A Systematic Comparison of Designs to Study Human Fecundity.

BACKGROUND: Several epidemiologic designs allow studying fecundability, the monthly probability of pregnancy occurrence in noncontracepting couples in the general population. These designs may, to varying extents, suffer from attenuation bias and other biases. We aimed to compare the main designs: incident and prevalent cohorts, pregnancy-based, and current duration approaches. METHODS: A realistic simulation model produced individual reproductive lives of a fictitious population. We drew random population samples according to each study design, from which the cumulative probability of pregnancy was estimated. We compared the abilities of the designs to highlight the impact of an environmental factor influencing fecundability, relying on the Cox model with censoring after 12 or 6 months. RESULTS: Regarding the estimation of the cumulative probability of pregnancy, the pregnancy-based approach was the most prone to bias. When we considered a hypothetical factor associated with a hazard ratio (HR) of pregnancy of 0.7, the estimated HR was in the 0.78-0.85 range, according to designs. This attenuation bias was largest for the prevalent cohort and smallest for the current duration approach, which had the largest variance. The bias could be limited in all designs by censoring durations at 6 months. CONCLUSION: Attenuation bias in HRs cannot be ignored in fecundability studies. Focusing on the effect of exposures during the first 6 months of unprotected intercourse through censoring removes part of this bias. For risk factors that can accurately be assessed retrospectively, retrospective fecundity designs, although biased, are not much more strongly so than logistically more intensive designs entailing follow-up.

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.

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.

A Pilot Study of the ELFE Longitudinal Cohort: Feasibility and Preliminary Evaluation of Biological Collection.

Etude Longitudinale Française depuis l'Enfance (ELFE) will be a national French cohort of 20,000 children followed from birth to adulthood. Biological samples will be taken at birth to evaluate the fetal exposition to several substances. A pilot study was carried out in October 2007 to test the preanalytical factors that affected sample quality. A variety of fractions were collected by the midwife after delivery from different blood collection tubes. Options in the collection process were 2 daily transports of samples, centralized and standardized processing methodology, and storage of multiple aliquots in liquid nitrogen or at -80°C. We analyzed preanalytical factors that could have affected coagulation and then soluble CD40 Ligand (sCD40L) as a quality control tool for serum quality. Cord blood and urine were collected from 82% and 84% of women, respectively, who agreed to be followed up in the ELFE project. The use of syringe was the main factor correlated with coagulation (relative risk: 2.79 [1.47; 5.31], P<0.01). Maternity unit status was also associated with coagulation (RR: 1.48 [1.03; 2.13] in a private maternity unit vs. a public maternity) as well as time between collection and centrifugation (RR 1.03 [1; 1.07] when time between collection and centrifugation increases from 1 h). There were no extremely low sCD40L values indicating extreme exposures to room temperatures. This first evaluation study allowed us to stress the importance of carefully recording all potentially critical preanalytical variables that might be used at a large-scale level.

Bisphenol-A and phthalates contamination of urine samples by catheters in the Elfe pilot study: implications for large-scale biomonitoring studies.

Exposure to phthalates and Bisphenol A could cause developmental and reproductive toxicity. This study provides a first assessment of these exposures for more than 250 French pregnant women. The median concentrations of total and free Bisphenol A in urine were similar to those in other studies except the highest concentrations (5% of women had total and free Bisphenol A >50µg/L). Our study highlights high levels of Di-(2-ethylhexyl)-phthalate metabolites in pregnant women, suggesting recent exposure, probably in hospital. Differences between types of delivery (caesarean vs. natural) support this hypothesis. This is a significant implication for large-scale biomonitoring studies among this population.

Changes in sexual behaviours: from secular trends to public health policies.

