A survival analysis approach to modeling human fecundity

Understanding conception probabilities is important not only for helping couples to achieve pregnancy but also in identifying acute or chronic reproductive toxicants that affect the highly timed and interrelated processes underlying hormonal profiles, ovulation, libido, and conception during menstrual cycles. Currently, 2 statistical approaches are available for estimating conception probabilities depending upon the research question and extent of data collection during the menstrual cycle: a survival approach when interested in modeling time-to-pregnancy (TTP) in relation to women or couples' purported exposure(s), or a hierarchical Bayesian approach when one is interested in modeling day-specific conception probabilities during the estimated fertile window. We propose a biologically valid discrete survival model that unifies the above 2 approaches while relaxing some assumptions that may not be consistent with human reproduction or behavior. This approach combines both the survival and the hierarchical models allowing investigators to obtain the distribution of TTP and day-specific probabilities during the fertile window in a single model. Our model allows for the consideration of covariate effects at both the cycle and the daily level while accounting for daily variation in conception. We conduct extensive simulations and utilize the New York State Angler Prospective Pregnancy Cohort Study to illustrate our approach. We also provide the code to implement the model in R software in the supplemental section of the supplementary material available at Biostatistics online.     

Bayesian inferences on predictors of conception probabilities

Reproductive scientists and couples attempting pregnancy are interested in identifying predictors of the day-specific probabilities of conception in relation to the timing of a single intercourse act. Because most menstrual cycles have multiple days of intercourse, the occurrence of conception represents the aggregation across Bernoulli trials for each intercourse day. Because of this data structure and dependency among the multiple cycles from a woman, implementing analyses has proven challenging. This article proposes a Bayesian approach based on a generalization of the Barrett and Marshall model to incorporate a woman-specific frailty and day-specific covariates. The model results in a simple closed form expression for the marginal probability of conception, and has an auxiliary variables formulation that facilitates efficient posterior computation. Although motivated by fecundability studies, the approach can be used for efficient variable selection and model averaging in general applications with categorical or discrete event time data.     

A new approach to modeling daily probabilities of conception

Standard conception probabilities models assume that different acts of intercourse make independent contributions to the probability of conception in viable cycles. We propose an alternative, approximate model based on the assumption that the act of intercourse closest to the time of maximum fertility is the one most likely to have caused conception. We describe an adaptive algorithm [the most fertile intercourse day (MFID) algorithm] that estimates the most fertile intercourse day in each cycle. The approach is easily extended to include covariates and random between-couple differences in fecundability that affect the probability of conception in a given cycle. Reanalyses of two data sets reported in the literature are presented. Estimates of the probability of conception during the most fertile period of the cycle and of the effects of covariates are similar to estimates found using standard models.     

Modeling human fertility in the presence of measurement error

The probability of conception in a given menstrual cycle is closely related to the timing of intercourse relative to ovulation. Although commonly used markers of time of ovulation are known to be error prone, most fertility models assume the day of ovulation is measured without error. We develop a mixture model that allows the day to be misspecified. We assume that the measurement errors are i.i.d. across menstrual cycles. Heterogeneity among couples in the per cycle likelihood of conception is accounted for using a beta mixture model. Bayesian estimation is straightforward using Markov chain Monte Carlo techniques. The methods are applied to a prospective study of couples at risk of pregnancy. In the absence of validation data or multiple independent markers of ovulation, the identifiability of the measurement error distribution depends on the assumed model. Thus, the results of studies relating the timing of intercourse to the probability of conception should be interpreted cautiously.     

Hierarchical models for the probabilities of conception

In the last thirty years, there has been considerable interest in finding better models to fit data for probabilities of conception. An important early model was proposed by Barrett and Marshall (1969) and extended by Schwartz, MacDonald and Heuchel (1980). Recently, researchers have further extended these models by adding covariates. However, the increasingly complicated models are challenging to analyze with frequentist methods such as the EM algorithm. Bayesian models are more feasible, and the computation can be done via Markov chain Monte Carlo (MCMC). We consider a Bayesian model with an effect for protected intercourse to analyze data from the California Women's Reproductive Health Study and assess the effects of water contaminants and hormones. There are two main contributions in the paper. (1) For protected intercourse, we propose modeling the ratios of daily conception probabilities with protected intercourse to corresponding daily conception probabilities with unprotected intercourse. Due to the small sample size of our data set, we assume the ratios are the same for each day but unknown. (2) We consider Bayesian analysis under a unimodality assumption where the probabilities of conception increase before ovulation and decrease after ovulation. Gibbs sampling is used for finding the Bayesian estimates. There is some evidence that the two covariates affect fecundability.     

