Ethical considerations in the field of assisted reproductive technology.

Human reproduction has always generated more than its share of emotion that exceeds the life and death issues of medicine. For patients that are unable to conceive naturally, medical advances have greatly expanded treatment options. Assisted reproductive technology (ART) is a highly evolving, complex, and controversial field of medicine in which ethical principles play a large role in decision-making. The following highlights ethical considerations regarding ART, specifically in vitro fertilization (IVF), that practicing obstetricians and indeed all physicians may encounter. The aim was to encourage practitioners to consider these issues, and more, when developing guidelines for their own practice.

Effect of cranial irradiation on sperm concentration of adult survivors of childhood acute lymphoblastic leukemia: a report from the St. Jude Lifetime Cohort Study†.

STUDY QUESTION: Does lower dose (<26 Gy) cranial radiation therapy (CRT) used for central nervous system prophylaxis in acute lymphoblastic leukemia (ALL) adversely affect sperm concentration or morphology? SUMMARY ANSWER: CRT doses <26 Gy had no demonstrable adverse effect on sperm concentration or morphology. WHAT IS KNOWN ALREADY: Treatment with alkylating agents produces oligospermia and azoospermia in some patients. No prior study has been large enough to evaluate the independent effects of alkylating agents and lower dose (<26 Gy) CRT on sperm concentration or morphology. STUDY DESIGN, SIZE, DURATION: This cross-sectional study included male adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT and who enrolled in the St. Jude Lifetime Cohort Study (SJLIFE) from September 2007 to October 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: The inclusion criteria were males, ≥18 years of age, ≥10 years after diagnosis, treated at St. Jude Children's Research Hospital for ALL, and received alkylating agent chemotherapy. Semen analyses were performed on 173 of the 241 (78.1%) adult survivors of pediatric ALL who had received alkylating agent chemotherapy with or without CRT. Cumulative alkylating agent treatment was quantified using the cyclophosphamide equivalent dose (CED). Log-binomial multivariable models were used to calculate relative risks (RRs) and 95% CI. MAIN RESULTS AND THE ROLE OF CHANCE: Compared to those without CRT, risk of oligospermia or azoospermia was not increased for CRT <20 Gy (P = 0.95) or 20-26 Gy (P = 0.58). Participants 5-9 years of age at diagnosis compared to those 0-4 years of age (RR = 1.30, 95% CI, 1.05-.61) or those treated with 8-12 g/m2 CED (RR = 2.06, 95% CI, 1.08-3.94) or ≥12 g/m2 CED (RR = 2.12, 95% CI, 1.09-4.12) compared to those treated with >0 to <4 g/m2 CED had an increased risk for oligospermia or azoospermia. LIMITATIONS, REASONS FOR CAUTION: Our study relied on the results of one semen analysis. ALL survivors who did not participate in SJLIFE or who declined to submit a semen analysis may also have biased our results regarding the proportion with azoospermia or oligospermia, since those who provided a semen specimen were less likely to have previously fathered children compared to those who did not. The lower rate of previous parenthood among participants may have resulted in a higher observed frequency of azoospermia and oligospermia. WIDER IMPLICATIONS OF THE FINDINGS: Treatment with <26 Gy CRT did not increase the risk of oligospermia or azoospermia, although a CED exceeding 8 g/m2 and an age at diagnosis of 5-9 years did increase risk of oligospermia and azoospermia. These findings can be used to counsel adult survivors of pediatric ALL. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Institutes of Health (grant numbers CA 21765, CA 195547, CA00874) and the American Lebanese Syrian Associated Charities (ALSAC). The authors have no competing interests to declare.

Subchorionic hematomas are increased in early pregnancy in women taking low-dose aspirin.

OBJECTIVE: To determine the frequency of subchorionic hematomas (SCH) in first-trimester ultrasound examinations of patients with infertility and recurrent pregnancy loss (RPL) and in patients from a general obstetric population. To determine if the method of assisted reproduction utilized or the use of anticoagulants, such as heparin and aspirin (ASA), influenced frequency of SCH. DESIGN: Prospective, cohort study. SETTING: Fertility clinic and general obstetrics clinic. PATIENT(S): Five hundred and thirty-three women who were pregnant in the first-trimester. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Frequencies of subchorionic hematomas in women based on diagnosis, use of anticoagulants, and fertility treatment. RESULT(S): SCH were identified in 129/321 (40.2%) in the study group compared to 23/212 (10.9%) in the control group. Fertility diagnosis and the use of heparin did not appear to affect the frequency of SCH in the first trimester; however, SCH occurred at an almost four-fold increase in patients taking ASA compared to those not taking ASA, regardless of fertility diagnosis or method of fertility treatment. CONCLUSION(S): The use of ASA may be associated with an increased risk of developing a SCH during the first trimester. The increased frequencies of SCH in pregnancies of patients attending a fertility clinic compared to women from a general obstetrical practice was highly correlated with the use of ASA.

