J.M.J. Smeenk

Added value of ovarian reserve testing on patient characteristics in the prediction of ovarian response and ongoing pregnancy: an individual patient data approach

BACKGROUND Although ovarian reserve tests (ORTs) are frequently used prior to IVF treatment for outcome prediction, their added predictive value is unclear. We assessed the added value of ORTs to patient characteristics in the prediction of IVF outcome. METHODS An individual patient data (IPD) meta-analysis from published studies was performed. Studies on FSH, anti-Müllerian hormone (AMH) or antral follicle count (AFC) in women undergoing IVF were identified and authors were contacted. Using random intercept logistic regression models, we estimated the added predictive value of ORTs for poor response and ongoing pregnancy after IVF, relative to patient characteristics. RESULTS We were able to collect 28 study databases, comprising 5705 women undergoing IVF. The area under the receiver-operating characteristic curve (AUC) for female age in predicting poor response was 0.61. AFC and AMH each significantly improved the model fit (P-value <0.001). Moreover, almost a similar accuracy was reached using AMH or AFC alone (AUC 0.78 and 0.76, respectively). Combining the two tests, however, did not improve prediction (AUC 0.80, P = 0.19) of poor response. In predicting ongoing pregnancy after IVF, age was the best single predictor (AUC 0.57), and none of the ORTs added any value. CONCLUSIONS This IPD meta-analysis demonstrates that AFC and AMH clearly add to age in predicting poor response. As single tests, AFC and AMH both fully cover the prediction of poor ovarian response. In contrast, none of the ORTs add any information to the limited capacity of female age to predict ongoing pregnancy after IVF. The clinical usefulness of ORTs prior to IVF will be limited to the prediction of ovarian response.

Stress and marital satisfaction among women before and after their first cycle of in vitro fertilization and intracytoplasmic sperm injection

OBJECTIVEnTo determine differences in emotional status (anxiety and depression) and marital satisfaction in pregnant and nonpregnant women before and after their first cycle of IVF and intracytoplasmic sperm injection (ICSI).nnnDESIGNnRepeated measurement.nnnSETTINGnFertility department at a university and a regional hospital.nnnPATIENT(S)nWomen entering their first treatment cycle of IVF or ICSI.nnnINTERVENTION(S)nQuestionnaires on psychological factors were administered 3 to 12 days before the start of their first treatment cycle and repeated 3 weeks after the pregnancy test.nnnMAIN OUTCOME MEASURE(S)nState anxiety, depression, mood, and marital satisfaction.nnnRESULT(S)nAt pretreatment, the women who became pregnant showed lower levels of depression than those who did not. Higher levels of depression in the pregnant women after the first cycle were due to higher scores on vital aspects of depression, related to signs of early pregnancy. Higher levels of depression in the nonpregnant women were due to a higher score on cognitive aspects of depression.nnnCONCLUSION(S)nDifferences in emotional status between pregnant and nonpregnant women were present before treatment and became more apparent after the first IVF and ICSI cycle. There were no differences in emotional status between the women who underwent IVF and those who underwent ICSI.

Risk of borderline and invasive ovarian tumours after ovarian stimulation for in vitro fertilization in a large Dutch cohort

BACKGROUND Long-term effects of ovarian stimulation for IVF on the risk of ovarian malignancies are unknown. METHODS We identified a nationwide historic cohort of 19 146 women who received IVF treatment in the Netherlands between 1983 and 1995, and a comparison group of 6006 subfertile women not treated with IVF. In 1997–1999, data on reproductive risk factors were obtained from 65% of women and data on subfertility (treatment) were obtained from the medical records. The incidence of ovarian malignancies (including borderline ovarian tumours) through 2007 was assessed through linkage with disease registries. The risk of ovarian malignancies in the IVF group was compared with risks in the general population and the subfertile comparison group. RESULTS After a median follow-up of 14.7 years, the risk of borderline ovarian tumours was increased in the IVF group compared with the general population [standardized incidence ratio (SIR) = 1.76; 95% confidence interval (CI) = 1.16–2.56]. The overall SIR for invasive ovarian cancer was not significantly elevated, but increased with longer follow-up after first IVF (P = 0.02); the SIR was 3.54 (95% CI = 1.62–6.72) after 15 years. The risks of borderline ovarian tumours and of all ovarian malignancies combined in the IVF group were significantly increased compared with risks in the subfertile comparison group (hazard ratios = 4.23; 95% CI = 1.25–14.33 and 2.14; 95% CI = 1.07–4.25, respectively, adjusted for age, parity and subfertility cause). CONCLUSIONS Ovarian stimulation for IVF may increase the risk of ovarian malignancies, especially borderline ovarian tumours. More large cohort studies are needed to confirm these findings and to examine the effect of IVF treatment characteristics.

Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE.

STUDY QUESTIONnThe 16th European IVF-monitoring (EIM) report presents the data of the treatments involving assisted reproductive technology (ART) and intrauterine insemination (IUI) initiated in Europe during 2012: are there any changes compared with previous years?nnnSUMMARY ANSWERnDespite some fluctuations in the number of countries reporting data, the overall number of ART cycles has continued to increase year by year, the pregnancy rates (PRs) in 2012 remained stable compared with those reported in 2011, and the number of transfers with multiple embryos (3+) and the multiple delivery rates were lower than ever before.nnnWHAT IS KNOWN ALREADYnSince 1997, ART data in Europe have been collected and re-ported in 15 manuscripts, published in Human Reproduction.nnnSTUDY DESIGN, SIZE, DURATIONnRetrospective data collection of European ART data by the EIM Consortium for the European Society of Human Reproduction and Embryology (ESHRE). Data for cycles between 1 January and 31 December 2012 were collected from National Registers, when existing, or on a voluntary basis by personal information.nnnPARTICIPANTS/MATERIALS, SETTING, METHODSnFrom 34 countries (+1 compared with 2011), 1111 clinics reported 640 144 treatment cycles including 139 978 of IVF, 312 600 of ICSI, 139 558 of frozen embryo replacement (FER), 33 605 of egg donation (ED), 421 of in vitro maturation, 8433 of preimplantation genetic diagnosis/preimplantation genetic screening and 5549 of frozen oocyte replacements (FOR). European data on intrauterine insemination using husband/partners semen (IUI-H) and donor semen (IUI-D) were reported from 1126 IUI labs in 24 countries. A total of 175 028 IUI-H and 43 497 IUI-D cycles were included.nnnMAIN RESULTS AND THE ROLE OF CHANCEnIn 18 countries where all clinics reported to their ART register, a total of 369 081 ART cycles were performed in a population of around 295 million inhabitants, corresponding to 1252 cycles per million inhabitants (range 325-2732 cycles per million inhabitants). For all IVF cycles, the clinical PRs per aspiration and per transfer were stable with 29.4 (29.1% in 2011) and 33.8% (33.2% in 2011), respectively. For ICSI, the corresponding rates also were stable with 27.8 (27.9% in 2011) and 32.3% (31.8% in 2011). In FER cycles, the PR per thawing/warming increased to 23.1% (21.3% in 2011). In ED cycles, the PR per fresh transfer increased to 48.4% (45.8% in 2011) and to 35.9% (33.6% in 2011) per thawed transfer, while it was 45.1% for transfers after FOR. The delivery rate after IUI remained stable, at 8.5% (8.3% in 2011) after IUI-H and 12.0% (12.2% in 2011) after IUI-D. In IVF and ICSI cycles, 1, 2, 3 and 4+ embryos were transferred in 30.2, 55.4, 13.3 and 1.1% of the cycles, respectively. The proportions of singleton, twin and triplet deliveries after IVF and ICSI (added together) were 82.1, 17.3 and 0.6%, respectively, resulting in a total multiple delivery rate of 17.9% compared with 19.2% in 2011 and 20.6% in 2010. In FER cycles, the multiple delivery rate was 12.5% (12.2% twins and 0.3% triplets). Twin and triplet delivery rates associated with IUI cycles were 9.0%/0.4% and 7.2%/0.5%, following treatment with husband and donor semen, respectively.nnnLIMITATIONS, REASONS FOR CAUTIONnThe method of reporting varies among countries, and registers from a number of countries have been unable to provide some of the relevant data such as initiated cycles and deliveries. As long as data are incomplete and generated through different methods of collection, results should be interpreted with caution.nnnWIDER IMPLICATIONS OF THE FINDINGSnThe 16th ESHRE report on ART shows a continuing expansion of the number of treatment cycles in Europe, with more than 640 000 cycles reported in 2012 with an increasing contribution to birthrate in many countries. However, the need to improve and standardize the national registries, and to establish validation methodologies remains manifest.nnnSTUDY FUNDING/COMPETING INTERESTSnThe study has no external funding; all costs are covered by ESHRE. There are no competing interests.

Predicting Emotional Response to Unsuccessful Fertility Treatment: A Prospective Study

The predictive value of a comprehensive model with personality characteristics, stressor related cognitions, coping and social support was tested in a sample of 187 nonpregnant women. The emotional response to the unsuccessful treatment was predicted out of vulnerability factors assessed before the start of the treatment. The results indicated the importance of neuroticism as a vulnerability factor in emotional response to a severe stressor. They also underlined the importance of helplessness and marital dissatisfaction as additional risk factors, and acceptance and perceived social support as additional protective factors, in the development of anxiety and depression after a failed fertility treatment. From clinical point of view, these results suggest fertility-related cognitions and social support should receive attention when counselling women undergoing IVF or ICSI treatment.

