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.

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.

The Relationship of Preconception and Early Pregnancy Isoprostanes with Fecundability and Pregnancy Loss.

BACKGROUND: Although redox stress likely plays an important role in reproductive health, the utility of peripheral biomarkers of oxidative stress, such as isoprostanes, during the periconception period remains underexplored. We evaluated the relationship between isoprostanes during preconception and gestational week 4 and women's reproductive health outcomes. METHODS: The Effects of Aspirin in Gestation and Reproduction trial (2007-2011) enrolled 1228 women attempting pregnancy and followed them for up to 6 menstrual cycles and throughout pregnancy if they became pregnant. We measured creatinine-adjusted, log-transformed isoprostanes 8-iso-prostaglandin F 2α (8-iso-PGF2α), its metabolite 2,3-dinor-iPF2α-III, and stereoisomers 5-iso-PGF2α-VI and 8,12-iso-iPF2α-VI in urine during preconception and 4 weeks gestation. We evaluated pregnancy among participants in each menstrual cycle using human chorionic gonadotropin (hCG) and defined pregnancy loss as observed loss following positive hCG. We calculated fecundability odds ratios (FOR) and 95% confidence intervals (CI) using discrete-time Cox proportional hazards models and relative risk of pregnancy loss using adjusted log-binomial models. RESULTS: Higher preconception isoprostane levels were associated with lower fecundability [e.g., FOR = 0.89; 95% CI = 0.81, 0.97 per interquartile range (IQR) increase in 8-iso-PGF2α]. Among 797 pregnancies, isoprostane levels increased from preconception to 4 weeks gestation (e.g., mean difference = 0.12; 95% CI = 0.10, 0.14 ng/mL for 8-iso-PGF2α) and higher isoprostanes at 4 weeks gestation were associated with lower risk of pregnancy loss (e.g., RR = 0.79; 95% CI = 0.62, 1.00 per IQR increase in 8-iso-PGF2α). CONCLUSIONS: Preconception urinary isoprostanes may identify redox stress pathways associated with lower fecundability. However, the increase in isoprostanes into gestational week 4 and the associated lower risk of pregnancy loss may suggest confounding by latent factors in early pregnancy.

Gamma models for estimating the odds ratio for a skewed biomarker measured in pools and subject to errors.

Measuring a biomarker in pooled samples from multiple cases or controls can lead to cost-effective estimation of a covariate-adjusted odds ratio, particularly for expensive assays. But pooled measurements may be affected by assay-related measurement error (ME) and/or pooling-related processing error (PE), which can induce bias if ignored. Building on recently developed methods for a normal biomarker subject to additive errors, we present two related estimators for a right-skewed biomarker subject to multiplicative errors: one based on logistic regression and the other based on a Gamma discriminant function model. Applied to a reproductive health dataset with a right-skewed cytokine measured in pools of size 1 and 2, both methods suggest no association with spontaneous abortion. The fitted models indicate little ME but fairly severe PE, the latter of which is much too large to ignore. Simulations mimicking these data with a non-unity odds ratio confirm validity of the estimators and illustrate how PE can detract from pooling-related gains in statistical efficiency. These methods address a key issue associated with the homogeneous pools study design and should facilitate valid odds ratio estimation at a lower cost in a wide range of scenarios.

A multistate competing risks framework for preconception prediction of pregnancy outcomes.

BACKGROUND: Preconception pregnancy risk profiles-characterizing the likelihood that a pregnancy attempt results in a full-term birth, preterm birth, clinical pregnancy loss, or failure to conceive-can provide critical information during the early stages of a pregnancy attempt, when obstetricians are best positioned to intervene to improve the chances of successful conception and full-term live birth. Yet the task of constructing and validating risk assessment tools for this earlier intervention window is complicated by several statistical features: the final outcome of the pregnancy attempt is multinomial in nature, and it summarizes the results of two intermediate stages, conception and gestation, whose outcomes are subject to competing risks, measured on different time scales, and governed by different biological processes. In light of this complexity, existing pregnancy risk assessment tools largely focus on predicting a single adverse pregnancy outcome, and make these predictions at some later, post-conception time point. METHODS: We reframe the individual pregnancy attempt as a multistate model comprised of two nested multinomial prediction tasks: one corresponding to conception and the other to the subsequent outcome of that pregnancy. We discuss the estimation of this model in the presence of multiple stages of outcome missingness and then introduce an inverse-probability-weighted Hypervolume Under the Manifold statistic to validate the resulting multivariate risk scores. Finally, we use data from the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial to illustrate how this multistate competing risks framework might be utilized in practice to construct and validate a preconception pregnancy risk assessment tool. RESULTS: In the EAGeR study population, the resulting risk profiles are able to meaningfully discriminate between the four pregnancy attempt outcomes of interest and represent a significant improvement over classification by random chance. CONCLUSIONS: As illustrated in our analysis of the EAGeR data, our proposed prediction framework expands the pregnancy risk assessment task in two key ways-by considering a broader array of pregnancy outcomes and by providing the predictions at an earlier, preconception intervention window-providing obstetricians and their patients with more information and opportunities to successfully guide pregnancy attempts.

