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To develop evidence-based recommendations for the optimum numbers of blastocyst stage embryos to transfer in womenor=38 years old.Retrospective analysis of national Society for Assisted Reproductive Technology data from 2000 to 2004.National writing group.Five thousand five hundred sixty-nine day 5 and day 6 ETs in womenor=38 years of age undergoing their first assisted reproductive technology cycle.None.Logistic regression was used to model the probability of a delivery, twins, and high-order multiples based on patient characteristics.In 38- and 39-year-old women there was an increase in delivery rates up to transfer of two embryos. Beyond that, number transferred increased multiple rates but not delivery rates. Transfer of three embryos in 40-year-old women increased delivery but not multiple rate. For 41- to 42-year-olds delivery rate was level after transfer of three, but twin rate continued to increase. Multivariate analysis showed that age, embryo cryopreservation, and use of intracytoplasmic sperm injection influence delivery rate. Increasing numbers of oocytes retrieved showed a trend but was not an independent predictor.Optimal numbers of blastocyst stage embryos to transfer in first cycles for women 38 to 39 years old differ from those in womenor=40 years. Number transferred should be modified as determined by a model that includes availability of excess embryos to cryopreserve, use of intracytoplasmic sperm injection, and, possibly, number of oocytes retrieved.

To evaluate the effect of teamwork training on the occurrence of adverse outcomes and process of care in labor and delivery.A cluster-randomized controlled trial was conducted at seven intervention and eight control hospitals. The intervention was a standardized teamwork training curriculum based on crew resource management that emphasized communication and team structure. The primary outcome was the proportion of deliveries at 20 weeks or more of gestation in which one or more adverse maternal or neonatal outcomes or both occurred (Adverse Outcome Index). Additional outcomes included 11 clinical process measures.A total of 1,307 personnel were trained and 28,536 deliveries analyzed. At baseline, there were no differences in demographic or delivery characteristics between the groups. The mean Adverse Outcome Index prevalence was similar in the control and intervention groups, both at baseline and after implementation of teamwork training (9.4% versus 9.0% and 7.2% versus 8.3%, respectively). The intracluster correlation coefficient was 0.015, with a resultant wide confidence interval for the difference in mean Adverse Outcome Index between groups (-5.6% to 3.2%). One process measure, the time from the decision to perform an immediate cesarean delivery to the incision, differed significantly after team training (33.3 minutes versus 21.2 minutes, P=.03).Training, as was conducted and implemented, did not transfer to a detectable impact in this study. The Adverse Outcome Index could be an important tool for comparing obstetric outcomes within and between institutions to help guide quality improvement.(www.ClinicalTrials.gov), NCT00381056I.

Although the fetal death rate has declined over the past 30 years among women of all ages, it is unknown whether particular characteristics of the mother, such as age, still affect the risk of fetal death. We undertook a study to determine whether older age, having a first child (nulliparity), or other characteristics of the mother are risk factors for fetal death.We used data from the McGill Obstetrical Neonatal Database to evaluate risk factors for fetal death among all deliveries at the Royal Victoria Hospital in Montreal (n = 94,346) from 1961 through 1993. Data were available for two time periods (1961 through 1974 and 1978 through 1993); data for 1975 through 1977 have not been entered into the data base and were therefore not included. Using logistic regression, we estimated the effect of specific maternal characteristics and complications of pregnancy on the risk of fetal death.The fetal death rate decreased significantly from 11.5 per 1000 total births (including live births and stillbirths) in the 1960s to 3.2 per 1000 in 1990 through 1993 (P0.001). Between these periods, the average maternal age at delivery increased from 27 to 30 years (P0.001), and the frequency of the diagnosis of diabetes and hypertension during pregnancy increased fivefold (P0.001). Nevertheless, after we controlled for these and other maternal characteristics, women 35 years of age or older continued to have a significantly higher rate of fetal death than their younger counterparts (odds ratio for women 35 to 39 years of age as compared with women30 years of age, 1.9; 95 percent confidence interval, 1.3 to 2.7; for those 40 or older, 2.4; 95 percent confidence interval, 1.3 to 4.5).Changes in maternal health and obstetrical practice have resulted in a 70 percent decline in the rate of fetal death among pregnant women of all ages since the 1960s. Advancing maternal age, however, continues to be a risk factor for fetal death.

