Infant sex at birth and long-term maternal mortality.

BACKGROUND: Maternal adaptations may vary by foetal sex. Whether male infants influence long-term mortality in mothers remains uncertain. OBJECTIVE: The objective of the study was to examine whether male infants increase the risk of maternal mortality. METHODS: This study included pregnant women enrolled at 12 US sites from 1959 to 1966 in the Collaborative Perinatal Project (CPP). Collaborative Perinatal Project records were linked to the National Death Index and the Social Security Master Death File to ascertain deaths until 2016. Foetal sex was determined by infant sex at birth, defined as the total number of male or female infants in pregnancies prior to or during enrolment in the CPP. In secondary analyses, exposure was defined as infant sex at the last CPP delivery. Outcomes included all-cause and underlying causes of mortality. We used Cox proportional hazards models weighted by the number of prior live births and stratified our models by parity and race/ethnicity. RESULTS: Among 48,188 women, 50.8% had a male infant at their last registered CPP pregnancy and 39.0% had a recorded death after a mean follow-up of 47.8 years (SD 10.5 years). No linear association was found between the number of liveborn males and all-cause mortality (primipara women: HR 1.02, 95% CI 0.95, 1.09, multipara women, 1 prior live birth: HR 0.96, 95% CI 0.89, 1.03, multipara women, ≥2 prior live births: HR 0.97, 95% CI 0.85, 1.11). A similar trend was noted for cardiovascular- and cancer-related mortality. At the last delivery, women with a male infant did not have an increased risk of all-cause or cause-specific mortality compared to women with a female infant. These findings were consistent across racial/ethnic groups. CONCLUSIONS: Women who give birth to male infants, regardless of number, are not at increased risk of all-cause and cause-specific mortality. These findings suggest that giving birth to male infants may not independently influence the long-term health of women.

The Role of Maternal Preconception Adiposity in Human Offspring Sex and Sex Ratio.

We evaluated relationships between preconception adiposity and human offspring sex and sex ratio. Using data from a prospective preconception cohort nested within a randomized controlled trial based at 4 US clinical sites (2006-2012), we used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for male:female sex ratio, and log-identity regression to estimate risk differences (RDs) and 95% CIs for male and female livebirth according to preconception adiposity measures. Inverse-probability weights accounted for potential selection bias. Among 603 women attempting pregnancy, there were meaningful reductions in sex ratio for the highest category of each adiposity measure. The lowest sex ratios were observed for obesity (body mass index of ≥30, calculated as weight (kg)/height (m)2, OR = 0.48, 95% CI: 0.26, 0.88) relative to normal body mass index, and the top tertiles (tertile 3) of serum leptin (OR = 0.50, 95% CI: 0.32, 0.80) and skinfold measurements (OR = 0.50, 95% CI: 0.32, 0.79) relative to the lowest tertiles. Reductions were driven by 11-15 fewer male livebirths per 100 women (for obesity, RD = -15, 95% CI: -23, -6.7; for leptin tertile 3, RD = -11, 95% CI: -20, -3.2; and for skinfolds tertile 3, RD = -11, 95% CI: -19, -3.3). We found that relationships between preconception adiposity measures and reduced sex ratio were driven by a reduction in male births.

Longitudinal semen parameter assessments and live birth: variability and implications for treatment strategies.

OBJECTIVE: To examine whether semen parameters are associated with live birth among couples seeking infertility treatment after accounting for semen parameter variability. DESIGN: Folic Acid and Zinc Supplementation Trial (FAZST) prospective cohort. SETTING: Four US reproductive endocrinology and infertility care study centers, 2013-2017. PATIENT(S): Couples (n = 2,369) seeking fertility consultations at 4 US infertility care study centers. INTERVENTION(S): Semen volume, pH, sperm viability, morphology, progressive and total motility, concentration, count, and total and progressive motile count assessed at baseline and at 2, 4, and 6 months after enrollment. MAIN OUTCOME MEASURE(S): Log-binomial models stratified by fertility treatment received (in vitro fertilization [IVF], intrauterine insemination [IUI], ovulation induction [OI], or no treatment) estimated risk differences (RDs) between semen parameter quartiles and live birth and accounted for multiple semen assessments per person. We accounted for abstinence time, the biological interdependence of semen parameters, and potential selection bias because of loss to follow-up. RESULT(S): Among couples using OI only or no treatment, 39% had a live birth, and relative to the highest quartile, the lowest quartiles of morphology (RD, -19 [95% CI, -23 to -15] per 100 couples), motility (RD, -13 [95% CI, -17 to -9]), concentration (RD, -22 [95% CI, -26 to -19]), and total motile count (RD, -18 [95% CI, -22 to -14]) were associated with fewer live births. For IUI, 26% had a live birth, and the lowest quartiles of volume (RD, -6 [95% CI, -11 to -0.4]), concentration (RD, -6 [95% CI, -11 to -0.1]), count (RD, -10 [95% CI, -15 to -4]), and total motile count (RD, -7 [95% CI, -13 to -1]) were associated with fewer live births. For IVF, 61% had a live birth, and only morphology (Q1 RD, -7 [95% CI, -14 to 0.2]; Q2 RD, -10 [95% CI, -17 to -2.2]) was associated with live birth. CONCLUSION(S): Semen parameters are critical in couples undergoing OI/IUI. Only low morphology was important for live birth after IVF. Although data supporting the use of semen parameters are fragmented across differing populations, current findings are generalizable across the range of male fertility and couple fertility treatments, providing evidence about which semen parameters are most relevant in which settings. CLINICAL TRIAL REGISTRATION NUMBER: NCT#01857310.

