Realizing a desired family size: when should couples start?

STUDY QUESTION: Until what age can couples wait to start a family without compromising their chances of realizing the desired number of children? SUMMARY ANSWER: The latest female age at which a couple should start trying to become pregnant strongly depends on the importance attached to achieving a desired family size and on whether or not IVF is an acceptable option in case no natural pregnancy occurs. WHAT IS KNOWN ALREADY: It is well established that the treatment-independent and treatment-dependent chances of pregnancy decline with female age. However, research on the effect of age has focused on the chance of a first pregnancy and not on realizing more than one child. STUDY DESIGN, SIZE, DURATION: An established computer simulation model of fertility, updated with recent IVF success rates, was used to simulate a cohort of 10 000 couples in order to assess the chances of realizing a one-, two- or three-child family, for different female ages at which the couple starts trying to conceive. PARTICIPANTS/MATERIALS, SETTING, METHODS: The model uses treatment-independent pregnancy chances and pregnancy chances after IVF/ICSI. In order to focus the discussion, we single out three levels of importance that couples could attach to realizing a desired family size: (i) Very important (equated with aiming for at least a 90% success chance). (ii) Important but not at all costs (equated with a 75% success chance) (iii) Good to have children, but a life without children is also fine (equated with a 50% success chance). MAIN RESULTS AND THE ROLE OF CHANCE: In order to have a chance of at least 90% to realize a one-child family, couples should start trying to conceive when the female partner is 35 years of age or younger, in case IVF is an acceptable option. For two children, the latest starting age is 31 years, and for three children 28 years. Without IVF, couples should start no later than age 32 years for a one-child family, at 27 years for a two-child family, and at 23 years for three children. When couples accept 75% or lower chances of family completion, they can start 4-11 years later. The results appeared to be robust for plausible changes in model assumptions. LIMITATIONS, REASONS FOR CAUTION: Our conclusions would have been more persuasive if derived directly from large-scale prospective studies. An evidence-based simulation study (as we did) is the next best option. We recommend that the simulations should be updated every 5-10 years with new evidence because, owing to improvements in IVF technology, the assumptions on IVF success chances in particular run the risk of becoming outdated. WIDER IMPLICATIONS OF THE FINDINGS: Information on the chance of family completion at different starting ages is important for prospective parents in planning their family, for preconception counselling, for inclusion in educational courses in human biology, and for increasing public awareness on human reproductive possibilities and limitations. STUDY FUNDING/COMPETING INTERESTS: No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.

Too old to have children? Lessons from natural fertility populations.

STUDY QUESTION: Is it possible to construct an age curve denoting the ages above which women are biologically too old to reproduce? SUMMARY ANSWER: We constructed a curve based on the distribution of female age at last birth in natural fertility populations reflecting the ages above which women have become biologically too old to have children. WHAT IS KNOWN ALREADY: The median age at last birth (ALB) for females is ∼40-41 years of age across a range of natural fertility populations. This suggests that there is a fairly universal pattern of age-related fertility decline. However, little is known about the distribution of female ALB and in the present era of modern birth control, it is impossible to assess the age-specific distribution of ALB. Reliable information is lacking that could benefit couples who envisage delaying childbearing. STUDY DESIGN, SIZE, DURATION: This study is a review of high-quality historical data sets of natural fertility populations in which the distributions of female age at last birth were analysed. The studies selected used a retrospective cohort design where women were followed as they age through their reproductive years. PARTICIPANTS/MATERIALS, SETTING, METHODS: Using a common set of eligibility criteria, large data files of natural fertility populations were prepared such that the analysis could be performed in parallel across all populations. Data on the ALB and confounding variables are presented as box and whisker plots denoting the 5th, 25th, 50th, 75th and 95th percentile distribution of the age at last birth for each population. The analysis includes the estimation of Kaplan-Meier curves for age at last birth of each population. The hazard curve for ALB was obtained by plotting the smoothed hazard curve of each population and taking the lowest hazard within a time period of at least 5 years. This lowest hazard curve was then transformed into a cumulative distribution function representing the composite curve of the end of biological fertility. This curve was based on the data from three of the six populations, having the lowest hazards of end of fertility. MAIN RESULTS AND THE ROLE OF CHANCE: We selected six natural fertility populations comprising 58 051 eligible women. While these populations represent different historical time periods, the distribution of the ages at last birth is remarkably similar. The curve denoting the end of fertility indicates that <3% of women had their last birth at age 20 years meaning that almost 98% were able to have at least one child thereafter. The cumulative curve for the end of fertility slowly increases from 4.5% at age 25 years, 7% at age 30 years, 12% at age 35 years and 20% at age 38 years. Thereafter, it rises rapidly to about 50% at age 41, almost 90% at age 45 years and approaching 100% at age 50 years. LIMITATIONS, REASONS FOR CAUTION: It may be argued that these historical fertility data do not apply to the present time; however, the age-dependent decline in fertility is similar to current populations and is consistent with the pattern seen in women treated by donor insemination. Furthermore, for reproductive ageing, we note that it is unlikely that such a conserved biological process with a high degree of heritability would have changed significantly within a century or two. WIDER IMPLICATIONS OF THE FINDINGS: We argue that the age-specific ALB curve can be used to counsel couples who envisage having children in the future. Our findings challenge the unsubstantiated pessimism regarding the possibility of natural conception after age 35 years. STUDY FUNDING/COMPETING INTEREST(S): No external funding was either sought or obtained for this study. There are no conflicts of interest to be declared.

