The burden of very early dropout in infertility care: a nationwide population-based cohort study.

STUDY QUESTION: What is the frequency and the associated factors of very early dropout following unsuccessful clomiphene citrate (CC)/gonadotropin treatment in the context of full coverage of treatment cost. SUMMARY ANSWER: Despite free treatment, almost one in four women had a very early dropout following unsuccessful CC/gonadotropin treatment, with patients below the poverty line being more likely to drop out early. WHAT IS KNOWN ALREADY: Success of infertility care is tarnished by very high dropout rates. Infertility care dropout has been considered as resulting principally from financial barriers because of the high cost of treatment. Nearly all previous work addressed dropout following IVF/ICSI. Factors associated with dropout following CC/gonadotropins may be different and also need to be investigated. STUDY DESIGN, SIZE, DURATION: Nationwide population-based cohort study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using the French national health insurance and hospital databases, we included in the cohort 27 416 women aged 18-49 years unsuccessfully treated with CC/gonadotropins in 2017. The main outcome was very early dropout, defined as discontinuation of all infertility treatment after unsuccessful treatment for 1-3 months. Very early treatment dropout was analysed by multivariate logistic regression. MAIN RESULTS AND THE ROLE OF CHANCE: Among women unsuccessfully treated with CC/gonadotropins, 22% dropped out of infertility care within 3 months. In multivariate analysis, higher early dropout following unsuccessful CC/gonadotropin treatment was associated with older and younger ages (≥35 and <25 years), being below the poverty line, being treated with CC prescribed by a general practitioner and lack of infertility tests or monitoring. LIMITATIONS, REASONS FOR CAUTION: This study is based on health administrative data that do not include reasons for dropout and record only a limited amount of information. It is thus not possible to analyse the reason for early dropout. WIDER IMPLICATIONS OF THE FINDINGS: Despite full coverage of all infertility treatment, women under the poverty line have a higher risk of very early dropout following unsuccessful CC/gonadotropin treatment. Better understanding is needed of the non-financial barriers and difficulties faced by these patients. To address disparities in infertility treatment, practitioner training could be reinforced to adapt to patients from different social and cultural backgrounds. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the ANR StimHo project, grant ANR-17-CE36-0011-01 from the French Agence Nationale de la Recherche. The authors have no conflict of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Strong social disparities in access to IVF/ICSI despite free cost of treatment: a French population-based nationwide cohort study.

BACKGROUND: Access to IVF/ICSI is facilitated when the financial barrier is removed. In a national context where in vitro fertilisation (IVF)/intracytoplasmic sperm Injection (ICSI) treatment is cost-free, how many women do not access IVF/ICSI and what are the factors associated with non-access? METHODS: Using French national health insurance databases, the cohort included 20,240 women aged 18-43 years living in France who underwent unsuccessful treatment (no pregnancy) with clomiphene citrate (CC) and/or gonadotropins with treatment started between January and August 2016. The outcome measure was non-access to IVF/ICSI during the 24-month following start of infertility care. Factors associated with non-access to IVF/ICSI were explored using mixed effects logistic regression. RESULTS: In the cohort, 65.4% of women did not access IVF/ICSI. In multivariable analysis, non-access to IVF/ICSI was higher in younger women (18-25 years: (OR 2.17, 95% CI: 1.85-2.54) and in older women (40-43 years: (OR=3.60, 95% CI: 3.25-3.98)). Non-access was higher among women below the poverty line (OR=3.76, 95% CI: 3.34-4.23) and showed a significant upward trend with increasing deprivation of place of residence. Distance to the nearest fertility centre was not significantly associated with non-access to IVF/ICSI. CONCLUSIONS: In a national context of cost-free ART treatment, a large proportion of women did not access treatment, with a strong social gradient that raises important issues. We need to understand the underlying social mechanisms to develop an efficient and equitable health policy regarding infertility care.

Seven out of 10 couples treated by IVF achieve parenthood following either treatment, natural conception or adoption.

