Predictors and outcomes in breast cancer patients who did or did not pursue fertility preservation.

PURPOSE: Breast cancer is the most common cancer in reproductive age women, and treatment can affect fertility; however, there is often concern regarding the safety of increased estradiol (E2) levels and potential delays in treatment with ovarian stimulation for fertility preservation (FP). The aim of this study was to compare recurrence and survival in breast cancer patients who pursued FP without concurrent letrozole to those who did not (non-FP). METHODS: We reviewed charts of women with breast cancer who contacted the FP patient navigator (PN) at Northwestern University from 01/2005-01/2018. Oncology and fertility outcome data were collected. Data were analyzed by Chi-square test or regression, as appropriate. Kaplan-Meier curves were used to examine breast cancer recurrence and survival. Statistical analyses were performed with SPSS IBM Statistics 26.0 for Windows. RESULTS: 332 patients were included, of which 157 (47.3%) underwent FP. Median days to treatment after consulting the PN was 35 in the FP group and 21 in non-FP (p < 0.05). Cancer recurrence was noted in 7 (4.7%) FP patients and 13 (7.9%) non-FP patients (NS), and mortality in 5 (3.2%) FP patients and 7 (4.2%) non-FP patients (NS). Within the FP group, no significant differences were found in recurrence or mortality based on ER status, age, BMI, peak E2 level or total gonadotropin dose. Likelihood of pursuing FP was primarily a function of age and parity, and was not affected by breast cancer stage. To date, 21 have used cryopreserved specimens, and 13 (62%) had a live birth. CONCLUSIONS: FP is safe and effective in breast cancer patients, regardless of receptor status; E2 elevations and the 2-week delay in treatment start are unlikely to be clinically significant. These findings are unique in that our institution does not use concomitant letrozole during stimulation to minimize E2 elevations in breast cancer patients.

Psychological Counseling of Female Fertility Preservation Patients.

Young cancer patients are increasingly interested in preserving their fertility prior to undergoing gonadotoxic therapies. Although the medical safety and treatment protocols for fertility preservation have been well documented, limited research has addressed the emotional issues that arise in fertility preservation patients. We briefly review the literature on the psychosocial issues in adult female fertility preservation treatment and describe our experiences within this patient population. Our findings suggest that several important issues to be addressed during the psychological counseling of adult female fertility preservation patients include: (1) preexisting psychological distress in patients undergoing treatment, (2) choice of fertility preservation strategy in the face of an uncertain relationship future, (3) decision making regarding use of third-party reproduction (e.g., sperm/egg donation, gestational surrogacy), (4) treatment expectations regarding pregnancy and miscarriage, (5) ethical issues related to treatment including the creation, cryopreservation, and disposition of embryos/oocytes, and (6) decision regret from patients who declined fertility preservation.

Long-term outcomes in cancer patients who did or did not pursue fertility preservation.

OBJECTIVE: To compare long-term outcomes of cancer patients who pursued fertility preservation (FP) with those who did not and compare random-start (RS) and menstrual cycle-specific (CS) protocols for FP. DESIGN: Retrospective cohort. SETTING: Single urban academic institution. PATIENT(S): Oncology patients who contacted the FP patient navigator, 2005-2015. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Time to cancer treatment, disease-free survival, and reproductive outcomes in FP versus no-FP patients and cycle outcomes for RS versus CS protocols. Data were analyzed by χ2 and logistic regression. RESULT(S): Of 497 patients who met the inclusion criteria, 41% elected FP. The median number of days to cancer treatment was 33 and 19 days in the FP and no-FP groups, respectively. There was no difference in cancer recurrence or mortality. There were no differences in stimulation parameters, outcomes, or days to next cancer treatment in RS versus CS protocols. Twenty-one patients returned to use cryopreserved specimens, resulting in 16 live births. Eight of 21 returning patients used a gestational carrier. Thirteen FP (6.4%) and 16 no-FP (5.5%) patients experienced a spontaneous pregnancy. CONCLUSION(S): FP is both safe and efficacious for eligible cancer patients. Only 10% of patients returned to use cryopreserved specimens, and almost half used a gestational carrier, suggesting the need for further research into reproductive decision-making in cancer survivors.

