History of multifetal gestation and long-term maternal mortality.

BACKGROUND: Multifetal gestation could be associated with higher long-term maternal mortality because it increases the risk of pregnancy complications such as preeclampsia and preterm birth, which are in turn linked to postpartum cardiovascular risk. OBJECTIVES: We examined whether spontaneously conceived multifetal versus singleton gestation was associated with long-term maternal mortality in a racially diverse U.S. METHODS: We ascertained vital status as of 2016 via linkage to the National Death Index and Social Security Death Master File of 44,174 mothers from the Collaborative Perinatal Project (CPP; 1959-1966). Cox proportional hazards models with maternal age as the time scale assessed associations between history of spontaneous multifetal gestation (in the last CPP observed pregnancy or prior pregnancy) and all-cause and cardiovascular mortality, adjusted for demographics, smoking status, and preexisting medical conditions. We calculated hazard ratios (HR) for all-cause and cause-specific mortality over the study period and until age 50, 60, and 70 years (premature mortality). RESULTS: Of eligible participants, 1672 (3.8%) had a history of multifetal gestation. Participants with versus without a history of multifetal gestation were older, more likely to have a preexisting condition, and more likely to smoke. By 2016, 51% of participants with and 38% of participants without a history of multifetal gestation had died (unadjusted all-cause HR 1.14, 95% confidence interval [CI] 1.07, 1.23). After adjustment for smoking and preexisting conditions, a history of multifetal gestation was not associated with all-cause (adjusted HR 1.00, 95% CI 0.93, 1.08) or cardiovascular mortality (adjusted HR 0.99, 95% CI 0.87, 1.11) over the study period. However, history of multifetal gestation was associated with an 11% lower risk of premature all-cause mortality (adjusted HR 0.89, 95% CI 0.82, 0.96). CONCLUSIONS: In a cohort with over 50 years of follow-up, history of multifetal gestation was not associated with all-cause mortality, but may be associated with a lower risk of premature mortality.

Maternal educational attainment in pregnancy and epigenome-wide DNA methylation changes in the offspring from birth until adolescence.

Maternal educational attainment (MEA) shapes offspring health through multiple potential pathways. Differential DNA methylation may provide a mechanistic understanding of these long-term associations. We aimed to quantify the associations of MEA with offspring DNA methylation levels at birth, in childhood and in adolescence. Using 37 studies from high-income countries, we performed meta-analysis of epigenome-wide association studies (EWAS) to quantify the associations of completed years of MEA at the time of pregnancy with offspring DNA methylation levels at birth (n = 9 881), in childhood (n = 2 017), and adolescence (n = 2 740), adjusting for relevant covariates. MEA was found to be associated with DNA methylation at 473 cytosine-phosphate-guanine sites at birth, one in childhood, and four in adolescence. We observed enrichment for findings from previous EWAS on maternal folate, vitamin-B12 concentrations, maternal smoking, and pre-pregnancy BMI. The associations were directionally consistent with MEA being inversely associated with behaviours including smoking and BMI. Our findings form a bridge between socio-economic factors and biology and highlight potential pathways underlying effects of maternal education. The results broaden our understanding of bio-social associations linked to differential DNA methylation in multiple early stages of life. The data generated also offers an important resource to help a more precise understanding of the social determinants of health.

Gestational weight change in a diverse pregnancy cohort and mortality over 50 years: a prospective observational cohort study.

