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Preeclampsia and gestational hypertension are common complications of pregnancy associated with significant maternal and infant morbidity. Despite extensive research evaluating risk factors during pregnancy, most women who develop a hypertensive disorder of pregnancy are not considered high-risk and strategies for prevention remain elusive. We evaluated preconception blood pressure and its change into early pregnancy as novel risk markers for development of a hypertensive disorder of pregnancy. The EAGeR (Effects of Aspirin in Gestation and Reproduction) trial (2007–2011) randomized 1228 healthy women with a history of pregnancy loss to preconception-initiated low-dose aspirin versus placebo and followed participants for up to 6 menstrual cycles attempting pregnancy and throughout pregnancy if they became pregnant. Blood pressure was measured during preconception and throughout early gestation. The primary outcomes, preterm preeclampsia, term preeclampsia, and gestational hypertension, were abstracted from medical records. Among 586 women with a pregnancy >20 weeks’ gestation, preconception blood pressure levels were higher for preterm preeclampsia (87.3±6.7 mm Hg mean arterial pressure), term preeclampsia (88.3±9.8 mm Hg), and gestational hypertension (87.9±9.1 mm Hg) as compared with no hypertensive disorder of pregnancy (83.9±8.6 mm Hg). Change in blood pressure from preconception into very early pregnancy was associated with development of preeclampsia (relative risk, 1.13 [95% CI, 1.02–1.25] per 2 mm Hg increase in mean arterial pressure at 4 weeks’ gestation), particularly preterm preeclampsia (relative risk, 1.21 [95% CI, 1.01–1.45]). Randomization to aspirin did not alter blood pressure trajectory or risk of hypertension in pregnancy. Preconception blood pressure and longitudinal changes during early pregnancy are underexplored but crucial windows in the detection and prevention of hypertensive disorders of pregnancy. Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00467363.

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.

Background Inflammation and elevated blood lipids are associated with infertility. Aspirin and statin therapy may improve infertility treatment outcomes among overweight and obese women with systemic inflammation, but little is known about the short-term effects of statins in this population. We conducted a pilot study of aspirin, pravastatin, or combined treatment among a group of overweight and obese, reproductive-aged women. Our goal was to characterize short-term changes in inflammatory and lipid biomarkers during and after treatment. Methods In this open-label trial, women aged 18–40 years with a body mass index ≥25 kg/m2 were randomized to receive either 162 mg aspirin, 40 mg pravastatin, or both. The study medication was taken daily for 2 weeks, and participants were then followed for a two-week washout period. Participants provided blood samples at baseline, after the intervention period, and after the washout period. The outcomes were changes in biomarkers of inflammation and lipids measured in blood components at each timepoint. Results Nine, 8, and 8 women were randomized to the aspirin, pravastatin, and combined arms, respectively. Analyses were conducted among 8, 7, and 7 women in the aspirin, pravastatin, and combined arms for whom biomarker data was available at baseline. High-sensitivity C-reactive protein (hsCRP) levels were lower after treatment in all arms and continued to decrease after washout in the pravastatin and combined arms. Results were consistent between the whole sample and women with baseline hsCRP between 2 and 10 mg/L. Low-density lipoprotein (LDL) cholesterol was lower after treatment in the pravastatin and combined arms and rose slightly after washout. Conclusions Our results provide preliminary evidence that short-term aspirin and pravastatin therapy reduces hsCRP and LDL cholesterol among overweight and obese women of reproductive age, including those with low-grade inflammation. Because of these short-term effects, these drugs may improve infertility treatment outcomes in this population, which we will assess in a future randomized trial.

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

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.