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.

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..

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.

Serum antioxidant vitamin concentrations and oxidative stress markers associated with symptoms and severity of premenstrual syndrome: a prospective cohort study.

BACKGROUND: It has been suggested that premenstrual syndrome (PMS) may derive from either elevated oxidative stress or reduced antioxidant vitamin levels in the body; however, these relationships have been minimally studied in a large cohort of healthy women. Our objective was to estimate the association between serum concentrations of antioxidant vitamins (A, C, and E) and markers of oxidative stress (F2-isoprostane) with symptoms and severity of PMS. METHODS: The BioCycle study was a prospective cohort study following 259 healthy premenopausal women aged 18-44 years for up to 2 menstrual cycles. Frequency/severity of 20 PMS symptoms were assessed via questionnaires 4 times/cycle, and antioxidant vitamins and oxidative stress biomarkers were measured up to 8 times/cycle to correspond with specific cycle phases. Generalized linear models were used to estimate associations between mean antioxidant concentrations and oxidative stress biomarkers with PMS symptoms and severity; linear mixed models were used to evaluate associations with symptom severity scores within groups (e.g. depression, cravings, pain). RESULTS: Higher concentrations of serum antioxidant vitamins were largely not associated with prevalence or severity of PMS symptoms. Though a few associations were observed, only associations between mean γ-tocopherol and decreased odds of swelling of the hands/feet survived adjustment for multiple comparisons (OR 0.33, 95% CI 0.16, 0.65, per ug/dL). However, F2-isoprostanes were associated with prevalence and severity of several symptoms specifically related to depression and cravings (depression score ß = 0.07, 95% CI 0.02, 0.12, per 10 ug/dL; cravings score ß = 0.16, 95% CI 0.10, 0.22, per 10 ug/dL), as well as with classification of PMS severity (OR 1.07, 95% CI 1.01, 1.14, per 10 pg/dL), with these associations surviving adjustment for false discovery rate. CONCLUSIONS: F2-isoprostanes, but not antioxidant vitamins, were associated with select PMS symptoms, as well as symptom and severity categories. Specific symptom relationships merit further research.

Methodological Issues in Population-Based Studies of Multigenerational Associations.

Laboratory-based animal research has revealed a number of exposures with multigenerational effects-ones that affect the children and grandchildren of those directly exposed. An important task for epidemiology is to investigate these relationships in human populations. Without the relative control achieved in laboratory settings, however, population-based studies of multigenerational associations have had to use a broader range of study designs. Current strategies to obtain multigenerational data include exploiting birth registries and existing cohort studies, ascertaining exposures within them, and measuring outcomes across multiple generations. In this paper, we describe the methodological challenges inherent to multigenerational studies in human populations. After outlining standard taxonomy to facilitate discussion of study designs and target exposure associations, we highlight the methodological issues, focusing on the interplay between study design, analysis strategy, and the fact that outcomes may be related to family size. In a simulation study, we show that different multigenerational designs lead to estimates of different exposure associations with distinct scientific interpretations. Nevertheless, target associations can be recovered by incorporating (possibly) auxiliary information, and we provide insights into choosing an appropriate target association. Finally, we identify areas requiring further methodological development.

A Randomized Trial to Evaluate the Effects of Folic Acid and Zinc Supplementation on Male Fertility and Livebirth: Design and Baseline Characteristics.