The structures that underlie normal reproductive function.

The mechanisms and physiology of reproductive function have fascinated scientists throughout time. Recent cellular and molecular level structural studies have provided unprecedented insights into reproductive systems and signaling networks. This 'cutting edge' editorial provides a recent example in each of these areas, namely, the anatomical integrity of the follicle, the molecular structure of activin with its binding partners and the molecular regulation of inhibin. These three examples of structure informing function help explain reproductive health and may provide solutions to reproductive disease.

Cancer survivors and infertility: a review of a new problem and novel answers.

Improvements in cancer treatment have changed the way in which cancer is viewed and experienced. However, these same treatments have led to numerous early and late effects, including the loss of fertility. Infertility can influence the biologic and psychologic health of both male and female survivors. Reproductive science can now offer methods to address this concern and provide promising new approaches that may eliminate or mitigate this treatment-related outcome. For current and future reproductive options to serve the needs of survivors more fully, health providers must understand the complexities of infertility as well as their role in delivering answers their patients require. This review will discuss what is known about the causes and experience of infertility among cancer survivors as well as the forms of fertility preservation available.

First-trimester bleeding and twin pregnancy outcomes after in vitro fertilization.

OBJECTIVE: To examine the association between first-trimester bleeding and live-birth rates in twin pregnancies conceived with in vitro fertilization (IVF). DESIGN: Retrospective cohort study. SETTING: Academic infertility practice. PATIENT(S): Women with two gestational sacs on first-trimester ultrasound after transfer of fresh embryos derived from autologous oocytes between January 1, 1999, and December 31, 2010. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate. RESULT(S): Sixty-five women reported vaginal bleeding, and 288 did not. The baseline characteristics were similar between the two groups, except for an increased prevalence of subchorionic hematoma in women with first-trimester vaginal bleeding (26.2% vs. 1.7%). Live-birth rates were similar between women with bleeding and those with no bleeding (87.7% vs. 91.7%, adjusted odds ratio [OR] 0.73; 95% confidence interval [CI], 0.31-1.73). Two hundred eighty-eight women gave birth to live twins. Among the women who delivered twins, those with first-trimester bleeding had an increased risk of low birth weight of at least one twin (75.0% vs. 59.7%). The association between bleeding and low birth weight persisted after controlling for possible confounders with logistic regression (adjusted OR 2.33, 95% CI, 1.14-4.74). CONCLUSION(S): Live-birth rates are high in IVF twin gestations, regardless of the presence of first-trimester bleeding. Among women giving birth to IVF twins, however, first-trimester bleeding is associated with increased odds of low birth weight.

Increased endometrial thickness is associated with improved treatment outcome for selected patients undergoing in vitro fertilization-embryo transfer.

OBJECTIVE: To examine possible relationships between endometrial thickness and treatment outcome after IVF and embryo transfer, and to explore the role of potential confounding factors that may influence such relationships. DESIGN: Retrospective study. SETTING: A university-affiliated clinical IVF center. PATIENT(S): Patients undergoing IVF-embryo transfer with their own oocytes. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometrial thickness was determined on the day of hCG administration, 2 days before oocyte retrieval. Clinical pregnancy was confirmed by ultrasound observation of fetal heart activity. RESULT(S): The study analyzed 897 IVF-embryo transfer cycles. Treatment outcome (clinical pregnancy) after IVF-embryo transfer was positively associated with increased endometrial thickness and peak E(2) concentrations in serum, and negatively associated with advanced age. Endometrial thickness was dependent on peak E(2) concentrations in serum, but was independent of patient age or duration of ovarian stimulation. Thin endometrium reduced PRs in relatively young patients (<38 years old), in patients who required more than 10 days of gonadotropin stimulation, or in patients whose embryo transfers consisted of poor quality embryos. CONCLUSION(S): Increased endometrial thickness was associated with improved treatment outcome, but this association was dependent on patient age, duration of ovarian stimulation, and embryo quality.

