The cumulative live birth rate and cost-effectiveness of the clomiphene and gonadotropin cotreatment protocol versus the mid-luteal GnRH agonist protocol in women over 35 years old.

The decrease in assisted reproductive technology success among older women, attributed to decreased oocyte quantity and quality, poses a significant challenge. Currently, no consensus on the optimal ovarian stimulation protocol for older women undergoing IVF exists. This retrospectively registered cohort study aimed to compare the cumulative live birth rate (CLBR), time to live birth (TTLB), and cost-effectiveness among women older than 35 years who were receiving either the gonadotropin-releasing hormone agonist (GnRHa) or clomiphene citrate and gonadotropin cotreatment with ovarian stimulation (CC cotreatment) protocol. To compare treatment outcomes, we performed propensity score matching (PSM) on 2871 IVF cycles in women older than 35 years who received either the GnRHa or CC cotreatment protocol, resulting in 375 cycles in each group. Additionally, a decision tree model was utilized to assess the cost-effectiveness of the two protocols. Following PSM, both groups had similar baseline characteristics. The CC cotreatment protocol resulted in a greater rate of cycle cancellation (13.07% vs. 8.00%, p = 0.032), but the groups maintained comparable fertilization rates and embryo quality. Although the TTLB was longer in the CC cotreatment group, the CLBR per initial cycle (41.07% vs. 45.33%, p = 0.269) and delivery outcomes were similar between the two groups at the 24 months follow-up. Additionally, the average cost per live birth in the CC cotreatment group was 21.27% lower than in the GnRHa group (¥32,301.42 vs. ¥39,174.22). In conclusion, for women older than 35 years undergoing IVF, the CC cotreatment protocol offered a comparable CLBR to the GnRHa protocol but with reduced costs, indicating its potential as a viable and cost-effective ovarian stimulation option.Clinical trial registration: https://www.chictr.org.cn/ , identifier [ChiCTR2300076537].

Gonadotrophins versus clomiphene citrate with or without IUI in women with normogonadotropic anovulation and clomiphene failure: a cost-effectiveness analysis.

