Modified natural cycle IVF and mild IVF: a 10 year Swedish experience

Reproductive BioMedicine Online (2010) 20, 156 162 www.sciencedirect.com www.rbmonline.com ARTICLE Modified natural cycle IVF and mild IVF: a 10 year Swedish experience Arthur Aanesen *, Karl-Gösta Nygren, Lars Nylund IVF Unit, Queen Sophia Hospital, Box 5605, 114 86 Stockholm, Sweden * Corresponding author. E-mail address: arthur.aanesen@telia.com (A Aanesen). Dr Aanesen completed his studies in medicine in 1990 at the Faculty of Medicine, University of Oslo, Norway. After his internship, he started his residency at the Department of Gynaecology and Obstetrics, Karolinska Hospital, Sweden, Stockholm in 1992, and became a specialist in 1997. He has had a research interest in sperm physiology and andrology and received his PhD 1998. Since 2001, Dr Aanesen has been working at the IVF Unit, Queen Sophia Hospital. His present research focuses on intracellular signalling and mild IVF. Abstract Modified natural cycle IVF (mnc-ivf) or mild IVF (m-ivf) was offered to selected patients between 1996 and 2007; 43 patients during 129 cycles were treated with mnc-ivf and 145 couples during 250 cycles were treated with m-ivf. Comparison with outcome from conventional IVF cycles during the same time period and in the same clinic was performed. Although 53.5 and 39.6% of started cycles respectively never reached embryo transfer, the ongoing pregnancy rates per embryo transfer were 26.7% for mnc-ivf and 27.2% for m-ivf. During the same time period, cancellation rate for conventional IVF was 13.7% and the ongoing pregnancy rate per embryo transfer was 34.3%. For patients 38 years of age, the ongoing pregnancy rate per embryo transfer was 17.5% in the m- IVF group. None of the patients aged 38 years in the mnc-ivf group achieved an ongoing pregnancy. For patients treated with conventional IVF, the 38 years of age pregnancy rate per embryo transfer was 27.0%. Costs of medication for m-ivf and mnc-ivf were 96.3 and 97.5% less than for the least expensive conventional IVF cycle respectively. Pregnancy rates per embryo transfer are acceptable for these treatment modalities, the cost for medication is low, risks for complications are dramatically reduced, and the treatments may be more psychologically acceptable to the patients. RBMOnline ª 2009, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. KEYWORDS: clomiphene citrate, low cost IVF, mild IVF, modified natural cycle IVF, natural cycle Introduction The trend towards single embryo transfer and increasing focus on patient friendly IVF has lately led to a growing interest in modified natural cycle IVF (mnc-ivf) and mild IVF (m-ivf). Several countries now have legislation regulating the number of embryos transferred per treatment cycle, and population studies of children born after IVF clearly show the health benefits from treatments leading to deliveries of singletons (Bergh 2007; Nygren et al. 2007). mnc- IVF and m-ivf are both treatment modalities involving less medical intervention, leading to a reduced number of oocytes retrieved. Stimulation protocols vary between clinics, and until recently there was no consensus on the nomenclature used to describe these treatments. The International Society for Mild Approaches to Assisted Reproduction 1472-6483/$ - see front matter ª 2009, Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.rbmo.2009.10.017