Studies of gene expression in human cumulus cells indicate pentraxin 3 as a possible marker for oocyte quality.

OBJECTIVE: To search for differentially expressed genes in cumulus cells from two groups of oocytes with different developmental outcome in vitro. DESIGN: Analyses of gene expression in human cumulus cells from oocytes that failed to fertilize in vitro (group A) and those that developed into normal-appearing embryos on day 3 (group B). SETTING: University-based facilities for clinical service and research. PATIENT(S): Women undergoing IVF treatment for infertility. INTERVENTION(S): Cumulus cells were collected from oocytes that were aspirated from ovarian follicles for IVF. The oocytes were cultured individually for IVF and embryo development. Total RNA was extracted from the cumulus cells for gene expression analyses. MAIN OUTCOME MEASURE(S): General gene expression profiles and relative abundance of pentraxin 3 (Ptx3) mRNA. RESULT(S): DNA microarray analysis identified 160 genes, including Ptx3, that were differentially expressed between cumulus cells in group A and group B. Quantitative analysis confirmed that the relative abundance of Ptx3 mRNA in cumulus cells was highly associated with oocyte development. CONCLUSION(S): This study demonstrated that changes in the expression levels of 160 genes, including particularly Ptx3, in human cumulus cells may be indicative of the quality of their enclosed oocyte.

Endometrial biopsy should be abandoned as a routine component of the infertility evaluation.

Endometrial biopsies are of little value in the evaluation of infertile couples. Their usefulness in the evaluation of couples with repeated early pregnancy loss remains to be demonstrated.

A pilot study of the relationship between selective serotonin reuptake inhibitors and in vitro fertilization outcome.

In a retrospective chart review study women taking selective serotonin reuptake inhibitors antidepressants were compared with a matched comparison group to determine whether there were any differences in IVF outcome-related variables. There were no significant differences between the groups in peak E(2), number of oocytes retrieved, number of oocytes fertilized, percentage of 8-cell or blastocysts developed, day of transfer, or initial hCG values; however, 40% of women taking selective serotonin reuptake inhibitors had ongoing pregnancies compared to 51% of women not taking selective serotonin reuptake inhibitors.

Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles after embryo transfer on day 3 or day 5.

OBJECTIVE: To examine the relationships between peak serum estradiol (E(2)) levels and treatment outcome in in vitro fertilization (IVF) cycles after embryo transfer (ET) on day 3 or day 5. DESIGN: Retrospective analysis of 697 IVF-ET cycles between January 1999 and December 2001. SETTING: A university-affiliated assisted reproduction program. PATIENT(S): Infertile patients undergoing IVF-ET cycles. INTERVENTION(S): Peak E(2) concentration in serum was determined on the day of human chorionic gonadotropin (hCG) administration. The IVF-generated embryos were cultured for 2 days until transfer on day 3. If more than four 8-cell embryos were present on day 3, embryo culture was continued until day 5 for blastocyst transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): High peak E(2) levels did not adversely affect treatment outcome. After the cycles were divided according to the day of ET, high peak E(2) levels were associated with improved pregnancy rates after ET on day 5 but not on day 3. CONCLUSION(S): Increasing peak E(2) levels in IVF cycles are associated with improved pregnancy rates after ET on day 5.

Delay of embryo transfer to day 5 results in decreased initial serum beta-human chorionic gonadotropin levels.