Several autoimmune conditions have adverse effects on reproductive outcomes, but the relationship between family history of autoimmune disease in women without these conditions and pregnancy is uncertain. The objective of this study was to determine if there is an association between a family history of an autoimmune condition and time-to-pregnancy (TTP), pregnancy loss, and live birth. This was a prospective cohort study from a RCT of 1228 adult women ages 18–40, who were healthy, had no history of infertility, were actively attempting to conceive, and had one or two prior pregnancy losses. Of these, 1172 women had data available regarding family history of autoimmune conditions. Women with an affected first-degree relative had similar TTP when compared to those without a FHx (fecundability odds ratio 0.90, 95% confidence interval [CI] 0.70, 1.15). Women with an affected first-degree relative had a lower likelihood of live birth (relative risk [RR] 0.83, 95% CI 0.69, 0.99). Among women who achieved pregnancy, FHx of autoimmune disease was associated with a higher likelihood of pregnancy loss (RR 1.49, 95% CI 1.10, 2.03). Women who had a first-degree relative with an autoimmune disease had a similar TTP as unaffected women but a lower likelihood of live birth and higher risk of pregnancy loss. This information may encourage clinicians to evaluate women with a family history of autoimmune conditions prior to pregnancy and highlights the need for further studies to ascertain the effects of autoimmunity and pregnancy., Highlights • Some autoimmune conditions may negatively impact reproductive health. • Autoimmune disease can cluster in families highlighting relevance of family history. • Women with family history of autoimmunity had higher risk of pregnancy loss. • Results suggest possible shared mechanism of miscarriage and predisposition to autoimmunity. • Family history may be important for understanding risk factors for pregnancy loss.

Objective To determine if transferring a lower-quality embryo with a good-quality blastocyst is detrimental, given that evidence suggests that embryos can signal the endometrium and that embryo quality may affect negatively endometrial receptivity. Design Retrospective cohort study. Setting In vitro fertilization center. Intervention(s) Single- versus double-embryo transfer. Patient(s) Patients with a double-embryo transfer of a good-quality blastocyst plus a lower-quality blastocyst, early blastocyst, or morula were compared with patients receiving a single good-quality blastocyst. Main Outcome Measure(s) Live birth, multiple gestation. Result(s) In this study, 4,640 in vitro fertilization cycles were analyzed. In none of the analyses did transferring a second lower-quality embryo negatively affect birth rate. In the primary analysis, transferring a second lower-quality embryo increased live birth by 10% and the multiple birth rate by 15%. The addition of a fair- or poor-quality blastocyst or early blastocyst markedly increased the twin birth rate by 22%–27% with an 8%–12% increase in live birth. The addition of a morula did not increase live birth but resulted in 12% more multiples. In women younger than 38 years, adding a lower-quality embryo increased the birth rate by 7% but resulted in 18% increase in multiples. In women 38 years or older, adding a lower-quality embryo increased the live birth rate by 9% with a 15% increase in multiples. Conclusion(s) Addition of a lower-quality embryo does not have a detrimental effect on a good-quality blastocyst and results in a small increase in live births. However, this is at the expense of a marked increase in the likelihood of multiple gestations.

Context Phytoestrogens may influence fecundability, although biological mechanisms remain elusive. Since it is hypothesized that phytoestrogens may act through influencing hormone levels, we investigated associations between phytoestrogens and menstrual cycle length, a proxy for the hormonal milieu, in healthy women attempting pregnancy. Design A population-based prospective cohort of 326 women ages 18 to 40 with self-reported cycles of 21 to 42 days were followed until pregnancy or for 12 months of attempting pregnancy. Methods Urinary genistein, daidzein, O-desmethylangolensin, equol, enterodiol, and enterolactone were measured upon enrollment. Cycle length was determined from fertility monitors and daily journals. Linear mixed models assessed associations with continuous cycle length and were weighted by the inverse number of observed cycles. Logistic regression models assessed menstrual regularity (standard deviation > 75th vs ≤ 75th percentile). Models were adjusted for age, body mass index, race, creatinine, exercise, supplements, lipids, lead, cadmium, cotinine, parity, alcohol, and other phytoestrogens. Results Individual phytoestrogens were not associated with cycle length, although total phytoestrogens were associated with shorter cycles (−0.042 days; 95% confidence interval [CI], −0.080 to −0.003, per 10% increase). Each 1 nmol/L increase in enterolactone (odds ratio [OR] 0.88; 95% CI, 0.79-0.97) and total lignans (OR 0.85; 95% CI, 0.76-0.95) was associated with reduced irregularity, and each 1 nmol/L increase in genistein with irregularity (OR 1.19; 95% CI, 1.02-1.38). Conclusion Phytoestrogens were not meaningfully associated with cycle length but may be associated with menstrual regularity, among women with self-reported regular cycles. These results highlight differences between isoflavones and lignans and are reassuring for women attempting pregnancy.