STUDY QUESTION: Are six cycles of ovulation induction with gonadotrophins more cost-effective than six cycles of ovulation induction with clomiphene citrate (CC) with or without IUI in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC? SUMMARY ANSWER: Both gonadotrophins and IUI are more expensive when compared with CC and intercourse, and gonadotrophins are more effective than CC. WHAT IS KNOWN ALREADY: In women with normogonadotropic anovulation who ovulate but do not conceive after six cycles with CC, medication is usually switched to gonadotrophins, with or without IUI. The cost-effectiveness of these changes in policy is unknown. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation of ovulation induction with gonadotrophins compared with CC with or without IUI in a two-by-two factorial multicentre randomized controlled trial in normogonadotropic anovulatory women not pregnant after six ovulatory cycles with CC. Between December 2008 and December 2015 women were allocated to six cycles with gonadotrophins plus IUI, six cycles with gonadotrophins plus intercourse, six cycles with CC plus IUI or six cycles with CC plus intercourse. The primary outcome was conception leading to a live birth achieved within 8 months of randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We performed a cost-effectiveness analysis on direct medical costs. We calculated the direct medical costs of ovulation induction with gonadotrophins versus CC and of IUI versus intercourse in six subsequent cycles. We included costs of medication, cycle monitoring, interventions, and pregnancy leading to live birth. Resource use was collected from the case report forms and unit costs were derived from various sources. We calculated incremental cost-effectiveness ratios (ICER) for gonadotrophins compared to CC and for IUI compared to intercourse. We used non-parametric bootstrap resampling to investigate the effect of uncertainty in our estimates. The analysis was performed according to the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: We allocated 666 women in total to gonadotrophins and IUI (n = 166), gonadotrophins and intercourse (n = 165), CC and IUI (n = 163), or CC and intercourse (n = 172). Mean direct medical costs per woman receiving gonadotrophins or CC were €4495 versus €3006 (cost difference of €1475 (95% CI: €1457-€1493)). Live birth rates were 52% in women allocated to gonadotrophins and 41% in those allocated to CC (relative risk (RR) 1.24:95% CI: 1.05-1.46). The ICER was €15 258 (95% CI: €8721 to €63 654) per additional live birth with gonadotrophins. Mean direct medical costs per woman allocated to IUI or intercourse were €4497 versus €3005 (cost difference of €1510 (95% CI: €1492-€1529)). Live birth rates were 49% in women allocated to IUI and 43% in those allocated to intercourse (RR = 1.14:95% CI: 0.97-1.35). The ICER was €24 361 (95% CI: €-11 290 to €85 172) per additional live birth with IUI. LIMITATIONS, REASONS FOR CAUTION: We allowed participating hospitals to use their local protocols for ovulation induction and IUI, which may have led to variation in costs, but which increases generalizability. Indirect costs generated by transportation or productivity loss were not included. We did not evaluate letrozole, which is potentially more effective than CC. WIDER IMPLICATIONS OF THE FINDINGS: Gonadotrophins are more effective, but more expensive than CC, therefore, the use of gonadotrophins in women with normogonadotropic anovulation who have not conceived after six ovulatory CC cycles depends on society's willingness to pay for an additional child. In view of the uncertainty around the cost-effectiveness estimate of IUI, these data are not sufficient to make recommendations on the use of IUI in these women. In countries where ovulation induction regimens are reimbursed, policy makers and health care professionals may use our results in their guidelines. STUDY FUNDING/COMPETING INTEREST(S): This trial was funded by the Netherlands Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). The Eudract number for this trial is 2008-006171-73. The Sponsor's Protocol Code Number is P08-40. CBLA reports unrestricted grant support from Merck and Ferring. BWM is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva and Guerbet. TRIAL REGISTRATION NUMBER: NTR1449.

Effect of simultaneously started clomiphene citrate and gonadotropins in antagonist regimes, on cumulative live births, fresh-cycle live births and cost of stimulation in IVF cycles.

AIM: The aim of the study was to compare simultaneously started clomiphene citrate (CC) and gonadotropins (Gn) with gonadotropins alone in conventional antagonist regimes with respect to fresh-cycle live births, cumulative live births and cost of ovarian stimulation per started cycle. METHODS: This was a single-center prospective cohort study conducted over 1 year. Women undergoing autologous in vitro fertilization (IVF) treatment in antagonist protocols and who consented to participate in the study were divided into two cohorts. The CC cohort (n = 86) received 50 mg CC for 5 days and individualized Gn daily until the hCG trigger, both starting from day 2 and antagonist daily from day 8 of menstrual cycle. The Gn-only cohort (n = 349) received individualized Gn from day 2 and the antagonist from day 7 of menstrual cycle. IVF outcomes and cost of stimulation were compared between two cohorts across expected ovarian response categories. RESULTS: The CC cohort used a mean lower dose of Gn (1741.38 ± 604.46 vs 1980.54 ± 686.42; MD = -239.16; 95%CI = -348.03 to -189.24; P = 0.003) over fewer days (8.54 ± 1.86 vs 9.25 ± 1.97; MD =-0.71;95% CI = -1.17 to -0.25; P = 0.0026) to achieve similar retrieved oocytes, (9.19 ± 5.92 vs 9.36 ± 6.96; MD = -0.17; 95%CI -1.77 to + 1.43; P = 0.83), positive bhCG rates (40% vs 29.6%, MD = 10.4%; OR = 1.65, 95%CI = 0.95-2.86; P = 0.078) and live births in fresh cycles (32.31% vs 21.30%; MD = 11.01%; OR = 1.76; 95%CI = 0.97-3.19; P = 0.06) and cumulative live births per initiated cycle (30.23% vs 20.34%; MD = 9.89%; OR = 1.697; 95%CI = 0.99-2.88; P = 0.0501). The dose lowering achieved a 28-40% reduction in the cost of stimulation, which was most noticeable in the hyper-responder category for both hMG cycles, (Rs.11 602.3 ± 3365.9 vs 19615 ± 2677.1; MD = -8012.7; %age reduction: 40.8%; P = 0.0007) and recombinant FSH cycles (Rs. 22 459.6 ± 6255.3 vs 33 022.1 ± 9891.2; MD: -10 562; %age reduction: -32%; P = 0.0001). CONCLUSION: CC started simultaneously with Gn in antagonist regimes helps lower the cost of stimulation without affecting IVF outcomes.