Objectives To review current practice in the analysis and reporting of epidemiological research and to identify limitations. Design Examination of articles published in January 2001 that investigated associations between risk factors/exposure variables and disease events/measures in individuals. Setting Eligible English language journals including all major epidemiological journals, all major general medical journals, and the two leading journals in cardiovascular disease and cancer. Main outcome measure Each article was evaluated with a standard proforma. Results We found 73 articles in observational epidemiology; most were either cohort or case-control studies. Most studies looked at cancer and cardiovascular disease, even after we excluded specialty journals. Quantitative exposure variables predominated, which were mostly analysed as ordered categories but with little consistency or explanation regarding choice of categories. Sample selection, participant refusal, and data quality received insufficient attention in many articles. Statistical analyses commonly used odds ratios (38 articles) and hazard/rate ratios (23), with some inconsistent use of terminology. Confidence intervals were reported in most studies (68), though use of P values was less common (38). Few articles explained their choice of confounding variables; many performed subgroup analyses claiming an effect modifier, though interaction tests were rare. Several investigated multiple associations between exposure and outcome, increasing the likelihood of false positive claims. There was evidence of publication bias. Conclusions This survey raises concerns regarding inadequacies in the analysis and reporting of epidemiological publications in mainstream journals.

We evaluated menopausal symptoms, menstrual cycle bleeding characteristics and reproductive hormones for their associations with thyroid stimulating hormone (TSH) concentrations in women at the mid-life from five ethnic groups.This report is from the baseline evaluation of the Study of Women's Health Across the Nation (SWAN), a community-based multiethnic study of the natural history of the menopausal transition. Enrollees were 42-52 years old (pre- and early perimenopausal) African American, Caucasian, Chinese, Hispanic and Japanese women (n = 3242). Enrollees were interviewed about self-reported diagnosed hypo- and hyperthyroidism or thyroid treatment, menopausal symptoms and menstrual cycle bleeding characteristics. Serum was assayed for TSH, oestradiol, testosterone, FSH and SHBG.There were 6.2% of women with TSH5.0 mIU/ml and 3.2% with TSH0.5 IU/ml, cutpoints that have been used to encompass clinical and subclinical hypo- and hyperthyroidism, respectively. African American women had significantly lower mean TSH concentrations than Caucasian, Hispanic and Chinese women. Of the more than 15 menopause symptoms evaluated, only fearfulness was associated with having a TSH value5.0 mIU/ml (P0.008) or0.5 mIU/ml (P0.02). Women with TSH values outside the range of 0.5-5.0 mIU/ml were more likely to report shorter or longer menstrual periods (P = 0.004 for both) than women within that range. FSH, SHBG, dehydroepiandrosterone sulphate (DHEA-S), testosterone, and oestradiol concentrations were not associated with TSH concentrations.In mid-aged women, there was a 9.6% prevalence of TSH values outside the euthyroid range of 0.5-5.0 mIU/ml. Although TSH was associated with bleeding length and self-reported fearfulness, it was not associated with indicators of the menopausal transition, including menopausal stage defined by bleeding regularity, menopausal symptoms or reproductive hormone concentrations.

Objective To determine whether day 3 FSH and E 2 levels at the upper limits of normal affect live-birth rates and treatment trajectory in a conventional versus "fast track" treatment program for IVF. Design Secondary analysis of two randomized controlled trials, FASTT and FORT-T. Setting Not applicable. Patient(s) Infertile women ages 21–42 years randomized to conventional or accelerated treatment with controlled ovarian hyperstimulation (COH)-IUI and/or IVF (n = 603 patients contributing 2,717 total cycles). Intervention(s) Patients were stratified according to basal FSH and E 2 : FSH 2 2 ≥40 pg/mL (group 1B), FSH, 10–15 mIU/mL and E 2 2 ≥40 pg/mL (group 2B). Main Outcome Measure(s) Number of cancelled cycles, disenrollment for poor response, and cumulative live-birth rates per couple. Result(s) Women in groups 2A and 2B were more likely to have cancelled cycles and be disenrolled for poor response. While no live births occurred in group 2B during COH-IUI (0/19 couples, 0/58 cycles), IVF still afforded these patients a reasonable chance of success (6/18 couples, 6/40 cycles, 33.3% live-birth rate per couple). The specificity and positive predictive value of basal FSH of 10–15 mIU/mL and E 2 ≥40 pg/mL for no live birth during COH-IUI treatment were both 100%. Conclusion(s) Women who initiated infertility treatment with FSH of 10–15 mIU/mL and E 2 ≥40 pg/mL on day 3 testing were unlikely to achieve live birth after COH-IUI treatment.