Age-related normograms of serum antimüllerian hormone levels in a population of infertile women: a multicenter study

OBJECTIVEnTo produce age-related normograms for serum antimüllerian hormone (AMH) level in infertile women without polycystic ovaries (non-PCO).nnnDESIGNnRetrospective cohort analysis.nnnSETTINGnFifteen academic reproductive centers.nnnPATIENT(S)nA total of 3,871 infertile women.nnnINTERVENTION(S)nBlood sampling for AMH level.nnnMAIN OUTCOME MEASURE(S)nSerum AMH levels and correlation between age and different percentiles of AMH.nnnRESULT(S)nAge-related normograms for the 3rd, 10th, 25th, 50th, 75th, 90th, and 97th percentiles of AMH were produced. We found that the curves of AMH by age for the 3rd to 50th percentiles fit the model and appearance of linear relation, whereas the curves of >75th percentiles fit cubic relation. There were significant differences in AMH and FSH levels and in antral follicle count (AFC) among women aged 24-33 years, 34-38 years, and ≥39 years. Multivariate stepwise linear regression analysis of FSH, age, AFC, and the type of AMH kit as predictors of AMH level shows that all variables are independently associated with AMH level, in the following order: AFC, FSH, type of AMH kit, and age.nnnCONCLUSION(S)nAge-related normograms in non-PCO infertile women for the 3rd to 97th percentiles were produced. These normograms could provide a reference guide for the clinician to consult women with infertility. However, future validation with longitudinal data is still needed.

Prediction of an excessive response in in vitro fertilization from patient characteristics and ovarian reserve tests and comparison in subgroups: an individual patient data meta-analysis

OBJECTIVEnTo evaluate whether ovarian reserve tests (ORTs) add prognostic value to patient characteristics, such as female age, in the prediction of excessive response to ovarian hyperstimulation in patients undergoing IVF, and whether their performance differs across clinical subgroups.nnnDESIGNnAuthors of studies reporting on basal FSH, antimüllerian hormone (AMH), or antral follicle count (AFC) in relation to ovarian response to ovarian hyperstimulation were invited to share original data. Random intercept logistic regression models were used to estimate added value of ORTs on patient characteristics, while accounting for between-study heterogeneity. Receiver operating characteristic regression analyses were performed to study the effect of patient characteristics on ORT accuracy.nnnSETTINGnInxa0vitro fertilization clinics.nnnPATIENT(S)nA total of 4,786 women for the main analysis, with a subgroup of 1,023 women with information on all three ORTs.nnnINTERVENTION(S)nNone.nnnMAIN OUTCOME MEASURE(S)nExcessive response prediction.nnnRESULT(S)nWe included 57 studies reporting on 32 databases. Female age had an area under the receiver operating characteristic curve of 0.61 for excessive response prediction. Antral follicle count and AMH significantly added prognostic value to this. A model with female age, AFC, and AMH had an area under the receiver operating characteristic curve of 0.85. The combination of AMH and AFC, without age, had similar accuracy. Subgroup analysis indicated that FSH performed significantly worse in predicting excessive response in higher age groups, AFC did significantly better, and AMH performed the same.nnnCONCLUSION(S)nWe demonstrate that AFC and AMH add value to female age in the prediction of excessive response and that, for AFC and FSH, the discriminatory performance is affected by female age.

The relationship between autobiographical memory specificity and depressed mood following a stressful life event: A prospective study

OBJECTIVESnIn the present prospective study, the relationship between autobiographical memory specificity and the emotional reactions to a stressful event was investigated.nnnDESIGN AND METHODSnThe Autobiographical Memory Test (AMT) was administered to 74 women before they underwent an in vitro fertilization (IVF) treatment, which subsequently failed. Symptoms of emotional reactions - depression and anxiety - were measured both before and after the (failed) IVF treatment.nnnRESULTSnIt was found that the number of reported specific memories at baseline was negatively related to depressive and anxiety symptoms after the treatment, even when initial depressive and anxiety symptoms and verbal fluency were controlled for.nnnCONCLUSIONSnTaken together, the findings indicate that a lack of autobiographical memory specificity predicts changes in depressive mood after a stressful event.