Modelling multiple ovulation,fertilization, and embryo loss in human fertility studies

Models of human fertility that incorporate information on timing of intercourse have assumed that a single ovum is released each menstrual cycle. These models are misspecified if two or more viable ova are sometimes released in a single cycle, which is known to occur in dizygotic twin pregnancies. In this paper, we propose a model for multiple ovulation in humans. We assume that the unobservable number of viable ova in each cycle follows a multinomial distribution. Successful fertilization of each ovum depends on the ability of the cycle to support a pregnancy and on the aggregate of a set of unobservable Bernoulli trials representing the fertilizing effects of intercourse on various days. Our model accommodates general covariate effects, allows for heterogeneity among couples, and accounts for a sterile subpopulation of couples. Information on early detection of pregnancy can be incorporated to estimate the probability of embryo loss. We outline a Markov chain Monte Carlo algorithm for estimation of the posterior distributions of the parameters. The methods are applied to data from a North Carolina pregnancy study, and applications to studies of assisted reproduction are described.     

The timing of the "fertile window" in the menstrual cycle: day specific estimates from a prospective study

ObjectivesTo provide specific estimates of the likely occurrence of the six fertile days (the “fertile window”) during the menstrual cycle.DesignProspective cohort study.Participants221 healthy women who were planning a pregnancy.ResultsThe fertile window occurred during a broad range of days in the menstrual cycle. On every day between days 6 and 21, women had at minimum a 10% probability of being in their fertile window. Women cannot predict a sporadic late ovulation; 4-6% of women whose cycles had not yet resumed were potentially fertile in the fifth week of their cycle.ConclusionsIn only about 30% of women is the fertile window entirely within the days of the menstrual cycle identified by clinical guidelines—that is, between days 10 and 17. Most women reach their fertile window earlier and others much later. Women should be advised that the timing of their fertile window can be highly unpredictable, even if their cycles are usually regular.     

The use of a urinary estrone conjugates assay for detection of optimal mating time in the cynomolgus macaque (Macaca fascicularis)

Forty-four female cynomolgus macaques (Macaca fascicularis) were examined to determine the optimum fertile period for mating. Daily urinary estrone conjugates (E1C) were measured, beginning on day 7 of the menstrual cycle, until a 1.5-gold E1C rise above the baseline was detected. The females were bred the next morning. Pregnancies were verified in all animals at day 18 postbreeding, and/or on day 25 postbreeding. Serum progesterone levels were used to correlate the relationship between ovulation and the E1C peak. Forty-four of the 57 cycles indicated a urinary E1C peak between days 10-15 of the menstrual cycle; this peak occurred on the day following the initial 1.5-fold to twofold rise in 90% of the cycles. A single 2-hr mating period the day before, the day of, or the day after the E1C peak resulted in conception in 17 of 44 (38.6%) animals.     

Standardized protocols for characterizing women's fertility: A data-driven approach

Experts are divided on whether women's cognition and behavior differs between fertile and non-fertile phases of the menstrual cycle. One of the biggest criticisms of this literature concerns the use of indirect, imprecise, and flexible methodologies between studies to characterize women's fertility. To resolve this problem, we provide a data-driven method of best practices for characterizing women's fertile phase. We compared the accuracy of self-reported methods and counting procedures (i.e., the forward- and backward-counting methods) in estimating ovulation using data from 140 women whose fertility was verified with luteinizing hormone tests. Results revealed that no counting method was associated with ovulation with > 30% accuracy. A minimum of 39.5% of the days in the six-day fertile window predicted by the counting methods were non-fertile, and correlations between counting method conception probabilities and actual conception probability were weak to moderate, rs = 0.11–0.30. Poor results persisted when using a lenient window for predicting ovulation, across alternative estimators of the onset of the next cycle, and when removing outliers to increase the homogeneity of the sample. By contrast, combining counting methods with a relatively inexpensive test of luteinizing hormone predicted fertility with accuracy > 95%, but only when specific guidelines were followed. To this end, herein we provide a cost-effective, pragmatic, and standardized protocol that will allow researchers to test whether fertility effects exist or not.     