Objective To determine the optimal infertility therapy for women at the end of their reproductive potential. Design Randomized clinical trial. Setting Academic medical centers and private infertility center in a state with mandated insurance coverage. Patient(s) Couples with ≥6 months of unexplained infertility; female partner aged 38–42 years. Intervention(s) Randomized to treatment with two cycles of clomiphene citrate (CC) and intrauterine insemination (IUI), follicle stimulating hormone (FSH)/IUI, or immediate IVF, followed by IVF if not pregnant. Main Outcome Measure(s) Proportion with a clinically recognized pregnancy, number of treatment cycles, and time to conception after two treatment cycles and at the end of treatment. Result(s) We randomized 154 couples to receive CC/IUI (N = 51), FSH/IUI (N = 52), or immediate IVF (N = 51); 140 (90.9%) couples initiated treatment. The cumulative clinical pregnancy rates per couple after the first two cycles of CC/IUI, FSH/IUI, or immediate IVF were 21.6%, 17.3%, and 49.0%, respectively. After all treatments, 110 (71.4%) of 154 couples had conceived a clinically recognized pregnancy, and 46.1% had delivered at least one live-born baby; 84.2% of all live-born infants resulting from treatment were achieved via IVF. There were 36% fewer treatment cycles in the IVF arm compared with either COH/IUI arm, and the couples conceived a pregnancy leading to a live birth after fewer treatment cycles. Conclusion(s) A randomized controlled trial in older women with unexplained infertility to compare treatment initiated with two cycles of controlled ovarian hyperstimulation/IUI versus immediate IVF demonstrated superior pregnancy rates with fewer treatment cycles in the immediate IVF group. Clinical Trial Registration Number NCT00246506.

Little is known about the micronutrient status of Chinese women of childbearing age. We assessed nonfasting plasma concentrations of folic acid, vitamin B-12, vitamin B-6 (as pyridoxal-5'-phosphate), hemoglobin (Hb), ferritin and transferrin receptor (TfR) in 563 nonpregnant textile workers aged 21-34 y from Anqing, China. All women had obtained permission to become pregnant and were participating in a prospective study of pregnancy outcomes. Mean (SD) plasma concentrations were 9.7 (4.1) nmol/L folic acid, 367 (128) pmol/L vitamin B-12, 40.2 (15.8) nmol/L vitamin B-6, 108 (12. 9) g/L Hb, 42.6 (34.2) microgram/L ferritin and 5.2 (2.7) mg/L TfR. Twenty-three percent of women had biochemical evidence of folic acid deficiency, 26% were deficient in vitamin B-6 and 10% had low vitamin B-12. Overall, 44% of women were deficient in at least one B vitamin. Although anemia (Hb120 g/L) was detected in 80% of women, only 17% had depleted iron stores (ferritin12 microgram/L); 11% had elevated TfR concentrations. Distinct seasonal trends were observed in the prevalence of moderate anemia (Hb100 g/L) and deficiencies of folic acid and vitamin B-6, with significantly lower concentrations of folate and Hb occurring in summer and lower concentrations of vitamin B-6 occurring in winter and spring than in other seasons. We conclude that deficiencies of folic acid, vitamin B-6 and iron were relatively common in this sample of Chinese women of childbearing age and were contributing to the high prevalence of anemia. Without appropriate supplementation, these deficiencies could jeopardize the women's health and increase their risk of adverse pregnancy outcomes.

This introductory chapter discusses what is meant by women health. As women's health has gained recognition as a discipline, there have been legislative and organizational attempts to define its scope, research and clinical priorities, and fundamental tenets. Since the 1970s, a number of definitions have been proposed. Early definitions of women's reproductive health were based on the biomedical model, while more recent ones recognize that a variety of factors influences a woman's health during her life span. These later definitions encompass all diseases and disorders that affect women, include an awareness of the impact of social, cultural, economic, and political influences, and emphasize prevention as well as treatment. A familiar paradox of women's health is that women live longer than men but have poorer health. Worldwide, women usually live longer than men in similar socioeconomic circumstances. In most of the developed countries, the difference between female and male life expectancy is about 6.5 years.

