Cumulative live birth rates and number of oocytes retrieved in women of advanced age. A single centre analysis including 4500 women ≥38 years old.

STUDY QUESTION: Is there any relationship between the number of oocytes retrieved and cumulative live birth rates (CLBRs) in women of advanced age? SUMMARY ANSWER: CLBRs increase with the number of oocytes retrieved in women of advanced reproductive age up to 41 years old, the added value is minimal in women more than 41 years and futile in women 44 years or older. WHAT IS KNOWN ALREADY: CLBR is actually the most relevant outcome of IVF from patients' perspective. There are several studies that have analysed CLBR's but some of them have included several stimulation cycles, others have not included the frozen embryo transfers (FETs) in their analysis and none has focused on women of advanced reproductive age. We aimed to assess CLBR in women ≥38 years after a single stimulation cycle plus the subsequent frozen embryo transfers. STUDY DESIGN, SIZE, DURATION: This is a retrospective analysis carried out in a University-affiliated tertiary centre between January 2000 and December 2013. Overall, 4570 infertile women aged ≥38 years who underwent their first cycle in our centre were included. PARTICIPANT/MATERIALS, SETTING, METHODS: Patients were categorized in four age-groups: 38-39 years (G1 = 1875 cycles), 40-41 years (G2 = 1380 cycles), 42-43 years (G3 = 833 cycles) and ≥44 years (G4 = 482 cycles). CLBR's were evaluated by adding the pregnancies and live births achieved in the FET's to the ones obtained in the fresh cycle. In order to find out the actual effect of the number of oocytes retrieved in these patients, a predictive model of CLBR according to age and oocyte yield was built. MAIN RESULTS AND THE ROLE OF CHANCE: CLBRs significantly decrease with increasing age among women ≥38 years of age, with the most prominent and clinically relevant decline observed at 42-43 years old, and clear evidence for futility in women aged ≥44 years (25.9% at 38-39 years, 16.4% at 40-41 years, 7% at 42-43 years and 1.2% from 44 years onwards). The higher the number of oocytes retrieved, the higher the CLBR; however, this is more evident up to 41 years old and no clear benefit is observed from 44 years and beyond. LIMITATIONS, REASONS FOR CAUTION: Limitations are related to the retrospective nature of the study; however, no significant differences were observed in the treatment protocols used. Other potential limitations could be the fact that embryo cryopreservation was carried out with slow freezing in 80% of cases and that a small proportion of patients still have frozen embryos; nevertheless, we do not expect a relevant impact of these issues as slow freezing showed excellent results that did not differ significantly compared to vitrification and, on the other hand, the extra benefit coming from the FETs was very limited. WIDER IMPLICATIONS OF THE FINDINGS: The number of oocytes retrieved is significantly associated with CLBR also in women of advanced reproductive age. However, the added benefit appears to be restricted mainly in women up to 41 years old. Women over 43 do not experience any benefit in CLBR irrespective of the number of oocytes retrieved, and thus should be discouraged from doing an IVF cycle with their own oocytes; for the other age-groups, recommendations should be given considering the age and the expected ovarian response. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: NA.

Obstetric and perinatal complications in an oocyte donation programme. Is it time to limit the number of embryos to transfer?

The aim of this study is to describe obstetric and perinatal complications in pregnancies from oocyte donation (OD) cycles, delivering in our centre and to determine the impact of maternal age. Retrospective observational study of a 225 singleton pregnancies, 113 multiple pregnancies and 447 live birth. Pearson's χ(2) test or Fisher's exact test were used for the statistical analysis. A higher incidence of obstetric complications was observed in multiple compared to singleton pregnancies with regard to preeclampsia (24.8% versus 8%), premature rupture of membranes (9.7% versus 1.8%), preterm delivery at <37 weeks (54.9% versus 10.2%) and caesarean section (81.4% versus 64%) (p < 0.05). If the age factor is added, the caesarean sections are higher in the single pregnancy group aged ≥40 years than in the group of <40 years (73.5% versus 49.4%) (p < 0.05). A higher incidence is found in multiple versus singleton pregnancies for low birth weight (<2500 g) (61.1% versus 8.2%), admissions to the intensive care unit (15.2% versus 4.7%) and perinatal mortality (13.5‰ versus 0‰) (p < 0.05). It is necessary to consider preconception counselling prior to an OD cycle to inform patients about the incidence complications observed and recommend to transfer only a single embryo.