BACKGROUND: High weight gain in pregnancy is associated with greater postpartum weight retention, yet long-term implications remain unknown. We aimed to assess whether gestational weight change was associated with mortality more than 50 years later. METHODS: The Collaborative Perinatal Project (CPP) was a prospective US pregnancy cohort (1959-65). The CPP Mortality Linkage Study linked CPP participants to the National Death Index and Social Security Death Master File for vital status to 2016. Adjusted hazard ratios (HRs) with 95% CIs estimated associations between gestational weight gain and loss according to the 2009 National Academy of Medicine recommendations and mortality by pre-pregnancy BMI. The primary endpoint was all-cause mortality. Secondary endpoints included cardiovascular and diabetes underlying causes of mortality. FINDINGS: Among 46 042 participants, 20 839 (45·3%) self-identified as Black and 21 287 (46·2%) as White. Median follow-up time was 52 years (IQR 45-54) and 17 901 (38·9%) participants died. For those who were underweight before pregnancy (BMI <18·5 kg/m2; 3809 [9·4%] of 40 689 before imputation for missing data]), weight change above recommendations was associated with increased cardiovascular mortality (HR 1·84 [95% CI 1·08-3·12]) but not all-cause mortality (1·14 [0·86-1·51]) or diabetes-related mortality (0·90 [0·13-6·35]). For those with a normal pre-pregnancy weight (BMI 18·5-24·9 kg/m2; 27 921 [68·6%]), weight change above recommendations was associated with increased all-cause (HR 1·09 [1·01-1·18]) and cardiovascular (1·20 [1·04-1·37]) mortality, but not diabetes-related mortality (0·95 [0·61-1·47]). For those who were overweight pre-pregnancy (BMI 25·0-29·9 kg/m2; 6251 [15·4%]), weight change above recommendations was associated with elevated all-cause (1·12 [1·01-1·24]) and diabetes-related (1·77 [1·23-2·54]) mortality, but not cardiovascular (1·12 [0·94-1·33]) mortality. For those with pre-pregnancy obesity (≥30·0 kg/m2; 2708 [6·7%]), all associations between gestational weight change and mortality had wide CIs and no meaningful relationships could be drawn. Weight change below recommended levels was associated only with a reduced diabetes-related mortality (0·62 [0·48-0·79]) in people with normal pre-pregnancy weight. INTERPRETATION: This study's novel findings support the importance of achieving healthy gestational weight gain within recommendations, adding that the implications might extend beyond the pregnancy window to long-term health, including cardiovascular and diabetes-related mortality. FUNDING: National Institutes of Health.

Pregnancy Complications and Long-Term Mortality in a Diverse Cohort.

BACKGROUND: Pregnancy complications are associated with increased risk of development of cardiometabolic diseases and earlier mortality. However, much of the previous research has been limited to White pregnant participants. We aimed to investigate pregnancy complications in association with total and cause-specific mortality in a racially diverse cohort and evaluate whether associations differ between Black and White pregnant participants. METHODS: The Collaborative Perinatal Project was a prospective cohort study of 48 197 pregnant participants at 12 US clinical centers (1959-1966). The Collaborative Perinatal Project Mortality Linkage Study ascertained participants' vital status through 2016 with linkage to the National Death Index and Social Security Death Master File. Adjusted hazard ratios (aHRs) for underlying all-cause and cause-specific mortality were estimated for preterm delivery (PTD), hypertensive disorders of pregnancy, and gestational diabetes/impaired glucose tolerance (GDM/IGT) using Cox models adjusted for age, prepregnancy body mass index, smoking, race and ethnicity, previous pregnancies, marital status, income, education, previous medical conditions, site, and year. RESULTS: Among 46 551 participants, 45% (21 107 of 46 551) were Black, and 46% (21 502 of 46 551) were White. The median time between the index pregnancy and death/censoring was 52 years (interquartile range, 45-54). Mortality was higher among Black (8714 of 21 107 [41%]) compared with White (8019 of 21 502 [37%]) participants. Overall, 15% (6753 of 43 969) of participants had PTD, 5% (2155 of 45 897) had hypertensive disorders of pregnancy, and 1% (540 of 45 890) had GDM/IGT. PTD incidence was higher in Black (4145 of 20 288 [20%]) compared with White (1941 of 19 963 [10%]) participants. The following were associated with all-cause mortality: preterm spontaneous labor (aHR, 1.07 [95% CI, 1.03-1.1]); preterm premature rupture of membranes (aHR, 1.23 [1.05-1.44]); preterm induced labor (aHR, 1.31 [1.03-1.66]); preterm prelabor cesarean delivery (aHR, 2.09 [1.75-2.48]) compared with full-term delivery; gestational hypertension (aHR, 1.09 [0.97-1.22]); preeclampsia or eclampsia (aHR, 1.14 [0.99-1.32]) and superimposed preeclampsia or eclampsia (aHR, 1.32 [1.20-1.46]) compared with normotensive; and GDM/IGT (aHR, 1.14 [1.00-1.30]) compared with normoglycemic. P values for effect modification between Black and White participants for PTD, hypertensive disorders of pregnancy, and GDM/IGT were 0.009, 0.05, and 0.92, respectively. Preterm induced labor was associated with greater mortality risk among Black (aHR, 1.64 [1.10-2.46]) compared with White (aHR, 1.29 [0.97-1.73]) participants, while preterm prelabor cesarean delivery was higher in White (aHR, 2.34 [1.90-2.90]) compared with Black (aHR, 1.40 [1.00-1.96]) participants. CONCLUSIONS: In this large, diverse US cohort, pregnancy complications were associated with higher mortality nearly 50 years later. Higher incidence of some complications in Black individuals and differential associations with mortality risk suggest that disparities in pregnancy health may have life-long implications for earlier mortality.