Advanced maternal age, short interpregnancy interval, and perinatal outcome.

OBJECTIVE: The purpose of this study was to evaluate whether the association between short interpregnancy intervals and perinatal outcome varies with maternal age. STUDY DESIGN: We performed a retrospective cohort study among 263,142 Dutch women with second deliveries that occurred between 2000 and 2007. Outcome variables were preterm delivery (<37 weeks of gestation), low birthweight in term deliveries (<2500 g) and small-for-gestational age (<10th percentile for gestational age on the basis of sex- and parity-specific Dutch standards). RESULTS: Short interpregnancy intervals (<6 months) was associated positively with preterm delivery and low birthweight, but not with being small for gestational age. The association of short interpregnancy interval with the risk of preterm delivery was weaker among older than younger women. There was no clear interaction between short interpregnancy interval and maternal age in relation to low birthweight or small for gestational age. CONCLUSION: The results of this study indicate that the association of short interpregnancy interval with preterm delivery attenuates with increasing maternal age.

The effect of in vitro fertilization on birth rates in western countries.

BACKGROUND: We will assess to what extent in vitro fertilization (IVF) is effective in increasing the number of births overall and whether earlier application of IVF will increase this number. METHODS: We simulate 100 000 women trying for their first and second child. Natural and IVF pregnancy rates and infertility rates are age-dependent and based on published data. The age at which women start trying for their first child is based on the Netherlands 2002 data. Three cycles of IVF are given during a 12-month period after 1 or 3 years of trying to conceive unsuccessfully. Main outcome measures are live born deliveries and children, both naturally conceived or after IVF, as well as numbers of singletons, twins and triplets, the total fertility rate (TFR) and the number of IVF cycles performed. RESULTS: Full access to IVF after 3 years increases the TFR by 0.08 children. Applying IVF after 1 year leads to an additional TFR increase of 0.04, with double the number of IVF cycles and twin and triplet children, and a shift from naturally conceived children to IVF children. CONCLUSIONS: Full access to IVF after 3 years is important. It does increase the TFR. Early availability of IVF would further increase the TFR, but with side-effects and high costs.

A mild treatment strategy for in-vitro fertilisation: a randomised non-inferiority trial.