Minimal intervention IVF in Sweden 157 published guidelines for terminology and description of protocols (Nargund et al., 2007; see also Edwards et al., 2007). Although the nomenclature is now settled, the terminology still encompasses a wide variety of clinical approaches to the mnc-ivf and m-ivf treatments (Verberg et al., 2009a,b). Treatment strategies for mnc-ivf and m-ivf include FSH stimulation, clomiphene citrate (CC) and use of gonadotrophin-releasing hormone (GnRH) antagonists, as well as luteal phase support administered both vaginally and as injections (Kolibianakis et al., 2004; Pelinck et al., 2006; Teramoto and Kato, 2007). The present study approaches both treatment modalities in a minimalistic way, exploring the potential of IVF as a treatment when there is a demand for less intervention using fewer resources. New studies are still needed to optimize these protocols in an era when IVF clinics meet new challenges in terms of cost-effectiveness, minimal intervention, maximizing results and singleton deliveries. This study presents a 10 year retrospective study describing mnc-ivf and m-ivf in a Swedish private IVF clinic during the years 1996 2007. Materials and methods mnc-ivf or m-ivf was offered to selected patients, based on both medical criteria and the woman s desire for a low interference treatment. Medical reasons for the choice of a mild approach included previous history of ovarian hyperstimulation syndrome (OHSS), undesired side effects of drugs during previous full scale treatments, and medical conditions requiring none or low grade hormonal stimulation (e.g. previous breast cancer). Only patients with regular menstrual cycles were accepted. The study was carried out in a private IVF centre (IVF unit at Queen Sophia Hospital, Stockholm, Sweden). The centre performs 450 600 fresh IVF cycles annually; more than 95% of the cycles are conventional IVF/intracytoplasmic sperm injection (ICSI) protocols using gonadotrophin stimulation and GnRH agonists or antagonists. A treatment cycle (mnc-ivf or m-ivf) was defined as started when the first ultrasound was performed and accepted as normal. Ovarian pathology such as functional cysts or other abnormal findings at the entry ultrasound led to exclusion prior to start. Obvious endometrial pathology also led to exclusion prior to start of the treatment cycle. Modified natural cycle IVF Between 1996 and 2007, 43 patients during 129 cycles were treated with mnc-ivf (Figure 1). Monitoring included one baseline ultrasound examination between cycle days 1 4 and additional ultrasound examinations in combination with analyses of serum oestradiol concentrations starting on cycle day 9. Ovulation induction was given, as 5000 IU of human chorionic gonadotrophin (HCG), when the dominant follicle reached 17 19 mm and with oestradiol concentrations between 500 and 750 pmol/l. Oocyte retrieval was performed approximately 37 h later. Flushing of the follicles was performed on occasional patients, depending on the operating gynaecologist, but not as routine procedure. All follicles >14 15 mm were punctured. Oocyte retrieval was performed 7 days/week, daytime only. Embryos were transferred on day 2 following oocyte retrieval and no luteal phase support was administered. Between 1997 and 2007, 145 couples during 250 cycles were treated with m-ivf (Figure 2). Ovarian stimulation was performed with clomiphene citrate, 100 mg daily on cycle days 3 7. Ovulation induction with 5000 IU HCG was given when the dominant follicle was 18 mm. Oocyte retrieval was performed approximately 37 h later. Flushing of the follicles was performed on occasional patients depending on the operating gynaecologist, but not as routine procedure. All follicles >14 15 mm were punctured. Embryos were Figure 1 Modified natural cycle IVF. Entry ultrasound examination was performed on cycle day 1 5 and thereafter repeated ultrasound and oestradiol analysis commencing on cycle day 9 were performed until the leading follicle reached 17 19 mm with oestradiol concentrations between 500 and 750 pmol/l. Ovulation induction was given, as 5000 IU of human chorionic gonadotrophin (HCG). Oocyte retrieval (OR) was performed approximately 37 h later. Embryos were transferred on day 2 following oocyte retrieval. No luteal phase support was given. CD = cycle day; ET = embryo transfer.

