L.V. Farland

Endometriosis: a high-risk population for major chronic diseases?

BACKGROUND Despite an estimated prevalence of 10% in women, the etiology of endometriosis remains poorly understood. Over recent decades, endometriosis has been associated with risk of several chronic diseases, such as cancer, autoimmune diseases, asthma/atopic diseases and cardiovascular diseases. A deeper understanding of these associations is needed as they may provide new leads into the causes or consequences of endometriosis. This review summarizes the available epidemiological findings on the associations between endometriosis and other chronic diseases and discusses hypotheses for underlying mechanisms, potential sources of bias and methodological complexities. METHODS We performed a comprehensive search of the PubMed/Medline and ISI Web of Knowledge databases for all studies reporting on the associations between endometriosis and other diseases published in English through to May 2014, using numerous search terms. We additionally examined the reference lists of all identified papers to capture any additional articles that were not identified through computer searches. RESULTS We identified 21 studies on the associations between endometriosis and ovarian cancer, 14 for breast cancer, 8 for endometrial cancer, 4 for cervical cancer, 12 for cutaneous melanoma and 3 for non-Hodgkins lymphoma, as well as 9 on the links between endometriosis and autoimmune diseases, 6 on the links with asthma and atopic diseases, and 4 on the links with cardiovascular diseases. Endometriosis patients were reported to be at higher risk of ovarian and breast cancers, cutaneous melanoma, asthma, and some autoimmune, cardiovascular and atopic diseases, and at decreased risk of cervical cancer. CONCLUSIONS Increasing evidence suggests that endometriosis patients are at higher risk of several chronic diseases. Although the underlying mechanisms are not yet understood, the available data to date suggest that endometriosis is not harmless with respects to womens long-term health. If these relationships are confirmed, these findings may have important implications in screening practices and in the management and care of endometriosis patients.

Pregnancy Complications as Markers for Subsequent Maternal Cardiovascular Disease: Validation of a Maternal Recall Questionnaire

BACKGROUND We designed and tested the validity of a questionnaire to characterize maternal recall of pregnancy complications associated with increased future cardiovascular disease risk, based on the 2011 American Heart Association (AHA) guidelines. METHODS A maternal recall questionnaire of pregnancy history was administered to 971 patients who had participated in a previous cohort study of 1,608 pregnant women. Medical records from the study pregnancy served as the gold standard. Prevalence, sensitivity (sens), specificity (spec), positive predictive value (PPV), negative predictive value (NPV), and/or Spearmans correlation coefficients (r) were calculated for each question. RESULTS A total of 526 (54%) individuals recontacted responded. Respondents were more likely to be older, white, educated, and nulliparous and were less likely to deliver low-birthweight infants in the study pregnancy than were individuals who did not respond. Mean length of recall was 4.35 years (standard deviation [SD] 0.46) postpartum. Maternal recall was most accurate for gestational diabetes (sens: 92%, spec: 98%, PPV: 79%, NPV: 99%), infant birthweight (r=0.95), and gestation length (r=0.85). Maternal recall was modest for preeclampsia (sens: 79%, spec: 97%, PPV: 68%, NPV: 98%) and pregnancy-associated hypertension, including preeclampsia or gestational hypertension (sens: 60%, spec: 95%, PPV: 64%, NPV: 94%). CONCLUSIONS This validation study demonstrated that the majority of women could accurately recall a history of gestational diabetes, infant birthweight, and gestational age at delivery, 4 years postpartum on average. Recall of preeclampsia and pregnancy-associated hypertension overall was modest. Maternal report of these pregnancy conditions may help clinicians identify women at increased risk for cardiovascular disease.

Predicting the likelihood of live birth for elective oocyte cryopreservation: a counseling tool for physicians and patients

