Najmabadi S et al., 2022·Hum Reprod Open·
Open Access
Does sexual intercourse enhance the cycle fecundability in women without known subfertility? Sexual intercourse (regardless of timing during the cycle) was associated with cycle characteristics suggesting higher fecundability, including longer luteal phase, less premenstrual spotting and more than 2 days of cervical fluid with estrogen-stimulated qualities. Human females are spontaneous ovulators, experiencing an LH surge and ovulation cyclically, independent of copulation. Natural conception requires intercourse to occur during the fertile window of a woman's menstrual cycle, i.e. the 6-day interval ending on the day of ovulation. However, most women with normal fecundity do not ovulate on Day 14, thus the timing of the hypothetical fertile window varies within and between women. This variability is influenced by age and parity and other known or unknown elements. While the impact of sexual intercourse around the time of implantation on the probability of achieving a pregnancy has been discussed by some researchers, there are limited data regarding how sexual intercourse may influence ovulation occurrence and menstrual cycle characteristics in humans. This study is a pooled analysis of three cohorts of women, enrolled at Creighton Model FertilityCare centers in the USA and Canada: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006) and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cycle phase lengths, bleeding and cervical mucus patterns and estimated the fertile window in 2564 cycles of 530 women, followed for up to 1 year. Participants were US or Canadian women aged 18-40 and not pregnant, who were heterosexually active, without known subfertility and not taking exogenous hormones. Most of the women were intending to avoid pregnancy at the start of follow-up. Women recorded daily vaginal bleeding, mucus discharge and sexual intercourse using a standardized protocol and recording system for up to 1 year, yielding 2564 cycles available for analysis. The peak day of mucus discharge (generally the last day of cervical fluid with estrogen-stimulated qualities of being clear, stretchy or slippery) was used to identify the estimated day of ovulation, which we considered the last day of the follicular phase in ovulatory cycles. We used linear mixed models to assess continuous cycle parameters including cycle, menses and cycle phase lengths, and generalized linear models using Poisson regression with robust variance to assess dichotomous outcomes such as ovulatory function, short luteal phases and presence or absence of follicular or luteal bleeding. Cycles were stratified by the presence or absence of any sexual intercourse, while adjusting for women's parity, age, recent oral contraceptive use and breast feeding. MAIN Most women were <30 years of age (75.5%; median 27, interquartile range 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators and nulliparous (70.9%). Cycles with no sexual intercourse compared to cycles with at least 1 day of sexual intercourse were shorter (29.1 days (95% CI 27.6, 30.7) versus 30.1 days (95% CI 28.7, 31.4)), had shorter luteal phases (10.8 days (95% CI 10.2, 11.5) versus 11.4 days (95% CI 10.9, 12.0)), had a higher probability of luteal phase deficiency (<10 days; adjusted probability ratio (PR) 1.31 (95% CI 1.00, 1.71)), had a higher probability of 2 days of premenstrual spotting (adjusted PR 2.15 (95% CI 1.09, 4.24)) and a higher probability of having two or fewer days of peak-type (estrogenic) cervical fluid (adjusted PR 1.49 (95% CI 1.03, 2.15)). LIMITATIONS Our study participants were geographically dispersed but relatively homogeneous in regard to race, ethnicity, income and educational levels, and all had male partners, which may limit the generalizability of the findings. We cannot exclude the possibility of undetected subfertility or related gynecologic disorders among some of the women, such as undetected endometriosis or polycystic ovary syndrome, which would impact the generalizability of our findings. Acute illness or stressful events might have reduced the likelihood of any intercourse during a cycle, while also altering cycle characteristics. Some cycles in the no intercourse group may have actually had undocumented intercourse or other sexual activity, but this would bias our results toward the null. The Creighton Model FertilityCare System (CrM) discourages use of barrier methods, so we believe that most instances of intercourse involved exposure to semen; however, condoms may have been used in some cycles. Our dataset lacks any information about the occurrence of female orgasm, precluding our ability to evaluate the independent or combined impact of female orgasm on cycle characteristics. Sexual activity may change reproductive hormonal patterns, and/or levels of reproductive hormones may influence the likelihood of sexual activity. Future work may help with understanding the extent to which exposure to seminal fluid, and/or female orgasm and/or timing of intercourse could impact menstrual cycle function. In theory, large data sets from women using menstrual and fertility tracking apps could be informative if women can be appropriately incentivized to record intercourse completely. It is also of interest to understand how cycle characteristics may differ in women with gynecological problems or subfertility. Funding for the research on the three cohorts analyzed in this study was provided by the Robert Wood Johnson Foundation #029258 (Creighton Model MultiCenter Fecundability Study), the Eunice Kennedy Shriver National Institute of Child Health and Human Development 1K23 HD0147901-01A1 (Time to Pregnancy in Normal Fertility) and the Office of Family Planning, Office of Population Affairs, Health and Human Services 1FPRPA006035 (Creighton Model Effectiveness, Intentions, and Behaviors Assessment). The authors declare that they have no conflict of interest. N/A.