158 A Aanesen et al. Figure 2. Ovarian stimulation was performed with clomiphene citrate, 100 mg daily cycle day 3 7. Ovulation induction with 5000 IU human chorionic gonadotrophin (HCG) was given when the dominant follicle was 18 mm. Oocyte retrieval (OR) was performed approximately 37 h later. Embryos were transferred on day 2 following oocyte retrieval. No luteal phase support was given. CD = cycle day; ET = embryo transfer. transferred on day 2 following oocyte retrieval and no luteal phase support was administered. Historical controls All patients treated with conventional IVF/ICSI in the clinic during the years 1997, 1999, 2002, 2004 and 2006 (n = 3068 cycles) served as historical controls regarding IVF/ICSI (%), ongoing pregnancies per started cycle (%), ongoing pregnancies per embryo transfer (%), cancellation rates (%) and results for patients 38 years. Costs of medication The cost for medication regarding each of the treatment modalities was calculated. Price information was obtained from FASS, the catalogue of medical products marketed in Sweden (www.fass.se; accessed 23 October 2009). Prices in euros were based on exchange rates for March 2009. Results Modified natural cycle IVF The mean age of women undergoing mnc-ivf was 34.2 years and mean cycle day 3 FSH for these women was 8.0 ± 5.1 (1.4 24) IU/l (Table 1). The most frequent causes of infertility were unexplained infertility (28%), tubal damage (21%) and male infertility (16%). ICSI was performed in 31.7% of the treatment cycles. Of the 129 cycles started, 40 (31.0%) were cancelled prior to oocyte retrieval, 17 (13.2%) due to premature ovulation and 23 (17.8%) due to other reasons, including non-medical causes. Sixty cycles (46.5%) went on to embryo transfer. All embryo transfers in this group were single embryo transfers. The ongoing pregnancy rate in this group was 12.4% per started cycle and 26.7% per embryo transfer (Table 2). None of the mnc-ivf patients aged 38 or older (n = 8) became pregnant (24 treatment cycles). Table 1 Baseline demographics and clinical characteristics of patients. Parameter Modified natural cycle IVF (n =43) (n=145) Age of women at oocyte retrieval 34.2 ± 3.3 (25 40) [33.7 34.8] 32.8 ± 4.0 (20 44) [33.6 34.9] Duration of infertility (years) 3.0 ± 2.2 (0.5 10) [2.1 3.8] 2.6 ± 1.8 (0.5 10) [2.3 2.9] Primary infertility 30 (69.8) 102 (70.3) FSH on cycle day 3 IU/l 8.0 ± 5.1 (1.4 24) [6.0 8.7] 7.0 ± 3.2 (1.4 20) [6.5 7.5] Previous child 13 (30.2) 43 (29.7) Previous conventional IVF cycles 8 (18.6) 36 (24.8) Cause of infertility (%) Male 16 15 Tubal 21 21 Unexplained 28 33 Other 35 31 Values are means ± SD (range) [95% confidence interval] or number (% of all patients) unless otherwise stated.

Minimal intervention IVF in Sweden 159 Table 2 Cycle characteristic Cycle-specific characteristics of the IVF cycles. Modified natural cycle No. of patients 43 145 No. of cycles started 129 250 Cancelled cycles before oocyte retrieval (n) (% of all cycles) 40 (31.0) 34 (13.6) Due to ovulation Other reasons Due to ovulation Other reasons 17 (13.2) 23 (17.8) 17 (6.8) 17 (6.8) Endometrial thickness at final ultrasound (mm) (mean ± SD (range) [95% CI]) 8.8 ± 1.9 (4.9 16.0) [8.5 9.2] 7.4 ± 1.7 (3.0 13.0) [7.2 7.6] Oocyte retrieval (n) 89 217 Oocyte retrieval with no oocytes (n) (% of oocyte retrieval) 13 (14.6) 15 (6.9) No. of oocytes (oocytes/oocyte retrieval) (mean ± SD 0.9 ± 0.4 (0 2) [0.8 2.1] 1.9 ± 1.4 (0 10) [1.7 1.0] (range) [95% CI]) ICSI (n) (% of ET) 19 (31.7) 45 (29.8) Embryo transfer (n) (%/cycle) 60 (46.5) 151 (60.4) Single embryo transfer (n) (% of ET) 60 (100) 102 (67.5) Embryo transfer per oocyte retrieval (%) 67.4 74.4 Implantation rate (%/transferred embryo) 26.7 22.5 