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.

A SART data cost-effectiveness analysis of planned oocyte cryopreservation versus in vitro fertilization with preimplantation genetic testing for aneuploidy considering ideal family size.

OBJECTIVE: To determine the cost-effectiveness of planned oocyte cryopreservation (OC) as a strategy for delayed childbearing to achieve 1 or 2 live births (LB) compared with in vitro fertilization (IVF) and preimplantation genetic testing for aneuploidy (PGT-A) at advanced reproductive age. DESIGN: Decision tree model with sensitivity analyses using data from the Society for Assisted Reproductive Technology Clinical Outcome Reporting System and other clinical sources. SETTING: Not applicable. PATIENT(S): A data-driven simulated cohort of patients desiring delayed childbearing with an ideal family size of 1 or 2 LB. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Probability of achieving ≥1 or 2 LB, average and maximum cost per patient, cost per percentage point increase in chance of LB, and population-level cost/LB. RESULT(S): For those desiring 1 LB, planned OC at age 33 with warming at age 43 decreased the average total cost per patient from $62,308 to $30,333 and increased the likelihood of LB from 50% to 73% when compared with no OC with up to 3 cycles of IVF/PGT-A at age 43. For those desiring 2 LB, 2 cycles of OC at age 33 and warming at age 40 yielded the lowest cost per patient and highest likelihood of achieving 2 LB ($51,250 and 77%, respectively) when compared withpursuing only 1 cycle of OC ($75,373 and 61%, respectively), no OC and IVF/PGT-A with embryo banking ($79,728 and 48%, respectively), or no OC and IVF/PGT-A without embryo banking ($79,057 and 19%, respectively). Sensitivity analyses showed that OC remained cost-effective across a wide range of ages at cryopreservation. For 1 LB, OC achieved the highest likelihood of success when pursued before age 32 and remained more effective than IVF/PGT-A when pursued before age 39, and for 2 LB, 2 cycles of OC achieved the highest likelihood of success when pursued before age 31 and remained more effective than IVF/PGT-A when pursued before age 39. CONCLUSION(S): Among patients planning to postpone childbearing, OC is cost-effective and increases the odds of achieving 1 or 2 LB when compared with IVF/PGT-A at a more advanced reproductive age.

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.

Assessment of Caffeine Consumption and Maternal Cardiometabolic Pregnancy Complications.

