Reproductive Decision-Making in Women with BRCA1/2 Mutations.

Expanded genetic testing of BRCA mutations has led to identification of more reproductive-aged women who test positive for the mutation which might impact attitudes and decisions about relationships, childbearing and the use of preimplantation genetic diagnosis (PGD) and prenatal diagnosis (PND). A cross-sectional survey was administered to 1081 self-reported BRCA carriers to investigate how knowledge of BRCA status influences these issues. The mean age at BRCA test disclosure was 44 years and 36 % reported a personal history of cancer. Of 163 women who were unpartnered, 21.5 % felt more pressure to get married. Of 284 women whose families were not complete, 41 % reported that carrier status impacted their decision to have biological children. Women with a history of cancer were more likely to report that knowledge of BRCA+ status impacted their decision to have a child (OR 1.8, 95 % CI 1-3.2). Fifty-nine percent thought PGD should be offered to mutation carriers and 55.5 % thought PND should be offered. In conclusion, knowledge of BRCA status impacts attitudes regarding relationships and childbearing, and most carriers believe that PGD and PND should be offered to other carriers. This study suggests that BRCA carriers desire and would benefit from reproductive counseling after test disclosure.

Outcomes of ovarian stimulation after treatment with chemotherapy.

PURPOSE: Chemotherapeutic agents have a known gonadotoxic effect; however, it is difficult to predict the impact they may have on ovarian stimulation. The objective of this study was to evaluate response to ovarian stimulation in patients exposed to chemotherapy compared with patients who were chemotherapy-naïve. METHODS: A retrospective cohort study of 130 patients with cancer or autoimmune disease was performed. Demographics, ovarian reserve, ovarian response and stimulation parameters, and oocyte data were compared between patients who were pre- and post-chemotherapy. Logistic regression modeling was performed to identify risk factors for cancellation and low oocyte yield, adjusting for confounders as appropriate. RESULTS: Antral follicle count (AFC) was significantly lower in post-chemo patients (9 vs. 17, p < 0.001). Post-chemotherapy patients were more likely to be cancelled during stimulation (23 vs. 4 %, p = 0.003). Among those that went to retrieval, there was no difference in total number of oocytes (10 vs. 10, p = 0.31) or mature oocytes retrieved (8 vs. 8, p = 0.38), despite higher starting (300 vs. 450 IU, p < 0.001) and total gonadotropin (3075 vs. 4612.5 IU, p = 0.008) doses in post-chemotherapy patients. Low AFC (≤6) was associated with cycle cancellation (OR 7.7, 95 % CI 1.8-33.2) and low oocyte yield (<6) (OR 5.4, 95 % CI 1.6-17.7). CONCLUSIONS: Patients post-chemotherapy have lower AFC compared with the chemotherapy-naïve and have higher cancellation rates. Among those who underwent oocyte retrieval, oocyte yield was similar in both groups. Low AFC was most strongly associated with cycle cancellation and oocyte yield. Post-chemotherapy patients had higher rates of cycle cancellation but did equally well as pre-chemotherapy patients if they reached retrieval.

Response to ovarian stimulation in patients facing gonadotoxic therapy.

Chemotherapy naïve patients undergoing embryo/oocyte banking for fertility preservation (FP) were assessed for response to ovarian stimulation. Fifty FP patients facing gonadotoxic therapy were matched by age, race, cycle number, date of stimulation and fertilization method to patients undergoing IVF for infertility or oocyte donation. There were no differences in baseline FSH, anti-Müllerian hormone, antral follicle count and total gonadotrophin dose. FP patients had more immature oocytes (2.2 versus 1.1; P=0.03) and lower fertilization rates per oocyte retrieved (52% versus 70%; P=0.002). There were no differences in numbers of oocytes retrieved, mature oocytes or fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses (3077IU versus 2259IU; P=0.0477) and had more immature oocytes (3.4 versus 1.2; P=0.03) than matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. Overall, chemotherapy naïve FP patients had similar ovarian reserve, response to stimulation and oocyte and embryo yield compared to controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole. With improvement in cancer survival rates, there has been a shift in attention toward management of long-term consequences of cancer therapy, including infertility. Many young women with cancer, particularly those who will be treated with chemotherapy, pursue fertility preservation (FP) strategies for the purpose of banking oocytes or embryos for future use. We examined patients with no prior exposure to chemotherapy who underwent IVF to freeze embryos or oocytes for FP. Fifty FP patients were identified and matched to healthy controls by age, race, cycle number, date of stimulation and fertilization method. There were no differences in baseline measures of ovarian reserve or amount of medication needed to stimulate the ovaries. FP patients had more immature oocytes and lower fertilization rates than controls. There were no differences in number of oocytes retrieved, number of mature oocytes, rate of maturity or number of fertilized embryos. Subgroup analysis revealed that FP patients taking letrozole required higher gonadotrophin doses and had more immature oocytes compared with matched controls. There were no differences in gonadotrophin dose or oocyte immaturity among FP patients not taking letrozole. We demonstrated that FP patients not previously exposed to chemotherapy have similar ovarian reserve, response to stimulation and oocyte and embryo yield compared with infertile and donor controls. Patients who received letrozole required higher gonadotrophin doses and produced more immature oocytes, suggesting that response to ovarian stimulation may be impaired in patients with hormone-sensitive cancers receiving letrozole.