Prospectively assessed perceived stress associated with early pregnancy losses among women with history of pregnancy loss.

STUDY QUESTION: What is the association between perceived stress during peri-conception and early pregnancy and pregnancy loss among women who have experienced a prior pregnancy loss? SUMMARY ANSWER: Daily perceived stress above the median is associated with over a 2-fold risk of early pregnancy loss among women who have experienced a prior loss. WHAT IS KNOWN ALREADY?: Women who have experienced a pregnancy loss may be more vulnerable to stress while trying to become pregnant again. While prior research has indicated a link between psychological stress and clinically confirmed miscarriages, research is lacking among a pre-conceptional cohort followed prospectively for the effects of perceived stress during early critical windows of pregnancy establishment on risk of both hCG-detected pregnancy losses and confirmed losses, while considering important time-varying confounders. STUDY DESIGN, SIZE, DURATION: Secondary data analysis of the EAGeR trial (2007-2011) among women with an hCG-detected pregnancy (n = 797 women). PARTICIPANTS/MATERIALS, SETTING, METHODS: Women from four US clinical centers enrolled pre-conceptionally and were followed ≤6 cycles while attempting pregnancy and, as applicable, throughout pregnancy. Perceived stress was captured via daily diaries and end-of-month questionnaires. Main outcome measures include hCG-detected and clinically recognized pregnancy losses. MAIN RESULTS AND THE ROLE OF CHANCE: Among women who had an hCG-confirmed pregnancy, 188 pregnancies (23.6%) ended in loss. Women with high (>50th percentile) versus low (≤50th percentile) peri-implantation or early pregnancy weekly perceived stress had an elevated risk of experiencing any pregnancy loss (hazard ratio (HR): 1.69, 95% CI: 1.13, 2.54) or clinical loss (HR: 1.58, 95% CI: 0.96, 2.60), with higher risks observed for women experiencing an hCG-detected loss (HR: 2.16, 95% CI: 1.04, 4.46). Models accounted for women's age, BMI, employment, marital status, income, education, race, parity, prior losses, exercise and time-varying nausea/vomiting, caffeine, alcohol and smoking. LIMITATIONS, REASONS FOR CAUTION: We were limited in our ability to clearly identify the mechanisms of stress on pregnancy loss due to our sole reliance on self-reported perceived stress, and the lack of biomarkers of different pathways of stress. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insight on early pregnancy perceived stress and risk of pregnancy loss, most notably hCG-detected losses, among women with a history of a prior loss. Our study is an improvement over past studies in its ability to account for time-varying early pregnancy symptoms, such as nausea/vomiting, and lifestyle factors, such as caffeine, alcohol and smoking, which are also risk factors for psychological stress and pregnancy loss. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland (Contract numbers: HHSN267200603423, HHSN267200603424, HHSN267200603426, HHSN275201300023I). Additionally, K.C.S. was supported by the National Institute on Aging of the National Institutes of Health under Award Number K01AG058781. The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: #NCT00467363.

Preconception hemoglobin A1c concentration in healthy women is not associated with fecundability or pregnancy loss.