Importance: Women are recommended to limit caffeine consumption to less than 200 mg per day based on risks to fetal health. Impacts of caffeine on maternal health remain unclear. Objective: To determine whether caffeinated-beverage intake and plasma caffeine and paraxanthine are associated with cardiometabolic complications in pregnancy (ie, gestational diabetes [GDM], preeclampsia, and gestational hypertension [GH]). Design, Setting, and Participants: This cohort study used data from a longitudinal pregnancy cohort study from the National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies-Singletons (2009-2013). This post hoc secondary analysis of 2802 pregnant women without major chronic conditions enrolled at 12 US clinical sites was completed in 2021. The final sample for caffeinated beverage analyses included 2583 women. After excluding women who did not consent to have their biospecimens stored for future research (n = 54), plasma caffeine analyses included 2529 women. Analyses of caffeine consumption and fasting cardiometabolic profiles included 319 women. Exposures: Daily total caffeine intake was estimated at 10 to 13 gestational weeks and 16 to 22 gestational weeks based on self-reported past week intake of caffeinated coffee, tea, soda, and energy drinks. Plasma caffeine and paraxanthine were measured in specimens collected at 10 to 13 weeks. Main Outcomes and Measures: Clinical diagnoses of GDM, preeclampsia, GH, glucose concentrations from GDM screening, and blood pressure were extracted from medical records. Results: Participants had a mean (SD) age of 28.1 (5.5) years and 422 participants (16.3%) were Asian/Pacific Islander women, 741 (28.9%) were Hispanic women, 717 (27.8%) were non-Hispanic Black women, and 703 (27.2%) were non-Hispanic White women. At 10 to 13 weeks, 1073 women (41.5%) reported consuming no caffeinated beverages, 1317 (51.0%) reported consuming 1 mg/d to 100 mg/d, 173 (6.7%) reported consuming 101 mg/d to 200 mg/d, and 20 (0.8%) reported consuming more than 200 mg/d. At 16 to 22 weeks, 599 women (23.6%) reported consuming no caffeinated beverages, 1734 (68.3%) reported consuming 1 mg/d to 100 mg/d, 186 (7.3%) reported consuming 101 mg/d to 200 mg/d, and 20 (0.8%) reported consuming more than 200 mg/d caffeinated beverages. Intake at 16 to 22 weeks was associated with lower GDM risk and lower glucose concentrations (1 mg/d to 100 mg/d vs none: relative risk, 0.53 [95% CI, 0.35 to 0.80]; ß, -2.7 mg/dL [95% CI, -5.4 mg/dL to 0 mg/dL]) and lower C-reactive protein and C-peptide concentrations and favorable lipid profiles. Total plasma caffeine and paraxanthine at 10 to 13 weeks was inversely associated with glucose (quartile 4 vs quartile 1: ß = -3.8 mg/dL [95% CI, -7.0 mg/dL to -0.5 mg/dL]; trend of P = .01). No associations were observed with preeclampsia or GH. Conclusions and Relevance: In this cohort study, second trimester caffeinated beverage intake within current recommendations was associated with lower GDM risk, but not preeclampsia or GH. These findings may be reassuring for women with moderate caffeine intake.

Vital Status Ascertainment for a Historic Diverse Cohort of U.S. Women.

BACKGROUND: Studies linking large pregnancy cohorts with mortality data can address critical questions about long-term implications of gravid health, yet relevant US data are scant. We examined the feasibility of linking the Collaborative Perinatal Project, a large multiracial U.S. cohort study of pregnant women (n = 48,197; 1959-1966), to death records. METHODS: We abstracted essential National Death Index (NDI) (1979-2016) (n = 46,428). We performed a linkage to the Social Security Administration Death Master File through 2016 (n = 46,450). Genealogists manually searched vital status in 2016 for a random sample of women (n = 1,249). We conducted agreement analyses for women with abstracted data among the three sources. As proof of concept, we calculated adjusted associations between mortality and smoking and other sociodemographic factors using Cox proportional hazards regression. RESULTS: We successfully abstracted identifying information for most of the cohort (97%). National Death Index identified the greatest proportion of participants deceased (35%), followed by genealogists (31%) and Death Master File (23%). Estimates of agreement (κ [95% confidence interval]) between National Death Index and Death Master File were lower (0.52 [0.51, 0.53]) than for National Death Index and genealogist (0.66 [0.61, 0.70]). As expected, compared with nonsmokers, smoking ≥1 pack per day was associated with elevated mortality for all vital sources and was strongest for National Death Index. CONCLUSIONS: Linking this historic cohort with mortality records was feasible and agreed reasonably on vital status when compared with other data sources. Such linkage enables future examination of pregnancy conditions in relation to mortality in a diverse U.S. cohort.