Body mass index and severe postpartum hemorrhage.

BACKGROUND/AIMS: The purpose of this study was to determine the relationship between maternal characteristics and severe postpartum hemorrhage (PPH). METHODS: Medical records of women who delivered at Duke University Hospital between 2001 and 2004 with an ICD-9 code for PPH were reviewed. Women with PPH who received blood component therapy (severe PPH) were selected as cases and compared with controls matched for age, parity and mode of delivery. RESULTS: Among 12,476 deliveries, there were 109 women with severe PPH. Hispanic women had an almost fourfold increase in the odds of severe PPH [OR 3.9 (1.8, 8.7)] that persisted when controlling for other significant predictors of PPH. Women with PPH were almost two times more likely [OR 1.8 (1.1, 3.1)] to have a BMI <30 when controlling for Hispanic ethnicity, oxytocin exposure, labor induction, treatment with magnesium and chorioamnionitis. CONCLUSION: Systemic factors as well as obstetrical factors modify the risk of severe PPH. Hispanic women and women with a BMI <30 are more likely to have severe PPH. When mode of delivery is controlled for, BMI ≥30 is associated with a reduced risk of severe PPH.

Oxytocin exposure during labor among women with postpartum hemorrhage secondary to uterine atony.

OBJECTIVE: We sought to determine if women with severe postpartum hemorrhage (PPH) secondary to uterine atony received greater amounts of oxytocin during labor compared to women without PPH. STUDY DESIGN: Subjects with severe PPH secondary to uterine atony, who received a blood transfusion, were compared to matched controls. Total oxytocin exposure was calculated as the area under the concentration curve (mU/min*min). Variables were compared using paired t test, χ², and logistic regression. RESULTS: Women with severe PPH had a mean oxytocin area under the curve of 10,054 mU compared to 3762 mU in controls (P < .001). After controlling for race, body mass index, admission hematocrit, induction status, magnesium therapy, and chorioamnionitis using logistic regression, oxytocin area under the curve continued to predict severe PPH. CONCLUSION: Women with severe PPH secondary to uterine atony were exposed to significantly more oxytocin during labor compared to matched controls.

Risk factors for sexual dysfunction in BRCA mutation carriers after risk-reducing salpingo-oophorectomy.

OBJECTIVE: The aim of the study was to identify risk factors for sexual dysfunction in BRCA mutation carriers who have undergone risk-reducing salpingo-oophorectomy (RRSO). METHODS: A cross-sectional study was performed. BRCA1/2 mutation carriers with and without RRSO were surveyed to determine sexual function (Female Sex Function Index [FSFI]), demographics, medical history, sleep quality, depression, and anxiety scores. Characteristics of patients with the lowest quartile of FSFI scores (<14 ±â€Š8.8) were analyzed to identify risk factors for the most severe phenotype. RESULTS: In the 804 women surveyed, 764 underwent RRSO. Of the 529 (69%) carriers with completed FSFI questionnaires in the RRSO cohort, sexual dysfunction was reported in 77.3%. Poor sleep (P = 0.002), hot flashes (P = 0.002), lack of current systemic hormone therapy (HT) use (P = 0.002), depression (P < 0.001), and anxiety (P = 0.001) were associated with sexual dysfunction. In adjusted analyses, depression (adjusted odds ratio [aOR] 2.4, 95% CI, 1.4-4.1) and hot flashes (aOR 1.9, 95% CI, 1.2-3.0) remained significantly associated with sexual dysfunction. Depression was also a significant risk factor for the most severe degree of sexual dysfunction (OR 2.1, 95% CI, 1.3-3.5) and had the greatest impact on Arousal and Satisfaction domain scores of the FSFI. Current systemic HT use seemed to decrease the risk for sexual dysfunction (aOR 0.6, 95% CI, 0.4-1.0). CONCLUSIONS: Sexual dysfunction is highly prevalent in BRCA mutation carriers after RRSO. Depression seems to be a significant risk factor for sexual dysfunction in this patient population and may be under-recognized and undertreated. Patient and provider education on sexual side effects after surgery and risk factors for sexual dysfunction is necessary to decrease postoperative sexual distress. HT may be associated with improved sexual function after surgery.

