Robert J. Stillman

Smoking and reproduction

This article reviews currently available epidemiologic and experimental data on the effects of cigarette smoking on reproductive health. Specifically addressed are the evidence for and possible physiologic causes of disturbance in 3 areas: female fertility, male fertility, and the effect of smoking on reproduction and pregnancy. Approximately 30% of women and 36% of men of reproductive age in the US are smokers. The literature offers clear support for an association between smoking and decreased female fecundity and fertility, especially with a relationship to primary tubal infertility. Cigarette smoke appears to have adverse effects along a continuum of preimplantation and implantation reproductive processes, including gamete production and function, ovulation and cyclicity, fertilization, early embryonic cleavage, embryo transport, and implantation. In men, there is clear evidence that smoking results in fewer and less motile sperm as well as a lower proportion of normally shaped sperm; however, it remains unclear whether this impairment in spermatogenesis results in clinical impairment of fertility. Studies have demonstrated a significant increase among smoker both in the risk of spontaneously aborting a chromosomally normal fetus and in the risk of spontaneously aborting a chromosomally normal fetus and in the risk of prematurity. Moreover, smoling has been shown to cause a 150-300 gram decrease interm infant birthweight. Al these risks to fecundity and pregnancy outcome are minimized or absent in former smokers. It is stressed that efforts to persuade women to stop smoking have been inadequate. It is particularly imperative for women who have had divviculties conceving or have had a history of miscarraiges to give up cigarette smoking.

Tubal Infertility and the Intrauterine Device

To study the association between intrauterine devices (IUDs) and pelvic inflammatory disease, we compared contraceptive histories in 4185 while women--283 nulliparous women with primary tubal infertility, 69 women with secondary tubal infertility, and 3833 women admitted for delivery at seven collaborating hospitals from 1981 to 1983. The relative risk of tubal infertility associated with IUD use was calculated by means of multivariate logistic regression to control for confounding factors, including region, year of menarche, religion, education, smoking, and reported number of sexual partners. The adjusted risk of primary tubal infertility associated with any IUD use before a first live birth was 2.0 (95 per cent confidence limits, 1.5 to 2.6) relative to nonuse. Users of the Dalkon Shield had an adjusted risk of 3.3 (1.7 to 6.1), users of the Lippes Loop or Saf-T-Coil had a risk of 2.9 (1.7 to 5.2), and users of copper IUDs had a risk of 1.6 (1.1 to 2.4). Women who reported having only one sexual partner had no increased risk of primary tubal infertility associated with IUD use. The adjusted risk of secondary tubal infertility associated with use of a copper IUD after a first live birth was not statistically significant (1.5; 95 per cent confidence limits, 0.8 to 3.0), whereas the risk from similar use of noncopper devices was significant (2.8; 1.3 to 5.9). We conclude that tubal infertility is associated with IUD use, but less so with copper IUDs.

Ovarian failure in long-term survivors of childhood malignancy

The frequency and causes of ovarian failure among 182 long-term survivors of childhood cancer were examined. Twenty-two patients (12%) had ovarian failure. Ovarian failure was found in 17 of 25 patients (68%) who had both ovaries within abdominal radiotherapy fields, in five of 35 patients (14%) whose ovaries were at the edge of the treatment field, and in none of 122 patients with one or both ovaries outside of an abdominal treatment field (p < 10(-4)). The odds for ovarian failure in patients with both ovaries in the field are 19.7 higher than those for other irradiated patients (95% confidence interval, 5.3 to 72.8). Covariate and multivariate analyses of tumor type, age at diagnosis, duration of follow-up, abdominal tumor surgery, abdominal radiotherapy, number of chemotherapeutic agents administered, and cumulative doses of several drugs revealed that the location of the ovaries relative to radiation treatment fields was the only risk factor for subsequent ovarian failure.

