Quantifying the risk of ectopic pregnancy with a transient diagnosis of pregnancy of unknown location.

OBJECTIVE: To quantify the risk of ectopic pregnancy among a transient diagnosis of pregnancy of unknown location (PUL). METHODS: Retrospective cohort study between August 2016 and November 2020. The final cohort included 244 patients with 255 PULs who presented with vaginal bleeding and/or abdominal pain, positive serum quantitative ß-human chorionic gonadotropin, and negative transvaginal ultrasound, with a subsequent definitive diagnosis. Two-way analysis of variance was used with significance set at P < 0.050. Bonferroni-corrected significance values were used in post hoc analysis. Multinominal logistic regression was used to predict adjusted risk for pregnancy outcome. RESULTS: Definitive diagnosis consisted of 101 (39%) intrauterine pregnancies, 33 (13%) ectopic pregnancies, and 121 (48%) resolved PULs or resolved/treated persisting PULs. A total 68% of the PULs subsequently became nonviable. Vaginal bleeding was associated with increased risk of nonuterine pregnancies. CONCLUSION: A total of 13% of PULs were subsequently diagnosed as ectopic pregnancies, which is higher than the 2% to 3% risk of an ectopic pregnancy in the general reproductive population. A total of 68% of PULs were subsequently nonviable, which is higher than the 31% early pregnancy loss rate in the general reproductive population. This study quantitatively confirms that a transient diagnosis of a PUL increases the odds for ectopic pregnancy and early pregnancy loss.

Effect of an Active vs Expectant Management Strategy on Successful Resolution of Pregnancy Among Patients With a Persisting Pregnancy of Unknown Location: The ACT or NOT Randomized Clinical Trial.

Importance: Women with an early nonviable pregnancy of unknown location are at high risk of ectopic pregnancy and its inherent morbidity and mortality. Successful and timely resolution of the gestation, while minimizing unscheduled interventions, are important priorities. Objective: To determine if active management is more effective in achieving pregnancy resolution than expectant management and whether the use of empirical methotrexate is noninferior to uterine evacuation followed by methotrexate if needed. Design, Setting, and Participants: This multicenter randomized clinical trial recruited 255 hemodynamically stable women with a diagnosed persisting pregnancy of unknown location between July 25, 2014, and June 4, 2019, in 12 medical centers in the United States (final follow up, August 19, 2019). Interventions: Eligible patients were randomized in a 1:1:1 ratio to expectant management (n = 86), active management with uterine evacuation followed by methotrexate if needed (n = 87), or active management with empirical methotrexate using a 2-dose protocol (n = 82). Main Outcomes and Measures: The primary outcome was successful resolution of the pregnancy without change from initial strategy. The primary hypothesis tested for superiority of the active groups combined vs expectant management, and a secondary hypothesis tested for noninferiority of empirical methotrexate compared with uterine evacuation with methotrexate as needed using a noninferiority margin of -12%. Results: Among 255 patients who were randomized (median age, 31 years; interquartile range, 27-36 years), 253 (99.2%) completed the trial. Ninety-nine patients (39%) declined their randomized allocation (26.7% declined expectant management, 48.3% declined uterine evacuation, and 41.5% declined empirical methotrexate) and crossed over to a different group. Compared with patients randomized to receive expectant management (n = 86), women randomized to receive active management (n = 169) were significantly more likely to experience successful pregnancy resolution without change in their initial management strategy (51.5% vs 36.0%; difference, 15.4% [95% CI, 2.8% to 28.1%]; rate ratio, 1.43 [95% CI, 1.04 to 1.96]). Among active management strategies, empirical methotrexate was noninferior to uterine evacuation followed by methotrexate if needed with regard to successful pregnancy resolution without change in management strategy (54.9% vs 48.3%; difference, 6.6% [1-sided 97.5% CI, -8.4% to ∞]). The most common adverse event was vaginal bleeding for all of the 3 management groups (44.2%-52.9%). Conclusions and Relevance: Among patients with a persisting pregnancy of unknown location, patients randomized to receive active management, compared with those randomized to receive expectant management, more frequently achieved successful pregnancy resolution without change from the initial management strategy. The substantial crossover between groups should be considered when interpreting the results. Trial Registration: ClinicalTrials.gov Identifier: NCT02152696.

Miscarriage matters: the epidemiological, physical, psychological, and economic costs of early pregnancy loss.

Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5-18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3-11·4%), two miscarriages is 1·9% (1·8-2·1%), and three or more miscarriages is 0·7% (0·5-0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

Sporadic miscarriage: evidence to provide effective care.

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units.

Recurrent miscarriage: evidence to accelerate action.

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs.

Luteinizing Hormone Surge More Accurately Correlates With Ultrasound Dating of Early Pregnancy Compared to the Last Menstrual Period.

OBJECTIVES: To compare the use of the luteinizing hormone (LH) surge versus the last menstrual period (LMP) for the accuracy of pregnancy dating in fertile women with a diagnosis of recurrent early pregnancy loss (REPL). METHODS: This was an observational cohort study using prospectively collected data at 2 academic REPL programs between 2005 and 2018. Women with a history of REPL and at least 1 subsequent live birth after the evaluation were included. All patients conceived by intercourse timed to the LH surge. Transvaginal ultrasound was examinations were performed 2 weeks after missed menses. The gestational age (GA) was calculated by the LH surge (GALH ), LMP (GALMP ), and first crown-rump length (CRL) that measured 5 mm or greater (GACRL ). A secondary analysis compared GA based on the first measurable CRL of less than 5 mm versus GA based on the first CRL of 5 mm or greater. The GALH and GALMP were compared to determine which measure showed greater concordance with the CRL. The mean absolute difference in days between the GACRL versus GALH and GACRL versus GALMP was determined. RESULTS: A total of 115 women with 118 subsequent pregnancies resulting in live birth were included, with a mean age at delivery of 35.5 years and a mean of 3.6 prior pregnancy losses. The GALH showed a stronger correlation with the CRL (0.77) than the GALMP (0.63; P = .002). The GALH was more similar to the GACRL than the GALMP , with a mean absolute difference of 2.0 versus 3.1 days (P < .0001). CONCLUSIONS: When known, the LH surge appears to be more accurate than the LMP and should be used preferentially for dating of early pregnancy.

Prevalence and Neighborhood Geomapping of COVID-19 in an Underserved Chicago Pregnant Population.

Objective The Chicago area is known to harbor some of the deepest racial and ethnic socioeconomic inequalities in the United States. We studied the prevalence and neighborhood distribution of patients who tested positive for COVID-19 after implementation of universal screening at an academic hospital providing obstetrical services to an underserved Chicago population. Study Design From April 16 to June 16, 2020, a total of 369 patients were screened for COVID-19 at University of Illinois at Chicago with either the Abbott Point-of-Care (POC, n = 266) or reverse transcription polymerase chain reaction test (RT-PCR, n = 101). Patient residential data mapped using ESRI ArcGIS Pro was integrated in ESRI's Living Atlas with the Neighborhood Socioeconomic Status Index (NSEI). Results Precisely, 7.9% (29/369) of screened patients tested positive; 69% (17/29) with the POC test and 31% (12/29) by RT-PCR. The prevalence of an outpatient RT-PCR positive result was 8.9% (9/101). All but one of the 29 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive patients were either Hispanic or Black, and the majority resided in disadvantaged neighborhoods. Conclusion The disproportionate hit of COVID-19 pandemic on the Hispanic and Black communities reflects in SARS-CoV-2 positivity rates in the obstetrical population. Our report provides data that may be useful to policy makers when prioritizing resources to communities in need.

The Need for Dynamic Clinical Guidelines: A Systematic Review of New Research Published After Release of the 2017 ATA Guidelines on Thyroid Disease During Pregnancy and the Postpartum.

