Characterization of an Acinetobacter baumannii Monofunctional Phosphomethylpyrimidine Kinase That Is Inhibited by Pyridoxal Phosphate.

Thiamin and its phosphate derivatives are ubiquitous molecules involved as essential cofactors in many cellular processes. The de novo biosynthesis of thiamin employs the parallel synthesis of 4-methyl-5-(2-hydroxyethyl)thiazole (THZ-P) and 4-amino-2-methyl-5(diphosphooxymethyl) pyrimidine (HMP) pyrophosphate (HMP-PP), which are coupled to generate thiamin phosphate. Most organisms that can biosynthesize thiamin employ a kinase (HMPK or ThiD) to generate HMP-PP. In nearly all cases, this enzyme is bifunctional and can also salvage free HMP, producing HMP-P, the monophosphate precursor of HMP-PP. Here we present high-resolution crystal structures of an HMPK from Acinetobacter baumannii (AbHMPK), both unliganded and with pyridoxal 5-phosphate (PLP) noncovalently bound. Despite the similarity between HMPK and pyridoxal kinase enzymes, our kinetics analysis indicates that AbHMPK accepts HMP exclusively as a substrate and cannot turn over pyridoxal, pyridoxamine, or pyridoxine nor does it display phosphatase activity. PLP does, however, act as a weak inhibitor of AbHMPK with an IC50 of 768 µM. Surprisingly, unlike other HMPKs, AbHMPK catalyzes only the phosphorylation of HMP and does not generate the diphosphate HMP-PP. This suggests that an additional kinase is present in A. baumannii, or an alternative mechanism is in operation to complete the biosynthesis of thiamin.

Glycemic Load, Dietary Fiber, Added Sugar, and Spontaneous Abortion in Two Preconception Cohorts.

BACKGROUND: Spontaneous abortion (SAB)-pregnancy loss before the 20th week of gestation-has adverse psychological and physical sequelae. Some medical conditions known to affect insulin sensitivity, including polycystic ovary syndrome and diabetes, can affect the risk of SAB. No prior studies have examined glycemic load and incidence of SAB in populations without conditions known to affect insulin sensitivity. OBJECTIVES: We prospectively evaluated the association between preconception glycemic load and intake of carbohydrates, dietary fiber, and added sugar and risk of SAB. METHODS: During 2013-2020, we recruited pregnancy planners from Denmark (SnartForaeldre.dk; SF) and the United States and Canada (Pregnancy Study Online; PRESTO). Participants completed a baseline questionnaire and a cohort-specific FFQ evaluated for validity. We estimated preconception glycemic load and intake of carbohydrates, dietary fiber, and added sugar from individual foods and mixed recipes. We included 2238 SF and 4246 PRESTO participants who reported a pregnancy during the course of the study. SAB data were derived from questionnaires and population registries. We used Cox proportional hazards regression to estimate HRs and 95% CIs. RESULTS: In the study population, 15% of SF participants and 22% of PRESTO participants experienced SAB. Across both cohorts, there was no appreciable association between glycemic load, carbohydrate quality, dietary fiber, or added sugar intake and SAB. Compared with daily mean glycemic load <110, the HR for women with daily mean glycemic load ≥130 was 0.76 (95% CI: 0.52, 1.10) in SF and 1.01 (95% CI: 0.86, 1.19) in PRESTO. CONCLUSIONS: Diets with high glycemic load, carbohydrates, and added sugars were not consistently associated with risk of SAB in parallel analyses of 2 preconception cohort studies of women in North America and Denmark.

Dietary patterns and fecundability in 2 prospective preconception cohorts.

BACKGROUND: Diet is increasingly recognized as an important determinant of human fertility, with most research focused on specific nutrients or food groups. However, there has been limited assessment of the effect of dietary patterns on fertility. OBJECTIVES: We evaluated the association between 4 dietary patterns [the alternative Mediterranean Diet (aMed), the Healthy Eating Index-2010 (HEI-2010), the Danish Dietary Guidelines (DDGI), and the Dietary Inflammatory Index (DII)] and fecundability in 2 preconception cohorts of couples trying to conceive: SF (SnartForaeldre.dk) in Denmark and PRESTO (Pregnancy Study Online) in North America. METHODS: Participants completed a baseline questionnaire on sociodemographic, anthropometric, and lifestyle factors and, 10 d later, a validated cohort-specific FFQ. We used data from these respective FFQs to calculate adherence to each dietary pattern. Participants completed bimonthly follow-up questionnaires for ≤12 mo or until pregnancy, whichever came first. We restricted analyses to 3429 SF and 5803 PRESTO participants attempting pregnancy for ≤6 cycles at enrollment. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs, adjusting for potential confounders. RESULTS: Greater DII, indicative of a less anti-inflammatory diet (i.e., poorer diet quality), was associated with reduced fecundability in both SF and PRESTO (DII ≥ -1.5 compared with < -3.3: FR: 0.83; 95% CI: 0.71, 0.97 and FR: 0.82; 95% CI: 0.73, 0.93, respectively). In PRESTO, greater adherence to the aMed or to the HEI-2010 was associated with greater fecundability. In SF, there was no appreciable association between the aMed and fecundability, whereas greater adherence to the DDGI was associated with greater fecundability. CONCLUSIONS: In prospective preconception cohort studies from Denmark and North America, higher-quality diets, including diets lower in inflammatory effects, were associated with greater fecundability.