Day 3 morphology is a poor predictor of blastocyst quality in extended culture

OBJECTIVE To determine how the quality of blastocysts formed on day 5/6 of extended culture compares with their morphology on day 3. DESIGN Retrospective observational study of IVF laboratory records. SETTING Private assisted reproduction clinic. PATIENT(S) 101 IVF cycles in which 5 to 25 embryos were produced. The average maternal age was 33.1 years. INTERVENTION(S) Embryos were individually cultured in vitro in sequential media for an extended time to enable use of blastocysts for fresh transfer or cryopreservation. MAIN OUTCOME MEASURE(S) Comparison of embryo quality for putative ET or cryopreservation on day 3 with quality of embryos used for actual ET and cryopreservation on day 5/6. RESULT(S) Of 1,263 cleaving embryos, 559 were judged to have been suitable for use on day 3; 355 would have been used for ET (average per ET, 3.5) and 204 would have been frozen (equivalent to 44% utilization). In actuality, 471 blastocysts were used on day 5/6, of which 234 were transferred (average per ET, 2.3), and 237 were frozen (equivalent to 37% utilization). Only 48% embryos that would have been chosen for ET and/or cryopreservation on day 3 were eventually used in such a manner at the blastocyst stage. Historically, the rate of viable pregnancy from day 3 transfers was 30.5% per transfer; this rate increased to 45% with routine day 5/6 transfers. CONCLUSION(S) Extended culture of human embryos seems to increase discrimination of potential embryonic viability. Criteria for embryo selection on day 3 seem to be inadequate. Extended in vitro culture may therefore be an effective means of optimizing IVF clinical success.

Elective single embryo transfer: A 6-year progressive implementation of 784 single blastocyst transfers and the influence of payment method on patient choice

OBJECTIVE To evaluate efforts to reduce twin pregnancies through progressive implementation of elective single embryo transfer (eSET) among select patients over a 6-year period. DESIGN Retrospective review. SETTING Private practice IVF center. PATIENT(S) Infertile women undergoing 15,418 consecutive IVF-ET cycles. INTERVENTION(S) IVF-ET, including blastocyst-stage eSET among select patients with good prognosis and high risk of multiple pregnancy. MAIN OUTCOME MEASURE(S) Pregnancy, multiple pregnancy, method of payment. RESULT(S) Pregnancy rates were similar for autologous eSET versus double-blastocyst transfer (65% vs. 63%), while twin rates were much lower (1% vs. 44%). For recipients of donor oocytes, pregnancy rates were slightly lower with eSET (63% vs. 74%), while twin rates were much lower (2% vs. 54%). There was no decrease in overall pregnancy rates, despite a dramatic rise in eSET use over time (1.5% to 8.6% of all autologous transfers and 2.0% to 22.5% of all transfers to donor oocyte recipients between 2002 and 2007). Overall singleton pregnancy rates increased, while twin pregnancy rates declined significantly over time. Use of eSET was significantly more common among patients with insurance coverage or who were participating in our Shared Risk money-back guarantee program. CONCLUSION(S) Selective eSET use among good-prognosis patients can significantly reduce twin pregnancies without compromising pregnancy rates. Patients are more likely to choose eSET when freed from financial pressures to transfer multiple embryos.

The association between smoking and female infertility as influenced by cause of the infertility

Smoking histories were compared in 901 women with infertility of different types and 1264 women admitted for delivery at seven collaborating hospitals. The relative risk for infertility associated with cigarette smoking prior to the infertility diagnosis for nulliparous cases or first live birth for controls was calculated using a multivariate logistic-regression model to control for potential confounding factors, including center, age, religion, education, number of sexual partners, and contraceptive use. The adjusted risk for infertility attributed primarily to cervical factor (n = 96) was 1.7 (P = 0.04), to tubal disease unrelated to endometriosis (n = 225) was 1.6 (P = 0.009), to ovulatory factor (n = 389) was 1.0 (not significant [NS]), and to endometriosis (n = 191) was 0.9 (NS). The authors conclude that cigarette smoking is significantly associated only with certain types of primary female infertility.

Successful elective and medically indicated oocyte vitrification and warming for autologous in vitro fertilization, with predicted birth probabilities for fertility preservation according to number of cryopreserved oocytes and age at retrieval