Background: The American Thyroid Association Guidelines on Thyroid Disease During Pregnancy and the Postpartum (ATA Guidelines) were published in 2017, with an update not expected for another 5 years. Since release of the 2017 ATA Guidelines, greater than 500 articles have been published in the field. Furthermore, there are presently 14 prospective, interventional trials in progress registered at Clinicaltrials.gov Static guidelines updated every 5-7 years fail to provide timely evidence-based guidance to practicing clinicians. Consequently, guideline development should move toward the creation of dynamic documents. The present article reviews the literature published since the 2017 ATA Guidelines, both to benefit clinicians in practice and to make the case for Dynamic ATA Guidelines. Methods: Using the search terms "thyroid" and "pregnancy," a systematic review of literature published in Pubmed from 3/1/2017 to 12/31/2018 was conducted. The titles and/or abstracts of all articles were reviewed. All articles were classified by subject headings used in the 2017 ATA Guidelines. English-text articles classified under "hypothyroidism" or "thyroid autoimmunity" were examined in full-text. Using the questions and recommendations put forth by the previous ATA Guidelines, relevant articles were selected for discussion in this review. Results: At the time of the search, 659 unique articles on "thyroid and pregnancy" were identified, including 66 original studies on hypothyroidism and 26 on thyroid autoimmunity. Of these, 26 studies on hypothyroidism and 18 studies on thyroid autoimmunity were selected for inclusion in this review based on specific questions in the 2017 ATA Guidelines. Based on these 44 articles, we propose two specific changes to the 2017 ATA Guidelines. Conclusion: Based on new research, we recommend the 2017 ATA Guidelines be updated to recommend against treating thyroid antibody-negative women diagnosed with subclinical hypothyroidism in the second trimester or later; to reflect new, moderate-quality evidence supporting the treatment of thyroid peroxidase antibody-negative women with elevated thyroid stimulating hormone levels in the first trimester or earlier; and to recommend against treatment of euthyroid, thyroid peroxidase antibody-positive women undergoing assisted reproductive technology. Transitioning to a Dynamic ATA Guidelines would allow for these and future recommendations to be implemented in real time.

Subclinical hypothyroidism and thyroid autoimmunity in recurrent pregnancy loss: a systematic review and meta-analysis.

OBJECTIVE: To determine whether overt/subclinical hypothyroidism and/or thyroid autoimmunity is associated with recurrent pregnancy loss (RPL) and whether treatment improves outcomes. DESIGN: Systematic review and meta-analysis. SETTING: University obstetrics and gynecology departments. PATIENT(S): Women with RPL and overt/subclinical hypothyroidism, and/or thyroid autoimmunity. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Associations between RPL and overt/subclinical hypothyroidism and/or thyroid autoimmunity and any effects of treatment. RESULT(S): After our review of articles from PubMed, EMBASE, Web of Science, and CENTRAL, we found two interventional studies in which levothyroxine did not improve the subsequent live-birth rate in women with subclinical hypothyroidism with or without thyroid antibodies. A meta-analysis of five studies revealed the prevalence of subclinical hypothyroidism in RPL to be 12.9% (95% confidence interval [CI], 0%-35.2%). A meta-analysis of 17 studies revealed a statistically significant association between RPL and thyroid autoimmunity (odds ratio 1.94; 95% CI, 1.43-2.64). However, a randomized study suggested that levothyroxine does not benefit euthyroid women with thyroid autoimmunity. CONCLUSION(S): Based on the limited observational studies available, no association exists between RPL and subclinical hypothyroidism, nor does levothyroxine improve subsequent pregnancy outcomes. An association exists between RPL and thyroid autoimmunity, but levothyroxine does not improve subsequent pregnancy outcomes. Women with RPL should be screened/treated for overt thyroid disease but not thyroid autoimmunity. Thyroid antibody screening is not supported by the published studies, and further randomized studies are needed. No recommendation regarding the treatment of subclinical hypothyroidism can be made at this time; prospective and randomized studies are urgently needed.

Micronized vaginal progesterone to prevent miscarriage: a critical evaluation of randomized evidence.

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making.

Universal screening for thyroid disease during pregnancy should be performed.

Thyroid disease can significantly impact the pregnant woman and her child. Human and animal studies have firmly linked overt hypothyroidism and overt hyperthyroidism to miscarriage, preterm delivery and other adverse pregnancy outcomes. Overt hypothyroidism and overt hyperthyroidism affect 1% of all pregnancies. Treatment is widely available, and if detected early, results in decreased rates of adverse outcomes. Universal screening for thyroid disease in pregnancy can identify patients with thyroid disease requiring treatment, and ultimately decrease rates of complications. Universal screening is cost-effective compared to the currently accepted practice of targeted screening and may even be cost-saving in some healthcare systems. Targeted screening, which is recommended by most professional associations, fails to detect a large proportion of pregnant women with thyroid disease. In fact, an increasing number of providers are performing universal screening for thyroid disease in pregnancy, contrary to society guidelines. Limited evidence concerning the impact of untreated and treated subclinical disease and thyroid autoimmunity has distracted from the core rationale for universal screening - the beneficial impact of detecting and treating overt thyroid disease. Evidence supporting universal screening for overt disease stands independently from that of subclinical and autoimmune disease. The time to initiate universal screening is now.