Adherence to Nordic dietary patterns and risk of first-trimester spontaneous abortion.

PURPOSE: Evidence on the influence of modifiable risk factors on spontaneous abortion (SAB) is scarce. We investigated associations for adherence to national dietary guidelines and a healthy Nordic diet with first-trimester (≤ 12 weeks' gestation) SAB in a Danish cohort of couples trying to conceive. METHODS: Participants completed a questionnaire on sociodemographics, lifestyle and reproductive history and a validated food frequency questionnaire (FFQ). We ascertained pregnancies from follow-up questionnaires and restricted analyses to 3,043 women who became pregnant. We assessed adherence to the Danish Dietary Guidelines Index (DDGI, range of 0-6, from low to high), covering intake of fruit, vegetables, fish, red and processed meat, whole grains, saturated fat and added sugar. The Healthy Nordic Food Index (HNFI, range 0-6) covered intake of fish, cabbage, rye bread, apples, pears, root vegetables and oatmeal. Pregnancy outcomes were identified through Danish medical registries or self-reported. We used Cox proportional hazards regression to compute hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for sociodemographics and lifestyle. RESULTS: Fifteen percent of participants had a first-trimester SAB. Compared with a DDGI score < 3, adjusted HRs (95% CIs) for scores 3 to < 4, 4 to < 5 and ≥ 5 were 0.85 (0.59-1.23), 0.78 (0.54-1.12) and 0.71 (0.44-1.13), respectively. Compared with an HNFI score < 2, adjusted HRs (95% CIs) for scores 2 to < 3, 3 to < 4, 4 to < 5 and ≥ 5 were 0.84 (0.62-1.15), 0.88 (0.66-1.19), 0.94 (0.69-1.28) and 0.69 (0.49-0.96), respectively. CONCLUSION: Greater pre-pregnancy adherence to Danish dietary guidelines or a healthy Nordic diet was associated with a lower rate of first-trimester SAB, although estimates were imprecise.

A prospective study of preconception asthma and spontaneous abortion.

PURPOSE: To evaluate the relationships among history of asthma, asthma severity, and spontaneous abortion (SAB). METHODS: Pregnancy Study Online is a preconception cohort study of North American couples. During the preconception period, female participants reported their history of physician-diagnosed asthma, age at first diagnosis, and use of asthma medications in the previous 4 weeks. Asthma severity was classified by medication use proximal to conception, from level 0 to 3 in increasing severity. Pregnancy and SAB were identified using data from follow-up questionnaires. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Among 6325 participants who conceived, 19% experienced SAB and 17% reported a history of asthma. There was no appreciable association between asthma history and SAB incidence (HR = 0.98; 95% CI: 0.84, 1.14). HRs comparing severity levels 0, 1, and 2-3 with no asthma were 0.82 (95% CI: 0.67, 1.01), 1.20 (95% CI: 0.91, 1.60), and 1.31 (95% CI: 0.97, 1.78), respectively. Among women who conceived without the use of fertility treatment, level 2-3 severity was associated with SAB (HR = 1.39; 95% CI: 1.02, 1.89). CONCLUSIONS: While history of asthma diagnosis was not materially associated with SAB, having severe asthma (based on medication use) was associated with greater SAB risk.

Protein-rich food intake and risk of spontaneous abortion: a prospective cohort study.

PURPOSE: Diet quality is increasingly recognized as important for human reproductive capacity. We studied the association between intake of protein-rich foods and risk of spontaneous abortion (SAB). METHODS: During 2013-2020, we recruited pregnancy planners from the United States and Canada (Pregnancy Study Online; PRESTO) and Denmark (SnartForaeldre.dk; SF). Participants completed a baseline questionnaire and a validated cohort-specific food frequency questionnaire. We estimated preconception intake of red meat, poultry, processed meat, seafood, eggs, plant-based proteins, and dairy from individual foods and mixed recipes. We included 4,246 PRESTO and 2,953 SF participants who reported a pregnancy during the study. Data on SAB were derived from questionnaires and population registries. We used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CI), representing the effect of substituting one type of protein-rich food for another. RESULTS: SAB risk was 23% in PRESTO and 16% in SF. In PRESTO, substitution of seafood with other protein-rich foods was associated with higher SAB risk [for example, the HR for replacing 100 g of seafood/week with 100 g of red meat was 1.10 (95% CI 1.00, 1.20)]. In contrast, in SF, substituting seafood with other protein-rich foods was associated with lower SAB risk [HR for replacing 100 g of seafood/week with 100 g of red meat was 0.89 (95% CI 0.82, 0.98)]. Other protein-rich food substitutions were not meaningfully associated with SAB risk. CONCLUSIONS: Preconception intake of protein-rich foods was largely unrelated to SAB risk, with the exception of seafood, which was associated with higher risk of SAB in Denmark, but a lower risk in North America.