OBJECTIVE: To explore the relative contribution of secular trends and public health policies to changes in sexual behaviour. DESIGN: Three random probability surveys of the sexual behaviour of people aged 18-69 years were conducted in 1970, 1992 and 2006 in France. METHODS: Data of the 2006 survey (n = 12,364) were compared with those from two surveys carried out in 1970 (n = 2625) and 1992 (n = 20,055). RESULTS: Over the last decades, median age at first intercourse has decreased by 4 years for women (22.0 in the 1930s vs. 17.6 in the 2000s) and 1 year for men (18.1 vs. 17.2). Lifetime number of sexual partners increased for women (1.8 in 1970 vs. 4.4 in 2006), but not for men (11.8 vs. 11.6). At the same time, the proportion of respondents, especially women, who reported nonpenetrative sexual practices and considered sexual intercourse essential to well being was on the increase. These changes are mainly attributed to an increase in women's social status. A marked increase in condom use was observed following the first AIDS/HIV prevention campaigns in the 1980s. CONCLUSION: Public health interventions that are synergistic with trends in social norms are likely to be more effective than those that run counter to them. In France, sexual health and HIV prevention policies aimed at harm limitation appear to have chimed with secular trends. The evidence of greater diversification of sexual practices offers potential to increase the range of safer sex messages used in public health interventions.

Rationales, design and recruitment for the Elfe longitudinal study.

BACKGROUND: Many factors act simultaneously in childhood to influence health status, life chances and well being, including pre-birth influences, the environmental pollutants of early life, health status but also the social influences of family and school. A cohort study is needed to disentangle these influences and explore attribution. METHODS: Elfe will be a nationally representative cohort of 20 000 children followed from birth to adulthood using a multidisciplinary approach. The cohort will be based on the INSEE Permanent Demographic Panel (EDP) established using census data and civil records. The sample size has been defined in order to match the representativeness criteria and to obtain some prevalence estimation, but also to address the research area of low exposure/rare effects. The cohort will be based on repeated surveys by face to face or phone interview (at birth and each year) as well as medical interview (at 2 years) and examination (at 6 years). Furthermore, biological samples will be taken at birth to evaluate the foetal exposition to toxic substances, environmental sensors will be placed in the child's homes. Pilot studies have been initiated in 2007 (500 children) with an overall acceptance rate of 55% and are currently under progress, the 2-year survey being carried out in October this year. DISCUSSION: The longitudinal study will provide a unique source of data to analyse the development of children in their environment, to study the various factors interacting throughout the life course up to adulthood and to determine the impact of childhood experience on the individual's physical, psychological, social and professional development.

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 new estimate of permanent sterility by age: sterility defined as the inability to conceive.

The proportion of couples permanently sterile beyond a certain age is an important component of the reproductive process. Unless medical assistance is used, this age is the upper bound of the fecund period. Most estimates of sterility by age of the woman have been derived from natural fertility populations, in which the number of births and the timing of the last birth (of the complete reproductive history) were not controlled by the couples. Because data on these populations do not include pregnancies not ending in a live birth, the sterility estimates apply to the proportion of couples unable to conceive and to have a live birth. For this reason, it is useful to have an estimate of sterility based on the risk of conceiving, independently of the fate of the pregnancy. Using this new estimate, sterility increases with age much more slowly than with most previous estimates.

Studies of fertility and fecundity: comparative approaches from demography and epidemiology.

The approaches used by demographers and by epidemiologists for studying the fecundity of couples (i.e. their ability to conceive) have converged, whereas they were historically divergent. Demography traditionally focused on fertility - the circumstances in which livebirths occur - with the aim of predicting population changes, in particular. Demographers also rapidly became interested in fecundity, developing concepts such as fecundability and definitive sterility. The measurement of fecundability is based on determination of the time to pregnancy (TTP), the basic tool of the epidemiologist. However, while demographers were developing methods for estimating the distribution of fecundability among couples based on TTP, epidemiologists turned to methods for analysing the role of diverse factors potentially influencing fecundity at the individual level.

Contraception at the time of abortion: high-risk time or high-risk women?