Cost-effectiveness of ovarian stimulation with gonadotrophin and clomiphene citrate in an intrauterine insemination programme for subfertile couples.

Ovarian stimulation with low-dose human menopausal gonadotrophin (HMG) is superior to clomiphene citrate in intrauterine insemination (IUI) cycles with respect to clinical pregnancy rate, but it is unclear whether HMG is also the more cost-effective option. The aim of this study was to compare the cost-effectiveness of ovarian stimulation with low-dose subcutaneously administred HMG (37.5-75 IU per day) to orally administred clomiphene citrate (50 mg/day from day 3-7) in an IUI programme for subfertile couples. A cost-effectiveness analysis was conducted using the results of a randomized trial, including 620 IUI cycles. The primary outcome was the incremental cost-effectiveness ratio (ICER) of using HMG versus clomiphene citrate. Results are presented from the healthcare payer perspective. The total cost per patient associated with one IUI treatment with HMG is €764, whereas it is €558 if clomiphene citrate is used, resulting in an incremental cost of €206 for HMG per treatment. The incremental clinical pregnancy rate of using HMG instead of clomiphene citrate, however, is also 5.7 percentage points higher, resulting in an ICER of HMG versus clomiphene citrate of €3615 per additional clinical pregnancy achieved. On average, HMG was found to be more cost-effective than clomiphene citrate.

Modified repeated intracyclic clomiphene citrate therapy after conventional clomiphene therapy.

PURPOSE OF INVESTIGATION: We compared modified repeated intracyclic clomiphene citrate therapy (RICCT) to gonadotropin therapy to determine whether this modified regimen was an effective alternative after conventional clomiphene therapy. METHODS: Patients with ovulation disorder received treatment with modified RICCT and gonadotropin, and ovulation, pregnancy, total drug cost, and adverse effects were compared. RESULTS: Among a total of 16 patients, 14 successfully ovulated after modified RICCT and 11 ovulated after gonadotropin therapy; two did not respond to either therapy. The total drug cost was US $36.3+/-17.9 for modified RICCT, which was significantly lower than the cost of gonadotropin therapy, US $213.9+/-100.4 (p=0.0001). CONCLUSIONS: Because modified RICCT does not require the discomfort of daily injection and has excellent ovulation-inducing effects, it is a useful treatment after conventional clomiphene therapy.

A case-control pilot study of low-intensity IVF in good-prognosis patients.

