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.

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.

Occupational exposure to chemical substances and time to pregnancy: a systematic review.

BACKGROUND: Fertility problems are an important health issue, as 10-15% of couples have difficulties conceiving. Reproductive function is thought to be compromised by lifestyle behaviours, but environmental contaminants and work-related factors are also thought to play a role. The objective of this review was to systematically summarize the available evidence concerning the influence of occupational exposure to chemicals on time to pregnancy (TTP). METHODS: A structured search on occupational exposure to chemicals and TTP was carried out in PubMed and Embase. Studies were included if TTP was used as outcome measure and exposure to chemicals at the job level was described. In total, 49 studies were included in this review. RESULTS: Studies varied widely in characterization of exposure, hampering a meta-analytic approach across all studies. For lead, strong indications for adverse effects on TTP were present, supporting the mandatory provisions for pregnant women being exposed to lead in many countries. These indications were also found for pesticide exposure, and one could argue that couples working in agriculture or horticultural trades must be informed about the risks of pesticide exposure. Epidemiologic evidence on other chemicals, such as organic solvents, and other metals remains equivocal, hampering clear counselling of couples who are trying to become pregnant. CONCLUSIONS: Despite some uncertainties in the evidence base, it may still be prudent to advise against lead and pesticide exposure at the workplace for couples trying to conceive. This review also identifies several priorities for future studies in the field of occupational epidemiology.

The effect of postponement of first motherhood on permanent involuntary childlessness and total fertility rate in six European countries since the 1970s.

BACKGROUND: Postponement of childbearing since the 1970s has led to an increase in permanent involuntarily childlessness. We will address the magnitude of this trend, the effect of IVF/ICSI and the effect on total fertility rate (TFR an often used demographic measure for the level of fertility) in six EU countries. METHODS: Using a fertility micro-simulation model, we estimate the effect of postponement of first motherhood on permanent involuntary childlessness in six representative European countries since 1970/1985: Sweden, Austria, Czech Republic, The Netherlands, West Germany and Spain. To estimate the effect of IVF/ICSI on this trend, we use data on the results of all IVF/ICSI cycles performed in The Netherlands in 2003 and 2004. RESULTS: Permanent involuntary childlessness approximately doubled since 1970s and rose to ~4% in the Czech Republic and to ~7% in Spain with the other countries in between. If all couples entitled to have IVF/ICSI were to be treated, the effect of postponement would almost have been neutralized. However, only a limited proportion of eligible couple are being treated. Without postponement, TFRs would have been between 0.03 and 0.05 higher. CONCLUSIONS: The effect of postponement on permanent involuntary childlessness is considerable. So far IVF/ICSI only had a slight effect on this trend. The impact of postponement on TFRs is small compared with other demographic trends.

Occupational exposure to chemicals and fetal growth: the Generation R Study.

BACKGROUND: Developmental diseases, such as birth defects, growth restriction and preterm delivery, account for >25% of infant mortality and morbidity. Several studies have shown that exposure to chemicals during pregnancy is associated with adverse birth outcomes. The aim of this study was to identify whether occupational exposure to various chemicals might adversely influence intrauterine growth patterns and placental weight. METHODS: Associations between maternal occupational exposure to various chemicals and fetal growth were studied in 4680 pregnant women participating in a population-based prospective cohort study from early pregnancy onwards in the Netherlands (2002-2006), the Generation R Study. Mothers who filled out a questionnaire during mid-pregnancy (response: 77% of enrolment) were included if they conducted paid employment during pregnancy and had a spontaneously conceived singleton live born pregnancy (n = 4680). A job exposure matrix was used, linking job titles to expert judgement on exposure to chemicals in the workplace. Fetal growth characteristics were repeatedly measured by ultrasound and were used in combination with measurements at birth. Placental weight was obtained from medical records and hospital registries. Linear regression models for repeated measurements were used to study the associations between maternal occupational exposure to chemicals and intrauterine growth. RESULTS: We observed that maternal occupational exposure to polycyclic aromatic hydrocarbons, phthalates, alkylphenolic compounds and pesticides adversely influenced several domains of fetal growth (fetal weight, fetal head circumference and fetal length). We found a significant association between pesticide and phthalate exposure with a decreased placental weight. CONCLUSIONS: Our results suggest that maternal occupational exposure to several chemicals is associated with impaired fetal growth during pregnancy and a decreased placental weight. Further studies are needed to confirm these findings and to assess post-natal consequences.

