Katharine F. Correia

Predictors and variability of urinary paraben concentrations in men and women, including before and during pregnancy.

Background: Parabens are suspected endocrine disruptors and ubiquitous preservatives used in personal care products, pharmaceuticals, and foods. No studies have assessed the variability of parabens in women, including during pregnancy. Objective: We evaluated predictors and variability of urinary paraben concentrations. Methods: We measured urinary concentrations of methyl (MP), propyl (PP), and butyl paraben (BP) among couples from a fertility center. Mixed-effects regression models were fit to examine demographic predictors of paraben concentrations and to calculate intraclass correlation coefficients (ICCs). Results: Between 2005 and 2010, we collected 2,721 spot urine samples from 245 men and 408 women. The median concentrations were 112 µg/L (MP), 24.2 µg/L (PP), and 0.70 µg/L (BP). Urinary MP and PP concentrations were 4.6 and 7.8 times higher in women than men, respectively, and concentrations of both MP and PP were 3.8 times higher in African Americans than Caucasians. MP and PP concentrations we CI re slightly more variable in women (ICC = 0.42, 0.43) than men (ICC = 0.54, 0.51), and were weakly correlated between partners (r = 0.27–0.32). Among 129 pregnant women, urinary paraben concentrations were 25–45% lower during pregnancy than before pregnancy, and MP and PP concentrations were more variable (ICCs of 0.38 and 0.36 compared with 0.46 and 0.44, respectively). Conclusions: Urinary paraben concentrations were more variable in women compared with men, and during pregnancy compared with before pregnancy. However, results for this study population suggest that a single urine sample may reasonably represent an individual’s exposure over several months, and that a single sample collected during pregnancy may reasonably classify gestational exposure.

The association between severe obesity and characteristics of failed fertilized oocytes

STUDY QUESTION Is the cytoskeletal and chromosomal organization of failed fertilized oocytes from severely obese patients (BMI ≥ 35 kg/m²) altered compared with that in patients with normal BMI (BMI 18.5-24.9 kg/m²)? SUMMARY ANSWER Compared with normal BMI patients, severe obesity was associated with a greater prevalence of spindle anomalies and non-aligned chromosomes in failed fertilized oocytes. WHAT IS KNOWN AND WHAT THIS PAPER ADDS Obesity is associated with poor reproductive outcomes, but little is known regarding the underlying mechanisms. To address potential mechanisms, our study compared the cytoskeletal and chromosome organization in failed fertilized oocytes from severely obese and normal BMI patients. DESIGN The study population was drawn from IVF patients treated in a hospital-based infertility clinic between February 2010 and July 2011. The prevalence of meiotic spindle and chromosome alignment anomalies in failed fertilized oocytes from patients with severe obesity (i.e. Class II and III; BMI 35.0-50.1 kg/m²) was compared with those from patients with normal BMI (BMI 18.5-24.9 kg/m²). Oocytes were fixed and then labeled for tubulin, actin and chromatin. Spindle number and integrity, as well as chromosome alignment, were assessed using immunofluorescence microscopy and, in some cases, confocal microscopy. Generalized estimating equations were applied, which account for the correlation among oocytes from the same patient to estimate odds ratio (OR), 95% confidence intervals (CIs) and two-sided Wald P-values. Models were adjusted for continuous age at cycle start, cycle type (IVF or ICSI) and polycystic ovarian syndrome (PCOS) a priori. PARTICIPANTS AND SETTING University-affiliated infertility clinic. A total of 276 oocytes that failed to fertilize from 137 patients were evaluated: 105 oocytes from severely obese women (n = 47) and 171 oocytes from normal BMI patients (n = 90). MAIN RESULTS AND THE ROLE OF CHANCE (i) Significantly more oocytes from the severely obese group exhibited two spindles compared with those from the normal BMI group (58.9 versus 35.1%; OR = 2.68, CI = 1.39-5.15, P-value = 0.003). (ii) Among oocytes with a single spindle, those from severely obese patients showed a significantly higher prevalence of disarranged spindles with non-aligned chromosomes compared with those from normal BMI patients (28.6 versus 8.6%; OR = 4.58, CI = 1.05-19.86, P-value = 0.04). BIAS, CONFOUNDING AND OTHER REASONS FOR CAUTION Inclusion of only failed fertilized oocytes, small sample size, unknown factors such as non-PCOS comorbidity. GENERALIZABILITY TO OTHER POPULATIONS For this study, by design, it is unclear whether the findings are generalizable to successfully fertilized oocytes, and whether this oocyte-level influence of obesity is generalizable to infertile women who do not undergo stimulation or, more broadly, to spontaneous conceptions in fertile women. STUDY FUNDING/COMPETING INTEREST(S) none. TRIAL REGISTRATION NUMBER n/a.