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.

CONTEXT: Fatty acids (FAs) are important for reproductive processes, including steroidogenesis, though associations with fecundability, as measured by time to pregnancy (TTP), are unclear. OBJECTIVE: To investigate the relationship between preconception plasma phospholipid FA (PPFA) levels and time to human chorionic gonadotropin–pregnancy among women with prior pregnancy loss. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort of 1228 women attempting pregnancy (aged 18 to 40 years, with one or two prior pregnancy losses) followed for up to six cycles at four US university medical centers during 2006 to 2012. PPFA levels were measured at baseline. MAIN OUTCOME MEASURES: Associations with fecundability overall and by body mass index (BMI) group after adjusting for confounders were estimated using fecundability odds ratios (FORs) and 95% CIs. False discovery rate (FDR) was used to account for multiple comparisons. RESULTS: Monounsaturated fatty acids (MUFAs) were associated with increased fecundability or shorter TTP [FOR, 1.08 (95% CI, 1.01 to 1.16) per unit increase in percentage of total FAs], whereas polyunsaturated fatty acids (PUFAs) were associated with decreased fecundability or longer TTP [FOR, 0.95 (95% CI, 0.91 to 1.00) per 1% change], though associations only remained significant after FDR adjustment among women with BMI

How does oocyte cohort size affect IVF treatment outcomes?Retrospective cohort analysis of 10,193 fresh autologous oocyte retrievals among good-prognosis patients35 years from 2009 to 2015. The primary outcome was live birth from a fresh transfer; secondary outcomes included cumulative live birth potential from the retrieved cohort and frequency of severe ovarian hyperstimulation syndrome (OHSS).Live birth per fresh transfer increased as the oocyte cohort increased up to 11-15 oocytes, then plateaued. Beyond 15 oocytes, live birth rates from fresh transfer did not decrease, even at the highest oocyte yields. When accounting for the availability of cryopreserved high-quality supernumerary blastocysts, the cumulative number of potential live births per retrieval continued to increase as oocyte yield increased. Rates of severe OHSS increased rapidly with increasing cohort size above 7-10 oocytes when final oocyte maturation was triggered with human chorionic gonadotrophin (HCG), up to nearly 7% of HCG-triggered retrievals of25 oocytes, but when triggered with gonadotrophin-releasing hormone (GnRH) agonist the severe OHSS rate remained relatively low and stable at approximately 1% even among retrievals of the largest oocyte cohorts.Live birth rates per fresh embryo transfer are highest among cycles with retrieval of 11 or more oocytes. Larger cohorts are not associated with any decline in fresh transfer birth rates. Total potential births per retrieval continue to increase as the number of retrieved oocytes increases. Rates of OHSS remain relatively low after retrieval of large oocyte cohorts if final maturation is triggered with GnRH agonist rather than HCG.