Sanders JN et al., 2022·Reprod Health·
Open Access
In vitro fertilization (IVF) births contribute to a considerable proportion of preterm birth (PTB) each year. However, there is no formal surveillance of adverse perinatal outcomes for less invasive fertility treatments. The study objective was to describe associations between fertility treatment (in vitro fertilization, intrauterine insemination, usually with ovulation drugs (IUI), or ovulation drugs alone) and preterm birth, compared to no treatment in subfertile women. The Fertility Experiences Study (FES) is a retrospective cohort study conducted at the University of Utah between April 2010 and September 2012. Women with a history of primary subfertility self-reported treatment data via survey and interviews. Participant data were linked to birth certificates and fetal death records to asses for perinatal outcomes, particularly preterm birth. A total 487 birth certificates and 3 fetal death records were linked as first births for study participants who completed questionnaires. Among linked births, 19% had a PTB. After adjustment for maternal age, paternal age, maternal education, annual income, religious affiliation, female or male fertility diagnosis, and duration of subfertility, the odds ratios and 95% confidence intervals (CI) for PTB were 2.17 (CI 0.99, 4.75) for births conceived using ovulation drugs, 3.17 (CI 1.4, 7.19) for neonates conceived using IUI and 4.24 (CI 2.05, 8.77) for neonates conceived by IVF, compared to women with subfertility who used no treatment during the month of conception. A reported diagnosis of female factor infertility increased the adjusted odds of having a PTB 2.99 (CI 1.5, 5.97). Duration of pregnancy attempt was not independently associated with PTB. In restricting analyses to singleton gestation, odds ratios were not significant for any type of treatment. IVF, IUI, and ovulation drugs were all associated with a higher incidence of preterm birth and low birth weight, predominantly related to multiple gestation births.
What is the normal range of cervical mucus patterns and number of days with high or moderate day-specific probability of pregnancy (if intercourse occurs on a specific day) based on cervical mucus secretion, in women without known subfertility, and how are these patterns related to parity and age? The mean days of peak type (estrogenic) mucus per cycle was 6.4, the mean number of potentially fertile days was 12.1; parous versus nulliparous, and younger nulliparous (<30 years) versus older nulliparous women had more days of peak type mucus, and more potentially fertile days in each cycle. The rise in estrogen prior to ovulation supports the secretion of increasing quantity and estrogenic quality of cervical mucus, and the subsequent rise in progesterone after ovulation causes an abrupt decrease in mucus secretion. Cervical mucus secretion on each day correlates highly with the probability of pregnancy if intercourse occurs on that day, and overall cervical mucus quality for the cycle correlates with cycle fecundability. No prior studies have described parity and age jointly in relation to cervical mucus patterns. STUDY DESIGN, SIZE, This study is a secondary data analysis, combining data from three cohorts of women: 'Creighton Model MultiCenter Fecundability Study' (CMFS: retrospective cohort, 1990-1996), 'Time to Pregnancy in Normal Fertility' (TTP: randomized trial, 2003-2006), and 'Creighton Model Effectiveness, Intentions, and Behaviors Assessment' (CEIBA: prospective cohort, 2009-2013). We evaluated cervical mucus patterns and estimated fertile window in 2488 ovulatory cycles of 528 women, followed for up to 1 year. PARTICIPANTS/MATERIALS, SETTING, Participants were US or Canadian women age 18-40 years, not pregnant, and without any known subfertility. Women were trained to use a standardized protocol (the Creighton Model) for daily vulvar observation, description, and recording of cervical mucus. The mucus peak day (the last day of estrogenic quality mucus) was used as the estimated day of ovulation. We conducted dichotomous stratified analyses for cervical mucus patterns by age, parity, race, recent