Low-intensity IVF (LI-IVF) is rapidly gaining in popularity. Yet studies comparing LI-IVF to standard IVF are lacking. This is a case-control pilot study, reporting on 14 first LI-IVF and 14 standard IVF cycles in women with normal age-specific ovarian reserve under age 38, matched for age, laboratory environment, staff and time of cycle. LI-IVF cycles underwent mild ovarian stimulation, utilizing clomiphene citrate, augmented by low-dose gonadotrophin stimulation. Control patients underwent routine ovarian stimulation. LI-IVF and regular IVF patients were similar in age, body mass index, FSH and anti-Müllerian hormone. Standard IVF utilized more gonadotrophins (P<0.001), yielded more oocytes (P<0.001) and cryopreserved more embryos (P<0.001). With similar embryo numbers transferred, after ethnicity adjustments, standard IVF demonstrated better odds for pregnancy (OR 7.07; P=0.046) and higher cumulative pregnancy rates (63.3% versus 21.4%; OR 6.6; P=0.02). Adjustments for age, ethnicity and diagnosis maintained significance but oocyte adjustment did not. Cost assessments failed to reveal differences between LI-IVF and standard IVF. In this small study, LI-IVF reduced pregnancy chances without demonstrating cost advantages, raising questions about its utility. In the absence of established clinical and/or economic foundations, LI-IVF should be considered an experimental procedure. Low-intensity IVF (LI-IVF) is increasingly propagated as an alternative to standard IVF. LI-IVF has, however, never been properly assessed in comparison to standard IVF. Such a comparison is presented in the format of a small pilot study, matching LI-IVF cycles with regular IVF cycles and comparing outcomes as well as costs. The study suggests that LI-IVF, at least in this setting, is clinically inferior and economically at best similar to standard IVF. LI-IVF should, therefore, as of this point not be offered as routine IVF treatment but only as an experimental procedure.

Affordable ART: a different perspective.

BACKGROUND: Although ≈ 10% of the population is affected by infertility, the treatment option of in-vitro fertilisation (IVF) remains unaffordable for the majority of infertile couples. We have initiated a lowcost programme incorporating an uncommonly used, but recognized, ovarian stimulation protocol, together with certain costlimiting initiatives in an established assisted reproductive technology (ART) set up. METHODS: The medical records of women who underwent the lowcost programme were analysed. Clomiphene citrate 50 mg daily was administered from Day 2 of the cycle and continued till the day of hCG trigger, thus preventing the LH surge. Intermittent doses of human menopausal gonadotrophin 150 IU were administered on alternate days from the 5th day onwards. Oocyte retrieval was carried out once at least two follicles of >18 mm were identified. The cycle was monitored by ultrasound only, with embryo transfer being carried out on Day 3. Clinical outcomes were recorded together with an estimation of the direct costs per cycle. Direct cost calculations did not include professional charges or facility costs. RESULTS: Of 143 women evaluated, 104 women underwent embryo transfer. The live birth rate and clinical pregnancy rate per embryo transfer were 19 and 22%. The live birth rate per initiated cycle was 14% (20/143). The multiple pregnancy rate was 26% with no case of ovarian hyperstimulation syndrome being recorded. The average direct cost per cycle was US$ 675 for IVF and US$ 725 for an ICSI treatment cycle. CONCLUSIONS: Using this protocol, together with several costcutting measures, we achieved an acceptable live birth rate per transfer of 19% at a reasonable cost. This approach could be used by established ART centres to provide treatment to couples who cannot afford conventional ART.

Estimating rates of multiple gestation pregnancies: sample size calculation from the assessment of multiple intrauterine gestations from ovarian stimulation (AMIGOS) trial.

Infertility afflicts 15% of couples who wish to conceive. Despite intensive evaluation of both male and female partners, the etiology may remain unknown leading to a diagnosis of unexplained infertility. For such couples, treatment often entails ovulation induction (OI) with fertility medications coupled with intrauterine insemination. Complications of this therapy include ovarian hyperstimulation syndrome and creation of multiple gestation pregnancies, which can be complicated by preterm labor and delivery, and the associated neonatal morbidity and expense of care for preterm infants. The Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) study is designed to assess whether OI in couples with unexplained infertility with an aromatase inhibitor produces mono-follicular development in most cycles, thereby reducing multiple gestations while maintaining a comparable pregnancy success rate to that achieved by OI with either gonadotropins or clomiphene citrate. These results will provide future guidance of therapy for couples with unexplained infertility, and if comparable pregnancy rates are achieved with a substantial reduction in multiple gestations, the public health benefit will be considerable.

Fertility treatment in women with polycystic ovary syndrome: a decision analysis of different oral ovulation induction agents.