Fertility Preservation Through Oocyte Cryopreservation in a Patient with Ovarian Dysgerminocarcinoma: A Case Report.

BACKGROUND: This case evaluates a 20-year-old patient diagnosed with recurrent dysgerminoma who desired fertility preservation. CASE: A 20-year-old woman, GOPO, with a history of fertility-preserving right salpingo-oophorectomy and staging for dysgerminoma presented with interval change of a 5-cm left ovarian solid mass on ultrasound evaluation concerning for recurrent carcinoma. She underwent controlled ovarian hyperstimulation with injectable gonadotropins followed by transvaginal oocyte retrieval immediately followed by laparotomy, at which time ovarian dysgerminoma was confirmed. Completion total abdominal hysterectomy, left salpingo-oophorectomy, and exploratory surgery were performed. Forty-five oocytes were obtained, of which 37 mature oocytes were isolated and cryopreserved. The patient had an unremarkable postoperative course and was discharged home. CONCLUSION: Oncofertility preservation through oocyte cryopreservation may be considered a viable option for young women with ovarian cancer.

Fertility preservation in the age of assisted reproductive technologies.

The desire to reproduce is one of the strongest human instincts. Many men and women in our society may experience situations that compromise their future fertility. The past several decades have seen an explosion of technologies that have changed the historical limitations regarding fertility preservation. This review offers an overview of the state of the art within fertility preservation including surgical and medical interventions and therapies that necessitate the need for cryopreservation of eggs, sperm, and embryos. The review also addresses the psychological consequences of banking/not banking materials among patients in need of fertility preservation, particularly in the oncofertility context.

Cumulative alkylating agent exposure and semen parameters in adult survivors of childhood cancer: a report from the St Jude Lifetime Cohort Study.

BACKGROUND: Few data define the dose-specific relation between alkylating agent exposure and semen variables in adult survivors of childhood cancer. We undertook this study to test the hypothesis that increased exposure to alkylating agents would be associated with decreased sperm concentration in a cohort of adult male survivors of childhood cancer who were not exposed to radiation therapy for their childhood cancer. METHODS: We did semen analysis on 214 adult male survivors of childhood cancer (median age 7·7 years [range 0·01-20·3] at diagnosis, 29·0 years [18·4-56·1] at assessment, and a median of 21·0 years [10·5-41·6] since diagnosis) who had received alkylating agent chemotherapy but no radiation therapy. Alkylating agent exposure was estimated using the cyclophosphamide equivalent dose (CED). Odds ratios (ORs) and 95% CIs for oligospermia (sperm concentration >0 and <15 million per mL) and azoospermia were calculated with logistic regression modelling. FINDINGS: Azoospermia was noted in 53 (25%) of 214 participants, oligospermia in 59 (28%), and normospermia (sperm concentration ≥15 million per mL) in 102 (48%) participants. 31 (89%) of 35 participants who received CED less than 4000 mg/m(2) were normospermic. CED was negatively correlated with sperm concentration (correlation coefficient=-0·37, p<0·0001). Mean CED was 10 830 mg/m(2) (SD 7274) in patients with azoospermia, 8480 mg/m(2) (4264) in patients with oligospermia, and 6626 mg/m(2) (3576) in patients with normospermia. In multivariable analysis, CED was significantly associated with an increased risk per 1000 mg/m(2) CED for azoospermia (OR 1·22, 95% CI 1·11-1·34), and for oligospermia (1·14, 1·04-1·25), but age at diagnosis and age at assessment were not. INTERPRETATION: Impaired spermatogenesis was unlikely when the CED was less than 4000 mg/m(2). Although sperm concentration decreases with increasing CED, there was substantial overlap of CED associated with normospermia, oligospermia, and azoospermia. These data can inform pretreatment patient counselling and use of fertility preservation services. FUNDING: US National Cancer Institute, American Lebanese Syrian Associated Charities.