A Prospective Cohort Study of COVID-19 Vaccination, SARS-CoV-2 Infection, and Fertility.

Some reproductive-aged individuals remain unvaccinated against coronavirus disease 2019 (COVID-19) because of concerns about potential adverse effects on fertility. Using data from an internet-based preconception cohort study, we examined the associations of COVID-19 vaccination and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with fertility among couples trying to conceive spontaneously. We enrolled 2,126 self-identified female participants aged 21-45 year residing in the United States or Canada during December 2020-September 2021 and followed them through November 2021. Participants completed questionnaires every 8 weeks on sociodemographics, lifestyle, medical factors, and partner information. We fit proportional probabilities regression models to estimate associations between self-reported COVID-19 vaccination and SARS-CoV-2 infection in both partners with fecundability (i.e., the per-cycle probability of conception), adjusting for potential confounders. COVID-19 vaccination was not appreciably associated with fecundability in either partner (female fecundability ratio (FR) = 1.08, 95% confidence interval (CI): 0.95, 1.23; male FR = 0.95, 95% CI: 0.83, 1.10). Female SARS-CoV-2 infection was not strongly associated with fecundability (FR = 1.07, 95% CI: 0.87, 1.31). Male infection was associated with a transient reduction in fecundability (for infection within 60 days, FR = 0.82, 95% CI: 0.47, 1.45; for infection after 60 days, FR = 1.16, 95% CI: 0.92, 1.47). These findings indicate that male SARS-CoV-2 infection may be associated with a short-term decline in fertility and that COVID-19 vaccination does not impair fertility in either partner.

Dietary folate intake and fecundability in two preconception cohorts.

STUDY QUESTION: To what extent is dietary folate intake and total folate intake (dietary and supplemental intakes) associated with fecundability, the per cycle probability of conception? SUMMARY ANSWER: Preconception dietary folate intake was positively associated with fecundability in a monotonic pattern. WHAT IS KNOWN ALREADY: Supplemental folic acid has been associated with improved fertility, but little is known about the relation between dietary folate and fecundability. STUDY DESIGN, SIZE, DURATION: A prospective cohort study including 9559 women trying to conceive without fertility treatment and enrolled in the period 2013-2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: We used data from two internet-based prospective cohort studies of pregnancy planners from Denmark, where folic acid fortification is not performed (SnartForældre.dk (SF); n = 3755) and North America, where the food supply is fortified with folic acid (Pregnancy Study Online (PRESTO); n = 5804). Women contributed menstrual cycles at risk until they reported conception or experienced a censoring event. We used proportional probabilities regression models to compute fecundability ratios (FRs) and 95% CI, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: Compared with a dietary folate intake ≥400 µg/day, the adjusted FRs for women in SF were 0.92 (95% CI: 0.85-0.99) for intake 250-399 µg/day, and 0.80 (95% CI: 0.68-0.94) for intake of <250 µg/day. The corresponding FRs in PRESTO were 0.95 (95% CI: 0.89-1.01) and 0.81 (95% CI: 0.65-1.00). Compared with the highest level of total folate intake (diet folate ≥400 µg/day plus folic acid supplementation), in both cohorts fecundability was lowest among women with the lowest dietary intake <250 µg/day dietary folate and no supplementation (FR: 0.76, 95% CI: 0.59-0.98 [SF] and 0.49, 95% CI: 0.31-0.77 [PRESTO]). Further, total intake dietary folate <250 µg/day plus supplementation was associated with reduced fecundability for SF participants (FR; 0.79, 95% CI: 0.65-0.98) and for PRESTO participants (FR; 0.92, 95% CI: 0.72-1.16). LIMITATIONS, REASONS FOR CAUTION: It is unknown whether dietary folate and folic acid intake affect fecundability on its own or if there is an interaction with other micronutrients provided in healthy diet. Thus, the observed associations may not reflect dietary folate intake alone, but overall healthy diet. WIDER IMPLICATIONS OF THE FINDINGS: Recommendations for preconception dietary folate intake and folic acid supplementation are of importance not only to prevent neural tube defects but also to enhance fecundability. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by the National Institute of Child Health and Human Development (R01-HD086742). The authors report no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Female dietary patterns and outcomes of in vitro fertilization (IVF): a systematic literature review.