The Folic Acid and Zinc Supplementation Trial (FAZST) was a multicenter, double-blind, block-randomized, placebo-controlled trial to determine whether folic acid and zinc supplementation in men improves semen quality and increases livebirth rate among couples seeking infertility treatment (2013-2017). Eligible men were aged 18 years or older with female partners aged 18-45 years, seeking infertility treatment. Men were randomized (1:1) to 5 mg folic acid and 30 mg elemental zinc daily or matching placebo for 6 months. Randomization was stratified by site and intended infertility treatment (in vitro fertilization (IVF), non-IVF/study site, and non-IVF/outside clinic). Follow-up of men continued for 6 months, and female partners were passively followed for a minimum of 9 months. Women who conceived were followed throughout pregnancy. Overall, 2,370 men were randomized during 2013-2017 (1,185 folic acid and zinc, 1,185 placebo); they had a mean age of 33 years and body mass index (weight (kg)/height (m)2) of 29.8. Most participants were white (82%), well educated (83% with some college), and employed (72%). Participant characteristics were balanced across intervention arms. Study visits were completed by 89%, 77%, and 75% of men at months 2, 4, and 6, respectively. Here we describe the study design, recruitment, data collection, lessons learned, and baseline participant characteristics.

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.

Prediction of pregnancy loss by early first trimester ultrasound characteristics.

BACKGROUND: Pregnancy loss prediction based on routinely measured ultrasound characteristics is generally aimed toward distinguishing nonviability. Physicians also use ultrasound indicators for patient counseling, and in some cases to decide upon the frequency of follow-up sonograms. To improve clinical utility, allocation of cut-points should be based on clinical data for multiple sonographic characteristics, be specific to gestational week, and be determined by methods that optimize prediction. OBJECTIVES: To identify routinely measured features of the early first trimester ultrasound and the gestational age-specific cut-points that are most predictive of pregnancy loss. MATERIALS AND METHODS: This was a secondary analysis of 617 pregnant women enrolled in the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial; all women had 1-2 previous pregnancy losses and no documented infertility. Each participant had a single ultrasound with a detectable fetal heartbeat between 6 weeks 0 days and 8 weeks 6 days. Cut-points for low fetal heart rate and small crown-rump length were separately defined for gestational weeks 6, 7, and 8 to optimize prediction. Identity and log-binomial regression models were used to estimate absolute and relative risks, respectively, and 95% confidence intervals between jointly categorized low fetal heart rate, small crown-rump length, and clinical pregnancy loss. Adjusted models accounted for gestational age at ultrasound in weeks. Missing data were addressed using multiple imputation. RESULTS: A total of 64 women experienced a clinical pregnancy loss following the first ultrasound (10.4%), 7 were lost to follow-up (1.1%), and 546 women (88.5%) had a live birth. Low fetal heart rate and small crown-rump length (≤122, 123, and 158 bpm; ≤6.0, 8.5, and 10.9 mm for gestational weeks 6, 7, and 8, respectively) were independent predictors of clinical pregnancy loss, with greatest risks observed for pregnancies having both characteristics (relative risk, 2.08; 95% confidence interval, 1.24-2.91). The combination of low fetal heart rate and small crown-rump length was linked to a 16% (95% confidence interval, 9.1-23%) adjusted absolute increase in risk of subsequent loss, from 5.0% (95% confidence interval, 1.5-8.5%) to 21% (95% confidence interval, 15-27%). Abnormal yolk sac diameter or the presence of a subchorionic hemmhorage did not improve prediction of clinical pregnancy loss. CONCLUSION: Identified cut-points can be used by physicians for patient counseling, and in some cases to decide upon the frequency of follow-up sonograms. The specified criteria should not be used to diagnose nonviability.

Platelet activation and placenta-mediated adverse pregnancy outcomes: an ancillary study to the Effects of Aspirin in Gestation and Reproduction trial.