Endocrine basis for recurrent pregnancy loss.

Common endocrinopathies are a frequent contributor to spontaneous and recurrent miscarriage. Although the diagnostic criteria for luteal phase defect (LPD) is still controversial, treatment of patients with both recurrent pregnancy loss and LPD using progestogen in early pregnancy seems beneficial. For patients who are hypothyroid, thyroid hormone replacement therapy along with careful monitoring in the preconceptual and early pregnancy period is associated with improved outcome. Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy loss. Management of PCOS with normalization of weight or metformin seems to reduce the risk of pregnancy loss.

Lack of specificity of plasma concentrations of inhibin B and follicle-stimulating hormone for identification of azoospermic survivors of childhood cancer: a report from the St Jude lifetime cohort study.

PURPOSE: Many male survivors of childhood cancer are at risk for azoospermia. Although both the levels of follicle-stimulating hormone (FSH) and inhibin B are correlated with sperm concentration, their ability to predict azoospermia in survivors of childhood cancer remains uncertain. PATIENTS AND METHODS: Semen analysis was performed and serum levels of FSH and inhibin B were measured in 275 adult male survivors of childhood cancer who had received gonadotoxic therapy. Receiver operating characteristic (ROC) analysis was performed to determine the optimal inhibin B and FSH values for identifying patients with azoospermia. The patient sample was divided into a learning set and a validation set. Sensitivity, specificity, and positive and negative predictive value were calculated. RESULTS: Inhibin B was dichotomized as ≤ 31 ng/L or more than 31 ng/L and FSH was dichotomized as ≤ 11.5 mIU/mL or more than 11.5 mIU/mL based on results of the ROC analysis. Using these values, the specificity of the serum level of inhibin B for identifying azoospermic survivors was 45.0%, and the positive predictive value was 52.1%. The specificity for FSH was 74.1%, and the positive predictive value was 65.1%. CONCLUSION: Neither serum inhibin B nor FSH is a suitable surrogate for determination of sperm concentration in a semen sample. Young men and their physicians should be aware of the limitations of these measures for assessment of fertility potential.

Preimplantation genetic screening: a practical guide.

The past several decades have seen tremendous advances in the field of medical genetics. The application of genetic technologies to the field of reproductive medicine has ushered in a new era of medicine that is likely to greatly expand in the coming years. Concurrent with an in vitro fertilization (IVF) cycle, it is now possible to obtain a cellular biopsy from a developing embryo and genetically evaluate this sample with increasing sophistication and detail. Preimplantation genetic screening (PGS) is the practice of determining the presence of aneuploidy (either too many or too few chromosomes) in a developing embryo. However, how and in whom PGS should be offered is a topic of much debate.

CD9 Expression by Human Granulosa Cells and Platelets as a Predictor of Fertilization Success during IVF.

Objective. To determine whether CD9 expression on human granulosa cells (GCs) and platelets could predict the success of conventional fertilization of human oocytes during in vitro fertilization (IVF). Methods. Thirty women undergoing IVF for nonmale factor infertility participated. Platelets from venous blood and GCs separated from retrieved oocytes were prepared for immunofluorescence. Flow cytometry quantified the percent of GCs expressing CD9, and CD9 surface density on GCs and platelets. Fertilization rate was determined for the total number of oocytes, and the number of mature oocytes per patient. Correlations tested for significant relationships (P < .05) between fertilization rates and CD9 expression. Results. CD9 surface density on human GCs is inversely correlated with fertilization rate of oocytes (P = .04), but the relationship was weak. Conclusion. More studies are needed to determine if CD9 expression on GCs would be useful for predicting conventional fertilization success during IVF.

Lipoprotein compositional changes with combination hormone therapy (conjugated estrogen and medroxyprogesterone) in African American women.