Length of Fellowship Training in Population Health Research and Long-term Bibliometric Outcomes.

BACKGROUND: The length of research fellowships, the number of doctorates pursuing them, and the academic job market have changed dramatically in recent years. However, there is limited investigation on attributes of fellowships most relevant to future scientific achievement. We analyzed the association of a modifiable aspect of research training, fellowship length, with future achievement and differences across research discipline in the Division of Intramural Population Health Research (DIPHR), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. METHODS: Demographics of 88 DIPHR trainees from 1998 to 2016 were collected from publicly available annual reports. Research performance metrics, including total publication count and H index through 2016, were collected via Scopus. We used linear regression models for associations between fellowship length, including both total exposure to research training and duration of postdoctoral training alone, and research performance adjusted for start year, publications at entry, branch (e.g., Biostatistics and Bioinformatics, Epidemiology, and Health Behavior), and mentor seniority. RESULTS: Each additional year of research training in DIPHR was associated with a 15% increase in H index (95% confidence interval [CI] = 3.0, 28.4) and 21% more lifetime publications (95% CI = 3.0, 41.9). Results were similar, although attenuated, when evaluating postdoctoral training alone. Differences by discipline were observed, with the strongest positive associations in the Biostatistics and Bioinformatics and Epidemiology Branches. CONCLUSIONS: Longer training at DIPHR was associated with improved measures of research performance, though this relationship varied by discipline. Additional research is needed to tailor training programs to optimize success of trainees.

The Preconception Period analysis of Risks and Exposures Influencing health and Development (PrePARED) consortium.

BACKGROUND: Preconception health may have intergenerational influences. We have formed the PrePARED (Preconception Period Analysis of Risks and Exposures influencing health and Development) research consortium to address methodological, conceptual, and generalisability gaps in the literature. OBJECTIVES: The consortium will investigate the effects of preconception exposures on four sets of outcomes: (1) fertility and miscarriage; (2) pregnancy-related conditions; (3) perinatal and child health; and (4) adult health outcomes. POPULATION: A study is eligible if it has data measured for at least one preconception time point, has a minimum of selected core data, and is open to collaboration and data harmonisation. DESIGN: The included studies are a mix of studies following women or couples intending to conceive, general-health cohorts that cover the reproductive years, and pregnancy/child cohort studies that have been linked with preconception data. The majority of the participating studies are prospective cohorts, but a few are clinical trials or record linkages. METHODS: Data analysis will begin with harmonisation of data collected across cohorts. Initial areas of interest include nutrition and obesity; tobacco, marijuana, and other substance use; and cardiovascular risk factors. PRELIMINARY RESULTS: Twenty-three cohorts with data on almost 200 000 women have combined to form this consortium, begun in 2018. Twelve studies are of women or couples actively planning pregnancy, and six are general-population cohorts that cover the reproductive years; the remainder have some other design. The primary focus for four was cardiovascular health, eight was fertility, one was environmental exposures, three was child health, and the remainder general women's health. Among other cohorts assessed for inclusion, the most common reason for ineligibility was lack of prospectively collected preconception data. CONCLUSIONS: The consortium will serve as a resource for research in many subject areas related to preconception health, with implications for science, practice, and policy.

Effect of preconception low dose aspirin on pregnancy and live birth according to socioeconomic status: A secondary analysis of a randomized clinical trial.