BACKGROUND: Platelet activation may play a role in the pathophysiology of placenta-mediated obstetrical complications, as evidenced by the efficacy of aspirin in preventing preeclampsia, but published data regarding the relationship between biomarkers for platelet activation and adverse obstetrical outcomes are sparse. In particular, it is unknown whether prepregnancy biomarkers of platelet activation are associated with adverse pregnancy outcomes. OBJECTIVE: This study aimed to determine the following: (1) whether maternal plasma concentrations of platelet factor 4 are associated with risk of placenta-mediated adverse obstetrical outcomes, and (2) whether these associations are modified by low-dose aspirin. STUDY DESIGN: This ancillary study included measurement of platelet factor 4 among 1185 of 1228 women of reproductive age enrolled in the Effects of Aspirin in Gestation and Reproduction trial with available plasma samples, with relevant outcomes assessed among 584 women with pregnancies lasting at least 20 weeks' gestation. We measured platelet factor 4 in plasma samples obtained at the prepregnancy study visit (before randomization to low-dose aspirin or placebo), 12 weeks' gestation, and 28 weeks' gestation. The primary outcome was a composite of hypertensive disorders of pregnancy, placental abruption, and small-for-gestational-age infant. We estimated the relative risks (RRs) and 95% confidence intervals (CIs) for the association between platelet factor 4 and the composite and individual outcomes at each time point using log-binomial regression that was weighted to account for potential selection bias and adjusted for age, body mass index, education, income, and smoking. To evaluate the potential effect modification of aspirin, we stratified the analyses by aspirin treatment assignment. RESULTS: During follow-up, 95 women experienced the composite adverse obstetrical outcome, with 57 cases of hypertensive disorders of pregnancy, 35 of small for gestational age, and 6 of placental abruption. Overall, prepregnancy platelet factor 4 was positively associated with the composite outcome (third tertile vs first tertile; relative risk, 2.36; 95% confidence interval, 1.38-4.03) and with hypertensive disorders of pregnancy (third tertile vs first tertile; relative risk, 2.14; 95% confidence interval, 1.08-4.23). In analyses stratified by treatment group, associations were stronger in the placebo group (third tertile vs first tertile; relative risk, 3.36; 95% confidence interval, 1.42-7.93) than in the aspirin group (third tertile vs first tertile; relative risk, 1.78; 95% confidence interval, 0.90-3.50). CONCLUSION: High concentrations of platelet factor 4 before pregnancy are associated with increased risk of placenta-mediated adverse pregnancy outcomes, particularly for hypertensive disorders of pregnancy. Aspirin may mitigate the increased risk of these outcomes among women with higher plasma concentrations of preconception platelet factor 4, but low-dose aspirin nonresponders may require higher doses of aspirin or alternate therapies to achieve obstetrical risk reduction.

Vaginal bleeding and nausea in early pregnancy as predictors of clinical pregnancy loss.

BACKGROUND: Although nausea and vaginal bleeding are commonly experienced in early pregnancy, their prognostic value in predicting clinical pregnancy loss is not well understood. OBJECTIVE: This study aimed to understand whether timing of bleeding and nausea symptoms can be used to predict risk of pregnancy loss among women with ultrasound-confirmed pregnancies. STUDY DESIGN: A cohort of 701 women with clinically confirmed pregnancies and 1 to 2 previous pregnancy losses were preconceptionally enrolled in the Effects of Aspirin in Gestation and Reproduction trial (2006-2012). Participants completed daily symptom diaries from 2 to 8 weeks' gestation and were prospectively monitored for detection of pregnancy loss. The risk of pregnancy loss was estimated for each observed bleeding and nausea pattern, and positive and negative predictive values for each pattern were calculated. RESULTS: Among 701 women, 211 (30.1%) reported any vaginal bleeding, and 639 (91.2%) reported any nausea. Most bleeding experienced by women was spotting and contained within a single episode. Within 2 to <4, 4 to <6, and 6 to 8 weeks' gestation, vaginal bleeding occurred in 5.9% (41) (5.7% live birth, 7.1% clinical pregnancy loss), 14.6% (102) (13.9% live birth, 18.6% clinical pregnancy loss), and 20.8% (146) (18.4% live birth, 32.4% clinical pregnancy loss) of women, respectively. Within the same gestational periods, nausea was reported in 22.7% (159) (23.2% live birth, 20.4% clinical pregnancy loss), 65.9% (462) (67.5% live birth, 58.4% clinical pregnancy loss), and 87.0% (610) (90.6% live birth, 69.0% clinical pregnancy loss) of women. Women who had bleeding without nausea between 6 and 8 weeks' gestation (3.6% prevalance) had the greatest risk of clinical pregnancy loss (risk difference=56.1%; 95% confidence interval, 37.6-74.7), a positive predictive value of 68.0% (49.7%, 86.3%), negative predictive value of 85.8% (83.2%, 88.4%), positive likelihood ratio of 11.1 (2.04, 20.1), and negative likelihood ratio of 0.86 (0.79, 0.93). Nausea and bleeding are clinical factors that predicted clinical pregnancy loss (area under the curve, 0.87; 95% confidence interval, 0.81-0.88) similar to age, body mass index, blood pressure, and waist-to-hip ratio (area under the curve, 0.81; 95% confidence interval, 0.78-0.88) measured preconceptionally. CONCLUSION: Women experiencing bleeding without nausea between 6 and 8 weeks' gestation had an increased risk of clinical pregnancy loss. Bleeding and nausea were not predictive risk factors of clinical pregnancy loss prior to 6 weeks' gestation.