The aim of this study was to explore the achievement of parenthood 8 years after starting IVF, considering multiple pathways to parenthood during and after IVF treatment. Medical data on 6507 couples who began IVF between 2000 and 2002 were obtained from the databases of eight French IVF centres. Information on long-term outcome was available for participants in the 2008-2010 postal survey. Multiple imputation methods were used to account for missing data. Eight years after starting IVF, 71% (95% CI 69 to 74) of treated couples had a child. This included 41% live births after IVF in the IVF centre, 7% live births after another treatment or after IVF in another centre, 12% live births after spontaneous conception and 11% adoptions. This study provides a longitudinal overview of paths to parenthood among couples successfully and unsuccessfully treated by IVF. These results should give hope to infertile couples as seven out of 10 couples finally became parents. However, IVF is not the only path to parenthood, and couples should be informed of the other possible avenues.

Medical factors associated with early IVF discontinuation.

Even when IVF is reimbursed by the social insurance system, as in France, high discontinuation rates have been reported and some patients drop out as soon as the first failed IVF cycle. This study aims to investigate medical factors associated with treatment discontinuation in an IVF centre after the first unsuccessful cycle. The study included 5135 couples recruited in eight French IVF centres and who had had an unsuccessful first IVF cycle in these centres in 2000-2002 (i.e. no live birth). Of these couples with a first failed IVF, 1337 did not have a second IVF in the centre (26%, 'early discontinuation group') and 3798 continued treatment with a second IVF in the centre. The characteristics of couples who discontinued IVF treatment were compared with those who continued using logistic regressions. Older women, women with duration of infertility >5years, with female factor or unexplained infertility, with 0 or 1 oocyte retrieved and no embryo transfer during the first IVF were more likely to discontinue treatment early. Risk of early discontinuation was associated with medical factors that are also well known to be associated with impaired chance of successful IVF. Even when IVF is reimbursed by the social insurance system, as in France, high discontinuation rates have been reported and some patients drop out as soon as the first failed IVF cycle. This study aims to investigate medical factors associated with treatment discontinuation in an IVF centre after the first unsuccessful cycle. The study included 5135 couples recruited in eight French IVF centres who had had an unsuccessful first IVF cycle in these centres in 2000-2002 (i.e. who remained childless after a first cycle). Of these couples with a first failed IVF, 1337 did not have a second IVF in the centre and 3798 continued treatment with a second IVF in the centre. The characteristics of couples who discontinued IVF treatment were compared with those who continued. After a first failed IVF cycle, more than one-quarter (26%) of couples discontinued IVF treatment. Older women, women with duration of infertility >5years, with female factor or unexplained infertility, with 0 or 1 oocyte retrieved and with no embryo transfer during the first IVF were more likely to discontinue treatment early. The risk of early discontinuation was associated with medical factors that are also well known to be associated with impaired chance of success during IVF treatment. A next step would be to examine whether the early discontinuation results from a decision of the couple themselves, from medical, psychological and/or social staff counselling or from some combination of all of these factors.

Joint modeling of success and treatment discontinuation in in vitro fertilization programs: a retrospective cohort study.

BACKGROUND: As discontinuation in in vitro fertilization (IVF) programs has been associated with a poor prognosis, one hypothesis is that some couple-specific predictive factors in IVF may be shared with opposite effect by both success (i.e. live birth) and treatment discontinuation processes. Our objective was to perform a joint analysis of these two processes to examine the hypothesis of a link between the two processes. METHODS: Analyses were conducted on a retrospective cohort of 3,002 women who began IVF between 1998 and 2002 in two French IVF centers: a Parisian center and a center in a medium-sized city in central France. A shared random effects model based on a joint modelization of IVF treatment success and discontinuation was used to study the link between the two processes. RESULTS: Success and discontinuation processes were significantly linked in the medium-sized city center, whereas they were not linked in the Parisian center. The center influenced risk of treatment discontinuation but not chance of success. The well-known inverse-J relation between the woman's age and chance of success was observed, as expected. Risk of discontinuation globally increased as the woman's age increased. CONCLUSIONS: The link between success and discontinuation processes could depend on the fertility center. In particular, the woman's decision to pursue or to discontinue IVF in a particular center could depend on the presence of other IVF centers in the surrounding area.