Low socioeconomic status (SES) is associated with adverse pregnancy outcomes and infertility. Low-dose aspirin (LDA) was shown to improve livebirth rates in certain subsets of women, and therefore, may impact pregnancy rates differentially by SES status. Therefore, the aim of the current study was to examine whether daily preconception-initiated LDA affects rates of pregnancy, livebirth, and pregnancy loss differently across strata of socioeconomic status (SES). This is a secondary analysis of The Effects of Aspirin in Gestation and Reproduction (EAGeR) Trial, a multisite, block- randomized, placebo-controlled trial conducted at four U.S. medical centers (n = 1,228, 2007-2012). Women attempting spontaneous conception with a history of pregnancy loss were randomly allocated preconception to 81mg of aspirin + 400mcg of folic acid (n = 615) or placebo + 400mcg of folic acid (n = 613). Study medication was administered for six menstrual cycles or until 36 weeks' gestation if pregnancy was achieved. For this analysis, women were stratified by SES, which included income (low, mid, high) and a combined grouping of education and income (low-low, low-high, high-low, high-high). Log binomial models with robust variance estimated risks of pregnancy, livebirth, and pregnancy loss for LDA versus placebo. LDA increased pregnancy and livebirth rates (RR 1.23, 95% CI: 1.03, 1.45) in the high-income, but not mid- or low-income groups. LDA increased pregnancy rates in both the low education-low income group (RR 1.22, 95% CI: 1.02, 1.46) and the high education-high income group (RR 1.23, 95%CI: 1.06, 1.42), with no effect observed in mid-SES groupings. LDA, a low-cost and widely available treatment, may be particularly beneficial to women at the highest and lowest ends of the socioeconomic spectrum, though underlying mechanisms of this disparity are unclear. Confirming these findings and identifying factors which may modulate the effectiveness of LDA will ultimately facilitate personalized clinical care and improvements in population-level reproductive health. Trial registration number: ClinicalTrials.gov, NCT00467363.

Good practices for the design, analysis, and interpretation of observational studies on birth spacing and perinatal health outcomes.

BACKGROUND: Meta-analyses of observational studies have shown that women with a shorter interpregnancy interval (the time from delivery to start of a subsequent pregnancy) are more likely to experience adverse pregnancy outcomes, such as preterm delivery or small for gestational age birth, than women who space their births further apart. However, the studies used to inform these estimates have methodological shortcomings. METHODS: In this commentary, we summarise the discussions of an expert workgroup describing good practices for the design, analysis, and interpretation of observational studies of interpregnancy interval and adverse perinatal health outcomes. RESULTS: We argue that inferences drawn from research in this field will be improved by careful attention to elements such as: (a) refining the research question to clarify whether the goal is to estimate a causal effect vs describe patterns of association; (b) using directed acyclic graphs to represent potential causal networks and guide the analytic plan of studies seeking to estimate causal effects; (c) assessing how miscarriages and pregnancy terminations may have influenced interpregnancy interval classifications; (d) specifying how key factors such as previous pregnancy loss, pregnancy intention, and maternal socio-economic position will be considered; and (e) examining if the association between interpregnancy interval and perinatal outcome differs by factors such as maternal age. CONCLUSION: This commentary outlines the discussions of this recent expert workgroup, and describes several suggested principles for study design and analysis that could mitigate many potential sources of bias.

Is thromboprophylaxis cost effective in ovarian hyperstimulation syndrome: A systematic review and cost analysis.