Menstrual cycle variation in women's preferences for the scent of symmetrical men.

Evidence suggests that female sexual preferences change across the menstrual cycle. Women''s extra-pair copulations tend to occur in their most fertile period, whereas their intra-pair copulations tend to be more evenly spread out across the cycle. This pattern is consistent with women preferentially seeking men who evidence phenotypic markers of genetic benefits just before and during ovulation. This study examined whether women''s olfactory preferences for men''s scent would tend to favour the scent of more symmetrical men, most notably during the women''s fertile period. College women sniffed and rated the attractiveness of the scent of 41 T-shirts worn over a period of two nights by different men. Results indicated that normally cycling (non-pill using) women near the peak fertility of their cycle tended to prefer the scent of shirts worn by symmetrical men. Normally ovulating women at low fertility within their cycle, and women using a contraceptive pill, showed no significant preference for either symmetrical or asymmetrical men''s scent. A separate analysis revealed that, within the set of normally cycling women, individual women''s preference for symmetry correlated with their probability of conception, given the actuarial value associated with the day of the cycle they reported at the time they smelled the shirts. Potential sexual selection processes and proximate mechanisms accounting for these findings are discussed.     

Describing Ovarian Cycles,Pregnancy Characteristics,and the Use of Contraception in Female White‐Faced Marmosets,Callithrix geoffroyi

Endocrine data and characteristics of nonconceptive ovarian cycling and pregnancy are limited within the genus Callithrix to the common marmoset (C. jacchus) and Wied's black tufted‐ear marmoset (C. kuhlii). This article presents patterns of urinary pregnanediol‐3‐glucuronide (PdG) excretion, as determined by enzyme immunoassay, throughout the course of ovarian cycling and pregnancy in white‐faced marmosets (C. geoffroyi). Furthermore, characteristics of reproductive parameters including litter size, duration of gestation, maternal age, and information about ovarian cycling following administration of contraceptives are also described. A steep increase in PdG, an indication of ovulation, characterizes normative ovarian cycles, with peak‐to‐peak intervals between cycles being 27.82 ± 1.49 days in length. PdG excretion (μg/mg Cr) across pregnancy peaked during the 1st and 2nd trimesters (1st = 20.71 ± 2.98, 2nd = 21.16 ± 2.60) and declined gradually to near preconception levels over the 3rd trimester until parturition (3rd = 5.74 ± 1.60). Gestation lasted 148.55 ± 1.89 days. Most pregnancies (82.8%) resulted in an immediate postpartum ovulation (PPO) of 17.45 ± 2.22 days with 58.3% of PPOs resulting in conception. No differences in PdG excretion during the 1st trimester between full pregnancies and miscarriages were found, and pregnancy characteristics such as litter size, duration of gestation, and maternal age were not associated with PdG concentrations. Administration of cloprostenol resulted in shorter peak‐to‐peak cycle durations, but ovulation was detectable with similar concentrations of peak PdG to a normal nonconceptive cycle. Conversely, medroxyprogesterone acetate (DMPA) injections resulted in little to no PdG excretion across the ovarian cycle. Both methods of contraception providing effective prevention of conception. Overall, these results show that strong similarities in reproductive parameters persist within the genus Callithrix and to a lesser extent across the Callitrichidae family. Am. J. Primatol. 74:1044‐1053, 2012. © 2012 Wiley Periodicals, Inc.     