Who does not participate in a follow-up postal study? a survey of infertile couples treated by in vitro fertilization.

BACKGROUND: A good response rate has been considered as a proof of a study's quality. Decreasing participation and its potential impact on the internal validity of the study are of growing interest. Our objective was to assess factors associated with contact and response to a postal survey in a epidemiological study of the long-term outcome of IVF couples. METHODS: The DAIFI study is a retrospective cohort including 6,507 couples who began an IVF program in 2000-2002 in one of the eight participating French IVF centers. Medical data on all 6,507 couples were obtained from IVF center databases, and information on long-term outcome was available only for participants in the postal survey (n = 2,321). Logistic regressions were used to assess firstly factors associated with contact and secondly factors associated with response to the postal questionnaire among contacted couples. RESULTS: Sixty-two percent of the 6,507 couples were contacted and 58% of these responded to the postal questionnaire. Contacted couples were more likely to have had a child during IVF treatment than non-contactable couples, and the same was true of respondents compared with non-respondents. Demographic and medical characteristics were both associated with probability of contact and probability of response. After adjustment, having a live birth during IVF treatment remained associated with both probabilities, and more strongly with probability of response. Having a child during IVF treatment was a major factor impacting on participation rate. CONCLUSIONS: Non-response as well as non-contact were linked to the outcome of interest, i.e. long-term parenthood success of infertile couples. Our study illustrates that an a priori hypothesis may be too simplistic and may underestimate potential bias. In the context of growing use of analytical methods that take attrition into account (such as multiple imputation), we need to better understand the mechanisms that underlie attrition in order to choose the most appropriate method.

Optimal timing for oocyte denudation and intracytoplasmic sperm injection.

Objectives. To analyze the impact of oocyte denudation and microinjection timings on intracytoplasmic sperm injection (ICSI) outcomes. Study Design. We included ICSI cycles with the following parameters: rank 1 or 2, female age <36 years, male factor infertility, long protocol using GnRH agonist and rFSH for ovarian stimulation, and use of freshly ejaculated sperm (n = 110). Several ICSI parameters were analyzed according to the time between oocyte retrieval and denudation (T(1)) and the time between denudation and ICSI (T(2)) using a statistical logistic regression analysis. Results. Neither T(1) nor T(2) had a significant influence on the Metaphase II (MII) rate but the fertilisation rate (FR) showed a significant improvement when T(1) was longer (optimal results at T(1) = 3 hours) while FR significantly decreased with the increase of T(2). Optimal implantation (IR) and pregnancy (PR) rates were obtained when T(1) was around 2 hours. Conclusion. Incubation of oocytes around 2 hours between retrieval and denudation may not increase MII rate but appears to lead to the optimal combination of FR and IR.

Spontaneous pregnancies among couples previously treated by in vitro fertilization.

OBJECTIVE: To determine the frequency of live births following spontaneous pregnancy (BSP) and to examine their associated factors among couples who have unsuccessfully or successfully experienced fertility treatments. DESIGN: Retrospective cohort. SETTING: Eight IVF centers. PATIENT(S): A total of 2,134 couples who began IVF treatment in the centers in 2000-2002 and were followed up by a postal questionnaire sent 7-9 years after they started treatment in the inclusion center. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Rates of BSP and factors associated with BSP. Univariate and multivariate analyses were conducted using logistic regression. RESULT(S): The BSP rate was 17% (218/1,320) among couples who had previously had a child through medical treatment and 24% (193/814) among couples who had remained childless after treatment. In both groups, the probability of BSP was higher among younger women and increased with a smaller number of IVF attempts. Probability was also higher when the cause of infertility was unexplained. CONCLUSION(S): Our results should give hope to couples who have been unsuccessfully treated by IVF, especially young couples with unexplained infertility. Nonetheless, it should be remembered that the BSP rates are cumulative rates observed over a long period of time and that these couples have a very low monthly probability of conceiving.

Effect of the woman's age on discontinuation of IVF treatment.