OBJECTIVE: To determine whether combination hormone therapy (HT) significantly alters lipoprotein composition in healthy African American women. METHODS: Postmenopausal African American women, 45 to 65 years old, were randomly assigned to receive daily HT (conjugated equine estrogen, 0.625 mg, and medroxyprogesterone, 2.5 mg) or placebo (treated, 44; placebo, 16) for 12 weeks. Lipoproteins were separated by gradient ultracentrifugation into very-low-density, intermediate-density, and low-density lipoproteins (VLDL, IDL, and LDL) and 3 high-density lipoprotein (HDL) subfractions (light, medium, and dense--L, M, and D). Apolipoprotein (apo) A-I, A-II, C-III, C-II, and C-I were measured by high-performance liquid chromatography. Apo B, phospholipids, triglycerides, cholesterol, and free cholesterol were measured by standard assays. RESULTS: Total plasma cholesterol, triglycerides, LDL apo B, and total apo B did not change during HT. A small, transient reduction occurred in LDL cholesterol, and a persistent reduction was noted in VLDL apo B, apo C-II, and apo C-III. Total HDL phospholipids, cholesterol, apo A-I, and apo A-II increased, whereas the LDL/HDL ratio and the apo B/apo A-I ratio decreased. Cholesterol ester increased in both HDL-L and HDL-M, but only a transient increase occurred in HDL-L phospholipids. Apo A-I increased in HDL-L, HDL-M, and HDL-D; however, a similar increase occurred in HDL-D apo A-I in the control subjects. Moreover, an increase occurred in apo A-II in HDL-M. A reduction in the apo A-II:A-I ratio in HDL-L but not in HDL-M indicated an increase in HDL-L LpA-I particles. The increase in HDL particles in HDL-M was entirely due to an increase in LpA-I:A-II particles. Apo C-III increased in both HDL-L and HDL-M. The absence of changes in the HDL lipid ratios indicated an unaltered lipid composition of these particles. No changes were found in IDL compositional measurements. In 12 treated patients and 4 control subjects, Lp(a) was detected by ultracentrifugation; no changes were noted in Lp(a) composition or quantity with HT. Total Lp(a) measured by enzyme immunosorbent assay showed a trend toward an increase in treated patients after 12 weeks of HT. CONCLUSION: African American women had a beneficial response to HT by increasing the number of LpA-I particles in HDL-L and LpA-I:A-II particles in HDL-M as well as cholesterol esters in both. There was a small reduction in VLDL apo B (and thus particle number) but only a transient reduction in LDL cholesterol. A shift of apo C-III from VLDL to HDL was noted. No detrimental changes occurred in any lipoprotein subfraction (specifically, no increase in triglycerides).

Effect of short-term hormone therapy on oxidative stress and endothelial function in African American and Caucasian postmenopausal women.

In postmenopausal women (PMW), the effect of a short-term course of estrogen/progestin HT on free radical oxidative stress was evaluated. In addition, HT's effect on plasma nitric oxide (NO) activity was determined as a measure of vascular endothelial function. We investigated the relationship of these markers and HT across race and the cardiovascular risk factors of smoking, diabetes and hypertension.A prospective, observational study comparing preintervention and postintervention. Academic research center.Twenty-seven (14 African American and 13 Caucasian) PMW volunteers. Six weeks of continuous, combined estrogen/progestin HT. Plasma concentrations of free 8-epi-prostaglandin F(2alpha) (8-isoprostane) before and after HT were compared as a measure of oxidative stress. Nitrite, the stable oxidation metabolite of NO, was measured by the Greiss reaction after nitrate reduction to nitrite with cadmium. Plasma levels of free 8-isoprostane decreased significantly after 6 weeks of HT. Although almost all subjects benefited from the reduction in free 8-isoprostane, PMW with at least one cardiovascular risk factor (n = 19) demonstrated higher free 8-isoprostane than did subjects with no risk factors. Plasma levels of nitrite increased after 6 weeks of HT, but the difference was not statistically significant. Caucasian PMW demonstrated a greater increase in plasma levels of nitrite after 6 weeks of HT as compared with African American subjects, who exhibited almost no change.Short-term administration of HT significantly reduces oxidative stress in PMW and is consistent across race. However, there was an observed racial difference in endothelial NO response to HT between African American and Caucasian PMW.

Effect of rosiglitazone on spontaneous and clomiphene citrate-induced ovulation in women with polycystic ovary syndrome.