BACKGROUND: Mild in-vitro fertilisation (IVF) treatment might lessen both patients' discomfort and multiple births, with their associated risks. We aimed to test the hypothesis that mild IVF treatment can achieve the same chance of a pregnancy resulting in term livebirth within 1 year compared with standard treatment, and can also reduce patients' discomfort, multiple pregnancies, and costs. METHODS: We did a randomised, non-inferiority effectiveness trial. 404 patients were randomly assigned to undergo either mild treatment (mild ovarian stimulation with gonadotropin-releasing hormone [GnRH] antagonist co-treatment combined with single embryo transfer) or a standard treatment (stimulation with a GnRH agonist long-protocol and transfer of two embryos). Primary endpoints were proportion of cumulative pregnancies leading to term livebirth within 1 year after randomisation (with a non-inferiority threshold of -12.5%), total costs per couple up to 6 weeks after expected date of delivery, and overall discomfort for patients. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Clinical Trial, number ISRCTN35766970. FINDINGS: The proportions of cumulative pregnancies that resulted in term livebirth after 1 year were 43.4% with mild treatment and 44.7% with standard treatment (absolute number of patients=86 for both groups). The lower limit of the one-sided 95% CI was -9.8%. The proportion of couples with multiple pregnancy outcomes was 0.5% with mild IVF treatment versus 13.1% (p<0.0001) with standard treatment, and mean total costs were 8333 euros and 10745 euros, respectively (difference 2412 euros, 95% CI 703-4131). There were no significant differences between the groups in the anxiety, depression, physical discomfort, or sleep quality of the mother. INTERPRETATION: Over 1 year of treatment, cumulative rates of term livebirths and patients' discomfort are much the same for mild ovarian stimulation with single embryos transferred and for standard stimulation with two embryos transferred. However, a mild IVF treatment protocol can substantially reduce multiple pregnancy rates and overall costs.

Expected poor ovarian response in predicting cumulative pregnancy rates: a powerful tool.

Poor ovarian response in IVF cycles is associated with poor pregnancy rates. Expected poor responders may represent the worst prognostic group. Data were used from 222 patients starting the first of three IVF treatment cycles. The predictability of ongoing pregnancy after three cycles was analysed using survival analysis and hazard rate ratios. If first cycle poor responders were also predicted to have a poor response, they were classified as expected poor responders. The predicted pregnancy rate in cycles 2 and 3 for women with an observed poor response in the first cycle was approximately 24% for women aged 30 years and approximately 14% for women aged 40 years. For women with an expected poor response these rates were 12% and 6%, respectively. In contrast, women aged 40 years with an unexpected poor response still had a predicted cumulative pregnancy rate of 24%. Age as a sole predictor of cumulative pregnancy does not help to identify poor prognosis cases. Cumulative pregnancy rates in subsequent cycles for patients with an observed poor response in the first cycle may be a reason to refrain from further treatment. However, if such poor response has been expected, further treatment may be avoided because of an unfavourable prognosis for pregnancy.

Female reproductive ageing: current knowledge and future trends.

Over the past few decades, postponement of childbearing has led to a decrease in family size and increased rates of age-related female subfertility. Age-related decrease in ovarian follicle numbers and a decay in oocyte quality dictate the occurrence of natural loss of fecundity and, ultimately, menopause. The rate of this ovarian ageing process is highly variable among women. Identification of women who have severely decreased ovarian reserve for their age is, therefore, clinically relevant. Endocrine and imaging tests for ovarian reserve relate mainly to the quantitative aspect of ovarian reserve, but their capacity to predict the chances for pregnancy is limited. Genetic factors regulating the size of the follicle pool and the rate of its depletion might be identified in the near future and, possibly, assist the accurate prediction of a woman's reproductive lifespan.

Predicting the chances of a live birth after one or more complete cycles of in vitro fertilisation: population based study of linked cycle data from 113 873 women.

OBJECTIVE:  To develop a prediction model to estimate the chances of a live birth over multiple complete cycles of in vitro fertilisation (IVF) based on a couple's specific characteristics and treatment information. DESIGN:  Population based cohort study. SETTING:  All licensed IVF clinics in the UK. National data from the Human Fertilisation and Embryology Authority register. PARTICIPANTS:  All 253 417 women who started IVF (including intracytoplasmic sperm injection) treatment in the UK from 1999 to 2008 using their own eggs and partner's sperm. MAIN OUTCOME MEASURE:  Two clinical prediction models were developed to estimate the individualised cumulative chance of a first live birth over a maximum of six complete cycles of IVF-one model using information available before starting treatment and the other based on additional information collected during the first IVF attempt. A complete cycle is defined as all fresh and frozen-thawed embryo transfers arising from one episode of ovarian stimulation. RESULTS:  After exclusions, 113 873 women with 184 269 complete cycles were included, of whom 33 154 (29.1%) had a live birth after their first complete cycle and 48 925 (43.0%) after six complete cycles. Key pretreatment predictors of live birth were the woman's age (31 v 37 years; adjusted odds ratio 1.66, 95% confidence interval 1.62 to 1.71) and duration of infertility (3 v 6 years; 1.09, 1.08 to 1.10). Post-treatment predictors included number of eggs collected (13 v 5 eggs; 1.29, 1.27 to 1.32), cryopreservation of embryos (1.91, 1.86 to 1.96), the woman's age (1.53, 1.49 to 1.58), and stage of embryos transferred (eg, double blastocyst v double cleavage; 1.79, 1.67 to 1.91). Pretreatment, a 30 year old woman with two years of unexplained primary infertility has a 46% chance of having a live birth from the first complete cycle of IVF and a 79% chance over three complete cycles. If she then has five eggs collected in her first complete cycle followed by a single cleavage stage embryo transfer (with no embryos left for freezing) her chances change to 28% and 56%, respectively. CONCLUSIONS:  This study provides an individualised estimate of a couple's cumulative chances of having a baby over a complete package of IVF both before treatment and after the first fresh embryo transfer. This novel resource may help couples plan their treatment and prepare emotionally and financially for their IVF journey.