Is it justified to transfer two embryos in oocyte donation? A pilot randomized clinical trial.

Multiple pregnancies involve high obstetric and perinatal risks. The aim of this study is to evaluate, in a pilot randomized control study, if the cumulative pregnancy and live birth rates of elective single embryo transfer (eSET) are comparable to the ones obtained with elective double embryo transfer (eDET). A total of 65 patients with at least two good quality embryos was randomized, 34 (52.3%) assigned to the eSET group and 31 (47.7%) to the eDET group. The cumulative pregnancy rates (eSET: 73.5% and eDET: 77.4%. RR: 0.95 95% CI: 0.72-1.25) and live birth rates (eSET: 58.8% and eDET: 61.3%. RR: 0.96 95% CI: 0.64-1.42) were similar in the two groups. The twin pregnancy rate in the fresh transfers of eDET group was 47.7% and 0% in the eSET group. The medical team decided to interrupt the study for reasons related to risks associated with elevated twin pregnancy rate, leaving low numbers of patients within the study as a result. When considering cumulative success rates, eSET and eDET are similar in terms of efficacy. However, eDET involves an increased and unacceptable twin pregnancy rate. The only prevention strategy is single embryo transfer.

Comparison of starting ovarian stimulation on day 2 versus day 15 of the menstrual cycle in the same oocyte donor and pregnancy rates among the corresponding recipients of vitrified oocytes.

OBJECTIVE: To assess the clinical pregnancy rate per transfer in recipients of embryos from donor oocytes obtained after ovarian stimulation initiated on day 2 (D2) or day 15 (D15) of the menstrual cycle with a secondary end point of comparing the response to stimulation. DESIGN: Prospective observational comparative study. SETTING: Private in vitro fertilization (IVF) program. PATIENT(S): Oocyte donors (OD) and recipients. INTERVENTION(S): Donors stimulated within 3 months, starting on day 2 or day 15 after bleeding, with recombinant follicle-stimulating hormone (FSH), gonadotropin-releasing hormone (GnRH) antagonist, and GnRH agonist trigger, and oocytes vitrified and later assigned to recipients, followed by routine IVF procedures one to two embryos transferred. MAIN OUTCOME MEASURE(S): Primary outcome pregnancy rate, and secondary outcome number of mature oocytes retrieved. RESULT(S): Nine D2 and nine D15 cycles were performed in nine donors. There were no differences between D2 and D15 in the number of mature oocytes obtained (14.0±6.96 vs. 16.89±7.52). To date, 20 recipients have received vitrified oocytes (8 recipients received D2 oocytes and 12 recipients received D15 oocytes). There were no differences between the groups of recipients in fertilization rate (77.3% vs. 76.5%) or number of embryos transferred (1.50±0.53 vs. 1.67±0.65). Twelve clinical pregnancies were obtained. No differences were noted in pregnancy rates (62.5% vs. 58.3%) or implantation rates (41.67% vs. 45%) between recipients of D2 oocytes and recipients of D15 oocytes. CONCLUSION(S): Donor oocytes obtained after ovarian stimulation initiated on day 15 of the cycle achieve good pregnancy rates. This information is useful for patients with cancer undergoing fertility preservation. CLINICAL TRIAL REGISTRATION NUMBER: NCT 01645241.

Live birth using vitrified--warmed oocytes in invasive ovarian cancer: case report and literature review.

This article reports the live birth of a healthy newborn using vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after insemination of warmed oocytes. Eighteen days after the transfer, she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. As far as is known, this is the first live birth reported through vitrified-warmed oocytes in a patient with invasive ovarian cancer. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, controversial issues are discussed. Fertility preservation is a proven possibility in some cancer patients according to their age, disease and time available until the beginning of their oncological treatment. Although oocyte vitrification is an alternative to be considered for fertility preservation in highly selected cases of ovarian cancer, no live birth has been reported. We report the live birth of a healthy newborn through vitrified-warmed oocytes in a young patient with invasive mucinous ovarian carcinoma (stage Ic). Diagnosis was performed after a laparoscopic left adnexectomy. She underwent two cycles of ovarian stimulation, and 14 oocytes were vitrified before fertility-sparing surgery with uterus preservation went ahead. One year later, a transfer of two embryos was performed after the insemination of the warmed oocytes. Eighteen days after the transfer she underwent a laparotomy because of abdominal pain, vaginal bleeding and haemoperitoneum. A right cornual ectopic pregnancy in the uterus was diagnosed and a wedge resection was performed to resolve it. One week later, a viable intrauterine pregnancy was confirmed under ultrasound. An elective Caesarean section was performed at week 38 of gestation, resulting in the birth of a healthy boy weighing 2650 g. To our knowledge, this is the first live birth reported using vitrified-warmed oocytes in invasive ovarian cancer. Controversial issues are reviewed and discussed.