Biochemical Pathways and Myometrial Cell Differentiation Leading to Nodule Formation Containing Collagen and Fibronectin.

Utilizing both primary myometrial cells and a myometrial cell line, we show here that myometrial cells undergo transition to a myofibroblast-like phenotype after a biological insult of 72 hours serum starvation and serum add-back (SB: 1% to 10% FBS). We also found that thrombospondin-1 was increased and that the transforming growth factor-beta (TGFB)-SMAD3/4 pathway was activated. This pathway is a key mediator of fibrosis and extracellular matrix (ECM) deposition. Applying the same insult supplemented with TGFB3 (1-10ng/ml) and ascorbic acid (100µg/ml) in the serum add-back treatment, we further demonstrated that cells migrated into nodules containing collagen and fibronectin. The number of cellnodules was inversely related to the percentage serum add-back. Using transmission electron microscopy we demonstrated myofibroblast-like cells and fibril-like structures in the extracellular spaces of the nodules. This study is the first direct evidence of induction of myofibroblast transdifferentiation in cultured myometrial cells which is related to the increase of thrombospondin-1 (THBS1) and the activation of TGFBSMAD 3 / 4 pathways. Combined, these observations provide biochemical and direct morphological evidence that fibrotic responses can occur in cultured myometrial cells. The findings are the first to demonstrate uterine healing mechanisms at a molecular level. Our data support the concept that fibrosis may be an initial event in formation of fibroid which exhibits signaling pathways and molecular features of fibrosis and grow by both cellular proliferation and altered extracellular matrix accumulation. Our data assists in further understanding of myometrium tissue remodeling during gestation and postpartum.

Black women with polycystic ovary syndrome (PCOS) have increased risk for metabolic syndrome and cardiovascular disease compared with white women with PCOS [corrected].

OBJECTIVE: To determine the prevalence of metabolic syndrome (MetSyn) and Framingham cardiovascular disease (CVD) risk in white and black adolescents and adult women with polycystic ovary syndrome (PCOS) compared with controls. DESIGN: Retrospective cohort study. SETTING: Center for PCOS. PATIENT(S): Subjects with PCOS with data on race and cardiometabolic risk (n = 519). Controls were age and race matched from the National Health and Nutrition Examination Survey (NHANES) population (1999-2006). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): MetSyn, coronary heart disease risk, and general CVD risk. RESULT(S): Black adolescents and young adults with PCOS had an increased prevalence of MetSyn compared with their white counterparts (adolescents relative risk 2.65 [95% confidence interval 1.29-5.4], adults relative risk 1.44 [95% confidence interval 1.21-2.6]). In contrast, there was no difference in risk of MetSyn between black and white adolescents and adult women in the NHANES dataset. After controlling for age and body mass index, black women with PCOS had a significantly increased prevalence of low high-density lipoprotein and high glucose. The general CVD risk was significantly increased in black adults with PCOS. CONCLUSION(S): This is the first study to comprehensively demonstrate increased risk of MetSyn in both black adolescents and adult women with PCOS compared with white subjects with PCOS. This racial disparity was not present in the NHANES controls. Longitudinal studies are needed to assess the independent impact of PCOS and race on CVD risk in women.

Antimüllerian hormone and antral follicle count are lower in female cancer survivors and healthy women taking hormonal contraception.