Objective: To examine the relationship of preconception hemoglobin A1c, a marker of cumulative exposure to glucose over the preceding 2-3 months, with time to pregnancy, pregnancy loss, and live birth among fecund women without diagnosed diabetes or other medical diseases. Design: A secondary analysis of a prospective cohort of women participating in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial. Setting: Four US academic medical centers. Patients: A total of 1,194 healthy women aged 18-40 years with a history of one or two pregnancy losses attempting spontaneous conception were observed for up to six cycles while attempting pregnancy and throughout pregnancy if they conceived. Interventions: Not applicable. Main Outcome Measures: Time to pregnancy, human chorionic gonadotropin pregnancy, clinical pregnancy, pregnancy loss, and live birth. Results: Although increasing preconception A1c level was associated with reduced fecundability (fecundability odds ratio [FOR] per unit increase in A1c 0.74; 95% confidence interval [CI] 0.57, 0.96) in unadjusted models and models adjusted for age, race, smoking and treatment arm (FOR 0.79; 95% CI 0.60, 1.04), results were attenuated after further adjustment for body mass index (FOR 0.91; 95% CI 0.68, 1.21). Preconception A1c levels among women without diagnosed diabetes were not associated with live birth or pregnancy loss. Conclusionss: Among healthy women without diagnosed diabetes, we observed no association of A1c with live birth or pregnancy loss. The association between A1c and fecundability was influenced by body mass index, a strong risk factor for both diabetes and infertility. These data support current recommendations that preconception A1c screening should be reserved for patients with risk factors for diabetes. Clinical Trial Registration Number: ClinicalTrials.gov: NCT00467363.

Long-Term Mortality in Women With Pregnancy Loss and Modification by Race/Ethnicity.

Pregnancy loss is a common reproductive complication, but its association with long-term mortality and whether this varies by maternal race/ethnicity is not well understood. Data from a racially diverse cohort of pregnant women enrolled in the Collaborative Perinatal Project (CPP) from 1959 to 1966 were used for this study. CPP records were linked to the National Death Index and the Social Security Death Master File to identify deaths and underlying cause (until 2016). Pregnancy loss comprised self-reported losses, including abortions, stillbirths, and ectopic pregnancies. Among 48,188 women (46.0% White, 45.8% Black, 8.2% other race/ethnicity), 25.6% reported at least 1 pregnancy loss and 39% died. Pregnancy loss was associated with a higher absolute risk of all-cause mortality (risk difference, 4.0 per 100 women, 95% confidence interval: 1.4, 6.5) and cardiovascular mortality (risk difference, 2.2 per 100 women, 95% confidence interval: 0.8, 3.5). Stratified by race/ethnicity, a higher risk of mortality persisted in White, but not Black, women. Women with recurrent losses are at increased risk of death, both overall and across all race/ethnicity groups. Pregnancy loss is associated with death; however, it does not confer an excess risk above the observed baseline risk in Black women. These findings support the need to assess reproductive history as part of routine screening in women.

Preconception caffeine metabolites, caffeinated beverage intake, and fecundability.

BACKGROUND: Caffeine is the most frequently used psychoactive substance in the United States and >90% of reproductive-age women report some amount of intake daily. Despite biological plausibility, previous studies on caffeine and fecundability report conflicting results. Importantly, prior studies measured caffeine exposure exclusively by self-report, which is subject to measurement error and does not account for factors that influence caffeine metabolism. OBJECTIVES: Our objective was to examine associations between preconception serum caffeine metabolites, caffeinated beverage intake, and fecundability. METHODS: Participants included 1228 women aged 18-40 y with a history of 1-2 pregnancy losses in the EAGeR (Effects of Aspirin in Gestation and Reproduction) trial. We prospectively evaluated associations of preconception caffeine metabolites (i.e., caffeine, paraxanthine, and theobromine) measured from 1191 serum samples untimed to a specific time of day, self-reported usual caffeinated beverage intakes at baseline, and time-varying cycle-average caffeinated beverage intake, with fecundability. Using Cox proportional hazards models, we estimated fecundability odds ratios (FORs) and 95% CIs according to each metabolite. Follow-up was complete for 89% (n = 1088) of participants. RESULTS: At baseline, 85%, 73%, and 91% of women had detectable serum caffeine, paraxanthine, and theobromine, respectively. A total of 797 women became pregnant during ≤6 cycles of preconception follow-up. After adjusting for potential confounders, neither serum caffeine [tertile (T)3 compared with T1 FOR: 0.87; 95% CI: 0.71, 1.08], paraxanthine (T3 compared with T1 FOR: 0.92; 95% CI: 0.75, 1.14), nor theobromine (T3 compared with T1 FOR: 1.15; 95% CI: 0.95, 1.40) were associated with fecundability. Baseline intake of total caffeinated beverages was not associated with fecundability (>3 compared with 0 servings/d adjusted FOR: 0.99; 95% CI: 0.74, 1.34), nor was caffeinated coffee (>2 compared with 0 servings/d adjusted FOR: 0.93; 95% CI: 0.45, 1.92) or caffeinated soda (>2 servings/d adjusted FOR: 0.92; 95% CI: 0.71, 1.20). CONCLUSIONS: Our findings are reassuring that caffeine exposure from usual low to moderate caffeinated beverage intake likely does not influence fecundability.This trial was registered at clinicaltrials.gov as NCT00467363.

The Safety of Low-Dose Aspirin on the Mode of Delivery: Secondary Analysis of the Effect of Aspirin in Gestation and Reproduction Randomized Controlled Trial.