Investigations into implantation failure in oocyte-donation recipients.

In recent decades, the Western world has been experiencing a societal trend to prioritize the professional careers of women who postpone motherhood to about 40 years of age, when, unfortunately, natural reproductive potential declines. This is the reason why these women increasingly find it necessary to resort to oocyte donation to have a child. Thanks to the young age of the donors, the efficacy of oocyte donation is the highest of all assisted reproduction treatments and pregnancy rates achieved with this technique exceed 50%. Moreover, the large registries from ESHRE and ASRM show live birth rates close to this figure. However, there are patients who experience repeated failures in several oocyte-donation cycles, and so far oocyte-donation repeated implantation failure has not been clearly defined. This study analysed the results obtained from 2531 oocyte-donation cycles carried out in 1990 patients and defines oocyte-donation repeated implantation failure as failure to implant with more than two embryo transfers and more than four high-grade embryos transferred. This study observed this condition in 140 oocyte recipients (7%). Also, oocyte cohort size, uterine factors and systemic thrombophilias as important aetiological factors were identified were to offer new therapeutic strategies to patients.

Endometriosis and IVF: are agonists really better? Analysis of 1180 cycles with the propensity score matching.

OBJECTIVE: To compare the outcomes of patients with confirmed endometriosis undergoing in vitro fertilization (IVF)-embryo transfer (ET) treated with either gonadotropin-releasing hormone agonist (GnRHa) or gonadotropin-releasing hormone antagonist (GnRHant) using the propensity score (PS) matching. DESIGN: Observational, retrospective analysis from January 2000 to December 2010. SETTING: Private tertiary fertility clinic. PATIENT(S): Patients with endometriosis confirmed by ultrasound or surgery (American Fertility Society; AFS grades I-IV) that underwent an IVF-ET, stimulated with standard controlled ovarian hyperstimulation (COH) and GnRHa or GnRHant. INTERVENTION(S): A PS was assigned to all patients, which calculates the conditional probability of receiving a certain treatment; a higher PS (1) meant a higher probability of receiving treatment with GnRHa, and a lower PS (0) meant a higher probability of receiving GnRHant. The PS was calculated with a logistic regression model adjusted specifically for age, follicle stimulating hormone, antral follicle count and previous IVF cycles. All patients were divided into three groups according to their PS. MAIN OUTCOME MEASURE(S): pregnancy rate (PR) per cycle. RESULTS: 1180 patients were analyzed. Raw PR per cycle was 41.8% and 23.4%, and PR per ET was 44.3 and 27%, respectively. PR per cycle: 41.9 versus 30% in group A; in group B, 39.7% versus 36.4% and in group C, 15.4% versus 18.9%. The overall odds ratio for PR adjusted by PS was 1.10 [0.58-2.19]. CONCLUSIONS: After matching patients by PS, PR after COH with either GnRHa or GnRHant may be equally effective.

Is AMH useful to reduce low ovarian response to GnRH antagonist protocol in oocyte donors?

We aimed to establish the reference values of Anti-Müllerian hormone (AMH) in our oocyte donor population and correlate them with the ovarian response to an antagonist stimulation protocol and to study the predictive capacity of AMH for poor response (PR). Normal AMH curves were obtained for 172 candidates. AMH levels decreased with age although they showed great heterogeneity and spread in absolute values at any age range. AMH levels showed a positive correlation, statistically significant, with the Antral Follicle Count (r = 0,705), and number of oocytes retrieved (r = 0,356). In receiver operating characteristic curve analysis a threshold value of AMH = 2.31 ng/ml predictive for retrieval <6 MII (area under the curve (AUC) 0.675) was identified. This cut-off predicted PR with a sensitivity of 70.4% and a specificity of 61.8%, (PPV = 39.6%; NPV = 85.5%, p = 0.004). When performing a multiple logistic regression analysis including age, AFC and FSH, an AUC = 0.668 for PR was obtained whereas if AMH was added to the model it resulted in an AUC = 0.713. In oocyte donors aged 18 to 35 with an AFC ≥ 10 and basal FSH <10 mIU/ml, measuring AMH levels improved just slightly the prediction for PR.