OBJECTIVE: To investigate the impact of delaying the transfer of in vitro fertilized embryos to day 5 on embryo development by comparing serum beta-hCG levels in pregnancies established after day 3 embryo transfers and those after day 5 blastocyst transfers at equivalent time intervals after fertilization. DESIGN: A retrospective analysis. SETTING: Assisted reproductive technology center in an academic research environment. PATIENT(S): Women who had an embryo transfer procedure performed after in vitro fertilization (IVF) at Northwestern University's IVF Program between January 1999 and December 2001 were included in this study. INTERVENTION(S): Embryo transfer was performed either on day 3 or day 5 after oocyte retrieval for IVF (day 0), depending on the availability of good-quality embryos on day 3. MAIN OUTCOME MEASURE(S): Serum beta-hCG concentrations determined 13 and 15 days after fertilization in pregnancies established by transferring cleavage-stage embryos on day 3 or blastocysts on day 5. RESULT(S): In singleton pregnancies, serum beta-hCG concentrations were 75 +/- 54 (mean +/- SD, n = 203) or 62 +/- 41 (n = 109) IU/mL after day 3 or day 5 transfers, respectively. In twin pregnancies, the beta-hCG concentrations were 162 +/- 105 (n = 52) or 109 +/- 55 (n = 49) after day 3 or day 5 transfers, respectively. The percentage increases in beta-hCG concentrations between the first and second measurements were similar in the two groups (day 3: 144 +/- 109, day 5: 142 +/- 63, not statistically significant). CONCLUSION(S): Initial beta-hCG concentrations in pregnancies resulting from day 5 transfers were lower than those from day 3 transfers when assessed at equivalent intervals from fertilization. This suggests that embryo development or implantation may be impaired by the additional 2 days in culture.

Fertility preservation outcomes may differ by cancer diagnosis.

CONTEXT: Cancer survival has improved significantly and maintaining fertility is both a major concern and an important factor for the quality of life in cancer patients. AIMS: To explore differences in oocyte stimulation for fertility preservation (FP) patients based on cancer diagnosis. SETTINGS AND DEIGN: Between 2005 and 2011, 109 patients elected to pursue FP at a single institution. MATERIALS AND METHOD: In vitro fertilization (IVF) outcome variables between four cancer diagnostic groups (breast, gynecologic, lymphoma/leukemia and other) and age-matched male factor or tubal factor infertility IVF control group were compared. STATISTICAL ANALYSIS: ANOVA and Chi-square analyses were employed to compare variables between the groups that were normally distributed. Kruskal-Wallis with subsequent Mann-Whitney U-test were used for data that were not normally distributed. RESULTS: Women with gynecologic malignancies were significantly older than the women in the other three groups, but tended to have a better ovarian response. Women with hematologic malignancies were most likely to have been exposed to chemotherapy and had the longest stimulations with a similar number of oocytes retrieved. The age-matched IVF controls had higher peak estradiol levels, number of oocytes obtained, and fertilization rates when compared to cancer patients with or without a history of prior chemotherapy. CONCLUSIONS: Factors including age, type of cancer and chemotherapy exposure, can influence response to ovarian stimulation. Discussing these findings with patients presenting for FP may aid in setting realistic treatment expectations.

Prospective study of depression and anxiety in female fertility preservation and infertility patients.

OBJECTIVE: To prospectively assess anxiety, depression, coping, and appraisal in female fertility preservation (FP) patients compared with infertile patients. DESIGN: Prospective pre- and post-treatment survey. SETTING: Academic medical center. PATIENT(S): Forty-seven women with cancer (FP patients) and 91 age-matched infertile patients. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Depression, anxiety, coping, infertility-related stress, appraisal of treatment, and medical outcomes. RESULT(S): FP patients reported more symptoms of anxiety and depression than infertile patients, but infertile patients' symptoms worsened over time; 44% of FP and 14% of infertile patients' scores exceeded the clinical cutoff for depression before treatment. The interval between surveys and medical treatment data did not predict changes in mood symptoms. Coping strategies and infertility-related stress did not differ between groups, and avoidant coping predicted higher depression and anxiety scores. CONCLUSION(S): FP patients reported more anxiety and depression than infertile patients at enrollment in treatment, with more than one-third of FP patients reporting clinically significant depressive symptoms. However, infertile patients' anxiety and depressive symptoms increased across treatment. This increase was not related to time between registration for IVF and oocyte retrieval or the medical aspects of treatment. FP and infertile patients should be provided psychologic consultation before treatment to identify mood and anxiety symptoms and to refer patients for counseling as needed to prevent worsening of symptoms.

Aneuploidy rates in failed pregnancies following assisted reproductive technology.