BACKGROUND: Infertility affects up to 15% of couples. In vitro fertilization (IVF) treatment has modest success rates and some factors associated with infertility and poor treatment outcomes are not modifiable. Several studies have assessed the association between female dietary patterns, a modifiable factor, and IVF outcomes with conflicting results. We performed a systematic literature review to identify female dietary patterns associated with IVF outcomes, evaluate the body of evidence for potential sources of heterogeneity and methodological challenges, and offer suggestions to minimize heterogeneity and bias in future studies. METHODS: We performed systematic literature searches in EMBASE, PubMed, CINAHL, and Cochrane Central Register of Controlled Trials for studies with a publication date up to March 2020. We excluded studies limited to women who were overweight or diagnosed with PCOS. We included studies that evaluated the outcome of pregnancy or live birth. We conducted an initial bias assessment using the SIGN 50 Methodology Checklist 3. RESULTS: We reviewed 3280 titles and/or titles and abstracts. Seven prospective cohort studies investigating nine dietary patterns fit the inclusion criteria. Higher adherence to the Mediterranean diet, a 'profertility' diet, or a Dutch 'preconception' diet was associated with pregnancy or live birth after IVF treatment in at least one study. However, causation cannot be assumed. Studies were potentially hindered by methodological challenges (misclassification of the exposure, left truncation, and lack of comprehensive control for confounding) with an associated risk of bias. Studies of the Mediterranean diet were highly heterogenous in findings, study population, and methods. Remaining dietary patterns have only been examined in single and relatively small studies. CONCLUSIONS: Future studies with rigorous and more uniform methodologies are needed to assess the association between female dietary patterns and IVF outcomes. At the clinical level, findings from this review do not support recommending any single dietary pattern for the purpose of improving pregnancy or live birth rates in women undergoing IVF treatment.

Predictive models of pregnancy based on data from a preconception cohort study.

STUDY QUESTION: Can we derive adequate models to predict the probability of conception among couples actively trying to conceive? SUMMARY ANSWER: Leveraging data collected from female participants in a North American preconception cohort study, we developed models to predict pregnancy with performance of ∼70% in the area under the receiver operating characteristic curve (AUC). WHAT IS KNOWN ALREADY: Earlier work has focused primarily on identifying individual risk factors for infertility. Several predictive models have been developed in subfertile populations, with relatively low discrimination (AUC: 59-64%). STUDY DESIGN, SIZE, DURATION: Study participants were female, aged 21-45 years, residents of the USA or Canada, not using fertility treatment, and actively trying to conceive at enrollment (2013-2019). Participants completed a baseline questionnaire at enrollment and follow-up questionnaires every 2 months for up to 12 months or until conception. We used data from 4133 participants with no more than one menstrual cycle of pregnancy attempt at study entry. PARTICIPANTS/MATERIALS, SETTING, METHODS: On the baseline questionnaire, participants reported data on sociodemographic factors, lifestyle and behavioral factors, diet quality, medical history and selected male partner characteristics. A total of 163 predictors were considered in this study. We implemented regularized logistic regression, support vector machines, neural networks and gradient boosted decision trees to derive models predicting the probability of pregnancy: (i) within fewer than 12 menstrual cycles of pregnancy attempt time (Model I), and (ii) within 6 menstrual cycles of pregnancy attempt time (Model II). Cox models were used to predict the probability of pregnancy within each menstrual cycle for up to 12 cycles of follow-up (Model III). We assessed model performance using the AUC and the weighted-F1 score for Models I and II, and the concordance index for Model III. MAIN RESULTS AND THE ROLE OF CHANCE: Model I and II AUCs were 70% and 66%, respectively, in parsimonious models, and the concordance index for Model III was 63%. The predictors that were positively associated with pregnancy in all models were: having previously breastfed an infant and using multivitamins or folic acid supplements. The predictors that were inversely associated with pregnancy in all models were: female age, female BMI and history of infertility. Among nulligravid women with no history of infertility, the most important predictors were: female age, female BMI, male BMI, use of a fertility app, attempt time at study entry and perceived stress. LIMITATIONS, REASONS FOR CAUTION: Reliance on self-reported predictor data could have introduced misclassification, which would likely be non-differential with respect to the pregnancy outcome given the prospective design. In addition, we cannot be certain that all relevant predictor variables were considered. Finally, though we validated the models using split-sample replication techniques, we did not conduct an external validation study. WIDER IMPLICATIONS OF THE FINDINGS: Given a wide range of predictor data, machine learning algorithms can be leveraged to analyze epidemiologic data and predict the probability of conception with discrimination that exceeds earlier work. STUDY FUNDING/COMPETING INTEREST(S): The research was partially supported by the U.S. National Science Foundation (under grants DMS-1664644, CNS-1645681 and IIS-1914792) and the National Institutes for Health (under grants R01 GM135930 and UL54 TR004130). In the last 3 years, L.A.W. has received in-kind donations for primary data collection in PRESTO from FertilityFriend.com, Kindara.com, Sandstone Diagnostics and Swiss Precision Diagnostics. L.A.W. also serves as a fibroid consultant to AbbVie, Inc. The other authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Characterizing Differences in Thymic Function in Women With and Without Vulvodynia: A Community-Based Study.