Cancer and fertility preservation: Barcelona consensus meeting.

Improvements in early diagnosis and treatment strategies in cancer patients have enabled younger women with cancer to survive. In addition to the stressful event of the diagnosis, patients with malignant diseases face the potential loss of the opportunity to have children. Preservation of fertility has become a challenging issue and it is still surrounded by controversies. On the basis of available evidence, a group of experts reached a consensus regarding the options for trying to preserve fertility in women with cancer: among established methods, in postpubertal women, oocyte cryopreservation is the preferred option, whereas ovarian tissue cryopreservation is the only possibility for prepubertal girls. Combining several strategies on an individual basis may improve the chances of success. Realistic information should be provided before any intervention is initiated. Counseling should offer support for patients and provide better care by understanding emotional needs, psychological predictors of distress and methods of coping. Early referral to the fertility specialist is essential as fertility preservation (FP) may improve quality of life in these patients. The information summarized here is intended to help specialists involved in the treatment of cancer and reproductive medicine to improve their understanding of procedures available for FP in young cancer patients.

Elective single-embryo transfer in oocyte donation programmes: Should it be the rule?

The aim of this study is to compare the cumulative clinical pregnancy and live birth rates (fresh embryo transfers followed by frozen-thawed embryo transfers from the same stimulated cycle) between single-embryo transfer (SET) and double-embryo transfer (DET) in an oocyte donation programme. A retrospective analysis of the outcome in 1139 recipient fresh cycles (1073 from DET and 66 from SET) with at least three available embryos for transfer was performed. The clinical pregnancy rates were similar after SET (45.5%, 30/66) and DET (57.1%, 613/1073), whereas the multiple pregnancy rate was 0% and 39.5% for SET and DET, respectively. After evaluating the results using the Kaplan-Meier survival analysis in a period of 1 year, no statistically significant differences were observed in the cumulative clinical pregnancy and live birth rates (SET 82.8% and 76.4% versus DET 77.2% and 63.7%). The results indicate that for women who have at least three available embryos in oocyte donation programmes, one single embryo should be transferred as no significant decrease in the success rate is observed and multiple pregnancy can be avoided. Clinical pregnancy rate is higher when transferring two embryos compared with one. However, this also results in a higher incidence of twin pregnancy, which is associated with increased obstetric and perinatal risks. The aim of this study was to compare the cumulative clinical pregnancy and live birth rates (fresh embryo transfers followed by frozen-thawed embryo transfers from the same stimulated cycle) between single-embryo transfer (SET) and double-embryo transfer (DET) cycles in our oocyte donation programme. A retrospective analysis of the outcome in 1139 recipient fresh cycles (1076 from DET and 66 from SET) with at least three available embryos for transfer was performed. The clinical pregnancy rates were similar after SET (45.5%, 30/66) and DET (57.1%, 613/1073), whereas the multiple pregnancy rate was 0% and 39.5% for SET and DET, respectively. The cumulative clinical pregnancy and live birth rates were similar between the two strategies (SET 82.8% versus DET 77.2%) and the same was found for the cumulative live birth rates (SET 76.4% versus DET 63.7%). Our results indicate that for women who have at least three available embryos in OD programmes, one single embryo should be transferred as no significant decrease in the success rate is observed while multiple pregnancy is avoided.

Triggering ovulation with 250 µg or 500 µg of r-hCG in oocyte donors treated with antagonist protocol has no effect on the number of mature oocytes retrieved: a randomized clinical trial.