To investigate the risk of uterine leiomyomata in relation to reproductive factors and oral contraceptive use.A prospective study.A cohort of female registered nurses from 14 states in the United States who completed mailed questionnaires in 1989, 1991, and 1993.Premenopausal nurses (n=95,061) aged 25-42 years with intact uteri and no history of diagnosed uterine leiomyomata or cancer in 1989.None.Incidence of self-reported uterine leiomyomata confirmed by ultrasound or hysterectomy. In a sample of 243 cases, 93% of the self-reported diagnoses were confirmed in the medical record.During 326,116 person-years of follow-up, 3,006 cases of uterine leiomyomata, confirmed by ultrasound or hysterectomy, were reported. After adjustment for other risk factors, the risk of uterine leiomyomata was significantly inversely associated with age at menarche, parity, and age at first birth, and positively associated with a history of infertility and years since last birth. The only notable association with any aspect of oral contraceptive use was a significantly elevated risk among women who first used oral contraceptives at ages 13-16 years compared with those who had never used oral contraceptives.Reproductive factors and oral contraceptive use at a young age influence the risk of uterine leiomyomata among premenopausal women.The 95,061 US women enrolled in the 1989 cohort of the Nurses' Health Study II were queried, in the 1993 questionnaire, about any recent history of uterine leiomyomata. At study enrollment (at ages 25-42 years), all women were premenopausal and had intact uteri with no history of diagnosed uterine leiomyomata or cancer. During 326,116 woman-years of follow-up, 3006 new cases of uterine leiomyomata (confirmed by ultrasound or hysterectomy) were reported. After adjustment for other risk factors, the risk of uterine leiomyomata was significantly inversely associated with age at menarche, parity, and age at first birth and significantly positively associated with a history of infertility and years since last birth. The only significant oral contraceptive (OC)-related association was an elevated risk among women who first used OCs at ages 13-16 years compared with OC never-users. The excess risk persisted after controls for histories of menstrual cycle irregularity in high school and severe teenage acne--factors that may have led to the prescription of OCs in early adolescence. The increased risk among women with an early menarche and decreased risks among parous and high-parity women support the hypothesis that myometrial responses to estrogens may be important in the etiology of uterine leiomyomata. The role of exogenous hormones resulting from OC use remains unclear.

Objective: To quantify the incidence of uterine leiomyoma confirmed by hysterectomy, ultrasound, or pelvic examination according to age and race among premenopausal women. Methods: From September 1989 through May 1993, 95,061 premenopausal nurses age 25–44 with intact uteri and no history of uterine leiomyoma were followed to determine incidence rates of uterine leiomyoma. The self-reported diagnosis was confirmed in 93% of the medical records obtained for a sample of cases. Using pooled logistic regression, we estimated relative risks (RRs) of uterine leiomyoma according to race and examined whether adjustment for other potential risk factors could explain the variation in the race-specific rates. Results: During 327,065 woman-years, 4181 new cases of uterine leiomyoma were reported. The incidence rates increased with age, and the age-standardized rates of ultrasound- or hysterectomy-confirmed diagnoses per 1000 woman-years were 8.9 among white women and 30.6 among black women. After further adjustment for marital status, body mass index, age at first birth, years since last birth, history of infertility, age at first oral contraceptive use, and current alcohol consumption, the rates among black women were significantly greater for diagnoses confirmed by ultrasound or hysterectomy (RR 3.25; 95% confidence interval [CI] 2.71, 3.88) and by hysterectomy (RR 1.82; 95% CI 1.17, 2.82) compared with rates among white women. We observed similar RRs when the cohort was restricted to participants who reported undergoing a screening physical examination within the 2 years before baseline. Conclusion: A higher prevalence of known risk factors did not explain the excess rate of uterine leiomyoma among premenopausal black women.

OBJECTIVE. The purpose of this study was to investigate the relationship between moderate alcohol intake and fertility. METHODS. Interviews were conducted with 3833 women who recently gave birth and 1050 women from seven infertility clinics. The case subjects were categorized based on the infertility specialist's assignment of the most likely cause of infertility: ovulatory factor, tubal disease, cervical factor, endometriosis, or idiopathy. Separate logistic regression models were used to assess the relationship between alcohol use and each type of infertility, adjusted for age, infertility center, cigarette smoking, caffeine use, number of sexual partners, use of an intrauterine device (for tubal disease), and body mass index and exercise (for ovulatory factor). RESULTS. We found an increase in infertility, due to ovulatory factor or endometriosis, with alcohol use. The odds ratio for ovulatory factor was 1.3 (95% confidence interval [CI] = 1.0, 1.7) for moderate drinkers and 1.6 (95% CI = 1.1, 2.3) for heavier drinkers, compared with nondrinkers. The risk of endometriosis was roughly 50% higher in case subjects with any alcohol intake than in control subjects (OR = 1.6, 95% CI = 1.1, 2.3, at moderate levels; OR = 1.5, 95% CI = 0.8, 2.7, at heavier levels). CONCLUSIONS. Moderate alcohol use may contribute to the risk of specific types of infertility.