BACKGROUND: Despite the widespread use of highly effective contraception in France, the incidence of abortion is high. A retrospective population-based cohort study was designed to analyse women's contraceptive history. METHOD: We compared the contraceptive use of 163 women, whose last pregnancy ended in abortion, 6 months before, at the time of, 1 month and 6 months after the event with that of 1787 women who had never had an abortion. RESULTS: A total of 46% of women who experienced an abortion used a highly effective form of contraception 6 months before the event (versus 76% among women who had never had an abortion, P < 0.001). This proportion dropped to 33% at the time of the abortion and increased to 71%, 1 month after. In addition, 50% of women who had an abortion had changed their contraceptive method in the 6 months before the event (compared with 16% in the 6 months before the interview in women who had not had an abortion, P < 0.001). Women with socially deprived backgrounds were less likely to use a highly effective contraception after an abortion. CONCLUSIONS: Abortion is a good opportunity for intervention, but especially so for socially disadvantaged women. It is essential to draw the attention of prescribers and women to the higher risk of contraceptive failure at the start of use of a method.

Feasibility of the current-duration approach to studying human fecundity.

Approaches for monitoring time trends in couples' fecundity and for studying its sensitivity to environmental factors are needed. Two approaches rely on the inclusion of a cross-sectional sample of couples currently "at risk" of pregnancy either with follow up (prevalent cohort) or without follow up (current-duration design). To illustrate the feasibility of the current-duration design, we contacted a random sample of 1204 French women age 18 to 44 years in 2004 and recruited those who were currently having unprotected sexual intercourse. The current duration since the beginning of unprotected intercourse was defined for 69 women (5.7%). An additional 15 women (1.2%) were planning to start trying to become pregnant within the next 6 months. Parametric methods allowed, based on current duration of unprotected intercourse, estimation of fecundity as if the couples had been followed prospectively. The estimated proportion of couples not pregnant after 12 months of unprotected intercourse was 34% (95% confidence interval [CI] = 15-54%). The accelerated-failure time model allows study of the influence of environmental factors on fecundity. As an illustration, tobacco smoking by the woman was associated with a doubling in the median duration of unprotected intercourse before pregnancy (adjusted time ratio = 2.4; 95% CI = 1.1-5.2). We quantified the influence of time trends in the prevalence of smoking on this estimate. We suggest ways to quantify or avoid other potential bias. In conclusion, it is possible to recruit a sample of couples currently having unprotected intercourse. The current-duration design appears feasible with approximately 5 times as many women eligible for study as for an incident cohort design.

Demographic effects of the introduction of steroid contraception in developed countries.

The use of the contraceptive pill increased very rapidly in the 1970s in many developed countries, and fertility almost simultaneously started to decline. We discuss here the possibility of a causal link between these two major changes. We first provide evidence for a relationship between the spread of oral contraceptive use and the change in fertility in many European countries over the last three or four decades. The situation of specific countries is examined more in depth on the basis of available literature. We then review the various theories attempting to explain these trends and see how the family planning variables are treated in these approaches. At the country level, the conclusion is unambiguous: within individual countries, there is no systematic negative correlation between fertility and contraceptive pill use. The development of hormonal contraception cannot be considered as responsible for either starting or the size of the fertility decline. A more subtle chain of causality must be considered, but there is no agreement on a general theory of fertility changes. Most authors, however, agree that the diffusion of modern contraception has certainly contributed to the reduction in the number of unwanted pregnancies and has also facilitated and favoured the adoption of new (more restrictive) norms for the ideal family size.

Towards less confusing terminology in reproductive medicine: a proposal.

The use of the term 'infertility' and related terms in reproductive medicine is reviewed. Current terminology is found to be ambiguous, confusing, and misleading. We recommend that the fertility investigation report of a couple should consist of statements concerning description, diagnosis, and prognosis. The description concerns the duration of nonpregnancy before consulting the clinician. A system for prognostic grading is proposed. The fertility investigation report forms the basis for further action, including the possibility of waiting with treatment in case of almost normal or only slightly reduced fertility. The use of the terms 'infertility', 'subfertility', and 'fecundity' is not necessary, and it is recommended to avoid them.