Treatment discontinuations are an important issue in IVF programmes. In the French context, financial constraint does not intervene in discontinuation until older ages. This study examined treatment discontinuation in IVF programmes, according to the woman's age and when there is no financial burden for couples. Medical records were collected for 3037 women who began their IVF programme between 1998 and 2002 in two French IVF units. Up to four attempts were taken into consideration. Cumulative success (delivery) rates were calculated, as well as discontinuation rates. Multiple imputation was applied to estimate a theoretical cumulative success rate as if no woman discontinued treatment before the end of the IVF programme without delivering. Cumulative discontinuation rates at the end of the IVF programme increased with the woman's age (41% for age <35, 56% for age 35-39, 80% for age ⩾40). The benefit in terms of delivery rates of pursuing treatment would be smaller for older women (∼10% for age <35, 7% for age 35-39, 4% for age ⩾40). Even when treatment is reimbursed, the discontinuation rate is high for older women, suggesting that the strong decrease in success rate with age induces older women to discontinue. Treatment discontinuations are an important issue in IVF programmes. In the French context, financial constraint does not intervene in discontinuation until older ages. We aimed to examine treatment discontinuation in IVF programmes, according to the woman's age and when there is no financial burden for couples. Medical records were collected for 3037 women who began their IVF programme between 1998 and 2002 in two French IVF units. Up to four attempts were taken into consideration. Cumulative success (delivery) rates were calculated, as well as discontinuation rates. Multiple imputation was applied to estimate a theoretical cumulative success rate as if no woman discontinued treatment before the end of the IVF programme without delivering. Cumulative discontinuation rates at the end of the IVF programme increased with the woman's age (41% for age <35, 56% for age 35-39, 80% for age ⩾40). The benefit in terms of delivery rates of pursuing treatment would be smaller for older women (∼10% for age <35, 7% for age 35-39, 4% for age ⩾40). Even when treatment is reimbursed, the discontinuation rate is high for older women, suggesting that the strong decrease in success rate with age induces older women to discontinue.

Cumulative results including obstetrical and neonatal outcome of fresh and frozen-thawed cycles in elective single versus double fresh embryo transfers.

OBJECTIVE: To assess the efficacy of elective single embryo transfer (e-SET) compared to a double embryo transfer (DET) in a selected population including obstetrical and neonatal outcome of fresh and frozen-thawed cycles. DESIGN: Prospective nonrandomized study. SETTING: Department of reproductive medicine. PATIENT(S): Elective single embryo transfer was proposed to women < 36 years with adequate ovarian function, in their first or second IVF or intracytoplasmic sperm injection (ICSI) attempt with ejaculated sperm, with at least 4 mature oocytes and 2 fertilized top quality embryos. Patients who refused e-SET had two top embryos transferred (DET group). INTERVENTION(S): Medical management and IVF-ICSI. MAIN OUTCOME MEASURE(S): Cumulative delivery rate, twin delivery rate, obstetrical and neonatal outcome. RESULT(S): According to patients' decision, 53 women had an e-SET and 98 a DET. The cumulative delivery rate per patient was 54.7% in the e-SET group and 49.0% in the DET group (P>0.05). Twin delivery rate was significantly different between the two groups (3.5% versus 37.5% respectively, P<0.05). Neonatal outcome in twins resulting from IVF-ICSI was found to be poorer than in singletons, considering the mean gestational age, mode of delivery, birthweight, and risk of neonatal intensive care unit admission for the infants. CONCLUSION(S): In a selected population, the elective transfer of one embryo with high implantation potential helped to avoid twin pregnancies without decreasing delivery rate.

Long-term outcome of parenthood project during in vitro fertilization and after discontinuation of unsuccessful in vitro fertilization.