Objective: Our aim was to examine the association between body mass index at age 18 and subsequent primary ovulatory infertility. Study Design: A nested case-control study was conducted within a cohort of 116,678 female registered nurses residing in 14 U.S. states. Cases comprised 2527 married nulliparous nurses unable to become pregnant for at least 1 year because of ovulatory disorder; controls comprised 46,718 married parous nurses with no history of infertility. The risk of ovulatory infertility for women at different levels of body mass index at age 18 was compared with that for women whose body mass index at age 18 was 20 to 21.9 (median for the cohort). Logistic regression was used to adjust for age at infertility or first birth, year of birth, age at menarche, physical activity during ages 18 to 22, smoking at ages 15 to 19, ethnicity, alcohol use at ages 18 to 22, use of oral contraceptives before age 22, and diagnosis of diabetes mellitus. Results: Multivariate relative risks for infertility were: 1.2 (body mass index > 16), 1.1 (body mass index 16 to 17.9), 1.0 (body mass index 18 to 19.9), 1.0 (referent body mass index 20 to 21.9), 1.1 (body mass index 22 to 23.9), 1.3 (body mass index 24 to 25.9), 1.7 (body mass index 26 to 27.9),2.4 (body mass index 28 to 29.9),2.7 (body mass index 30 to 31.9), and 2.7 (body mass index ≤32). The relative risks for all categories of body mass index above 23~9 were statistically significantly elevated. Greater body mass index at age 18 was a predictor of ovulatory infertility in women with and without a diagnosis of polycystic ovary syndrome. Conclusion: These findings suggest that elevated body mass index at age 18, even at levels lower than those considered to be obese, is a risk factor for subsequent ovulatory infertility.

Objective: We used data from a large multicenter case-control study of tubal infertility to analyze further the relationship among demographic variables, behavioral measures, history of previous sexually transmitted diseases, and past contraceptive practices, for women with and without a history of pelvic inflammatory disease. Study Design: We identified 283 white women with tubal infertility who requested care at seven participating institutions. Of these women, 238 (84%) did not have a history of pelvic inflammatory disease ("atypical pelvic inflammatory disease") whereas 45 reported a history of pelvic inflammatory disease ("overt pelvic inflammatory disease"). We compared these groups with 1629 white women without a history of either infertility or pelvic inflammatory disease who were delivered of their first live-born child at the same institutions as the infertile cases. Results: Women with atypical pelvic inflammatory disease were demographically more like fertile control subjects and had behavioral characteristics midway between those of the overt pelvic inflammatory disease group and the fertile group. Both oral contraceptive and diaphragm use protected against tubal infertility for women with either atypical or overt pelvic inflammatory disease. Atypical pelvic inflammatory disease was related to a history of Trichomonas infection but not to a reported history of gonorrhea, genital herpes, or other vaginitis. Conclusion: Atypical pelvic inflammatory disease is probably more common than its symptomatic counterpart. Whereas this condition is associated with some characteristics of a sexually transmitted infection, clinical predictors remain elusive.

Over 1.5 billion prescriptions were filled by pharmacies in 1990, but little information exists on the effect that pharmaceutical agents have on female reproductive capacity. As part of a case-control study of risk factors for primary ovulatory infertility, we examined self-reported use of several prescription and nonprescription medications in 597 women with ovulatory infertility and 3,833 controls admitted for delivery at seven hospitals. Only women reporting use of a drug for at least 6 months, beginning before the onset of infertility in cases and before conception in controls, were considered exposed. An elevated risk of ovulatory infertility was found for women who ever used thyroid preparations [relative risk (RR) = 2.3, 95% confidence interval (CI) = 1.5-3.5] or antidepressants (RR = 2.9, 95% CI = 0.9-8.3), although the latter estimate was based on only five cases who reported having taken antidepressants. Current users of tranquilizers and ever-users for more than 2 years were also at greater risk of infertility than never-users (RR = 3.2, 95% CI = 1.1-8.5 and RR = 2.9, 95% CI = 0.8-11, respectively). Women who used asthma medication before age 21 had more than a twofold increase in risk of ovulatory infertility (RR = 2.5, 95% CI = 1.0-5.9).