Human reproduction is an inefficient process. There are several drivers of complications along the path to and during pregnancy, one of which is inflammation. Treatments to mitigate the deleterious effects of aberrant inflammation with something inexpensive and widely available like aspirin could have dramatic global impact. The Effects of Aspirin in Gestation and Reproduction (EAGeR) trial enrolled women aged 18 to 40 years with one to two prior pregnancy losses and no diagnosis of infertility. Patients were randomized to either low-dose aspirin or placebo. Here, we review the collective findings of the EAGeR trial to date and discuss several important lessons learned from the unique data resulting from this groundbreaking trial. Findings reported from this trial provide significant advances in the understanding of aspirin's potential mechanisms in modulating reproductive processes and the role of inflammation in these processes. This review describes the collective findings of the EAGeR trial in the context of the existing literature regarding aspirin and inflammation in reproduction to inform relevant next steps in fertility and obstetric research, as well as potential implications for clinical care.

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, {"type":"clinical-trial","attrs":{"text":"NCT00467363","term_id":"NCT00467363"}}NCT00467363.

Background Most studies of folate metabolism and reproduction have been conducted after pregnancy and in folate-deficient populations. However, measurement of maternal folate status preconceptionally may be most relevant to certain folate-linked early processes preceding a successful pregnancy, and there has been a major increase in folate concentrations in women of childbearing age in high resource settings. Objective To examine associations between preconceptional biomarkers of maternal folate status (folate and homocysteine) and reproductive outcomes in folate-replete women. Study Design Cohort nested within the Effects of Aspirin in Gestation and Reproduction trial, a block-randomized, double-blind, placebo-controlled trial whereby women were randomized to daily low-dose aspirin (81 mg/day) or placebo and all women received folic acid (400 μg/day). In total, 1228 women with 1–2 previous pregnancy losses and no documented infertility were recruited from 4 clinical sites in the United States (2006–2012) and were attempting pregnancy for up to 6 menstrual cycles. Log-binomial regression models were used to estimate relative risks and 95% confidence intervals between preconception serum folate and plasma homocysteine for anovulation, pregnancy, and pregnancy loss. Results Greater plasma homocysteine was nonlinearly associated with greater risks of pregnancy loss only among women with 2 previous losses: a relative risk of 1.43 (95% confidence interval, 1.08–1.89) was found for plasma homocysteine concentrations at the study median of 8.0 μmol/L compared with a US population median of 6.0 μmol/L. No meaningful relationships were found between serum folate and any reproductive outcome or between plasma homocysteine and anovulation or becoming pregnant. Conclusion These data justify further study of the role of folate and homocysteine metabolism in normal and abnormal early pregnancy.

Background Despite years of studies evaluating prevention strategies for intrauterine adhesion formation after operative hysteroscopy, it is still unclear which strategies are most effective. Objective The objective of the study was to perform a systematic review and meta-analysis to evaluate the effectiveness of postoperative prevention strategies on intrauterine adhesion formation following operative hysteroscopy. Study Design Literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases. Inclusion criteria were published randomized controlled clinical trials from 1989 to 2014 comparing any postoperative preventative measures of intrauterine adhesion after hysteroscopy. The main outcome measure was a reduction in postoperative intrauterine adhesion. Heterogeneity of the studies was evaluated using a Q test and an I 2 index. Analyses were performed using a random-effects model with outcome data reported as relative risk with 95% confidence interval. Results Twelve studies were included in the systematic review. Eight studies compared similar treatment methods and were included in the meta-analysis. Three studies evaluated hyaluronic acid gel, of which 2 reported a significant decrease in intrauterine adhesion with treatment. The meta-analysis demonstrated a significant reduction of intrauterine adhesion when using hyaluronic acid gel. Two studies evaluated polyethylene oxide-sodium carboxymethylcellulose gel, 1 of which demonstrated a decrease in intrauterine adhesion with treatment. A meta-analysis showed a significant reduction of intrauterine adhesion with polyethylene oxide-sodium carboxymethyl cellulose gel. However, these 3 studies demonstrating a benefit of the gels in preventing adhesion formation were all conducted by the same research group. Other research groups have not confirmed these results. A sensitivity analysis excluding these trials from this single group demonstrated no benefit to adhesion prevention with either gel formation. Three studies investigated oral estrogen therapy after hysteroscopy and found no difference in intrauterine adhesion. A meta-analysis showed no decrease in intrauterine adhesion with estrogen therapy after hysteroscopy. Data were lacking to perform metaanalyses on the use of intrauterine balloon, intrauterine device, and other adhesion prevention barriers in preventing intrauterine adhesion. Conclusion There was a lack of definitive evidence to conclude that any treatment is effective in preventing posthysteroscopy uterine adhesion formation. The available literature has significant heterogeneity and a high risk of bias, making any definitive conclusions difficult.