OBJECTIVE: This study aimed to examine whether prenatal low-dose aspirin (LDA) therapy affects risk of cesarean versus vaginal delivery. STUDY DESIGN: This study is a secondary analysis of the randomized clinical effects of aspirin in gestation and reproduction (EAGeR) trial. Women received 81-mg daily aspirin or placebo from preconception to 36 weeks of gestation. Mode of delivery and obstetric complications were abstracted from records. Log-binomial regression models estimated relative risk (RR) of cesarean versus vaginal delivery. Data were analyzed among the total preconception cohort, as well as restricted to women who had a live birth. RESULTS: Among 1,228 women, 597 had a live birth. In the intent-to-treat analysis, preconception-initiated LDA was not associated with risk of cesarean (RR = 1.02; 95% confidence interval [CI]: 0.98-1.07) compared with placebo. Findings were similar in just women with a live birth and when accounting prior cesarean delivery and parity. CONCLUSION: Preconception-initiated daily LDA was not associated with mode of delivery among women with one to two prior losses. KEY POINTS: · Aspirin was not associated with risk of cesarean section.. · Aspirin was not associated with mode of delivery.. · No increased risk of bleeding with use of aspirin..

The impact of zinc and folic acid supplementation on sperm DNA methylation: results from the folic acid and zinc supplementation randomized clinical trial (FAZST).

OBJECTIVE: To determine if 6-month folic acid (5 mg) and zinc (30 mg) supplementation impacts sperm DNA methylation patterns. DESIGN: A multicenter, double-blind, block randomized, placebo-controlled trial titled "The Folic Acid and Zinc Supplementation Trial (FAZST)." SETTING: Infertility care centers. PATIENT(S): Male partners (18 years and older) from heterosexual couples (female partners aged 18-45 years) seeking fertility treatment were recruited. INTERVENTION(S): Men were randomized 1:1 to receive folic acid (5 mg) and elemental zinc (30 mg) (n = 713) or a matching placebo (n = 757) daily for 6 months. MAIN OUTCOME MEASURE(S): Sperm DNA methylation was analyzed using the EPIC methylation array (Illumina) at 6 months. Differential sperm DNA methylation was assessed at multiple levels (regional, single cytosine phosphate guanine, etc.). We additionally assessed the impact of supplementation on epigenetic age. RESULT(S): No significant differences were identified between the treatment and placebo groups although some trends appeared to be present. To determine if these trends were noteworthy, we implemented various permutations and found that the patterns we identified were no more than would be expected by random chance. CONCLUSION(S): The data presented here strongly suggest that this supplementation regimen is not effective at altering sperm DNA methylation. These data comport well with previous findings from the FAZST study that found no impact of supplementation on basic semen analysis parameters or live birth. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT01857310.

Preconception leukocyte telomere length and pregnancy outcomes among women with demonstrated fecundity.

STUDY QUESTION: Is preconception leukocyte telomere length associated with fecundability, pregnancy loss and live birth among women attempting natural conception with a history of 1-2 prior pregnancy losses? SUMMARY ANSWER: Preconception leukocyte telomere length is not associated with fecundability, pregnancy loss or live birth. WHAT IS KNOWN ALREADY: As women increasingly delay childbearing, accessible preconception biomarkers to predict pregnancy outcomes among women seeking natural conception could improve preconception counseling. Findings of small case-control or cross-sectional studies suggest that telomere attrition is associated with adverse pregnancy outcomes among women undergoing fertility treatment, but prospective studies in non-clinical populations are lacking. STUDY DESIGN, SIZE, DURATION: Participants included 1228 women aged 18-40 years with a history of 1-2 prior pregnancy losses who were recruited at four university medical centers (2006-2012). PARTICIPANTS/MATERIALS, SETTING, METHODS: Preconception leukocyte telomere length was measured at baseline using PCR and reported as a ratio (T/S) in relation to population-specific standard reference DNA. Women were followed for up to six cycles while attempting to conceive. Associations of telomere length with fecundability, live birth and pregnancy loss were estimated using discrete Cox proportional hazards models and log-binomial models. MAIN RESULTS AND THE ROLE OF CHANCE: After adjustment for age, BMI, smoking and other factors, preconception telomere length was not associated with fecundability (Q4 vs Q1 FOR = 1.00; 95% CI = 0.79, 1.27), live birth (Q4 vs Q1 RR = 1.00; 95% CI = 0.85, 1.19), or pregnancy loss (Q4 vs Q1 RR = 1.12; 95% CI = 0.78, 1.62). LIMITATIONS, REASONS FOR CAUTION: Telomere length was measured in leukocytes, which is an accessible tissue in women attempting natural conception but may not reflect telomere length in oocytes. Most women were younger than 35 years, limiting our ability to evaluate associations among older women. Participants had a history of 1-2 prior pregnancy losses; therefore, our findings may not be widely generalizable. WIDER IMPLICATIONS OF THE FINDINGS: Despite prior research suggesting that telomere length may be associated with pregnancy outcomes among women seeking fertility treatment, our findings suggest that leukocyte telomere length is not a suitable biomarker of pregnancy establishment or maintenance among women attempting natural conception. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (National Institutes of Health, Bethesda, MD, USA; contract numbers HHSN267200603423, HHSN267200603424 and HHSN267200603426). The authors have no conflicts of interest to disclose. TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov, number NCT00467363.