Context.—High-dose iodine 131 is the treatment of choice in the United States for most adults with hyperthyroid disease. Although there is little evidence to link therapeutic 131I to the development of cancer, its extensive medical use indicates the need for additional evaluation.Objective.—To evaluate cancer mortality among hyperthyroid patients, particularly after 131I treatment.Design.—A retrospective cohort study.Setting.—Twenty-five clinics in the United States and 1 clinic in England.Patients.—A total of 35,593 hyperthyroid patients treated between 1946 and 1964 in the original Cooperative Thyrotoxicosis Therapy Follow-up Study; 91% had Graves disease, 79% were female, and 65% were treated with 131I.Main Outcome Measure.—Standardized cancer mortality ratios (SMRs) after 3 treatment modalities for hyperthyroidism.Results.—Of the study cohort, 50.5% had died by the end of follow-up in December 1990. The total number of cancer deaths was close to that expected based on mortality rates in the general population (2950 vs 2857.6), but there was a small excess of mortality from cancers of the lung, breast, kidney, and thyroid, and a deficit of deaths from cancers of the uterus and the prostate gland. Patients with toxic nodular goiter had an SMR of 1.16 (95% confidence interval [CI], 1.03-1.30). More than 1 year after treatment, an increased risk of cancer mortality was seen among patients treated exclusively with antithyroid drugs (SMR, 1.31; 95% CI, 1.06-1.60). Radioactive iodine was not linked to total cancer deaths (SMR, 1.02; 95% CI, 0.98-1.07) or to any specific cancer with the exception of thyroid cancer (SMR, 3.94; 95% CI, 2.52-5.86).Conclusions.—Neither hyperthyroidism nor 131I treatment resulted in a significantly increased risk of total cancer mortality. While there was an elevated risk of thyroid cancer mortality following 131I treatment, in absolute terms the excess number of deaths was small, and the underlying thyroid disease appeared to play a role. Overall, 131I appears to be a safe therapy for hyperthyroidism.

BACKGROUND Children diagnosed with retinoblastoma, a rare cancer of the eye, tend to develop and die of second primary cancers in childhood and adolescence, but few investigations have followed patients into adulthood. Retinoblastoma is frequently caused by inherited mutations of the RB1 tumor suppressor gene. Most patients with germline (hereditary) mutations have bilateral disease. PURPOSE We sought to quantify the mortality from second malignancies among long-term survivors of retinoblastoma and to identify factors that predispose to these deaths. METHODS A retrospective cohort study examined mortality among 1603 patients enrolled at 1 year after diagnosis of retinoblastoma during the period 1914-1984. Data on demography, family history, and retinoblastoma treatment were collected by medical chart review and questionnaire interview. Number of deaths, by cause, was compared with the corresponding expected figure based on U.S. mortality data for the general population for 1925-1990. RESULTS Follow-up was complete for 1458 patients (91%) for a median of 17 years after retinoblastoma diagnosis. A total of 305 deaths occurred, 167 of them from retinoblastoma. There were 96 deaths from second primary tumors (relative risk [RR] = 30), 21 from other known causes (RR = 1.0), and 21 from ill-defined or unknown causes. Statistically significant excess mortality was found for second primary cancers of bone, connective tissue, and malignant melanoma and benign and malignant neoplasms of brain and meninges. Among 919 children with bilateral retinoblastoma, 90 deaths from second primary tumors occurred (RR = 60). Deaths from second tumors were more frequent among females (RR = 39) than males (RR = 22) (P = .007). The cumulative probability of death from second primary neoplasms was 26% at 40 years after bilateral retinoblastoma diagnosis, and additional cancer deaths occurred thereafter. Radiotherapy for retinoblastoma further increased the risk of mortality from second neoplasms. An excess of mortality from a second cancer, not seen in prior studies, was found among the 684 children with unilateral disease (RR = 3.1; 95% confidence interval = 1.0-7.3). CONCLUSIONS These findings implicate germinal mutations in the retinoblastoma gene in second cancer mortality. Radiotherapy treatment for retinoblastoma appears to further enhance the inborn susceptibility to development of a second cancer. IMPLICATIONS Patients with retinoblastoma, particularly bilateral retinoblastoma, should have careful follow-up, and interventions should be developed to reduce mortality from a second cancer.