oral contraceptive use (within 60 days), partial breast feeding, alcohol, and smoking. Focusing on the clinical characteristics most correlated to cervical mucus patterns, linear mixed models were used to assess continuous cervical mucus parameters and generalized linear models using Poisson regression with robust variance were used to assess dichotomous outcomes, stratifying by women's parity and age, while adjusting for recent oral contraceptive use and breast feeding. MAIN The majority of women were <30 years of age (75.4%) (median 27; IQR 24-29), non-Hispanic white (88.1%), with high socioeconomic indicators, and nulliparous (70.8%). The mean (SD) days of estrogenic (peak type) mucus per cycle (a conservative indicator of the fertile window) was 6.4 (4.2) days (median 6; IQR 4-8). The mean (SD) number of any potentially fertile days (a broader clinical indicator of the fertile window) was 12.1 (5.4) days (median 11; IQR 9-14). Taking into account recent oral contraceptive use and breastfeeding, nulliparous women age ≥30 years compared to nulliparous women age <30 years had fewer mean days of peak type mucus per cycle (5.3 versus 6.4 days, P = 0.02), and fewer potentially fertile days (11.8 versus 13.9 days, P < 0.01). Compared to nulliparous women age <30 years, the likelihood of cycles with peak type mucus ≤2 days, potentially fertile days ≤9, and cervical mucus cycle score (for estrogenic quality of mucus) ≤5.0 were significantly higher among nulliparous women age ≥30 years, 1.90 (95% confidence interval (CI) 1.18, 3.06); 1.46 (95% CI 1.12, 1.91); and 1.45 (95% CI 1.03, 2.05), respectively. Between parous women, there was little difference in mucus parameters by age. Thresholds set a priori for within-woman variability of cervical mucus parameters by cycle were examined as follows: most minus fewest days of peak type mucus >3 days (exceeded by 72% of women), most minus fewest days of non-peak type mucus >4 days (exceeded by 54% of women), greatest minus least cervical mucus cycle score >4.0 (exceeded by 73% of women), and most minus fewest potentially fertile days >8 days (found in 50% of women). Race did not have any association with cervical mucus parameters. Recent oral contraceptive use was associated with reduced cervical mucus cycle score and partial breast feeding was associated with a higher number of days of mucus (both peak type and non-peak type), consistent with prior research. Among the women for whom data were available (CEIBA and TTP), alcohol and tobacco use had minimal impact on cervical mucus parameters. LIMITATIONS, We did not have data on some factors that may impact ovulation, hormone levels, and mucus secretion, such as physical activity and body mass index. We cannot exclude the possibility that some women had unknown subfertility or undiagnosed gynecologic disorders. Only 27 women were age 35 or older. Our study participants were geographically dispersed but relatively homogeneous with regard to race, ethnicity, income, and educational level, which may limit the generalizability of the findings. Patterns of cervical mucus secretion observed by women are an indicator of fecundity and the fertile window that are consistent with the known associations of age and parity with fecundity. The number of potentially fertile days (12 days) is likely greater than commonly assumed, while the number of days of highly estrogenic mucus (and higher probability of pregnancy) correlates with prior identifications of the fertile window (6 days). There may be substantial variability in fecundability between cycles for the same woman. Future work can use cervical mucus secretion as an indicator of fecundity and should investigate the distribution of similar cycle parameters in women with various reproductive or gynecologic pathologies. STUDY FUNDING/COMPETING INTEREST(S): Funding for the three cohorts analyzed was provided by the Robert Wood Johnson Foundation (CMFS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (TTP), and the Office of Family Planning, Office of Population Affairs, Health and Human Services (CEIBA). The authors declare that they have no conflict of interest. N/A.