Improving the reproductive performance of Egyptian buffalo cows by changing the management system

The objective of the present study was to determine the possibility to improve the reproductive performance of buffalo cows through the continuous exposure to bull with grazing and free-stall housing management. Sixty-four Egyptian multiparous buffalo cows raised under two different management systems in two farms were used in this study. The cows in the first farm (management system 1, MS1) were loose--housed in a free-stall yard, grazed for 4 h per day, suckled their calves for 2-3 months and were continuously exposed to a fertile bull. The cows in the second farm (management system 2, MS2 ) were confined in an open-fronted tie-stall shed, not grazed, suckled their calves for only 7 days and were exposed to a fertile bull twice per day (30 min per session). All the cows were fed a diet of green berseem (Trifolium alexandrinum), rice straw and concentrates to meet their maintenance and production requirements. The cows during both the treatments were milked twice per day after weaning. The cows in both groups were between the second and the sixth parity, weighed 450-480 kg and had average daily milk yields of 5.0-6.0 kg. In each farm, cows were visually checked twice daily at 07:00 and 17:00 h for the signs of oestrus and animals proved standing heat were naturally mated. Rectal palpation was used to monitor uterine involution and for pregnancy diagnosis. Blood was sampled twice per week from 7 to 150 days post-partum for serum progesterone assay. The results revealed that post-partum intervals to each of first ovulation, first oestrus, conception and next parturition were significantly (P < 0.05) shorter in MS1 group than in MS2 group. In the meantime, MS1 increased (P < 0.01) the conception and calving rates by 21 and 25%, respectively compared to MS2. Percentages of post-partum cyclic animals and animals exhibiting ovulatory oestrus were greater (P < 0.01) in MS1 group than in MS2 group. However, the percentage of animals cycling before day 60 post-partum was significantly (P < 0.01) lower in MS1 group than in MS2 group (13% versus 28%). By day 120 post-partum, only 63% of the buffaloes were cycling in MS2 group versus 94% in MS1 group. Percentage of silent ovulation was insignificantly higher in MS2 group (34%) than in MS1 group (25%). However, the percentage of false oestrus was higher (P < 0.01) in MS1 group than in MS2 group (16% versus 3%). In addition, percentage of short ovulatory cycles (15-17 days) was greater (P < 0.01) in MS1 group than in MS2 group, whereas percentage of long ovulatory cycle (25-28 days) was higher (P < 0.01) in MS2 group than in MS1 group. It was concluded that continuous exposure of buffalo cows to a fertile bull with grazing management under free-stall housing system enhances resumption of post-partum ovarian activity and improves conception and calving rates.     

The effects of 5-bromo-2-thienyl-ethyl-ketone thiosenicarbazone on ovarian cyclicity and ovulation in the rat.

Pseudopregnant and cyclic rats were injected for 5 to 26 days with daily doses of 5 and/or 3 mg of 5-bromo-2-thienyl-ethyl-ketone thiosemicarbazone (70026) starting on Day 0 (the day of oestrus). The vaginal smear cytology, record of ovulation and ability to breed and conceive were compared with the results for corn oil-injected controls. Both doses of 70026 were found to cause a reappearance of pro-oestrous and/or oestrous vaginal smears within 4 to 6 days in the pseudopregnant rats, but ovulations did not occur. The 5-mg dose of 70026 inhibited ovulation and interrupted the oestrous cycle in cyclic rats, even though the daily 3-mg dose seemed to have little effect on ovulation, ovarian cyclicity, breeding or conception. In spite of the absence of an ovulation accompanying the induced pro-oestrous and/or oestrous vaginal smears in the pseudopregnant rats, the pattern of the vaginal smears suggested the occurrence of a 'delayed pseudopregnancy' in most of the pseudopregnant rats treated daily with 3 mg, but in few of those treated with 5 mg, 70026.     

Probably never human. Review of chimpanzee material culture: Implications for human evolution,by W.C. McGrew. Cambridge,U.K., Cambridge University Press, 1992, 277 pp, $79.95, cloth

Pregnanediol-3α-glucuronide (PdG) was measured in the urine of six Goeldi's monkeys during pregnancy and the postpartum period. A stress-free, non-invasive urine sampling technique permitted frequent collection of urine from members of the breeding group. A comparison of the periovulatory profiles of PdG and estrone conjugates revealed close agreement. The day of ovulation was defined as that immediately preceding a 2-4 day period with two consecutive urine samples for which the PdG content was in excess of 0.20 μg/mg Cr and 0.40 μg/mg Cr, respectively. In urine samples collected from parturition to the next ovulation, 70.9% of the PdG-values were below 0.20 μg/mg Cr, whereas 99.2% of the urinary PdG concentrations measured during pregnancy were greater than this “threshold concentration”. A conception cycle was therefore defined as one in which the concentration of urinary PdG remained above 0.20 μg/mg Cr in all urine samples collected between day 1 and day 20 after ovulation. Gestation length was 151.5 ± 1.6 days (mean ± SEM, n = 6; range 147-157 days). The postpartum ovulation occurred 22.6 ± 4.7 days (mean ± SEM, n = 9; range 11-53 days) following birth. With the exception of two non-conception postpartum cycles observed in one female, with inter-ovulatory intervals of 26 and 27 days, postpartum ovulation resulted in conception, giving a 77.8% conception rate for nine observed cycles. The simple and rapid radioimmunoassay used in this study requires 5 h from urine collection to the final result, hence permitting daily monitoring of a large sample of females. It thus has important potential for conservation breeding programs and for other scientific investigations carried out with this endangered primate species. © 1994 Wiley-Liss, Inc.     