Translation, Adaptation, and Assessment of the Communication Assessment Tool in Tigray, Northern Ethiopia.

BACKGROUND: Ethiopia has experienced tremendous growth in medical education beginning in the early 2000s. Research shows a need for emphasis on empathy and compassionate care in this setting. In the United States, the Communication Assessment Tool (CAT) is a widely used, validated survey measuring provider-patient interactions. OBJECTIVE: The goal of this study was to translate, culturally adapt, and pilot the CAT to allow it to be used with trainees and patients in Ethiopia. METHODS: Bilingual experts translated the CAT into Tigrigna, the primary language of the Tigray region in northern Ethiopia, followed by focus group discussions, back translation, and review by the original author of the CAT. The translated tool was administered to the patients of resident physicians in 6 specialties at Ayder Referral Hospital between December 2016 and February 2017. RESULTS: Our translation of the CAT into Tigrigna had semantic, idiomatic, and experiential equivalence. Of 1024 patients recruited, 1002 (98%) completed interviews using the CAT. Mean score was 3.09; 3% of all scores were excellent and 54% were good. Cronbach's alpha score for the full survey was 0.942, demonstrating high reliability. CONCLUSIONS: The translated CAT in Tigrigna can be used to assess communication skills in Ethiopian residents. Both mean score and percentage of excellent scores were considerably lower than scores in other countries, suggesting that there may be opportunities for improvement in residents' communication skills.

Maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss.

OBJECTIVE: To determine whether an association exists between maternal antithyroid antibodies and euploid miscarriage in women with recurrent early pregnancy loss (REPL). DESIGN: Observational cohort study. SETTING: Two academic medical centers. PATIENT(S): Women seen between 2004-2015 with a history of REPL, who were euthyroid or had subclinical hypothyroidism, had maternal antithyroid antibody testing and had at least one subsequent early pregnancy loss (<10 weeks' gestation). INTERVENTION(S): Thyroid function and antibodies were measured at consultation. Subsequent miscarriages were assessed by conventional cytogenetic analysis, and when indicated, microsatellite analysis and/or comparative genomic hybridization/single nucleotide polymorphisms were performed. MAIN OUTCOME MEASURE(S): Determine whether maternal antithyroid antibodies are associated with euploid miscarriage. RESULT(S): Cohort consisted of 74 subjects with REPL who had 130 subsequent early pregnancy losses. The prevalence of maternal antithyroid antibodies in the cohort was 17.6%. Mean TSH was significantly higher among subjects with maternal antithyroid antibodies. Otherwise, no significant differences in demographics were noted. When comparing types of early pregnancy losses between the two groups, a trend toward having more miscarriages than nonvisualized pregnancy losses was noted among subjects with maternal antithyroid antibodies (70% and 30%) compared with subjects without maternal antithyroid antibodies (55% and 43%). No significant difference was noted in the frequency of euploid miscarriage between subjects with and without maternal antithyroid antibodies (42% vs. 56%). CONCLUSION(S): Our study did not demonstrate an association between euploid miscarriage and maternal antithyroid antibodies in subjects with a history of REPL. Therefore, testing or treatment in this cohort may not be warranted.

Kidney Outcomes and Risk Factors for Nephritis (Flare/De Novo) in a Multiethnic Cohort of Pregnant Patients with Lupus.