Background Despite years of studies evaluating prevention strategies for intrauterine adhesion formation after operative hysteroscopy, it is still unclear which strategies are most effective. Objective The objective of the study was to perform a systematic review and meta-analysis to evaluate the effectiveness of postoperative prevention strategies on intrauterine adhesion formation following operative hysteroscopy. Study Design Literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases. Inclusion criteria were published randomized controlled clinical trials from 1989 to 2014 comparing any postoperative preventative measures of intrauterine adhesion after hysteroscopy. The main outcome measure was a reduction in postoperative intrauterine adhesion. Heterogeneity of the studies was evaluated using a Q test and an I 2 index. Analyses were performed using a random-effects model with outcome data reported as relative risk with 95% confidence interval. Results Twelve studies were included in the systematic review. Eight studies compared similar treatment methods and were included in the meta-analysis. Three studies evaluated hyaluronic acid gel, of which 2 reported a significant decrease in intrauterine adhesion with treatment. The meta-analysis demonstrated a significant reduction of intrauterine adhesion when using hyaluronic acid gel. Two studies evaluated polyethylene oxide-sodium carboxymethylcellulose gel, 1 of which demonstrated a decrease in intrauterine adhesion with treatment. A meta-analysis showed a significant reduction of intrauterine adhesion with polyethylene oxide-sodium carboxymethyl cellulose gel. However, these 3 studies demonstrating a benefit of the gels in preventing adhesion formation were all conducted by the same research group. Other research groups have not confirmed these results. A sensitivity analysis excluding these trials from this single group demonstrated no benefit to adhesion prevention with either gel formation. Three studies investigated oral estrogen therapy after hysteroscopy and found no difference in intrauterine adhesion. A meta-analysis showed no decrease in intrauterine adhesion with estrogen therapy after hysteroscopy. Data were lacking to perform metaanalyses on the use of intrauterine balloon, intrauterine device, and other adhesion prevention barriers in preventing intrauterine adhesion. Conclusion There was a lack of definitive evidence to conclude that any treatment is effective in preventing posthysteroscopy uterine adhesion formation. The available literature has significant heterogeneity and a high risk of bias, making any definitive conclusions difficult.

Background Prior studies have reported mixed results regarding relationships between vitamin D, androgens, and sex hormone–binding globulin in patients with polycystic ovary syndrome. However, less is known regarding these associations in eumenorrheic, premenopausal women. Objective Our objective was to study the relationships between serum vitamin D and androgen biomarkers in eumenorrheic women with a history of pregnancy loss who were attempting pregnancy. Study Design This was an analysis of a cohort of 1191 participants from the Effects of Aspirin in Gestation and Reproduction trial (2006–2012). Participants were attempting to conceive, aged 18–40 years, with 1–2 documented prior pregnancy losses and no history of infertility, and recruited from 4 academic medical centers in the United States. Serum vitamin D (25-hydroxyvitamin D) and hormone concentrations were measured at baseline. Results Vitamin D concentration was negatively associated with free androgen index (percentage change [95% confidence interval, –5% (–8% to –2%)] per 10 ng/mL increase) and positively associated with sex hormone–binding globulin (95% confidence interval, 4% [2–7%]), although not with total testosterone, free testosterone, or dehydroepiandrosterone sulfate after adjusting for age, body mass index, smoking status, race, income, education, physical activity, and season of blood draw. Conclusion Overall, vitamin D was associated with sex hormone–binding globulin and free androgen index in eumenorrheic women with prior pregnancy loss, suggesting that vitamin D may play a role in the bioavailability of androgens in eumenorrheic women. We are limited in making assessments regarding directionality, given the cross-sectional nature of our study.