The role of maternal preconception vitamin D status in human offspring sex ratio.

Evolutionary theory suggests that some animal species may experience shifts in their offspring sex ratio in response to maternal health and environmental conditions, and in some unfavorable conditions, females may be less likely to bear sons. Experimental data in both animals and humans indicate that maternal inflammation may disproportionately impact the viability of male conceptuses; however, it is unknown whether other factors associated with both pregnancy and inflammation, such as vitamin D status, are associated with the offspring sex ratio. Here, we show that among 1,228 women attempting pregnancy, preconception 25-hydroxyvitamin D concentrations are positively associated with the live birth of a male infant, with notably stronger associations among women with elevated high sensitivity C-reactive protein, a marker of systemic low-grade inflammation. Our findings suggest that vitamin D may mitigate maternal inflammation that would otherwise be detrimental to the implantation or survival of male conceptuses in utero.

Associations between blood cadmium and endocrine features related to PCOS-phenotypes in healthy women of reproductive age: a prospective cohort study.

BACKGROUND: Cadmium is an endocrine disrupting chemical that affects the hypothalamic-pituitary-gonadal axis. Though evidence suggests its potential role in altering androgen synthesis and metabolic pathways that are characteristic of polycystic ovary syndrome (PCOS), its relation in healthy women of reproductive age is largely unknown. As women with mild sub-clinical features of PCOS who do not meet the diagnostic criteria of PCOS may still experience reduced fecundability, investigating associations between cadmium and PCOS-phenotypes among healthy women may provide unique insight into the reproductive implications for many on the PCOS spectrum. Therefore, the objective of this study was to evaluate associations between cadmium and androgens, anti-Müllerian hormone (AMH), and metabolic markers in women of reproductive age. METHODS: This was a prospective cohort study of 251 healthy premenopausal women without self-reported PCOS (mean age 27.3 years and BMI 24.1 kg/m2). Cadmium was measured in blood collected at baseline. Reproductive hormones and metabolic markers were measured in fasting serum 8 times per menstrual cycle for 2 cycles. Linear mixed models and Poisson regression with a robust error variance were used to examine associations between cadmium and reproductive hormones and metabolic markers and anovulation, respectively. RESULTS: Median (interquartile range) blood cadmium concentrations at baseline were 0.30 (0.19-0.43) µg/L. Higher levels of testosterone (2.2 %, 95 % confidence interval [CI] 0.4, 4.1), sex hormone-binding globulin (2.9 %, 95 % CI 0.5, 5.5), and AMH (7.7 %, 95 % CI 1.1, 14.9) were observed per 0.1 µg/L increase in cadmium concentrations. An 18 % higher probability of a mild PCOS-phenotype (95 % CI 1.06, 1.31), defined by a menstrual cycle being in the highest quartile of cycle-averaged testosterone and AMH levels, was also found per 0.1 µg/L increase in cadmium levels. No associations were observed for insulin and glucose. These findings were consistent even after analyses were restricted to non-smokers or further adjusted for dietary factors to account for potential sources of exposure. CONCLUSIONS: Overall, among healthy reproductive-aged women, cadmium was associated with endocrine features central to PCOS, but not with metabolic markers. These suggest its potential role in the hormonal milieu associated with PCOS even at low levels of exposure.

Low Intake of Vegetable Protein is Associated With Altered Ovulatory Function Among Healthy Women of Reproductive Age.