Study question Can a counseling tool be developed for women desiring elective oocyte cryopreservation to predict the likelihood of live birth based on age and number of oocytes frozen? Summary answer Using data from ICSI cycles of a population of women with uncompromised ovarian reserve, an evidence-based counseling tool was created to guide women and their physicians regarding the number of oocytes needed to freeze for future family-building goals. What is known already Elective oocyte cryopreservation is increasing in popularity as more women delay family building. By undertaking elective oocyte freezing at a younger age, women hope to optimize their likelihood of successful live birth(s) using their thawed oocytes at a future date. Questions often arise in clinical practice regarding the number of cryopreserved oocytes sufficient to achieve live birth(s) and whether or not additional stimulation cycles are likely to result in a meaningful increase in the likelihood of live birth. As relatively few women who have electively cryopreserved oocytes have returned to use them, available data for counseling patients wishing to undergo fertility preservation are limited. Study design, size, duration A model was developed to determine the proportion of mature oocytes that fertilize and then form blastocysts as a function of age, using women with presumably normal ovarian reserve based on standard testing who underwent ICSI cycles in our program from January, 2011 through March, 2015 (n = 520). These included couples diagnosed exclusively with male-factor and/or tubal-factor infertility, as well as cycles utilizing egg donation. Age-specific probabilities of euploidy were estimated from 14 500 PGS embryo results from an external testing laboratory. Assuming survival of thawed oocytes at 95% for women <36 y and for egg donors, and 85% for women ≥36 y, and 60% live birth rate per transferred euploid blastocyst, probabilities of having at least one, two or three live birth(s) were calculated. Participants/materials, setting, method First fresh male-factor and/or tubal-factor only autologous ICSI cycles (n = 466) were analyzed using Poisson regression to calculate the probability that a mature oocyte will become a blastocyst based on age. Egg donation cycles (n = 54) were analyzed and incorporated into the model separately. The proportion of blastocysts expected to be euploid was determined using PGS results of embryos analyzed via array comparative genomic hybridization. A counseling tool was developed to predict the likelihood of live birth, based on individual patient age and number of mature oocytes. Main results and the role of chance This study provides an evidence-based model to predict the probability of a woman having at least one, two or three live birth(s) based on her age at egg retrieval and the number of mature oocytes frozen. The model is derived from a surrogate population of ICSI patients with uncompromised ovarian reserve. A user-friendly counseling tool was designed using the model to help guide physicians and patients. LIMITATIONS, REASONS FOR CAUTION The data used to develop the prediction model are, of necessity, retrospective and not based on patients who have returned to use their cryopreserved oocytes. The assumptions used to create the model, albeit reasonable and data-driven, vary by study and will likely vary by center. Centers are therefore encouraged to consider their own blastocyst formation and thaw survival rates when counseling patients. Limitations, reasons for caution Our model will provide a counseling resource that may help inform women desiring elective fertility preservation regarding their likelihood of live birth(s), how many cycles to undergo, and when additional cycles would bring diminishing returns. Study funding/competing interests None. Trial registration number Not applicable.

National survey on use of time-lapse imaging systems in IVF laboratories

PurposeSeveral time-lapse imaging (TLI) systems for non-invasive continuous monitoring of developing embryos are currently available. The present study explored the prevalence, means of acquisition, and clinical application of TLI systems in USA in vitro fertilization (IVF) laboratories.MethodsAn online cross-sectional survey of 294 USA IVF laboratory directors was conducted in February and March 2016. Those directing more than one laboratory were asked to complete the survey for their home program and for their smallest laboratory by number of IVF/intracytoplasmic sperm injection (ICSI) cycle starts. Use of TLI was analyzed using logistic regression to calculate odds ratios (OR).ResultsOf 294 directors surveyed, 162 (55%) reported data on 204 laboratories. Thirty-five laboratories (17%) possessed at least one TLI system (median 2, interquartile range 1–4, total range 1–11). The more oocyte retrievals a laboratory performed annually, the more likely the laboratory was to possess a TLI system. Fifteen laboratories (43%) purchased their own systems, while others leased, loaned, or received donated systems. Twenty-five laboratories (71%) reported using TLI for embryo selection; all used TLI always, or usually, in combination with standard morphology evaluation. Twenty laboratories (80%) offered TLI to all patients. Some laboratories charged patients for TLI. Directors with TLI systems were more inclined to believe that TLI has value for embryo selection in clinical IVF.ConclusionsTLI system possession in USA IVF laboratories is low, although positively associated with the number of retrievals performed and with directors’ opinions on the technology’s utility. Over 70% of laboratories with TLI systems use them clinically, and less than half purchased their systems.

History of breast feeding and risk of incident endometriosis: prospective cohort study