Bisphenol-A and human oocyte maturation in vitro

STUDY QUESTION Does exposure to bisphenol-A (BPA) affect the maturation of human oocytes in vitro? SUMMARY ANSWER There was a dose-response association of BPA exposure with altered human oocyte maturation in vitro. WHAT IS KNOWN ALREADY There is widespread exposure of the general population to BPA. BPA has been detected in the human follicular fluid. Animal studies have shown that BPA exposure is associated with maturation arrest and spindle abnormalities in maturing oocytes. STUDY DESIGN, SIZE, DURATION A randomized trial, using 352 clinically discarded oocytes from 121 patients. PARTICIPANTS/MATERIALS, SETTING, METHODS The study population was drawn from patients undergoing IVF/ICSI cycles in our program at Brigham and Womens Hospital from March 2011 to April 2012. Oocytes from only one cycle for each patient were included in the study. Cycles with at least two germinal vesicle stage oocytes were included with random allocation of one oocyte to culture for 30 h without BPA and remaining sibling oocytes to medium-containing BPA (20, 200 ng/ml or 20 µg/ml). Oocytes were fixed and labeled for tubulin, actin and chromatin and examined with immunofluorescence and confocal microscopy. Oocytes were assessed for meiotic stage (n = 292), and those at metaphase II (MII, n = 175) were further classified according to their spindle configurations and patterns of chromosome alignment. McNemars test was used to compare dichotomized maturation status. Generalized estimating equations were used to account for the correlation between oocytes from the same woman and for the spindle analysis. MAIN RESULTS AND THE ROLE OF CHANCE As the BPA dose increased, there was a decrease in the percentage of oocytes that progressed to MII (P = 0.002) and increases in the percentage of oocytes that were degenerated (P = 0.01) or that had undergone spontaneous activation (P = 0.007). Among MII oocytes, as the BPA dose increased, there was a significant trend (by test for trend) for a decreased incidence of bipolar spindles (P < 0.0001) and aligned chromosomes (P = 0.02). LIMITATIONS, REASONS FOR CAUTION Although we used sibling oocytes to overcome potential confounders, such as infertility diagnosis and maternal age, additional studies with a larger number of oocytes are required to confirm the present results. Having access only to clinically discarded oocytes, we were limited to evaluating only those oocytes that failed to mature in vivo despite having been exposed to gonadotrophin stimulation and the ovulatory trigger of HCG. WIDER IMPLICATIONS OF THE FINDINGS To our knowledge, this is the first study investigating the effect of BPA on oocyte meiotic maturation, spindle morphology and chromosome alignment in human oocytes. Together with prior animal studies, the data support the negative influences of BPA on cell cycle progression, spindle architecture and chromosome organization during oocyte maturation. Furthermore, the increased rates of abnormal maturation in oocytes exposed to BPA may be relevant to our understanding of the decrease in fertility reported in the last decades. STUDY FUNDING/COMPETING INTEREST(S) This study was funded by the NIEHS Center Grant Pilot Project (P30-ES000002). R.M. was sponsored by a fellowship from the Environmental Health Fund, Israel and by the Frederick L. Hisaw Endowment, Harvard School of Public Health. There are no conflicts of interest. TRIAL REGISTRATION NUMBER n/a.

Robot-assisted laparoscopic myomectomy compared with standard laparoscopic myomectomy.

OBJECTIVE: To compare surgical outcomes of laparoscopic myomectomy and robot-assisted laparoscopic myomectomy. METHODS: Retrospective cohort study of 115 consecutive laparoscopic myomectomy and 174 consecutive robot-assisted laparoscopic myomectomy performed at Brigham and Womens Hospital over a period of 31 months. Uterine incisions were closed in multiple layers (running barbed suture was used for most cases in the laparoscopic myomectomy group). Surgical outcomes measured included operative time, estimated intraoperative blood loss, length of hospital stay, and perioperative complications. Odds ratios and 95% confidence intervals were calculated from multivariable logistic regression models; adjusted geometric means were estimated from linear regression models on logged outcomes because of skewed distributions. RESULTS: Surgical groups were similar in age, body mass index, and leiomyoma characteristics. Robot-assisted laparoscopic myomectomy had significantly longer operative time than laparoscopic myomectomy (adjusted geometric mean of 195.1 compared with 118.3 minutes, P<.001) and higher estimated blood loss (adjusted geometric mean of 110.0 compared with 85.9 mL, P=.04), but postoperative complications were similar. CONCLUSION: Robot-assisted laparoscopic myomectomy and laparoscopic myomectomy have similar operative outcomes in a high-volume surgical practice. Operative time and intraoperative estimated blood loss were significantly greater in the robot-assisted laparoscopic myomectomy group, but the level of statistical significance for intraoperative estimated blood loss was marginal and the clinical significance was undetermined. Use of barbed suture in the laparoscopic myomectomy group may account for these differences. LEVEL OF EVIDENCE: II