Lack of support for relation between woman's masculinity preference,estradiol level and mating context

It has been proposed that women's preferences for male facial sexual dimorphism are positively correlated with conception probability and differ between short- and long-term mating contexts. In this study, we tested this assumption by analyzing relationships between estradiol levels to the women's preferences of male faces that were manipulated to vary in masculinity. Estradiol was measured in daily saliva samples throughout the entire menstrual cycle collected by Polish women with regular menstrual cycles. In our analyses, we included the three most commonly used definitions of the fertile window in the literature. After computing the overall masculinity preference of each participant and measuring hormone levels, we found that i) the timing of ovulation varied greatly among women (between − 11 and − 17 days from the onset of the next menses, counting backwards), ii) there was no relationship between daily, measured during the day of the test (N = 83) or average for the cycle (N = 115) estradiol levels and masculinity preferences, iii) there were no differences in masculinity preferences between women in low- and high-conception probability phases of the cycle, and iv) there were no differences in masculinity preferences between short- and long-term mating contexts. Our results do not support the idea that women's preferences for a potential sexual partner's facial masculinity fluctuate throughout the cycle.     

Consequences of different dietary energy sources during follicular development on subsequent fertility of cyclic gilts

The objective of the present study was to investigate the effects of dietary-induced insulin enhancement during the late luteal phase on subsequent fertility of gilts. Fifty-two littermate cyclic gilts were subjected to dietary treatments where two energy sources were tested: corn starch (T1) and soybean oil (T2). The experimental diets were supposed to provide similar amounts of dietary energy, but from different sources. Gilts were fed ad libitum, starting day 8 of the estrous cycle, until the next standing heat. Blood sampling was performed in a subgroup of 20 gilts on days 14 and 21 of the cycle for analyses of glucose and insulin, and after ovulation detection until 18 h after ovulation for progesterone. All gilts were slaughtered on day 28 of pregnancy and the reproductive tracts recovered for further analysis. T1 gilts showed higher postprandial insulin peak on days 14 and 21 and lower glucose levels 4 h after feeding on day 14 (P<0.05), however, there were no treatment effects on plasma progesterone concentrations. Dietary energy sources did not affect average daily feed intake, body weight and backfat on day 28 of pregnancy. Estrous cycle length, estrus duration and time of ovulation were not affected by previous nutritional treatments either. T1 gilts showed higher ovulation rates, number of embryos, embryo weight and placental weight (P<0.05). There were no treatment effects on pregnancy rate, embryo survival rate and volume of amniotic fluid. A positive correlation between progesterone concentration 18 h after ovulation and ovulation rate was observed (r=0.75; P<0.01). These results suggest that it is possible to manipulate dietary insulin response in cyclic gilts and, thus, improve reproductive efficiency when feeding starch as the main energy source during the late luteal and follicular phases of the cycle.     

"Natural family planning": effective birth control supported by the Catholic Church.

During 20-22 September Manchester is to host the 1993 follow up to last year''s "earth summit" in Rio de Janeiro. At that summit the threat posed by world overpopulation received considerable attention. Catholicism was perceived as opposed to birth control and therefore as a particular threat. This was based on the notion that the only method of birth control approved by the church--natural family planning--is unreliable, unacceptable, and ineffective. In the 20 years since E L Billings and colleagues first described the cervical mucus symptoms associated with ovulation natural family planning has incorporated these symptoms and advanced considerably. Ultrasonography shows that the symptoms identify ovulation precisely. According to the World Health Organisation, 93% of women everywhere can identify the symptoms, which distinguish adequately between the fertile and infertile phases of the menstrual cycle. Most pregnancies during trials of natural family planning occur after intercourse at times recognised by couples as fertile. Thus pregnancy rates have depended on the motivation of couples. Increasingly studies show that rates equivalent to those with other contraceptive methods are readily achieved in the developed and developing worlds. Indeed, a study of 19,843 poor women in India had a pregnancy rate approaching zero. Natural family planning is cheap, effective, without side effects, and may be particularly acceptable to the efficacious among people in areas of poverty.     