OBJECTIVE: To compare different oral ovulation induction agents in treating infertile women with polycystic ovary syndrome (PCOS). DESIGN: Decision-analytic model comparing three treatment strategies using probability estimates derived from literature review and sensitivity analyses performed on the baseline assumptions. SETTING: Outpatient reproductive medicine and gynecology practices. PATIENT(S): Infertile women with PCOS. INTERVENTION(S): Metformin, clomiphene citrate, or metformin with clomiphene citrate. MAIN OUTCOME MEASURE(S): Live birth. RESULT(S): Within the baseline assumptions, combination therapy with metformin and clomiphene citrate was the preferred therapy for achieving live birth in women with PCOS. Sensitivity analysis revealed the model to be robust over a wide range of probabilities. CONCLUSION(S): Combination therapy with metformin and clomiphene citrate should be considered as first-line treatment for infertile women with PCOS.

An assessment of lifestyle modification versus medical treatment with clomiphene citrate, metformin, and clomiphene citrate-metformin in patients with polycystic ovary syndrome.

OBJECTIVE: To compare the effect of clomiphene citrate, metformin, and lifestyle modification on treatment of patients with polycystic ovary syndrome (PCOS). DESIGN: Prospective randomized double-blind study. SETTING: University-based infertility clinic and research center. PATIENT(S): Three hundred forty-three overweight infertile women with PCOS. INTERVENTION(S): The participating women were assigned to four groups: clomiphene (n = 90), metformin (n = 90), clomiphene + metformin (n = 88), and lifestyle modification (n = 75). The patients in each group received standardized dietary and exercise advice from a dietitian. MAIN OUTCOME MEASURE(S): The primary outcome variables were change in menstrual cycle, waist circumference measurements, endocrine parameters, and lipid profile. The main secondary outcome variable was clinical pregnancy rate. RESULT(S): The clinical pregnancy rate was 12.2% in clomiphene group, 14.4% in metformin group, 14.8% in clomiphene + metformin group, and 20% in lifestyle modification group. Lifestyle modification group achieved a significant reduction in waist circumference, total androgen, and lipid profile. CONCLUSION(S): Lifestyle modification improves the lipid profile in PCOS patients. Therefore, lifestyle modification may be used as the first line of ovulation induction in PCOS patients.

Discussion: 'Novel clomiphene protocol in polycystic ovarian syndrome' by Hurst et al.

In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Hurst BS, Hickman JM, Matthews ML, Usadi RS, Marshburn PB. Novel clomiphene "stair-step" protocol reduces time to ovulation in women with polycystic ovarian syndrome. Am J Obstet Gynecol 2009;200:510.e1-510.e4.

Clomifene citrate or unstimulated intrauterine insemination compared with expectant management for unexplained infertility: pragmatic randomised controlled trial.

OBJECTIVE: To compare the effectiveness of clomifene citrate and unstimulated intrauterine insemination with expectant management for the treatment of unexplained infertility. DESIGN: Three arm parallel group, pragmatic randomised controlled trial. SETTING: Four teaching hospitals and a district general hospital in Scotland. PARTICIPANTS: Couples with infertility for over two years, confirmed ovulation, patent fallopian tubes, and motile sperm. INTERVENTION: Expectant management, oral clomifene citrate, and unstimulated intrauterine insemination. MAIN OUTCOME MEASURES: The primary outcome was live birth. Secondary outcome measures included clinical pregnancy, multiple pregnancy, miscarriage, and acceptability. RESULTS: 580 women were randomised to expectant management (n=193), oral clomifene citrate (n=194), or unstimulated intrauterine insemination (n=193) for six months. The three randomised groups were comparable in terms of age, body mass index, duration of infertility, sperm concentration, and motility. Live birth rates were 32/193 (17%), 26/192 (14%), and 43/191 (23%), respectively. Compared with expectant management, the odds ratio for a live birth was 0.79 (95% confidence interval 0.45 to 1.38) after clomifene citrate and 1.46 (0.88 to 2.43) after unstimulated intrauterine insemination. More women randomised to clomifene citrate (159/170, 94%) and unstimulated intrauterine insemination (155/162, 96%) found the process of treatment acceptable than those randomised to expectant management (123/153, 80%) (P=0.001 and P<0.001, respectively). CONCLUSION: In couples with unexplained infertility existing treatments such as empirical clomifene and unstimulated intrauterine insemination are unlikely to offer superior live birth rates compared with expectant management. TRIAL REGISTRATION: ISRCT No: 71762042.