OBJECTIVE: The aim of the study was to evaluate the association between vulvodynia and thymic function. MATERIALS AND METHODS: In this case-control study of 200 clinically confirmed cases of vulvodynia and 205 general population controls residing in the Minneapolis/Saint Paul metropolitan area, we used DNA extracted from whole blood to measure levels of signal joint T-cell receptor excision circles (sjTRECs), a measure of thymic output. We used logistic regression to evaluate the association between vulvodynia and thymic function. RESULTS: In 405 participants (aged 18-40 years), we observed an association between decreasing thymic function and increasing age. Women with vulvodynia had a steeper decline in sjTREC values across age categories compared with women without vulvodynia. In addition, at younger ages, women with vulvodynia had higher sjTREC values compared with women without vulvodynia. In older women, those with vulvodynia had lower sjTREC than those without vulvodynia. When accounting for recency of vulvar pain onset, women with a shorter time since pain onset had higher thymic function compared with women with a longer time since vulvar pain onset. CONCLUSIONS: These findings suggest that at younger ages, women with vulvodynia have higher thymic output and a more precipitous decline of thymic function than those without vulvodynia. It also seems that a strong immune inflammatory response is present proximate to the onset of vulvar pain and may wane subsequently over time.

Identifying barriers to accessing skilled maternal health care in rural Morocco.

Over the past 30 years, the Moroccan government has made enormous strides towards improving maternal health care for Moroccan women, but outcomes for rural women remain much worse than those of their urban counterparts. This study aimed to understand the experiences of women giving birth in rural Morocco, and to identify the barriers they face when accessing facility-based maternity care. Fifty-five participants were recruited from villages in Morocco's rural south to participate in focus group discussions (FGDs), using appreciative inquiry as the guiding framework. Several themes emerged from the analysis of the focus group data. Women felt well-cared for and safe giving birth both at home and in the large, tertiary care hospitals, but not in the small, primary care hospitals. Women who gave birth at the primary care hospitals reported a shortage of some equipment and supplies and poor treatment at the hands of hospital staff. Locating and paying for transportation was identified as the biggest hurdle in accessing maternity care at any hospital. The findings of this study indicate the need for change within primary care health facilities.

Accuracy of self-reported birth outcomes relative to birth certificate data in an Internet-based prospective cohort study.

BACKGROUND: The accuracy of birth outcome data provided by Internet-based cohort study participants has not been well studied. METHODS: We compared self-reported data on birth characteristics in Pregnancy Study Online (PRESTO), an Internet-based prospective cohort study of North American pregnancy planners, with birth certificate data. At enrolment, participants were aged 21-45 years, attempting conception, and not using fertility treatment. Women completed online questionnaires during preconception, early and late pregnancy, and postpartum. We requested birth certificate data during 2014-2019 from seven health departments in states with the most participants. After restricting to singleton births, we assessed specificity, sensitivity, and agreement comparing self-reported data from postpartum questionnaires with birth certificate data for gestational age at delivery (GA) and birthweight (grams). Our primary measure of self-reported GA (weeks) was calculated as [280-(due date-birth date)]/7. We used log-binomial regression to assess predictors of agreement. RESULTS: We linked 85% (771/909) of women in selected states. Median age of women was 30 years (range: 21-42), 84% had ≥ 16 years of education, nearly 96% were married, 12% had household incomes <$50 000, 32% were parous, and 85% identified as non-Hispanic White. Median recall interval was 6 months. Among those with self-reported data, 89% reported the same GA as the birth certificate and 98% reported GA within 1 week of the birth certificate. Self-report of preterm birth (GA < 37 weeks) agreed with information from birth certificates for 100% of women; sensitivity was 100%, and specificity was 99%. Self-reported low birthweight (<2500 grams) agreed with birth certificates for 93% of women; sensitivity and specificity were 93% and ≥99%, respectively. Predictors of poorer agreement included higher parity and longer pregnancy attempt time for GA, and lower education and longer recall interval for birthweight. CONCLUSION: Self-reported data on GA and birthweight from an Internet-based cohort showed high accuracy compared with birth certificates.

Maternal age at birth and daughter's fecundability.