Effect of Folic Acid and Zinc Supplementation in Men on Semen Quality and Live Birth Among Couples Undergoing Infertility Treatment: A Randomized Clinical Trial.

Importance: Dietary supplements marketed for male fertility commonly contain folic acid and zinc based on limited prior evidence for improving semen quality. However, no large-scale trial has examined the efficacy of this therapy for improving semen quality or live birth. Objective: To determine the effect of daily folic acid and zinc supplementation on semen quality and live birth. Design, Setting, and Participants: The Folic Acid and Zinc Supplementation Trial was a multicenter randomized clinical trial. Couples (n = 2370; men aged ≥18 years and women aged 18-45 years) planning infertility treatment were enrolled at 4 US reproductive endocrinology and infertility care study centers between June 2013 and December 2017. The last 6-month study visit for semen collection occurred during August 2018, with chart abstraction of live birth and pregnancy information completed during April 2019. Interventions: Men were block randomized by study center and planned infertility treatment (in vitro fertilization, other treatment at a study site, and other treatment at an outside clinic) to receive either 5 mg of folic acid and 30 mg of elemental zinc (n = 1185) or placebo (n = 1185) daily for 6 months. Main Outcomes and Measures: The co-primary outcomes were live birth (resulting from pregnancies occurring within 9 months of randomization) and semen quality parameters (sperm concentration, motility, morphology, volume, DNA fragmentation, and total motile sperm count) at 6 months after randomization. Results: Among 2370 men who were randomized (mean age, 33 years), 1773 (75%) attended the final 6-month study visit. Live birth outcomes were available for all couples, and 1629 men (69%) had semen available for analysis at 6 months after randomization. Live birth was not significantly different between treatment groups (404 [34%] in the folic acid and zinc group and 416 [35%] in the placebo group; risk difference, -0.9% [95% CI, -4.7% to 2.8%]). Most of the semen quality parameters (sperm concentration, motility, morphology, volume, and total motile sperm count) were not significantly different between treatment groups at 6 months after randomization. A statistically significant increase in DNA fragmentation was observed with folic acid and zinc supplementation (mean of 29.7% for percentage of DNA fragmentation in the folic acid and zinc group and 27.2% in the placebo group; mean difference, 2.4% [95% CI, 0.5% to 4.4%]). Gastrointestinal symptoms were more common with folic acid and zinc supplementation compared with placebo (abdominal discomfort or pain: 66 [6%] vs 40 [3%], respectively; nausea: 50 [4%] vs 24 [2%]; and vomiting: 32 [3%] vs 17 [1%]). Conclusions and Relevance: Among a general population of couples seeking infertility treatment, the use of folic acid and zinc supplementation by male partners, compared with placebo, did not significantly improve semen quality or couples' live birth rates. These findings do not support the use of folic acid and zinc supplementation by male partners in the treatment of infertility. Trial Registration: ClinicalTrials.gov Identifier: NCT01857310.

Combining Biomarker Calibration Data to Reduce Measurement Error.