Oral ovulation induction agents combined with low-dose gonadotropin injections and intrauterine insemination: cost- and clinical effectiveness.

OBJECTIVE: To compare the efficacy and cost-effectiveness of different induction protocols involving gonadotropins with intrauterine insemination (IUI). STUDY DESIGN: We performed a retrospective chart review of 648 IUI cycles. Some patients had gonadotropin injections alone before human chorionic gonadotropin (hCG) and IUI (human menopausal gonadotropin protocol); others were given oral medications, then gonadotropins before hCG and IUI (combination protocol). Outcomes included pregnancy rates, multiple birth rates, endometrial thickness, number of ovarian follicles, injection days, ampules of gonadotropins and cost. RESULTS: The combination protocol was more cost-effective. In first cycles, pregnancy rates, multiple birth rates, number of large follicles produced and cancellation rates were similar. The combination group had fewer days of injections and fewer ampules used. When all cycles were analyzed, the multiple birth rate was lower in the combination group. Comparing the different oral medications in the combination protocols, letrozole yielded higher pregnancy rates than tamoxifen or clomiphene. Multiple birth rates were similar for all oral medications. CONCLUSION: Combination protocols are less costly and equally effective, with potentially fewer multiple births than with gonadotropins alone. Letrozole may be more effective than clomiphene and tamoxifen in a combination protocol.

Stimulated intrauterine insemination: efficient, cost-effective, safe?

A retrospective report of pregnancy and birth rates achieved in 1010 cycles of stimulated intrauterine insemination (SIUI). Over the years there has been an increasing emphasis on safety, particularly towards reducing the number of high order multiple pregnancies. SIUI is a complex form of assisted conception and requires a high level of clinical judgement to maintain an optimal balance between maximising pregnancy and birth rates and minimising complications, of which the most serious is multiple pregnancy. Extrapolating from these results, it is concluded that a well managed SIUI programme that selects patients appropriately, monitors them intensively and has in place effective strategies to manage over-responders safely, should be able to deliver at least a 15% live birth rate per cycle started with only a 5% cycle cancellation rate. Although SIUI birth rates are lower than IVF rates, the much lower cost of SIUI means that this treatment can be more cost-effective than IVF. However SIUI remains more risky than IVF and, despite careful management, high order multiple pregnancy rates will occasionally occur. It is estimated that the rate of unavoidable high order multiple pregnancies (triplets and above) is 4 per 1000 cycles started.

[The use of clomiphene citrate in ambulatory medicine practice in the Midi-Pyrénées area: compliance to national guidelines applicable to infertility diagnosis and to prescription and monitoring rules applicable to clomiphene citrate treatments]. / Utilisation du citrate de clomifène en médecine de ville dans la région Midi-Pyrénées: qualité du bilan explorant la stérilité, de la prescription et de la surveillance du traitement.