STUDY QUESTION: Do daughters of older mothers have lower fecundability? SUMMARY ANSWER: In this cohort study of North American pregnancy planners, there was virtually no association between maternal age ≥35 years and daughters' fecundability. WHAT IS KNOWN ALREADY: Despite suggestive evidence that daughters of older mothers may have lower fertility, only three retrospective studies have examined the association between maternal age and daughter's fecundability. STUDY DESIGN, SIZE, DURATION: Prospective cohort study of 6689 pregnancy planners enrolled between March 2016 and January 2020. PARTICIPANTS/MATERIALS, SETTING, METHODS: Pregnancy Study Online (PRESTO) is an ongoing pre-conception cohort study of pregnancy planners (age, 21-45 years) from the USA and Canada. We estimated fecundability ratios (FR) for maternal age at the participant's birth using multivariable proportional probabilities regression models. MAIN RESULTS AND THE ROLE OF CHANCE: Daughters of mothers ≥30 years were less likely to have previous pregnancies (or pregnancy attempts) or risk factors for infertility, although they were more likely to report that their mother had experienced problems conceiving. The proportion of participants with prior unplanned pregnancies, a birth before age 21, ≥3 cycles of attempt at study entry or no follow-up was greater among daughters of mothers <25 years. Compared with maternal age 25-29 years, FRs (95% CI) for maternal age <20, 20-24, 30-34, and ≥35 were 0.72 (0.61, 0.84), 0.92 (0.85, 1.00), 1.08 (1.00, 1.17), and 1.00 (0.89, 1.12), respectively. LIMITATIONS, REASONS FOR CAUTION: Although the examined covariates did not meaningfully affect the associations, we had limited information on the participants' mother. Differences by maternal age in reproductive history, infertility risk factors and loss to follow-up suggest that selection bias may partly explain our results. WIDER IMPLICATIONS OF THE FINDINGS: Our finding that maternal age 35 years or older was not associated with daughter's fecundability is reassuring, considering the trend towards delayed childbirth. However, having been born to a young mother may be a marker of low fecundability among pregnancy planners. STUDY FUNDING/COMPETING INTEREST(S): PRESTO was funded by NICHD Grants (R21-HD072326 and R01-HD086742) and has received in-kind donations from Swiss Precision Diagnostics, FertilityFriend.com, Kindara.com, and Sandstone Diagnostics. Dr Wise is a fibroid consultant for AbbVie, Inc. TRIAL REGISTRATION NUMBER: n/a.

Bystander Prevention for Sexual Violence: #HowIWillChange and Gaps in Twitter Discourse.

Twitter has rapidly gained popularity as a space for the public to discuss sexual violence (SV) prevention due to a number of high-profile SV cases. This study aimed to examine Twitter discourse on SV prevention through the hashtag #HowIWillChange, which encouraged Twitter users to come forward and report plans to engage in bystander prevention. We analyzed 1,493 #HowIWillChange tweets from October 2017 through a directed content analysis approach rooted in an evidence-based framework for the continuum of bystander intervention. We assessed emergent themes around how Twitter users discuss SV to identify gaps and misinformation in public Twitter discourse. Although Twitter users discussed a range of prevention strategies, misinformation was also spread, including perpetuation of the myth that only strangers commit rape, that only male children need lessons on consent, and that SV prevention vilifies men. These results can inform health promotion programs aiming to educate the public on bystander prevention.

Post-partum interval and time to pregnancy in a prospective preconception cohort.

BACKGROUND: Little is known about the influence of the post-partum interval-defined as the time between giving birth and attempting to conceive again-on subsequent fecundability. OBJECTIVES: We evaluated the association between the post-partum interval and fecundability in Pregnancy Study Online (PRESTO), a web-based prospective preconception cohort of pregnancy planners from the United States and Canada. METHODS: Eligible women were aged 21-45 years, attempting pregnancy, and not using fertility treatment. Women completed a baseline questionnaire to ascertain information on demographics, life style factors, and reproductive history, including detailed information on all previous pregnancies. They completed bi-monthly follow-up questionnaires for up to 12 months to update pregnancy status over time. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% confidence intervals (CIs) adjusted for sociodemographic and reproductive history covariates. Analyses were restricted to multiparous women who had been attempting pregnancy with the same male partner for ≤6 menstrual cycles at enrolment. RESULTS: During 2013-2019, 1489 female participants contributed 959 pregnancies and 5003 cycles. The median post-partum interval was 18 months. Compared with a 12- to 23-month post-partum interval, FRs for post-partum intervals of <12, 24-47, and ≥48 months were 0.89 (95% CI 0.77, 1.04), 1.06 (95% CI 0.91, 1.23), and 0.81 (95% CI 0.62, 1.05), respectively. When restricting to women without a history of subfertility, results were consistent for long post-partum interval and attenuated for short post-partum interval. CONCLUSIONS: Among North American pregnancy planners, long post-partum intervals (≥48 months) were associated with slightly reduced fecundability. Short post-partum intervals (<12 months) were weakly associated with reduced fecundability in some subgroups including women with a history of caesarean delivery and planned pregnancies.

Fecundability in relation to use of mobile computing apps to track the menstrual cycle.