PR (n) (%/cycle;%/et) 16 (12.4; 26.7) 41 (16.4; 27.2) Multiple PR (n) (%/pregnancy;%/delivery) 0 (0.0; 0.0) 4 (9.8; 2.7) OR = oocyte retrieval; PR = pregnancy rate; ET = embryo transfer; ICSI = intracytoplasmic sperm injection. In patients <38 years of age at the time of oocyte retrieval (n = 35), the pregnancy rate per started cycle was 15.2%. The implantation rate for patients <38 years was 30.8% and the take home baby rate per embryo transfer 28.8%. There were no multiple births and no cases of OHSS. The mean age in the m-ivf group was 32.8 years and the mean cycle day 3 FSH was 7.0 ± 3.2 (1.4 20) IU/l (Table 1). The most frequent causes of infertility were unexplained infertility (33%), tubal damage (21%) and male infertility (15%). ICSI was performed in 29.8% of the cycles. Of the 250 cycles started, 34 (13.6%) were cancelled prior to oocyte retrieval, 17 (6.8%) due to premature ovulation and 17 (6.8%) for other reasons. Of the started cycles, 151 (60.4%) went on to embryo transfer. The ongoing pregnancy rate per started cycle was 16.4 and 27.2% per embryo transfer (Table 2). Age related results for patients undergoing m-ivf are shown in Table 3. In the age group <38 years (n = 114), the cancellation rate prior to embryo transfer was 40.0%. In this group, the ongoing pregnancy rate per started cycle was 18.4% and the implantation rate 30.6%. In women 38 years Table 3 : age-specific results. (age <38 years) (age 38 years) No. of patients 114 31 FSH on cycle day 3 IU/l (mean ± SD (range) [95% CI]) 7.0 ± 2.7 (1.4 20) 8.6 ± 4.9 (1.7 20) [6.9 10.3] [6.6 7.4] No. of cycles started (n) 185 65 Cancelled cycles before oocyte retrieval (n) (% of all cycles) 15 (8.1) 8 (12.3) Oocyte retrieval (n) 160 57 No. of oocytes (oocytes/or) (mean ± SD (range) [95% CI]) 1.9 ± 1.5 (0 10) 1.9 ± 1.3 (0 6) [1.5 2.3] [1.7 2.2] ICSI (n) (% of ET) 30 (27.0) 15 (37.5) Embryo transfer (n) (%/cycle) 111 (60.0) 40 (61.5) Embryo transfer per oocyte retrieval (%) 69.4 70.2 Implantation rate (%/transferred embryo) 25.4 15.5 PR (n) (%/cycle;%/et) 34 (18.4; 30.6) 7 (10.8; 17.5) Multiple PR (n) (%/pregnancy;%/delivery) 2 (5.9; 3.0) 2 (28.6; 0) OR = oocyte retrieval; PR = pregnancy rate; ET = embryo transfer; ICSI = intracytoplasmic sperm injection; cd 3 = cycle day 3 of the patient s menstrual cycle. Modified natural cycle IVF, age 38 years: 24 cycles, 8 patients; no pregnancies.

160 A Aanesen et al. (n = 31), the cancellation rate prior to embryo transfer was 38.5%, the ongoing pregnancy rate 10.8% and the implantation rate 15.5% per started cycle. Single embryo transfer was performed in 67.5%. Four twin pregnancies were observed, but due to spontaneous reduction this resulted in one twin delivery. No case of OHSS was observed. The endometrium was considerably thicker in the mnc- IVF group on the day of the final ultrasound as compared with the m-ivf group (Table 2). Historical controls In order to relate results from mnc-ivf and m-ivf to conventional IVF cycles, it was decided to study key figures from conventional IVF cycles performed in the clinic during the years 1997, 1999, 2002, 2004 and 2006. All conventional IVF cycles performed in the clinic during these years were included, totalling 3068 cycles. The ongoing pregnancy rate was 29.6% per started cycle, and 34.3% per embryo transfer. The cancellation rate prior to embryo transfer was 13.7%. Results from these cycles are presented together with key data from the mnc-ivf and m-ivf cycles in Table 4. Costs of medication The cost of medication was calculated for each type of treatment; mnc-ivf, m-ivf and conventional IVF (agonist/ antagonist cycle). The detailed prices can be found in Table 5. The costs of medication for m-ivf and mnc-ivf