Biomarker assay measurement often consists of a two-stage process where laboratory equipment yields a relative measure which is subsequently transformed to the unit of interest using a calibration curve. The calibration curve establishes the relation between the measured relative units and sample biomarker concentrations using stepped samples of known biomarker concentrations. Samples from epidemiologic studies are often measured in multiple batches or plates, each with independent calibration experiments. Collapsing calibration information across batches before statistical analysis has been shown to reduce measurement error and improves estimation. Additionally, collapsing in practice can also create an additional layer of quality control (QC) and optimization in a part of the laboratory measurement process that is often highly automated. Principled recalibration is demonstrated via. a three-step process of identifying batches where recalibration might be beneficial, forming a collapsed calibration curve and recalibrating identified batches, and using QC data to assess the appropriateness of recalibration. Here, we use inhibin B measured in biospecimens from the BioCycle study using 50 enzyme-linked immunosorbent assay (ELISA) batches (3875 samples) to motivate and display the benefits of collapsing calibration experiments, such as detecting and overcoming faulty calibration experiments, and thus improving assay coefficients of variation from reducing unwanted measurement error variability. Differences in the analysis of inhibin B by testosterone quartile are also demonstrated before and after recalibration. These simple and practical procedures are minor adjustments implemented by study personnel without altering laboratory protocols which could have positive estimation and cost-saving implications especially for population-based studies.

Metabolic Syndrome and the Effectiveness of Low-dose Aspirin on Reproductive Outcomes.

BACKGROUND: Metabolic syndrome is associated with increases in both inflammation and aspirin resistance, but effectiveness of aspirin in improving reproductive health among women with metabolic syndrome is unknown. We evaluated the effectiveness of low-dose aspirin in improving reproductive outcomes across metabolic syndrome score. METHODS: The EAGeR trial randomly assigned 1228 women with a history of pregnancy loss to receive 81 mg aspirin or placebo for up to six menstrual cycles of attempting pregnancy and, if they became pregnant, throughout pregnancy. We assessed components of metabolic syndrome at enrollment, including: waist circumference ≥88 cm, triglycerides ≥150 mg/dl, high-density lipoprotein ≤50 mg/dl, blood pressure ≥130 mmHg systolic or ≥85 mmHg diastolic, and glucose ≥100 mg/dl. We summed components to calculate metabolic syndrome score. RESULTS: A total of 229 participants (20%) met full criteria for metabolic syndrome, 207 (18%) had two components, 366 (31%) one component, and 372 (32%) no components. Among those without any component of metabolic syndrome, aspirin was associated with 10.7 [95% confidence interval (CI) = 1.2, 20.2] more pregnancies and 13.7 (95% CI = 3.3, 24.0) more live births per 100 couples. Effects were attenuated as metabolic syndrome score increased and we observed no clear effect of aspirin on pregnancy or live birth among women with metabolic syndrome. CONCLUSIONS: Low-dose aspirin is most effective in increasing pregnancy and live birth among women with no or few components of metabolic syndrome. Reduced effectiveness among women with metabolic syndrome may be due to differences in effective dose or aspirin resistance.

Associations Between Preconception Plasma Fatty Acids and Pregnancy Outcomes.

BACKGROUND: Although fatty acids are involved in critical reproductive processes, the relationship between specific fatty acids and fertility is uncertain. We investigated the relationship between preconception plasma fatty acids and pregnancy outcomes. METHODS: We included 1,228 women attempting pregnancy with one to two previous pregnancy losses from the EAGeR trial (2007-2011). Plasma fatty acids were measured at baseline. We used log-binomial regression to assess associations between fatty acids and pregnancy, pregnancy loss, and live birth, adjusting for age, race, smoking, BMI, physical activity, income, parity, treatment arm, and cholesterol. RESULTS: Although total saturated fatty acids (SFAs) were not associated with pregnancy outcomes, 14:0 (myristic acid; relative risk [RR] = 1.10, 95% confidence interval [CI] = 1.02, 1.19, per 0.1% increase) and 20:0 (arachidic acid; RR = 1.05, 95% CI = 1.01, 1.08, per 0.1% increase) were positively associated with live birth. Findings suggested a positive association between total monounsaturated fatty acids (MUFAs) and pregnancy and live birth and an inverse association with loss. Total polyunsaturated fatty acids (PUFAs) were associated with lower probability of pregnancy (RR = 0.97, 95% CI = 0.95, 1.00) and live birth (RR = 0.96, 95% CI = 0.94, 0.99), and increased risk of loss (RR = 1.10, 95% CI = 1.00, 1.20), per 1% increase. Trans fatty acids and n-3 fatty acids were not associated with pregnancy outcomes. CONCLUSIONS: Preconception total plasma MUFAs were positively associated with pregnancy and live birth. PUFAs were inversely associated with pregnancy outcomes. Specific SFAs were associated with a higher probability of live birth. Our results suggest that fatty acids may influence pregnancy outcomes.