STUDY QUESTION: To what extent does the use of mobile computing apps to track the menstrual cycle and the fertile window influence fecundability among women trying to conceive? SUMMARY ANSWER: After adjusting for potential confounders, use of any of several different apps was associated with increased fecundability ranging from 12% to 20% per cycle of attempt. WHAT IS KNOWN ALREADY: Many women are using mobile computing apps to track their menstrual cycle and the fertile window, including while trying to conceive. STUDY DESIGN, SIZE, DURATION: The Pregnancy Study Online (PRESTO) is a North American prospective internet-based cohort of women who are aged 21-45 years, trying to conceive and not using contraception or fertility treatment at baseline. PARTICIPANTS/MATERIALS, SETTING, METHODS: We restricted the analysis to 8363 women trying to conceive for no more than 6 months at baseline; the women were recruited from June 2013 through May 2019. Women completed questionnaires at baseline and every 2 months for up to 1 year. The main outcome was fecundability, i.e. the per-cycle probability of conception, which we assessed using self-reported data on time to pregnancy (confirmed by positive home pregnancy test) in menstrual cycles. On the baseline and follow-up questionnaires, women reported whether they used mobile computing apps to track their menstrual cycles ('cycle apps') and, if so, which one(s). We estimated fecundability ratios (FRs) for the use of cycle apps, adjusted for female age, race/ethnicity, prior pregnancy, BMI, income, current smoking, education, partner education, caffeine intake, use of hormonal contraceptives as the last method of contraception, hours of sleep per night, cycle regularity, use of prenatal supplements, marital status, intercourse frequency and history of subfertility. We also examined the impact of concurrent use of fertility indicators: basal body temperature, cervical fluid, cervix position and/or urine LH. MAIN RESULTS AND THE ROLE OF CHANCE: Among 8363 women, 6077 (72.7%) were using one or more cycle apps at baseline. A total of 122 separate apps were reported by women. We designated five of these apps before analysis as more likely to be effective (Clue, Fertility Friend, Glow, Kindara, Ovia; hereafter referred to as 'selected apps'). The use of any app at baseline was associated with 20% increased fecundability, with little difference between selected apps versus other apps (selected apps FR (95% CI): 1.20 (1.13, 1.28); all other apps 1.21 (1.13, 1.30)). In time-varying analyses, cycle app use was associated with 12-15% increased fecundability (selected apps FR (95% CI): 1.12 (1.04, 1.21); all other apps 1.15 (1.07, 1.24)). When apps were used at baseline with one or more fertility indicators, there was higher fecundability than without fertility indicators (selected apps with indicators FR (95% CI): 1.23 (1.14, 1.34) versus without indicators 1.17 (1.05, 1.30); other apps with indicators 1.30 (1.19, 1.43) versus without indicators 1.16 (1.06, 1.27)). In time-varying analyses, results were similar when stratified by time trying at study entry (<3 vs. 3-6 cycles) or cycle regularity. For use of the selected apps, we observed higher fecundability among women with a history of subfertility: FR 1.33 (1.05-1.67). LIMITATIONS, REASONS FOR CAUTION: Neither regularity nor intensity of app use was ascertained. The prospective time-varying assessment of app use was based on questionnaires completed every 2 months, which would not capture more frequent changes. Intercourse frequency was also reported retrospectively and we do not have data on timing of intercourse relative to the fertile window. Although we controlled for a wide range of covariates, we cannot exclude the possibility of residual confounding (e.g. choosing to use an app in this observational study may be a marker for unmeasured health habits promoting fecundability). Half of the women in the study received a free premium subscription for one of the apps (Fertility Friend), which may have increased the overall prevalence of app use in the time-varying analyses, but would not affect app use at baseline. Most women in the study were college educated, which may limit application of results to other populations. WIDER IMPLICATIONS OF THE FINDINGS: Use of a cycle app, especially in combination with observation of one or more fertility indicators (basal body temperature, cervical fluid, cervix position and/or urine LH), may increase fecundability (per-cycle pregnancy probability) by about 12-20% for couples trying to conceive. We did not find consistent evidence of improved fecundability resulting from use of one specific app over another. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by grants, R21HD072326 and R01HD086742, from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, USA. In the last 3 years, Dr L.A.W. has served as a fibroid consultant for AbbVie.com. Dr L.A.W. has also received in-kind donations from Sandstone Diagnostics, Swiss Precision Diagnostics, FertilityFriend.com and Kindara.com for primary data collection and participant incentives in the PRESTO cohort. Dr J.B.S. reports personal fees from Swiss Precision Diagnostics, outside the submitted work. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: N/A.

The Association between Seafood Intake and Fecundability: Analysis from Two Prospective Studies.

BACKGROUND: Seafood is an important source of omega-3 fatty acids, which have been associated with improved oocyte quality and embryo morphology in some studies. However, seafood is also a source of persistent organic pollutants and heavy metals, which may adversely affect fecundity. Previous studies of seafood intake and fecundity have generated inconsistent results. METHODS: In two prospective cohort studies of 7836 female pregnancy planners from Denmark (Snart Foraeldre, n = 2709) and North America (PRESTO, n = 5127), we evaluated the association of dietary intake of total seafood and marine-sourced long-chain omega-3 fatty acids (eicosapentaenoic acid, docosahexaenoic acid, and docosapentaenoic acid) with fecundability. Participants completed a baseline questionnaire on sociodemographics, behavioral factors, anthropometrics, and medical history, and a food frequency questionnaire. Pregnancy status was updated bimonthly for up to 12 months or until reported conception. We estimated fecundability ratios (FRs) and 95% confidence intervals (CIs) using proportional probabilities regression models, adjusted for energy intake and other potential confounders. We restricted analyses to women with ≤6 menstrual cycles of attempt time at enrollment. RESULTS: Intake of total seafood or marine-sourced long-chain omega-3 fatty acids was not appreciably associated with fecundability in either cohort (≥200 vs. <50 g/week total seafood: FR = 0.94, 95% CI: 0.79-1.10 in Snart Foraeldre; FR = 1.00, 95% CI: 0.90-1.13 in PRESTO; marine fatty acids: ≥90th vs. <25th percentile: FR = 1.00, 95% CI: 0.85-1.18 in Snart Foraeldre; FR = 0.97, 95% CI: 0.86-1.09 in PRESTO). In PRESTO, where we collected additional data on seafood preparation, we observed an inverse association between fecundability and fried shellfish (≥10 g/week vs. none: FR = 0.77, 95% CI: 0.61-0.98), but not unfried shellfish (≥20 g/week vs. none: FR = 0.98, 95% CI: 0.89-1.07); in Snart Foraeldre, there was no association with total shellfish intake. CONCLUSIONS: We found little association between seafood intake and fecundability overall, but greater intake of fried shellfish was associated with reduced fecundability among North American participants.