Why do people postpone parenthood? Reasons and social policy incentives.

BACKGROUND: Never before have parents in most Western societies had their first children as late as in recent decades. What are the central reasons for postponement? What is known about the link between the delay of childbearing and social policy incentives to counter these trends? This review engages in a systematic analysis of existing evidence to extract the maximum amount of knowledge about the reasons for birth postponement and the effectiveness of social policy incentives. METHODS: The review followed the PRISMA procedure, with literature searches conducted in relevant demographic, social science and medical science databases (SocINDEX, Econlit, PopLine, Medline) and located via other sources. The search focused on subjects related to childbearing behaviour, postponement and family policies. National, international and individual-level data sources were also used to present summary statistics. RESULTS: There is clear empirical evidence of the postponement of the first child. Central reasons are the rise of effective contraception, increases in women's education and labour market participation, value changes, gender equity, partnership changes, housing conditions, economic uncertainty and the absence of supportive family policies. Evidence shows that some social policies can be effective in countering postponement. CONCLUSIONS: The postponement of first births has implications on the ability of women to conceive and parents to produce additional offspring. Massive postponement is attributed to the clash between the optimal biological period for women to have children with obtaining additional education and building a career. A growing body of literature shows that female employment and childrearing can be combined when the reduction in work-family conflict is facilitated by policy intervention.

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.

Is human fecundity declining in Western countries?

Since Carlsen and co-workers reported in 1992 that sperm counts have decreased during the second half of the last century in Western societies, there has been widespread anxiety about the adverse effects of environmental pollutants on human fecundity. The Carlsen report was followed by several re-analyses of their data set and by many studies on time trends in sperm quality and on secular trends in fecundity. However, the results of these studies were diverse, complex, difficult to interpret and, therefore, less straightforward than the Carlsen report suggested. The claims that population fecundity is declining and that environmental pollutants are involved, can neither be confirmed nor rejected, in our opinion. However, it is of great importance to find out because the possible influence of widespread environmental pollution, which would adversely affect human reproduction, should be a matter of great concern triggering large-scale studies into its causes and possibilities for prevention. The fundamental reason we still do not know whether population fecundity is declining is the lack of an appropriate surveillance system. Is such a system possible? In our opinion, determining total sperm counts (as a measure of male reproductive health) in combination with time to pregnancy (as a measure of couple fecundity) in carefully selected populations is a feasible option for such a monitoring system. If we want to find out whether or not population fecundity will be declining within the following 20-30 years, we must start monitoring now.

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.

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.

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.

A case study of the applicability of a prediction model for the selection of patients undergoing in vitro fertilization for single embryo transfer in another center.

OBJECTIVE: To evaluate the application in a different fertility clinic of a prediction model for selecting IVF patients for elective single embryo transfer. DESIGN: Retrospective analysis of a large database obtained from a tertiary infertility center. SETTING: University medical center. PATIENT(S): The model, derived at the "development center" was applied in 494 consecutive first IVF cycles carried out at the "application center." INTERVENTION(S): After adjustment of embryo scoring system to be compatible with that used by the prediction model, it was applied to the development center data. A score chart for predicting the probability of singleton or twin pregnancy was constructed. MAIN OUTCOME MEASURE(S): The area under the receiver operator curve (ROC) was determined to measure the ability of the model to discriminate between ongoing pregnancy and twin pregnancy. Calibration plots were made to assess agreement between predicted and observed pregnancy rates (PR). RESULTS: The areas under the ROC for predicting ongoing pregnancy and twin pregnancy were 0.63 and 0.66, respectively. Insertion of a correction factor equivalent to the difference in odds ratios for ongoing PR between the two centers was required to improve the calibration of the model. CONCLUSION(S): After adaptation, the model performed well in the application center.

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.