Lancet. 2018; 391: 758-765Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar). Therefore
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