OBJECTIVE: To explore the long-term outcome of patients who began IVF treatment by considering not only treatment outcome in the center but also the parenthood project outcome after discontinuation of unsuccessful IVF. DESIGN: Retrospective cohort follow-up study. SETTING: Two French IVF centers. PATIENT(S): Seven hundred twenty-four patients who began IVF treatment in 1998. INTERVENTION(S): Postal and phone contacts with unsuccessful IVF patients. MAIN OUTCOME MEASURE(S): Long-term outcome of parenthood project. RESULT(S): Of the 724 patients, a minimum of 53% and a maximum of 81% finally succeeded in their parenthood project during or after IVF treatment (depending on the hypotheses that the 204 patients not contacted either failed or succeeded in their parenthood project). An intermediate hypothesis gave an estimation of 66% of patients finally succeeding in having a child (40% during IVF treatment in the center and 26% after). Achievement of the parenthood project after IVF discontinuation was due mainly to adoption of a child (46%) or a birth following a spontaneous pregnancy (42%). CONCLUSION(S): Unsuccessful patients should not lose hope, because nearly half may subsequently succeed in having a child.

[Assisted procreation technology and people with HIV]. / Aide médicale à la procréation chez les personnes infectées par le VIH.

In France, a ministerial decree dated 10 May 2001 authorizes the use of assisted reproduction technologies (ART) for people infected with the human immunodeficiency virus (HIV), either to reduce the risk of transmission between partners or to treat the couple's infertility. The HIV patient must have a CD4 T lymphocyte count>200/mm(3) and a stable viral load (no increase exceeding 0.5 log(10) copies/mm(3)) between 2 samples during the 6 months preceding ART. Co-infections with hepatitis B or C must be assessed by a specialist. When the man is infected, only ART allows conception while simultaneously ensuring safe sexual relations between the couple. ART is performed with prepared spermatozoa, validated negative for HIV RNA. The particular ART method depends on the results of the couple's fertility assessment and the quantity of virus in the seminal fluid. Antiretroviral treatment is not required for ART but may be necessary if the seminal viral load is elevated. When the woman is infected, the couple must be informed about the risks of HIV transmission to the child and of toxicity to mother and fetus from the antiretroviral treatments. These risks must guide optimization of the antiretroviral treatment, which is not routine during ART but is systematic during the last trimester. Management of pregnancy planning should propose artificial insemination and rapid recourse to ART because ovarian function appears to deteriorate quickly in women with HIV. Several thousand couples in Europe have used ART without any cases of contamination reported so far. Approximately half of these couples can hope to have a child, but approximately one third decide against ART after consultation.

Pregnancy after in vitro fertilization-intracytoplasmic sperm injection obtained with a modified natural cycle in a BRCA1 mutation carrier.

OBJECTIVE: To report a successful pregnancy after a semi-natural IVF cycle for a BRCA1 gene mutation carrier. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 26-year-old patient with BRCA1 gene mutation. INTERVENTION(S): Semi-natural IVF cycle and intracytoplasmic sperm injection. MAIN OUTCOME MEASURE(S): Pregnancy rate. RESULT(S): A modified natural IVF cycle was performed, resulting in pregnancy and delivery. CONCLUSION(S): A modified natural IVF cycle is an effective and safe solution for BRCA1 or BRCA2 mutation gene carrier women with couple infertility.

Successful delivery after the transfer of embryos obtained from a cohort of incompletely in vivo matured oocytes at retrieval time.

OBJECTIVE: To report a case of successful delivery of a healthy baby after intracytoplasmic sperm injection (ICSI) in a patient with no mature oocytes at the time of oocyte retrieval. DESIGN: Case report. SETTING: Department of Reproductive Medicine. PATIENT: After a controlled ovarian hyperstimulation cycle, a total of seven immature oocytes were collected. INTERVENTION(S): Medical management. MAIN OUTCOME MEASURE(S): The timing of polar body extrusion was checked every 2 hours, and ICSI was performed as soon as the first polar body was extruded. RESULT(S): Following incubation in culture medium, five oocytes reached the metaphase II stage within 8-8.5 hours. Three oocytes were fertilized after ICSI, and two of three cleaved embryos were transferred on day 3. The embryo transfer was followed by a single pregnancy and the delivery of a healthy baby. CONCLUSION: This case report demonstrates that embryos obtained from in vitro matured oocytes retain the developmental competence for full-term. It illustrates the importance of regularly monitoring the polar body extrusion when all collected oocytes are immature.