Antral follicle count in the prediction of poor ovarian response and pregnancy after in vitro fertilization: a meta-analysis and comparison with basal follicle-stimulating hormone level.

OBJECTIVE: To assess the predictive performance of the antral follicle count (AFC) as a test for ovarian reserve in IVF patients and to compare this performance with that of basal FSH level. DESIGN: Meta-analysis. SETTING: Tertiary fertility center. PATIENT(S): Patients undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Poor ovarian response, nonpregnancy. RESULT(S): We identified 11 studies on AFC and an updated total of 32 studies on basal FSH from the literature on the basis of preset criteria. The estimated summary receiver operating characteristic (ROC) curves showed AFC to perform well in the prediction of poor ovarian response. Also, prediction of poor ovarian response seemed to be more accurate with AFC compared with basal FSH. The estimated summary ROC curves for the prediction of nonpregnancy indicated a poor performance for both AFC and basal FSH. CONCLUSION(S): Transvaginal ultrasonography is an easy-to-perform and noninvasive method that provides essential predictive information on ovarian responsiveness. The predictive performance of AFC toward poor response is significantly better than that of basal FSH. Therefore, AFC might be considered the test of first choice in the assessment of ovarian reserve prior to IVF.

The antral follicle count is a better marker than basal follicle-stimulating hormone for the selection of older patients with acceptable pregnancy prospects after in vitro fertilization.

This observational study shows that the antral follicle count is a better predictor of ongoing pregnancy in IVF patients aged >38 years of age than is basal FSH. Patients aged <44 years with a normal antral follicle count still have acceptable pregnancy rates after IVF and therefore deserve treatment.

Antral follicle counts are related to age at natural fertility loss and age at menopause.

OBJECTIVE: The variability in ultrasound-based antral follicle counts sized 2-10 mm after allowing for age-related decline is considerable. This may represent differences in actual reproductive age among women. This hypothesis was tested by cohort comparison for distribution of age at occurrence of reproductive events. DESIGN: A model with a nonlinear mean decline with age was fitted to antral follicle counts (AFC) obtained in 163 regularly cycling fertile volunteers. Ages at last child birth and menopause were predicted from the individual AFC by using thresholds to represent these events and the model for decline with age. Distributions of the observed ages at last childbirth (proxy variable for loss of natural fertility) and ages at menopause were obtained from the BALSAC demographic database and the Prospect-EPIC study, respectively. The observed distributions were compared with the predicted distributions by using visual comparison and quantile-quantile plots. Predictions of age at last child and age at menopause were done using percentiles of the modeled AFC distribution for given age, and corresponding percentiles of the predicted distributions of age at these reproductive events, with predictions following from the position of a woman's AFC relative to these percentiles. RESULTS: The predicted distributions of age at last child and age at menopause showed good agreement with the observed distributions in the BALSAC and EPIC cohort. Compared with age alone, antral follicle counts gave some additional information for individual prediction of age at last child and menopause. CONCLUSIONS: The link between declining antral follicle counts and reproductively significant events like loss of natural fertility and menopause is strengthened by the high degree of similarity among the predicted and observed age distributions. Predictive usefulness of this relationship in a clinical setting may be more marginal, except in the case of women who have low AFCs for their age.

Factor V Leiden mutation accelerates the onset of natural menopause.