OBJECTIVE: In women suffering from polycystic ovary syndrome (PCOS), correction of hyperinsulinemia results enhances spontaneous ovulation or alternatively, the responsiveness to ovulation induction agents such as clomiphene citrate (CC). We investigated the effect of rosiglitazone maleate on ovulation induction in overweight and obese, CC-resistant women with PCOS. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: Academic reproductive endocrinology clinic. PATIENT(S): Overweight and obese women with clinical and laboratory manifestations of PCOS who desired pregnancy and were resistant to CC. INTERVENTION(S): Twenty-five women were randomized into two treatment groups. Subjects in Group I (n = 12) were randomized to receive rosiglitazone 4 mg b.i.d. with a placebo on cycle days 5-9. Group II (n = 13) was randomized to receive rosiglitazone 4 mg b.i.d. with CC on cycle days 5-9. The duration of the study was 2 months. MAIN OUTCOME MEASURE(S): The primary outcome was ovulation as defined by luteal serum progesterone greater than 5 ng/dL assessed on days 21, 24, and 28 of the cycle. Secondary outcomes were pregnancy and changes in insulin sensitivity, serum lipoproteins, and androgens. RESULT(S): Overall, 14 of 25 (56%) women, who were previously resistant to CC, successfully ovulated. In subjects taking rosiglitazone alone (Group I), 4 of 12 (33%) subjects ovulated compared with 10 of 13 (77%) women randomized to rosiglitazone with CC (Group II) (P=.04, Fisher's exact). One subject in Group I became pregnant, resulting in one uncomplicated live birth; two subjects in Group II conceived, with one successful live birth and one first trimester, spontaneous abortion. For all subjects, fasting insulin declined from 29.4 +/- 13.8 microU/mL to 17.3 +/- 7.8 microU/mL after rosiglitazone (P=.003, paired t-test). Although mean levels of total testosterone (T) and dehydroepiandrosterone sulfate (DHEAS) did not decline significantly, sex hormone-binding globulin (SHBG) did increase from 0.7 +/- 0.3 microg/dL to 1.0 +/- 0.3 microg/dL after rosiglitazone therapy (P=.001, paired t test). There was also a decrease in luteinizing hormone (LH) from 9.4 +/- 6.3 mU/mL to 7.2 +/- 3.7 mU/mL (P=.01). Lipoproteins including total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglycerides did not change. CONCLUSIONS: Short-term rosiglitazone therapy enhances both spontaneous and clomiphene-induced ovulation in overweight and obese women with PCOS. Rosiglitazone therapy improves insulin sensitivity and decreases hyperandrogenemia primarily through increases in SHBG.

Increased prevalence of insulin resistance in women with a history of recurrent pregnancy loss.

OBJECTIVE: To determine whether insulin resistance is associated with recurrent pregnancy loss (RPL). DESIGN: Single center, case-controlled, prospective study. SETTING: University-associated reproductive endocrinology clinical practice. PATIENT(S): Seventy-four nonpregnant, nondiabetic women with RPL. Controls were 74 fertile, nonpregnant, nondiabetic women without RPL who had at least one live infant, and were matched by age, race, and body mass index (BMI). INTERVENTION(S): Both groups consented to obtaining fasting insulin and glucose levels. MAIN OUTCOME MEASURE(S): Insulin resistance was defined as a fasting insulin level >20 microU/mL or a fasting glucose to insulin ratio of <4.5. RESULT(S): Among the 74 women with RPL, 20 (27.0%) demonstrated insulin resistance, whereas only 7 of 74 (9.5%) of the matched controls were insulin resistant (odds ratio 3.55; 95% confidence interval 1.40-9.01). The RPL and control groups were similar with respect to age, ethnicity, and BMI. The RPL and control groups had similar fasting glucose levels and glucose-to-insulin ratios. However, fasting insulin levels > or =20 microU/mL were statistically different between the two groups (odds ratio 3.92). CONCLUSION(S): Women with RPL have a significantly increased prevalence of insulin resistance when compared with matched fertile controls.

Live birth after treatment of a heterotopic cornual pregnancy with fetal intrathoracic KCI. A case report.

BACKGROUND: Heterotopic pregnancy, in which an ectopic gestation coexists with an intrauterine one, occurs more frequently following in vitro fertilization than with spontaneous conception. However, it is rare to find an ectopic gestation in the interstitial (or cornual) portion of the fallopian tube. This scenario poses challenges in diagnosis as well as difficulties in managing the cornual pregnancy while maintaining the viability of the intrauterine gestation. CASE: A 29-year-old nulligravida with stage IV endometriosis completed in vitro fertilization for primary infertility. A heterotopic pregnancy involving the right interstitial portion of the fallopian tube as well as a viable singleton intrauterine pregnancy was diagnosed using serial ultrasound. Successful termination of the cornual pregnancy was accomplished by transabdominal fetal intrathoracic injection of KCl under ultrasound guidance. CONCLUSION: Pregnancy reduction of a heterotopic cornual gestation using KCl is a treatment alternative for this uncommon but potentially devastating complication of in vitro fertilization.