OBJECTIVE To evaluate a single treatment centers experience with autologous IVF using vitrified and warmed oocytes, including fertilization, embryonic development, pregnancy, and birth outcomes, and to estimate the likelihood of live birth of at least one, two, or three children according to the number of mature oocytes cryopreserved by elective fertility preservation patients. DESIGN Retrospective cohort study. SETTING Private practice clinic. PATIENT(S) Women undergoing autologous IVF treatment using vitrified and warmed oocytes. Indications for oocyte vitrification included elective fertility preservation, desire to limit the number of oocytes inseminated and embryos created, and lack of available sperm on the day of oocyte retrieval. INTERVENTION(S) Oocyte vitrification, warming, and subsequent IVF treatment. MAIN OUTCOME MEASURE(S) Post-warming survival, fertilization, implantation, clinical pregnancy, and live birth rates. RESULT(S) A total of 1,283 vitrified oocytes were warmed for 128 autologous IVF treatment cycles. Postthaw survival, fertilization, implantation, and birth rates were all comparable for the different oocyte cryopreservation indications; fertilization rates were also comparable to fresh autologous intracytoplasmic sperm injection cycles (70% vs. 72%). Implantation rates per embryo transferred (43% vs. 35%) and clinical pregnancy rates per transfer (57% vs. 44%) were significantly higher with vitrified-warmed compared with fresh oocytes. However, there was no statistically significant difference in live birth/ongoing pregnancy (39% vs. 35%). The overall vitrified-warmed oocyte to live born child efficiency was 6.4%. CONCLUSION(S) Treatment outcomes using autologous oocyte vitrification and warming are as good as cycles using fresh oocytes. These results are especially reassuring for infertile patients who must cryopreserve oocytes owing to unavailability of sperm or who wish to limit the number of oocytes inseminated. Age-associated estimates of oocyte to live-born child efficiencies are particularly useful in providing more explicit expectations regarding potential births for elective oocyte cryopreservation.

Contribution of male age to outcomes in assisted reproductive technologies

OBJECTIVE To evaluate the relationship between male age and pregnancy outcome in donor oocyte assisted reproductive technology cycles. DESIGN Retrospective cohort. SETTING Private IVF center. PATIENT(S) A total of 1,392 donor cycles from 1,083 female recipients and their male partners. INTERVENTION(S) Oocyte donor cycles. MAIN OUTCOME MEASURE(S) Live birth. RESULT(S) Increasing male age was associated with semen parameters including volume and motility; however, male age was not observed to have a statistically significant association with likelihood of live birth in donor cycles after adjustment for female recipient age. CONCLUSION(S) When treatment cycle number and female recipient age were taken into account, male age had no significant association with pregnancy outcomes in assisted reproductive technology donor cycles in this study population.

Inhibition of Adrenal Steroidogenesis by Danazol in Vivo

The concentrations of various steroids of adrenal origin were assessed in vivo before and after acute adrenocorticotropic hormone (ACTH) stimulation to determine the effects of danazol on adrenal steroidogenesis. Five healthy, normal menstruating women were studied on the 6th day of two consecutive menstrual cycles, once as a pretreatment control and again after administration of 600mg of danazol daily for 6days. While taking danazol, baseline levels of progesterone (P) (P ∆ 4 A) (P ∆ 5 P) (P 0.05). Consequently, the ∆ 5 P:P (P β -ol-hydroxysteroid dehydrogenase ∆ 5 - ∆ 4 isomerase and 11 β -hydroxylase enzymes.

Gonadotropins enhance HLA-DR antigen expression in human granulosa cells

Abstract OBJECTIVES: To determine whether HLA-DR expression in the human ovary is controlled by endocrine or immune mediators, we examined the effects of several lectins, lymphokines, and hormones on granulosa cells in vitro. STUDY DESIGN: HLA-DR antigens were detected by indirect immunofluorescence on granulosa cells obtained at oocyte retrieval for in vitro fertilization. RESULTS: When cultured with concanavalin A, pokeweed mitogen, phytohemagglutinin, interleukin-1, or interleukin-2, granulosa cells failed to express HLA-DR antigens. Both interferon alfa and interferon beta induced only a modest expression of HLA-DR molecules (4.1% ± 0.9% and 2.5% ± 0.8%, respectively) in comparison with the marked increase in HLA-DR expression (25.2% ± 2.8%), when granulosa cells were exposed to interferon gamma. The gonadotropins follicle-stimulating hormone and human chorionic gonadotropin alone were unable to induce HLA-DR antigens, but acted synergistically with interferon gamma to enhance expression in a dose-dependent manner. The addition of 0.1 and 10 IU/ml of follicle-stimulating hormone with 10,000 IU/ml of interferon gamma significantly increased expression by 11.5% ± 2.5% and 15.5% ± 2. 7%, respectively, over that of interferon gamma alone. Similarly, 1 and 10 IU/ml of human chorionic gonadotropin produced a 7.8% ± 2.0% and 12.4% ± 2.2% increase in HLA-DR expression over baseline. CONCLUSION: These studies demonstrate that factors from both the immune and endocrine systems can interact to control HLA-DR expression in the ovary. (AM J OBSTET GYNECOL 1992;167:1768-73.)