Najmabadi S et al., 2020·Paediatr Perinat Epidemiol·
There is variability between women for days of menstrual bleeding, cycle lengths, follicular phase lengths, and luteal phase lengths, related to age and parity. To describe total cycle length; anovulatory cycles; follicular and luteal phase lengths; and days and intensity of menstrual and non-menstrual bleeding in women without known subfertility over the course of 1 year. 581 women (3,324 cycles) with no known subfertility (18-40 years of age) were followed for up to 1 year. Women recorded vaginal bleeding and mucus discharge daily. We used the peak day of cervical mucus as the estimated day of ovulation and the last day of the follicular phase. We used generalised linear mixed models stratified by age and parity to describe menstrual cycle parameters. The majority of women were <30 years of age (74.5%), non-Hispanic White (88.6%), and nulliparous (70.4%). The mean menses length was 6.2 (1.5) days, median 6; cycle length 30.3 (6.7) days, median 29; follicular phase length 18.5 (6.5) days, median 17; and luteal phase length 11.7 (2.8) days, median 12. Nulliparous women aged ≥30 years vs nulliparous women aged <30 had shorter cycles (29.2 days, 95% confidence interval (CI) 27.8, 30.7 vs 31.5 days, 95% CI 30.8, 32.2) and shorter follicular phases (17.6 days, 95% CI 16.2, 18.9 vs 19.6 days, 95% CI 18.9, 20.2). Among all women, within-woman differences between the longest and shortest menses length >3 days, total cycle length >7 days, follicular phase >7 days, and luteal phase >3 days were found in 11.6%, 43.0%, 41.7%, and 58.8% of women, respectively. Our findings confirm variability between women of menstrual cycle parameters related to age and parity, and also highlight within-woman variability in the follicular and luteal phases.
Hemmert R et al., 2018·Paediatr Perinat Epidemiol·
Caffeine, alcohol, smoking and physical activity are known to alter sex steroid synthesis, which may affect hormone-dependent gynaecologic disease risk, such as endometriosis; however, few studies have assessed life style factors prior to endometriosis diagnosis. Four hundred and seventy three women, ages 18-44 years, underwent laparoscopy or laparotomy, regardless of clinical indication, at 14 clinic sites, 2007-2009. Women with prior surgically confirmed endometriosis were excluded. Life style factors were assessed prior to surgery. Adjusted risk ratios (RR) of endometriosis by caffeine, alcohol, smoking (serum cotinine), and physical activity were estimated, adjusting for age, marital status, education, race/ethnicity, age at menarche, gravidity, BMI, study site, and other life style factors. There were no associations between women with endometriosis and alcohol consumption (RR 0.9, 95% CI 0.7, 1.3), caffeine consumption (RR 1.1, 95% CI 0.8, 1.5), or smoking (serum cotinine <10 vs ≥10 ng/mL; RR 1.0, 95% CI 0.7, 1.6). Similar null findings were found between endometriosis and weekly occurrences of physical activity and total walking, moderate, and vigorous activity; a modest trend was found between total daily sitting time and increased endometriosis risk. This study, which is unique in its capture of life style exposures prior to incident endometriosis diagnosis, largely found no association between alcohol, caffeine, smoking, and physical activity and risk of endometriosis.
To explore the relationship between the type of clinician (generalist vs subspecialist) initially seen by infertile women, the treatment received, and the time to pregnancy. We analyzed mixed-mode questionnaire data from 867 women with primary infertility enrolled into a retrospective cohort through population- and fertility clinic-based sampling. We compared women presenting first to generalist providers with women presenting first to fertility subspecialists, with the main outcomes of receiving in vitro fertilization (IVF), time to pregnancy, and live birth. The first contact for most (84%) women with infertility was a generalist provider. Only 8% of women sought care first from a fertility subspecialist, and these women were older and had been trying longer to conceive. Women who presented first to a generalist provider were less likely to receive IVF (adjusted odds ratio, 0.48; 95% confidence interval, 0.28-0.82), were equally likely to achieve pregnancy, and had similar times to pregnancy (adjusted hazard ratio, 1.11; 95% confidence interval, 0.80-1.53) compared with women who presented first to a subspecialist. Generalist providers are frequently the first point of care for women with difficulty conceiving and are uniquely positioned to promote the balanced management of infertility.