Objective To investigate the association between lifetime breast feeding, exclusive breast feeding, postpartum amenorrhea, and incidence of endometriosis among parous women. Design Prospective cohort study. Setting Nurses’ Health Study II, 1989-2011. Participants 72 394women who reported having one or more pregnancies that lasted at least six months, 3296 of whom had laparoscopically confirmed endometriosis. For each pregnancy, women reported duration of total breast feeding, exclusive breast feeding, and postpartum amenorrhea. Main outcome measures Incident self reported laparoscopically confirmed endometriosis (96% concordance with medical record) in parous women. Multivariable Cox proportional hazard models were used to calculate hazard ratios and 95% confidence intervals for diagnosis of endometriosis. Results Duration of total and exclusive breast feeding was significantly associated with decreased risk of endometriosis. Among women who reported a lifetime total length of breast feeding of less than one month, there were 453 endometriosis cases/100 000 person years compared with 184 cases/100 000 person years in women who reported a lifetime total of ≥36 months of breast feeding. For every additional three months of total breast feeding per pregnancy, women experienced an 8% lower risk of endometriosis (hazard ratio 0.92, 95% confidence interval 0.90 to 0.94; P<0.001 for trend) and a 14% lower risk for every additional three months of exclusive breast feeding per pregnancy (0.86, 0.81 to 0.90; P<0.001 for trend). Women who breastfed for ≥36 months in total across their reproductive lifetime had a 40% reduced risk of endometriosis compared with women who never breast fed (0.60, 0.50 to 0.72). The protective association with breast feeding was strongest among women who gave birth within the past five years (P=0.04 for interaction). The association with total breast feeding and exclusive breast feeding on endometriosis was partially influenced by postpartum amenorrhea (% mediated was 34% (95% confidence interval 15% to 59%) for total breast feeding and 57% (27% to 82%) for exclusive breast feeding). Conclusion Among women who experienced at least one pregnancy that lasted at least six months, breast feeding was inversely associated with risk of incident endometriosis. This association was partially, but not fully, influenced by postpartum amenorrhea, suggesting that breast feeding could influence the risk of endometriosis both through amenorrhea and other mechanisms. Given the chronic and incurable nature of endometriosis, breast feeding should be further investigated as an important modifiable behavior to mitigate risk for pregnant women.

Limitations on the compensation of gamete donors: a public opinion survey

OBJECTIVE To determine public opinion on gamete donor compensation. DESIGN Cross-sectional web-based survey. SETTING Not applicable. PATIENT(S) A nationally representative sample of 1,427 people in the United States. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES Support for the compensation of gamete donors. RESULTS Of 1,427 respondents, 51 (4%) disagreed with use of IVF for any indication, and 232 (16%) believed that oocyte and/or sperm donation to be always unacceptable. Of the remaining 1,185 respondents, 953 (80%) supported and 41 (4%) opposed paying sperm donors; 1,063 (90%) supported and 24 (2%) opposed paying oocyte donors. Of respondents, 90% believed that appropriate compensation for one cycle of oocyte donation should be less than

Menstrual cycle characteristics and steroid hormone, prolactin, and growth factor levels in premenopausal women

10,000. A total of 559 (47%) supported a limit on sperm donor compensation and 544 (46%) supported a limit on oocyte donor compensation. Individuals who had personal knowledge of someone with infertility or who used assisted reproductive technology (ART), and Republicans compared with Democrats, were more likely to support limits on both oocyte and sperm donor compensation. Divorced compared with married respondents were less likely to support limits on gamete donor compensation. Men were less likely to support limits on sperm donor compensation. CONCLUSIONS Most respondents in a nationally representative cohort support compensating gamete donors. Although most do not support limits on gamete donor compensation, most agree the appropriate payment for one cycle of oocyte donation is in line with former American Society for Reproductive Medicine guidelines.

Flexible Carbon Dioxide Laser Fiber Versus Ultrasonic Scalpel in Robot-Assisted Laparoscopic Myomectomy

PurposeMenstrual cycle characteristics are markers of endocrine milieu. However, associations between age at menarche and adulthood sex steroid hormone levels have been inconsistent, and data on menstrual characteristics and non-sex steroid hormones are sparse.MethodsWe assessed the relations of menstrual characteristics with premenopausal plasma sex steroid hormones, sex hormone binding globulin (SHBG), prolactin, and growth factors among 2,745 premenopausal women (age 32–52) from the Nurses’ Health Study II. Geometric means and tests for trend were calculated using multivariable general linear models.ResultsEarly age at menarche was associated with higher premenopausal early-follicular free estradiol (percent difference < 12 vs. > 13 years = 11%), early-follicular estrone (7%), luteal estrone (7%), and free testosterone (8%) (all ptrend < 0.05). Short menstrual cycle length at age 18–22 was associated with higher early-follicular total (< 26 vs. > 39 days = 18%) and free estradiol (16%), early-follicular estrone (9%), SHBG (7%), lower luteal free estradiol (− 14%), total (− 6%), and free testosterone (− 15%) (all ptrend < 0.05). Short adult menstrual length was associated with higher early-follicular total estradiol (< 26 vs. > 31 days = 14%), SHBG (10%), lower luteal estrone (− 8%), progesterone (− 9%), total (− 11%) and free testosterone (− 25%), and androstenedione (− 14%) (all ptrend < 0.05). Irregularity of menses at 18–22 was associated with lower early-follicular total (irregular vs. very regular = − 14%) and free estradiol (− 14%), and early-follicular estrone (− 8%) (All ptrend < 0.05). Irregularity of adult menstrual cycle was associated with lower luteal total estradiol (irregular vs. very regular = − 8%), SHBG (− 3%), higher total (8%), and free testosterone (11%) (all ptrend < 0.05).ConclusionsEarly-life and adulthood menstrual characteristics are moderately associated with mid-to-late reproductive year’s hormone concentrations. These relations of menstrual characteristics with endogenous hormone levels could partially account for associations between menstrual characteristics and reproductive cancers or other chronic diseases.