OBJECTIVE: Smoking is consistently associated with a younger age for menopause. Although this may be because of the direct toxic effects of tobacco smoke on follicles, we hypothesize that there may also be a relationship between smoking and a vascular origin of early menopausal onset. Several lifestyle factors have been investigated, but never factors of the clotting cascade. The objective of this study, then, was to determine the effect of factor V Leiden mutation and smoking with respect to age at menopause. DESIGN: Data were used from a subset of 373 postmenopausal participants of a Dutch population-based cohort, born between 1911 and 1925. All women had experienced natural menopause, without use of hormone replacement therapy. RESULTS: Female carriers of the factor V Leiden mutation (n = 14) reported the onset of menopause at an earlier age than noncarriers (n = 359; difference, 3.1 years; 95% CI: 0.3, 5.9). Smoker carriers (n = 5) were 4.3 years younger at menopause than smoker noncarriers (n = 92; 95% CI: 0.9,7.6). In nonsmokers, this relationship was less strong. CONCLUSIONS: We found that the factor V Leiden mutation was related, but not statistically significant, to an earlier age at menopause; smoking possibly enhances this effect. The mutation can be one of the genetic determinants of menopausal age operating through a vascular mechanism.

Anti-müllerian hormone is a promising predictor for the occurrence of the menopausal transition.

OBJECTIVE: Age at menopause and age at the start of the preceding period of cycle irregularity (menopausal transition) show considerable individual variation. In this study we explored several markers for their ability to predict the occurrence of the transition to menopause. DESIGN: A group of 81 normal women between 25 and 46 years of age visited the clinic two times (at T1 and T2) with an average interval of 4 years. All had a regular menstrual cycle pattern at T1. At T1, anti-mullerian hormone (AMH), follicle-stimulating hormone (FSH), inhibin B and estradiol (E2) were measured, and an antral follicle count (AFC) was made during the early follicular phase. At T2, information regarding cycle length and variability was obtained. Menopause transition was defined as a mean cycle length of less than 21 days or more than 35 days or as a mean cycle length of 21 to 35 days, but with the next cycle not predictable within 7 days during the last half year. A logistic regression analysis was performed, with the outcome measure as menopause transition. The area under the receiver operating curve (ROCAUC) was calculated as a measure of predictive accuracy. RESULTS: In 14 volunteers, the cycle had become irregular at T2. Compared with women with a regular cycle at T2, these women were significantly older (median 44.7 vs 39.8 y, P < 0.001) and differed significantly in AFC, AMH, FSH, and inhibin B levels assessed at T1. All parameters with the exception of E2 were significantly associated with the occurrence of cycle irregularity; AMH, AFC, and age had the highest predictive accuracy (ROCAUC 0.87, 0.80, and 0.82, respectively). After adjusting for age, only AMH and inhibin B were significantly associated with cycle irregularity. Inclusion of inhibin B and age to AMH in a multivariable model improved the predictive accuracy (ROCAUC 0.92). CONCLUSIONS: The novel marker AMH is a promising predictor for the occurrence of menopausal transition within 4 years. Adding inhibin B improved the prediction. Therefore, AMH alone or in combination with inhibin B may well prove a useful indicator for the reproductive status of an individual woman.

A poor response in the first in vitro fertilization cycle is not necessarily related to a poor prognosis in subsequent cycles.

OBJECTIVE: To calculate the cumulative ongoing pregnancy rate in patients with a poor response in their first IVF cycle. DESIGN: Retrospective cohort study. SETTING: In vitro fertilization unit of a university hospital. PATIENT(S): Two hundred twenty-five women who experienced a poor response in their first IVF or intracytoplasmic sperm injection cycle. These patients were divided into 64 expected (aged > or =41 years and/or elevated FSH level) and 161 unexpected poor responders (aged <41 years and FSH level not elevated). INTERVENTION(S): In vitro fertilization treatment with a long-suppression protocol with FSH-urofollitropin or recombinant FSH. MAIN OUTCOME MEASURE(S): Cumulative ongoing pregnancy rate. This rate was calculated in two ways to correct for dropouts: pessimistic (zero chance of pregnancy for the dropouts) and optimistic (the same chance for the dropouts as for patients who continued). RESULT(S): The cumulative ongoing pregnancy rate of women with an unexpected poor response in the first cycle was 37% (pessimistic) to 47% (optimistic) after three cycles. Women with an expected poor response had a cumulative ongoing pregnancy rate of 16% (pessimistic) to 19% (optimistic) after 3 cycles. Sixty-four percent of the unexpected poor responders and 31% of the expected poor responders had a normal response in the second cycle, most of them after receiving a higher dose of gonadotropins. CONCLUSION(S): Most patients with an unexpected poor response in the first cycle had a normal response in the second cycle, leading to an acceptable cumulative ongoing pregnancy rate after three cycles. Patients with an expected poor response in the first cycle should be advised to withdraw from treatment after the first cycle because of a poor prognosis.