CONTEXT: Diets high in plant-based protein have gained popularity due to increasing health concerns regarding consumption of animal products. Though links between intakes of certain protein-rich foods and reproductive disorders have been suggested, the relationship of overall animal and vegetable proteins with reproductive hormones among reproductive-aged women is unknown. OBJECTIVE: To evaluate the associations between the intake of dietary protein with reproductive hormones and sporadic anovulation among reproductive-aged women. DESIGN: A prospective cohort study, 2005-2007. SETTING: University at Buffalo, western New York, United States. PARTICIPANTS: A total of 259 premenopausal women (18-44 years) without dietary restrictions. MAIN OUTCOME MEASURE(S): Serum reproductive hormones were determined up to 8 times per cycle for 2 cycles. Protein intake was assessed the day prior to hormone assessment at 4 visits/cycle using 24-hour recalls. RESULTS: Overall, 84% of participants met the recommended dietary allowance for total protein set for reproductive-aged women. Neither total nor animal protein intake were associated with reproductive hormones or anovulation. However, vegetable protein intake in the lowest tertile was associated with lower luteal phase progesterone (-18.0%, 95% confidence interval [CI] -30.2, -3.6), higher follicle-stimulating hormone (3.8%, 95% CI 0.2, 7.6), and a higher risk of anovulation (risk ratio [RR] 2.53, 95% CI 1.21, 5.26), compared with the middle tertile. Nuts and seeds were the only protein-rich foods associated with an elevated risk of anovulation (RR 2.12, 95% CI 1.17, 3.85). CONCLUSIONS: Findings suggest that among women who meet the recommended dietary allowance for total protein, low intake of vegetable, but not animal, protein may disturb normal ovulatory function.

The Effect of Preconception-Initiated Low-Dose Aspirin on Human Chorionic Gonadotropin-Detected Pregnancy, Pregnancy Loss, and Live Birth : Per Protocol Analysis of a Randomized Trial.

BACKGROUND: A previous large randomized trial indicated that preconception-initiated low-dose aspirin (LDA) therapy did not have a positive effect on pregnancy outcomes. However, this trial was subject to nonadherence, which was not taken into account by the intention-to-treat approach. OBJECTIVE: To estimate per protocol effects of preconception-initiated LDA on pregnancy loss and live birth. DESIGN: The EAGeR (Effects of Aspirin on Gestation and Reproduction) trial was used to construct a prospective cohort for a post hoc analysis. (ClinicalTrials.gov: NCT00467363). SETTING: 4 university medical centers in the United States. PARTICIPANTS: 1227 women between the ages of 18 and 40 years who had 1 or 2 previous pregnancy losses and were attempting pregnancy. MEASUREMENTS: Adherence to LDA or placebo, assessed by measuring pill bottle weights at regular intervals during follow-up. Primary outcomes were human chorionic gonadotropin (hCG)-detected pregnancies, pregnancy losses, and live births, determined by pregnancy tests and medical records. RESULTS: Relative to placebo, adhering to LDA for 5 of 7 days per week led to 8 more hCG-detected pregnancies (95% CI, 4.64 to 10.96 pregnancies), 15 more live births (CI, 7.65 to 21.15 births), and 6 fewer pregnancy losses (CI, -12.00 to -0.20 losses) for every 100 women in the trial. In addition, compared with placebo, postconception initiation of LDA therapy led to a reduction in the estimated effects. Furthermore, effects were obtained in a minimum of 4 of 7 days per week. LIMITATION: The EAGeR trial data for this study were analyzed as observational data, thus are subject to the limitations of prospective observational studies. CONCLUSION: Per protocol results suggest that preconception use of LDA at least 4 days per week may improve reproductive outcomes for women who have had 1 or 2 pregnancy losses. Increasing adherence to daily LDA seems to be key to improving effectiveness. PRIMARY FUNDING SOURCE: National Institutes of Health.

Adiposity is associated with anovulation independent of serum free testosterone: A prospective cohort study.

BACKGROUND: Obesity, a body mass index (BMI) ≥30 kg/m2 , is linked to infertility, potentially through a greater risk of anovulation due to elevated androgens. Yet, previous studies have not directly assessed the impact of adiposity, or body fat, on anovulation in the absence of clinical infertility. OBJECTIVE: To characterise the associations between adiposity and anovulation among women menstruating on a regular basis. METHODS: Women from the EAGeR trial (n = 1200), a randomised controlled trial of low-dose aspirin and pregnancy loss among women trying to conceive, were used to estimate associations between adiposity and incident anovulation. Participants completed baseline questionnaires and anthropometry, and provided blood specimens. Women used fertility monitors for up to six consecutive menstrual cycles, with collection of daily first morning voids for hormone analysis in the first two menstrual cycles for prospective assessment of anovulation. Anovulation was assessed by urine pregnanediol glucuronide or luteinising hormone concentration or the fertility monitor. Weighted mixed-effects log-binomial regression was used to estimate associations between measures of adiposity and incident anovulation, adjusted for free (bioavailable) testosterone, anti-Mullerian hormone (AMH), serum lipids, and demographic and life style factors. RESULTS: 343 (28.3%) women experienced at least one anovulatory cycle. Anovulation risk was higher per kg/m2 greater BMI (relative risk [RR] 1.03, 95% confidence interval (CI) 1.01, 1.04), cm waist circumference (RR 1.01, 95% CI 1.00, 1.02), mm subscapular skinfold (RR 1.02, 95% CI 1.01, 1.03), and mm middle upper arm circumference (RR 1.04, 95% CI 1.01, 1.06) adjusted for serum free testosterone, AMH, lipids, and other factors. CONCLUSIONS: Adiposity may be associated with anovulation through pathways other than testosterone among regularly menstruating women. This may account in part for reported associations between greater adiposity and infertility among women having menstrual cycles regularly. Understanding the association between adiposity and anovulation might lead to targeted interventions for preventing infertility.