Outpatient endometrial aspiration: an alternative to methotrexate for pregnancy of unknown location

STUDY OBJECTIVE To compare the effectiveness and safety of a flexible carbon dioxide (CO2) laser fiber to the ultrasonic scalpel when employed through a robotic surgical system. DESIGN Retrospective cohort study. DESIGN CLASSIFICATION Level II-2 evidence. SETTING Reproductive surgery practice at an academic hospital. PATIENTS Two hundred thirty-six women who had undergone robot-assisted laparoscopic myomectomy with either CO2 laser (n = 85) or the ultrasonic scalpel (n = 151). INTERVENTIONS Robot-assisted laparoscopic myomectomy employing either a flexible CO2 laser fiber or a robotic ultrasonic scalpel as the primary energy tool. MEASUREMENTS AND MAIN RESULTS Perioperative outcomes (estimated blood loss, operative time, length of hospital stay) of patients undergoing robot-assisted myomectomy with a flexible laser fiber or ultrasonic scalpel. Estimated blood loss and operative time were comparable (p = .95 and p = .55, respectively) between the 2 groups after adjusting for all confounders, whereas length of hospital stay remained significantly different (p = .004). Odds ratio for complications was 0.35 (95% confidence interval 0.08-1.56; p = .17), which denotes no difference in the risk for complications between the 2 groups. CONCLUSION Robot-assisted laparoscopic myomectomy with a flexible CO2 laser fiber is safe and has comparable operative outcomes to the ultrasonic scalpel. The small size and flexibility of this device allows robotic surgeons to employ safe focal energy without sacrificing operative ergonomics.

Early Pregnancy Cravings, Dietary Intake, and Development of Abnormal Glucose Tolerance

BACKGROUND: Pregnancies of unknown location with abnormal beta‐human chorionic gonadotropin trends are frequently treated as presumed ectopic pregnancies with methotrexate. Preliminary data suggest that outpatient endometrial aspiration may be an effective tool to diagnose pregnancy location, while also sparing women exposure to methotrexate. OBJECTIVE: The purpose of this study was to evaluate the utility of an endometrial sampling protocol for the diagnosis of pregnancies of unknown location after in vitro fertilization. STUDY DESIGN: A retrospective cohort study of 14,505 autologous fresh and frozen in vitro fertilization cycles from October 2007 to September 2015 was performed; 110 patients were diagnosed with pregnancy of unknown location, defined as a positive beta‐human chorionic gonadotropin without ultrasound evidence of intrauterine or ectopic pregnancy and an abnormal beta‐human chorionic gonadotropin trend (<53% rise or <15% fall in 2 days). These patients underwent outpatient endometrial sampling with Karman cannula aspiration. Patients with a beta‐human chorionic gonadotropin decline ≥15% within 24 hours of sampling and/or villi detected on pathologic analysis were diagnosed with failing intrauterine pregnancy and had weekly beta‐human chorionic gonadotropin measurements thereafter. Those patients with beta‐human chorionic gonadotropin declines <15% and no villi identified were diagnosed with ectopic pregnancy and treated with intramuscular methotrexate (50 mg/m2) or laparoscopy. RESULTS: Across 8 years of follow up, among women with pregnancy of unknown location, failed intrauterine pregnancy was diagnosed in 46 patients (42%), and ectopic pregnancy was diagnosed in 64 patients (58%). Clinical variables that included fresh or frozen embryo transfer, day of embryo transfer, serum beta‐human chorionic gonadotropin at the time of sampling, endometrial thickness, and presence of an adnexal mass were not significantly different between patients with failed intrauterine pregnancy or ectopic pregnancy. In patients with failed intrauterine pregnancy, 100% demonstrated adequate postsampling beta‐human chorionic gonadotropin declines; villi were identified in just 46% (n=21 patients). Patients with failed intrauterine pregnancy had significantly shorter time to resolution (negative serum beta‐human chorionic gonadotropin) after sampling compared with patients with ectopic pregnancy (12.6 vs 26.3 days; P<.001). CONCLUSION: With the use of this safe and effective protocol of endometrial aspiration with Karman cannula, a large proportion of women with pregnancy of unknown location are spared methotrexate, with a shorter time to pregnancy resolution than those who receive methotrexate.