Impact of repeated antral follicle counts on the prediction of poor ovarian response in women undergoing in vitro fertilization.

OBJECTIVE: To study the value of a single antral follicle count and the additional value of repeated counts in different cycles for the prediction of poor ovarian response in IVF. DESIGN: Prospective. SETTING: Tertiary fertility center. PATIENT(S): One hundred twenty women undergoing their first IVF cycle. INTERVENTION(S): Measurement of the number of antral follicles on cycle day 3 in two spontaneous cycles. Ovarian response. RESULT(S): A single antral follicle count is clearly predictive of poor ovarian response and there is good agreement between repeated measurements in subsequent cycles (area under the receiver operating characteristic curve [ROC(AUC)]; cycle 1: 0.87, cycle 2: 0.85). In a logistic regression analysis, information obtained after the second cycle contributed significantly to the prediction of poor response by the antral follicle count of the first cycle. The predictive accuracy of the highest of two counts (ROC(AUC) 0.89) was slightly better than that of each single count. The predictive model with the highest count yielded slightly higher values of specificity and positive predictive value. Sensitivity, negative predictive value, and error rates were slightly lower. CONCLUSION(S): A single antral follicle count is a good predictor of poor ovarian response in IVF. Although the impact of a second antral follicle count on ovarian response predictions in IVF is statistically significant, clinical relevance is very limited. Repeating an antral follicle count in a subsequent cycle is not recommended.

High follicle-stimulating hormone levels should not necessarily lead to the exclusion of subfertile patients from treatment.

OBJECTIVE: To determine ongoing pregnancy rates in subfertile patients with elevated FSH levels and regular cycles and to assess whether or not it is justified to exclude such patients from treatment on the basis of elevated FSH levels alone. DESIGN: Retrospective follow-up study. SETTING: Tertiary fertility center. PATIENT(S): One hundred twenty-two patients with normal FSH levels <10.0 IU/L, 126 with FSH between 10.0 and 15.0 IU/L, and 53 with FSH levels >15.0 IU/L, all having regular cycles and belonging to a general subfertility population. INTERVENTION(S): Follow-up. MAIN OUTCOME MEASURE(S): Overall and treatment-independent and treatment-dependent ongoing pregnancy rates and time to ongoing pregnancy. RESULT(S): Overall ongoing pregnancy rates declined from 65% in the normal FSH group to 47%, and 28% in the respective elevated FSH groups. However, when adjusting for differences in age and whether or not treatment was applied, this declining trend became inconsistent for both treatment-independent and treatment-dependent ongoing pregnancy rates. Only when FSH levels exceeded 20 IU/L was a clear fall in ongoing pregnancy rate observed, independent of age. In a Cox regression analysis, FSH seemed significantly associated with the outcome time to overall ongoing pregnancy (odds ratio = 0.94, 95% confidence interval, 0.88-0.99), but after adjusting for age and being on treatment or not this significance disappeared (odds ratio = 0.97, 95% confidence interval, 0.91-1.01). CONCLUSION(S): The contribution of FSH in the initial evaluation of subfertile couples is restricted to counseling patients on the probability of having lower chances of conceiving. It does not seem justified to exclude patients with normal regular cycles from treatment on the basis of the FSH value alone.

A low number of retrieved oocytes at in vitro fertilization treatment is predictive of early menopause.