were 3.7 and 2.5% respectively of the costs for the least expensive conventional IVF cycle. Discussion The results reported in this study are based on consecutive cycles where all patients treated with mnc-ivf (1996 2007) and m-ivf (1997 2007) were included. The retrospective design is due to the limited number of patients who historically have asked for low interference IVF. The lack of randomization is an obvious source of bias, where the good prognosis patients were advised to choose mnc-ivf or m- IVF. An increased demand for light stimulation protocols and a paradigm shift towards single embryo transfer to be the new norm for IVF in many countries, now put emphasis on the need for experience with these protocols from different centres (Saldeen and Sundstrom, 2005; Ubaldi et al., 2007; Verberg et al., 2009a,b). Meta-analyses are difficult to perform, as only a few studies are properly randomized and treatment protocols differ widely. The current approach in selecting the protocols used for treatments in this study was minimal intervention. This led to the choice of CC only for ovarian stimulation. As far as is known, few previous studies have been published using CC exclusively as the ovarian stimulating drug with no other pretreatment (Hojgaard et al., 2001; MacDougall et al., 1994). Until sufficient data is available from properly randomized studies, data from retrospective studies may add valuable information to the field of low interference IVF. In spite of the probable selection of patients with good prognosis in this material, a small number of patients with elevated FSH and previous repeated failure in conventional IVF cycles were also included. Several previous studies have been presented, indicating that mnc-ivf and NC-IVF may offer acceptable pregnancy rates to selected patient groups. A role for mnc-ivf in the treatment of so-called low responders has been discussed (Matsuura et al., 2008). The results from both mnc-ivf and m-ivf in the present study indicate that these treatment modalities are less attractive for older patients (Table 3). No pregnancies were observed in the mnc-ivf group among patients >38 years and a marked difference in ongoing pregnancy rate per embryo transfer between younger and older patients (30.6 versus 17.5%) was observed using 38 years as a cut-off threshold. A wide variety of stimulation protocols for m-ivf have been published. The largest study so far, using an m-ivf protocol, is by Teramoto and Kato (2007). This large scale study used a protocol with a combination of CC and gonadotrophins, adding 150 IU of FSH from cycle day 8. The present study indicates that acceptable pregnancy rates can be achieved with even less sophisticated treatment protocols, excluding the use of gonadotrophins and hence diminishing Table 4 Conventional IVF, mild IVF and modified natural cycle IVF. ICSI (%) started cycle (%) ET (%) Cancellation prior to ET (%) started cycle 38 years (%) ET 38 years (%) All conventional IVF cycles years 1997, 1999, 2002, 2004 and 2006, n = 3068 cycles (1997 2007) n = 250 cycles Natural cycle IVF (1996 2007) n = 129 cycles 44.9 ± 2.6 (41.1 47.5) [41.7 48.2] 29.6 ± 2.3 (26.8 32.3) [26.7 32.5] 34.3 ± 2.3 (31.9 36.9) [31.4 37.2] 13.7 ± 1.9 (11.2 16.0) [11.4 16.0] 22.7 ± 3.0 (19.3 25.0) [15.2 30.2] 29.8 16.4 27.2 39.6 10.8 17.5 31.7 12.4 26.7 53.5 0 0 27.0 ± 3.35 (23.2 29.4) [18.7 35.4] Figures for conventional IVF represent all patients treated with stimulated IVF cycles (agonist and antagonist) during the years 1997, 1999, 2002, 2004 and 2006. Values are mean ± SD (range) [95% confidence interval]. Figures for conventional IVF are intended to act as historical controls for treatments during the time period studied.