Sporadic anovulation is not an important determinant of becoming pregnant and time to pregnancy among eumenorrheic women: A simulation study.

BACKGROUND: Attaining pregnancy is conditional upon a series of complex processes, including adequately timed intercourse, ovulation, fertilisation, and implantation. Anovulation is a first-line treatment target for couples with difficulty conceiving and is frequently examined in studies of fecundability. OBJECTIVES: To identify whether sporadic anovulation is an important determinant of cumulative pregnancy rates and time to pregnancy among fertile women with regular menstrual cycles. METHODS: We simulated cumulative pregnancy rates and time to pregnancy for 12 consecutive menstrual cycles among 100 000 women based on data-driven probabilities of implantation, fertilisation, ovulation, and intercourse occurring in the fertile window. We assumed anovulation probabilities of 1%, 8%, or 14.5% and intercourse averaging once per week, every other day, or daily. The model incorporated reductions in implantation and fertilisation rates for successive cycles of non-pregnancy. RESULTS: After 12 cycles, a reduction in the per cycle incidence of anovulation from 14.5% to 1% resulted in a 4.0% higher cumulative pregnancy rate (86.7% vs 90.7%) and similar time to pregnancy (1-cycle median difference). In contrast, increasing mean unscheduled sexual intercourse frequency from weekly to every other day was associated with a 5-cycle median reduction in time to pregnancy (weekly: 7 cycles; every other day or daily: 2 cycles) and a 28.9% increase in the cumulative pregnancy rate (weekly: 59.9%, every other day: 88.8%; daily: 91.6%). CONCLUSIONS: In presumed fertile women with regular menstrual cycles, routine investigation of anovulation may not be an informative outcome in studies of fecundability, and routine testing to ensure ovulation and treatment of anovulation are unlikely to be medically necessary. While biomarkers or cervical fluid may help time intercourse to the fertile window, time to pregnancy can also be improved through increasing the frequency of unscheduled intercourse. These findings need corroboration in large preconception time to pregnancy studies.

Circulating Vascular Endothelial Growth Factor and Soluble fms-Like Tyrosine Kinase-1 as Biomarkers for Endometrial Remodeling Across the Menstrual Cycle.

OBJECTIVE: To characterize variation in circulating vascular endothelial growth factor (VEGF) and its receptor, soluble fms-like tyrosine kinase-1 (sFLT-1), across the menstrual cycle in normal ovulating women in relation to reproductive hormones to identify the utility of VEGF and sFLT-1 as peripheral biomarkers of endometrial remodeling. METHODS: Ninety-six healthy, regularly menstruating ovulatory women, aged 18-44 years, enrolled in the BioCycle Study, a prospective cohort study at a U.S. academic research center. Vascular endothelial growth factor and sFLT-1 were measured in concurrently collected plasma, serum, and urine up to eight times across a single cycle. Reproductive hormones were measured in serum. Mean concentrations of VEGF and sFLT-1 were compared across phases of the cycle, and correlations between specimen types were calculated. Harmonic models estimated associations between VEGF and sFLT-1 and characteristics of hormonal patterns. RESULTS: No variation in VEGF or sFLT-1 levels were detected over the menstrual cycle. Median (25th percentile, 75th percentile) concentrations of VEGF during the menstrual cycle were 31.2 pg/mL (24.1, 56.9) in plasma, 194.1 pg/mL (125.4, 350.2) in serum, and 101.7 pg/mL (64.2, 165.8) in urine. Plasma and serum measures were consistently correlated, whereas urinary measures were not. Vascular endothelial growth factor was not consistently associated with reproductive hormone concentrations, although sFLT-1 was associated with higher mean and amplitude of estradiol. CONCLUSION: Circulating VEGF and sFLT-1 did not vary across the menstrual cycle and therefore are unlikely to be useful peripheral biomarkers of endometrial changes across the menstrual cycle. For studies measuring circulating VEGF for other reasons, plasma may be the preferred medium and timing to menstrual cycle phase need not be considered for reproductive-age women.

Is opioid use safe in women trying to conceive?