Safety and efficacy of sperm washing in HIV-1-serodiscordant couples where the male is infected: results from the European CREAThE network.

OBJECTIVE: To examine the safety and effectiveness of assisted reproduction using sperm washing for HIV-1-serodiscordant couples wishing to procreate where the male partner is infected. DESIGN AND METHODS: A retrospective multicentre study at eight centres adhering on the European network CREAThE and involving 1036 serodiscordant couples wishing to procreate. Sperm washing was used to obtain motile spermatozoa for 3390 assisted reproduction cycles (2840 intrauterine inseminations, 107 in-vitro fertilizations, 394 intra-cytoplasmic sperm injections and 49 frozen embryo transfers). An HIV test was performed in female partners at least 6 months after assisted reproduction attempt. The outcome measures recorded were number of assisted reproduction cycles, pregnancy outcome and HIV test on women post-treatment. RESULTS: A total of 580 pregnancies were obtained from 3315 cycles. Pregnancy outcome was unknown in 47 cases. The 533 pregnancies resulted in 410 deliveries and 463 live births. The result of female HIV testing after assisted reproduction was known in 967 out of 1036 woman (7.1% lost to follow-up). All tests recorded were negative. The calculated probability of contamination was equal to zero (95% confidence interval, 0-0.09%). CONCLUSION: This first multicentre retrospective study of assisted reproduction following sperm washing demonstrates the method to be effective and to significantly reduce HIV-1 transmission risk to the uninfected female partner. These results support the view that assisted reproduction with sperm washing could not be denied to serodiscordant couples in developed countries and, where possible, could perhaps be integrated into a global public health initiative against HIV in developing countries.

Pregnancy outcome and live birth after IVF and ICSI according to embryo quality.

PURPOSE: The pregnancy outcome and the chances of birth were assessed according to embryo quality after IVF or ICSI. METHODS: The implantation rate (IR), the loss of gestational sacs rate (LGSR), and birth rate (BR) were determined according to the cleavage stage and the integrity of blastomeres after day-2 homogeneous embryo transfers (n = 1812). RESULTS: The LGSR was higher after transfers of 2-3-cell or 5-6-cell embryos and was significantly increased when more than 20% of the embryo volume was fragmented in 4-cell embryos. After transfers of 4-cell embryos without fragmentation, the BR was significantly higher than the BR after transfers of 4-cell embryos with 1-20% fragmentation (16.6% vs 13.1%). The difference was the consequence of a higher IR (20.4% vs 17.3%) but also of a lower LGSR (18.9% vs 24.2%). CONCLUSIONS: Not only implantation and the ability to give a pregnancy, but also the capacity to give a live birth are dependent on the embryo quality.

Artificial versus stimulated cycles for endometrial preparation prior to frozen-thawed embryo transfer.

The objective of this study was to compare the implantation rate, pregnancy rate and endometrial thickness of frozen-thawed embryo transfers using endometrial preparation with either an artificial cycle or stimulated cycle. This was a prospective randomized trial at a single academic IVF centre. Seventy-seven patients undergoing artificial cycles received oral oestradiol; patients with endometrium < 7 mm on day 9-10 were switched to vaginal oestradiol. Eighty-six patients undergoing stimulated cycles received recombinant FSH followed by human gonadotrophin hormone injection. Vaginal progesterone was begun 2 or 3 days prior to embryo transfer. There was no difference in implantation rate (8.5% versus 7.3%), pregnancy rate (16% versus 13%), cancellation rate (both 23%) or endometrium thickness (8.7 +/- 1.1 mm versus 8.7 +/- 1.0 mm) between artificial and stimulated cycles. Stimulated cycles had a higher incidence of thin endometrium (27% versus 5%, P < 0.01). In artificial cycles, patients switched to vaginal oestradiol had improved pregnancy rate (31%) versus patients who received oral oestradiol alone (13%) (P = 0.05). It is concluded that artificial and stimulated cycles produce comparable pregnancy rates, implantation rates, cancellation rates and endometrial thickness, although stimulated cycles have a higher incidence of thin endometrium. Vaginal oestradiol supplementation improved implantation rates.