The aim of this study is to compare two r-hCG doses to trigger ovulation (250 µg vs. 500 µg of r-hCG) in an oocyte donation program. A prospective, randomized study was conducted in 118 oocyte donors. Group DI received 250 µg and Group DII received 500 µg of r-hCG. Both the groups were homogeneous. No significant differences were found in the total dose of gonadotropins, duration of the treatment, total number of oocytes, or Metaphase II (MII)oocytes. The pregnancy rate per embryo transfer in the corresponding recipients was similar for both the groups (58.2% for DII recipients and 56.1% for DI recipients). Mild hyperstimulation was observed in 17 donors in Group DI (29%) and in 23 donors in Group DII (39%). No cases of severe ovarian hyperstimulation syndrome (SOHSS) were observed. In conclusion, a double dose of r-hCG in oocyte donors to trigger ovulation after stimulation with r-FSH and antagonist does not translate into a higher number of MII oocytes retrieved or into higher pregnancy rates among recipients. Our results confirm that the optimal dose to induce the final oocyte maturation with r-hCG is 250 µg, and that a higher dose does not add any benefit.

Prevention of prematurity by single embryo transfer.

The development of assisted reproduction techniques (ART) represents an important advance in the treatment of human infertility. However, their great effectiveness has brought with it an excessive increase in multiple pregnancy rates with the serious medical, financial and social consequences that they entail. Now, the scientific societies, the health professionals, and the infertile couples themselves are aware of these risks and have worked together to implement various strategies to deal with this situation. The result that is being obtained from the strategy of selectively reducing the number of embryos transferred is obvious. The pandemic of multiple pregnancies is being brought under control and so we have effective prevention of the obstetric and neonatal complications arising from it. It is to be hoped that it will also contribute to significantly reducing the rates of prematurity and thus of severe neonatal complications.

GnRH antagonist rescue of a long-protocol IVF cycle and GnRH agonist trigger to avoid ovarian hyperstimulation syndrome: three case reports.

OBJECTIVE: To describe three clinical cases involving patients at high risk of severe ovarian hyperstimulation syndrome (OHSS) during IVF stimulation. DESIGN: Description of clinical management of IVF cycles and outcomes in patients at risk of developing OHSS. SETTING: Reproductive medicine unit, private hospital. PATIENT(S): Three infertile patients undergoing stimulation for IVF/intracytoplasmic sperm injection presenting high risk of OHSS. INTERVENTION(S): IVF patients treated under long protocol presenting high risk of OHSS had their cycles rescued by withdrawing the agonist and replacing it with an antagonist and triggering ovulation with an agonist bolus. MAIN OUTCOME MEASURE(S): OHSS symptoms, pregnancy. RESULT(S): None of the three patients developed OHSS. One patient got pregnant after fresh embryo transfer, one patient got pregnant after frozen embryo transfer, and one patient had no oocytes retrieved despite the detection of LH in urine after the GnRH bolus. CONCLUSION(S): When a patient undergoing an IVF cycle with long protocol is at high risk of severe OHSS, rescuing the cycle by withdrawing the agonist and replacing it with an antagonist and triggering ovulation with an agonist bolus could be considered without jeopardizing the safety of the patient while retaining the opportunity for success of the cycle. Further broader studies are needed.

Gonadotrophin-releasing hormone-antagonists vs long agonist in in-vitro fertilization patients with polycystic ovary syndrome: a meta-analysis.

AIM: This article is a systematic review of the literature to establish whether there is an advantage in the use of GnRH antagonists (Ant) compared to the long agonist protocol (Ago) in patients with polycystic ovarian syndrome (PCOS). MATERIAL AND METHODS: The meta-analysis was conducted using the MIX software with Mantel?Haenszel weighting method and the fixed effect model. RESULTS: Five studies were identified. We analyzed 269 Ant and 303 Ago cycles. Pregnancy rates and the incidence of ovarian hyperstimulation syndrome (OHSS) were analyzed in all five studies, abortion rates were analyzed on three. Pregnancy rates did not differ between the groups: 137/269 (Ant Group) versus 172/303 (Ago Group) (OR: 0.80 CI: [0.57-1.11]). The incidence of OHSS per Ant (13/269) was significantly lower compared to the Ago (35/303) (OR: 0.47 CI: [0.24-0.92]). No difference was found between the two groups in the abortion rate: 10/77 (Ant Group) versus 9/88 (Ago Group) (OR: 1.29 CI: [0.49-3.36]). CONCLUSION: The limited evidence present in literature suggests that in patients with PCOS there is no difference between a long Ago and an Ant protocol in terms of pregnancy and abortion rates. It seems more likely that the use of the Ant may reduce the incidence of OHSS.