Urine estrogens of 144 primiparous women and 122 nulliparous women of similar age were measured. The primiparae were at least 6 months post pregnancy. The ratio of the estriol concentration to the sum of the concentrations of estrone and estradiol (the estriol ratio) was higher among primiparous women under 25 years of age than among nulliparous women of the same age. The difference was greater in specimens collected in the luteal phase of the menstrual cycle than in those collected in the follicular phase and was statistically significant (P less than 0.05, one-tailed t-test) only in the luteal phase. The high estriol ratios of the primiparous women did not decline with increasing interval after pregnancy, at least up to 24 months. Among the younger women, significantly lower levels of pregnanediol, suggestive of a higher frequency of anovular menstrual cycles, were also seen in the nulliparous women. The findings were consistent with the hypothesis that the protective effect against breast cancer of a full-term pregnancy at an early age operates either through a change in the pattern of estrogen metabolism induced by the pregnancy or through a change in the frequency of ovular cycles.

Several studies have reported an association between caffeine intake and delay to conception. To study this relation further, the authors examined caffeine use in 1,050 women with primary infertility and 3,833 women who had recently given birth during the period 1981-1983 in the United States and Canada. The cases were separated by the cause of their infertility: ovulatory factor, tubal disease, cervical factor, endometriosis, or idiopathic infertility. The relative risks of each type of infertility associated with caffeine were calculated using separate logistic regression models and controlling for relevant confounding factors, such as age, center, cigarette smoking, lifetime number of sexual partners, alcohol consumption, contraception, body mass index, and exercise. A significant increase in the risk of infertility due to tubal disease or endometriosis was observed for the upper levels of caffeine intake, indicating a threshold effect. For tubal infertility, a relative risk of 1.5 (95% confidence interval (CI) 1.1-2.0) was found in women who consumed more than 7 g of caffeine per month as compared with those who consumed 3 g or less per month. For endometriosis, the relative risk was 1.9 (95% CI 1.2-2.9) in women who consumed 5.1-7 g/month and 1.6 (95% CI 1.1-2.4) in those with an intake of more than 7 g/month. These data suggest that caffeine deserves further study with regard to its effects on the female reproductive system.

When medical practitioners are faced with critical decisions to make, they may turn to clinical research to help them decide if a new drug or treatment regimen surpasses the old or if a newly developed diagnostic test is safe as well as accurate. Thus, to decide whether to critique a published research article or to design a clinical or preventive trial in a special area of interest, the physician needs to understand research methods. This new book on scientific investigation will help the clinical researcher acquire the perspective needed to understand research principles and design. "a literate and thought-provoking presentation of what can be a dry topic." In a concise and lucidly written volume, Dr William Silverman presents a persuasive case for the need for clinical trials in medical research. The author asserts that the randomized clinical trial is necessary to evaluate the efficacy and safety of medical innovations before

We studied past contraceptive use in 283 nulliparous infertile women who had a diagnosis of tubal adhesions or occlusion and in 3833 women admitted for delivery at seven collaborating hospitals from 1981 to 1983. The relative risk of tubal infertility associated with barrier contraceptive use or oral contraceptive use was calculated using multivariate logistic regression to control for confounding by region, age, religion, education, smoking, number of sexual partners, time since menarche, and use of other contraceptive methods. Women who had ever used barrier methods of contraception were at a significantly decreased risk of tubal infertility (relative risk = 0.6; 95% confidence limits, 0.5 and 0.8). When type of barrier method used for the longest time was evaluated, those who used the diaphragm or condoms plus spermicides were at lower risk than those who used condoms or spermicides alone. Overall, past use of oral contraceptives neither increased nor decreased a woman's risk of tubal infertility, but there was evidence that the association between oral contraceptives and tubal infertility may vary by the amount of estrogen and type of progestogen in the oral contraceptive used. We conclude that contraceptive users who use barrier methods that combine both a mechanical and chemical barrier, such as diaphragms, cervical caps, and condoms plus spermicides, have the clearest protection against tubal damage. (JAMA1987;257:2446-2450)