OBJECTIVE: To investigate whether women with a low number of retrieved oocytes at the first in vitro fertilization (IVF) attempt have an increased risk of early menopause. DESIGN: Nested case-control study. SETTING: Twelve IVF clinics in the Netherlands. PATIENT(S): Women participating in a nationwide Dutch cohort study (OMEGA) of ovarian stimulation for IVF and subsequent gynecologic diseases (n = 26,428). Each patient who experienced natural menopause at or before 46 years (n = 38) was individually matched to five controls (n = 190) who had not yet entered menopause at the age the patient became postmenopausal. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Relative risk of reaching natural menopause at an early age ( three oocytes). Women who were stimulated with gonadotropins during IVF treatment but did not undergo an IVF puncture because of an anticipated poor response (canceled IVF cycle) had a relative risk of 8.3 (95% confidence interval: 2.9-23.9). CONCLUSION: These results suggest that women with a low number of retrieved oocytes at the first IVF treatment are more likely to become postmenopausal at an early age than women with a higher number of retrieved oocytes. Our study is the first longitudinal study to provide strong evidence for the quantitative aspect of the ovarian concept of reproductive aging.

A nomogram to predict the probability of live birth after clomiphene citrate induction of ovulation in normogonadotropic oligoamenorrheic infertility.

OBJECTIVE: To establish whether initial screening characteristics of normogonadotropic anovulatory infertile women can aid in predicting live birth after induction of ovulation with clomiphene citrate (CC). DESIGN: Prospective longitudinal single-center study. SETTING: Specialist academic fertility unit. PATIENT(S): Two hundred fifty-nine couples with a history of infertility, oligoamenorrhea, and normal follicle-stimulating hormone (FSH) concentrations who have not been previously treated with any ovulation-induction medication. INTERVENTION(S): 50, 100, or 150 mg of oral CC per day, for 5 subsequent days per cycle. MAIN OUTCOME MEASURE(S): Conception leading to live birth after CC administration. RESULT(S): After receiving CC, 98 (38%) women conceived, leading to live birth. The cumulative live birth rate within 12 months was 42% for the total study population and 56% for the ovulatory women who had received CC. Factors predicting the chances for live birth included free androgen index (testosterone/sex hormone-binding globulin ratio), body mass index, cycle history (oligomenorrhea versus amenorrhea), and the woman's age. CONCLUSION(S): It is possible to predict the individual chances of live birth after CC administration using two distinct prediction models combined in a nomogram. Applying this nomogram in the clinic may be a step forward in optimizing the decision-making process in the treatment of normogonadotropic anovulatory infertility. Alternative first line of treatment options could be considered for some women who have limited chances for success.

Performance of basal follicle-stimulating hormone in the prediction of poor ovarian response and failure to become pregnant after in vitro fertilization: a meta-analysis.

OBJECTIVE: To assess the predictive performance and clinical value of basal FSH as a test for ovarian reserve in in vitro fertilization (IVF) patients. DESIGN: Meta-analysis. SETTING: Tertiary fertility center. PATIENT(S): Patients undergoing IVF. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Poor ovarian response, nonpregnancy. RESULT(S): We located 21 studies that had reported on basal FSH and IVF outcome. No single study met high standards of methodological rigor; most studies are of moderate methodological quality only. The summary receiver operating characteristic curve indicated a moderate predictive performance for poor response, and a low predictive performance for nonpregnancy. Predictions with a substantial shift from pre-FSH-test probability to post-FSH test probability are only achieved at extreme cut-off levels for basal FSH. Sensitivity of such cut-off levels, for both the prediction of poor response and nonpregnancy, is limited. CONCLUSION(S): Clinical value of testing for basal FSH is restricted to a small minority of patients. Basal FSH should not be regarded as a useful routine test for the prediction of IVF outcome. The development of better tests to assess ovarian reserve remains of importance.

Validation of a model predicting spontaneous pregnancy among subfertile untreated couples.

OBJECTIVE: To provide external validation of the Eimers model, which predicts spontaneous pregnancy among subfertile couples within the first year after the definitive establishment of the diagnostic category. DESIGN: Live birth rates predicted by an adapted version of the Eimers model were tested against observed live birth rates in a Canadian cohort study. SETTING: Fertility clinics in university medical centers. PATIENT(S): One thousand sixty-one couples consulting for subfertility due to cervical hostility, male subfertility, or unexplained subfertility. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): We measured the discriminative ability and reliability of the predictions from the model. RESULT(S): The live birth rate was lower in the Canadian population than in the Eimers population. Overall, the prognostic effect of the predictors did not differ significantly in both populations. The model showed moderate predictive power in the Canadian population. With adjustment of the average live birth rate, the reliability of the model was satisfactory. CONCLUSION(S): The Eimers model gave reliable spontaneous pregnancy predictions in the Canadian validation population after adjustment of the average live birth rate.