BACKGROUND: The majority of serious thromboembolic events occurring in assisted reproductive technologies (ART) are in women with ovarian hyperstimulation syndrome (OHSS). OBJECTIVES: The purpose of this study was to present a thorough review and cost analysis regarding the use of venous thromboembolism (VTE) prophylaxis in OHSS to inform clinical management. DATA SOURCES: Databases used were Pubmed and Embase, in addition to checking reference lists of retrieved articles (inception to November 2017). METHODS: The systematic search strategy identified 365 titles and abstracts. Articles included in the qualitative synthesis had identified venous thrombosis incidence rates or ratios. A separate search for the cost model was conducted recognizing all associated complications of VTE. The decision tree was modeled to best fit the patient population and a sensitivity analysis was performed over a range of variables. RESULTS: The cost of VTE event per OHSS patient not on prophylaxis was €5940 (range €3405 to €38,727), versus €4134 (€2705 to €23,192) per event per patient on prophylaxis, amounting to a saving of (€19 to €23,192) per VTE per patient. Sensitivity analysis found VTE prophyaxis to be cost effective if the incidence of VTE in the OHSS population was greater than 2.79%. Prophylactic therapy was cost effective through 16 weeks of treatment. LIMITATIONS: OHSS is infrequent and hence, the incidence of VTE in patients with OHSS is low; therefore, the data used to inform the incidence of VTE in OHSS in the model carry some uncertainty. Further, low molecular weight heparin (LMWH) has side effects therefore individualization of care must be considered. CONCLUSIONS: With the increasing incidence of infertility and requirement for ART, thromboembolism in OHSS poses a major health threat for patients. VTE prophylaxis using enoxaparin was cost effective in patients with severe OHSS over a wide range of costs and incidences. Prophylaxis was also cost effective through the completion of the first trimester of pregnancy.

Hysteroscopic polypectomy prior to infertility treatment: A cost analysis and systematic review.

The cost of fertility treatment is expensive and interventions that reduce cost can lead to greater efficiency and fewer embryos transferred. Endometrial polyps contribute to infertility and are frequently removed prior to infertility treatment. It is unclear whether polypectomy reduces fertility treatment cost and if so, the magnitude of cost reduction afforded by the procedure. The aim of this study was to determine whether performing office or operative hysteroscopic polypectomy prior to infertility treatment would be cost-effective. PubMed, Embase, and Cochrane libraries were used to identify publications reporting pregnancy rates after hysteroscopic polypectomy. Studies were required to have a polypectomy treatment group and control group of patients with polyps that were not resected. The charges of infertility treatments and polypectomy were obtained through infertility organizations and a private healthcare cost reporting website. These charges were applied to a decision tree model over the range of pregnancy rates observed in the representative studies to calculate an average cost per clinical or ongoing pregnancy. A sensitivity analysis was conducted to assess cost savings of polypectomy over a range of pregnancy rates and polypectomy costs. Pre-treatment office or operative hysteroscopic polypectomy ultimately saved €6658 ($7480) and €728 ($818), respectively, of the average cost per clinical pregnancy in women treated with four cycles of intrauterine insemination. Polypectomy prior to intrauterine insemination was cost-effective for clinical pregnancy rates greater than 30.2% for office polypectomy and 52.6% for operative polypectomy and for polypectomy price <€4414 ($4959). Office polypectomy or operative polypectomy saved €15,854 ($17,813) and €6644 ($7465), respectively, from the average cost per ongoing pregnancy for in vitro fertilization/intracytoplasmic sperm injection treated women and was cost-effective for ongoing pregnancy rates greater than 26.4% (office polypectomy) and 31.7% (operative polypectomy) and polypectomy price <€6376 ($7164). These findings suggested that office or operative hysteroscopic polypectomy was cost-effective when performed prior to both intrauterine insemination and in vitro fertilization over a range of plausible pregnancy rates and procedural costs.

The Changing Face of Epidemiology: Gender Disparities in Citations?