Minimal intervention IVF in Sweden 161 Table 5 Costs a for medication per treatment cycle. Conventional IVF, agonist cycle Conventional IVF, antagonist cycle Modified natural cycle IVF Type of ovarian stimulation GnRH protocol Ovulation induction Luteal phase support Follitropin alfa, 12 days stimulation, standard dose 150 IU/day, cost: SEK 10799 Agonist, long protocol, nafarelin nasal spray, 2 60 doses, cost: SEK 2269 Human chorionicgonadotrophin alpha, 250 lg/0.5 ml 1, cost: SEK 342 Progesterone, micronized, 400 mg 3 for 14 days, cost: SEK 855 Follitropin alfa, 12 days stimulation, standard dose 150 IU/day, cost: SEK 10799 Antagonist, ganirelix 0.25 mg, 5 injections, cost: SEK1521 Human chorionic gonadotrophin alpha, 250 lg/0.5 ml 1, cost: SEK 342 Progesterone, micronized. 400 mg 3 for 14 days, bost: SEK 855 Clomiphene citrate, 100 mg/day, 5 days of stimulation, cost: SEK 162 Human chorionic gonadotrophin alpha, 250 lg/0.5 ml 1, cost: SEK 342 Human chorionic gonadotrophin alpha, 250 lg/0.5 ml 1, cost: SEK 342 Total cost of medication per cycle, SEK ( ) b SEK 14,265, 1215.52 SEK 13,517, 1151.78 SEK 504, 42.95 SEK 342, 29.14 a Price information from FASS, the catalogue of medical products marketed in Sweden (2009). b Prices in euros based on exchange rates March 2009. SEK = Swedish Krona. the risk for OHSS. The use of CC only in the ovarian stimulation protocol is attractive, as patients with the desire to undergo a treatment with minimal intervention avoid injections except on the day of ovulation induction. A major concern for both mnc-ivf and m-ivf is the cancellation rate (Hojgaard et al., 2001; Ingerslev et al., 2001). In the present material, the cancellation rate prior to oocyte retrieval was 31% in the mnc-ivf group, and 46.5% of the started mnc-ivf cycles reached embryo transfer. It can be argued that cancelled mnc-ivf has a low grade of intervention prior to oocyte retrieval, and consequently a high cancellation rate is acceptable. The emotional stress that IVF patients are exposed to is, however, present regardless of treatment protocol. After an unsuccessful treatment cycle, 25% of the women have mild or moderate depression (Newton et al., 1990). In the present study, drop-outs prior to oocyte retrieval in mnc-ivf cycles were also more likely for non-medical reasons, possibly because the formal start of a treatment cycle does not include a drug regime. In this study, 57.5% (n = 23) of the cancelled cycles in the mnc-ivf group were due to reasons other than premature ovulation. As systematic interviews were not performed in this study, no information is available about the actual reasons for cancellation. The cancellation rate in the m-ivf group was 13.6% (n = 34) prior to oocyte retrieval and 60.4% of the started cycles reached embryo transfer. The low proportion may reflect the partial antagonist effect that CC has on oestrogen receptors, preventing premature LH surge, as well as a psychological effect on patients as the cycle is initiated with a drug regime immediately following the initial ultrasound. The selection bias in a non-randomized study like this calls for cautious interpretation of data. However, the thinner endometrium observed in the m-ivf group may reflect the anti-oestrogenic effect of CC. This could possibly explain the observation that the implantation rate seems to be higher in the mnc-ivf group (Table 2). In a retrospective study, it is difficult to make a clear estimation of cost per pregnancy or baby born, comparing different treatment modalities. A method being less costeffective per cycle in terms of ongoing pregnancies may, however, be advantageous in terms of patient friendliness. Patient drop-out out prior to the achievement of a pregnancy is a concern, as many of these couples may eventually become successful if they continue treatment with repeated cycles. In a recently published study (Verberg et al., 2008) it was reported that a mild treatment strategy significantly reduced the risk of drop-out. Resources for ultrasound monitoring, costs for oocyte retrieval and embryo transfer as well as counselling and doctors appointments may be equal for mild IVF and conventional treatments. An isolated analysis of the costs for medication is, however, easily achieved and may add important information about costs for IVF treatments. In the present study, a dramatic reduction in costs for medication could be observed due to the minimal intervention approach chosen in the mnc-ivf and even in the mild IVF group. The costs for medication are shown in Table 5. In a global perspective, minimal intervention and low costs for medication may be arguments for choosing these types of treatment in countries with restricted economical resources. Acknowledgements This study was supported by an unrestricted grant from the research council at Queen Sophia Hospital, Stockholm,

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