BACKGROUND AND OBJECTIVES: Kidney disease is a critical concern in counseling patients with lupus considering pregnancy. This study sought to assess the risk of renal flares during pregnancy in women with previous lupus nephritis in partial or complete remission, particularly in those with antidouble-stranded DNA antibodies and low complement levels, and the risk of new-onset nephritis in patients with stable/mildly active SLE. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We assessed active nephritis (renal flares and de novo kidney disease) and associated predictors during pregnancy in patients with lupus with urine protein ≤1000 mg and serum creatinine <1.2 mg/dl at baseline; 373 patients (52% ethnic/racial minorities) enrolled between 2003 and 2012 were prospectively followed in the Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus Study. Active nephritis was defined by proteinuria increase of >500 mg and/or red blood cell casts. RESULTS: Of 118 patients with previous kidney disease, 13 renal flares (11%) occurred (seven of 89 in complete remission and six of 29 in partial remission) compared with four with de novo kidney involvement (2%) in 255 patients without past kidney disease (P<0.001). Active nephritis was not associated with ethnicity, race, age, creatinine, BP, or antihypertensive and other medications. In multivariable logistic regression analyses, patients with past kidney disease in complete or partial remission more often experienced active nephritis (adjusted odds ratio, 6.88; 95% confidence interval, 1.84 to 25.71; P=0.004 and adjusted odds ratio, 20.98; 95% confidence interval, 4.69 to 93.98; P<0.001, respectively) than those without past kidney disease. Low C4 was associated with renal flares/de novo disease (adjusted odds ratio, 5.59; 95% confidence interval, 1.64 to 19.13; P<0.01) but not low C3 or positive anti-dsDNA alone. CONCLUSIONS: De novo kidney involvement in SLE, even in ethnic/racial minorities, is uncommon during pregnancy. Past kidney disease and low C4 at baseline independently associate with higher risk of developing active nephritis. Antibodies to dsDNA alone should not raise concern, even in patients with past kidney disease, if in remission.

Luteal start vaginal micronized progesterone improves pregnancy success in women with recurrent pregnancy loss.

OBJECTIVE: To assess the effectiveness of luteal start vaginal micronized P in a recurrent pregnancy loss (RPL) cohort. DESIGN: Observational cohort study using prospectively collected data. SETTING: Not applicable. PATIENT(S): Women seen between 2004 and 2012 with a history of two or more unexplained pregnancy losses <10 weeks in size; endometrial biopsy (EB) performed 9-11 days after LH surge; and one or more subsequent pregnancy(ies). Women were excluded if concomitant findings, such as endometritis, maturation delay, or glandular-stromal dyssynchrony, were identified on EB. INTERVENTION(S): Vaginal micronized P was prescribed at a dose of 100-200 mg every 12 hours starting 3 days after LH surge (luteal start) if glandular epithelial nuclear cyclin E (nCyclinE) expression was elevated (>20%) in endometrial glands or empirically despite normal nCyclinE (≤20%). Women with normal nCyclinE (≤20%) who did not receive P were used as controls. MAIN OUTCOME MEASURE(S): Pregnancy success was an ongoing pregnancy >10 weeks in size. RESULT(S): One hundred sixteen women met the inclusion criteria, of whom 51% (n = 59) had elevated nCyclinE and 49% (n = 57) had normal nCyclinE. Pregnancy success in the 59 women with elevated nCyclinE significantly improved after intervention: 6% (16/255) in prior pregnancies versus 69% (57/83) in subsequent pregnancies. Pregnancy success in subsequent pregnancies was higher in women prescribed vaginal micronized P compared with controls: 68% (86/126) versus 51% (19/37); odds ratio = 2.1 (95% confidence interval, 1.0-4.4). CONCLUSION(S): In this study, we found that the use of luteal start vaginal micronized P was associated with improved pregnancy success in a strictly defined cohort of women with RPL.

Expression Quantitative Trait Locus Mapping Studies in Mid-secretory Phase Endometrial Cells Identifies HLA-F and TAP2 as Fecundability-Associated Genes.

Fertility traits in humans are heritable, however, little is known about the genes that influence reproductive outcomes or the genetic variants that contribute to differences in these traits between individuals, particularly women. To address this gap in knowledge, we performed an unbiased genome-wide expression quantitative trait locus (eQTL) mapping study to identify common regulatory (expression) single nucleotide polymorphisms (eSNPs) in mid-secretory endometrium. We identified 423 cis-eQTLs for 132 genes that were significant at a false discovery rate (FDR) of 1%. After pruning for strong LD (r2 >0.95), we tested for associations between eSNPs and fecundability (the ability to get pregnant), measured as the length of the interval to pregnancy, in 117 women. Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the TAP2 gene (P = 1.3x10-4) and the HLA-F gene (P = 4.0x10-4), respectively. The effects of these SNPs on fecundability were replicated in an independent sample. The two eSNPs reside within or near regulatory elements in decidualized human endometrial stromal cells. Our study integrating eQTL mapping in a primary tissue with association studies of a related phenotype revealed novel genes and associated alleles with independent effects on fecundability, and identified a central role for two HLA region genes in human implantation success.