BACKGROUND: Female biomedical scientists tend to publish fewer articles as last author than their male colleagues and accrue fewer citations per publication. We seek to understand whether epidemiology follows this pattern. METHODS: We gathered aggregate information on the current gender distribution of epidemiology departments (n = 29 of 71 surveyed), societies (n = 4 of 8), and journal editorial boards (n = 6 of 6) using two online surveys and publicly available online information. Bibliometric data from 4,149 articles published between 2008 and 2012 in six high-impact epidemiology journals were drawn from Web of Science and PubMed. RESULTS: We observed a higher prevalence of female than male doctoral students and epidemiology faculty, particularly at lower faculty ranks. A total of 54% of society members were female. Among editorial boards, all current and emeritus editors-in-chief were male and board membership was largely male (64%). Females were more likely to be first authors, but less likely to be last authors. There were no differences in accrued citations at the 50th percentile by first or last author gender. However, articles with male first and last authors tend to accrue more citations (5.7 citations, 95% CI: 2.1, 9.4), mostly driven by the most highly cited articles. This disparity is not fully explained by potential confounders, including seniority. CONCLUSIONS: We found a greater number of female epidemiologists in early-career positions and further evidence of potential gender disparity in publication metrics in epidemiology. If epidemiology continues to be practiced by a majority of women, it remains to be seen if these patterns will change over time.

Trying to Conceive After an Early Pregnancy Loss: An Assessment on How Long Couples Should Wait.

OBJECTIVE: To compare time to pregnancy and live birth among couples with varying intervals of pregnancy loss date to subsequent trying to conceive date. METHODS: In this secondary analysis of the Effects of Aspirin in Gestation and Reproduction trial, 1,083 women aged 18-40 years with one to two prior early losses and whose last pregnancy outcome was a nonectopic or nonmolar loss were included. Participants were actively followed for up to six menstrual cycles and, for women achieving pregnancy, until pregnancy outcome. We calculated intervals as start of trying to conceive date minus pregnancy loss date. Time to pregnancy was defined as start of trying to conceive until subsequent conception. Discrete Cox models, accounting for left truncation and right censoring, estimated fecundability odds ratios (ORs) adjusting for age, race, body mass index, education, and subfertility. Although intervals were assessed prior to randomization and thus reasoned to have no relation with treatment assignment, additional adjustment for treatment was evaluated given that low-dose aspirin was previously shown to be predictive of time to pregnancy. RESULTS: Couples with a 0-3-month interval (n=765 [76.7%]) compared with a greater than 3-month (n=233 [23.4%]) interval were more likely to achieve live birth (53.2% compared with 36.1%) with a significantly shorter time to pregnancy leading to live birth (median [interquartile range] five cycles [three, eight], adjusted fecundability OR 1.71 [95% confidence interval 1.30-2.25]). Additionally adjusting for low-dose aspirin treatment did not appreciably alter estimates. CONCLUSION: Our study supports the hypothesis that there is no physiologic evidence for delaying pregnancy attempt after an early loss.

Is Myomectomy Prior to Assisted Reproductive Technology Cost Effective in Women with Intramural Fibroids?

AIM: To evaluate the cost effectiveness of surgery to remove intramural (IM) fibroids prior to assisted reproductive technology (ART). METHODS: The decision tree mathematical model along with sensitivity analysis was performed to analyze cost effectiveness of: (1) myomectomy followed by ART or (2) ART with IM myoma(s) in situ. RESULTS: At the median ongoing pregnancy (OP) rate (OPR) reported in the literature for a fresh, autologous ART cycle with IM fibroids in situ vs. post-IM myomectomy, average cost per OP was $72,355 vs. 66,075, indicating a cost savings with myomectomy. Sensitivity analysis over the range of reported OPRs demonstrated that pre-ART IM myomectomy was always cost effective when OPR among women with in situ myomas was <15.4%. However, for OPRs ≥15.4%, pre-ART IM myomectomy was only cost effective if it increased OPR by at least 9.6%. At the high end of OPRs reported for patients with IM myomas in situ (31.4%), a 19.5% improvement in OPR was needed to justify IM myomectomy from a cost perspective. CONCLUSION: Myomectomy should be used sparingly in cases where the goal of surgery is to achieve improvement in the outcomes of ART.