Pharmacokinetics of Human Chorionic Gonadotropin Injection in Obese and Normal-Weight Women

CONTEXT Obese women have poorer in vitro fertilization outcomes, but underlying mechanisms remain unclear. OBJECTIVE The objectives of the study were to compare the pharmacokinetics of human chorionic gonadotropin (hCG) and ovarian steroid hormone production, after subcutaneous (s.c.) and intramuscular (i.m.) injection of hCG in obese and normal-weight women. DESIGN AND SETTING This was a randomized, experimental study. PATIENTS OR OTHER PARTICIPANTS Twenty-two women aged 18-42 years with body mass index of 18.5-24.9 (normal) or 30-40 kg/m(2) (obese). INTERVENTIONS Participants received im urinary hCG or s.c. recombinant hCG and returned for a second injection type after a 4-week washout. Intramuscular injections were performed under ultrasound guidance. Blood was taken 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 36 hours after injection. MAIN OUTCOME MEASURES hCG was measured at each time point; estradiol, progesterone, 17-hydroxyprogesterone (17-OHP), testosterone (T), dehydroepiandrosterone, and SHBG were measured at 0 and 36 hours. RESULTS Twenty-two women completed the study. In both normal-weight and obese women, peak serum concentration (Cmax), area under the curve (AUC), and average hCG concentration were higher after i.m. injection as compared with s.c. injection (all P < .003). Obese women had markedly lower Cmax, AUC, and average hCG concentration after s.c. injection as compared with normal-weight women (P = .02, P = .009, and P = .008, respectively). After i.m. injection, Cmax, AUC, and average concentration were similar for normal-weight and obese women (P = .31, P = .25, and P = .18, respectively). Thirty-six percent of obese women had muscular layers beyond the reach of a standard 1.5 inch needle. hCG caused a significant rise in 17-OHP in both obese and normal-weight women and an increase in T in obese but not normal-weight women (all P < .04). CONCLUSIONS Subcutaneous injection yields lower hCG levels in obese women. Standard-length needles are insufficient to administer i.m. injections in many obese women.

Population-based study of attitudes toward posthumous reproduction

OBJECTIVE To measure public attitudes toward posthumous reproduction. DESIGN Cross-sectional study. SETTING Electronic survey. PATIENT(S) A total of 1,049 men and women living in the United States between the ages of 18 and 75 years. INTERVENTION(S) Multiple-choice questionnaire. MAIN OUTCOME MEASURE(S) Descriptive statistics regarding support for posthumous reproduction, such as regarding emergency harvesting of gametes, and attitudes toward consent; multivariable analyses of demographic and personal experiences associated with support for posthumous reproduction. RESULT(S) Results showed that 47.8% supported and 31.1% opposed retrieving gametes from men, and 42.7% supported and 35.9% opposed retrieving gametes from women. The remainder was undecided. Among supporters, 69.8% believed prior consent from the deceased was required. Support was positively associated with younger age, higher education, higher income, Democratic political party affiliation, history of infertility, and currently attempting conception. Gender, religion, race, and region of the country were not associated with support. Organ donors and those who support IVF were more likely to support posthumous reproduction (odds ratio [95% confidence interval] 1.68 [1.19-2.38] and 12.30 [6.56-23.04], respectively). Most respondents were initially unfamiliar with posthumous reproduction. CONCLUSION(S) Almost 50% of the general population support posthumous reproduction in men and women. The majority favored prior consent from the deceased. These data caution against emergency gamete harvesting without prior consent.

Prenatal food allergen exposures and odds of childhood peanut, tree nut, or sesame seed sensitization

BACKGROUND The prevalence of peanut (PN) and tree nut (TN) allergy in children has tripled in the past decade. Prenatal exposures, including maternal diet and medications, may account for some of this increase. In the United States, progesterone for luteal support in assisted reproduction is commonly formulated in PN or sesame seed (SS) oil. OBJECTIVE To determine whether prenatal exposure to PN or SS oil as progesterone in oil increases the childs odds of PN, TN, or SS allergy. METHODS Parents of 1,272 children evaluated by allergists from May 2005 through October 2009 completed questionnaires on conception, prenatal exposures, dietary history, and allergic history, with review of the childs medical record and skin prick and specific IgE test results. Odds ratios and 95% confidence intervals were calculated using multivariable adjusted logistic regression models. RESULTS Children of mothers with a history of infertility, in vitro fertilization, or use of progesterone in oil did not have increased odds of PN, TN, and/or SS sensitization. Maternal consumption of TNs during first 2 trimesters was associated with 60% higher odds of having a PN/TN/SS-sensitized child (95% confidence interval 1.01-2.51), with similarly increased odds with maternal SS ingestion. Odds of PN/TN/SS sensitization were doubled in children with asthma or environmental allergies. CONCLUSION Neither maternal infertility nor exposure to PN or SS oils through progesterone support during assisted reproduction treatment was associated with increased odds of PN/TN/SS sensitization in the child. However, maternal ingestion of TNs and SS during pregnancy was associated with increased odds of PN/TN/SS sensitization in the child.