OBJECTIVE: Evaluate the compliance to the national guidelines from ANDEM (1996) and AFSSAPS (2003) concerning the diagnosis of infertility, the prescription of clomiphene and the monitoring of these treatments. PATIENTS AND METHODS: Retrospective study of female patients from 16 to 50 y.o. having benefited from reimbursement of clomiphene citrate treatment between 1st April 2002 and 30th June 2002. After random sampling stratified on age, data on diagnosis procedures and treatments were extracted from the Social Security reimbursement database. These data were validated and completed by patients' interviews. RESULTS: A total of 283 women were included. 30% were subject to the basic hormonal tests (FSH, LH, estradiol). The proportion of patients explored by hysterosalpingogram, post-coital test and echography were respectively 50%, 35% and 68%. A semen analysis was found in 60% of the partners. The complete set of recommended tests before start of treatment was realised in 1.5% of women. In 7% of cases, women were treated without prior exploration. The proportion of tests performed was comparable below and above the age of 35. 77% of treatments were initiated after at least one year of waiting for a spontaneous conception. 69% of women were monitored during treatment by other methods than clinical follow-up. CONCLUSION: Prescription of clomifene citrate is too frequently realised without compliance to guidelines applicable to infertility investigations and therefore without persuasive diagnosis. These practices can lead to loss of childbearing opportunities and complications.

The use of clomiphene citrate/human menopausal gonadotrophins in conjunction with GnRH antagonist in an IVF/ICSI program is not a cost effective protocol.

OBJECTIVE: To evaluate the cost effectiveness of a clomiphene citrate (CC)/human menopausal gonadotropin (hMG)/GnRH antagonist protocol versus a long-acting GnRH agonist/hMG protocol. PARTICIPANTS AND METHODS: One hundred eighty nine couples having their first trial of ICSI for male factor infertility were divided into two groups. Group I (no = 33) received CC 100-150 mg/day for five days starting from day 2 of the cycle and 150 IU of hMG/day on days 6-10. GnRH antagonist (Centrorelix) 0.25 mg/day was started when the leading follicle reached 16 mm in the absence of an LH surge. Group II (no = 156) received 0.1 mg Deacapeptyl/day as our standard long protocol. RESULTS: Clinical pregnancy was observed in 8 out of the 33 cases in group I (24%) while in group II, 92 out of 156 achieved clinical pregnancy (59%), the difference was statistically significant (P = 0.019). The cost of medications/cycle was estimated to be 1110+/-492 E.P in group I, while it was 1928+/-456 E.P. in group II. However, the total cost per pregnancy was 19653 EP in group I and 10047 EP in group II. CONCLUSION: The use of the clomid/hMG/antagonist protocol is not a cost effective strategy and should not be recommended in IVF-ICSI cycles.

Assisted reproductive interventions and multiple birth.

OBJECTIVE: To investigate the contributions of ovulation-inducing drugs and assisted reproductive technologies to multiple birth. METHODS: This historic prospective study was conducted in a cohort of 13,151 women who delivered after 20 weeks' gestation between October 1996 and December 1999. The study setting was a Colorado health maintenance organization. Cases were women who were pregnant as a result of exposure to treatment with either assisted reproductive technologies or ovulation induction in the absence of assisted reproductive technologies. The main outcome measure was multiple birth. RESULTS: There was a significant association between assisted conception and multiple birth. Compared with women with naturally conceived pregnancies, there was a 25-fold likelihood (95% confidence interval 18, 35, P <.001) of multiple birth among women exposed to any of those treatments. In the total cohort the proportion of multiple births attributable to those treatments was 33%. After adjusting for the use of assisted conception and other covariates, we found no association between advanced maternal age and multiple birth. CONCLUSION: In this cohort, assisted reproductive interventions were strongly associated with multiple birth. Although a higher proportion of older women sought assisted reproductive technologies, we did not find an independent relationship between advanced maternal age and multiple birth. The increasing number of multiple births attributable to assisted conception raises public health concerns regarding multiple gestation-related maternal and infant morbidities.

Perinatal outcome of twin pregnancies obtained after in vitro fertilization: comparison with twin pregnancies obtained spontaneously or after ovarian stimulation.