OBJECTIVE: To determine the impact of hormonal contraception (HC) on markers of ovarian reserve, including antimüllerian hormone (AMH) and antral follicle count (AFC). DESIGN: Longitudinal prospective cohort. SETTING: University hospital. PATIENT(S): Young adult female cancer survivors and healthy similar-age women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Participants were followed annually to determine hormone levels and for transvaginal ultrasound. Subjects who used HC within the preceding 3 months were considered to be exposed. Linear mixed effects models were used to incorporate repeated measures and adjust for potential confounders. RESULT(S): A total of 249 women (126 survivors, 123 control subjects; average age 25.5 years) were followed for an average of 2.1 visits and 2.15 years. After adjusting for confounders, AMH was found to be 21% lower among survivors using HC and 55% lower among control subjects using HC (relative risk [RR] 0.79, 95% confidence interval [CI] 0.68-0.93; and RR 0.45, 95% CI 0.30-0.68; respectively). AFC was 20% lower among survivors and control subjects using HC (RR 0.80, 95% CI 0.69-0.93). When considering an individual subject, AMH was 17%-35% lower when a subject had recently used HC than when she had not (survivors: RR 0.83, 95% CI 0.75-0.93; control subjects: RR 0.65, 95% CI 0.55-0.78), and AFC was 11% lower (RR 0.89, 95% CI 0.82-0.96). Additive HC exposure across multiple visits was not associated with differences in AMH or AFC. CONCLUSION(S): AMH and AFC are significantly lower among women with recent exposure to HC. AMH and AFC should be interpreted with caution when measured in the setting of recent hormone use.

Medical and obstetric complications among pregnant women aged 45 and older.

OBJECTIVE: The number of women aged 45 and older who become pregnant is increasing. The objective of this study was to estimate the risk of medical and obstetric complications among women aged 45 and older. METHODS: The Nationwide Inpatient Sample was used to identify pregnant woman during admission for delivery. Deliveries were identified using International Classification of Diseases, Ninth Revision (ICD-9-CM) codes. Using ICD-9-CM codes, pre-existing medical conditions and medical and obstetric complications were identified in women at the time of delivery and were compared for women aged 45 years and older to women under age 35. Outcomes among women aged 35-44 were also compared to women under age 35 to determine if women in this group demonstrated intermediate risk between the older and younger groups. Logistic regression analyses were used to calculate odds ratios with 95% confidence intervals for pre-existing medical conditions and medical and obstetric complications for both older groups relative to women under 35. Multivariable logistic regression analyses were also developed for outcomes at delivery among older women, while controlling for pre-existing medical conditions, multiple gestation, and insurance status, to determine the effect of age on the studied outcomes. RESULTS: Women aged 45 and older had higher adjusted odds for death, transfusion, myocardial infarction/ischemia, cardiac arrest, acute heart failure, pulmonary embolism, deep vein thrombosis, acute renal failure, cesarean delivery, gestational diabetes, fetal demise, fetal chromosomal anomaly, and placenta previa compared to women under 35. CONCLUSION: Pregnant women aged 45 and older experience significantly more medical and obstetric complications and are more likely to die at the time of a delivery than women under age 35, though the absolute risks are low and these events are rare. Further research is needed to determine what associated factors among pregnant women aged 45 and older may contribute to these findings.

Does intracytoplasmic sperm injection improve the fertilization rate and decrease the total fertilization failure rate in couples with well-defined unexplained infertility? A systematic review and meta-analysis.

OBJECTIVE: To determine if intracytoplasmic sperm injection (ICSI), compared with conventional insemination, improves fertilization rates and prevents total failed fertilization (TFF) in couples with unexplained infertility. DESIGN: Systematic review and meta-analysis. SETTING: IVF centers. PATIENT(S): Couples with well-defined unexplained infertility undergoing IVF. INTERVENTION(S): A systematic review was performed by searching Medline and Embase for 1992-2012. Studies in which sibling oocytes were randomly split between conventional insemination and ICSI were included. A random effects model was utilized for the meta-analysis. Meta-analysis of Observational Studies in Epidemiology guidelines were applied. MAIN OUTCOME MEASURE(S): Fertilization rate and TFF rate by insemination method. RESULT(S): Eleven studies with a total of 901 couples (female age range 30-35 years) with 11,767 sibling oocytes were included in the meta-analysis. The pooled relative risk (RR) of a mature oocyte fertilizing was higher with ICSI than with conventional insemination (RR 1.49, 95% confidence interval [CI] 1.35-1.65.) The pooled RR of fertilization per allocated oocyte (before randomization) was higher with ICSI than with conventional insemination (RR 1.27, 95% CI 1.02-1.58; n = 5 studies.) The pooled RR of TFF was significantly higher with conventional insemination than with ICSI (RR 8.22, 95% CI 4.44-15.23). The number of subjects needed to treat with ICSI to prevent one case of TFF was five. CONCLUSION(S): This meta-analysis favors the use of ICSI to increase fertilization rates and decrease the risk of TFF in couples with well-defined unexplained infertility. Further studies are needed to determine the impact on clinical pregnancy and live birth rate.