Sanders JN et al., 2016·Paediatr Perinat Epidemiol·
Most cohort-based research for subfertility has been conducted in clinic-based cohorts, which may differ from population-based cohorts. We retrospectively recruited parallel cohorts of subfertile women: one by sampling two specialty fertility clinics in Utah, and one by population-based sampling based on marriage and birth records. The index date (of first clinic visit or subfertility status) was between 2000 and 2009, and we linked the women recruited to subsequent birth certificate records through December 2010. We enrolled 459 women through clinic-based sampling and 501 women through population-based sampling. Clinic-based women were older, had higher annual household income and more likely to have had a most intensive treatment of intrauterine insemination (31%) or in vitro fertilisation (46%) than women from population recruitment (19% and 14% respectively). Conversely, they were less likely to have received no medical treatment (9%) compared to women from population recruitment (41%). For both types of sampling, prior to eligibility screening, non-responders were less likely to link to a live birth than responders: 51% vs. 58% for clinic-based, and 69% vs. 76% for the population-based with an index date in 2004. Population-based sampling for subfertility cohort research identifies women who were more likely to have had less intensive treatment or no treatment. However, in both clinic-based and population-based sampling, women who have had a live birth are more likely to respond to retrospective recruitment.
Measurement and Statistics · Instrument Development and Validation
Many women throughout the world have history of subfertility (resolved or unresolved), but much remains unknown about services and treatments chosen. We developed a mixed-mode fertility experiences questionnaire (FEQ) in 2009 through literature review and iterative pilot work to optimize question format and mode of administration. The focus of the FEQ is to collect data retrospectively on time at risk for pregnancy, fertility treatments received and declined, pregnancy, time to pregnancy and pregnancy outcomes. We conducted a validation of key elements of the FEQ with comparison to medical records in 2009 and 2010. The validation sample was selected from women initially seen at a specialized fertility treatment center in Utah in 2004. The FEQ was optimized with two components: 1) written (paper or web-based), self-administered, followed by 2) telephoneadministered questions. In 63 patients analyzed, high levels of correlation were identified between patient self-report and medical records for the use of intrauterine insemination and assisted reproductive technology, pregnancy and live birth histories, time at risk for pregnancy and time to pregnancy. There was low correlation between medical records and self-report for the use of oral ovulation drugs and injectable ovulation drugs. Compared to the medical record, the FEQ was over 90% sensitive for all elements, except injectable ovulation drugs (70% sensitivity). The FEQ accurately captured elements of fertility treatment history at 5-6 years after the first visit to a specialty clinic.
To investigate perinatal outcomes associated with fertility treatments, including assisted reproductive technology (ART), intrauterine insemination with ovulation stimulation (IUI), and ovulation stimulation alone (OS). Population-representative cross-sectional survey of women with live births, 2004-2008. Florida, Maryland, and Utah, USA. 21 803 women, weighted to represent 1 022 597 women. Survey and birth certificate data were analysed with logistic regression models adjusted for age, education, race, income, and parity, using separate models for singletons and all births. We used two referent groups: (1) women who never used fertility treatment and (2) subfertile women conceiving without treatment. Preterm birth (<37 weeks), very preterm birth (<34 weeks), low birthweight (<2500 g), and very low birthweight (<1500 g). Referent group 1: In singletons, ART was associated with preterm birth (OR 3.28; 95% CI 1.74, 6.20) and low birthweight (OR 2.91; 95% CI 1.99, 4.26). OS was also associated with low birthweight (OR 1.62; 95% CI 1.19, 2.19). Including all births, treatment was associated with preterm birth and low birthweight: ART (OR 6.21; 95% CI 4.21, 9.16 and OR 6.51; 95% CI 4.85, 8.73); IUI (OR 2.10; 95% CI 1.24, 3.56 and OR 2.41; 95% CI 1.54, 3.76); OS (OR 1.40; 95% CI 1.01, 1.94 and OR 2.10; 95% CI 1.60, 2.75), respectively. Referent group 2: ART was associated with both outcomes in all births, but not singletons. Preterm birth and low birthweight associated with fertility treatments are largely attributable to multiple gestation, but are also related to underlying subfertility. Preterm birth is associated with subfertility, and with fertility treatments through multiple gestation.