Transferencia selectiva de un único embrión como prevención del embarazo múltiple / Prevention of prematurity by single embryo transfer

El desarrollo de las Técnicas de Reproducción Asistida ha representadoun importante avance en el tratamiento de la infertilidad humana.Sin embargo, la alta eficacia de las mismas ha traído consigoun incremento excesivo de las tasas de embarazo múltiple con las gravesconsecuencias médicas, económicas y sociales que ello comporta.Actualmente tanto las sociedades científicas como los profesionalesde la salud como las propias parejas estériles son conscientes de estosriesgos y de forma coordinada se han establecido diversas estrategiaspara hacer frente a esta situación.El resultado que se está obteniendo de la estrategia de reducir selectivamenteel número de embriones transferidos es evidente. La pandemiade embarazos múltiple se está controlando y con ello estamoshaciendo una prevención eficaz de las complicaciones obstétricas yneonatales derivadas de los mismos. Esperamos que ello contribuirátambién a reducir significativamente las tasas de prematuridad y portanto de complicaciones neonatales severas(AU)

Prevention of prematurity by single embryo transfer.The development of Assisted Reproduction Techniques representsan important advance in the treatment of human infertility. However,their great effectiveness has brought with it an excessive increase inmultiple pregnancy rates with the serious medical, financial and socialconsequences that they entail. Now, the scientific societies, thehealth professionals, and the infertile couples themselves are awareof these risks and have worked together to implement various strategiesto deal with this situation.The result that is being obtained from the strategy of selectivelyreducing the number of embryos transferred is obvious. The pandemicof multiple pregnancies is being brought under control and so wehave effective prevention of the obstetric and neonatal complicationsarising from it. It is to be hoped that it will also contribute to significantlyreducing the rates of prematurity and thus of severe neonatalcomplications(AU)

Analysis of factors associated with multiple pregnancy in an oocyte donation programme.

The aim of this study is to identify the factors associated with multiple pregnancy in an oocyte donation programme. A retrospective study (2000-2007) of 945 synchronous cycles was performed. Two embryos were transferred in all cycles on day 2 after oocyte retrieval. All variables (egg donor and recipient age, number of inseminated oocytes, fertilized oocytes, cleaved embryos, good-quality embryos available, good-quality embryos transferred and frozen embryos) were analysed in relation to the clinical pregnancy rate per transfer (PR) and the multiple pregnancy rate (MPR). The donor age was 26.8±4.5 years and recipient age was 41.0±5.4. The number of good-quality embryos per recipient was 3.1±2.5. The PR was 55.1% and the MPR 36.5%. The number of good-quality embryos transferred (2 versus 0) was significantly associated (P<0.05) with the PR (60.6% versus 43.5%). The relationship between the MPR and the number of good-quality embryos transferred was adjusted by donor and recipient's age. For those patients who received 2 versus 0 good-quality embryos, the odds ratio of a multiple pregnancy was 2.1 (95% CI 1.121-3.876). The only predictive factor for multiple pregnancies in an oocyte donation programme is the quality of the transferred embryos. Since the development of assisted reproduction techniques, most countries have witnessed increased rates of multiple pregnancy. In IVF/intracytoplasmic sperm injection, effective strategies must be established to prevent multiple pregnancy without reducing overall pregnancy rates. In oocyte donation programmes, there is less awareness about the related risks. Actually, a minimum of two embryos are still transferred in most centres. The patient's age is higher and this fact implies more obstetric and perinatal complications. The aim of this study is to identify the factors associated with multiple pregnancy to contribute to establish future guidelines to avoid those risks.

Endometriosis-associated infertility: surgery and IVF, a comprehensive therapeutic approach.

Infertility is a common problem presented by patients with endometriosis. At present, whichever treatment is chosen, half of patients with advanced stages of the disease will remain infertile afterwards. This observational study looked at the reproductive outcome achieved after treating a group of 825 patients aged between 20 and 40 years with endometriosis-associated infertility during the period 2001-2008. Of the 483 patients who had surgery as the primary option, 262 became pregnant (54.2%). Among the patients who did not become pregnant, 144 underwent 184 IVF cycles and 56 additional pregnancies were obtained (30.4% clinical pregnancy rate per retrieval). It is notable that, before any treatment, patients with endometriosis had a poorer ovarian reserve than the control group. The combined strategy of endoscopic surgery and subsequent IVF led to a total of 318 pregnancies, which represents a combined clinical pregnancy rate of 65.8%. This percentage is significantly higher than that obtained with surgery alone (P < 0.0001), with 173 patients who were not operated on and who went to IVF as the primary option (P < 0.0001) and with 169 patients who had no treatment and achieved 20 spontaneous pregnancies (P < 0.0001).