OBJECTIVE: To compare the perinatal outcome of IVF-ET twin pregnancies to twin pregnancies conceived spontaneously or after ovarian stimulation without IVF-ET. DESIGN: Retrospective analysis. PATIENTS: Three groups of patients: those who conceived after IVF-ET (n = 72), after ovarian stimulation without IVF-ET (stimulation group, n = 82), or spontaneously (spontaneous group, n = 164). MAIN OUTCOME MEASURES: High blood pressure, premature rupture of membrane, threatened premature labor, prematurity, low birth, small-for-gestational-age, cesarean section, and perinatal mortality. RESULTS: Patients of the IVF-ET group were older and of higher socioeconomic class. We did not find any significant difference in the data analyzed, with the exception of the rate of emergency cesarean sections. In the IVF-ET group the prematurity rate (38.9%), small-for-gestational-age (18%), and perinatal mortality (3.47%) were not statistically different with respect to the stimulation group (45.1%, 23.2%, and 3.05%, respectively) or the spontaneous group (39.6%, 22.7%, and 4.27%, respectively). CONCLUSIONS: Twin pregnancies account for 20% to 25% of all IVF-ET pregnancies. Their risk of adverse perinatal outcome does not seem to be increased when compared with spontaneous pregnancies or to pregnancies obtained after ovarian stimulation but without IVF-ET. However, a reduction in the proportion of multiple pregnancies, including twin gestation, should be a goal for IVF-ET teams.

Minimal stimulation achieves pregnancy rates comparable to human menopausal gonadotropins in the treatment of infertility.

OBJECTIVE: To examine the effectiveness of a novel clomiphene citrate (CC) and hMG combination protocol ("minimal stimulation") for controlled ovarian hyperstimulation. Minimal stimulation consists of administering 100 mg/d CC for 5 days followed by a single dose of 150 IU hMG. The results of this analysis are compared with those of an hMG-alone protocol. In vitro fertilization-embryo transfer and donor insemination patients are excluded from this analysis. DESIGN: Retrospective review of minimal stimulation and hMG cycles from January 1, 1989 to December 31, 1992. SETTING: Tertiary care center reproductive endocrinology and infertility clinic. PATIENTS: Two hundred thirty-two women who underwent 549 treatment cycles. MAIN OUTCOME MEASURES: Clinical and multiple pregnancy rates (PRs) and medication costs. RESULTS: Sixty-one women received 106 cycles of minimal stimulation and 183 received 443 cycles of hMG. Although subject groups were not assigned randomly, multivariate analysis detected no significant differences between the treatment groups. The total ampules of hMG required differed significantly (2.0 for minimal stimulation versus 16.8 +/- 8.5 [mean +/- SD] for hMG). Pregnancy rates and multiple gestation rates were similar. Medication expense of minimal stimulation is 21% that of the hMG protocol. CONCLUSIONS: Minimal stimulation is as effective as hMG in the population examined. The comparable PRs and decreased medication costs of minimal stimulation justifies further evaluation of its role in the treatment of infertility.

Use of fertility drugs in Denmark 1973-1993. An analysis based on sale statistics.

OBJECTIVES: The increasing use of drugs for ovarian stimulation and the possibility of long-term risks has actualized a quantitative assessment of the use of such therapy. The aim of the study was to analyze the development in the sale of different types of drugs used for ovarian stimulation in Denmark during the last two decades. MATERIAL: Sale statistics of clomiphene citrate, cyclophenile, human menopausal gonadotropin (hMG), mare menopausal gonadotropin (mMG) and human chorionic gonadotropin (hCG) in Denmark 1973-1993. METHODS: The number of defined daily doses (DDD) was calculated for each product group. On given assumptions the number of cycles of different treatment regimens and the number of treated women was calculated. RESULTS: The sale has increased almost exponentially throughout the last two decades: Clomiphene citrate 11 fold, hMG 30 fold, and hCG 5 fold. Today, among women 15-44 years old, the estimated incidence rate of women treated with clomiphene alone is about 2.7/1,000/year, and the incidence rate of women treated with clomiphene/hCG and hMG/hCG account for about 3.1/1,000/year and 1.9/1,000/year, respectively. CONCLUSION: Any study concerning short- and long-term effects of ovarian stimulation have to consider this secular trend.