Background: Opioids are commonly prescribed to women of reproductive age, including after delivery and miscarriage. However, to our knowledge, opioid use has not been frequently studied in relation to the common reproductive complications of impaired fecundability and pregnancy. We examined the association of opioid use during the critical window of pregnancy establishment with fecundability and pregnancy loss. Methods: We measured opioid use by urine screening and self-report at multiple time points during preconception and early pregnancy in a prospective cohort of women attempting conception (n=1228). The main outcomes included time to hCG-detected pregnancy and incidence of live birth and pregnancy loss. We estimated fecundability odds ratios (FOR) and risk ratios (RR) with 95% confidence intervals (CI) adjusting for sociodemographic characteristics, reproductive characteristics, and use of antidepressants, tobacco, alcohol, and marijuana. Results: Prevalence of preconception opioid use was 18% (n=226 of 1228), and in early pregnancy was 5% (n=33 of 685). Opioid use while attempting pregnancy was associated with reduced fecundability (FOR: 0.71; 95% CI: 0.50, 1.0). Risk of pregnancy loss increased as opioid exposure was detected later in gestation, from the beginning of the cycle of conception (RR: 1.5; 95% CI 0.85, 2.6), to week 4 of pregnancy (RR: 2.1; 95% CI: 1.1, 4.1), and to week 4 and 8 of pregnancy (RR: 2.5; 95% CI: 1.3, 5.0). Conclusions: Our results are consistent with the hypothesis that opioid exposure while trying to conceive may be harmful, even among healthy, non-opioid-dependent women. Possible risks to fecundability and pregnancy viability are relevant to patients and providers when evaluating pain management approaches.ClinicalTrials.gov registration number: #NCT00467363.

Urinary selective serotonin reuptake inhibitors across critical windows of pregnancy establishment: a prospective cohort study of fecundability and pregnancy loss.

OBJECTIVE: To prospectively investigate the association of selective serotonin reuptake inhibitor (SSRI) exposure through critical windows of pregnancy establishment with fecundability and pregnancy loss. DESIGN: Prospective cohort study using longitudinal urine measurements of common SSRIs while women are actively trying to conceive. SETTING: Four clinical sites. PATIENT(S): A total of 1,228 women without uncontrolled depression/anxiety, attempting natural conception while participating in a randomized trial of preconception-initiated low-dose aspirin. INTERVENTIONS(S): Not applicable. MAIN OUTCOME MEASURE(S): Urinary SSRIs (fluoxetine, sertraline, escitalopram/citalopram) were measured while trying to conceive and, for women who became pregnant, at weeks 0, 4, and 8 of pregnancy. Fecundability odds ratios and incidence of pregnancy loss and live birth were estimated. RESULT(S): A total of 172 women (14%) were exposed to SSRIs while trying to conceive. SSRI exposure was associated with 24% reduced fecundability, and accordingly, a nonsignificant 9% lower live birth incidence, with significantly lower live birth in fluoxetine-exposed women. SSRI exposure was not associated with subsequent pregnancy loss, whether exposure was before conception or at 0, 4, or 8 weeks of gestation, although estimates varied by specific SSRI drug. CONCLUSION(S): Women using SSRIs may have more difficulty becoming pregnant, and although SSRI exposure overall was not associated with pregnancy loss, fluoxetine deserves caution and future study. CLINICAL TRIAL REGISTRATION NUMBER: NCT00467363.

Prescription Opioid Use Among Populations of Reproductive Age: Effects on Fertility, Pregnancy Loss, and Pregnancy Complications.

Prescription opioid use is common among men and women of reproductive age, including during assisted-reproduction procedures. Opioid use disorder and chronic use are associated with harms to fertility and pregnancy outcomes, but it is unclear whether these associations extend to common short-term patterns of prescription opioid use. We conducted a literature review using PubMed, Embase, Web of Science, and Scopus to identify studies of nonchronic, nondependent opioid use and reproductive endpoints including fertility, pregnancy loss, and pregnancy complications (i.e., preterm birth, birth weight, gestational diabetes, and hypertensive disorders of pregnancy). Seventeen studies were included. Although results of the studies suggest possible harms of short-term opioid use on fertility and pregnancy loss, methodologic limitations and the small number of studies make the literature inconclusive. This review highlights important data gaps that must be addressed to make conclusions about potential reproductive effects of short-term opioid use. These include the need for additional data on opioid use before clinically recognized pregnancy; accurate measurement of opioid exposure by multiple means with detailed information on the types and quantity of opioids used; assessment of important confounders, including opioid use indication, comorbidities, and use of other medications and substances; and studies of paternal opioid use, fertility, and pregnancy outcomes. A primary limitation of this review targeting studies of nonchronic opioid exposure is the possibility that selected studies included populations with unspecified chronic or dependent opioid use. Efforts to understand the impact of the prescription opioid epidemic should address potential reproductive harms of these medications among people of reproductive age.