Peri-implantation intercourse does not lower fecundability.

STUDY QUESTION: Does sexual intercourse in the implantation time window (5-9 days after ovulation) reduce fecundability? SUMMARY ANSWER: After adjustment for intercourse in the fecund window and clustering by couple, there was no association between intercourse in the implantation time window and fecundity. WHAT IS KNOWN ALREADY: Previous research has suggested an association between intercourse in the peri-implantation time window (5-9 days after estimated ovulation) and reduced fecundability. STUDY DESIGN, SIZE, DURATION: We used data from the FERTILI study, a prospective observational study conducted in five European countries, with data collected from 1992 to 1996. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women who were experienced in fertility awareness tracking kept a daily diary of cervical mucus observations, basal body temperature measurements, coitus and clinically identified pregnancy. We estimated the day of ovulation as cycle length minus 13 days. From 661 women, 2606 cycles had intercourse during the fecund window (from 5 days before to 3 days after the estimated day of ovulation), resulting in 418 pregnancies (conception cycles). An established Bayesian fecundability model was used to estimate the fecundability ratio (FR) of peri-implantation intercourse on fecundability, while adjusting for each partner's age, prior pregnancy, the couple's probability of conception and intercourse pattern(s). We conducted sensitivity analyses estimating ovulation as cycle length minus 12 days, or alternatively, as the peak day of estrogenic cervical mucus. MAIN RESULTS AND THE ROLE OF CHANCE: There was no effect of peri-implantation intercourse on fecundability: adjusted FR for three or more acts of peri-implantation intercourse versus none: 1.00, 95% credible interval: 0.76-1.13. Results were essentially the same with sensitivity analyses. There was an inverse relationship between frequency of intercourse in the fecund window and intercourse in the peri-implantation window. LIMITATIONS, REASONS FOR CAUTION: Women with known subfertility were excluded from this study. Many couples in the study were avoiding pregnancy during much of the study, so 61% of otherwise eligible cycles in the database were not at meaningful risk of pregnancy and did not contribute to the analysis. Some couples may not have recorded all intercourse. WIDER IMPLICATIONS OF THE FINDINGS: We believe the current balance of evidence does not support a recommendation for avoiding intercourse in the peri-implantation period among couples trying to conceive. STUDY FUNDING/COMPETING INTEREST(S): No external funding. The authors have no potential competing interests. TRIAL REGISTRATION NUMBER: N/A.

A prospective study of influenza vaccination and time to pregnancy.

BACKGROUND: Although pregnancy planners are a priority group for influenza vaccination in the United States, little is known about the extent to which influenza vaccination affects fecundability. METHODS: We analyzed data from Pregnancy Study Online (PRESTO), an ongoing preconception cohort study of North American pregnancy planners. During June 2013 to August 2019, 8654 female participants and 2137 of their male partners completed a baseline questionnaire and were followed until reported pregnancy, fertility treatment initiation, loss to follow-up, or 12 menstrual cycles of attempt time, whichever came first. At baseline, male and female participants reported whether they received an influenza vaccination in the past year and the date of vaccination. We used proportional probabilities regression models to estimate fecundability ratios (FR) and 95% confidence intervals (CI) comparing those who did and did not report influenza vaccination, adjusting for demographics, anthropometrics, behavioral factors, and medical history. RESULTS: Influenza vaccination in the past year was more common among female participants than male participants (47% vs. 37%). FRs were 1.04 (95% CI: 0.98-1.10) for female vaccination and 1.03 (95% CI: 0.93-1.14) for male vaccination. Among the 2137 couples with complete data on both partners, for 40% neither partner was vaccinated, 23% had female-only vaccination, 9% had male-only vaccination, and in 28% both partners were vaccinated. Compared with couples in which neither participant was vaccinated, FRs were 1.13 for female-only vaccination (95% CI: 0.99-1.29), 0.94 for male-only vaccination (95% CI: 0.78-1.12), and 1.07 when both partners were vaccinated (95% CI: 0.94-1.21). When restricted to recent vaccination before peak influenza season, results were similar. CONCLUSIONS: Our data indicate no adverse effect of influenza vaccination on fecundability.