The purpose of this study was to compare the utilization of medical help for fertility among women who reported up to a year versus more than a year of trying to become pregnant and to describe the characteristics of those women seeking early treatment. Data from the 2004-2008 Pregnancy Risk Assessment Monitoring System (PRAMS) survey were used to assess attempt duration and use of fertility treatments in a sample of 9,517 women who had a recent live birth in Utah. PRAMS respondents who were trying to become pregnant at the time of conception were asked questions about fertility treatments (sampling n = 5,238; representative n = 153,036). Univariate and bivariate analyses were used to describe and compare characteristics of women who sought treatment after attempting pregnancy for a year or less and women who waited at least a year to seek treatment. Among women who were trying to become pregnant, 9.5 % reported using some medical assistance to conceive. Among the women trying to become pregnant, 89.3 % had been trying for ≤12 months and 10.7 % reported having tried >12 months. 5.2 % of those trying to become pregnant for up to a year reported use of fertility treatment, compared with 45.8 % of those trying for a year or more. Women who had previous live births were significantly more likely to use early treatment than nulliparous women (aOR = 2.4, 95 % CI = 1.5, 3.9). The use of fertility drugs and other treatments were more common than ART among recipients of early treatment (aOR = 3.7, 95 % CI = 1.7, 7.9). Some women may be receiving fertility treatment before it is clinically indicated. Instead of invasive treatment, these women may benefit from preconception counseling on folic acid, healthy prepregnancy weight and use of ovulation monitoring to time intercourse.
To describe the characteristics of women seeking infertility treatment and the types of fertility treatment sought within a population-based sample. We analyzed data from the cross-sectional Pregnancy Risk Assessment Monitoring System (PRAMS) of women with a live birth using data from seven states. Logistic regression was used to determine factors associated with infertility treatment utilization. Infertility treatment was reported by 10.5% of women who were trying to become pregnant. The most common treatment reported was fertility enhancing drugs (29%), followed by assisted reproductive technology including in vitro fertilization (21%), and artificial insemination together with fertility enhancing drugs (15%). Some women reported using other types of treatment (23%). The PRAMS data provide insights into the use of infertility treatment among women giving birth in the United States. Further research is needed to understand the true prevalence of infertility, factors that influence treatment choices, and the longitudinal impact of infertility treatment on outcomes.
Outcomes and Effectiveness · Cumulative Versus Per Cycle Reporting
To model the cumulative probability of pregnancy among couples with subfertility without a definitive diagnosis, according to different treatment strategies. A beta distribution of fecundity was fitted that reproduced the cumulative probability of pregnancy in prospective studies of natural fertility, and this distribution was applied to simulated cohorts starting with one million couples each. Probabilities of pregnancy were generated for each cycle of each couple. Simulation study. PATIENT(S): Hypothetic subfertile population. INTERVENTION(S): After 2 or 4 years of attempting pregnancy and diagnostic evaluation to exclude anovulation, tubal obstruction, and severe male factor, simulated treatments were applied to the remaining nonpregnant couples, with treatment effects based on published literature. MAIN OUTCOME MEASURE(S): Simulated cumulative probability of pregnancy. RESULT(S): Initially, the cumulative probability of pregnancy was highest for early treatment with IVF, but over time, conservative treatment or frequent intercourse approached the same cumulative probability. CONCLUSION(S): In couples without clear indications for IVF, the main benefit of early IVF may be to shorten time to pregnancy, a benefit that must be weighed against costs and potential adverse outcomes. Couples should be encouraged to maintain regular intercourse to maximize chances of pregnancy, even after unsuccessful treatment attempts.