It's all in the timing: coital frequency and fertility awareness-based methods of family planning

Fertility awareness-based methods of family planning help women to identify the days of the cycle they should avoid unprotected intercourse to prevent pregnancy. Therefore using fertility awareness-based methods influences the timing of sexual activity, which may affect the nature of the sexual relationship. Data are used from the clinical trials of two fertility awareness-based methods--the Standard Days Method and the TwoDay Method--to determine the frequency and timing of intercourse during the cycle, and the determinants of coital frequency. The mean coital frequency of study participants was similar to that reported by users of other methods. Results suggest that coital frequency increases with consecutive cycles of method use. At the same time the frequency of intercourse during the identified fertile days and during menses decreases. This evidence implies a behavioural change as couples get more experience using their method and communicating about the fertile days. Coital frequency was also influenced by the method used and by the study sites. Potential differences between the methods and sites that may contribute to this effect are discussed.     

Urinary gonadotropin and estrogen excretion during the postpartum estrus,conception, and pregnancy in the cotton-top tamarin (Saguinus oedipus oedipus)

Hormonal profiles during postpartum estrus, time of conception, and pregnancy were determined in urine samples from six cotton-top tamarins (Saguinus oedipus oedipus). Noninvasive collection techniques permitted daily sampling throughout lactation and pregnancy. Urinary estrone (E1), estradiol (E2), and both bioactive and immunoreactive luteinizing hormone/chorionic gonadotropin (LH/CG) measures revealed an interval of 19 ± 2.07 (S E M) days between parturition and the postpartum ovulatory LH peak. An increase in both E1 and E2 was seen prior to the LH peak; however, E1 and E2 continued to increase to their highest concentrations after the LH peak. Since postpartum ovulations resulted in pregnancy, neither postpartum estrus nor conception was suppressed by lactation. The length of gestation (measured from the LH peak to parturition) was 183.7 ± 1.14 (S E M) days, which is at least 30 days longer than that previously reported for other callitrichid species. Both E1 and E2 reached their maximum levels during midpregnancy but showed a rapid decline at parturition. Gestational levels of CG were first detectable approximately 20 days after the LH peak and continued to be elevated for approximately 80 days. The Sub-Human Primate Tube Test (SHPTT) for pregnancy did not detect the LH Peak and was less sensitive than other methods in detecting CG. Two RIA methods and a bioassay technique could not distinguish between LH and CG. We concluded that monitoring both estrogen and LH concentration was needed to determine when ovulation occurs in the cotton-top tamarin, since peak values of estrogen are seen after the ovulatory LH peak. Also, these tamarins were pregnant the majority of the time, indicating an unusually high fertility rate in contrast to most noncallitrichid primate species.     

Women's attractiveness judgments of self-resembling faces change across the menstrual cycle

Two lines of reasoning predict that women's preferences for people exhibiting cues to kinship will be lower in the follicular phase than in the luteal phase of the menstrual cycle. Women may avoid kinship cues during the follicular phase when they are most fertile due to the costs of inbreeding. Alternatively, women may seek kinship cues during the luteal phase as a byproduct of the benefits of associating with kin during pregnancy, which is also characterized by high progesterone. We find that preferences for facial resemblance, a putative kinship cue, follow this predicted pattern and are positively correlated with estimated progesterone levels based on cycle day. Neither estimated estrogen levels nor conception risk predicted preferences for self-resemblance, and the cyclic shift was stronger for preferences for female faces than male faces. These findings lead to the possibility that this cyclic change in preference for self-resemblance may be a byproduct of a hormonal mechanism for increasing affiliative behavior toward kin during pregnancy rather than a mechanism for preventing inbreeding during fertile periods.