Objective To compare live-birth rates, blastocyst to live-birth efficiency, gestational age, and birth weights in a large cohort of patients undergoing single versus double thawed blastocyst transfer. Design Retrospective cohort study. Setting Assisted reproduction technology (ART) practice. Patient(s) All autologous frozen blastocyst transfers (FBT) of one or two vitrified-warmed blastocysts from January 2009 through April 2012. Intervention(s) Single or double FBT. Main Outcome Measure(s) Live birth, blastocyst to live-birth efficiency, preterm birth, low birth weight. Result(s) Only supernumerary blastocysts with good morphology (grade BB or better) were vitrified, and 1,696 FBTs were analyzed. No differences were observed in patient age, rate of embryo progression, or postthaw blastomere survival. Double FBT yielded a higher live birth per transfer, but 33% of births from double FBT were twins versus only 0.6% of single FBT. Double FBT was associated with statistically significant increases in preterm birth and low birth weight, the latter of which was statistically significant even when the analysis was limited to singletons. Of the blastocysts transferred via single FBT, 38% resulted in a liveborn child versus only 34% with double FBT. This suggests that two single FBTs would result in more liveborn children with significantly fewer preterm births when compared with double FBT. Conclusion(s) Single FBT greatly decreased multiple and preterm birth risk while providing excellent live-birth rates. Patients should be counseled that a greater overall number of live born children per couple can be expected when thawed blastocysts are transferred one at a time.

Objective To summarize the available published randomized controlled trial data regarding timing of P supplementation during the luteal phase of patients undergoing assisted reproductive technology (ART). Design A systematic review. Setting Not applicable. Patient(s) Undergoing IVF. Intervention(s) Different starting times of P for luteal support. Main Outcome Measure(s) Clinical pregnancy (PR) and live birth rates. Result(s) Five randomized controlled trials were identified that met inclusion criteria with a total of 872 patients. A planned meta-analysis was not performed because of a high degree of clinical heterogeneity with regard to the timing, dose, and route of P. Two studies compared P initiated before oocyte retrieval versus the day of oocyte retrieval and PRs were 5%–12% higher when starting P on the day of oocyte retrieval. One study compared starting P on day 6 after retrieval versus day 3, reporting a 16% decrease in pregnancy in the day 6 group. Trials comparing P start times on the day of oocyte retrieval versus 2 or 3 days after retrieval showed no significant differences in pregnancy. Conclusion(s) There appears to be a window for P start time between the evening of oocyte retrieval and day 3 after oocyte retrieval. Although some studies have suggested a potential benefit in delaying vaginal P start time to 2 days after oocyte retrieval, this review could not find randomized controlled trials to adequately assess this. Further randomized clinical trials are needed to better define P start time for luteal support after ART.

Despite the highest historical live birth success rates for couples undergoing in vitro fertilization (IVF), there has been an epidemic of iatrogenic twin and higher order gestation conceived from this treatment. Continued improvement in cryopreservation techniques have allowed preservation of supernumerary embryos for use in future cycles, and refinements in culture systems and embryo selection have resulted in the transfer of fewer embryos while maintaining favorable pregnancy rates. The voluntary transfer of a single high quality embryo, elective single embryo transfer (eSET), has significantly reduced multiple gestation rates and maximized the rate of singleton pregnancy without compromising overall success rates. Although eSET is the standard of care in several developed countries, utilization in the United States has been slow. States with mandated IVF insurance have seen decreases in preterm birth rates yielding down stream health care savings. Herein, the evolution and future applications of this practice to reduce the risk of iatrogenic twins is reviewed.