Poor prognosis for ovarian response to stimulation: results of a randomised trial comparing the flare-up GnRH agonist protocol vs. the antagonist protocol.

OBJECTIVE: To determine the efficacy of the flare-up agonist and the antagonist protocols in patients with poor prognosis for ovarian response. METHODS: A randomised trial was conducted on two hundred and twenty-one women considered as having poor prognosis for ovarian response to stimulation, based on previous cycles or clinical criteria. All women were prospectively randomised into two groups of treatment (flare-up group and antagonist group) by computer-assisted randomisation in a 1:1 ratio. The main outcome measure was clinical pregnancy rate. RESULTS: Groups were homogeneous in age and baseline characteristics. Duration of stimulation, gonadotropin consumption, number of oocytes retrieved and number and quality of embryos transferred did not differ significantly between the groups. E(2) level the day of hCG administration was significantly higher in the flare-up group. Pregnancy rates per started cycle were 15% in the flare-up group and 14.1% in the antagonist group. Cancellation rates were 12.5% in the flare-up group and 16.3% in the antagonist group. None of these differences reached statistical significance. CONCLUSIONS: No statistically significant differences were observed between the two protocols regarding clinical pregnancy rates. In patients with poor prognosis for ovarian response, the flare-up agonist and the antagonist protocols were comparable regarding clinical pregnancy rates.

Mild stimulation in assisted reproduction.

The conventional ovarian stimulation protocols currently applied have several drawbacks arising from the intense ovarian stimulation and from the high financial cost. Recently, new concepts such as mild stimulation and friendly in vitro fertilisation have rapidly acquired great popularity among infertile patients although the medical world is still reluctant to apply these protocols generally. We have observed that although with soft stimulation fewer oocytes are retrieved, pregnancy rates are not affected if more than five oocytes are obtained in the follicular aspiration. Another important issue is the additional value of the embryo cryopreservation programmes that will result in cumulative pregnancy rates no different from those obtained with conventional protocols. The benefits of combining these mild stimulation protocols with a selective reduction of the number of embryos to replace have helped us in reducing the incidence of multiple pregnancies and the global cost of the treatment.

Use of letrozole in assisted reproduction: a systematic review and meta-analysis.

BACKGROUND: Letrozole is the third-generation aromatase inhibitor (AI) most widely used in assisted reproduction. AIs induce ovulation by inhibiting estrogen production; the consequent hypoestrogenic state increases GnRH release and pituitary follicle-stimulating hormone (FSH) synthesis. METHODS: A systematic search of the literature was performed for both prospective and retrospective studies. Meta-analyses of randomized clinical trials (RCTs) were performed for three comparisons: letrozole versus clomiphene citrate (CC), letrozole + FSH versus FSH in intrauterine insemination (IUI) and letrozole + FSH versus FSH in IVF. In the absence of RCTs, non-randomized studies were pooled. RESULTS: Nine studies were included in the meta-analysis. Four RCTs compared the overall effect of letrozole with CC in patients with polycystic ovary syndrome. The pooled result was not significant for ovulatory cycles (OR = 1.17; 95% CI 0.66-2.09), or for pregnancy rate per cycle (OR = 1.47; 95% CI 0.73-2.96) or for pregnancy rate per patient (OR = 1.37; 95% CI 0.70-2.71). In three retrospective studies which compared L + FSH with FSH in ovarian stimulation for IUI, the pooled OR was 1.15 (95% CI 0.78-1.71). A final meta-analysis included one RCT and one cohort study that compared letrozole + gonadotrophin versus gonadotrophin alone: the pooled pregnancy rate per patient was not significantly different (OR = 1.40; 95% CI 0.67-2.91). CONCLUSIONS: Letrozole is as effective as other methods of ovulation induction. Further randomized-controlled studies are warranted to define more clearly the efficacy and safety of letrozole in human reproduction.