Can assisted reproduction technology compensate for the natural decline in fertility with age? A model assessment.

BACKGROUND: Maternal age is an important factor in reproduction. Can assisted reproduction technologies (ART) fully compensate for the decline in fertility with age? METHODS: We used a computer simulation (Monte Carlo) model of reproduction, combining the monthly probabilities of conceiving, the risk of miscarriage and the probability of becoming age-dependently permanently sterile. RESULTS: Under natural conditions, 75% of women starting to try to conceive at age 30 years will have a conception ending in a live birth within 1 year, 66% at age 35 years and 44% at age 40 years. Within 4 years the success rates will be respectively 91, 84 and 64%. If women turn to ART after 4, 3 or 2 years respectively without conception, and if the rate of success is as observed after two cycles of insemination in IVF, ART makes up for only half of the births lost by postponing a first attempt of pregnancy from age 30 to 35 years, and <30% after postponing from 35 to 40 years. CONCLUSIONS: Even if we relax some of the assumptions, ART in its present form cannot make up for all births lost by the natural decline of fertility after age 35 years.

Contraception: from accessibility to efficiency.

BACKGROUND: Despite the widespread use of medical contraception in France, the prevalence of abortion remains stable. A cross-sectional population-based survey was designed to study the characteristics of current contraceptive use in France, the different types of contraceptive failure, and the reasons reported for not using contraception. METHODS: A representative sample of 14 704 French households was randomly selected from the telephone directory. All women who in the last 5 years had had an abortion or whose last pregnancy was unintended were selected (n = 1034), whilst a fraction (n = 1829) of the other women were randomly selected. Altogether, 2863 women answered the questionnaire. RESULTS: Only 2.7% of the women aged 18-44 years who did not wish to conceive and were sexually active did not use any contraception. However, 33% of pregnancies were estimated to be unplanned, of which 50% ended in an abortion. A total of 65% of the reported unplanned pregnancies occurred among women using contraception (21% the pill, 9% IUD, 12% condoms, 23% other method). The main reasons given for these contraceptive failures were the misuse of the methods or the failure of the partner to withdraw. Reasons for not using any contraception go beyond a simple lack of information. CONCLUSIONS: The importance of-and the reasons mentioned for-contraceptive failure show a misadaptation between women's contraceptive needs and the method they use. Improving the training of family planning providers remains a major goal to ensure that women use a contraceptive method that fits their social and sexual lifestyle.

[The many states of aging: a meeting and some demographic aspects]. / Le vieillissement dans tous ses états: un colloque et quelques données démographiques.

With an expectation of life at birth of 27 years in the middle of the 18th century, 21% of males reached their 60th birthday with a remaining expectation of life of 12 years. Under the conditions of mortality of 1950, in France, 70 percent could celebrate their 60th birthday, and they had still 15 years (only) to live on the average. This last figure started increasing after 1950: the expectancy of life at age 60 is now over 20 years, and it will exceed 25 years around 2050 (for women, the mean will be 31 years). Longevity is an individual capacity. It is now increasing fast, and becomes more and more responsible for the ageing of the population (the rise in the proportion of older persons in the population). We now try to forecast the number of centenarians, and even of super-centenarians (aged 110 years and more), and speculate about the maximum life span. We are in fact entering an entirely new era, when three, four, even five generations can survive simultaneously. Are we prepared to it? The French Ministers for Research and for Social affairs set up a Committee of 15 members (chaired by Henri Leridon) to prepare a National Meeting of Researchers on Ageing, in order to review the situation of research in France on this issue and to make proposals for organising and orienting new studies. The life span of human species, as well as the one of individuals, is undoubtedly depending upon genetic factors. But interactions with environmental factors and with behaviour also play a major role. To be able to disentangle these complex associations, it will be necessary to combine the work of biologists, clinicians and social sciences specialists. The main conclusions of the June 2001 meeting are reported here, together with some orientations of demographic research on mortality at oldest ages and the limits of longevity.