Anxiety and depression have no influence on the cancellation and pregnancy rates of a first IVF or ICSI treatment

BACKGROUNDnAfter many years of research, the impact of psychological distress on the IVF treatment outcome is still unclear. This study aimed to determine the influences of anxiety and depression before and during IVF or ICSI treatment on the cancellation and pregnancy rates of inductees.nnnMETHODSnIn a multicentre prospective cohort study, we assessed anxiety and depression at baseline and the procedural anxiety level one day before oocyte retrieval, with the short versions of the State Anxiety Inventory (STAI) and the Beck Depression Inventory-Primary Care (BDI-PC). The effect of baseline anxiety and depression on the cancellation and pregnancy rates of 783 women in their first IVF or ICSI treatment was evaluated. We also determined if a change in anxiety from the start of treatment until just before oocyte retrieval affects the pregnancy rate. The predictive value of distress was assessed while controlling for several factors in subfertility treatment.nnnRESULTSnNeither baseline nor procedural anxiety, nor depression affected the ongoing pregnancy rates, with odds ratios (ORs) of 1.04 (95% CI 0.82-1.33), 0.96 (95% CI 0.77-1.20) and 0.85 (95% CI 0.65-1.10), respectively. Neither did the anxiety gain score affect the pregnancy rate, OR 1.08 (95% CI 0.83-1.41). A cancellation of treatment could not be predicted by either anxiety or depression, OR 1.16 (95% CI 0.83-1.63) and 0.85 (95% CI 0.59-1.22), respectively.nnnCONCLUSIONSnInductees in IVF treatment can be reassured that anxiety and depression levels before and during treatment have no significant influence on the cancellation and pregnancy rates.

Prevention of multiple pregnancies in couples with unexplained or mild male subfertility: randomised controlled trial of in vitro fertilisation with single embryo transfer or in vitro fertilisation in modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation

Objectives To compare the effectiveness of in vitro fertilisation with single embryo transfer or in vitro fertilisation in a modified natural cycle with that of intrauterine insemination with controlled ovarian hyperstimulation in terms of a healthy child. Design Multicentre, open label, three arm, parallel group, randomised controlled non-inferiority trial. Setting 17 centres in the Netherlands. Participants Couples seeking fertility treatment after at least 12 months of unprotected intercourse, with the female partner aged between 18 and 38 years, an unfavourable prognosis for natural conception, and a diagnosis of unexplained or mild male subfertility. Interventions Three cycles of in vitro fertilisation with single embryo transfer (plus subsequent cryocycles), six cycles of in vitro fertilisation in a modified natural cycle, or six cycles of intrauterine insemination with ovarian hyperstimulation within 12 months after randomisation. Main outcome measures The primary outcome was birth of a healthy child resulting from a singleton pregnancy conceived within 12 months after randomisation. Secondary outcomes were live birth, clinical pregnancy, ongoing pregnancy, multiple pregnancy, time to pregnancy, complications of pregnancy, and neonatal morbidity and mortality Results 602 couples were randomly assigned between January 2009 and February 2012; 201 were allocated to in vitro fertilisation with single embryo transfer, 194 to in vitro fertilisation in a modified natural cycle, and 207 to intrauterine insemination with controlled ovarian hyperstimulation. Birth of a healthy child occurred in 104 (52%) couples in the in vitro fertilisation with single embryo transfer group, 83 (43%) in the in vitro fertilisation in a modified natural cycle group, and 97 (47%) in the intrauterine insemination with controlled ovarian hyperstimulation group. This corresponds to a risk, relative to intrauterine insemination with ovarian hyperstimulation, of 1.10 (95% confidence interval 0.91 to 1.34) for in vitro fertilisation with single embryo transfer and 0.91 (0.73 to 1.14) for in vitro fertilisation in a modified natural cycle. These 95% confidence intervals do not extend below the predefined threshold of 0.69 for inferiority. Multiple pregnancy rates per ongoing pregnancy were 6% (7/121) after in vitro fertilisation with single embryo transfer, 5% (5/102) after in vitro fertilisation in a modified natural cycle, and 7% (8/119) after intrauterine insemination with ovarian hyperstimulation (one sided P=0.52 for in vitro fertilisation with single embryo transfer compared with intrauterine insemination with ovarian hyperstimulation; one sided P=0.33 for in vitro fertilisation in a modified natural cycle compared with intrauterine insemination with controlled ovarian hyperstimulation). Conclusions In vitro fertilisation with single embryo transfer and in vitro fertilisation in a modified natural cycle were non-inferior to intrauterine insemination with controlled ovarian hyperstimulation in terms of the birth of a healthy child and showed comparable, low multiple pregnancy rates. Trial registration Current Controlled Trials ISRCTN52843371; Nederlands Trial Register NTR939.