BACKGROUND: Approximately 10%-15% of clinically recognized pregnancies end with a first trimester loss. Cytogenetic analysis of products of conception (POC) has revealed that a large proportion of these spontaneous miscarriages are a result of chromosomal abnormalities. However, relatively few studies have evaluated chromosomal abnormalities in pregnancies achieved using assisted reproductive technologies (ART). Here, we review the incidence and type of chromosomal abnormalities that occurred in our infertility patient population undergoing ART and provide a review of the literature pertaining to this subject. METHODS: A retrospective chart review of all patients from our medical center who conceived using ART between January 2000 and January 2008, who experienced a subsequent early pregnancy loss, and whose POCs were successfully karyotyped were included. We also conducted a literature review in PubMed, searching for other articles on this subject. RESULTS: Two hundred fourteen patients conceived with ART, experienced an early loss, and subsequently underwent a dilation and curettage (D&C) between 2000 and 2008. A total of 59 (27%) patients chose to have cytogenetic testing, and their POCs were successfully karyotyped. The overall rate of aneuploidy in this group was 83%. Our PubMed search revealed a total of 12 studies that were identified and evaluated and deemed appropriate for review. CONCLUSIONS: Consistent with most of the literature, we found a high rate of aneuploidy present in infertile patients conceiving using ART. Because an abnormal karyotype provides an explanation for an early loss, this and other studies seem to suggest that routinely carrying out this assessment in such patients may be of value.

Comparing thaw survival, implantation and live birth rates from cryopreserved zygotes, embryos and blastocysts.

CONTEXT: Most in vitro fertilization (IVF) programs employ embryo cryopreservation to enhance pregnancies from a single ovarian stimulation. More embryos are created, some of which are not transferred to the uterus immediately, generating a need for improved cryopreservation protocols. One protocol may involve growing embryos to a further stage of development, allowing only embryos with proven developmental capabilities to be cryopreserved. Here we examined thaw survival, implantation and live birth rates of embryos cryopreserved at different stages. AIMS: We examined thaw survival, implantation and live birth rates of embryos cryopreserved at the zygote, day 3 (D3) embryos or blastocyst stage. SETTINGS AND DESIGN: This is a retrospective study from a single academic IVF program. PATIENTS AND METHODS: A retrospective study of all patients who had frozen embryos transferred to their uteri from year 2002 to 2008 at a single academic IVF program was conducted. STATISTICAL ANALYSIS USED: Analysis of variance followed by Fisher's Exact Test was performed to compare the survival after thaw, implantation and live birth rates between the three groups. RESULTS: One thousand nine hundred and ninety-one zygotes, 2880 D3 embryos and 503 blastocysts were frozen using a slow freeze technique, thawed and transferred. Significantly more D3 embryos and blastocysts survived the thawing process compared to zygotes and significantly higher implantation rate per number of thawed blastocysts was achieved than that for zygotes. Live birth rates were similar between the three groups. CONCLUSIONS: Growing embryos to blastocyst stage prior to cryopreservation is associated with fewer frozen embryos but does not appear compromise patients' chance of achieving pregnancy.

The progressive simplification of the infertility evaluation.

OBJECTIVE: With the advent of evidence-based medicine, much of the complex testing that infertile couples used to undergo is no longer recommended as part of the routine evaluation. Examples of tests no longer implemented include the postcoital test, Rubin test of tubal patency, endometrial biopsy, sperm antibody testing, and the zona-free hamster test. The role of routine diagnostic laparoscopy and hysteroscopy is also reviewed. CONCLUSIONS: In 2010, the simplicity of the current evaluation of couples presenting with infertility is essential information for patients to know at the initial visit. Ideally, it can help alleviate anxiety and provide patients with a road-map during a visit that is often associated with stress and high emotions. TARGET AUDIENCE: Obstetricians & Gynecologists, Family Physicians. LEARNING OBJECTIVES: After completion of this educational activity, the obstetrician/gynecologist should be better able to assess the current recommendations for evaluating infertile couples; examine the various ways to assess ovarian reserve, the uterine cavity, and fallopian patency; and appraise the controversy surrounding diagnostic surgery.