Efficacy of intrauterine inseminations as a training modality for performing embryo transfer in reproductive endocrinology and infertility fellowship programs

OBJECTIVE To assess pregnancy rates before and after a training intervention in which reproductive endocrinology and infertility fellows were required to perform 100 IUIs before performing ETs. DESIGN Retrospective cohort study. SETTING Large, academic training program. PATIENT(S) Not applicable. INTERVENTION(S) Comparing pregnancy rates between two time periods: July 1998-June 2001 (before IUI intervention) and July 2001-June 2010 (after IUI intervention). MAIN OUTCOME MEASURE(S) Clinical pregnancy rate (PR) for the first 100 ETs performed by fellows before and after the IUI training; median attending physician PR during each time period served as the referent. Multivariate generalized estimating equations were used to calculate odds of pregnancy per ET for fellows as compared with attending physicians. RESULT(S) Multivariate analyses revealed no significant difference in PR for the first 100 ETs performed by fellows as compared with attending physicians, before or after the IUI training requirement (odds ratio 0.99, 95% confidence interval 0.82-1.20 and odds ratio 0.91, 95% confidence interval 0.81-1.30, respectively). The median attending physician PR in the preintervention group was exceeded by fellows after the first 70 ETs; fellows in the postintervention group exceeded the median attending physician PR after 100 ETs. The PR in both groups improved as fellows progressed from the first 20 to 100 ETs. CONCLUSION(S) The PR for the first 100 ETs performed by fellows was unchanged after implementing an IUI training requirement. The substantial variation noted among individual fellows decreased as more ETs were completed.

Early beta-human chorionic gonadotropin trends in vanishing twin pregnancies

OBJECTIVE To describe the early β-hCG trends in vanishing twins compared with normally progressing singleton and twin pregnancies. DESIGN Retrospective cohort study. SETTING University-based infertility clinic. PATIENT(S) Women undergoing fresh IVF/intracytoplasmic sperm injection (ICSI) cycles between 1998 and 2010. INTERVENTION(S) Early β-hCG level increase in vanished twin pregnancies was compared with the level increase in normally progressing singleton and twin pregnancies. MAIN OUTCOME MEASURE(S) Two-day percent increase in β-hCG level. RESULT(S) Pregnancies with vanishing twins demonstrated a significantly lower mean 2-day percent increase in β-hCG level than singletons and twins (114.3% vs. 128.8% and 125.4%, respectively). Vanishing twins arresting at earlier developmental stages demonstrated significantly further reduced β-hCG level increases. Infrequently, all groups had β-hCG level increases less than previously established clinical thresholds that led to a live birth. CONCLUSION(S) Early β-hCG level increases are slower in vanishing twins than in singleton and twin pregnancies, with the slowest increases seen when the spontaneous fetal losses occur at earlier developmental stages. All increases, however, are within clinically accepted normal limits. Therefore, abnormal β-hCG level increases should not be attributed to a vanishing twin. Of note, an abnormal β-hCG level trend--even an initial decrease--does not preclude live birth, even in a singleton pregnancy.

Ovarian Reserve in Women Treated for Acute Lymphocytic Leukemia or Acute Myeloid Leukemia with Chemotherapy, but Not Stem Cell Transplantation

Purpose. It is well known that chemotherapy regimens may have a negative effect on ovarian reserve, leading to amenorrhea or premature ovarian failure. There are little data regarding the effects of leukemia chemotherapy on ovarian reserve, specifically in women who received the chemotherapy as adults and are having regular menstrual periods. Our primary objective was to determine if premenopausal women with a history of chemotherapy for leukemia, without subsequent stem cell transplantation, have decreased ovarian reserve. Materials and Methods. We measured ovarian reserve in five women who had been treated for acute lymphocytic leukemia (ALL) or acute myeloid leukemia (AML) and compared them to age-matched control women without a history of chemotherapy. Results. There appeared to be a trend towards lower antimullerian hormone and antral follicle counts and higher follicle-stimulating hormone levels in the leukemia group. Conclusion. Our results indicate that chemotherapy for AML or ALL without stem cell transplantation may compromise ovarian reserve. Although our results should be confirmed by a larger study, oncologists, infertility specialists, and patients should be aware of the potential risks to ovarian function and should be counseled on options for fertility preservation.